Modulators of alpha-1 antitrypsin

Abstract

7- or 8-hydroxy-isoquinoline and 7- or 8-hydroxy-quinoline derivatives as alpha-1-antitrypsin modulators for the treatment of alpha-1-antitrypsin deficiency (AATD).

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 004,683, filed April 3, 2020, the contents of which are incorporated herein by reference in their entirety.

[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. [Background technology]

[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).

[0005] 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 PiZZ individuals, 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 PiZZ individuals who smoke, resulting in an even further shortened lifespan (58 years) (Piitulainen and Tanash, COPD 2015;12(1):36-41). PiZZ individuals represent a large proportion of those with clinically relevant AATD lung disease. Thus, there is a need for additional and effective treatments for AATD. 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. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] American thoracic society / European respiratory society,Am J Respir Crit Care Med.2003;168(7):818-900 [Non-patent document 2] Ogushi et al.J Clin Invest.1987;80(5):1366-74 [Non-patent document 3] Tanash et al.Int J Chron Obstruct Pulm Dis.2016;11:1663-9 [Non-patent document 4] Piitulainen and Tanash, COPD 2015;12(1):36-41 [Non-patent document 5] Fregonese and Stolk,Orphanet J Rare Dis.2008;33:16 Summary of the Invention [Means for solving the problem]

[0007] The current standard of care for individuals with AAT deficiency who show or demonstrate signs of 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 Formula I, i.e., Ia(i) to Ia(vi), Ib(i) to Ib(vi), Ic(i) to Ic(vi), and Id(i) to Id(vi), as well as tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, that may be employed in the treatment of AATD. For example, a compound of Formula I, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, may be [ka] where: R 1 and R 1’ is selected from hydrogen, halogen, —OH, and —NH; R 1 and R 1’ one of which is -OH or NH2 and the other is hydrogen or halogen; W 1 and W 2are respectively -CR x and R x is hydrogen or halogen, X is -C=O, -CR 2 , N, and -NR 3 is selected from Y is -C=O, -CR 2 , N, and -NR 3 is selected from When X is -C=O, Y is -NR 3 and X is -CR 2 then Y is N; If X is N, then Y is -CR 2 and X is -NR 3 when Y is -C=O, (z) is a double bond unless X or Y is C=O, when X or Y is C=O, (z) is a single bond; R 2 are -CN, -C(=O)OH, -C(=O)NH2, -C(=O)NHR7, -C(=O)NHCH2R 7 , -OCH2R 7 , -OR 7 , -NHR 7 , -NHCH2R 7 , C6 or C 10 selected from aryl, 5- to 10-membered heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 heteroalkyl, and 3- to 10-membered heterocyclyl; R 2 The alkyl, heteroalkyl, alkenyl, heterocyclyl, aryl, or heteroaryl in the formula (I) are independently selected from halogen, —C(═O)OH, and C1-C6 alkyl, C3-C8 cycloalkyl, C6 or C 10 Aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl (optionally further substituted with halogen, -OH, -OCH3, -C(=O)OH), and / or C3-C6 cycloalkyl (optionally further substituted with halogen, -OH, optionally further substituted with —OCH3, and / or —C(═O)OH; R 2 wherein the heteroalkyl contains 1 to 3 heteroatoms selected from N, O, and S; R 3 is hydrogen, C6 or C 10 selected from aryl, C1-C8 alkyl, and C3-C8 cycloalkyl; R 3 is optionally substituted with 1 to 3 groups independently selected from =O, -OH, CHOH, -C(=O)OH, NH, C-C cycloalkyl (optionally substituted with =O, -CHOH, and / or -C(=O)OH), and 3-6 membered heterocyclyl (optionally substituted with =O, -CHOH, and / or -C(=O)OH); R 3 The heterocyclyl contains 1 to 3 nitrogen atoms, R 3 is optionally fused to a C3-C6 cycloalkyl; R 4 is halogen, -NR y R y , C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C2-C6 heteroalkyl, 3- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl; R 4 wherein the heteroalkyl, heterocyclyl, or heteroaryl contains 1 to 3 atoms selected from N, O, and S; R 4 wherein the alkyl, alkenyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1 to 3 groups independently selected from halogen, ═O, —OH, —OCH, —CH, and —C(═O)OH; R y are independently selected from hydrogen and C1-C3 alkyl; R y C1-C3 alkyl is halogen, ═O, optionally substituted with -OH, -OCH3, -CH3, and -C(=O)OH; R 5 is halogen, hydrogen, C1 to C6 alkyl, C6 or C 10 aryl, -O(phenyl), 5- or 6-membered heteroaryl, C3-C6 carbocyclyl, and 3- to 6-membered heterocyclyl, wherein the heterocyclyl or heteroaryl contains 1 to 3 nitrogen atoms, and R 5 is (R 6 ) n and n is 1, 2 or 3, However, R 5 is not imidazolyl, R 6 are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy; R 7 is C1 to C8 alkyl, C3 to C8 cycloalkyl, C6 or C 10 selected from aryl, C2-C8 heteroalkyl, 3- to 8-membered heterocyclyl, and 5- to 8-membered heteroaryl; R 7 is halogen, =O, -OH, -OCH3, -CH3, -C(=O)OH, -C(=O)NR 8 , -CN, -NH2, C1-C6 alkyl (optionally substituted with 1 to 3 groups selected from =O, -OH, -CN, -C(=O)OH, and -NH2), C3-C6 cycloalkyl (optionally substituted with 1 to 3 groups selected from =O, -OH, -CN, -C(=O)OH, and -NH2), C6 or C 10 aryl (optionally substituted with 1 to 3 groups selected from =O, -OH, -CN, -C(=O)OH, and -NH2), C2-C6 heteroalkyl (optionally substituted with 1 to 3 groups selected from =O, -OH, -CN, -C(=O)OH, and -NH2), and 3- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups selected from =O, OH, CN, COOH, and NH2), 5- or 6-membered heteroaryl (optionally substituted with 1 to 3 groups selected from =O, OH, CN, COOH, and NH2); R 7wherein the heteroalkyl, heterocyclyl, or heteroaryl contains 1 to 3 atoms selected from N, O, and S; R 8 is C1 to C6 alkyl, C6 or C 10 aryl, and R 8 is optionally substituted with halogen and / or -OH.

[0009] The compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), are modulators of AAT activity. In some embodiments, the compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), 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 EC2 of 2.0 μM or less when tested in an AAT functional assay. 50 In some embodiments, the compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), 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 0.5 μM or less when tested in an AAT functional assay. 50 It has.

[0010] In some embodiments, the compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), 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. 50In some embodiments, the compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), 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 2.0 μM or less when tested in a Z-AAT elastase activity assay. 50 It has.

[0011] In some embodiments, the compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), 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 AAT 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, the compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), 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 0.5 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, the compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), 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. 50and has an IC of less than 2.0 μM when tested in the Z-AAT elastase activity assay 50 In some embodiments, the compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), 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 activity 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 Formula I, i.e., Ia(i) to Ia(vi), Ib(i) to Ib(vi), Ic(i) to Ic(vi), and Id(i) to Id(vi), and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, are provided for use in treating AATD.

[0013] In one aspect of the disclosure, the compound of Formula I is selected from compounds 1-361, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing for use in the treatment of AATD. In some embodiments, the compound is selected from compounds 1-361, tautomers of compounds 1-361, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing for use in the treatment of AATD.

[0014] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of Formulae Ia(i), Ia(ii), Ia(iii), Ia(iv), Ia(v), and Ia(vi) (“Formulas Ia(i)-Ia(vi)”), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of Formulae Ib(i), Ib(ii), Ib(iii), Ib(iv), Ib(v), and Ib(vi) (“Formulas Ib(i)-Ib(vi)”), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of formulae Ic(i), Ic(ii), Ic(iii), Ic(iv), Ic(v), and Ic(vi) ("Formulas Ic(i)-Ic(vi)"), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of formulae Id(i), Id(ii), Id(iii), Id(iv), Id(v), and Id(vi) ("Formulas Id(i)-Id(vi)"), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, pharmaceutical compositions can include a compound selected from Compounds 1-361, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions can further include at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0015] Another aspect of the present disclosure provides a method of treating AATD, comprising administering to a subject in need thereof at least one compound selected from the compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), tautomers of those compounds, deuterated derivatives of those 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 1-361, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0016] 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 Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), 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. In some embodiments, the 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 additional active agent, or as a separate composition. In some embodiments, the method comprises administering to a subject in need thereof a compound selected from Compounds 1-361, 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. 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.

[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 Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), 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 alpha-1 antitrypsin protein (AAT) from plasma of a healthy human donor. In some embodiments, a method comprises administering a compound selected from Compounds 1-361, 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 as a separate composition, wherein the additional active agent is alpha-1 antitrypsin protein (AAT) from plasma of a healthy human donor.

[0018] 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 or as a separate composition, at least one compound selected from the compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), 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. In some embodiments, a method comprises administering a compound selected from Compounds 1-361, 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 a separate composition, wherein the additional active agent is recombinant AAT.

[0019] Also provided are methods for modulating AAT, comprising administering to a subject in need thereof at least one compound selected from the compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), tautomers of those compounds, deuterated derivatives of those 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 for modulating AAT comprises administering to a subject in need thereof at least one compound selected from compounds 1-361, tautomers of those compounds, deuterated derivatives of those 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.

[0020] Also provided are compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi), 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 compounds selected from Compounds 1-361, 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] Also provided are pharmaceutical compositions comprising a compound of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi), 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 1-361, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy.

[0022] I. Definition The term "AAT" as used herein 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.

[0023] 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.

[0024] As used herein, a patient who is "homozygous" for a particular genetic mutation has the same mutation on each allele.

[0025] As used herein, a patient with the PiZZ genotype is a patient who is homozygous for the Z mutation in the AAT protein.

[0026] The term "AATD" as used herein means alpha-1 antitrypsin deficiency, an inherited disorder characterized by low circulating levels of AAT.

[0027] 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 variation 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.

[0028] The compounds of the present disclosure can be optionally substituted with one or more substituents. The phrase "optionally substituted" should be 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.

[0029] The term "isotopically modified" refers to a species whose chemical structure differs from a specific compound of this disclosure only in its isotopic composition. Additionally, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, 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.

[0030] Unless otherwise indicated, structures depicted herein are also intended 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 present compounds are within the scope of this disclosure. Unless otherwise specified, all tautomeric forms of the compounds of this disclosure are within the scope of this disclosure.

[0031] The term "tautomer" as used herein 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.

[0032] "Stereoisomer" refers to both enantiomers and diastereomers.

[0033] 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 origin of the chemicals used in the synthesis. Despite this variation, the concentration of naturally abundant 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).

[0034] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0035] 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 some embodiments, alkyl groups contain 1-8 aliphatic carbon atoms. In some 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.

[0036] The term "heteroalkyl" as used herein means an aliphatic group in which one or two 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.

[0037] The term "alkenyl," as used herein, means a straight-chain (ie, linear or unbranched), branched, substituted or unsubstituted hydrocarbon chain containing one or more carbon-carbon double bonds.

[0038] "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.

[0039] The terms "heterocycle," "heterocyclyl," or "heterocyclic" as used herein 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 independently heteroatoms selected from oxygen, sulfur, nitrogen, phosphorus, and silicon, and each ring member 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.

[0040] 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:

[0041] The term "alkoxy" as used herein refers to an alkyl group as previously defined, where one carbon 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.

[0042] The terms "haloalkyl" and "haloalkoxy" refer to alkyl or alkoxy, as the case may be, 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.

[0043] As used herein, "=O" refers to an oxo group.

[0044] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0045] As used herein, a "hydroxy" group refers to an --OH group.

[0046] 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.

[0047] 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. Non-limiting examples of aryl groups include phenyl rings.

[0048] 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.

[0049] Examples of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, t-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. 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 are available, for example, in P.J. Kocienski, Protecting Groups, Thieme, 1994, and Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999), which are incorporated herein by reference in their entireties.

[0050] 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).

[0051] 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).

[0052] The present disclosure includes pharmaceutically acceptable salts of the compounds disclosed herein, which are formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0053] 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, either 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.

[0054] Acids commonly employed 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, but are not limited to, 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, butyne-1,4-dioate, hexyne-1,6-diol ... Included are oate, 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.

[0055] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1~4(Alkyl) 4 salts are included. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups 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, lower alkyl sulfonates, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0056] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0057] The terms "effective dose," "effective amount," "therapeutically effective dose," and "therapeutically effective amount" are used interchangeably herein and refer to that amount of compound for which it is administered that produces the desired effect (e.g., amelioration of AATD or AATD symptoms, reduction in the severity of AATD or AATD symptoms, and / or reduction in the occurrence or incidence of AATD or AATD symptoms). The exact amount of the effective dose will depend on the purpose of treatment and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0058] As used herein, "treatment" and its cognates (e.g., "treat," "treating") refer to an improvement in AATD or a symptom thereof in a subject, a delay in the onset of AATD or a symptom thereof in a subject, or a reduction in the severity of AATD or a symptom thereof in a subject. "Treatment" and its cognates as used herein include, but are not limited to, the following: improved liver and / or spleen function, reduction in macula, improved lung function, reduction in lung disease and / or exacerbations (e.g., emphysema), reduction in skin disease (e.g., necrotizing panniculitis), increased growth in children, improved appetite, and reduced fatigue. Improvement or reduction in severity of any of these symptoms can be readily assessed according to methods and techniques known in the art or subsequently developed.

[0059] 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 particular dose, amount, or weight percent value, or a range of doses, amounts, or weight percents, that would be recognized by one of ordinary skill in the art as providing an equivalent pharmacological effect to that obtained from the particular 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.

[0060] Any one or more of the compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), 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, any one or more of the compounds is selected from compounds 1-361, 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, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), Id(i)-Id(vi), 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 1-361, 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, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), Id(i)-Id(vi), 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 1-361, 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, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), Id(i)-Id(vi), 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 1-361, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered three times daily.

[0061] Any one or more of the compounds of Formula I, i.e., Ia(i) to Ia(vi), Ib(i) to Ib(vi), Ic(i) to Ic(vi), and Id(i) to Id(vi), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, can be administered in combination with AAT augmentation therapy or AAT replacement therapy for the treatment of AATD. In some embodiments, any one or more compounds is selected from compounds 1-361, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0062] 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.

[0063] 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, i.e., Ia(i) to Ia(vi), Ib(i) to Ib(vi), Ic(i) to Ic(vi), Id(i) to Id(vi), deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is 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 1-361 is administered once daily, twice daily, or three times daily.

[0064] 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).

[0065] As used herein, the term "ambient conditions" means room temperature, outside air conditions, and uncontrolled humidity conditions.

[0066] Reference herein to methods of treatment (e.g., methods of treating AATD) using one or more compounds (e.g., compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi)), and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds) also refers to One or more compounds (e.g., compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi), and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds), for example, for use in methods of treating AATD, and / or For example, it should be construed as a reference to the use of one or more compounds (e.g., compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi)), and 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.

[0067] Exemplary embodiments: Some embodiments of the present disclosure include, but are not limited to, the following. 1. A compound of formula I, [ka] Deuterated derivatives of compounds of formula I, and / or pharmaceutically acceptable salts of any of the foregoing, wherein: R 1 and R 1’ is selected from hydrogen, halogen, —OH, —O(benzyl), and —NH; R 1 and R 1’ one of which is -OH, -O(benzyl), or NH2, and the other is hydrogen or halogen; W 1 and W 2 are respectively, -CR x and R x is hydrogen or halogen, X is -C=O, -CR 2 , N, and -NR 3 is selected from Y is -C=O, -CR 2 , N, and -NR 3 is selected from When X is -C=O, Y is -NR 3 and X is -CR 2 then Y is N; If X is N, then Y is -CR 2 and X is -NR 3 when Y is -C=O, (z) is a double bond unless X or Y is C=O, when X or Y is C=O, (z) is a single bond; R 2 is -CN, -C(=O)OH, -C(=O)NH2, -C(=O)NHR7, -C(=O)NHCH2R 7 , -OCH2R 7 , -OR 7 , -NHR 7 , -NHCH2R 7 , C6 or C 10 selected from aryl, 5- to 10-membered heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 heteroalkyl, and 3- to 10-membered heterocyclyl; R 2 The alkyl, heteroalkyl, alkenyl, heterocyclyl, aryl, or heteroaryl in the formula (I) are independently selected from halogen, —C(═O)OH, and C1-C6 alkyl, C3-C8 cycloalkyl, C6 or C 10 Aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl (halogen, -OH, -OCH3, -C(=O)OH), and / or C3-C6 cycloalkyl (halogen, -OH, optionally further substituted with —OCH3, and / or —C(═O)OH; R 2 wherein the heteroalkyl contains 1 to 3 heteroatoms selected from N, O, and S; R 3 is hydrogen, C6 or C 10 selected from aryl, C1-C8 alkyl, and C3-C8 cycloalkyl; R3 are independently ═O, -OH, -CH2OH, -C(═O)OH, NH2, C3-C6 cycloalkyl (═O, optionally substituted with 1 to 3 groups selected from -CHOH, and / or -C(=O)OH), and 3- to 6-membered heterocyclyl (optionally substituted with =O, -CHOH, and / or -C(=O)OH); R 3 wherein the heterocyclyl contains 1 to 3 nitrogen atoms; R 3 is optionally fused to a C3-C6 cycloalkyl; R 4 But halogen, -NR y R y , C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C2-C6 heteroalkyl, 3- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl; R 4 wherein the heteroalkyl, heterocyclyl, or heteroaryl contains 1 to 3 atoms selected from N, O, and S; R 4 wherein the alkyl, alkenyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1 to 3 groups independently selected from halogen, ═O, —OH, —OCH, —CH, and —C(═O)OH; R y are independently selected from hydrogen and C1-C3 alkyl; R y C1-C3 alkyl is halogen, ═O, optionally substituted with -OH, -OCH3, -CH3, and -C(=O)OH; R 5 is halogen, hydrogen, C1 to C6 alkyl, C6 or C 10 aryl, -O(phenyl), 5- or 6-membered heteroaryl, C3-C6 carbocyclyl, and 3- to 6-membered heterocyclyl, wherein the heterocyclyl or heteroaryl contains 1 to 3 nitrogen atoms, and R 5 However, (R 6 ) nand n is 1, 2 or 3, However, R 5 is not imidazolyl, R 6 are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy; R 7 is C1 to C8 alkyl, C3 to C8 cycloalkyl, C6 or C 10 selected from aryl, C2-C8 heteroalkyl, 3- to 8-membered heterocyclyl, and 5- to 8-membered heteroaryl; R 7 are independently halogen, =O, -OH, -OCH3, -CH3, -C(=O)OH, -C(=O)NR 8 , -CN, -NH2, C1 to C6 alkyl (=O, -OH, -CN, -C(=O)OH, and -NH2), C3-C6 cycloalkyl (=O, -OH, -CN, -C(=O)OH, and -NH2), C or C 10 aryl (optionally substituted with 1 to 3 groups selected from =O, -OH, -CN, -C(=O)OH, and -NH2), C2-C6 heteroalkyl (optionally substituted with 1 to 3 groups selected from =O, -OH, -CN, -C(=O)OH, and -NH2), and 3- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups selected from =O, -OH, -CN, -COOH, and -NH2), 5- or 6-membered heteroaryl (optionally substituted with 1 to 3 groups selected from =O, -OH, -CN, -COOH, and -NH2); R 7 wherein the heteroalkyl, heterocyclyl, or heteroaryl contains 1 to 3 atoms selected from N, O, and S; R 8 is C1 to C6 alkyl, C6 or C 10 aryl, and R 8is optionally substituted with halogen and / or -OH, or a deuterated derivative or pharmaceutically acceptable salt thereof. 2. Compounds of formula Ia(i), Ia(ii), Ia(iii), Ia(iv), Ia(v), and Ia(vi), [ka] and selected from deuterated derivatives of formulae Ia(i), Ia(ii), Ia(iii), Ia(iv), Ia(v), and Ia(vi), and pharmaceutically acceptable salts of any of the foregoing; In the formula, R 1’ is selected from hydrogen and halogen, and R 2 , R 3 , R 4 , R 5 , R 6 and n is as defined in embodiment 1, a deuterated derivative, or a pharmaceutically acceptable salt of formula I according to embodiment 1. 3. Compounds of formula Ib(i), Ib(ii), Ib(iii), Ib(iv), Ib(v), and Ib(vi), [ka] selected from deuterated derivatives of formula Ib(i), Ib(ii), Ib(iii), Ib(iv), Ib(v), and Ib(vi), and pharmaceutically acceptable salts of any of the foregoing; In the formula, R 1’ is selected from hydrogen and halogen, and R 2 , R 3 , R 4 , R 5 , R 6 and n is as defined in embodiment 1. 4. Compounds of formula Ic(i), Ic(ii), Ic(iii), Ic(iv), Ic(v), and Ic(vi), [ka] and selected from deuterated derivatives of formula Ic(i), Ic(ii), Ic(iii), Ic(iv), Ic(v), and Ic(vi), and pharmaceutically acceptable salts of any of the foregoing; In the formula, R 1 is selected from hydrogen and halogen, and R 2 , R 3 , R 4 , R 5 , R 6 and n is as defined in embodiment 1. 5. Compounds of formula Id(i), Id(ii), Id(iii), Id(iv), Id(v), and Id(vi), [ka] selected from deuterated derivatives of formulae Id(i), Id(ii), Id(iii), Id(iv), Id(v), and Id(vi), and pharmaceutically acceptable salts of any of the foregoing; In the formula, R 1 is selected from hydrogen and halogen, and R 2 , R 3 , R 4 , R 5 , R 6 and n is as defined in embodiment 1. 6.R 1 is —OH. 7.R 1’ is —OH. 8.R 1 is —NH 2 , a deuterated derivative, or a pharmaceutically acceptable salt of embodiment 1. 9.R 1’ is —NH 2 , a deuterated derivative, or a pharmaceutically acceptable salt of embodiment 1. 10.R 3 is selected from phenyl and C3-C8 cycloalkyl; -R 3But independently, =O, -OH, -CHOH, -C(=O)OH, -NH, C-C cycloalkyl (optionally further substituted with 1-2 groups independently selected from =O, -CHOH, and -C(=O)OH), and 3-6 membered heterocyclyl (independently selected from =O, -CHOH, -C(=O)OH, and -C(=O)OH; - 3- to 6-membered heterocyclyl contains 1 to 2 nitrogen atoms, -R 3 is optionally fused to a C3-C6 cycloalkyl, a deuterated derivative, or a pharmaceutically acceptable salt of any one of embodiments 1-9. 11.R 3 are independently ═O, —OH, —CHOH, —C(═O)OH, —NH, C3-C6 cycloalkyl (independently ═O, C1-C6 alkyl optionally substituted with 1-2 groups selected from -CH2OH, and -C(=O)OH), and 3-6 membered heterocyclyl (optionally further substituted with 1-3 groups independently selected from -O, -CH2OH, and -C(=O)OH); - 3- to 6-membered heterocyclyl contains 1 to 2 nitrogen atoms, -R 3 is optionally fused to a C3-C6 cycloalkyl, a deuterated derivative, or a pharmaceutically acceptable salt of any one of embodiments 1-9. 12.R 3 is independently selected from C4 cyclic alkyl and C8 spirocyclic alkyl, optionally substituted with 1-2 groups selected from =O, -OH, -CH2OH, -C(=O)OH, and -NH2, 13.R 3 but, [ka] 10. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-9, selected from: 14.R 3 The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-9, wherein is hydrogen. 15.R 4 But halogen, -NR y R y , C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, and 5- or 6-membered heteroaryl; -R 4 wherein the heterocyclyl or heteroaryl contains 1 to 2 atoms selected from N, O, and S; -R 4 is optionally substituted with 1 to 3 groups independently selected from halogen, —OH, —OCH3, and —CH3; -R y are independently selected from hydrogen and C1-C3 alkyl; -R y 15. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-14, wherein the C1-C3 alkyl of is optionally substituted with -OCH3. 16.R 4 But halogen, -NR y R y , C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen, —OH, —OCH3, and —CH3), 5- or 6-membered heterocyclyl (optionally substituted with 1 to 3 groups independently selected from halogen, —OH, —OCH3, and —CH3), and 5-membered heteroaryl; heterocyclyl contains 1 to 2 heteroatoms selected from N, O, and S; -R y The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-15, wherein is C1-C2 alkyl optionally substituted with -OCH3. 17.R 4 but, Cl, [ka] 14. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-13, selected from: 18.R 4 but, [ka] 18. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-17, wherein: 19.R 4 but, [ka] 18. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-17, wherein: 20.R 5 But C6 or C 10 The compound, deuterated derivative, or pharmaceutically acceptable salt of embodiments 1-19, wherein the aryl is selected from aryl, -O(phenyl), 5- or 6-membered heteroaryl, C3-C6 carbocyclyl, and 3- to 6-membered heterocyclyl. 21.R 5 is selected from phenyl, 5- or 6-membered heteroaryl, C3-C6 carbocyclyl, and 3- to 6-membered heterocyclyl; -R 5 is optionally substituted with one or two groups independently selected from halogen and —CH3. 22.R 5 but, Hydrogen, Br, -CH3, [ka] 22. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-21, selected from: 23.R 5 but, [ka] 23. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-22, selected from: 24.R 2 The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-23, wherein is selected from -OR7. 25.R 2 is selected from -NHR7. 26.R 2 -C(=O)NHR 7 24. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-23, selected from: 27.R 2 But -NHCH2R 7 24. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-23, selected from: 28.R 2 is -CN, -C(=O)OH, -C(=O)NH2, -C(=O)NHCHR 7 , and -OCH2R 7 24. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-23, selected from: 29.R 7 is selected from C1-C8 alkyl and C3-C8 cycloalkyl, each of which is independently Br, Cl, F, —CH3, The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 24-28, optionally substituted with 1-3 groups selected from -C(=O)OH, =O, -OCH3, and -OH. 30.R 7 is selected from C2-C8 heteroalkyl and 3- to 8-membered heterocyclyl; -heteroalkyl or heterocyclyl contains 1 to 3 heteroatoms selected from N, O, and S; -heteroalkyl or heterocyclyl is independently Br, Cl, F, -CH3、 The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 24-28, optionally substituted with 1-3 groups selected from -C(=O)OH, =O, -OCH3, and -OH. 31.R 7 is selected from aryl and 3- to 8-membered heteroaryl; -heteroalkyl or heterocyclyl contains 1 to 3 heteroatoms selected from N, O, and S; The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 24-28, wherein heteroalkyl or heterocyclyl is optionally substituted with 1-3 groups independently selected from Br, Cl, F, —CH3, —C(═O)OH, ═O, —OCH3, and —OH. 32.R 7 is selected from C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 heteroalkyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 8-membered heteroaryl; -R 7 are independently selected from halogen, ═O, —C(═O)OH, phenyl, 5-8 membered heteroaryl, C1-C6 alkyl (optionally further substituted with 1-3 groups selected from ═O, OH, CN, COOH, and NH2), C3-C6 cycloalkyl (═O, —OH, —CN, —COOH, and -NH2), C2-C6 heteroalkyl (optionally further substituted with 1-3 groups selected from halogen, =O, -OH, -CN, -COOH, and -NH2), and 3- to 6-membered heterocyclyl (optionally further substituted with 1-3 groups selected from =O, -OH, -CN, -COOH, and -NH2); -R 7 The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 24-28, wherein the heteroalkyl, heterocyclyl, or heteroaryl of 33.R 2 but, [ka] [ka] [ka] [ka] [ka] [ka] 24. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-23, selected from: 34.R 2 but, [ka] 24. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-23, selected from: 35.R 2 but, [ka] [ka] [ka] 24. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-23, selected from: 36.R 2 but, [ka] 24. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-23, selected from: 37. A compound selected from compounds 1-361, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing. 38. A pharmaceutical composition comprising a compound according to any one of embodiments 1-37, a deuterated derivative thereof, and / or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier. 39. A method for treating alpha-1 antitrypsin deficiency, comprising administering to a patient in need thereof at least one compound selected from the compounds, deuterated derivatives, and pharmaceutically acceptable salts of any one of embodiments 1 to 37, or the pharmaceutical composition of embodiment 38. 40. The method of embodiment 39, wherein the patient has a Z mutation in alpha-1 antitrypsin. 41. The method of embodiment 39, wherein the patient has an SZ mutation in alpha-1 antitrypsin. 42. The method of embodiment 40, wherein the patient is homozygous for the Z mutation in alpha-1 antitrypsin. 43. A method for modulating alpha-1 antitrypsin activity, comprising contacting the alpha-1 antitrypsin with at least one compound selected from the compounds, deuterated derivatives, and pharmaceutically acceptable salts of any one of embodiments 1 to 37, or the pharmaceutical composition of embodiment 38.

[0068] II. Compounds and Compositions In some embodiments, the compounds of the present disclosure are compounds of formula I: [ka] Deuterated derivatives of compounds of formula I, and / or pharmaceutically acceptable salts of any of the foregoing, wherein: R 1 and R 1’ is selected from hydrogen, halogen, —OH, and —NH; R 1 and R 1’ one of which is -OH or NH2 and the other is hydrogen or halogen; W1 and W 2 are respectively -CR x and R x is hydrogen or halogen, X is -C=O, -CR 2 , N, and -NR 3 is selected from Y is -C=O, -CR 2 , N, and -NR 3 is selected from When X is -C=O, Y is -NR 3 and X is -CR 2 then Y is N; If X is N, then Y is -CR 2 and X is -NR 3 when Y is -C=O, (z) is a double bond unless X or Y is C=O, when X or Y is C=O, (z) is a single bond; R 2 are -CN, -C(=O)OH, -C(=O)NH2, -C(=O)NHR7, -C(=O)NHCH2R 7 , -OCH2R 7 , -OR 7 , -NHR 7 , -NHCH2R 7 , C6 or C 10 selected from aryl, 5- to 10-membered heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 heteroalkyl, and 3- to 10-membered heterocyclyl; R 2 The alkyl, heteroalkyl, alkenyl, heterocyclyl, aryl, or heteroaryl in the formula (I) are independently selected from halogen, —C(═O)OH, and C1-C6 alkyl, C3-C8 cycloalkyl, C6 or C 10 Aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl (halogen, -OH, -OCH3, -C(=O)OH), and / or C3-C6 cycloalkyl (halogen, -OH, optionally further substituted with —OCH3, and / or —C(═O)OH; R 2 wherein the heteroalkyl contains 1 to 3 heteroatoms selected from N, O, and S; R 3 is hydrogen, C6 or C 10 selected from aryl, C1-C8 alkyl, and C3-C8 cycloalkyl; R 3 are independently ═O, -OH, -CH2OH, -C(═O)OH, NH2, C3-C6 cycloalkyl (═O, optionally substituted with 1 to 3 groups selected from -CHOH, and / or -C(=O)OH), and 3- to 6-membered heterocyclyl (optionally substituted with =O, -CHOH, and / or -C(=O)OH); R 3 The heterocyclyl contains 1 to 3 nitrogen atoms, R 3 is optionally fused to a C3-C6 cycloalkyl; R 4 is halogen, -NR y R y , C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C2-C6 heteroalkyl, 3- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl; R 4 wherein the heteroalkyl, heterocyclyl, or heteroaryl contains 1 to 3 atoms selected from N, O, and S; R 4 wherein the alkyl, alkenyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1 to 3 groups independently selected from halogen, ═O, —OH, —OCH, —CH, and —C(═O)OH; R y are independently selected from hydrogen and C1-C3 alkyl; R y C1-C3 alkyl is halogen, ═O, optionally substituted with -OH, -OCH3, -CH3, and -C(=O)OH; R 5 is halogen, hydrogen, C1 to C6 alkyl, C6 or C 10 aryl, -O(phenyl), 5- or 6-membered heteroaryl, C3-C6 carbocyclyl, and 3- to 6-membered heterocyclyl, wherein the heterocyclyl or heteroaryl contains 1 to 3 nitrogen atoms, and R 5 is (R 6 ) n and n is 1, 2 or 3, However, R 5 is not imidazolyl, R 6 are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy; R 7 is C1 to C8 alkyl, C3 to C8 cycloalkyl, C6 or C 10 selected from aryl, C2-C8 heteroalkyl, 3- to 8-membered heterocyclyl, and 5- to 8-membered heteroaryl; R 7 are independently halogen, =O, -OH, -OCH3, -CH3, -C(=O)OH, -C(=O)NR 8 , -CN, -NH2, C1 to C6 alkyl (=O, -OH, -CN, -C(=O)OH, and -NH2), C3-C6 cycloalkyl (=O, -OH, -CN, -C(=O)OH, and -NH2), C or C 10aryl (optionally substituted with 1 to 3 groups selected from =O, -OH, -CN, -C(=O)OH, and -NH2), C2-C6 heteroalkyl (optionally substituted with 1 to 3 groups selected from =O, -OH, -CN, -C(=O)OH, and -NH2), and 3- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups selected from =O, -OH, -CN, -COOH, and -NH2), 5- or 6-membered heteroaryl (optionally substituted with 1 to 3 groups selected from =O, -OH, -CN, -COOH, and -NH2); R 7 wherein the heteroalkyl, heterocyclyl, or heteroaryl contains 1 to 3 atoms selected from N, O, and S; R 8 is C1 to C6 alkyl, C6 or C 10 aryl, and R 8 is optionally substituted with halogen and / or -OH.

[0069] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by Formula Ia(i), Formula Ia(ii), Formula Ia(iii), Formula Ia(iv), Formula Ia(v), or Formula Ia(vi): [ka] In the formula, R 1’ is selected from hydrogen and halogen, R 2 , R 3 , R 4 , R 5 , R 6 , and n are as defined for formula I.

[0070] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by Formula Ib(i), Ib(ii), Ib(iii), Ib(iv), Ib(v), or Ib(vi): [ka] In the formula, R 1’ is selected from hydrogen and halogen, R 2 , R 3 , R 4 , R 5 , R 6 , and n are as defined for formula I.

[0071] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by Formula Ic(i), Formula Ic(ii), Formula Ic(iii), Formula Ic(iv), Formula Ic(v), or Formula Ic(vi): [ka] In the formula, R 1 is selected from hydrogen and halogen, R 2 , R 3 , R 4 , R 5 , R 6 , and n are as defined for formula I.

[0072] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by Formula Id(i), Id(ii), Id(iii), Id(iv), Id(v), or Id(vi): [ka] In the formula, R 1 is selected from hydrogen and halogen, R 2 , R 3 , R 4 , R 5 , R 6 , and n are as defined for formula I.

[0073] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is —OH, and all other variables are as defined for Formula I.

[0074] Alternatively, in some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is —NH 2 , and all other variables are as defined for Formula I.

[0075] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1’ is —NH 2 , and all other variables not specifically defined herein are as defined for Formula I.

[0076] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3 is selected from phenyl and C3-C8 cycloalkyl; -R 3 are independently, =O, -OH, -CHOH, -C(=O)OH, -NH, C-C cycloalkyl (optionally further substituted with 1-2 groups independently selected from =O, -CHOH, and -C(=O)OH), and 3-6 membered heterocyclyl (independently selected from =O, -CHOH, -C(=O)OH, and -C(=O)OH; -3- to 6-membered heterocyclyl contains 1 to 2 nitrogen atoms; -R 3 is optionally fused to a C3-C6 cycloalkyl; All other variables are as defined for any one of the preceding embodiments.

[0077] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3is independently selected from C1-C6 alkyl optionally substituted with 1-2 groups selected from =O, OH, CH2OH, -C(=O)OH, -NH2, C3-C6 cycloalkyl (optionally further substituted with 1-2 groups independently selected from =O, -CH2OH, and -C(=O)OH), and 3-6 membered heterocyclyl (optionally further substituted with 1-3 groups independently selected from =O, -CH2OH, and -C(=O)OH); -3- to 6-membered heterocyclyl contains 1 to 2 nitrogen atoms; -R 3 is optionally fused to a C3-C6 cycloalkyl; All other variables are as defined for any one of the preceding embodiments.

[0078] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3 is independently selected from C spirocycloalkyl optionally substituted with 1-2 groups selected from =O, -OH, -CHOH, -C(=O)OH, and -NH; All other variables are as defined for any one of the preceding embodiments.

[0079] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3 teeth, [ka] is selected from All other variables are as defined for any one of the preceding embodiments.

[0080] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3 is hydrogen, and all other variables are as defined for any one of the preceding embodiments.

[0081] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 is halogen, -NR y R y , C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, and 5- or 6-membered heteroaryl; -R 4 wherein the heterocyclyl or heteroaryl contains 1 to 2 atoms selected from N, O, and S; -R 4 is optionally substituted with 1 to 3 groups independently selected from halogen, —OH, —OCH3, and —CH3; -R y are independently selected from hydrogen and C1-C3 alkyl; -R y wherein the C1-C3 alkyl is optionally substituted with -OCH3; All other variables are as defined for any one of the preceding embodiments.

[0082] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 is a halogen, -NR y R y , C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen, —OH, —OCH3, and —CH3), 5- or 6-membered heterocyclyl (optionally substituted with 1 to 3 groups independently selected from halogen, —OH, —OCH3, and —CH3), and 5-membered heteroaryl; -heterocyclyl contains 1 to 2 heteroatoms selected from N, O, and S; -R y is a C1-C2 alkyl optionally substituted with —OCH3, All other variables are as defined for any one of the preceding embodiments.

[0083] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 teeth, Cl, [ka] is selected from All other variables are as defined for any one of the preceding embodiments.

[0084] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 teeth, [ka] and all other variables are as defined for any one of the preceding embodiments.

[0085] Alternatively, in some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 teeth, [ka] and all other variables are as defined for any one of the preceding embodiments.

[0086] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 5 is C6 or C 10 is selected from aryl, -O(phenyl), 5- or 6-membered heteroaryl, C3-C6 carbocyclyl, and 3- to 6-membered heterocyclyl, and all other variables are as defined for any one of the preceding embodiments.

[0087] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 5is selected from phenyl, 5- or 6-membered heteroaryl, C-C carbocyclyl, and C-C heterocyclyl; R 5 is optionally substituted with one or two groups independently selected from halogen and —CH 3 , and all other variables are as defined for any one of the preceding embodiments.

[0088] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 5 teeth, Hydrogen, Br, -CH3, [ka] is selected from All other variables are as defined for any one of the preceding embodiments.

[0089] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 5 teeth, [ka] is selected from All other variables are as defined for any one of the preceding embodiments.

[0090] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 -OR 7 and all other variables are as defined for any one of the preceding embodiments.

[0091] Alternatively, in some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 -NHR 7 and all other variables are as defined for any one of the preceding embodiments.

[0092] Alternatively, in some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 is -C(=O)NHR 7 and all other variables are as defined for any one of the preceding embodiments.

[0093] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 is NHCH2R 7 and all other variables are as defined for any one of the preceding embodiments.

[0094] Alternatively, in some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 is -CN, -C(=O)OH, -C(=O)NH2, -C(=O)NHCH2R 7 , and -OCH2R 7 and all other variables are as defined for any one of the preceding embodiments.

[0095] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 7 is selected from C1-C8 alkyl and C3-C8 cycloalkyl, each of which is optionally substituted with 1 to 3 groups independently selected from Br, Cl, F, —CH3, —C(═O)OH, ═O, —OCH3, and —OH, and all other variables are as defined with respect to any one of the preceding embodiments.

[0096] Alternatively, in some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 7 is selected from aryl and 3- or 8-membered heteroaryl; -heteroalkyl or heterocyclyl contains 1 to 3 heteroatoms selected from N, O, and S; -heteroalkyl or heterocyclyl are independently Br, Cl, F, -CH 3、 optionally substituted with 1 to 3 groups selected from -C(=O)OH, =O, -OCH3, and -OH; All other variables are as defined for any one of the preceding embodiments.

[0097] Alternatively, in some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 7 teeth, selected from C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 heteroalkyl, 3- to 8-membered heterocyclyl, and 5- to 8-membered heteroaryl; -R 7 are independently selected from halogen, ═O, —C(═O)OH, phenyl, 5-8 membered heteroaryl, C1-C6 alkyl (optionally further substituted with 1-3 groups selected from ═O, OH, CN, COOH, and NH2), C3-C6 cycloalkyl (═O, —OH, —CN, -COOH, and -NH), C2-C6 heteroalkyl (optionally further substituted with 1-3 groups selected from halogen, =O, -OH, -CN, -COOH, and -NH), and 3- to 6-membered heterocyclyl (optionally further substituted with 1-3 groups selected from =O, -OH, -CN, -COOH, and -NH), -R 7 wherein the heteroalkyl, heterocyclyl, or heteroaryl contains 1 to 3 atoms independently selected from N, O, and S; All other variables are as defined for any one of the preceding embodiments.

[0098] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 teeth, [ka] [ka] [ka] [ka] [ka] is selected from All other variables are as defined for any one of the preceding embodiments.

[0099] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 teeth, [ka] is selected from All other variables are as defined for any one of the preceding embodiments.

[0100] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 teeth, [ka] [ka] is selected from All other variables are as defined for any one of the preceding embodiments.

[0101] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 teeth, [ka] [ka] is selected from All other variables are as defined for any one of the preceding embodiments.

[0102] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is selected from compounds 1-361 (as shown in Table A), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24

[0103] Some embodiments of the present disclosure include derivatives of compounds 1-361, or compounds of formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), Id(i)-Id(vi), or tautomers thereof. In some embodiments, the derivatives are silicon derivatives in which at least one carbon atom in a compound selected from compounds 1-361, or compounds of formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), Id(i)-Id(vi), is replaced by silicon. In some embodiments, the derivative is a boron derivative in which at least one carbon atom in compounds 1-361 or a compound selected from compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), Id(i)-Id(vi), or a tautomer thereof, is replaced by boron. In some embodiments, the derivative is a phosphate derivative in which at least one carbon atom in compounds 1-361 or a compound selected from compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), Id(i)-Id(vi), or a tautomer 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.

[0104] In some embodiments, the derivative is a silicon derivative in which at least one carbon atom in a compound selected from compounds 1-361 or formula I, i.e., compounds Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), Id(i)-Id(vi), and tautomers thereof, is replaced by silicon. In other embodiments, two carbon atoms are replaced by silicon. The carbon replaced by silicon can be a non-aromatic carbon. In some embodiments, a quaternary carbon atom of a tert-butyl moiety can be replaced by silicon. In some embodiments, the silicon derivatives of the present disclosure can include one or more hydrogen atoms replaced by deuterium. For example, one or more hydrogen atoms of a tert-butyl moiety in which a carbon is replaced by silicon can be replaced by deuterium. In other embodiments, silicon derivatives of compounds 1-361 or compounds selected from Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), Id(i)-Id(vi), and tautomers thereof, can have silicon incorporated into a heterocycle.

[0105] Another aspect of the present disclosure provides pharmaceutical compositions comprising compounds according to Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), Id(i)-Id(vi), compounds selected from Compounds 1-361, 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 Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), Id(i)-Id(vi), and Compounds 1-361, 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.

[0106] 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.

[0107] It is also understood that the pharmaceutical compositions of the present disclosure can be employed 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, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), Id(i)-Id(vi), 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 1-361, 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.

[0108] In some embodiments, compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi), tautomers of these compounds, deuterated derivatives of these compounds or 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 Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi), 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 Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi), 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 all in the same pharmaceutical composition. In some embodiments, the compound is a compound selected from Compounds 1-361, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0109] In some embodiments, compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi), 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, the methods comprising co-administering the compound 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 1-361, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0110] In some embodiments, combinations of a compound of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and an additional active agent are provided for use in methods 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 1-361, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0111] 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 and a compound of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi), 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 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 1-361, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0112] In some embodiments, compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi), 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 1-361, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0113] In some embodiments, combinations of a compound of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and 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 1-361, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0114] In some embodiments, an additional active agent is provided for use in the methods of treating AATD, and the additional active agent is prepared for administration in combination with a compound of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), or Id(i)-Id(vi), 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 1-361, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0115] 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.

[0116] 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, the 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 suitable for the desired specific 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. 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, such as 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), saturated vegetable fatty acids, partial glyceride mixtures of 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 carboxymethylcellulose, sodium phosphate), and the like. The following ingredients may be used in the preparation of suppositories: corn starch, thorium, 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, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0117] In another aspect of the present disclosure, 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.

[0118] 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, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), and Id(i)-Id(vi), 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 of Formula (I) is selected from compounds 1-361, tautomers of these compounds, deuterated derivatives of these 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.

[0119] 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 selected from compounds Ia(i) through Ia(vi), Ib(i) through Ib(vi), Ic(i) through Ic(vi), and Id(i) through Id(vi), tautomers of these compounds, deuterated derivatives of these 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 1-361, 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 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.

[0121] III. Compound Preparation All generic, subgeneric, and specific compound formulas disclosed herein are considered to be part of this disclosure.

[0122] A. Compounds of Formula I The compounds of the present disclosure can be made according to standard chemical practices or as described herein. The following abbreviations are used throughout the synthetic schemes below and in the descriptions for preparing the compounds of Formula I, i.e., Ia(i)-Ia(vi), Ib(i)-Ib(vi), Ic(i)-Ic(vi), Id(i)-Id(vi), compounds 1-361, 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 = Di-tert-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 9-BBN = 9-borabicyclo[3.3.1]nonane

[0123] 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 depicted in the following Schemes 1-15, where all variables are as defined for Formula (I) above. [ka]

[0124] Scheme 1 shows a process for the preparation of compounds of formula I from compounds of formula 1-1. 1 is a group such as OPG, where PG is any suitable alcohol protecting group. For example, PG can be benzyl, MOM, or methyl. W 1In some embodiments, where PG is OBn, compounds of Formula I can be prepared from compounds of Formula 1-1 by treatment with any suitable reagent for removal of the benzyl group. In some examples, hydrogenolysis using a palladium-on-carbon catalyst can be used. The reaction can be carried out under an atmosphere of hydrogen gas at elevated pressure. In some examples, where PG is methyl or benzyl, the protecting group can be removed by treatment with a dealkylating agent such as BBr3. The reaction can be carried out in a solvent such as dichloromethane. In some embodiments, where W1 contains a MOM protecting group, compounds of Formula I can be prepared by treatment of compounds of Formula 1-1 with an acid reagent such as HCl. Any suitable reagent for removal of an alcohol or amine protecting group can be used to prepare compounds of Formula 1 from compounds of Formula 1-1. [ka]

[0125] The process for preparing a compound of Formula I from a compound of Formula 2-1 can be prepared as shown in Scheme 2. W2 is a group such as OPG or NHPG, where PG is any suitable group for protecting an alcohol or amine. For example, in some embodiments, W2 can be OBn or OMe.

[0126] Schemes 3-15 show processes for the preparation of compounds of formula 1-1. These processes can also be used to prepare compounds of formula 2-1. [ka]

[0127] Scheme 3 shows a method for the preparation of compounds 3-8 and 3-9, which can be used as intermediates in the preparation of compounds of Formula I. 1 is a halogen such as Br, Cl, or I. 1is H or SiMe3. Compounds of formula 3-3 can be prepared from compounds of formula 3-1 by Sonogashira coupling with an alkyne of formula 3-2. Any suitable conditions for performing aryl-alkyne coupling can be used. In some embodiments, a catalyst such as Pd(PPh3)2Cl2 can be used. The reaction can be carried out in the presence of copper iodide. The reaction can be carried out in the presence of a base such as triethylamine or diisopropylethylamine. A solvent such as dioxane can be used. The reaction can be carried out under heat (e.g., 90°C). Compounds of formula 3-4 can be prepared from 3-3 by reaction with a reagent such as hydroxylamine hydrochloride. The reaction can be carried out in a solvent such as pyridine, acetonitrile, and dichloromethane. The reaction can be carried out at elevated temperatures, e.g., 50°C. Compounds of formula 3-5 can be prepared from 3-4 by treatment with a reagent such as CuBr. A solvent such as N,N-dimethylacetate can be used. The reaction may be carried out in the presence of heat (e.g., 60°C). Compounds of formula 3-7 may be prepared by any suitable method for coupling an organometallic reagent (e.g., an alkylzinc reagent, or a boronic acid or ester) with an aryl halide. For example, in some embodiments, Suzuki coupling conditions may be used. For example, when 3-6 is a boronic acid or ester, a catalyst such as Pd(dppf)Cl2 may be used. The reaction may be carried out in the presence of a base such as Na2CO3. The reaction may be carried out in a solvent such as dioxane at 80°C. In some embodiments, when 3-6 is an alkylzinc reagent, the reaction may be carried out in the presence of Pd(PPh3)4 in THF at 80°C. Aryl chlorides of formula 3-8 may be prepared from 3-7 by treatment with a suitable chlorinating reagent. For example, in some embodiments, a reagent such as POCl3 may be used. Compounds of formula 3-9 may be prepared from the N-oxide of formula 3-7 by treatment with the DABCO reagent in the presence of a reagent such as trifluoroacetic anhydride. The reaction can be carried out in a solvent such as dichloromethane at room temperature. [ka]

[0128] Scheme 4 shows an alternative process for the preparation of compounds of formula 3-8. Q3 is any halogen, such as Cl, Br, or I. R 23 is hydrogen or any alkyl suitable for forming a boronate ester. Compounds of formula 4-3 can be prepared by coupling ethylamine with any suitable reagent for forming an amide. For example, HATU or T3P can be used. Compounds of formula 4-5 can be prepared from compounds of formula 4-2 using standard conditions suitable for Suzuki coupling reactions. For example, Pd(dppf)Cl2 can be used. The reaction can be carried out in the presence of a base such as Na2CO3. A solvent such as 1,4-dioxane can be used. Compounds of formula 4-7 can be prepared by reacting a nitrile compound of formula 4-6 with 4-5. The reaction can be carried out by treating a compound of formula 4-5 with a base such as LDA. The reaction can be carried out in a solvent such as THF at reduced temperatures (e.g., −20° C.). A process for preparing compound 3-8 from compound of formula 4-7 is also shown in Scheme 4. Treatment of a compound of formula 4-7 with a chlorinating reagent such as POCl3 or SOCl2 provides a compound of formula 3-8. [ka]

[0129] Scheme 5 shows a process for the preparation of compounds of formula I from aryl chlorides of formula 3-8. 24 is hydrogen or any suitable alkyl group that forms a boronic ester. X 2is a halogen such as I, Br, or Cl. W1 is defined as above. All other variables are defined as above. Compounds of formula 5-2 can be prepared by Suzuki coupling of a compound of formula 5-1 with an intermediate of formula 3-8. Any suitable conditions for carrying out a Suzuki coupling reaction can be used. Compounds of formula 5-5 can be prepared from a compound of formula 3-8 and an organozinc reagent of formula 5-3. In some embodiments, the reaction is carried out in the presence of a palladium catalyst such as Pd(PPh3)4. The reaction can be carried out in a solvent such as THF at elevated temperatures (e.g., 60°C). Compounds of formula I can be prepared from compounds of formula 5-2 and 5-5 using standard methods for deprotection of alcohol protecting groups. The reagents can vary depending on the exact protecting groups used. [ka]

[0130] Compounds of formula 6-3 can be prepared from N-oxides of formula 3-7 and amines of formula 6-1 by treatment with PyBrop in the presence of a base such as DIPEA. The reaction is carried out in a solvent such as 1,2-dichloroethane in the presence of heat (e.g., 80°C). [ka]

[0131] Scheme 7 shows a method for the preparation of compounds of formula 7-3. In some embodiments, compounds of formula 7-2 can be prepared by the reaction of an alcohol of formula 7-1 with an intermediate of formula 3-9 in the presence of a base such as NaH. The reaction can be carried out in a solvent such as DMF. Removal of the alcohol protecting group provides compounds of formula 6-3. [ka]

[0132] Scheme 8 shows a method for the preparation of compounds of formula 8-3 from isoquinolinone compounds of formula 4-7. 1is any suitable leaving group (e.g., tosylate, mesylate, or a halogen atom). Compounds of formula 8-2 can be prepared from compounds of formula 4-7 by alkylation with compounds of formula 8-1. LG 1 In some embodiments, where LG is a tosylate, the reaction is carried out in the presence of CsF. The reaction can be carried out in a solvent such as DMF at 50° C. 1 In certain embodiments where is a halogen, a base such as Cs2CO3 may be used. Any other suitable conditions for alkylation of isoquinolinones may be used. [ka]

[0133] Scheme 9 depicts a process for the preparation of compounds of formula 9-9. Q3 is a halogen such as Cl, I, or Br. E 1 is H or SiMe3. 25 is hydrogen or any suitable alkyl group resulting in a boronic ester. Compounds of formula 9-3 can be prepared from 9-1 using any suitable conditions for carrying out a Sonogashira coupling reaction. Compounds of formula 9-4 can be prepared from compounds of formula 9-3 by any suitable method for cyclization onto an alkyne. In some embodiments, treatment with iodine in dichloromethane solvent at room temperature provides compounds of formula 9-4. Suzuki coupling of compounds of formula 9-4 with an appropriate boronic acid reagent of formula 9-5 provides compounds of formula 9-6. A catalyst such as RuPhos Pd G3 and a base such as K3PO4 can be used. Compounds of formula 9-8 can be prepared from amines of formula 9-6 and formula 9-7 using HATU reagent and DIPEA as a base in a solvent such as DMF. Compounds of formula 9-9 can be prepared from 9-8 using standard deprotection methods appropriate for the protecting group used. For example, if a benzyl protecting group is used, hydrogenation can be used. [ka]

[0134] Scheme 10 shows a method for the preparation of compounds of formula 10-6 and 10-7. 26 is hydrogen or any suitable alkyl group that forms a boronate ester. Compounds of formula 10-6 and 10-7 can be used as intermediates in the preparation of compounds of formula I. Compounds of formula 10-4 can be prepared from 10-3 and a suitable boronic acid or ester. The reaction can be carried out in the presence of a ligand such as 5,5'-dimethyl-2,2'-dipyridyl and an acid such as methanesulfonic acid, in the presence of a catalyst such as Pd(TFA)2. The reaction can be carried out in a solvent such as 2-MeTHF at 80 °C. Compounds of formula 10-5 can be prepared by HATU coupling of a compound of formula 10-4 with the amine 10-3. Compounds of formula 10-6 can be prepared by treating 10-5 with a base such as NaOtBu in a solvent such as toluene at 110 °C. Compounds of formula 10-7 can be prepared from 10-6 using any suitable reagent for chlorination of quinolinones. For example, a reagent such as SOCl2 can be used. In an alternative embodiment, a reagent such as POCl3 can be used. [ka]

[0135] An alternative process for the preparation of compounds of formula 10-7 is shown in Scheme 11. 6 and Q 7 is a halogen atom such as Cl, Br or I. 26 is hydrogen or any suitable alkyl group that forms a boronic acid ester. Sequential Suzuki coupling reactions between boronic acids or esters and intermediates of formula 11-1 provide compounds of formula 11-4. Compounds of formula 11-5 can be prepared from 11-4 by oxidation with any oxidizing agent suitable for the preparation of N-oxides from pyridine. For example, in some embodiments, m-CPBA can be used. The reaction can be carried out in a solvent such as dichloromethane at room temperature. Compounds of formula 10-7 can be prepared from 11-5 using a chlorinating reagent such as POCl3. [ka]

[0136] Scheme 12 depicts a process for the preparation of compounds of formula 12-3 from alkylating agents such as 10-6 and 12-1. 2 is a halogen such as Br, Cl, or I, or a tosylate or mesylate. Compounds of formula 12-2 can be prepared from 10-6 by alkylation with 12-1 using a base such as CsCO. Any other suitable method for alkylation can be used. [ka]

[0137] Scheme 13 shows a process for the preparation of compounds of formula 13-3 from 10-7. In some embodiments, compounds of formula 13-2 can be prepared from the reaction of 10-7 and 13-1 using a base such as CsCO in a solvent such as DMF. The reaction can be carried out in the presence of heat. Deprotection using standard methods appropriate for the protecting group provides compounds of formula 13-3. [ka]

[0138] Scheme 14 shows a process for preparing compounds of formula 14-3. N-oxides of formula 11-5 can be treated with amines of formula 14-1 in the presence of PyBrop reagent and a base such as DIPEA to give compounds of formula 14-2. In an alternative process for preparing compounds of formula 14-2, compounds of formula 11-5 can be treated with amines of formula 14-1 and any suitable reagent for Buchwald amination. For example, the reaction can be carried out in the presence of a catalyst such as P(t-Bu)PdG and a base such as KCO. The reaction can be carried out in a solvent such as dioxane in the presence of heat (e.g., 80 °C). [ka]

[0139] Compounds of formula 15-3 can be prepared from compounds of formula 10-7 as depicted in Scheme 15. M is a metal such as Zn or B. X 3 is a halogen such as Br or I. Compounds of formula 15-1 are organometallic reagents such as alkylzinc reagents or boronic acids or esters. Compounds of formula 15-2 can be prepared using any suitable conditions for Negishi coupling reactions (M=Zn) or Suzuki coupling reagent conditions (M=B). Deprotection using standard methods for removal of alcohol protecting groups, where appropriate as defined by W1, provides compounds of formula 15-3. [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-S36 illustrates synthetic routes to intermediates used in the synthesis of compounds 1-361.

[0143] Preparation of S1 7-(benzyloxy)-4-(4-fluorophenyl)-3-(1-methoxy-2-methylpropan-2-yl)isoquinolin-1(2H)-one (S1) [ka] Step 1. Synthesis of 5-benzyloxy-2-bromo-benzoic acid (C2) To a solution of C1 (5 g, 15.57 mmol) in MeOH (20 mL) and THF (15 mL) was added aqueous NaOH (15 mL of 2 M, 30.00 mmol), and the resulting solution was stirred at room temperature for 2 h. The solution was concentrated and neutralized with 6 M HCl (5 mL). The aqueous phase was extracted with EtOAc (30 mL × 2), and the combined organic fractions were washed with brine (2 × 20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to provide C2 (4.7 g, 97%) as a white solid. 1 H NMR (400 MHz, chloroform-d): δ 7.64 (d, J = 3.1 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.49–7.35 (m, 6H), 7.04 (dd, J = 8.8, 3.1 Hz, 1H), 5.12 (s, 2H). LCMS m / z 306.94 [M+H] +

[0144] Step 2. Synthesis of 5-benzyloxy-2-bromo-N,N-diethyl-benzamide (C3) To a solution of C2 (4.7 g, 15.30 mmol) in EtOAc (50 mL) was added diethylamine (5 mL, 48.33 mmol), causing the collapse of a white precipitate. To this suspension was added EtOAc (25 mL), followed by the dropwise addition of T3P (14.6 g of 50% w / w, 22.94 mmol) in EtOAc. The solution turned yellow within minutes, and the solution was stirred for 2 h. The reaction was quenched by the addition of 1 M HCl (20 mL) and water (20 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with water (2 × 20 mL), brine (1 × 20 mL), dried over MgSO4, and concentrated to dryness to provide C3 as a yellow oil (5.6 g, quant.). 1H NMR (400MHz, chloroform-d) δ7.50~7.32(m, 6H), 6.91~6.84(m, 2H), 5.17~5.00(m, 2H), 3.85(dq,J=14.2, 7.1Hz, 1H), 3.32(dq,J=14.0, 7.1Hz, 1H), 3.15(qd,J=7.2, 3.9Hz, 2H), 1.28(t,J=7.1Hz, 3H), 1.02(t,J=7.1Hz, 3H). LCMS m / z 362.09[M+H] +

[0145] Step 3. Synthesis of 5-benzyloxy-N,N-diethyl-2[(4-fluorophenyl)methyl]benzamide (C4) A solution of C3 (6 g, 16.56 mmol), 2-[(4-fluorophenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5 g, 21.18 mmol), and Na2CO3 (28 mL of 2 M, 56.00 mmol) in dioxane (90 mL) and water (30 mL) was degassed with a stream of N2 for 5 minutes. PdCl(dppf) (605 mg, 0.8268 mmol) was then added, and the solution was stirred at 100 °C for 15 hours and kept overnight. The reaction mixture was then cooled, and EtOAc (50 mL) was added, followed by water (20 mL). The aqueous layer was separated and extracted with EtOAc (2 × 25 mL). The combined organic fractions were washed with brine (2 × 20 mL), dried over Na2SO4, and concentrated to dryness. Purification by silica gel chromatography (0-52% ethyl acetate in heptane) afforded C4 as a pale yellow oil (5.3 g, 82%). 1 H NMR (400MHz, chloroform-d) δ7.49~7.31(m, 5H), 7.21~7.08(m, 3H), 7.00~6.91(m, 3H), 6.80(d,J=2.7Hz, 1H), 5.07(d,J=9.2Hz, 2 H), 3.91(d,J=21.7Hz, 2H), 3.65(s, 1H), 3.33(s, 1H), 2.94(s, 1H), 2.77(s, 1H), 1.19(t,J=7.1Hz, 3H), 0.92(d,J=7.1Hz, 3H). LCMS m / z 392.25[M+H] +

[0146] Step 4. Synthesis of 7-(benzyloxy)-4-(4-fluorophenyl)-3-(1-methoxy-2-methylpropan-2-yl)isoquinolin-1(2H)-one (S1) To a solution of C4 (210 mg, 0.5364 mmol) and 3-methoxy-2,2-dimethyl-propanitrile C5 (70 mg, 0.6186 mmol) in THF (2 mL) was added LDA (310 μL of 2 M, 0.62 mmol) dropwise at 0° C. The solution was allowed to warm slowly to room temperature over 1 h, and the reaction was quenched by the addition of water (2 mL). The mixture was concentrated in vacuo, and EtOAc (50 mL) and water (10 ml) were added. The aqueous layer was separated and extracted with EtOAc (10 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated to give S1, which was used without further purification. (230 mg, 98%) 1 H NMR (400MHz, chloroform-d) δ10.25(s, 1H), 7.83(d,J=2.8Hz, 1H), 7.40~7.31(m, 2H), 7.13~7.06(m, 2H), 7.06~6.92(m, 7H), 6 .85~6.78(m, 4H), 6.67(d,J=2.7Hz, 2H), 6.62(d,J=9.1Hz, 1H), 5.06(s, 2H), 3.88~3.62(m, 2H), 3.33(s, 3H), 0.94(s, 6H). LCMS m / z 432.27[M+H] +

[0147] Preparation of S2 1-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-8-fluoro-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (S2) [ka] Step 1. Synthesis of 3-benzyloxy-2-fluoro-6-(3-methylbut-1-ynyl)benzaldehyde (C7) In a sealed tube, a suspension of C6 (3.0 g, 9.7047 mmol) in toluene (18.0 mL) and diisopropylamine (6.0 mL) was bubbled with nitrogen for 10 min. Bis(triphenylphosphine)palladium(II) dichloride (143 mg, 0.2032 mmol) and CuI (81 mg, 0.4253 mmol) were added, and N was bubbled for an additional 2 min. 3-Methylbut-1-yne (999.00 mg, 1.5 mL, 14.666 mmol) was added, and the tube was sealed, stirred, and heated at 50 °C overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc (100 mL). The organic layer was washed with 3 M aqueous HCl (2 × 30 mL), water (30 mL), brine, dried over anhydrous NaSO, filtered, loaded onto silica gel, and concentrated under reduced pressure. The residue was purified on silica gel chromatography eluting with 0% to 20% ethyl acetate in heptane to yield C7 (2.60 g, 89%) as an orange oil. 1 H NMR (300 MHz, chloroform-d) δ 1.22–1.32 (m, 6H), 2.67–2.90 (m, 1H), 5.18 (s, 2H), 7.04–7.24 (m, 2H), 7.30–7.47 (m, 5H), 10.50 (s, 1H). 19 F NMR (282 MHz, chloroform-d) δ -136.8 (d, J = 9.2 Hz, 1F). LCMS m / z 297.2 [M+H] +

[0148] Step 2. Synthesis of 3-benzyloxy-2-fluoro-6-(3-methylbut-1-ynyl)benzaldehyde oxime (C8) To a solution of hydroxylamine hydrochloride (6.17 g, 88.789 mmol) in pyridine (70.416 g, 72 mL, 890.22 mmol) was added acetonitrile (80 mL) at room temperature. The solution was then stirred and heated at 50° C., and a solution of C7 (8.74 g, 29.494 mmol) in 1,2-dichloroethane (55 mL) was added. The resulting mixture was heated at 50° C. for 1 h. The solution was cooled to room temperature, diluted with EtOAc (100 mL) and water (100 mL), and decanted. The organic layer was washed with 3 M HCl (4×50 mL), water (50 mL), brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give C8 as a pale yellow solid (8.71 g, 85%). 1 H NMR (300 MHz, chloroform-d) δ 1.28 (d, J = 6.8 Hz, 6H), 2.70–2.88 (m, 1H), 5.16 (s, 2H), 6.92 (t, J = 8.4 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.29–7.50 (m, 5H), 8.54 (s, 1H), 8.73 (br.s., 1H). 19 F NMR (282 MHz, chloroform-d) δ -136.3 (d, J = 9.2 Hz, 1F). LCMS m / z 312.2 [M+H] +

[0149] Step 3. Synthesis of 7-benzyloxy-4-bromo-8-fluoro-3-isopropyl-2-oxide-isoquinolin-2-ium (C9) CuBr (15.7 g, 70.292 mmol) was added to a solution of C8 (8.71 g, 27.975 mmol) in N,N-dimethylacetamide (70 mL), and the resulting mixture was heated at 60 °C for 1 h. The reaction mixture was cooled to room temperature and then to 0 °C. With vigorous stirring, an aqueous solution of ammonium hydroxide and water (2:1, 75 mL) was slowly added and stirred at 0 °C for 30 min. The suspended solid was then filtered and washed with water to give a tan solid. The solid was dissolved with dichloromethane through a filter paper, transferred to a separate vessel, dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and dried under vacuum. The residue was triturated in methyl tert-butyl ether (40 mL) for 1 h, filtered, and washed with heptane to give C9 (8.716 g, 80%) as a tan solid. 1 H NMR (300 MHz, chloroform-d) δ 1.56 (d, J = 7.0 Hz, 6H), 4.11 (br.s., 1H), 5.33 (s, 2H), 7.32–7.50 (m, 6H), 7.84 (d, J = 9.4 Hz, 1H), 8.87 (br.s., 1H). 19 F NMR (282 MHz, chloroform-d) δ -143.8 (d, J = 6.1 Hz, 1F). LCMS m / z 390.1 [M+H] +

[0150] Step 4. Synthesis of 7-benzyloxy-8-fluoro-4-(4-fluorophenyl)-3-isopropyl-2-oxide-isoquinolin-2-ium (C10) A suspension of C9 (3.0 g, 7.6875 mmol), (4-fluorophenyl)boronic acid (1.62 g, 11.578 mmol), and an aqueous solution of Na2CO3 (8.0 mL of 2 M, 16.0 mmol) in DMSO (27 mL) was heated to 100 °C and sparged with N2 for 10 min. .Dichloromethane (327 mg, 0.4004 mmol) was added, and the reaction was sparged for 2 minutes. The reaction was stirred at 100 °C overnight. After approximately 20 minutes, a solid crust formed on top of the mixture, making it difficult to stir, so additional amounts of DMSO (9 mL) and water (6 mL) were added. The reaction mixture was cooled to room temperature, water (60 mL) was added, and the mixture was stirred at room temperature for 15 minutes. The suspension was filtered and washed with water. The residue was then dissolved in dichloromethane (through a filter paper). The filtrate was decanted, dried over anhydrous sodium sulfate, filtered, loaded onto silica gel, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0% to 50% ethyl acetate in dichloromethane, to yield C10 (1.975 g, 63%) as a pale pink solid. 1 H NMR (300MHz, chloroform-d) δ1.40(d,J=6.8Hz, 6H), 3.21(br.s., 1H), 5.28(s, 2H), 6.81(d,J= 9.1Hz, 1H), 7.14(t,J=8.7Hz, 1H), 7.22(d,J=6.8Hz, 4H), 7.31~7.48(m, 5H), 8.96(s, 1H). 19 F NMR (282 MHz, chloroform-d) δ -144.8 (d, J = 6.1 Hz, 1F), -113.6 to -112.2 (m, 1F). LCMS m / z 406.2 [M+H] +

[0151] Step 5. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-8-fluoro-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (S2) A solution of C10 (1.1 g, 2.710 mmol) and DABCO (1000 mg, 8.915 mmol) in dichloromethane (25 mL) was cooled to 0 °C, and TFAA (1.5 mL, 10.79 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for an additional 1 h, and the reaction was concentrated to dryness. The residue was dissolved in minimal DMSO and purified by reverse-phase chromatography (C18, eluting with 10–100% acetonitrile in water with 0.1% TFA modifier) ​​to give S2 bistrifluoroacetate as a white solid (1.85 g, 68%). 1 H NMR (400MHz, methanol-d4) δ7.93(t,J=8.9Hz, 1H), 7.61~7.24(m, 10H), 5.37(s, 2H), 4.34 (t, J=7.3Hz, 6H), 3.63(t,J=7.3Hz, 6H), 2.99(p,J=6.8Hz, 1H), 1.27(d,J=6.8Hz, 6H). LCMS m / z 500.38[M+H] +

[0152] Preparation of S3 4-(4-Fluorophenyl)-3-isopropyl-7-methoxy-2H-isoquinolin-1-one (S3) [ka] Step 1. Synthesis of 2-bromo-N,N-diethyl-5-methoxy-benzamide (C12) To a solution of C11 (5 g, 21.64 mmol) and N,N-diethylamine (7 mL, 67.67 mmol) in dichloromethane (75 mL) was added HATU (10 g, 26.30 mmol) at room temperature. After stirring for 24 h, the reaction was quenched by the addition of water, and the organic layer was washed with 1 M HCl (30 mL), water, and aqueous saturated NaHCO. The organic layer was then concentrated in vacuo to give a light brown liquid, which was purified on silica gel chromatography eluting with 0% to 50% ethyl acetate in heptane to give C12 (5.63 g, 91%) as a colorless oil. 1H NMR (400MHz, chloroform-d) δ7.47~7.35(m, 1H), 6.76(dd,J=6.3, 3.1Hz, 2H), 3.76(d,J=3.4Hz, 4H), 3.38 ~3.22(m, 1H), 3.14(qt,J=7.4, 3.4Hz, 2H), 1.25(td,J=7.1, 3.0Hz, 4H), 1.06(td,J=7.2, 3.0Hz, 3H). LCMS m / z 286.14[M+H] +

[0153] Step 2. Synthesis of N,N-diethyl-2-[(4-fluorophenyl)methyl]-5-methoxy-benzamide (C13) A solution of C12 (2 g, 6.989 mmol), 2-[(4-fluorophenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 g, 10.59 mmol), and Na2CO3 (12 mL of 2 M, 24.00 mmol) in dioxane (36 mL) and water (12 mL) was degassed with N2 for 5 minutes. PdCl2(dppf) (255 mg, 0.3485 mmol) was then added, and the solution was heated to 80 °C for 3 hours. After that, the temperature was increased to 100 °C, and the solution was stirred for an additional 3 hours. LCMS indicated completion. The reaction mixture was cooled to room temperature, and EtOAc (50 mL) and water (20 mL) were added. The aqueous layer was separated and extracted with EtOAc (2 × 25 mL). The combined organic fractions were washed with brine (2 x 20 mL), dried over NaSO, and concentrated to dryness to give a dark residue, which was purified on silica gel chromatography eluting with 0% to 40% ethyl acetate in heptane to give C13 (2 g, 90%) as a pale yellow oil. 1 H NMR (400MHz, chloroform-d) δ7.20~7.06(m, 3H), 6.94(t,J=8.7Hz, 2H), 6.85(dd,J=8.5, 2.7Hz, 1H), 6.73(d,J=2 .7Hz, 1H), 3.80(s, 2H), 3.74~3.23(m, 2H), 3.08~2.65(m, 2H), 1.19(t,J=7.1Hz, 3H), 0.99(t,J=7.1Hz, 3H). LCMS m / z 316.26[M+H] +

[0154] Step 3. Synthesis of 4-(4-fluorophenyl)-3-isopropyl-7-methoxy-2H-isoquinolin-1-one (S3) To a solution of C13 (1 g, 3.171 mmol) in THF (15 mL) was added LDA (2.0 mL of 2 M, 4.0 mmol) at 0 °C. The colorless solution turned purple and was stirred for an additional 1 h at 0 °C, at which point isobutyronitrile (570 μL) was added dropwise and the reaction was allowed to warm to room temperature and stirred for an additional 12 h. The reaction solution was concentrated to dryness, and saturated NH4Cl (10 mL) and EtOAc (50 mL) were added. The organic layer was washed with brine, dried over Na2SO4, and then concentrated to give a residue that was purified on silica gel chromatography eluting with 0% to 50% ethyl acetate in dichloromethane to give S3 (428 mg, 43%) as a pale yellow oil. 1 H NMR (400MHz, chloroform-d) δ9.79 (s, 1H), 7.87 (d,J=2.8Hz, 1H), 7.26~7.10 (m, 5H), 6.97(d,J=8.9Hz, 1H), 3.95(s, 3H), 2.86(p,J=7.1Hz, 1H), 1.27(d,J=7.0Hz, 6H). LCMS m / z 312.21[M+H] +

[0155] Preparation of S4 7-benzyloxy-4-bromo-3-isopropyl-2-oxide-isoquinolin-2-ium (S4) [ka] Step 1. Synthesis of 5-benzyloxy-2-(3-methylbut-1-ynyl)benzaldehyde (C15) A solution of C14 (1.99 g, 6.8352 mmol) in dioxane (10.5 mL) and TEA (7.5 mL) in a three-neck flask equipped with a reflux condenser was sparged with N for 15 minutes. Bis(triphenylphosphine)palladium(II) dichloride (95 mg, 0.135 mmol) and CuI (56 mg, 0.294 mmol) were added under N, the reaction was bubbled for an additional 2 minutes, and 3-methylbut-1-yne (531.47 g, 0.84 mL, 7.4122 mmol) was added. The reaction turned from yellow to dark brown. The reaction was stirred overnight at 60 °C, cooled to room temperature, diluted with EtOAc (30 mL), and washed with 1 M aqueous HCl (2 × 30 mL), water (20 mL), and brine (20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a silica plug eluted with heptane / EtOAc (95:5) to give C15 (1.88 g, 99%) as a dark brown oil. 1 H NMR (300MHz, chloroform-d) δ1.29(d,J=6.8Hz, 6H), 2.84(dt,J=13.7, 6.8Hz, 1H), 5.12(s, 2H), 7.16(dd,J=8.5, 2.6Hz, 1H), 7.28~7.62(m, 7H), 10.50(s, 1H). LCMS m / z 279.2[M+H] +

[0156] Step 2. Synthesis of 5-benzyloxy-2-(3-methylbut-1-ynyl)benzaldehyde oxime (C16) To a solution of hydroxylamine hydrochloride (834 mg, 12.002 mmol) in pyridine (9.2308 g, 9.4 mL, 116.70 mmol) was added acetonitrile (11 mL) at room temperature. The solution was stirred at 50 °C, and a solution of C15 (1.155 g, 3.8798 mmol) in 1,2-dichloroethane (7 mL) was added. The resulting mixture was heated at 50 °C for 45 min. The suspension was cooled to room temperature, diluted with EtOAc (30 mL) and water (30 mL), and decanted. The organic layer was washed with 3 M aqueous HCl (2 × 20 mL), water (20 mL), brine (15 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting product still contained pyridine. The residue was dissolved in EtOAc (30 mL), washed with 3 M HCl (30 mL) and brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with heptane, filtered, and dried under reduced pressure to give C16 (844 mg, 74%) as a beige solid. 1 H NMR (300MHz, chloroform-d) δ1.28(s, 3H), 1.30(s, 3H), 2.82(dquin,J=13.7, 6.8Hz, 1H), 5. 08(s, 2H), 6.95(dd,J=8.7, 2.8Hz, 1H), 7.31~7.48(m, 7H), 7.58(br.s, 1H), 8.59(s, 1H). LCMS m / z 294.2[M+H] +

[0157] Step 3. Synthesis of 7-benzyloxy-4-bromo-3-isopropyl-2-oxide-isoquinolin-2-ium (S4) CuBr (10.599 g, 47.454 mmol) was added to a solution of C16 (5.6 g, 19.089 mmol) in N,N-dimethylacetamide (95 mL), and the resulting mixture was heated at 60 °C for 45 min. The reaction mixture was cooled to room temperature, then to 0 °C, and an aqueous solution of ammonium hydroxide and water (2:1, 42 mL) was slowly added with vigorous stirring and stirred at 0 °C for 30 min. The suspended solid was then filtered and washed with water to give a tan solid. The solid was passed through a filter paper and dissolved with dichloromethane. The organic filtrate was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum. The residue was triturated in methyl tert-butyl ether (±20 mL), filtered, washed with heptane and dried under reduced pressure to give S4 (4.735 g, 67%) as an off-white powder. 1 H NMR (300 MHz, chloroform-d): δ 1.55 (s, 3H), 1.58 (s, 3H), 4.13 (br.s., 1H), 5.19 (s, 2H), 6.97 (d, J = 2.3 Hz, 1H), 7.30–7.55 (m, 6H), 8.06 (d, J = 9.4 Hz, 1H), 8.61 (br.s., 1H). LCMS m / z 372.1 [M+H] +

[0158] Preparation of S5 7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-2H-isoquinolin-1-one (S5) [ka] Step 1. Synthesis of methyl 5-benzyloxy-2-bromo-benzoate (C18) To a solution of C17 (25.8 g, 111.67 mmol) in anhydrous DMF (180 mL) cooled at 0 °C was added K2CO3 (33.4 g, 241.67 mmol), followed by benzyl bromide (21.570 g, 15 mL, 126.12 mmol). The mixture was stirred at 0 °C for 15 minutes and then at room temperature for 5 hours. MTBE (1.25 L) was added, and the organic phase was washed with 5% aqueous NaHCO3 (5 × 250 mL), water (5 × 250 mL), and brine (1 × 250 mL), dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was triturated with heptane (1 × 125 mL), filtered, and dried to give C18 (34.2 g, 95%) as a white solid. 1 H NMR (300 MHz, chloroform-d): δ 7.53 (d, J = 8.7 Hz, 1H), 7.45–7.29 (m, 6H), 6.95 (dd, J = 8.7, 3.0 Hz, 1H), 5.06 (s, 2H), 3.93 (s, 3H). LCMS m / z 321.0 [M+H] +

[0159] Step 2. Synthesis of methyl 5-benzyloxy-2-[(4-fluorophenyl)methyl]benzoate (C19) A solution of C18 (10.0 g, 31.137 mmol), 2-[(4-fluorophenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.0 g, 42.357 mmol), Na2CO3 (60.0 mL of 2 M, 120.00 mmol) in a mixture of dioxane (180 mL) and water (60 mL) was heated at 100 °C and bubbled with nitrogen for 20 min. PdCl2(dppf) . Dichloromethane (1.28 g, 1.5674 mmol) was added and nitrogen was bubbled through for 5 minutes. The reaction mixture was heated at 100° C. for 2.25 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (300 mL) and water (200 mL), and decanted. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, loaded onto silica gel, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5% to 20% EtOAc in heptane to yield C19 (9.68 g, 82%) as a white solid.1 H NMR (300 MHz, chloroform-d) δ 3.82 (s, 3H), 4.27 (s, 2H), 5.08 (s, 2H), 6.88–7.01 (m, 2H), 7.02–7.17 (m, 4H), 7.30–7.49 (m, 5H), 7.54 (d, J = 2.6 Hz, 1H). 19 F NMR (282 MHz, chloroform-d) δ -118.0 to -117.6 (m, 1F). LCMS m / z 351.1 [M+H] +

[0160] Step 3. Synthesis of 5-benzyloxy-2-[(4-fluorophenyl)methyl]benzoic acid (C20) Crushed NaOH (4.44 g, 111.01 mmol) was added to a mixture of C19 (9.68 g, 27.627 mmol) in a mixture of THF (35 mL), MeOH (35 mL), and water (35 mL). The reaction mixture was stirred vigorously and heated at 50 °C for 2.25 h. The reaction mixture was concentrated under reduced pressure to remove most of the THF and MeOH, and then water (50 mL) was added. 1 M HCl (100 mL) was added, acidified to pH ± 1-2, and extracted with EtOAc (350 mL + 150 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to yield C20 (9.03 g, 89%) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 7.67 (d, J = 2.1 Hz, 1H), 7.52–7.30 (m, 5H), 7.17–7.05 (m, 4H), 7.01–6.88 (m, 2H), 5.10 (s, 2H), 4.34 (s, 2H). 19 F NMR (282 MHz, chloroform-d) δ -117.5 to -117.9 (m, 1F). LCMS m / z 359.1 [M+H] +

[0161] Step 4. Synthesis of 5-benzyloxy-N,N-diethyl-2[(4-fluorophenyl)methyl]benzamide (C4) To a suspension of C20 (9.0 g, 26.757 mmol) in dichloromethane (85 mL) was added triethylamine (10.890 g, 15 mL, 107.62 mmol) and N-ethylethanamine (2.9694 g, 4.2 mL, 40.601 mmol). The reaction mixture was placed in a cold water bath for the slow addition of T3P (50 wt % in EtOAc) (19.0 mL, 32.1 mmol) over 5 min. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (200 mL) and saturated Na2CO3 (75 mL). The layers were decanted, and the organic layer was washed with water:brine (1:1), brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 40% ethyl acetate in heptane. The oil was co-evaporated with THF (3 x 20 mL) and dried under vacuum to give C4 (9.77 g, 88%) as a pale yellow oil. 1 H NMR (300MHz, chloroform-d) δ7.48~7.29(m, 5H), 7.20~7.04(m, 3H), 7.00~6.87(m, 3H), 6.78(d,J=2.6Hz, 1H), 5.17~4.94(m, 2H) , 4.04~3.80(m, 2H), 3.71~3.51(m, 1H), 3.43~3.18(m, 1H), 3.04~2.59(m, 2H), 1.17(t,J=7.0Hz, 3H), 0.89(t,J=7.0Hz, 3H). LCMS m / z 392.3[M+H] +

[0162] Step 5. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-2H-isoquinolin-1-one (S5) To a solution of C4 (100 mg, 0.2401 mmol) in THF (1 mL) at −20° C. was added dropwise a THF / hexane solution of LDA (0.19 mL of 1.5 M, 0.2850 mmol), and the resulting mixture was stirred at −20° C. for 2 h. Then, 2-methylpropanenitrile (34.650 mg, 45 μL, 0.5014 mmol) was slowly added, and the reaction mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride (5 mL) and water (5 mL) was added, extracted with EtOAc (30 mL), and decanted. The organic layer was washed with brine and concentrated under reduced pressure to give a beige solid. The residue was triturated with acetonitrile (approximately 5 mL), filtered, and dried under vacuum to give S5 (44 mg, 47%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ11.14(s, 1H), 7.75(d,J=2.6Hz, 1H), 7.52~7.44(m, 2H), 7.44~7. 25(m, 8H), 6.83(d,J=8.8Hz, 1H), 5.22(s, 2H), 2.69~2.56(m, 1H), 1.16(d,J=7.0Hz, 6H). 19 F NMR (282MHz, DMSO-d6) δ -114.75~-115.06 (m, 1F). LCMS m / z 388.2[M+H] +

[0163] Preparation of S6 1-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (S6) [ka] Step 1. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-2-oxide-isoquinolin-2-ium (C21) A suspension of S4 (5 g, 13.432 mmol) and (4-fluorophenyl)boronic acid (2.82 g, 20.154 mmol), an aqueous solution of Na2CO3 (13.5 mL of 2 M, 27.000 mmol) in DMSO (45 mL) was heated to 100 °C and sparged with N2 for 15 min. PdCl2(dppf) . Dichloromethane (565 mg, 0.6919 mmol) was added and the reaction was sparged for 2 minutes. The reaction was stirred at 100°C overnight. The reaction mixture was cooled to room temperature, cooled to 0°C, water (90 mL) was added, stirred at 0°C for 20 minutes, and the suspension was filtered and washed with water. The residue was then dissolved (through a filter paper) with dichloromethane. The filtrate was decanted, dried over anhydrous NaSO, filtered, loaded onto silica gel, and concentrated under reduced pressure. The residue was purified on silica gel chromatography eluting with 0% to 60% EtOAc in dichloromethane to yield C21 (4.49 g, 86%) as a tan solid. 1 1H NMR (300MHz, chloroform d): δ8.71(s, 1H), 7.50~7.34(m, 5H), 7.24(d,J=6.8Hz, 4H), 7.15~6.99(m, 3H), 5.18(s, 2H), 3.21(br.s., 1H), 1.41(d,J=7.0Hz, 6H). 19 F NMR (282 MHz, chloroform-d) δ -113.06 to -113.52 (m, 1F) LCMS m / z 388.2 [M+H] +

[0164] Step 2. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (S6) To a solution of C21 (2000 mg, 5.147 mmol) and DABCO (2500 mg, 22.29 mmol) in dichloromethane (40 mL) was added TFAA (2000 μL, 14.39 mmol) at 0° C. The mixture was allowed to warm to room temperature, stirred for 1 h, concentrated in vacuo, and the residue was purified by chromatography (C18, 10-100% MeCN:water, 0.1% TFA modifier) ​​to give S6 bistrifluoroacetate (3.43 g, 83%) as an off-white solid. 1H NMR (300MHz, DMSO-d6) δ7.78(d, J=2.3Hz, 1H), 7.68(dd,J=9.4, 2.0Hz, 1H), 7.58~7.50(m, 2H), 7.50~7.31( m, 8H), 5.51(s, 2H), 4.15(t,J=7.3Hz, 6H), 3.36(t,J=7.3Hz, 6H), 2.97~2.82(m, 2H), 1.20(d,J=6.7Hz, 6H). LCMS m / z 482.37[M+H] +

[0165] Preparation of S7 7-Benzyloxy-1-chloro-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (S7) [ka] Step 1. Synthesis of 7-benzyloxy-1-chloro-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (S7) Oxalyl chloride (1 mL of 2 M, 2.000 mmol) was added to a solution of C21 (410 mg, 1.058 mmol) and DIEA (400 μL, 2.296 mmol) in dry dichloromethane (5 mL) at −78° C. The reaction was allowed to warm to 0° C. over 2 h and then quenched by the addition of methanol (approximately 0.5 mL). The mixture was concentrated in vacuo, and the residue was triturated with methanol, filtered (washed with cold methanol), and dried under vacuum to give S7 (395 mg, 92%) as a colorless solid. 1H NMR (300MHz, chloroform-d) δ7.69(d,J=2.4Hz, 1H), 7.58~7.48(m, 2H), 7.48~7.36(m, 3H), 7.32(dd,J= 9.2, 2.5Hz, 1H), 7.27~7.15(m, 5H), 5.25(s, 2H), 2.93(hept,J=6.7Hz, 1H), 1.24(d,J=6.7Hz, 6H). LCMS m / z 0.99[M+H] +

[0166] Preparation of S8 7-Benzyloxy-1,3-dichloro-4-(4-fluoro-3-methyl-phenyl)isoquinoline (S8) [ka] Step 1. Synthesis of 1,3-dichloro-4-iodo-7-methoxy-isoquinoline (C23) To a solution of C22 (1 g, 4.385 mmol) in THF (50 mL) was added LDA (2.6 mL of 2 M, 5.2 mmol) at room temperature, and the solution was stirred for 30 min, by which time the initially cloudy solution had become clear. I2 (2.3 g, 9.062 mmol) was then added in portions, and the solution was stirred for 15 h. Water (20 mL) was added, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with 1 M Na2S2O3 solution and brine, dried over MgSO4, then filtered and concentrated to give C23 as a yellow solid (1.38 g, 84%). 1 H NMR (400 MHz, chloroform-d) δ 8.05 (dd, J = 9.2, 0.5 Hz, 1H), 7.49-7.41 (m, 2H), 4.00 (s, 3H). LCMS m / z 354.37 [M+H] +

[0167] Step 2. Synthesis of 1,3-dichloro-4-(4-fluoro-3-methyl-phenyl)-7-methoxy-isoquinoline (C24) To a solution of C23 (1.38 g, 3.675 mmol) in 1,4-dioxane (40 mL) was added (4-fluoro-3-methyl-phenyl)boronic acid (720 mg, 4.677 mmol) and Na2CO3 (6 mL of 2 M, 12.00 mmol) in water (10 mL), then the solution was degassed by bubbling N2 for 10 min and PdCl2(dppf) . Dichloromethane (318 mg, 0.3894 mmol) was added and N was bubbled through for an additional 5 minutes. The solution was heated to 60° C. for 15 hours. EtOAc (100 mL) was added in one portion, and the solution was washed with water, aqueous NaHSO, and brine. After drying over MgSO and filtration, the solution was concentrated to dryness, and the residue was purified by MPLC:40 g column eluting with 0-30% EtOAc in hexanes to give the desired product of C24 as a white solid (1.25 g, 97%). 1 H NMR (400 MHz, chloroform-d) δ 7.57 (d, J = 2.5 Hz, 1H), 7.42 (dd, J = 9.3, 0.5 Hz, 1H), 7.33 (dd, J = 9.2, 2.6 Hz, 1H), 7.21–7.09 (m, 3H), 4.02 (s, 3H), 2.38 (d, J = 1.9 Hz, 3H). LCMS m / z 336.1 [M+H] +

[0168] Step 3. Synthesis of 1,3-dichloro-4-(4-fluoro-3-methyl-phenyl)isoquinolin-7-ol (C25) To a solution of C24 (1.9 g, 5.531 mmol) in dichloromethane (30 mL) was added BBr3 (11.5 mL of 1 M, 11.50 mmol) in a dropwise manner at 0 °C. The solution was then allowed to warm slowly to room temperature and stirred for 1 h. The solution was then cooled to 0 °C in an ice bath and ice was added to quench the reaction. The solution was concentrated and the residue was loaded onto a column with a MeOH / dichloromethane solution. MPLC:12 g column, eluting with 0-5% MeOH in dichloromethane, gave C25 (1.75 g, 96%). LCMS m / z 322.16 [M+H] +

[0169] Step 4. Synthesis of 7-benzyloxy-1,3-dichloro-4-(4-fluoro-3-methyl-phenyl)isoquinoline (S8) To a solution of C25 (1.75 g, 5.315 mmol) and K2CO3 (1.5 g, 10.85 mmol) in DMF (20 mL) was added BnBr (700 μL, 5.885 mmol), and the solution was stirred at room temperature for 15 h. Then, additional BnBr (700 μL, 5.885 mmol) and K2CO3 (1.5 g, 10.85 mmol) were added, and the solution was stirred for 24 h. A solution of saturated NH4Cl was then added, and the aqueous phase was extracted with EtOAc. After evaporation of the organic phase, the residue was purified by MPLC:12 g column eluting with 0–20% EtOAc in hexane to give two products S8 (1.02 g, 46%) as white solids. 1 H NMR (400MHz, chloroform-d) δ7.56(d,J=2.3Hz, 1H), 7.40(d,J=7.5Hz, 2H), 7.37~7.23(m, 5H), 7.14~6.98(m, 3H), 5.15(s, 2H), 2.26(d,J=1.9Hz, 3H)LCMS m / z 412.24[M+H] +

[0170] Preparation of S9 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-2-oxide-isoquinolin-2-ium (S9) [ka] Step 1. Synthesis of 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-2-oxide-isoquinolin-2-ium (S9) A suspension of S4 (14.635 g, 39.314 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (8.960 g, 58.202 mmol), and an aqueous solution of Na2CO3 (40 mL of 2 M, 80.000 mmol) in DMSO (130 mL) was heated to 100 °C and sparged with nitrogen for 15 min. .Dichloromethane (1.652 g, 2.0229 mmol) was added and the reaction was sparged with N for 2 minutes. The reaction was stirred at 100° C. for 15 hours. The reaction mixture was cooled to room temperature, cooled to 0° C., water (200 mL) was added, stirred at 0° C. for 20 minutes, and the suspension was filtered and washed with water. The residue was then dissolved with dichloromethane (through a filter paper). The filtrate was transferred to another solution, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on an ISCO CombiFlash® Companion (300 g SiO ) loaded with dichloromethane. 2、 The residue was purified by flash chromatography on an ISCO CombiFlash® Companion (120 g SiO, dichloromethane / EtOAc 100:0 to 30:70) loaded with dichloromethane. All fractions containing clean product were combined and the solvent removed by rotary evaporation. The product was dried under reduced pressure to give S9 (14.2 g, 90%) as a tan powder. 1 H NMR (300MHz, chloroform-d): δ8.70(s, 1H), 7.50~7.32(m, 5H), 7.21~6.98(m, 6H), 5.17(s, 2H), 3.21(br.s, 1H), 2.37(d,J=1.8Hz, 3H), 1.41(d,J=5.9Hz, 6H). 19 F NMR (282 MHz, chloroform-d): δ -117.7 (s, 1F). LCMS m / z 402.2 [M+H] +

[0171] Preparation of S10 1-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-isoquinoline (S10) [ka] Step 1. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-isoquinoline (S10) To a solution of S9 (2 g, 4.872 mmol) and DABCO (2.73 g, 24.34 mmol) in dichloromethane (45 mL) was added TFAA (2.0 mL, 14.39 mmol) at 0 °C. The reaction was stirred for 1 h and concentrated to a crude residue, which was purified via reverse-phase chromatography (ISCO, 50 g C18 column, 0-95% MeCN in HO gradient with TFA modifier) ​​to provide the desired product S10 as a white solid (monotrifluoroacetate salt) (2.4 g, 80%). LCMS m / z 496.38 [M+H] +

[0172] Preparation of S11 7-Benzyloxy-4-bromo-2-oxide-3-tetrahydropyran-4-yl-isoquinolin-2-ium (S11) [ka] Step 1. Synthesis of 5-benzyloxy-2-(2-tetrahydropyran-4-ylethynyl)benzaldehyde (C26) In a sealed tube, a solution of C14 (5.693 g, 19.554 mmol) in dioxane (20 mL) and triethylamine (20 mL) was degassed by bubbling N for 15 min. 4-Ethynyltetrahydropyran (3.765 g, 74.9% w / w, 25.600 mmol), PdCl(PPh) (271 mg, 0.3850 mmol), and CuI (139 mg, 0.7299 mmol) in dioxane (10 mL) were added under N, and the reaction was further stirred for 2 min. The reaction turned from yellow to dark brown. The vial was sealed, and the reaction was stirred at 50 °C for 2 h, cooled to room temperature, diluted with EtOAc (100 mL), and washed with 1 M aqueous HCl (2 × 50 mL), water (30 mL), and brine (30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with MeCN, filtered, washed with a minimum amount of ACN, and dried under reduced pressure to give C26 (4.598 g, 73%) as an off-white solid. 1 H NMR (300MHz, chloroform-d) δ1.71~1.86(m, 2H), 1.88~2.01(m, 2H), 2.92(tt,J=8.6, 4.3Hz, 1H), 3.58(ddd,J=11.4, 8.5, 2.9Hz, 2H), 3.90~4.02(m, 2H), 5.12(s, 2H), 7.17(dd,J=8.7, 2.8Hz, 1H), 7.31~7.51(m, 7H), 10.50(s, 1H). LCMS m / z 321.1[M+H] +

[0173] Step 2. Synthesis of 5-benzyloxy-2-(2-tetrahydropyran-4-ylethynyl)benzaldehyde oxime (C27) To a solution of hydroxylamine hydrochloride (12.637 g, 181.85 mmol) was added acetonitrile (210 mL). The reaction was warmed to 50 °C, and a solution of C26 (19.135 g, 59.726 mmol) in DCE (125 mL) was added. The reaction was stirred at 50 °C for 2 h, cooled to room temperature, and diluted with EtOAc (300 mL). The organic layer was washed with 1 M aqueous HCl (5 × 150 mL), water (100 mL), and brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated in acetonitrile, filtered, and dried under reduced pressure to give C27 (18.463 g, 92%) as a pale orange solid. 1 H NMR (300MHz, chloroform-d) δ1.70~1.86(m, 2H), 1.88~2.02(m, 2H), 2.89(tt,J=8.6, 4.2Hz, 1H), 3.58(ddd,J=11.6, 8.7, 2.9Hz, 2H ), 3.97(ddd,J=11.7, 5.4, 3.8Hz, 2H), 5.09(s, 2H), 6.95(dd,J=8.5, 2.6Hz, 1H), 7.30~7.48(m, 6H), 7.56(s, 1H), 8.59(s, 1H). LCMS m / z 336.2[M+H] +

[0174] Step 3. Synthesis of 7-benzyloxy-4-bromo-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (S11) CuBr (20.78 g, 93.036 mmol) was added to a solution of C27 (12.45 g, 37.120 mmol) in N,N-dimethylacetamide (100 mL), and the resulting mixture was heated at 60 °C for 1 h. The reaction mixture was cooled to room temperature and then to 0 °C. An aqueous solution of ammonium hydroxide and water (2:1, 75 mL) was slowly added with vigorous stirring and stirred at 0 °C for 45 min. The suspended solid was then filtered and washed with water to give a tan solid. The solid was dissolved with dichloromethane through a filter paper, transferred to a separate container, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether, filtered, washed with heptane, and then triturated in acetonitrile (50 mL) to give S11 (11.129 g, 72%) as a beige solid. 1 H NMR (300MHz, chloroform-d) δ1.54 (d,J=12.3Hz, 2H), 2.86~3.32 (m, 2H), 3.59 (t,J=11.7Hz, 2H), 3.87~4.24 (m, 3H), 5.20(s, 2H), 6.97(d,J=2.3Hz, 1H), 7.30~7.60(m, 6H), 8.08(d,J=9.4Hz, 1H), 8.64(br.s., 1H). LCMS m / z 414.1[M+H] +

[0175] Preparation of S12 1-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-tetrahydropyran-4-yl-isoquinoline (S12) [ka] Step 1. Synthesis of 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-2-oxide-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C28) A solution of S11 (7.66 g, 18.489 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (4.26 g, 27.672 mmol) and Na2CO3 (19 mL of 2 M in water, 38.000 mmol) in DMSO (80 mL) was heated to 100 °C and sparged with N2 for 15 min. PdCl2(dppf) . Dichloromethane (789 mg, 0.9662 mmol) was added and the reaction was sparged for 2 minutes. The reaction was stirred at 100° C. for 4 hours, cooled to room temperature, diluted with EtOAc (300 mL), and washed with pH 7, 0.1 M potassium phosphate buffer (2×150 mL). The solid precipitated, was filtered, dissolved in dichloromethane, filtered over Celite®, washed with dichloromethane, and concentrated under reduced pressure to give C28 (2.314 g, 28%) as a tan solid. The organic layer was further washed with water (3×100 mL), brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography on an ISCO CombiFlash® Companion loaded with dichloromethane (220 g SiO2, dichloromethane / MeOH 100:0 to 95:5). The product-containing fractions were combined, recrystallized in ACN (approximately 250 mL), filtered, and dried under reduced pressure to give C28 (3.7 g, 45%) as tan crystals. Both batches were combined to give C28 (6.014 g, 71%) as a gray solid. 1 H NMR (300 MHz, chloroform-d) δ 1.41 (d, J = 11.7 Hz, 2H), 2.38 (d, J = 1.5 Hz, 3H), 2.51–2.96 (m, 2H), 3.28 (t, J = 11.3 Hz, 3H), 3.97 (dd, J = 11.0 Hz, 3.4 Hz, 2H), 5.18 (s, 2H), 6.93–7.22 (m, 6H), 7.31–7.52 (m, 5H), 8.73 (s, 1H). 19F NMR (282 MHz, chloroform-d) δ −117.1 (s, 1F). LCMS m / z 444.2 [M+H] +

[0176] Step 2. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-tetrahydropyran-4-yl-isoquinoline (S12) To a solution of C28 (1.4 g, 3.068 mmol) and DABCO (1.72 g, 15.33 mmol) in dichloromethane (30.7 mL) was added TFAA (1.27 mL, 9.137 mmol) at 0 °C, and the reaction was stirred for an additional 1 h before warming to room temperature and stirring for an additional 3 h. The reaction mixture was then concentrated in vacuo, and the crude residue was purified by ISCO reverse-phase flash chromatography (5-95% MeCN in HO with 0.1% TFA modifier, 150 gram C18 column) to provide S12 (monotrifluoroacetate salt) as a white powder (1.52 g, 71%), LCMS m / z 538.36 [M+H]. +

[0177] Preparation of S13 1-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S13) [ka] Step 1. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-2-oxide-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C29) A suspension of S11 (2 g, 4.8275 mmol), (4-fluorophenyl)boronic acid (1.02 g, 7.2899 mmol), and Na2CO3 (4.80 mL of 2 M in water, 9.6000 mmol) in DMSO (20 mL) was heated to 100 °C and sparged with N2 for 15 min. PdCl2(dppf) .Dichloromethane (204 mg, 0.2498 mmol) was added and the reaction was sparged for 2 minutes. The reaction was stirred at 100° C. for 3 hours, cooled to room temperature, diluted with EtOAc (150 mL), washed with pH 7, 0.1 M potassium phosphate buffer (2×75 mL), water (3×75 mL), brine (75 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure, and the residue was triturated with acetonitrile (±30 mL) to yield C29 (1.196 g, 56%) as a gray solid. 1 H NMR (300MHz, chloroform-d) δ1.41(d,J=11.7Hz, 2H), 2.36~2.92(m, 2H), 3.16~3.38(m, 3H), 3.96(dd,J=11.3, 3.7H z, 2H), 5.18(s, 2H), 6.98~7.09(m, 2H), 7.09~7.17(m, 1H), 7.19~7.30(m, 5H), 7.31~7.57(m, 4H), 8.75(s, 1H). 19 F NMR (282 MHz, chloroform-d) δ -112.8 to -112.4 (m, 1F). LCMS m / z 430.2 [M+H] +

[0178] Step 2. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S13) To a solution of C29 (2.955 g, 6.550 mmol) and DABCO (3.67 g, 32.72 mmol) in dichloromethane (70 mL) was added TFAA (4.13 g, 19.66 mmol) at 0 °C. The reaction was then stirred at 0 °C for 1 h, then allowed to warm to room temperature, and stirring was continued for an additional 3 h. The reaction mixture was concentrated in vacuo to provide the desired S13 (tris-trifluoroacetate salt) (10.5 g, 93%) LCMS m / z 525.11 [M+H]. +

[0179] Preparation of S14 1-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-chlorophenyl)-3-isopropyl-isoquinoline (S14) [ka] Step 1. Synthesis of 7-benzyloxy-4-(4-chlorophenyl)-3-isopropyl-2-oxide-isoquinolin-2-ium (C30) A suspension of S4 (27 g, 72.53 mmol), (4-chlorophenyl)boronic acid (14 g, 100.1 mmol), and Na2CO3 (25 g, 235.9 mmol in 70 mL of water) in DMSO (400 mL) was heated to 100 °C and sparged with N2 for 5 min. PdCl2(dppf) . Dichloromethane (2.5 g, 3.061 mmol) was added and the reaction was sparged for 5 minutes. The resulting reaction mixture was warmed to 100° C. and stirred at this temperature for 2 hours, at which point TLC revealed consumption of the starting material. The reaction mixture was cooled to room temperature and partitioned between EtOAc (approximately 1 L) and ice / water (approximately 300 mL). The organic phase was separated, washed with water (approximately 60 mL), brine (approximately 100 mL), dried over MgSO4, filtered through a bed of Florisil®, and concentrated under reduced pressure. The residue was triturated with MTBE (approximately 1 L) to give C30 (21.6 g, 74%). 1 H NMR (400MHz, DMSO-d6) δ8.87(s, 1H), 7.69~7.61(m, 2H), 7.54~7.47(m, 2H), 7.46~7.29(m, 6H), 7.18(dd ,J=9.2, 2.6Hz, 1H), 6.93(d,J=9.2Hz, 1H), 5.21(s, 2H), 3.05(d,J=18.8Hz, 1H), 1.30(d,J=7.0Hz, 6H). LCMS m / z 404.41[M+H] +

[0180] Step 2. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(4-chlorophenyl)-3-isopropyl-isoquinoline (S14) To a solution of C30 (5 g, 12.38 mmol) and DABCO (4 g, 35.66 mmol) in dichloromethane (120 mL) was added TFAA (4 mL, 28.78 mmol) at −10° C. The reaction was then stirred for 3 h at −4° C. to 0° C. The reaction mixture was concentrated in vacuo and triturated with EtO (200 mL) to provide the desired S14 (9 g, 95%) (trifluoroacetate salt) as a tan solid. LCMS m / z 498.62 [M+H] +

[0181] Preparation of S15 N,N-Diethyl-2-[(4-fluorophenyl)methyl]-5-methoxy-benzamide (S15) [ka] Intermediate S15 was prepared as described for the preparation of C13 in the synthetic route to intermediate S3 above.

[0182] Preparation of S16 1-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(3,4-difluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S16) [ka] Step 1. Synthesis of 7-benzyloxy-4-(3,4-difluorophenyl)-2-oxide-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C31) A suspension of S11 (320 mg, 0.7692 mmol), (3,4-difluorophenyl)boronic acid (180 mg, 1.140 mmol), and an aqueous solution of Na2CO3 (1.0 mL of 2 M, 2.0 mmol) in DMSO (5 mL) was sparged with N2 for 5 minutes. Pd(dppf)Cl2·dichloromethane (50 mg, 0.0612 mmol) was added, and the reaction was sparged with N2 for an additional 5 minutes. The resulting mixture was heated to 100 °C and stirred for 4 hours. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The suspension was filtered and washed with water. The residue was then dissolved with dichloromethane. The filtrate was decanted, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give C31 (379 mg, 82%). LCMS m / z 448.51[M+H] +

[0183] Step 2. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(3,4-difluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S16) A solution of C31 (379 mg, 0.6298 mmol) and DABCO (300 mg, 2.674 mmol) in dichloromethane (20 mL) was cooled to 0 °C, and to it was added TFAA (300 μL, 2.158 mmol). The resulting mixture was allowed to warm to room temperature and stirred for an additional 1 h, then concentrated to dryness. The residue was dissolved in minimal DMSO and purified by reverse-phase chromatography (C18, eluting with 10% to 100% CH3CN in water with 0.1% TFA modifier) ​​to give S16 bistrifluoroacetate (440 mg, 90%). LCMS m / z 542.32 [M+H] +

[0184] Preparation of S17 1,3-Dichloro-4-iodo-7-methoxy-isoquinoline (S17) [ka] Compound S17 (equivalent to C23) was prepared as described for C23 in the preparation of S8.

[0185] Preparation of S18 4-Chloro-3-isopropenyl-7-methoxy-quinoline (S18) [ka] Synthesis of 4-chloro-3-isopropenyl-7-methoxy-quinoline (S18) A suspension of C32 (2.97 g, 10.90 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.0 mL, 10.64 mmol), K2CO3 (6.34 g, 45.87 mmol) in 1,4-dioxane (35 mL) and water (3 mL) was sparged with N2 for 2 min. Pd(dppf)Cl2 o Dichloromethane (431 mg, 0.5278 mmol) was added, and the reaction was heated at 70 °C and stirred for 12 h. The mixture was cooled to room temperature, diluted with water, and extracted with diethyl ether. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 40% EtOAc in heptane to yield S18 (1.78 g, 63%) as a colorless oil. 1 H NMR (300 MHz, chloroform-d) δ 8.56 (s, 1H), 8.09 (dd, J = 9.3, 0.4 Hz, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.22 (dd, J = 9.2, 2.6 Hz, 1H), 5.35 (p, J = 1.6 Hz, 1H), 5.08–4.98 (m, 1H), 2.13 (dd, J = 1.6, 0.9 Hz, 3H). LCMS m / z 233.72 [M+H] +

[0186] Preparation of S19 1,3-Dichloro-7-(methoxymethoxy)isoquinoline (S19) [ka] Step 1. Synthesis of 1,3-dichloroisoquinolin-7-ol (C33) A solution of BBr3 (150 mL of 1 M in dichloromethane, 150.0 mmol) was added dropwise to a solution of C22 (10 g, 43.85 mmol) at 0 °C. The resulting mixture was allowed to warm to room temperature and stirred for 18 h. After completion of the reaction, the mixture was cooled to 0 °C, quenched with ice, and concentrated to remove dichloromethane. Water was added, and the mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give C33 (9.1 g, 87%), which was used in the next step without further purification. LCMS m / z 214.06 [M+H] +

[0187] Step 2. Synthesis of 1,3-dichloro-7-(methoxymethoxy)isoquinoline (S19) To a solution of C33 (3.0 g, 14.02 mmol) in dichloromethane (100 mL) was added DIPEA (15 mL, 86.12 mmol) and chloro(methoxy)methane (8 mL, 105.3 mmol). The reaction was stirred at room temperature for 1 h. After complete conversion, the mixture was evaporated and purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give S19 (2.93 g, 72%). LCMS m / z 258.05 [M+H] +

[0188] Preparation of S20 1-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-isoquinoline (S20) [ka] Step 1. Synthesis of 7-benzyloxy-4-(2-methyl-4-pyridyl)-2-oxide-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C34) A suspension of S11 (2.97 g, 7.169 mmol), (2-methyl-4-pyridyl)boronic acid (1.83 g, 13.36 mmol), and an aqueous solution of Na2CO3 (7 mL of 2 M, 14.0 mmol) in DMSO (60 mL) was sparged with N2 for 5 min. Pd(dppf)Cl2 . Dichloromethane (400 mg, 0.4898 mmol) was added, and the reaction was sparged with N for an additional 5 minutes. The resulting mixture was heated at 100 °C and stirred for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water, and extracted three times with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to yield C34 (2.6 g, 85%) as a tan solid. 1 H NMR (300MHz, DMSO-d6) δ8.92(s, 1H), 8.65(dd,J=5.0, 0.8Hz, 1H), 7.54~7.33(m, 6H), 7.31~7.26(m, 1H), 7.24~7.17(m, 2H), 6.92(d, J=9.2Hz, 1H), 5.22(s, 2H), 3.82(dd,J=11.1, 3.7Hz, 2H), 3.06(t,J=11.5Hz, 3H), 2.82~2.59(m, 2H), 2.57(s, 3H), 1.42~1.27(m, 2H). LCMS m / z 427.3[M+H] +

[0189] Step 2. Synthesis of 1-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-isoquinoline (S20) A solution of C34 (513 mg, 1.203 mmol) and DABCO (500 mg, 4.457 mmol) in dichloromethane (10 mL) was cooled to 0 °C, and to it was added TFAA (450 μL, 3.237 mmol). The resulting mixture was allowed to warm to room temperature and stirred for an additional 1 h, then concentrated to dryness. The residue was dissolved in minimal DMSO and purified by reverse-phase chromatography (C18, eluting with 10% to 100% CH3CN in water with 0.1% TFA modifier) ​​to yield S20 bistrifluoroacetate (930 mg, 99%) as an off-white solid. LCMS m / z 521.35 [M+H] +

[0190] Preparation of S21 7-Benzyloxy-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinoline (S21) [ka] Step 1. Synthesis of 4-benzyloxy-2-nitro-benzonitrile (C36) CuCN (4.6507 g, 51.926 mmol) was added to a stirred solution of C35 (8.0 g, 25.963 mmol) in DMF (100 mL). The resulting mixture was heated at 150 °C and stirred for 3 h. After completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to give crude C36 (6 g, 91%) as a light gray solid, which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ8.1(d,J=8.6Hz, 1H), 7.97(d,J=2.44, 1H), 7.61(dd, J=2.48, 8.68Hz, 1H), 7.49(d,J=7.04Hz, 2H), 7.44~7.35(m, 3H), 5.34(s, 2H).

[0191] Step 2. Synthesis of 2-amino-4-benzyloxy-benzonitrile (C37) A solution of C36 (3 g, 11.800 mmol) in acetic acid (13 mL) was cooled to 0 °C, and to it was added Fe powder (13.179 g, 236.00 mmol). The reaction was allowed to warm to room temperature and stirred for 2 h. After completion of the reaction, the reaction mixture was filtered through Celite. The residue was diluted with Na2CO3 solution and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude C37 (2.3 g, 87%) as a white solid, which was used in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 7.37–7.25 (m, 6H), 6.38 (dd, J = 8.7, 2.2 Hz, 1H), 6.27 (d, J = 2.3 Hz, 1H), 5.04 (s, 2H), 4.37 (s, 2H).

[0192] Step 3. Synthesis of (2-amino-4-benzyloxy-phenyl)-(4-fluorophenyl)methanone (C38) To a stirred solution of C37 (16 g, 71.346 mmol) and (4-fluorophenyl)boronic acid (19.965 g, 142.69 mmol) in 2-MeTHF (160 mL) and water (80 mL), 5,5′-dimethyl-2,2′-dipyridyl (1.3145 g, 7.1346 mmol), Pd(TFA) (1.1860 g, 3.5673 mmol), and methanesulfonic acid (46.298 mL, 713.46 mmol) were added at room temperature under N. The resulting mixture was heated at 80° C. and stirred for 30 h. After completion of the reaction, the reaction mixture was quenched with NaCO solution and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-10% EtOAc in heptane to yield C38 (18.375 g, 80%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ7.61~7.52 (m, 2H), 7.48~7.36 (m, 4H), 7.39~7.26 (m, 6H), 7.25~7.17 (m, 1H), 5.75 (s, 1H), 5.10 (s, 2H).

[0193] Step 4. Synthesis of N-[5-benzyloxy-2-(4-fluorobenzoyl)phenyl]-2-tetrahydropyran-4-yl-acetamide (C39) A catalytic amount of DMF was added to a mixture of SOCl (4.6649 g, 2.8601 mL, 39.210 mmol) and 2-tetrahydropyran-4-ylacetic acid (3.3917 g, 23.526 mmol). The resulting mixture was refluxed for 1 h. After complete formation of the acid chloride, the reaction mixture was evaporated and then dissolved in dichloromethane (30 mL). This suspension was added to a mixture of C38 (6.3 g, 19.605 mmol) and pyridine (7.7538 g, 7.9282 mL, 98.025 mmol) in dichloromethane (147 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with 1 N HCl and extracted with dichloromethane (100 mL). The organic layer was dried over anhydrous NaSO and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc in heptane to afford C39 (7.4 g, 84%) as a pale yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 11.50 (s, 1H), 8.53 (d, J = 2.6 Hz, 1H), 7.70–7.61 (m, 2H), 7.53–7.30 (m, 6H), 7.20–7.10 (m, 2H), 6.64 (dd, J = 8.8, 2.6 Hz, 1H), 5.16 (s, 2H), 4.0 0~3.91(m, 2H), 3.43(td, J=11.8, 2.1Hz, 2H), 2.39(d, J=7.1Hz, 2H), 2.17(dp, J=11 .6, 4.0Hz, 1H), 1.75~1.67 (m, 2H), 1.44 (dd, J=12.2, 4.4Hz, 1H) 1.43~1.34 (m, 1H). LCMS m / z 448.3[M+H] +

[0194] Step 5. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinolin-2-ol (C40) To a stirred solution of C39 (6 g, 13.408 mmol) in toluene (125 mL) was added NaOtBu (3.8657 g, 40.224 mmol). The reaction mixture was refluxed for 16 hours. After completion of the reaction, the reaction mixture was evaporated. The residue was diluted with dichloromethane (300 mL) and washed with water. The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 30% EtOAc in heptane to yield C40 (3.2 g, 49%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6), 11.74(s, 1H), 7.45~7.27(m, 8H), 6.92(d, J=2.28Hz, 1H), 6.73(dd,J=9, 2.4Hz, 1H), 6.65(d,J=8 .92Hz, 1H), 5.12(s, 2H), 3.78(d,J=9.64Hz, 2H), 2.99(t,J=11.24Hz, 2H), 2.50(d,J=21.4, 3H), 1.22(d,J=8.68Hz, 2H). LCMS m / z 430.0[M+H] +

[0195] Step 6. Synthesis of 7-benzyloxy-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinoline (S21) A solution of C40 (300 mg, 0.6985 mmol) in toluene (1.5 mL) was cooled to 0 °C, to which SOCl (831.01 mg, 0.5095 mL, 6.9850 mmol) was added, followed by a catalytic amount of DMF. The resulting mixture was heated to 80 °C and stirred for 3 h. After completion of the reaction, the reaction mixture was evaporated. The residue was diluted with dichloromethane (20 mL) and washed with saturated NaHCO solution (10 mL) and water (10 mL). The organic layer was dried over anhydrous NaSO and concentrated. The residue was purified by silica gel chromatography eluting with 20% EtOAc in heptane to yield S21 (300 mg, 89%) as a pale yellow solid.1 H NMR (400MHz, DMSO-d6) δ7.49~7.33(m, 10H), 7.26~7.23(m, 1H), 7.03(d,J=9.4Hz, 1H), 5.76(s, 1H) , 5.30(s, 2H), 3.85(d,J=10.8Hz, 2H), 3.62(d,J=12.6Hz, 1H), 3.07(s, 4H), 1.44(d,J=13.1Hz, 2H). LCMS m / z 448.0[M+H] +

[0196] Preparation of S22 Synthesis of 2-chloro-4-(4-fluorophenyl)-3-isopropyl-7-methoxy-quinoline (S22) [ka] Step 1. Synthesis of 4-(4-fluorophenyl)-3-isopropenyl-7-methoxy-quinoline (C41) A suspension of S18 (3 g, 12.581 mmol), (4-fluorophenyl)boronic acid (2.1124 g, 15.097 mmol), and K2CO3 (3.4775 g, 25.162 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was sparged with N2 for 30 min. PCy3 (352.81 mg, 1.2581 mmol) and Pd(PPh3)4 (1.0177 g, 0.8807 mmol) were added under N2, and the reaction was heated to 100 °C and stirred for 18 h. After completion of the reaction, the reaction mixture was filtered through Celite, washed with EtOAc (80 mL), and concentrated. The residue was purified by silica gel chromatography eluting with 0–100% EtOAc in heptane to give C41 (4 g, 95%) as an off-white solid. 1 H NMR (400 MHz, chloroform-d): δ 8.76 (s, 1H), 7.52–7.43 (m, 2H), 7.35–7.25 (m, 2H), 7.19–7.13 (m, 2H), 7.12–7.08 (m, 1H), 5.20–5.14 (m, 1H), 5.05–4.96 (m, 1H), 3.95 (s, 3H), 1.63 (s, 3H). LCMS m / z 294.0 [M+H] +

[0197] Step 2. Synthesis of 4-(4-fluorophenyl)-3-isopropyl-7-methoxy-quinoline (C42) Pd (50 mg, 0.4698 mmol) was added to a solution of S18 (1.3 g, 4.432 mmol) in EtOH (20 mL) under N. The resulting mixture was stirred at room temperature under a H balloon for 18 h. The reaction mixture was filtered through a plug of Celite and concentrated under reduced pressure to give C42 (1.26 g, 92%) LCMS m / z 295.32 [M+H]. +

[0198] Step 3. Synthesis of 4-(4-fluorophenyl)-3-isopropyl-7-methoxy-1-oxide-quinolin-1-ium (C43) To a solution of C42 (1.36 g, 4.370 mmol) in dichloromethane (10 mL) was added m-CPBA (1.54 g, 8.924 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-20% MeOH in dichloromethane to give C43 (1.05 g, 69%). 1 H NMR (400MHz, chloroform-d) δ8.53(s, 1H), 8.04(d,J=2.6Hz, 1H), 7.19~7.13(m, 5H), 7.06 (dd,J=9.2, 2.7Hz, 1H), 3.94(s, 3H), 2.80(hept,J=7.0Hz, 1H), 1.13(d,J=7.0Hz, 6H). 19 F NMR (376 MHz, chloroform-d) δ -113.33. LCMS m / z 312.49 [M+H] +

[0199] Step 4. Synthesis of 2-chloro-4-(4-fluorophenyl)-3-isopropyl-7-methoxy-quinoline (S22) POCl (600 μL, 6.437 mmol) and DMF (150 μL, 1.937 mmol) were added successively in a dropwise manner to a solution of C43 (0.731 g, 2.113 mmol) in dichloromethane (10 mL) at 0 °C. The resulting mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was diluted with an aqueous solution of NaCO and extracted with dichloromethane. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure to yield S22 (695.4 mg, 85%) as an off-white solid. 1 H NMR (300 MHz, chloroform-d) δ 7.28 (dd, J = 2.3, 0.8 Hz, 1H), 7.17-7.08 (m, 4H), 6.99-6.94 (m, 2H), 3.85 (s, 3H), 3.22-2.98 (m, 1H), 1.25 (d, J = 7.2 Hz, 6H). 19 F NMR (282 MHz, chloroform-d) δ -113.52. LCMS m / z 329.66 [M+H]. +

[0200] Preparation of S23 7-Benzyloxy-2-chloro-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-quinoline (S23) [ka] Step 1. Synthesis of 4-(4-fluoro-3-methyl-phenyl)-3-isopropenyl-7-methoxy-quinoline (C44) A suspension of S18 (3.22 g, 13.78 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (5.3 g, 34.43 mmol), and Na2CO3 (5.9 g, 55.67 mmol) in DMF (30 mL) was sparged with N2 for 2 minutes. Pd(PPh3)4 (811 mg, 0.7018 mmol) was added, and the resulting mixture was heated at 120 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (200 mL), and washed with water (200 mL) and brine (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% to 90% EtOAc in hexane to yield C44 (3.6 g, 66%). LCMS m / z 307.34 [M+H] +

[0201] Step 2. Synthesis of 4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-7-methoxy-quinoline (C45) Pd (131.57 mg, 1.2363 mmol) was added to a stirred solution of C44 (380 mg, 1.2363 mmol) in EtOH (7 mL) under N. The resulting mixture was stirred at room temperature under a H balloon for 12 h. The reaction mixture was filtered through Celite, washed with EtOH, and concentrated under reduced pressure to give C45 (380 mg, 99%), which was used in the next step without further purification. LCMS m / z 310.2 [M+H] +

[0202] Step 3. Synthesis of 4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-quinolin-7-ol (C46) A solution of BBr3 (56.566 mL of 1 M in dichloromethane, 56.566 mmol) was added dropwise to a solution of C45 (2.5 g, 8.0808 mmol) in dichloromethane (25 mL) at 0 °C. The resulting mixture was heated at 60 °C for 4 h. The reaction mixture was concentrated, neutralized with saturated NaHCO3 solution, and extracted with dichloromethane (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-70% EtOAc in hexane to give C46 (1.8 g, 63%). LCMS m / z 296.1 [M+H] +

[0203] Step 4. Synthesis of 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-quinoline (C47) To a stirred solution of C46 (2 g, 6.7716 mmol) in DMF (10 mL) was added K2CO3 (2.3397 g, 16.929 mmol), followed by benzyl chloride (1.0286 g, 0.9351 mL, 8.1259 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The mixture was quenched with saturated NaHCO3 solution (10 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 20% EtOAc in hexane to yield C47 (1.65 g, 62%) as a white solid. LCMS m / z 387.6 [M+H] +

[0204] Step 5. Synthesis of 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-1-oxide-quinolin-1-ium (C48) To a solution of C47 (650 mg, 1.6862 mmol) in dichloromethane (15 mL) was added m-CPBA (581.96 mg, 3.3724 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO solution. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was then triturated with 10% dichloromethane in pentane and concentrated to give C48 (550 mg, 69%) as an off-white solid. LCMS m / z 386.2 [M+H] +

[0205] Step 6. Synthesis of 7-benzyloxy-2-chloro-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-quinoline (S23) POCl3 (840.25 mg, 0.5108 mL, 5.4800 mmol) and DMF (100.14 mg, 0.1061 mL, 1.3700 mmol) were added successively in a dropwise manner to a solution of C48 (550 mg, 1.3700 mmol) in dichloromethane (6 mL) at 0 °C. The resulting mixture was allowed to warm to room temperature and stirred at this temperature for 18 h. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was washed with saturated Na2CO3 solution (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5% to 10% EtOAc in hexane to give S23 (500 mg, 81%) as an off-white solid. LCMS m / z 420.49 [M+H] +

[0206] Preparation of S24 4-Chloro-3-isopropyl-2-methyl-quinolin-7-ol (S24) [ka] Step 1. Synthesis of 4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-7-methoxy-1-oxide-quinolin-1-ium (C49) To a solution of C42 (85 mg, 0.2747 mmol) in dichloromethane (5 mL) was added m-CPBA (185 mg, 0.8255 mmol). The resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with saturated NaHCO3 solution and extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 10% MeOH in dichloromethane to yield C49 (85 mg, 95%). 1 H NMR (300MHz, chloroform-d) δ8.61(s, 1H), 8.12(d,J=2.6Hz, 1H), 7.28(d,J=9.2Hz, 1H), 7.22~6.99(m , 4H), 4.02(s, 3H), 2.90(p, J=6.9Hz, 1H), 2.37(d,J=2.0Hz, 3H), 1.21(dd,J=6.9, 3.8Hz, 6H)ppm. LCMS m / z 326.59[M+H] +

[0207] Step 2. Synthesis of 2-chloro-4-(4-fluoro-3-methyl-phenyl)-3-isopropyl-7-methoxy-quinoline (S24) A mixture of C49 (80 mg, 0.2459 mmol) and POCl (1120 μL, 1.287 mmol) in CHCl (1.5 mL) was heated in a microwave at 80 °C for 3 hours. After completion of the reaction, the reaction was quenched with water. Saturated aqueous NaHCO was then added, and the mixture was extracted with dichloromethane (2 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give S24 (70 mg, 83%). 1 H NMR (300 MHz, chloroform-d): δ 7.40 (d, J = 2.4 Hz, 1H), 7.23–6.97 (m, 5H), 3.95 (s, 3H), 3.22 (s, 1H), 2.38 (d, J = 2.0 Hz, 3H), 1.45–1.29 (m, 6H) ppm. LCMS m / z 344.55 [M+H] +

[0208] Preparation of S25 4-Chloro-3-isopropyl-2-methylquinolin-7-ol (S25) [ka] Step 1. Synthesis of 4-chloro-3-isopropyl-7-methoxy-2-methyl-quinoline (C51) A mixture of C50 (1.0 g, 4.324 mmol) and SOCl2 (10 mL, 137.1 mmol) in DMF (500 μL, 6.457 mmol) was heated in a microwave at 80 °C for 2 hours. After completion of the reaction, the reaction mixture was concentrated. The residue was diluted with cold water and saturated NaHCO3 solution until a precipitate formed. The solid was filtered, washed with water, and dried to give C51 (1.0 g, 93%). 1 H NMR (300 MHz, chloroform-d) δ 8.12 (d, J = 9.3 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 7.21 (dd, J = 9.2, 2.6 Hz, 1H), 3.96 (s, 3H), 2.82 (s, 3H), 1.50 (d, J = 7.2 Hz, 6H) ppm. LCMS m / z 250.23 [M+H] +

[0209] Step 2. Synthesis of 4-chloro-3-isopropyl-2-methyl-quinolin-7-ol (S25) A solution of BBr3 (15 mL of 1 M in dichloromethane, 15.00 mmol) was added dropwise to a solution of C51 (900 mg, 3.604 mmol) in anhydrous dichloromethane (50 mL) at 0 °C under N2. The resulting mixture was allowed to warm to room temperature and stirred for 60 h. After completion of the reaction, the mixture was cooled to 0 °C, quenched with cold water, and evaporated to remove dichloromethane. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield S25 (650 mg, 75%). 1H NMR (300MHz, DMSO-d6) δ11.51(s, 1H), 8.29(d,J=9.3Hz, 1H), 7.57~7.31(m, 2H), 3.69(s, 1H), 2.92(s, 3H), 1.45(d,J=7.2Hz, 6H)ppm. LCMS m / z 236.19[M+H] +

[0210] Preparation of S26 7-Benzyloxy-2-chloro-4-(4-fluorophenyl)-3-(2-methoxy-1-methyl-ethyl)quinoline (S26) [ka] Step 1. Synthesis of 5-[(3-benzyloxyanilino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (C53) To a suspension of C52 (30 g, 150.57 mmol) and Meldrum's acid (25.607 g, 177.67 mmol) in EtOH (30 mL) was added trimethyl orthoformate (18.854 g, 177.67 mmol). The resulting mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temperature and stirring was continued for an additional 2 h. The suspension was filtered and the solid residue was stirred in absolute EtOH (150 mL) for 2 h. The solid residue was collected by filtration and dried in vacuo to give C53 (50 g, 92%). 1 H NMR (400MHz, DMSO-d6) δ11.21(d,J =14.4Hz, 1H), 8.61(d,J=14.5Hz, 1H), 7.47(d,J=7.4Hz, 2H), 7.40(t,J=7.4Hz, 2H), 7.37~7.2 9(m, 3H), 7.12(dd,J=8.2, 2.1Hz, 1H), 6.91(dd,J=8.2, 2.4Hz, 1H), 5.16(s, 2H), 1.68(s, 6H). LCMS m / z 354.0[M+H] +

[0211] Step 2. Synthesis of 7-benzyloxy-1H-quinolin-4-one (C54) A stirred mixture of C53 (50 g, 141.50 mmol) and Dowtherm A (100 mL) was heated at 220° C. for 30 minutes. The reaction mixture was cooled to room temperature and diluted with hexane (50 mL) until a precipitate formed. The solid residue was collected by filtration and washed with hexane to give C54 (30 g, 79%) as a white solid. LCMS m / z 252.0 [M+H] +

[0212] Step 3. Synthesis of 7-benzyloxy-3-bromo-1H-quinolin-4-one (C55) To a suspension of C54 (1 g, 3.9796 mmol) in anhydrous DMF (4 mL) was added pyridine (978 mg, 1.00 mL, 12.364 mmol). The mixture was cooled to −16° C., and pyridinium tribromide (905 mg, 2.8297 mmol) was added within 5 min. After stirring for 1 h and the temperature rose from −16 to −8° C., additional pyridinium tribromide (249 mg, 0.7786 mmol) was added. After another hour, when the temperature rose from −8 to −6° C., additional pyridinium tribromide (220 mg, 0.6879 mmol) was again added. The resulting mixture was stirred for another hour. NaOAc (1.35 g, 16.457 mmol) was added, followed by water (40 mL). The mixture was stirred at 0° C. for 10 min, then the solid was filtered, washed with water (5×10 mL), and dried under vacuum to give C55 (1.3 g, 96%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6): δ5.21 (s, 2H), 7.01~7.11 (m, 2H), 7.30~7.45 (m, 3H), 7.46 ~7.53(m, 2H), 8.00~8.07(m, 1H), 8.38(d,J=6.1Hz, 1H), 12.01~12.12(m, 1H);LCMS m / z 330.0[M+H] +

[0213] Step 4. Synthesis of 7-benzyloxy-3-bromo-4-chloro-quinoline (C56) To a suspension of C55 (11.59 g, 33.347 mmol) in SOCl2 (97.860 g, 60 mL, 822.55 mmol) was added DMF (28.320 mg, 0.03 mL, 0.3874 mmol). The mixture was heated to 70 °C and stirred for 1.5 h. After completion of the reaction, SOCl2 was co-evaporated with the addition of toluene (2 × 75 mL). The residue was diluted with saturated NaHCO3 solution (3 × 150 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na2SO4, filtered, and concentrated. The residue was triturated in CH3CN (50 mL) and stirred at room temperature for 3 h. The residue was filtered, washed with MTBE (2×5 mL), and dried in vacuo to give C56 (10.91 g, 91%) as a beige solid. 1 H NMR (300MHz, DMSO-d6) δ5.33(s, 2H), 7.31~7.46(m, 3H), 7.47~7.55(m, 3H), 7.56~7.63m, 1H), 8.15(d,J=9.2Hz), 8.98(s, 1H);LCMS m / z 348.0[M+H] +

[0214] Step 5. Synthesis of 7-benzyloxy-4-chloro-3-isopropenyl-quinoline (C57) A suspension of C56 (6 g, 15.490 mmol), potassium trifluoro(isopropenyl)borate (2.5214 g, 17.039 mmol), and K2CO3 (6.4224 g, 46.470 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was sparged with N2 for 30 minutes. Pd(dppf)Cl2·dichloromethane (1.2650 g, 1.5490 mmol) was added, and the reaction was heated at 100 °C for 18 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, washed with EtOAc, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 10% EtOAc in hexanes to give C57 (4.3 g, 84%) as a white solid. LCMS m / z 310.0 [M+H] +

[0215] Step 6. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-3-isopropenyl-quinoline (C58) A mixture of C57 (6 g, 19.368 mmol), (4-fluorophenyl)boronic acid (3.2520 g, 23.242 mmol), and K2CO3 (5.3535 g, 38.736 mmol) in 1,4-dioxane (60 mL) and HO (10 mL) was sparged with N2 for 10 min. Pd(PPh3)4 (1.5667 g, 1.3558 mmol) and PCy3 (543.13 mg, 1.9368 mmol) were added sequentially under N2, and the reaction was heated at 90 °C for 18 h. The reaction mixture was cooled to room temperature, filtered through Celite, washed with EtOAc, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 20% EtOAc in hexane to yield C58 (6 g, 79%) as a white solid. LCMS m / z 370.3[M+H] +

[0216] Step 7. Synthesis of 2-[7-benzyloxy-4-(4-fluorophenyl)-3-quinolyl]propan-1-ol (C59) 9-BBN (54.192 mL of 0.5 M, 27.096 mmol) was added dropwise to a solution of C58 (4.4 g, 7.7416 mmol) in THF (44.000 mL) at 0° C. After 1 h, additional 9-BBN (23.224 mL of 0.5 M, 11.612 mmol) was added dropwise at 0° C. Stirring was continued for another 1 h at room temperature, whereupon another lot of 9-BBN (30.966 mL of 0.5 M, 15.483 mmol) was added at 0° C. The resulting mixture was stirred at room temperature for 18 h. After completion of the reaction, the reaction mixture was cooled to 0° C. Aqueous solutions of NaOH (10.529 mL of 1 M, 10.529 mmol) and H2O2 (26.333 g, 23.723 mL, 232.25 mmol) were added successively in a dropwise manner. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (3 x 25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with 60% EtOAc in hexanes to afford C59 (2.8 g, 90%) as a sticky pale yellow gum. LCMS m / z 388.0 [M+H] +

[0217] Step 8. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-3-(2-methoxy-1-methyl-ethyl)quinoline (C60) NaH (891.91 mg, 60% w / w, 22.300 mmol) was added to a stirred solution of C59 (1.8 g, 4.4600 mmol) in THF (40 mL) at 0 °C. The resulting mixture was stirred at this temperature for 30 min, and then CHI (2.5322 g, 1.1106 mL, 17.840 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. After completion, the mixture was diluted with saturated NH4Cl solution (10 mL) and extracted with dichloromethane (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 30% EtOAc in hexanes to give pure C60 (1.1 g, 61%) as a sticky yellow gum. 1H NMR (400MHz, DMSO-d6) δ8.91(s, 1H), 7.54~7.47(m, 3H), 7.37(dt,J=27.9, 7.4Hz, 7H), 7.23(dd,J=9.4, 2.5Hz, 1H), 7.1 5(d,J=9.2Hz, 1H), 5.29(s, 2H), 3.54(t,J=8.5Hz, 1H), 3.45(dd,J=9.5, 6.7Hz, 1H), 3.12(s, 3H), 1.18(d,J=6.9Hz, 3H). LCMS m / z 402.0[M+H] +

[0218] Step 9. Synthesis of 7-benzyloxy-4-(4-fluorophenyl)-3-(2-methoxy-1-methyl-ethyl)-1-oxide-quinolin-1-ium (C61) To a solution of C60 (1.1 g, 2.7399 mmol) in dichloromethane (30 mL) was added m-CPBA (709.21 mg, 4.1098 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated Na2CO3 solution (25 mL), water (25 mL), and brine (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give C61 (1 g, 83%), which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ8.71(s, 1H), 8.07(d,J=2.7Hz, 1H), 7.51(d,J=7.1Hz, 2H), 7.45~7.37(m, 4H), 7.41~7.31(m, 4H), 7.2 3(d,J=9.2Hz, 1H), 5.33(s, 2H), 3.52(dd,J=9.6, 7.7Hz, 1H), 3.41(dd,J=9.6, 6.3Hz, 1H), 3.13(s,3H), 1.14(d,J=7.0Hz, 3H). LCMS m / z 418.0[M+H] +

[0219] Step 10. Synthesis of 7-benzyloxy-2-chloro-4-(4-fluorophenyl)-3-(2-methoxy-1-methyl-ethyl)quinoline (S26) POCl (293.81 mg, 0.1786 mL, 1.9162 mmol) and a catalytic amount of DMF were added dropwise successively to a stirred solution of C61 (400 mg, 0.9581 mmol) in toluene (4 mL). The resulting mixture was heated at 80 °C and stirred for 2 h.

[0220] After completion of the reaction, the reaction mixture was evaporated, diluted with EtOAc (50 mL), and washed with saturated NaHCO (20 mL) solution. The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography eluting with 10% EtOAc in hexane to give S26 (350 mg, 82%) as a yellow gum. 1 H NMR (400MHz, DMSO-d6) δ7.53~7.30(m, 10H), 7.25(dd,J=9.3, 2.6Hz, 1H), 7.03(d ,J=9.3Hz, 1H), 5.30(s, 2H), 3.78(s, 1H), 3.51(s, 1H), 3.10(s, 3H), 1.23(s, 3H). LCMS m / z 436.0[M+H] +

[0221] Preparation of S27 4-(4-Fluoro-3-methyl-phenyl)-7-methoxy-2-methyl-quinoline (S27) [ka] To a solution of C62 (150 mg, 0.5950 mmol) and (4-fluoro-3-methyl-phenyl)boronic acid (140 mg, 0.9094 mmol) in DMF (3 mL) was added Pd(dppf)Cl2 (25 mg, 0.03061 mmol) under nitrogen. Na2CO3 (600 μL of 2 M, 1.2 mmol) was then added, and the reaction was heated at 110 °C in a microwave reactor for 30 min. The reaction mixture was diluted with water (30 mL) and filtered. Purification by silica gel chromatography (10-60% EtOAc in heptane) afforded S27 (149 mg, 88%). 1H NMR (300 MHz, chloroform-d): δ 7.73 (d, J = 9.2 Hz, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.34-7.29 (m, 1H), 7.28-7.24 (m, 1H), 7.20-7.05 (m, 3H), 3.98 (s, 3H), 2.75 (s, 3H), 2.39 (d, J = 2.0 Hz, 3H). LCMS m / z 281.93 [M+H] +

[0222] Preparation of S28 2-[7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-1-oxide-quinolin-1-ium-3-yl]propan-1-ol (S28) [ka] Step 1. 7-Benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropenyl-quinoline (C63) To a solution of C57 (3.5 g, 9.3209 mmol) in 1,4-dioxane (50 mL) was added a solution of (4-fluoro-3-methyl-phenyl)boronic acid (1.7219 g, 11.185 mmol) and K2CO3 (2.5764 g, 18.642 mmol) in water (10 mL). The reaction mixture was degassed with argon for 30 minutes, and PCy3 (261.39 mg, 0.9321 mmol) and Pd(PPh3)4 (754.00 mg, 0.6525 mmol) were added. The reaction was heated at 100 °C for 18 hours. The mixture was filtered through a plug of Celite, washed with EtOAc (150 mL), and concentrated. Purification by silica gel chromatography (15% EtOAc in hexanes) afforded C63 (2.9 g, 68%) as an off-white solid. 1 H NMR (400 MHz, chloroform-d): δ 8.74 (s, 1H), 7.56–7.44 (m, 4H), 7.44–7.29 (m, 3H), 7.21–7.12 (m, 1H), 7.16–7.03 (m, 2H), 5.22 (s, 2H), 5.16 (s, 1H), 4.98 (s, 1H), 2.33 (s, 3H), 1.65 (s, 3H). LCMS m / z 384.0 [M+H] +

[0223] Step 2. 2-[7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-quinolyl]propan-1-ol (C64) To a solution of C68 (2.9 g, 6.383 mmol) in dry THF (30 mL) was added dropwise a solution of 9-BBN in THF (44.680 mL of 0.5 M, 22.34 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h, followed by the dropwise addition of another portion of a solution of 9-BBN in THF (19.149 mL of 0.5 M, 9.5745 mmol) at 0° C. The reaction mixture was stirred at room temperature for an additional 1 h, and another portion of a solution of 9-BBN in THF (25.532 mL of 0.5 M, 12.766 mmol) was added at 0° C. The reaction was stirred at room temperature for an additional 18 h. The reaction mixture was cooled to 0 °C and an aqueous solution of NaOH (8.7 mL of 1 M, 8.7000 mmol) was added dropwise, followed by the dropwise addition of H2O2 (5.8442 g, 17.55 mL, 51.544 mmol). The reaction mixture was stirred at 0 °C for 45 min, warmed to room temperature, and stirred for an additional 1 h. The mixture was diluted with EtOAc (100 mL), washed successively with water (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated. Purification by silica gel chromatography (60% EtOAc in hexanes) afforded C64 (4 g, 94%) as a pale yellow solid. LCMS m / z 402.0 [M+H] +

[0224] Step 3. 2-[7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-1-oxide-quinolin-1-ium-3-yl]propan-1-ol (S28) To a solution of C64 (4 g, 5.9780 mmol) in dichloromethane (100 mL) was added m-CPBA (1.4737 g, 6.5758 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane (50 mL) and washed successively with saturated aqueous solutions of NaHCO (40 mL), water (40 mL), and brine (40 mL). The organic phase was dried over NaSO and concentrated to give S28 (2.2 g, 84%) as a light brown solid, which was carried forward without further purification. 1H NMR (400MHz, DMSO-d6) δ8.65(s, 1H), 8.06(d,J=2.7Hz, 1H), 7.92~7.86(m, 1H), 7.59~7.47(m, 2H), 7.45~7.12( m, 8H), 5.32(s, 2H), 4.73~4.68(m, 1H), 3.57~3.40(m, 1H), 2.80~2.71(m, 1H), 2.31(s, 3H), 1.21~1.09(m, 3H). LCMS m / z 418.0[M+H] +

[0225] Preparation of S29 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-1-oxide-3-tetrahydropyran-4-yl-quinolin-1-ium (S29) [ka] Step 1. 7-Benzyloxy-4-chloro-3-(3,6-dihydro-2H-pyran-4-yl)quinoline (C65) To a solution of KPO (9.74 g, 45.886 mmol) in water (9 mL), toluene (100 mL) was added, and the mixture was degassed with nitrogen for 15 minutes. C56 (8 g, 22.259 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.5 g, 26.181 mmol), PCy3 (1.26 g, 4.4931 mmol), and Pd(OAc)2 (575 mg, 2.5612 mmol) were then added sequentially. The reaction was heated at 95 °C for 18 hours. The mixture was cooled to room temperature, diluted with EtOAc (600 mL), washed successively with aqueous solutions of 5% NaHCO (150 mL × 3) and brine (150 mL × 2), dried over NaSO, filtered, and concentrated. The residue was triturated with heptane (50 mL) and acetonitrile (30 mL), filtered, and dried. Purification by silica gel chromatography (0 to 50% EtOAc in dichloromethane) afforded C65 (5.7 g, 73%) as a beige solid. 1 H NMR (300MHz, chloroform-d) δ2.45~2.62(m, 2H), 3.98(t,J=5.2Hz, 2H), 4.37(q,J=2.6Hz, 2H) , 5.22(s, 2H), 5.85~5.94(m, 1H), 7.29~7.58(m, 7H), 8.18(d,J=9.2Hz, 1H), 8.60(s, 1H). LCMS m / z 352.1[M+H] +

[0226] Step 2. 7-Benzyloxy-3-(3,6-dihydro-2H-pyran-4-yl)-4-(4-fluoro-3-methyl-phenyl)quinoline (C66) A suspension of C65 (2.9 g, 8.2427 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (1.5227 g, 9.8912 mmol), K2CO3 (2.2783 g, 16.485 mmol), and PCy3 (231.16 mg, 0.8243 mmol) in 1,4-dioxane (26 mL) and water (3.7 mL) was degassed with nitrogen for 10 min. Pd(PPh3)4 (666.76 mg, 0.5770 mmol) was then added, and the reaction mixture was heated at 100 °C for 12 h. The mixture was filtered through a Celite® plug and washed with EtOAc. The solution was concentrated, and purification by silica gel chromatography (20–30% EtOAc in hexanes) afforded C66 (2.5 g, 68%) as a white solid. LCMS m / z 426.0[M+H] +

[0227] Step 3. 4-(4-Fluoro-3-methyl-phenyl)-3-tetrahydropyran-4-yl-quinolin-7-ol (C67) A solution of C66 (1 g, 2.3502 mmol) in EtOH (20 mL) was degassed with nitrogen for 5 minutes, and 10% palladium on carbon (2 g, 50% w / w, 9.396 mmol) was added. The vessel was purged with hydrogen, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered through a Celite® plug, washed with methanol (150 mL), and concentrated to give C67 (600 mg, 72%) as a yellow solid. LCMS m / z 337.9 [M+H] +

[0228] Step 4. 7-Benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-tetrahydropyran-4-yl-quinoline (C68) To a solution of C67 (3.4 g, 10.08 mmol) in DMF (45 mL) was added K2CO3 (3.4818 g, 25.193 mmol). The mixture was then cooled to 0 °C, and benzyl chloride (1.531 g, 1.39 mL, 12.09 mmol) was added dropwise. The reaction was stirred at room temperature for 12 h. An additional 1 equivalent of benzyl chloride and 2.5 equivalents of K2CO3 were added at 0 °C, and the reaction was allowed to warm to room temperature for an additional 12 h. The mixture was diluted with EtOAc (250 mL), washed with ice-cold water (30 mL × 4), dried over Na2SO4, and concentrated. Purification by silica gel chromatography (50% EtOAc in hexanes) afforded C68 (2.5 g, 51%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ8.92(s, 1H), 7.50(dd,J=5.0, 2.3Hz, 3H), 7.40(dd,J= 8.2, 6.5Hz, 2H), 7.33(td,J=9.5, 8.4, 3.9Hz, 2H), 7.23(d,J=9.3, 2.6Hz, 2H), 7 .16(d,J=9.1Hz, 2H), 5.29(s, 2H), 3.88(t,J=5.8Hz, 2H), 3.16(t,J=11.5Hz, 2 H), 2.67~2.61(m, 1H), 2.31(s, 3H), 2.01~1.84(m, 2H), 1.56(d,J=13.0Hz, 2H). LCMS m / z 427.9[M+H] +

[0229] Step 5. 7-Benzyloxy-4-(4-fluoro-3-methyl-phenyl)-1-oxide-3-tetrahydropyran-4-yl-quinolin-1-ium (S29) To a solution of C68 (2.7 g, 6.315 mmol) in dichloromethane (25 mL) was added m-CPBA (1.35 g, 7.831 mmol) at 0 °C. The reaction was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (200 mL), washed with a saturated aqueous solution of NaHCO3 (30 mL), and concentrated. Purification by silica gel chromatography (5% MeOH in dichloromethane) afforded S29 (2.6 g, 84%) as a yellow solid. LCMS m / z 444.1 [M+H] +

[0230] Preparation of S30 7-Benzyloxy-2-chloro-4-(4-fluoro-3-methyl-phenyl)-3-tetrahydropyran-4-yl-quinoline (S30) [ka] To a solution of S29 (2.7 g, 6.089 mmol) in dichloromethane (25 mL) was added POCl (3.7338 g, 2.27 mL, 24.351 mmol) dropwise while in an ice bath, followed by DMF (472.0 mg, 0.5 mL, 6.457 mmol). The reaction was stirred at room temperature for 18 h. The solvent was evaporated, and a saturated aqueous solution of NaCO was added (30 mL). The mixture was extracted with EtOAc (100 mL × 2), and the organic phases were combined, dried over NaSO, and concentrated. Purification by silica gel chromatography (15% EtOAc in hexane) afforded S30 (2.5 g, 89%) as a white solid. 1 H NMR (400MHz, DMSO-d6), 7.50~7.30(m, 8H), 7.25(dd,J=9.2, 2.7Hz, 2H), 7.06(d,J=9.2Hz, 1H), 5.76(s, 1H), 5.29(s, 2H), 4.03(q, J=7.0Hz, 1H), 3.85(d,J=10.9Hz, 2H), 3.07(s, 4H), 2.32(d,J=2.0Hz, 4H), 1.99(s, 1H), 1.44(d,J=12.6Hz, 2H), 1.26~1.13(m, 1H). LCMS m / z 462.1[M+H] +

[0231] Preparation of S31 7-benzyloxy-4-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-1-oxide-quinolin-1-ium (S31) [ka] To a solution of C65 (1 g, 2.8423 mmol) in dichloromethane (15 mL) was added m-CPBA (589 mg, 3.410 mmol), and the mixture was stirred at room temperature for 6 hours. A saturated aqueous solution of Na2CO3 (20 mL) was added. The mixture was extracted with dichloromethane (30 mL x 2), and the organic phases were combined, dried over Na2SO4, and concentrated. The crude compound was washed with 20% EtOAc in hexane to give S31 (810 mg, 72%) as a white solid. LCMS m / z 368.0 [M+H] +

[0232] Preparation of S32 7-benzyloxy-4-(4-fluorophenyl)-3-isopropenyl-1-oxide-quinolin-1-ium (S32) [ka] Step 1. 7-Benzyloxy-4-(4-fluorophenyl)-3-isopropenyl-quinoline (C69) C57 (6.0 g, 19.368 mmol), (4-fluorophenyl)boronic acid (3.252 g, 23.242 mmol), and K2CO3 (5.354 g, 38.736 mmol) were suspended in a mixture of 1,4-dioxane (60 mL) and water (10 mL). The suspension was degassed for 10 min, and Pd(PPh3)4 (1.567 g, 1.3558 mmol) and PCy3 (543 mg, 1.9368 mmol) were added. The reaction was heated at 90 °C for 18 h. The mixture was filtered through a plug of Celite, washed with EtOAc, and concentrated. Purification by silica gel chromatography (10-20% EtOAc in hexanes) afforded C69 as a white solid. LCMS m / z 370.3 [M+H] +

[0233] Step 2. 7-Benzyloxy-4-(4-fluorophenyl)-3-isopropenyl-1-oxide-quinolin-1-ium (S32) To a solution of C69 (6.0 g, 16.241 mmol) in dichloromethane (80 mL) was added m-CPBA (3.3631 g, 19.489 mmol) and the reaction was stirred at room temperature for 6 h. The mixture was concentrated and a saturated aqueous solution of NaHCO was added. The resulting suspension was stirred for 15 min and the solid was filtered and dried to give S32 (5.2 g, 83%). LCMS m / z 386.3 [M+H] +

[0234] Preparation of S33 8-Benzyloxy-1-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S33) [ka] Step 1. Trimethyl(2-tetrahydropyran-4-ylethynyl)silane (C71) To a mixture of ethylmagnesium bromide (120 mL of 3 M, 360.0 mmol) in EtO and THF (200 mL), ethynyltrimethylsilane (50 mL, 353.8 mmol) was added dropwise while in an ice bath. The mixture was heated to reflux for 1 h. The mixture was cooled to room temperature, and NMP (300 mL), 4-iodotetrahydropyran (C70) (50 g of 97% w / w, 228.7 mmol), and FeBr (5 g, 23.19 mmol) were added sequentially. The mixture was placed under nitrogen and stirred at 30 °C for 4 h. MTBE and aqueous saturated ammonium chloride (1:1, 800 mL) were added to the reaction mixture. The mixture was extracted with MTBE (20 mL x 2), and the organic phases were combined, dried over Na2SO4, filtered through a silica gel plug, and washed with MTBE to give C71 (29.5 g, 70%) as an amber oil. 1 H NMR (300 MHz, chloroform-d) δ 3.88 (m, 2H), 3.48 (m, 2H), 2.64 (tt, J = 8.4, 4.1 Hz, 1H), 1.87–1.74 (m, 2H), 1.72–1.57 (m, 2H), 0.15 (s, 9H).

[0235] Step 2. 2-Benzyloxy-6-bromo-benzaldehyde (C73) To a solution of C72 (5.25 g, 26.12 mmol) and bromomethylbenzene (3.2 mL, 26.90 mmol) in DMF (50 mL) was added K2CO3 (4.97 g, 35.96 mmol). The mixture was stirred at room temperature for 3 h. The reaction was diluted with EtOAc, washed successively with water (3x) and brine, dried over Na2SO4, filtered, and concentrated to give C73 (7.35 g, 97%) as an off-white solid. 1 H NMR (300 MHz, chloroform-d) δ 10.50 (s, 1H), 7.54–7.23 (m, 7H), 7.02 (dd, J = 7.5, 2.0 Hz, 1H), 5.21 (s, 2H). LCMS m / z 290.8 [M+H] +

[0236] Step 3. 2-Benzyloxy-6-(2-tetrahydropyran-4-ylethynyl)benzaldehyde (C74) To a mixture of C71 (25 g, 85.87 mmol) and C73 (25 g, 137.1 mmol) in 1,4-dioxane (170 mL), N-isopropylpropan-2-amine (75 mL, 535.1 mmol), CuI (840 mg, 4.411 mmol), Pd(PPh)Cl (2.5 g, 3.562 mmol), and TBAF dihydrate (40 g, 126.8 mmol) were added sequentially. The reaction was heated at 50 °C for 2 h. The mixture was cooled to room temperature and poured into a mixture of water (50 mL), saturated aqueous NHCl (100 mL), and ethyl acetate (500 mL) and stirred for 10 min. The organic phase was washed successively with aqueous HCl 1M (100 mL × 2) and brine (100 mL), dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (0 to 70% EtOAc in heptane) afforded C74 (25 g, 91%) as a yellow viscous oil. 1H NMR (300MHz, chloroform-d) δ10.65(s, 1H), 7.50~7.30(m, 6H), 7.11(dd,J=7.7, 0.9Hz, 1H), 6.96(dd,J=8.5, 0.9Hz, 1H), 5.20(s, 2H), 3.97(ddd,J= 11.6, 5.9, 3.6Hz, 2H), 3.58(ddd,J=11.5, 8.2, 3.1Hz, 2H), 2.94(dt,J=8.3, 4.1Hz, 1H), 2.02~1.87(m, 2H), 1.80(dtd,J=13.5, 8.2, 3.6Hz, 2H). LCMS m / z 321.25[M+H] + .

[0237] Step 4. (1E)-2-Benzyloxy-6-(2-tetrahydropyran-4-ylethynyl)benzaldehyde oxime (C75) A mixture of hydroxylamine chlorohydrate (35 g, 503.7 mmol) in pyridine (130 mL, 1.607 mol) was stirred at room temperature for 30 minutes, and a solution of C74 (50 g, 156.1 mmol) in acetonitrile (500 mL) was added over 20 minutes. The suspension was stirred at room temperature for 2 hours. The reaction was concentrated, and dichloromethane (600 mL) and a cold aqueous solution of HCl 1 M (100 mL) were added to the residue. The mixture was stirred for 20 minutes, and the organic layer was separated and washed successively with an aqueous solution of HCl 1 M (100 mL × 2), water (100 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated. The residue was triturated with MTBE (200 mL) and dried to give C75 (40 g, 76%) as a white solid. 1 H NMR (300MHz, chloroform-d) δ9.21(s, 1H), 8.63(s, 1H), 7.48~7.28(m, 5H), 7.22~7.11(m, 1H), 7.08(dd,J=7.7, 1.2Hz, 1H), 6.88(dd,J=8.2, 1.2Hz, 1H), 5. 22(s, 2H), 3.95(ddd,J=11.6, 6.0, 3.6Hz, 2H), 3.56(ddd,J=11.4, 8.1, 3.1 Hz, 2H), 2.91(dq,J=8.3, 4.1Hz, 1H), 2.00~1.85(m, 2H), 1.85~1.67(m, 2H). LCMS m / z 336.08[M+H]+

[0238] Step 5. 8-Benzyloxy-4-bromo-2-oxido-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C76) To a solution of C75 (6.53 g, 19.470 mmol) in DMA (50 mL) was added CuBr (10.86 g, 48.622 mmol) and the mixture was heated at 60 °C for 1 h. The reaction was cooled to °C and a mixture of NHOH and water in water (2:1, 50 mL) was added slowly over 5 min. The suspension was stirred at room temperature for 30 min, and the solid was filtered and washed with water. The solid was dissolved in dichloromethane, dried over NaSO, filtered, concentrated to dryness. The residue was triturated with MTBE (35 mL), filtered, washed with heptane, and dried to give C76 (5.8 g, 69%) as a tan solid. 1 H NMR (300MHz, DMSO-d6) δ8.84(s, 1H), 7.69~7.62(m, 2H), 7.60~7.50(m, 2H), 7.49~7.33(m, 3H), 7.32~7.22( m, 1H), 5.36(s, 2H), 4.08~3.83(m, 3H), 3.43(t,J=11.2Hz, 2H), 3.07~2.78(m, 2H), 1.43(d,J=12.3Hz, 2H). LCMS m / z 414.1[M+H] +

[0239] Step 6. 8-Benzyloxy-4-(4-fluorophenyl)-2-oxide-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C77) To a solution of C76 (2.0 g, 4.828 mmol) and (4-fluorophenyl)boronic acid (1.008 g, 7.204 mmol) in DMSO (20 mL) was added an aqueous solution of NaCO (7.25 mL of 2 M, 14.50 mmol), and the suspension was degassed with nitrogen for 5 min. Pd(dppf)Cl .Dichloromethane (150 mg, 0.2460 mmol) was added, and the solution was degassed again with nitrogen for 5 minutes. The mixture was heated to 100° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with EtOAc (150 mL×3). The product was precipitated in EtOAc, and the organic phase was filtered and washed with cold EtOAc to give C77 (1.552 g, 64%). 1 H NMR (300MHz, chloroform-d) δ9.30(s, 1H), 7.52~7.37(m, 8H), 7.32(d,J=8.1Hz, 1H), 7.27~7.23(m, 5H), 6.92(d,J=7.6Hz, 1H) , 6.68(d,J=8.6Hz, 1H), 5.27(s, 2H), 3.98(dd,J=11.0, 4.0Hz, 3H), 3.28(t,J=10.8Hz, 1H), 1.43(dd,J=11.4, 2.6Hz, 1H). LCMS m / z 430.56[M+H] +

[0240] Step 7. 8-Benzyloxy-1-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S33) To a solution of C77 (1.2 g, 2.403 mmol) and DIEA (1.45 mL, 8.325 mmol) in dichloromethane (14 mL) was added oxalyl chloride (2.7 mL of 2 M, 5.4 mmol) dropwise while at −78° C. The reaction was stirred for 4 h and allowed to warm to 0° C. MeOH (6 mL) was added and the mixture was stirred for 10 min. The suspension was concentrated, MeOH (5 mL) was added, and the mixture was cooled to 0° C. for 1 h. The solid was filtered and washed with cold MeOH to give S33 (639 mg, 58%) as a white solid. 1H NMR (300MHz, chloroform-d) δ7.60(d,J=7.4Hz, 2H), 7.48~7.32(m, 4H), 7.25~7.19(m, 4H), 7.00(d,J=7.9Hz, 1H), 6.85(dd,J=8.5, 0.9Hz, 1H), 5 .32(s,2H), 4.00(dd,J=11.4, 4.3Hz, 2H), 3.30(t,J=12.1Hz, 2H), 2.80~2.65(m, 1H), 2.25(qd,J=12.5, 4.4Hz, 2H), 1.49(d,J=13.4Hz, 2H). LCMS m / z 448.47[M+H] +

[0241] Preparation of S34 8-benzyloxy-4-(3,4-difluorophenyl)-2-oxide-3-tetrahydropyran-4-yl-isoquinolin-2-ium (S34) [ka] To a suspension of C76 (5.0 g, 11.83 mmol) and (3,4-difluorophenyl)boronic acid (2.47 g, 15.64 mmol) in DMSO (62 mL) was added water (11.0 mL) and Na2CO3 (3.76 g, 35.48 mmol). The mixture was degassed with nitrogen for 5 minutes, and Pd(dppf)Cl2 was added (386.4 mg, 0.473 mmol). The suspension was degassed again with nitrogen for 5 minutes. The reaction was heated at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, poured into ice-cold brine, and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with brine (100 mL), dried, filtered, and concentrated. The solid was triturated with MTBE and filtered to provide S34 (4.62 g, 78%) as a brown solid. 1H NMR (300MHz, chloroform-d) δ9.28(d,J=0.9Hz, 1H), 7.50~7.27(m, 8H), 7.10(ddd, J=10.4, 7.4, 2.1Hz, 1H), 7.00(ddd,J=8.6, 4.3, 1.8Hz, 1H), 6.91(dd,J=7.9, 0. 7Hz, 1H), 6.64(dt,J=8.5, 0.9Hz, 1H), 5.25(s, 2H), 4.06~3.91(m, 2H), 3.29(q ,J=11.4, 10.4Hz, 3H), 2.67(d,J=31.8Hz, 1H), 1.44(s, 2H), 1.31~1.22(m, 1H). LCMS m / z 448.42[M+H] +

[0242] S35 Preparation of 8-benzyloxy-1-chloro-4-(3,4-difluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (S35) [ka] To a solution of S34 (599 mg, 1.34 mmol) and DIPEA (725 μL, 4.162 mmol) in dry dichloromethane (7 mL) was added oxalyl dichloride (1.42 mL of 2 M, 2.84 mmol) while at −78° C. The reaction was allowed to warm to 0° C. for 2 h. MeOH (2 mL) was then added and the mixture was stirred for 10 min. The reaction was concentrated, MeOH was added (5 mL), and the solid was filtered, washed with cold MeOH, and dried to give S35 (335 mg, 54%). 1 H NMR (400MHz, chloroform-d) δ7.60(ddt,J=7.5, 1.3, 0.7Hz, 2H), 7.49~7.41(m, 3H), 7.41~7.31(m, 2H), 7.09(ddd,J=10.5, 7.5, 2.1Hz, 1H), 7.05~6.96(m, 2 H), 6.84(dd,J=8.5, 0.9Hz, 1H), 4.08~3.96(m, 2H), 3.40~3.27(m, 2H), 2.7 2(tt,J=11.7, 3.8Hz, 1H), 2.35~2.19(m, 2H), 1.49(dd,J=12.7, 3.5Hz, 2H). LCMS m / z 466.38[M+H] +

[0243] Preparation of S36 8-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropenyl-1-oxide-quinolin-1-ium (S36) [ka] Step 1. 5-[(2-benzyloxyanilino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (C79) To a solution of C78 (25.0 g, 22.9 mL, 119.2 mmol) in EtOH (150 mL) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (20.616 g, 143.04 mmol) and trimethyl orthoformate (20.492 g, 21.17 mL, 193.10 mmol). The reaction was heated at 100° C. for 2 h. The mixture was stirred at room temperature for 1 h, and the solid was filtered, washed with EtOH, and dried to give C79 (39.0 g, 88%) as an off-white solid. LCMS m / z 354.0 [M+H] +

[0244] Step 2: 8-benzyloxy-1H-quinolin-4-one (C80) Dowtherm A (150 mL) was heated at 220° C. for 10 minutes and C79 (35.0 g, 99.047 mmol) was added portionwise. The reaction mixture was stirred for 30 minutes. The reaction was cooled to room temperature and stirred for 20 minutes. Hexane was then added and the solid was filtered, washed with hexane, and dried to give C80 (22 g, 78%) as a brown solid. LCMS m / z 252.0 [M+H] +

[0245] Step 3. 8-Benzyloxy-3-bromo-1H-quinolin-4-one (C81) To a solution of C80 (18.8 g, 65.839 mmol) in DMF (150.40 mL) was added NBS (12.890 g, 72.423 mmol) while in an ice bath. The reaction was stirred at room temperature for 3 hours. Cold water was added to the mixture, and the solid was filtered, washed with water, and dried to give C81 (20 g, 88%) as a brown solid. LCMS m / z 331.0 [M+H] + .

[0246] Step 4. 8-Benzyloxy-3-bromo-4-chloro-quinoline (C82) To a solution of C81 (20 g, 60.574 mmol) in toluene (150 mL) was added thionyl chloride (72.065 g, 44.212 mL, 605.74 mmol) and the reaction was refluxed for 2 h. The mixture was concentrated, and dichloromethane and an aqueous solution of NaHCO were added. The mixture was extracted with dichloromethane, and the organic phases were combined, washed with brine, dried over NaSO, and concentrated. Purification by silica gel chromatography (10-50% EtOAc in hexanes) afforded C82 (19 g, 85%). LCMS m / z 349.0 [M+H] +

[0247] Step 5. 8-Benzyloxy-4-chloro-3-isopropenyl-quinoline (C83) To a solution of C82 (14 g, 40.158 mmol) in 1,4-dioxane (120 mL) and water (30 mL) was added potassium isopropenyltrifluoroborate (5.9424 g, 40.158 mmol) and K2CO3 (16.650 g, 120.47 mmol). The mixture was degassed under nitrogen and Pd(dppf)Cl2 . Dichloromethane (3.3199 g, 4.0158 mmol) was added. The reaction was heated at 90° C. for 16 h. The reaction mixture was diluted with EtOAc, and water was added. The mixture was extracted with dichloromethane, and the organic phases were combined, washed with brine, dried over Na2SO4, and concentrated. Purification by silica gel chromatography (0-50% EtOAc in hexanes) afforded C83 (8.5 g, 65%) as a brown solid. LCMS m / z 310.0 [M+H]+

[0248] Step 6. 8-Benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropenyl-quinoline (C84) To a solution of C83 (4.35 g, 10.856 mmol) in 1,4-dioxane (40 mL) and water (8.70 mL) was added (4-fluoro-3-methyl-phenyl)boronic acid (2.5069 g, 16.284 mmol) and K2CO3 (4.5011 g, 32.568 mmol). The mixture was then degassed under N2, and Pd(PPh3)4 (1.25 g, 1.08 mmol) and PCy3 (304.43 mg, 1.0856 mmol) were added. The reaction was heated at 90 °C for 16 h. The reaction mixture was diluted with EtOAc, and water was added. The mixture was extracted with dichloromethane, and the organic phases were combined, washed with brine, dried over Na2SO4, and concentrated. Purification by silica gel chromatography (10–50% EtOAc in hexanes) afforded C84 (4.1 g, 90%). LCMS m / z 384.0[M+H] +

[0249] Step 7. 8-Benzyloxy-4-(4-fluoro-3-methyl-phenyl)-3-isopropenyl-1-oxide-quinolin-1-ium (S36) To a solution of C84 (2.5 g, 6.52 mmol) in dichloromethane (25 mL) was added m-CPBA (1.91 g, 11.08 mmol). The mixture was stirred at room temperature for 7 hours. A saturated aqueous solution of Na2CO3 (10 mL) was added. The mixture was extracted with dichloromethane (10 mL x 3), and the organic phases were combined and concentrated. Purification by trituration with hexanes gave S36 (1.5 g, 51%) as a pale yellow solid. LCMS m / z 400.0 [M+H] +

[0250] compound 1 (2S)-2-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]propanoic acid (1) [ka] Step 1. Synthesis of benzyl (2S)-2-[[7-benzyloxy-4-(4-fluorophenyl)-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]propanoate (C85) To a solution of S1 (120 mg, 0.2746 mmol) and benzyl (2R)-2-(p-tolylsulfonyloxy)propanoate (140 mg, 0.4187 mmol) in DMF (2 mL) was added CsF (200 mg, 1.317 mmol), and the resulting solution was stirred at 50 °C for 15 h. The mixture was extracted with EtOAc, and the organic layer was washed with NaHCO solution and dried. After evaporation, purification by silica gel chromatography (gradient: 0 to 50% EtOAc in heptane) gave the product as a colorless oil. (2S)-benzyl (2S)-2-[[7-benzyloxy-4-(4-fluorophenyl)-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]propanoate (50.2 mg, 31%). 1 H NMR (400 MHz, chloroform-d) δ 7.60 (d, J = 2.7 Hz, 1H), 7.46-7.36 (m, 2H), 7.36-7.30 (m, 2H), 7.30-7.26 (m, 1H), 7.26-7.18 (m, 6H), 7.18-7.12 (m, 2H), 7.12-6.99 (m, 3H) ), 6.84(d,J=9.3Hz, 1H), 5.47(q,J=7.0Hz, 1H), 5.24~5.03(m, 5H), 3.35(d,J=8. 7Hz, 1H), 3.08(d,J=2.1Hz, 4H), 1.70(d,J=7.0Hz, 3H), 1.03(s, 3H), 0.97(s, 3H). LCMS m / z 594.4[M+H] +

[0251] Step 2. Synthesis of (2S)-2-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]propanoic acid (1) To a solution of C85 (50 mg, 0.084 mmol) in MeOH (2 mL) and EtOAc (1 mL) was added Pd / C (8.9 mg, 0.08363 mmol) and a 1 atm balloon of H. The reaction mixture was stirred for 1 h, filtered through a pad of Celite®, and the clear solution was concentrated to give 1 as a white solid (33.2 mg, 95%). 1 H NMR (400 MHz, chloroform-d): δ 7.37–6.90 (m, 6H), 6.82–6.69 (m, 1H), 6.63 (d, J = 9.5 Hz, 1H), 5.28 (q, J = 6.8 Hz, 1H), 3.48–3.29 (m, 2H), 3.22 (s, 3H), 1.58 (d, J = 6.4 Hz, 3H), 1.00 (d, J = 8.8 Hz, 6H). ESI-MS m / z calculated: 413.16385, found: 414.27 (M+1). + , retention time: 0.49 minutes

[0252] Compounds 2 and 3 (2S)-2-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-hydroxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]propanoic acid (2) and 4-(4-fluorophenyl)-7-hydroxy-3-(1-hydroxy-2-methylpropan-2-yl)isoquinolin-1(2H)-one (3). [ka] To a solution of 1 (16 mg, 0.03870 mmol) in dichloromethane (0.5 mL) at 0 °C was added BBr3 (80 μL of 1 M, 0.08000 mmol) in dichloromethane, and the resulting solution was allowed to warm to room temperature. After stirring for 2 h, additional BBr3 (80 μL of 1 M, 0.08000 mmol) was added, and the reaction was stirred for 12 h, quenched with ice, and extracted with dichloromethane (3 × 2 mL). The combined organic phases were concentrated and purified by HPLC: 0–70% ACN in water (FA modifier) ​​to give 2 (8 mg, 52%). 1H NMR (400MHz, methanol-d4) δ8.97(d,J=2.8Hz, 1H), 8.69~8.52(m, 5H), 8.42(dd,J=8.9, 2.8H z, 1H), 8.08(d,J=8.9Hz, 1H), 4.64(p,J=1.6Hz, 2H), 3.34(p,J=2.5Hz, 1H), 2.36(s, 6H). LCMS m / z 400.36[M+H] + and 3 (4.7 mg, 34%) 1 H NMR (400 MHz, methanol-d4 / acetonitrile-d3) δ 8.97 (d, J = 2.8 Hz, 1H), 8.69–8.52 (m, 5H), 8.42 (dd, J = 8.9, 2.8 Hz, 1H), 8.08 (d, J = 8.9 Hz, 1H), 4.64 (p, J = 1.6 Hz, 2H), 3.34 (p, J = 2.5 Hz, 1H), 2.36 (s, 6H). LCMS m / z 328.1 [M+H] +

[0253] Compounds 4 and 5 3-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (4) and 3-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (5) [ka] Step 1. Synthesis of benzyl 3-[[7-benzyloxy-4-(4-fluorophenyl)-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylate (C86) To a solution of S1 (120 mg, 0.2746 mmol) and benzyl 3-(p-tolylsulfonyloxy)cyclobutanecarboxylate (150 mg, 0.4129 mmol) in DMF (2 mL), CsF (200 mg, 1.317 mmol) was added, and the reaction mixture was stirred at 50 °C for 15 h. The mixture was extracted with EtOAc, and the organic layer was washed with NaHCO solution and dried. After evaporation, purification by silica gel chromatography (gradient: 0 to 50% EtOAc in heptane) afforded C86 as a colorless oil (56 mg, 33%). 1 H NMR (400MHz, chloroform-d) δ7.50(d,J=2.6Hz, 1H), 7.40(ddd,J=8.1, 4.1, 1.4Hz, 2H), 7.36~7.20(m, 9H) ), 7.21~7.13(m, 2H), 7.10~7.00(m, 3H), 6.82(dd,J=9.2, 4.0Hz, 1H), 5.57(ttd,J=7.4, 6.4, 1.1Hz, 1H), 5.31(tt,J=8.2, 7.0Hz, 0H), 5.14(s, 2H), 5.09(d,J=1.5Hz, 2H), 3.28(s, 2H), 3.27~3.16(m, 1H) ), 3.10(d,J=4.7Hz, 3H), 2.85(dddd,J=11.5, 7.3, 4.4, 2.3Hz, 2H), 2.62~2.47(m, 2H), 1.04(s, 5H). LCMS m / z 642.38[M+H] +

[0254] Step 2. Synthesis of 3-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (4) and 3-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-methoxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (5) To a solution of C86 (55 mg, 0.08834 mmol) in MeOH (1 μL) and EtOAc (3 mL) was added Pd / C (10 mg of 10% w / w, 0.009397 mmol) and a 1 atm H2 balloon (50 mg, 24.80 mmol) for 1 h. The reaction mixture was stirred for 1 h, filtered through a pad of Celite®, and the clear solution was concentrated to give a white solid, which was purified by reverse-phase chromatography on C18 40-85% acetonitrile (0.1% TFA) to give 4 (36 mg, 91%). 1 H NMR (400MHz, chloroform-d) δ7.52(s,1H), 7.26(dd,J=5.8, 2.6Hz, 2H), 7.18(t,J=8.6Hz, 2H), 7.11(dd,J=9.2, 2.6Hz, 1H), 6.88(d,J=9.1Hz, 1H) , 5.61(q,J=6.7Hz, 1H), 3.56(s, 2H), 3.46(s, 3H), 3.34(t,J=10.0Hz, 1H), 2.97(t,J=5.5Hz, 2H), 2.72(q,J=12.2, 10.4Hz, 2H), 1.13(s, 6H). LCMS m / z 440.19[M+H] + and 5 (3.3 mg, 8%) 1 H NMR (400MHz, chloroform-d) δ7.48(d,J=2.6Hz, 1H), 7.28~7.21(m, 2H), 7.17(t,J=8.6Hz, 2H), 7.07(dd,J=9.1, 2.6Hz, 1H), 6.84(d,J =9.2Hz, 1H), 5.39(q,J=6.9Hz, 1H), 3.53(s, 2H), 3.43(s, 3H), 2.99(dt,J=22.8, 8.4Hz, 3H), 2.61(t,J=9.7Hz, 2H), 1.14(s, 6H). LCMS m / z 440.24[M+H] +

[0255] compound 6 3-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-hydroxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (6) [ka] Step 1. Synthesis of 3-[[4-(4-fluorophenyl)-7-hydroxy-3-(2-hydroxy-1,1-dimethyl-ethyl)-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (6) To a solution of 4 (11 mg, 0.02444 mmol) in dichloromethane (0.5 mL) was added BBr3 (50 μL of 1 M, 0.05 mmol) dropwise at 0 °C. The reaction was warmed to room temperature, and additional BBr3 (50 μL of 1 M, 0.05 mmol) was added at room temperature and stirred for an additional 2 h. The reaction was quenched with ice, and the mixture was evaporated to dryness. The residue was purified by reverse-phase MPLC 0–70% ACN in water (0.2% formic acid modifier) ​​to give 6 (6.5 mg, 63%). 1 H NMR (400MHz, methanol-d4) δ7.53~7.44(m, 1H), 7.27(t,J=6.8Hz, 2H), 7.19(t,J=8.5Hz, 2H), 7.07(dt,J=9.2, 1.9Hz, 1H), 6.85(d,J=9.1Hz, 1H) ), 5.57(p,J=6.8Hz, 1H), 3.71(s, 2H), 3.23(dq,J=9.7, 4.8, 4.3Hz, 1H), 2.96~2.81(m, 2H), 2.62(td,J=12.8, 11.6, 7.7Hz, 2H), 1.07(s, 6H). LCMS m / z 426.19[M+H] +

[0256] compound 7 Synthesis of (2S)-2-[[8-fluoro-4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-1-isoquinolyl]oxy]propanoic acid (7) [ka] Step 1: Synthesis of (2S)-2-[[8-fluoro-4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-1-isoquinolyl]oxy]propanoic acid (7) To a solution of S2 (45 mg, 0.06 mmol) in DMF (2 mL) was added NaH (30 mg, 0.75 mmol) at room temperature. The reaction was stirred at room temperature for 15 h and quenched by the addition of MeOH (4 mL). At this point, Pd / C (10 mg, 0.0094 mmol) was added and a balloon of H2 (1 atm) was attached to the reaction mixture. The reaction was stirred for 2 h, filtered through a pad of Celite®, and the residue was purified by reverse MPLC: 40 g C18 column eluting with 10-100% ACN in water with 0.1% FA to provide 7 (11.6 mg, 44%). 1 H NMR (400MHz, methanol-d4) δ7.22(d,J=7.2Hz, 4H), 6.83(dd,J=9.1, 1.5Hz, 1H), 5.35(q,J= 7.0Hz, 1H), 2.76(p,J=6.7Hz, 1H), 1.71(d,J=7.0Hz, 3H), 1.14(dd,J=20.3, 6.7Hz, 6H). LCMS m / z 388.2[M+H] +

[0257] Compounds 8~18 Compounds 8-18 (Table 1) were prepared from intermediate S2 according to the method described in 7. Any modifications to the method are described in Table 1 and the accompanying footnotes. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0258] compound 19 2-[2-[[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-1-isoquinolyl]oxy]-6-azaspiro[3.4]octan-6-yl]acetic acid (19) [ka] Step 1: Synthesis of tert-butyl 2-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-1-isoquinolyl]oxy]-6-azaspiro[3.4]octane-6-carboxylate (C87) To a mixture of S7 isoquinoline (200 mg, 0.4927 mmol) and tert-butyl 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (672 mg, 2.956 mmol) in dry DMF (12.00 mL) was slowly added NaH (130 mg of 60% w / w, 3.250 mmol) at room temperature. The reaction mixture was heated in a microwave oven at 85 °C under N for 2 hours. The reaction mixture was quenched with water (1 mL) and HCl (1 M, ca. 3 mL / pH = 6). The desired product was extracted with EtOAc, washed with water, saturated NaCl, and dried over sodium sulfate. Purification by silica gel chromatography afforded C87 (116 mg, 39%). LCMS m / z 597.37 [M+H] +

[0259] Step 2. Synthesis of 1-(6-azaspiro[3.4]octan-2-yloxy)-7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-isoquinoline (C88) To a solution of C87 (116 mg, 0.1944 mmol) in dichloromethane (2 mL) was added TFA (1 mL, 12.98 mmol). The reaction mixture was stirred at room temperature for 18 hours and excess solvent was removed to give C88 (trifluoroacetate salt) (110 mg, 93%), which was used without further purification. LCMS m / z 497.12 [M+H] +

[0260] Step 3. Synthesis of ethyl 2-[2-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-1-isoquinolyl]oxy]-6-azaspiro[3.4]octan-6-yl]acetate (C89) To a solution of C88 (110 mg, 0.1801 mmol), ethyl 2-oxoacetate (220.7 mg of 50% w / w, 1.081 mmol), and acetic acid (10.25 μL, 0.1802 mmol) in dichloromethane (4 mL) was added triacetoxy-hydrido-boron (sodium salt) (305.4 mg, 1.441 mmol). The resulting mixture was stirred for 6 h. The reaction was diluted with dichloromethane and slowly quenched with MeOH and saturated NaHCO3 (50 mL). After separation, the organic layer was washed with water, saturated NaCl, and dried over sodium sulfate. Evaporation afforded C89 (100 mg, 95%), which was used without further purification. LCMS m / z 583.47 [M+H] +

[0261] Step 4. Synthesis of ethyl 2-[2-[[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-1-isoquinolyl]oxy]-6-azaspiro[3.4]octan-6-yl]acetate (C90) A solution of palladium (30 mg of 10% w / w, 0.02819 mmol) and C89 (100 mg, 0.1716 mmol) in MeOH (20 mL) and EtOAc (40 mL) was stirred under H2 (1 atm) at room temperature for 18 h. The mixture was filtered through a pad of Celite® and concentrated to dryness. The residue was purified by silica gel chromatography (0-10% MeOH in dichloromethane) to give C90 (84 mg, 99%). LCMS m / z 493.52 [M+H] + .

[0262] Step 5. Synthesis of 2-[2-[[4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-1-isoquinolyl]oxy]-6-azaspiro[3.4]octan-6-yl]acetic acid (19) C90 (84 mg, 0.1705 mmol) and LiOH in water (1.5 mL) and THF (1.5 mL) .A solution of HO (63 mg, 1.501 mmol) was stirred at room temperature for 3 h, after which the reaction mixture was treated with HCl (1 N) until pH = 7. Excess solvent was removed and HPLC purification gave 19 (43 mg, 52%). 1 H NMR (300MHz, methanol-d4) δ7.53(dd,J=2.5, 0.6Hz, 1H), 7.35~6.93(m, 6H), 5.54(p,J=6.8Hz, 1H), 4.24~4.02(m , 2H), 4.02~3.77(m, 2H), 3.30(d,J=12.2Hz, 2H), 3.00~2.70(m, 3H), 2.65~2.20(m, 4H), 1.18(d,J=6.7Hz, 6H). LCMS m / z 465.19[M+H] +

[0263] Compound 20~30 Compounds 20-30 (Table 2) were prepared from intermediates C91 and C92 according to the method described in Table 2. Any modifications to the method are described in Table 2 and the accompanying footnotes. [ka]

[0264] Step 1. Synthesis of ethyl 2-[2-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-1-isoquinolyl]oxy]-5-oxo-6-azaspiro[3.4]octan-6-yl]acetate (C91) and ethyl 2-[2-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-1-isoquinolyl]oxy]-7-oxo-6-azaspiro[3.4]octan-6-yl]acetate (C92) To a solution of C89 (200 mg, 0.3432 mmol) and NaHCO3 (3.75 mL of 1 M, 3.750 mmol) in THF (13 mL) was added I2 (140 μL, 2.719 mmol). The reaction mixture was stirred for 6 h and quenched by the addition of saturated NaHCO3 and saturated sodium thiosulfate (10 mL). After extraction of the aqueous phase with EtOAc, the organic phase was dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel chromatography (0-25-50% EtOAc in heptane) to give C91 (135 mg, 66%) LCMS m / z 597.57 [M+H]. + and C92 (45 mg, 22%) LCMS m / z 597.57 [M+H] + This resulted in [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0265] Compounds 31~33 [ka] Step 1: Synthesis of ethyl 2-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-1-isoquinolyl]oxy]acetate (C93) To a solution of S5 (744 mg, 1.920 mmol) in DMF (8 mL) was added Cs2CO3 (1.30 g, 3.990 mmol), followed by ethyl 2-bromoacetate (385 μL, 3.472 mmol). The reaction was held at 90 °C for 90 min. The solvent was removed by rotary evaporation. The resulting crude material was purified by silica gel chromatography (0-60% EtOAc in heptane) to give C93 (644 mg, 69%), LCMS m / z 473.17 [M+H].+ was obtained and used directly in the next step.

[0266] Step 2: To a solution of 4-(4-fluorophenyl)-3-isopropyl-7-methoxy-1-[(3S)-pyrrolidin-3-yl]oxy-isoquinoline (trifluoroacetate) (50 mg, 0.1011 mmol) and 2-cyanoacetic acid (12 mg, 0.1411 mmol) in DMF (1 mL) was added TEA (50 μL, 0.3587 mmol), followed by HATU (58 mg, 0.1525 mmol). The reaction was stirred at room temperature for 3 h and quenched by the addition of water. The aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel chromatography eluting with 0–10% MeOH in dichloromethane to provide the desired product as a white solid C94 (34 mg, 75%). 1 H NMR (400MHz, chloroform-d) δ7.42(d,J=2.3Hz, 1H), 7.24~7.10(m, 6H), 5.94(dtt,J=11.3, 4.6, 2.1Hz, 1H), 4.09~3.99(m, 1H), 3.9 3(s, 3H), 3.91~3.70(m, 3H), 3.53(s, 1H), 3.46(s, 1H), 2.87(h,J=6.7Hz, 1H), 2.67~2.27(m, 2H), 1.17(dt,J=6.7, 1.8Hz, 6H). LCMS m / z 448.25[M+H] +

[0267] 44 1 H NMR (400MHz, chloroform-d) δ7.44 (dt, J=4.6, 1.6Hz, 1H), 7.18~7.08 (m, 4H), 7.06 (dd, J=4.8, 1.5Hz, 2H), 5.87 (dd, J= 28.9, 24.0Hz, 2H), 4.15~3.89(m, 2H), 3.87~3.70(m, 2H), 2.86~2.72(m, 1H), 2.55~2.16(m, 2H), 1.12~1.05(m, 6H). LCMS m / z 434.3[M+H] +

[0268] Compounds 31~42 Compounds 31-42 (Table 3) were prepared from the intermediates shown in Table 3. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5]

[0269] Compounds 43 and 44 [ka] Two-step procedure: Synthesis of ethyl 2-[[7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-1-isoquinolyl]oxy]acetate (C94) Step 1: To a solution of tert-butyl (3S)-3-[[4-(4-fluorophenyl)-3-isopropyl-7-methoxy-1-isoquinolyl]oxy]pyrrolidine-1-carboxylate (146 mg, 0.3034 mmol) in DCM (1 mL), TFA (250 μL, 3.245 mmol) was added at room temperature and the solution was stirred for 1 h. Evaporation of the crude reaction mixture resulted in the isolation of a white solid, ESI-MS m / z calculated 380.19, found 381.22 (M+1). + , yielding a retention time of 0.45 min, which was used directly in the next step.

[0270] Step 2: To a solution of 4-(4-fluorophenyl)-3-isopropyl-7-methoxy-1-[(3S)-pyrrolidin-3-yl]oxy-isoquinoline (trifluoroacetate) (50 mg, 0.1011 mmol) and 2-cyanoacetic acid (12 mg, 0.1411 mmol) in DMF (1 mL) was added TEA (50 μL, 0.3587 mmol), followed by HATU (58 mg, 0.1525 mmol). The reaction was stirred at room temperature for 3 h and quenched by the addition of water. The aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel chromatography eluting with 0–10% MeOH in dichloromethane to provide the desired product as a white solid C94 (34 mg, 75%). 1 H NMR (400MHz, chloroform-d) δ7.42(d,J=2.3Hz, 1H), 7.24~7.10(m, 6H), 5.94(dtt,J=11.3, 4.6, 2.1Hz, 1H), 4.09~3.99(m, 1H), 3.9 3(s, 3H), 3.91~3.70(m, 3H), 3.53(s, 1H), 3.46(s, 1H), 2.87(h,J=6.7Hz, 1H), 2.67~2.27(m, 2H), 1.17(dt,J=6.7, 1.8Hz, 6H). LCMS m / z 448.25[M+H] + 1) +

[0271] Compounds 43 and 44 were isolated following general procedure 2 (GP2) using BBr3 as the Lewis acid.

[0272] 43: 1H NMR (400MHz, chloroform-d) δ7.45(d,J=3.1Hz, 1H), 7.26~7.01(m, 6H), 5.93(d,J=10.1Hz, 1H), 4.21~3.65(m, 4H), 3.44 ~3.22(m, 2H), 2.92~2.75(m, 1H), 2.48(d,J=14.5Hz, 1H), 2.34(ddt,J=35.9, 9.4, 4.7Hz, 1H), 1.17(d,J=6.7Hz, 6H). ESI-MS m / z calculated value 451.19073, measured value 452.26(M+1) + , retention time: 0.44 minutes

[0273] 44: 1 H NMR (400MHz, chloroform-d) δ7.44(dt,J=4.6, 1.6Hz, 1H), 7.18~7.08(m, 4H), 7.06(dd,J=4.8, 1.5Hz, 2H), 5.87(dd,J= 28.9, 24.0Hz, 2H), 4.15~3.89(m, 2H), 3.87~3.70(m, 2H), 2.86~2.72(m, 1H), 2.55~2.16(m, 2H), 1.12~1.05(m, 6H). LCMS m / z 434.3[M+H] +

[0274] compound 45 3-((4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)oxy)-1-methylcyclobutane-1-carboxylic acid (45) [ka] Step 1: To a solution of S10 (trifluoroacetate) (60 mg, 0.098 mmol) and methyl 3-hydroxy-1-methyl-cyclobutanecarboxylate (35.4 mg, 0.245 mmol) in DMF (1 mL) was added NaH (7.8 mg, 0.196 mmol) at 0 °C, and the solution was stirred at this temperature for 1 h and then at room temperature for 4 h. After this time, LCMS showed complete consumption of the starting material. The reaction mixture was carried forward directly to the next step.

[0275] Step 2: To the previous reaction mixture, MeOH (1 mL) was added, and the reaction mixture was filtered through a Celite® plug to remove precipitate. To this solution, dihydroxypalladium (6.9 mg, 0.01 mmol) was added, and the solution was placed in a Parr vessel. The vessel was placed under a hydrogen atmosphere at 25 psi and stirred for 4 hours, at which point the reaction mixture was filtered through a 0.2 micron filter and then concentrated in vacuo to remove MeOH. The crude mixture in DMF was carried directly to the next step.

[0276] Step 3: To the previous DMF mixture was added KOH (98 μL of a 10 M solution) at room temperature, and the reaction mixture was stirred for 6 h, then diluted with HO (3 mL) and flash-frozen in a dry ice / acetone bath. The frozen solution was concentrated via lyophilization, and the crude residue was filtered through a Celite® pad, and DMF was added to a final volume of 2 mL. The sample was purified by automated reverse-phase HPLC purification (CAPER, formic acid modifier) ​​to provide 45. 1 H NMR (400MHz, DMSO-d6) δ7.44(d,J=2.6Hz, 1H), 7.33~7.04(m, 4H), 7.01(d,J=9.0Hz, 1H), 5.38(p,J=7.0Hz, 1H), 3.05~2 .98(m, 2H), 2.75(td,J=12.7, 12.1, 6.1Hz, 1H), 2.37~2.25(m, 3H), 2.20~2.03(m, 2H), 1.43(s, 3H), 1.20~0.89(m, 6H). LCMS m / z 424.24[M+H] + .

[0277] Compounds 46~59 Compounds 46-59 (Table 4) were prepared from the intermediates shown in Table 4. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0278] Compounds 60 and 61 2-((4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)oxy)-N-(methylsulfonyl)acetamide (60) and 2-((4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)oxy)acetic acid (61) [ka]

[0279] compound 60 Step 1: To a solution of S8 (1.03 g, 2.477 mmol) and 2-hydroxybenzyl acetate (510 μL, 3.594 mmol) in THF (15.45 mL) was added KOtBu in THF (3.6 mL of 1 M, 3.600 mmol). The solution was stirred for 30 min, and additional 2-hydroxybenzyl acetate (510 μL, 3.594 mmol) was added, followed by KOtBu in THF (3.6 mL of 1 M, 3.60 mmol). The solution was stirred for an additional 30 min, diluted with aqueous NH4Cl, and the aqueous phase was extracted with EtOAc. The combined organic phases were 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 C95 (1.03 g, 76%). LCMS m / z 542.32[M+H] + Step 2: A solution of C95 (200 mg, 0.3638 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (127 mg, 0.7558 mmol), and Na2CO3 (570 μL of 2 M, 1.140 mmol) in 1,4-dioxane (3 mL) and water (600 μL) was bubbled with N2 for 5 min. Then, Pd(OAc)2 (5 mg, 0.02227 mmol) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (23 mg, 0.04825 mmol) were added, and the solution was microwaved at 130 °C for 30 min. HCl (600 μL of 2 M) was added to acidify the solution, and EtOAc (10 mL) was added. After extraction of the aqueous phase with additional EtOAc (2×3 mL), the combined organic layers were washed with brine (2×2 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by MPLC: 0-20% MeOH in dichloromethane to give C97 (96 mg, 48%). 1 H NMR (400MHz, chloroform-d) δ7.66(d,J=2.6Hz, 1H), 7.45~7.37(m, 2H), 7.33(ddt,J =8.7, 6.4, 1.1Hz, 2H), 7.30~7.25(m, 2H), 7.19(dd,J=9.2, 2.6Hz, 2H), 7.03~6. 89(m, 3H), 5.16(s, 2H), 5.11(s, 2H), 5.06(s, 2H), 4.94(p, J=1.6Hz, 1H), 4.66( dt,J=1.9, 0.9Hz, 1H), 2.23(d,J=2.0Hz, 3H), 1.81(dd,J=1.5, 0.9Hz, 3H), LCMS m / z 548.36[M+H] + , and C96 (94 mg, 53%) LCMS m / z 458.29 [M+H] + This resulted in

[0280] Step 3: To a solution of C96 (95 mg, 0.1956 mmol), methanesulfonamide (22 mg, 0.2313 mmol), DMAP (30 mg, 0.2456 mmol), and TEA (55 μL, 0.3946 mmol) in dry dichloromethane (2 mL) cooled to 0 °C, EDCI (52 mg, 0.2713 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 15 h. The reaction mixture was then diluted with water, extracted with EtOAc, dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by MPLC:12 g column eluting with 0-50% EtOAc in dichloromethane to give C98 (60 mg, 56%). 1 H NMR (400MHz, chloroform-dδ7.54(d,J=2.6Hz, 1H), 7.41(d,J=7.5Hz, 2H), 7.28(ddt,J=33.7, 10.5, 7.7Hz, 6H), 7.06~6.91(m, 3H), 6.51( LCMS. m / z 535.3[M+H] +

[0281] Step 4: To a solution of C98 (60 mg, 0.1098 mmol) in MeOH (2 mL) was added Pd / C (10 mg of 10% w / w, 0.00939 mmol), a hydrogen balloon (1 atm) was attached to the reaction vial, and the reaction mixture was stirred for 24 h, after which the solution was filtered through a Celite® pad and concentrated to dryness. The residue was purified by silica gel chromatography (12 g ISCO column) using a 0-50% MeOH / dichloromethane gradient to give 60 (14.2 mg, 28%). 1H NMR (400 MHz, chloroform-d) δ 7.53 (d, J = 2.1 Hz, 1H), 7.19 (s, 1H), 7.14-7.00 (m, 3H), 7.01-6.88 (m, 3H), 5.03 (s, 2H), 3.26 (s, 3H), 2.81 (p, J = 6.7 Hz, 1H), 2.26 (s, 4H), 1.20 (q, J = 6.4, 5.2 Hz, 6H). LCMS m / z 447.26 [M+H] +

[0282] compound 61 To a solution of C97 (95 mg, 0.1710 mmol) in MeOH (2 mL) and EtOAc (2 mL) was added wet Pd / C (20 mg of 10% w / w, 0.01879 mmol), a hydrogen balloon (1 atm) was attached to the reaction vial, and the reaction mixture was stirred for 48 h, by which time the reaction was incomplete. The solution was transferred to a Parr shaker, the hydrogen pressure was adjusted to 50 psi, and stirring was continued for 15 h. The solution was then filtered and washed with MeOH (5 mL), and then NaOH (500 μL of 1 M, 0.5000 mmol) was added, and the solution was stirred at room temperature for 1 h and at 50 °C for 30 min. The solution was then neutralized to pH 4 and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over MgSO4, and then concentrated to give 61 (60.2 mg, 95%). 1 H NMR (400 MHz, chloroform-d): δ 7.51 (s, 1H), 7.11–6.69 (m, 6H), 5.01 (s, 2H), 2.78 (hept, J = 6.7 Hz, 1H), 2.24 (d, J = 1.9 Hz, 3H), 1.30–1.10 (m, 3H), 0.88–0.74 (m, 3H). LCMS m / z 371.68 [M+H] +

[0283] Compounds 62 and 63 4-(4-Fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinoline-1-carboxylic acid (62) and 4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinoline-1-carboxamide (63) [ka] To a solution of TMSCN (1.25 g, 12.60 mmol) and S9 (3000 mg, 7.345 mmol) in THF (60 mL) was added DBU (3.3 mL, 22.07 mmol), and the resulting solution was stirred at 50 °C for 15 h. The solution was cooled to room temperature and then diluted with EtOAc and aqueous bicarbonate. The two phases were separated, and the organic phase was concentrated to dryness and triturated with MeOH. The solid was taken up in acetonitrile and filtered. The solid was added to KOH / EtOAc (30 mL), and the solution was stirred at 70 °C for 1 h, cooled to room temperature, acidified to pH 2, and extracted with dichloromethane (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was taken up in a solution of dichloromethane / MeOH / EtOAc (1:1:4, 30 mL), and Pd(OH) (1 g, 1.424 mmol) was added. The solution was stirred for 15 h and then filtered over a Celite® pad. After evaporation, the residue was purified by reverse-phase flash chromatography (ISCO, C18 column, 30 g) eluting with CHCN / water (0-100%, 0.1% TFA) to give 62 (684 mg, 27%). 1 H NMR (400MHz, DMSO-d6) δ7.61(s, 1H), 7.27(m, 1H), 7.17(m, 1H), 7.07(m, 2H), 6.97(m, 1H), 2.92~2.73(m, 1H), 2.32(s, 3H), 1.12(m, 6H), and 63(2mg, by-product) 1 H NMR (400 MHz, DMSO-d) δ 10.16 (s, 1H), 8.47 (d, J = 2.5 Hz, 1H), 8.12 (s, 1H), 7.70 (s, 1H), 7.33–7.03 (m, 4H), 2.88 (m, 1H), 2.32 (m, 3H), 1.19 (m, 6H).

[0284] compound 64 (4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinoline-1-carbonyl)alanine (64) [ka] To a solution of 62 (50 mg, 0.1473 mmol), ethyl 2-aminopropanoate (HCl salt) (35 mg, 0.2279 mmol) in DMF (2 mL) was added T3P (95 mg, 0.2986 mmol) and DIPEA (80 μL, 0.4593 mmol) at room temperature. The resulting solution was stirred for 15 h, and KOH (150 μL of 10 M, 1.500 mmol) was added, and the solution was further stirred for 15 h. The solution was then syringed. Filtration and submission for preparative LCMS purification (water with C18 ACN / HCl modifier) ​​gave 64 (16.1 mg, 25%). LCMS m / z 411.39 [M+H] + .

[0285] Compounds 65~78 Compounds 65-78 (Table 5) were prepared from the intermediates shown in Table 5. Any modifications to the methods are described in Table 5 and the accompanying footnotes. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] a HATU was used in place of 3TP for the preparation of this compound.

[0286] compound 79 3-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)propanoic acid (79) [ka] Four-step procedure: synthesis of 3-[4-(4-fluoro-3-methyl-phenyl)-7-hydroxy-3-isopropyl-1-isoquinolyl]propanoic acid (79) Step 1: (COCl)2 (2 mL of 2 M in dichloromethane, 4.000 mmol) was added to a solution of S9 (800 mg, 1.993 mmol) and DIEA (800 μL, 4.593 mmol) in dichloromethane (9 mL) at -78 °C. The reaction was slowly warmed to 0 °C over 2 h and quenched by the addition of MeOH (2 mL). After stirring for 10 min, the mixture was concentrated to dryness. MeOH (3 mL) was added and the resulting solid was filtered, washed with cold MeOH, and dried under high vacuum to give C99 (620 mg, 74%). 1 H NMR (300MHz, chloroform-d) δ7.71~7.65(m, 1H), 7.57~7.49(m, 2H), 7.48~7.32(m, 1H), 7.30(d,J=2.4Hz, 1H), 7.27(d,J=0. 7Hz, 1H), 7.26~7.00(m, 3H), 5.25(s, 2H), 2.95(p,J=6.8Hz, 1H), 2.37(d,J=2.0Hz, 3H), 1.24(dd,J=6.7, 3.8Hz, 6H)ppm. LCMS m / z 419.94[M+H] +

[0287] Step 2: To a solution of C99 (350 mg, 0.8335 mmol) and Pd(PPh3)4 (78 mg, 0.06750 mmol) in THF (7 mL) under a N2 atmosphere, bromo-(3-ethoxy-3-oxopropyl)zinc (7 mL of 0.5 M, 3.500 mmol) was slowly added. The solution was then stirred at 80 °C for 8 h. The solvent was evaporated, and the residue was dissolved in dichloromethane. The organic phase was washed with NaOH (0.5 M, 6 mL), water, brine, and dried over sodium sulfate. After filtration and concentration to dryness, the residue was purified by silica gel chromatography (12 g ISCO column) using a 0-50% EtOAc / heptane gradient to give C100 (310 mg, 77%), LCMS m / z 485.87 [M+H]. + .

[0288] Step 3: A suspension of Pd / C (100 mg of 10% w / w, 0.09397 mmol) and C100 (310 mg, 0.6384 mmol) in MeOH / EtOAc (1:1) (100 mL) was stirred under H2 (balloon, 1 atm) at room temperature for 3 h. The suspension was then filtered through a Celite® pad and then concentrated to dryness to give C101 (250 mg, 99%). H NMR (300 MHz, chloroform-d) δ 7.43 (d, J = 2.5 Hz, 1H), 7.27–6.90 (m, 5H), 5.49 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.59 (t, J = 6.8 Hz, 2H), 3.08 (t, J = 6.8 Hz, 2H), 2.92 (p, J = 6.7 Hz, 1H), 2.35 (d, J = 1.9 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.19 (dd, J = 6.7, 3.8 Hz, 6H) ppm. LCMS m / z 396.24[M+H] + .

[0289] Step 4: C101 (240 mg, 0.6069 mmol) and LiOH in THF / water (2:1) (15 mL) . A solution of HO (380 mg, 9.055 mmol) was stirred for 6 h. The reaction mixture was then acidified with HCl (10 mL of 1 M, 10.00 mmol) and extracted with EtOAc. The organic layer was washed with water, saturated NaCl, dried over sodium sulfate, and concentrated to dryness to give 79 (hydrochloride salt) (215 mg, 83%). 1 H NMR (300MHz, DMSO-d6) δ12.03(s, 1H), 10.02(s, 1H), 7.39(d,J=2.3Hz, 1H), 7.28(dd,J=9.9, 8.3Hz, 1H), 7.22~7.15(m, 2H), 7.14~7 .03(m, 2H), 3.40(dd,J=7.3, 5.8Hz, 2H), 2.84(dp,J=20.0, 6.7, 6.2Hz, 3H), 2.30(d,J=1.9Hz, 3H), 1.14(dd,J=6.7, 3.8Hz, 6H)ppm. LCMS m / z 368.01[M+H] + .

[0290] Compound 80~86 Compounds 80-86 (Table 6) were prepared from the intermediates shown in Table 6. Any modifications to the methods are described in Table 6 and the accompanying footnotes. [Table 7-1] [Table 7-2] [Table 7-3] a The cyclopropyl group was released to an ethyl group during the hydrogenation step. b The Zn reagent was generated in situ using ZnCu (3 equivalents to 1 equivalent of alkyl halide) in toluene / DMA at 85° C. in a microwave (0.165 M). c The cis and trans isomers were separated using SFC after the Negishi coupling step.

[0291] Compounds 87 and 88 (E)-3-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)but-2-enoic acid (87) and 3-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)butanoic acid (88) [ka] Step 1: To a solution of C102 (100 mg, 0.2381 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (110 mg, 0.3616 mmol), and Pd(PPh3)4 (25 mg, 0.02163 mmol) in DMF (3.5 mL) was added Na2CO3 (550 μL of 2 M, 1.100 mmol) under an atmosphere of N2. The reaction mixture was then microwaved at 130 °C for 1 h. The reaction was then diluted with water, and the aqueous phase was extracted with EtOAc. The organic layer was washed with water, brine, and dried over sodium sulfate. After concentration to dryness, the residue was purified by silica gel chromatography (40 g ISCO column) using a 0-60% EtOAc / heptane gradient to give C103 (127 mg, 95%) LCMS m / z 562.41 [M+H] + .

[0292] Step 2: A suspension of Pd / C (35 mg of 10% w / w, 0.03289 mmol) and C103 (100 mg, 0.2010 mmol) in MeOH / EtOAc (1:1) (34 mL) was stirred under H (balloon, 1 atm) at room temperature for 3 h. The suspension was then filtered through a Celite® pad and concentrated to dryness to give C104. 1 H NMR (300MHz, chloroform-d) δ7.46(d,J=2.5Hz, 1H), 7.32(s, 1H), 7.21~7.02(m, 4H), 6.14(d, J=1.5Hz, 1H), 5.57(s, 1H), 4.29(q,J=7. 1Hz, 2H), 3.00(h,J=6.6Hz, 1H), 2.75(d,J=1.5Hz, 3H), 2.38(d,J=1.9Hz, 3H), 1.36(t,J=7.1Hz, 3H), 1.23(dd,J=6.7, 3.7Hz, 6H). LCMS m / z 408.55[M+H] +

[0293] Step 3: C104 (48 mg, 0.1178 mmol) and LiOH in THF / water (2:1) (3 mL) .A solution of HO (60 mg, 1.430 mmol) was stirred at room temperature for 2 h. The reaction mixture was then acidified with HCl (1.5 mL of 1 M, 1.5 mmol) and extracted with EtOAc. The organic layer was washed with water, saturated NaCl, dried over sodium sulfate, and concentrated to dryness to give a residue which was purified by silica gel chromatography (4 g ISCO column) using a 0-25% MeOH / dichloromethane gradient to give 87 (45 mg, 92%). 1 H NMR (300MHz, chloroform-d and MeOH-d4) δ7.39 (s, 1H), 7.32~7.00 (m, 5H), 6.11 (s, 1H), 3.36(s, 2H), 3.11~2.91(m, 1H), 2.68(s, 3H), 2.36(s, 3H), 1.22(d,J=3.1Hz, 6H). LCMS m / z 380.43[M+H] +

[0294] Step 4: A suspension of Pd / C (30 mg of 10% w / w, 0.02819 mmol) and 87 (45 mg, 0.1082 mmol) in MeOH / EtOAc (1:1) (16 mL) was stirred under H (balloon, 1 atm) at room temperature for 3 h. The suspension was then filtered through a Celite® pad and concentrated to dryness to give a residue that was purified by silica gel chromatography (12 g ISCO column) using a 0-25% MeOH / dichloromethane gradient to give 88 (25 mg, 53%). 1 H NMR (300MHz, methanol-d4) δ7.52(t,J=3.4Hz, 1H), 7.30(s, 2H), 7.26~6.90(m, 3H), 4.16(dt,J=14.4, 7.4Hz, 1H), 3.58~3.26(m, 2H), 2.98(d,J=16.4Hz, 1H), 2.37(s, 3H), 1.58(d,J=7.2Hz, 3H), 1.30(dq,J=6.5, 3.3Hz, 6H)ppm. LCMS m / z 382.05[M+H] +

[0295] compound 89 3-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (89) [ka] Step 1: MgSO (3.123 g, 25.945 mmol) was added to a solution of C (8.9 g, 27.179 mmol) and tert-butylamine (10.440 g, 15 mL, 142.75 mmol) in dichloromethane (70 mL). After 4 hours, the reaction 1 H NMR showed complete conversion. The reaction mixture was filtered over Celite® and washed with dichloromethane. The filtrate was concentrated under reduced pressure to give C105 (10.38 g, 97%) as an orange solid. 1 H NMR (300 MHz, chloroform-d) δ 1.03–1.46 (m, 15H), 2.83 (dt, J = 13.7, 6.7 Hz, 1H), 5.12 (s, 2H), 6.83–7.02 (m, 1H), 7.29–7.54 (m, 6H), 7.65 (d, J = 2.6 Hz, 1H), 8.78 (s, 1H).

[0296] Step 2: AgNO3 (1.063 g, 6.2576 mmol) and LiCO3 (2.540 g, 34.375 mmol) were added to a solution of C105 (10.387 g, 26.476 mmol) in dry DMA (130 mL). The reaction was stirred at room temperature for 2 minutes, and NBS (7.617 g, 42.796 mmol) was added. The reaction was stirred at room temperature for 2 hours, filtered, and the solid was washed with EtOAc (50 mL). The filtrate was diluted with EtOAc (100 mL) and washed with a 10% aqueous solution of Na2SO3 (100 mL). The combined organic layers were extracted with EtOAc (20 mL). The combined organic layers were washed with water (4 × 60 mL), brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (using 0-85% EtOAc / heptane) to give C106 (7.71 g, 82%). 1H NMR (300 MHz, chloroform-d) δ 1.36 (d, J = 6.8 Hz, 6H), 3.84 (dquin, J = 13.5, 6.7 Hz, 1H), 5.22 (s, 2H), 7.27–7.57 (m, 7H), 8.15 (d, J = 9.4 Hz, 1H), 9.04 (s, 1H). LCMS m / z 356.1 [M+H] +

[0297] Step 3: A solution of C106 (7.711 g, 21.645 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (4.60 g, 29.913 mmol), and Na2CO3 (21 mL of 2 M in water, 42.000 mmol) in DMSO (77 mL) was heated to 100 °C and sparged with N2 for 15 min. PdCl2(dppf) . Dichloromethane (1.22 g, 1.4939 mmol) was added. The reaction was stirred at 100° C. for 4 hours and cooled to room temperature. An aqueous solution of 0.1 M potassium phosphate buffer (150 mL) at pH 7 was added, and the resulting precipitate was filtered and washed with water (2×200 mL). The solid was dissolved in dichloromethane (200 mL), dried over NaSO, filtered over Celite®, washed with dichloromethane, and concentrated under reduced pressure. The crude product was purified by chromatography on a silica plug eluted with heptane (100%), then heptane / EtOAc (5:1) to give C107 (7.71 g, 91%). 1 H NMR (300 MHz, chloroform-d) δ 1.25 (m, 6H), 2.36 (s, 3H), 2.92–3.11 (m, 1H), 5.21 (s, 2H), 7.00–7.54 (m, 11H), 9.18 (s, 1H). 19 F NMR (282 MHz, chloroform-d) δ -119.3 (s, 1F). LCMS m / z 386.2 [M+H] +

[0298] Step 4: A clear vial was charged with C107 (50 mg, 0.1282 mmol), O3-(1,3-dioxoisoindolin-2-yl)O1-methylbicyclo[1.1.1]pentane-1,3-dicarboxylate (66 mg, 0.1916 mmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (3 mg, 0.00267 mmol), and the vial was purged with N2 three times. DMA (1.5 mL) and TFA (20 μL, 0.259 mmol) were then added, and the mixture was stirred under argon and irradiated with two blue LED Kessil lamps. After 2 h, the reaction was quenched with DIPEA (0.1 mL) and diluted with water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0 to 25% EtOAc:heptane gradient) to afford C108 (26 mg, 39%). 1 H NMR (400 MHz, chloroform-d) δ 7.51 (dd, J = 2.3, 0.8 Hz, 1H), 7.43–7.37 (m, 2H), 7.37–7.31 (m, 2H), 7.31–7.24 (m, 1H), 7.18 (d, J = 0.8 Hz, 1H), 7.17–7.14 (m, 1H), 7.04 (dd ,J=9.6, 8.2Hz, 1H), 7.00~6.91(m, 2H), 5.15(s, 2H), 3.70(s, 3H), 2.83(h,J=6.7H) z, 1H), 2.50(d,J=8.5Hz, 6H), 2.26(d,J=1.9Hz, 3H), 1.11(dd,J=6.7, 5.1Hz, 6H). LCMS m / z 510.26[M+H] +

[0299] Steps 5 and 6 were carried out in the same manner as steps 3 and 4 for compounds 87 and 88 to give 89 (9 mg, 43%). 1H NMR (400MHz, methanol-d4) δ7.66(d,J=2.3Hz, 1H), 7.20~7.13(m, 2H), 7.13~7.07(m, 2H), 7.04(ddd,J=7.8, 5.0, 2.2Hz, 1H), 2.90(p,J=6.7Hz, 1H), 2.65(s, 6H), 2.34(d,J=2.0Hz, 3H), 1.19(dd,J=6.7, 3.5Hz, 6H). LCMS m / z 406.35[M+H] +

[0300] compound 90 4-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropylisoquinolin-1-yl)benzoic acid (90) [ka] Step 1: A solution of C102 (100 mg, 0.2381 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (110 mg, 0.3616 mmol), and Pd(PPh3)4 (25 mg, 0.0216 mmol) in DMF (3.5 mL) and Na2CO3 (550 μL of 2 M, 1.100 mmol) was heated in a microwave at 130 °C for 1 h. The reaction was then diluted with water, and the aqueous phase was extracted with EtOAc. The organic layer was washed with water, brine, and dried over sodium sulfate. After concentration to dryness, the residue was purified by silica gel chromatography (12 g ISCO column) using a 0-50% EtOAc / heptane gradient to give C109 (127 mg, 95%), LCMS m / z 562.41 [M+H]. + .

[0301] Step 2: The hydrogenation reaction (H2, Pd / C) was carried out in the same manner as for compound 89.

[0302] Step 3: To the product formed in Step 2 (105 mg, 0.2227 mmol) was added HCl in dioxane (5 mL of 4 M, 20.0 mmol). The reaction mixture was microwaved at 100 °C for 30 min. Concentration to dryness afforded 90 (hydrochloride salt) (95 mg, 85%). 1 H NMR (300MHz, DMSO-d6) δ10.13(d,J=1.8Hz, 1H), 8.36~6.86(m, 10H), 2.94(d,J=8.6Hz, 1H), 2.34(s, 3H), 1.21(q,J=6.6, 4.5Hz, 6H)ppm. LCMS m / z 416.38[M+H] +

[0303] compound 91 (4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-(tetrahydro-2H-pyran-4-yl)isoquinoline-1-carbonyl)serine (91) [ka] Step 1: A solution of S11 (7.66 g, 18.489 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (4.26 g, 27.672 mmol), and Na2CO3 (19 mL of 2 M in water, 38.000 mmol) in DMSO (80 mL) was heated to 100 °C and sparged with N2 for 15 min. PdCl2(dppf) .Dichloromethane (789 mg, 0.9662 mmol) was added, and the reaction was sparged with N for 2 minutes. The reaction was stirred at 100 °C for 4 hours, cooled to room temperature, diluted with EtOAc (300 mL), and washed with pH 7 0.1 M potassium phosphate buffer (2 × 150 mL). The solid precipitated, was filtered, dissolved in dichloromethane, filtered over Celite®, washed with dichloromethane, and concentrated under reduced pressure to give C110 (2.3 g, 28%) as a tan solid. The organic layer was further washed with water (3 × 100 mL), brine (100 mL), dried over NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ISCO 220 g 0-5% MeOH / dichloromethane). The product-containing fractions were combined, recrystallized in ACN (approximately 250 mL), filtered, and dried under reduced pressure to give C110 (3.7 g, 45%) as tan crystals. Both batches were combined to give C110 (6.0 g, 71%). 1 H NMR (300MHz, chloroform-d) δ1.41(d,J=11.7Hz, 2H), 2.38(d,J=1.5Hz, 3H), 2.51~2.96(m, 2H), 3.28(t,J=11 .3Hz, 3H), 3.97(dd,J=11.0, 3.4Hz, 2H), 5.18(s, 2H), 6.93~7.22(m, 6H), 7.31~7.52(m, 5H), 8.73(s, 1H). 19 F NMR (282 MHz, chloroform-d) δ -117.1 (s, 1F). LCMS m / z 444.2 [M+H] + .

[0304] Steps 2 and 3: To a solution of C110 in 100 mL of 4:1 ACN / THF (125 mL) was added TMSCN (2.4 mL, 18.00 mmol) and TEA (2.2 mL, 15.78 mmol) under an atmosphere of N2. The solution was then heated to 40 °C for 3 days before being concentrated to dryness. The residue was purified by silica gel chromatography (220 g ISCO column) using a 0-60% EtOAc / heptane gradient to give the cyano derivative (2.38 g, 95%) dissolved in EtOH. Pd(OH)2 (778.0 mg, 1.108 mmol) was added, and the solution was stirred under H2 (balloon, 1 atm) at room temperature for 30 h. The suspension was then filtered through a Celite® pad and concentrated to dryness to give a residue that was diluted with dichloromethane / 1 N NaOH (1:1) (50 mL). The aqueous layer was acidified with 2M HCl, extracted with EtOAc, and dried over sodium sulfate. Concentration to dryness gave C111 (742 mg, 35%). 1 H NMR (300MHz, DMSO-d6) δ7.76(s, 1H), 7.35~7.06(m, 5H), 3.87(m, 2H), 3.17(s, 2H), 2.32(m, 3H), 2.18~1.96(m, 2H), 1.45(d, J=12.9Hz, 2H).

[0305] Step 4: To a solution of C111 (50 mg, 0.131 mmol), methyl 2-amino-3-hydroxypropanoate (HCl salt) (33 mg, 0.196 mmol) in DMF (2 mL) was added T3P (83 mg, 0.262 mmol) and DIPEA (68 μL, 0.393 mmol) at room temperature. The resulting solution was stirred for 15 h, and KOH (150 μL of 10 M, 1.500 mmol) was added, and the solution was stirred for an additional 15 h. The solution was then syringe filtered and submitted for preparative LCMS purification (C18 ACN / water with HCl modifier) ​​to give 91 (12.8 mg, 17.8%). 1H NMR (400MHz, DMSO-d6) δ10.29(s, 1H), 8.95(d,J=7.9Hz, 1H), 8.74(d,J=2.5Hz, 1H), 7.34(m, 1H), 7.27(dd,J=9.1, 2.6Hz, 2H), 7.18(dd,J=9.3, 4.6Hz, 2H) ), 4.56(dd,J=7.9, 3.9Hz, 1H), 4.03~3.79(m, 4H), 3.21(m, 2H), 2.87~2.69(m , 1H), 2.33(d,J=2.1Hz, 3H), 2.07(d,J=12.2Hz, 3H), 1.54(d,J=13.1Hz, 2H). LCMS m / z 469.25[M+H] + ;

[0306] Compounds 92~96 Compounds 92-96 (Table 7) were prepared from the intermediates shown in Table 7. When the amine coupling partner is not an ester, the final step (KOH hydrolysis) is not performed. Any modifications to the method are described in Table 7 and the accompanying footnotes. [Table 8-1] [Table 8-2] [Table 8-3] a No hydrolysis step (KOH) was performed

[0307] compound 97 4-((4-(4-Fluoro-3-methylphenyl)-7-hydroxy-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-1-yl)oxy)benzoic acid (97) [ka] Step 1: To a solution of S12 (trifluoroacetate salt) (600 mg, 0.919 mmol) and methyl 4-hydroxybenzoate (416 mg, 2.734 mmol) in DMF (3.33 mL) was added KCO (380 mg, 2.750 mmol) and the reaction was stirred at room temperature for 16 h. After this time, LCMS showed complete consumption of starting material and the reaction mixture was carried on directly to the next step.

[0308] Step 2: To the DMF reaction mixture was added MeOH (3.33 mL) and the resulting suspension was filtered through a Celite® pad to remove excess KCO. To this solution was added Pd(OH) (45 mg of 60% w / w, 0.1923 mmol). A H balloon (1 atmosphere) was attached to the reaction vessel and the reaction was stirred for 4 hours. The reaction mixture was filtered through a 0.2 micron filter and then concentrated in vacuo to remove MeOH, and the crude DMF reaction mixture was taken directly to the next step.

[0309] Step 3: To the DMF mixture from the previous step, KOH (920 μL of 10 M, 9.20 mmol) was added at room temperature. The reaction was stirred for 3 h, diluted with water (3 mL), and flash-frozen in a dry ice / acetone bath. The frozen solution was concentrated via lyophilization, and the crude residue was purified by ISCO reverse-phase flash chromatography (50 g C18, 5–95% MeCN in HO with 0.1% formic acid modifier) ​​to provide 97 (132.5 mg, 30%). 1 H NMR (300MHz, methanol-d4) δ8.18~8.06(m, 2H), 7.60(dd,J=2.1, 1.0Hz, 1H), 7.43~7.30(m, 2H), 7.23~7.11(m, 4H), 7.08(ddd,J=7.9, 5.1, 2.2Hz, 1 H), 3.84(dd,J=11.4, 4.0Hz, 2H), 3.29~3.16(m, 2H), 2.72(tt,J=11.6, 3.8Hz, 1H), 2.34(d,J=1.9Hz, 3H), 1.99~1.75(m, 2H), 1.52~1.35(m, 2H). LCMS m / z 474.25[M+H] +

[0310] Compounds 99~101 Compounds 98-101 (Table 8) were prepared from the intermediates shown in Table 8. Any modifications to the methods are described in Table 8 and the accompanying footnotes. [Table 9-1] [Table 9-2] a For step 1, NaH (21 equiv.) in DMSO (0.06 M) was used instead of K2CO3 in DMF. b No hydrolysis step is performed.

[0311] Compound 102 4-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-1-yl)butanoic acid (102) [ka]

[0312] Compounds 102~105 Compounds 102-105 (Table 9) were prepared from the intermediates shown in Table 9. Any modifications to the methods are described in Table 9 and the accompanying footnotes. [Table 10-1] [Table 10-2] a Compound 105 was prepared from S8 using two sequential Suzuki reactions (reaction with ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, respectively), followed by hydrogenation (H, Pd / C).

[0313] compound 106 4-(4-(4-Fluoro-3-methylphenyl)-7-hydroxy-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-1-yl)benzoic acid (106) [ka] Compound 106 was prepared using the same procedure as compound 90. 1 H NMR (300MHz, DMSO-d6) δ10.10(s, 1H), 8.28~8.06(m, 2H), 7.90~7.76(m, 2H), 7.42~7.12(m, 6H), 3.86(dd,J=11.3, 4.2Hz, 2H), 3.75~ 3.63(m, 1H), 3.55~3.42(m, 1H), 2.81(t,J=11.6Hz, 1H), 2.34(d,J=1.8Hz, 3H), 2.07(dt,J=12.4, 5.7Hz, 2H), 1.52(d,J=13.0Hz, 2H). LCMS m / z 458.32[M+H] +

[0314] Compound 107 4-(4-Fluoro-3-methylphenyl)-7-hydroxy-2-(3-hydroxypropyl)-3-isopropylisoquinolin-1(2H)-one (107) [ka] Step 1: In a sealed tube, a suspension of C1 (3.05 g, 9.4966 mmol) in TEA (22 mL) was bubbled with N2 for 10 min. PdCl2(PPh3)2 (657 mg, 0.9334 mmol) and CuI (56 mg, 0.2940 mmol) were then added, and N2 was bubbled for an additional 2 min. 3-Methylbut-1-yne (1.3986 g, 2.1 mL, 20.532 mmol) was added, and the tube was sealed, stirred, and heated at 70 °C for 15 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (100 mL). The organic layer was washed with 3 M HCl (2 × 60 mL), water (60 mL), brine, dried over anhydrous sodium sulfate, filtered, loaded onto silica gel, and concentrated under reduced pressure. The residue was purified on silica gel chromatography eluting with 0% to 20% ethyl acetate in heptane to yield C116 (2.7 g, 92%). 1 H NMR (300MHz, chloroform-d) δ1.29(d,J=6.8Hz, 6H), 2.83(spt,J=6.9Hz, 1H), 3.93(s, 3H) , 5.09(s, 2H), 7.04(dd,J=8.7, 2.8Hz, 1H), 7.31~7.47(m, 6H), 7.50(d,J=2.6Hz, 1H). LCMS m / z 309.2[M+H] +

[0315] Step 2: To a solution of C116 (2 g, 6.4792 mmol) in anhydrous dichloromethane (40 mL) at room temperature was added a solution of I2 (1.88 g, 7.4071 mmol) in anhydrous dichloromethane (50 mL) over 30 min. The reaction mixture was stirred at room temperature for an additional 20 min, and then EtOAc (300 mL) was added. The organic phase was washed with a mixture of 5% aqueous NaHCO3 and brine (3 × 100 mL, 90 / 10 ratio) and brine (2 × 50 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with 20–70% dichloromethane in heptane to give C117 (2.32 g, 85%) as a white solid. 1H NMR (300MHz, DMSO-d6) δ1.20(d,J=6.8Hz, 6H), 3.49(sept,J=6.8Hz, 1H), 5.27(s, 2H), 7.30~7.44(m , 3H), 7.45~7.51(m, 2H), 7.59(dd,J=8.8, 2.8Hz, 1H), 7.64(d,J=2.8Hz, 1H), 7.70(d,J=8.8Hz, 1H). LCMS m / z 421.0[M+H] +

[0316] Step 3: In a sealed tube, water (3.75 mL) and potassium phosphate (2.69 g, 12.673 mmol) were added. The mixture was stirred at room temperature for 10 minutes, and then toluene (48 mL) was added. Nitrogen was bubbled through the mixture for 15 minutes, and C117 (2.6 g, 6.1869 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (1.23 g, 7.9898 mmol), and XPhos Pd G2 (364.3 mg, 0.4630 mmol) were added. The tube was sealed and then transferred to a preheated oil bath set at 70 °C and stirred at this temperature for 2 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc (350 mL). The organic phase was washed with 5% aqueous NaHCO3 (3 × 75 mL) and brine (2 × 75 mL), dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography eluting with 30-90% dichloromethane in heptane to afford C118 (2.33 g, 93%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ1.12(d,J=6.6Hz, 6H), 2.29(s, 3H), 2.54~2.67(m, 1H), 5.25(s, 2H), 6.84(d,J=8.8Hz, 1H), 7.13~7.21(m, 1H), 7.23~7.51(m, 8H), 7.70(d,J=2.7Hz, 1H), 19 F NMR (282MHz, DMSO-d6) δ -118.4~-118.2 (m, 1F).

[0317] Step 4: A solution of C118 (500 mg, 1.241 mmol) and 3-aminopropan-1-ol (2000 μL, 26.18 mmol) was heated to 180° C. under microwave irradiation for 90 minutes. The mixture was diluted with dichloromethane (60 mL) and water (30 mL), and then 1 M HCl (approximately 26 mL) was added to bring the pH to approximately 1. At this point, the organic layer was removed, filtered, and concentrated on a phase separator. The mixture was dissolved in dichloromethane (10 mL), MsOH (20 μL, 0.3082 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. The mixture was concentrated and then redissolved in minimal dichloromethane for purification by silica gel chromatography eluting with 0-5% MeOH in dichloromethane to give 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-2-(3-hydroxypropyl)-3-isopropyl-isoquinolin-1-one (425 mg, 73%). 1 H NMR (400MHz, chloroform-d) δ7.97(d,J=2.8Hz, 1H), 7.55~7.30(m, 5H), 7.22~6.95(m, 4H), 6.81(s, 1H), 5.21(s, 2H), 4.46( s, 2H), 3.68(s, 2H), 3.33(p,J=7.3Hz, 1H), 2.40~2.27(m, 3H), 2.05(d,J=21.2Hz, 2H), 1.41~1.27(m, 3H), 1.07(s, 3H). LCMS m / z 460.35[M+H] +

[0318] Step 5: To a flask was added 7-benzyloxy-4-(4-fluoro-3-methyl-phenyl)-2-(3-hydroxypropyl)-3-isopropyl-isoquinolin-1-one (250 mg, 0.5440 mmol), Pd / C (100 mg, 0.01879 mmol), and EtOAc (15 mL). The suspension was purged with N three times, then with H five times, then stirred under H (60 psi) for 2 h, filtered through a pad of Celite®, and concentrated to dryness to give 107 (200 mg, 95%). 1H NMR (400MHz, DMSO-d6) δ9.89(s, 1H), 7.58(d,J=2.6Hz, 1H), 7.25(dd,J=9.8, 8.3Hz , 1H), 7.18(dd,J=7.7, 2.1Hz, 1H), 7.10(dt,J=8.4, 3.9Hz, 1H), 7.03(dd,J=8.8, 2.7 Hz, 1H), 6.61(d,J=8.9Hz, 1H), 4.68(t,J=5.1Hz, 1H), 4.16(s, 2H), 3.60~3.49(m, 2H) ), 3.17(d, J=5.3Hz, 1H), 2.29(d, J=1.8Hz, 3H), 1.83(d,J=8.4Hz, 2H), 1.23(s, 6H). LCMS m / z 370.3[M+H] +

[0319] Compounds 108~111 Compounds 108-111 (Table 10) were prepared from the intermediates shown in Table 10. Any modifications to the methods are described in Table 10 and the accompanying footnotes. [Table 11-1] [Table 11-2] a A hydrolysis reaction (10 equivalents of LiOH in MeOH at 80° C.) was carried out after the hydrogenation step.

[0320] Compounds 112 and 113 3-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-3-isopropyl-1-oxoisoquinolin-2(1H)-yl)propanoic acid (112) and 3-(4-(4-fluoro-3-methylphenyl)-3-isopropyl-1-oxoisoquinolin-2(1H)-yl)propanamide (113) [ka] Step 1: To a suspension of C119 (from Step 4 of the synthesis of 107) (20 mg, 0.04352 mmol) and NaHCO3 (9 mg, 0.1071 mmol) in dichloromethane (0.5 mL), Dess-Martin periodinane (19 mg, 0.04480 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. Additional Dess-Martin periodinane (19 mg, 0.04480 mmol) was added, and the reaction was stirred for 1 h. The reaction was quenched with a 1:1 mixture of saturated aqueous sodium bicarbonate and sodium thiosulfate (5 mL) for 30 min. The product was extracted with dichloromethane, and the organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to give the aldehyde, which was further purified and used in the next step.

[0321] Step 2: To a flask were added NaClO (20 mg, 0.2211 mmol), NaHPO (55 mg, 0.4546 mmol), and water (2 mL), and the mixture was stirred until the solids dissolved. In a separate flask, the crude aldehyde from the first step was dissolved in THF (1.3 mL) and t-BuOH (2 mL). 2-Methylbut-2-ene (450 μL of 2 M, 0.900 mmol) as a solution in THF was added, and the resulting biphasic mixture was stirred for 1 h. The mixture was diluted with EtOAc and water, and the pH was adjusted to pH 2 with 1 M HCl. The organic layer (containing C120) was concentrated and used in the next step without further purification.

[0322] Step 3: To a flask was added the solid from the previous step, Pd / C (10 mg, 0.001879 mmol), and EtOAc (2 mL). The suspension was purged with N three times, then with H five times, and then stirred under H (60 psi) for 78 h (10:40). The material was filtered over a syringe filter and concentrated to give 112 (5 mg, 20%). 1H NMR (400MHz, methanol-d4) 7.64 (d, J=2.7Hz, 1H), 7.19~7.00 (m, 5H), 6.75 (d,J=8.9Hz, 1H), 4.5 4~4.40(m, 2H), 2.84(t,J=7.9Hz, 2H), 2.33(d,J=1.9Hz, 3H), 2.27~2.15(m, 1H), 1.29(s, 6H). LCMS m / z 384.34[M+H] +

[0323] Step 4: The crude residue from the 100 mg scale reaction of Step 3 (described above) was added to DMF (4 mL), NH3 in dioxane (2 mL of 0.5 M, 1.000 mmol), DIPEA (100 μL, 0.5741 mmol), and HATU (100 mg, 0.2630 mmol), and the reaction mixture was stirred for 5 min. The mixture was diluted with water (50 mL) and EtOAc (50 mL), separated, and the organic mixture was washed with brine (2 × 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude solid was suspended in approximately 2 mL of dichloromethane and filtered to give 113 (35 mg, 42%). 1 H NMR (400MHz, DMSO-d6) δ9.93(s, 1H), 7.59(d,J=2.7Hz, 1H), 7.47(s, 1H), 7.26 (dd,J=9.8, 8.3Hz, 1H), 7.21~7.14(m, 1H), 7.09(ddd,J=7.8, 4.9, 2.3Hz, 1H), 7.04(dd,J=8.8, 2.7Hz, 1H), 6.97(s, 1H), 6.62(d,J=8.8Hz, 1H), 4.27(t,J=8. 0Hz, 2H), 3.25~3.11(m, 1H), 2.56(s, 2H), 2.29(d,J=1.8Hz, 3H), 1.21(s, 6H). LCMS m / z 383.4[M+H] +

[0324] compound 114 2-((4-(4-Fluoro-3-methylphenyl)-7-hydroxy-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-1-yl)oxy)acetic acid (114) [ka] Compound 114 was prepared from S8 using the same reaction sequence as compound 61, except that 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used as the coupling partner in the Suzuki coupling step. 1 H NMR (400MHz, methanol-d4) δ7.47(d,J=2.4Hz, 1H), 7.09~7.03(m, 1H), 7.03~6.97(m, 3H), 6.96~6.90(m, 1H), 4.93(s, 2H), 3. 88~3.78(m, 2H), 3.17(d,J=11.8Hz, 3H), 2.71~2.53(m, 1H), 2.22(d,J=1.9Hz, 2H), 2.14~1.96(m, 2H), 1.40~1.31(m, 2H). LCMS m / z 412.38[M+H] +

[0325] compound 115 (1r,3r)-3-(4-(4-fluoro-3-methylphenyl)-7-hydroxy-1-oxo-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-2(1H)-yl)cyclobutane-1-carboxylic acid (115) [ka] Step 1. To a solution of C1 (5 g, 15.57 mmol) in DMF (31 mL) and TEA (15.8 g, 156.1 mmol) was added CuI (178 mg, 0.9346 mmol), TBAF (6.4 g, 20.28 mmol), and TMS-alkyne (3.7 g, 20.29 mmol). The solution was purged with N for 5 min, and PdCl(PPh) (328 mg, 0.4673 mmol) was added. The solution was purged for an additional 5 min and then heated at 80 °C for 15 h. The solution was cooled to room temperature, and the TEA was removed in vacuo. Water (500 mL) was added, followed by EtOAc (450 mL). The organic phase was washed with brine and concentrated. The residue was purified by silica gel chromatography (120 g ISCO column) using a 0-40% EtOAc / heptane gradient to afford C121 (2.0 g, 37%). 1H NMR (300MHz, chloroform-d) δ7.46~7.23(m, 8H), 6.97(dd,J=8.6, 2.8Hz, 1H), 5.02(s, 2H), 3.91(ddd,J=11.5, 5.9, 3.6Hz, 2H), 3.84 (s, 3H), 3.50(ddd,J=11.4, 8.2, 3.1Hz, 2H), 2.83(tt,J=8.3, 4.1Hz, 1H), 1.92~1.80(m, 2H), 1.70(dtd,J=13.5, 8.3, 3.6Hz, 2H).

[0326] Step 2: To a solution of C121 (500 mg, 1.427 mmol) in THF (1.8 mL), methanol (600 μL), and HO (600 μL) was added LiOH (205 mg, 8.560 mmol) at room temperature, and the solution was stirred for 15 h. The reaction was acidified with 1 M HCl and extracted with EtOAc (10 mL). The organic solution was concentrated, and the product was triturated with heptane to give the corresponding acid (400 mg, 83%). 1 H NMR (300MHz, acetone-d6) δ7.70(d,J=2.7Hz, 1H), 7.59~7.29(m, 7H), 6.46(d,J=0.8Hz, 1H), 5.27(s, 2H), 3.98(ddd,J=11.6, 3.8, 1.9Hz, 2H ), 3.47(td,J=11.7, 2.2Hz, 2H), 2.73(dt,J=11.8, 3.8Hz, 1H), 1.90(ddd,J=12.9, 4.1, 2.0Hz, 2H), 1.72(dtd,J=13.1, 11.8, 4.5Hz, 2H).

[0327] Step 3: To a solution of the acid obtained above (50 mg, 0.1486 mmol) in acetone (3 mL) was added AgNO (7.57 mg, 0.04456 mmol). The reaction mixture was stirred at room temperature in the dark for 24 h. The reaction was concentrated, and the residue was purified by silica gel chromatography (12 g ISCO column) using a 0-40% EtOAc / heptane gradient to give C122 (33 mg, 66%). 1H NMR (300MHz, chloroform-d) δ7.70(d,J=2.3Hz, 1H), 7.46~7.15(m, 8H), 6.14(s, 1H), 5.08(s, 2H), 4.01(ddd,J=11.5, 4.2, 1.7Hz , 2H), 3.42(td,J=11.8, 2.2Hz, 2H), 2.63(tt,J=11.8, 3.8Hz, 1H), 2.00~1.61(m, 4H), 1.29~1.13(m, 3H), 0.86~0.75(m, 2H).

[0328] Step 4: To a suspension of C122 (102 mg, 0.3032 mmol), molecular sieves (400 mg), and methyl 3-aminocyclobutanecarboxylate (hydrochloride) (375 mg, 2.264 mmol), pyridine (2 mL) was added. The suspension was then heated at 140 °C for 15 h. The reaction was cooled to room temperature and diluted with dichloromethane. The reaction mixture was filtered through a Celite® pad and acidified with 1 M HCl. The organic layer was separated and concentrated. The product was purified by silica gel to give the corresponding ester (78 mg, 57%). 1 H NMR (300MHz, chloroform-d) δ7.88(d, J=2.6Hz, 1H), 7.54~7.30(m, 7H), 6.34(s, 1H), 5.20(s, 3H), 4.14(dt,J=11.7, 2.3Hz, 2 H), 3.78(s, 3H), 3.74~3.47(m, 5H), 2.93(td,J=10.5, 5.5Hz, 1H), 2.55(ddd,J=12.5, 9.3, 3.8Hz, 2H), 1.94~1.70(m, 4H).

[0329] Step 5: To a solution of the above ester (114 mg, 0.2547 mmol) in THF (2 mL) was added NBS (59 mg, 0.3315 mmol) at 0 °C. The reaction mixture was warmed to room temperature, stirred for 1 h, quenched with aqueous saturated NaHCO3, and extracted with EtOAc. The organic phase was concentrated, and the residue was purified by silica gel chromatography (0-30% EtOAc in heptane) to give C123 (84 mg, 63%). 1H NMR (300MHz, chloroform-d) δ7.93(d,J=9.0Hz, 1H), 7.89(d,J=2.7Hz, 1H), 7.53~7.33(m, 6H), 5.22(s, 2H), 4.24~4.14(m, 2 H), 3.80(s, 3H), 3.67~3.40(m, 5H), 2.61(t,J=8.9Hz, 2H), 2.34(d,J=10.8Hz, 3H), 1.77(d,J=13.0Hz, 2H), 1.59(s, 2H).

[0330] Step 6: In a 20 mL vial, water (100 μL) and potassium phosphate (57 mg, 0.2685 mmol) were added. The mixture was stirred at room temperature for 10 minutes, and then toluene (700 μL) was added. N2 was bubbled through the mixture for 15 minutes, and then C123 (40 mg, 0.07599 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (18 mg, 0.1169 mmol), and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane; methanesulfonate; N-methyl-2-phenyl-aniline Pd (13 mg, 0.01529 mmol) were added. The tube was sealed and then transferred to a preheated oil bath set at 70 °C and stirred at this temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc. The organic solution was dried over Na2SO4 and concentrated. The product was purified by silica gel chromatography to give the corresponding Suzuki product (35 mg, 67%) LCMS m / z 556.34 [M+H] +

[0331] Step 7: To a 20 mL vial was added Pd / C (1.6 mg, 0.001503 mmol), and the product from the previous step and MeOH (4 mL) were added via syringe. H2 was then bubbled in for 5 min, and the reaction was stirred at room temperature for 4 h, at which point complete reduction was observed. The reaction mixture was filtered, and the product was purified by ISCO to give the corresponding phenol. LCMS m / z 466.38 [M+H] + .

[0332] Step 8: The product from the previous step was dissolved in THF / MeOH / HO (3:1:1) (2 mL), LiCl (10 mg, 0.2359 mmol) was added, and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with HO and acidified with 1 N HCl. The product was extracted with EtOAc, and the organic solution was dried over NaSO and concentrated to give 115 (8 mg, 22%). 1 H NMR (300MHz, methanol-d4) δ7.65(d,J=2.6Hz, 1H), 7.23~7.08(m, 2H), 7.04(dt,J=8 .8, 3.3Hz, 2H), 6.73(d,J=8.8Hz, 1H), 5.43(p,J=8.7Hz, 1H), 3.95(dd,J=11.5, 4. 4Hz, 2H), 3.59(q,J=10.1Hz, 2H), 3.46~3.33(m, 1H), 3.08(dd,J=12.5, 10.0Hz, 3H ), 2.58(ddd,J=12.4, 9.1, 3.6Hz, 2H), 2.24~2.06(m, 2H), 1.60(d,J=13.1Hz, 2H). LCMS m / z 452.38[M+H] +

[0333] compound 116 (R)-2-((4-(4-fluorophenyl)-7-hydroxy-3-(tetrahydro-2H-pyran-4-yl)isoquinolin-1-yl)oxy)propanoic acid (116) [ka] Step 1: (2S)-2-[[7-benzyloxy-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]propanoic acid (C124) Method A: DABCO Catalyst S with Alcohols NAr reaction. To a mixture of S13 (170 mg, 0.1961 mmol) and (2S)-2-hydroxypropanoic acid (97 mg, 1.077 mmol) in dry DMF (4 mL) was added NaH (103 mg of 60% w / w, 2.575 mmol) under N2. The reaction mixture was stirred at room temperature for 18 h. Upon completion, the reaction mixture was quenched with water and 1 M HCl (5 mL). The residue was extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography eluting with 0-30% MeOH in dichloromethane to give C124 (65 mg, 66%). 1 H NMR (400 MHz, chloroform-d) δ 7.71 (d, J = 2.6 Hz, 1H), 7.55–7.49 (m, 2H), 7.46–7.41 (m, 2H), 7.38 (d, J = 7.2 Hz, 1H), 7.28–7.14 (m, 6H), 5.45 (q, J = 7.0 Hz, 1H), 5.22 (d, J = 3.5 Hz, 2H), 4.10–3.00 (m, 6H). .89(m, 2H), 3.33(dddd,J=17.5, 13.2, 11.5, 2.1Hz, 2H), 2.72(tt,J=11.7, 3.7Hz, 1H), 2.2 6(qd,J=12.7, 4.5Hz, 1H), 2.11~2.00(m, 1H), 1.83(d,J=7.1Hz, 3H), 1.49(d,J=7.0Hz, 2H). LCMS m / z 501.93[M+H] + .

[0334] Step 2: (2S)-2-[[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]propanoic acid (116) Method B: Pd-catalyzed transfer hydrogenation. Pd (16 mg of 10% w / w, 0.01503 mmol) was added to a solution of C124 (63 mg, 0.1256 mmol) in MeOH (10 mL) and EtOAc (10 mL). The resulting mixture was stirred at room temperature for 18 h under a H2 balloon. The reaction mixture was filtered through a plug of Celite and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20-30% MeOH in dichloromethane to give 116 (35 mg, 63%).1 H NMR (400MHz, methanol-d4) δ7.61(dd,J=2.5, 0.6Hz, 1H), 7.30~7.00(m, 6H), 5.45(q,J=7.0Hz, 1H), 3.96(ddd,J=20.5, 11.3, 4.3Hz, 2H), 3.35 ~3.22(m, 2H), 2.69(tt,J=11.6, 3.7Hz, 1H), 2.24(qd,J=12.7, 4.6Hz, 1H), 2.14~2.03(m, 1H), 1.75(d,J=7.0Hz, 3H), 1.56~1.39(m, 2H)ppm. LCMS m / z 412.29[M+H] + .

[0335] Compounds 117~142 Compounds 117-142 (Table 11) were prepared in two or three steps from intermediate S13 from the appropriate alcohol following the method described for compound 116. Any modifications to the method are described in Table 11 and the accompanying footnotes. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6] [Table 12-7] [Table 12-8] [Table 12-9] 1. Standard method D using KOH was performed after standard method B using Pd(OH)2. 2. An additional treatment with HCl to remove the acetal group was carried out after standard method B using Pd(OH)2. 3. TFA deprotection followed by standard method E using acetic anhydride and DIPEA was carried out before standard method B.

[0336] compound 143 3-[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]propanoic acid (143) [ka] Step 1: 7-benzyloxy-4-(4-fluorophenyl)-2-oxide-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C29) Method C-1: Suzuki Coupling Method. A suspension of S11 (14.41 g, 34.782 mmol), (4-fluorophenyl)boronic acid (7.29 g, 52.101 mmol), and aqueous Na2CO3 (35 mL of 2 M in water, 70.000 mmol) in DMSO (140 mL) was purged with N2 for 30 min. Pd(dppf)Cl2·dichloromethane (1.42 g, 1.7388 mmol) was added, and the reaction was purged with N2 for an additional 5 min. The reaction was heated to 100 °C for 2 h, cooled to room temperature, cooled to 0 °C, diluted with water (280 mL), and filtered. The residue was then dissolved with dichloromethane (through a filter paper). The filtrate was decanted, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The brown solid was triturated with ACN (50 mL), filtered, and washed with ACN. The residue was triturated again with a mixture of dichloromethane (10 mL) and ACN (25 mL), and the solid was filtered and washed with a minimum of dichloromethane to yield C29 (9.19 g, 59%) as a tan solid. 1H NMR (300MHz, CDCl3) δ1.40(d,J=11.7Hz, 2H), 2.67(br.s., 2H), 3.11~3.37(m, 3H), 3.95(dd,J=11. 0, 3.7Hz, 2H), 5.17(s, 2H), 6.94-7.18(m, 3H), 7.19~7.29(m, 4H), 7.31~7.51(m, 5H), 8.73(s, 1H). 19 F NMR (282 MHz, chloroform-d) δ -113.2 to -112.2 (m, 1F). LCMS m / z calculated 430.2 [M+H] + .

[0337] Step 1: 7-benzyloxy-1-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-isoquinoline (C125) Method C-2: Halogenation of isoquinoline N-oxide using oxalyl chloride. Oxalyl dichloride (6 mL of 2 M in dichloromethane, 12.00 mmol) was added to a solution of C29 (3 g, 6.985 mmol) and DIPEA (3 mL, 17.22 mmol) in dry dichloromethane (25 mL) at −78° C. The reaction was allowed to warm to 0° C. over 2 hours, and the dark reaction was quenched by the addition of MeOH (2 mL). After stirring for 10 minutes, the mixture was concentrated in vacuo. MeOH (5 mL) was added, and the resulting solid was filtered, washed with cold MeOH, and dried under high vacuum to give C125 (2.73 g, 87%) as a colorless solid. 1 H NMR (300MHz, chloroform-d) δ7.72~7.30(m, 7H), 7.27~7.20(m, 5H), 5.26(s, 2H), 4.01(dd,J=11.4, 4. 4Hz, 2H), 3.32(t,J=11.4Hz, 2H), 2.55~2.45(m, 1H), 2.34~2.11(m, 2H), 2.11(m, 2H), 1.50(m, 2H).

[0338] Steps 2-3: Ethyl 3-[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]propanoate (C126) Conversion of intermediate C125 to C127 was achieved via the standard Suzuki protocol using ethyl Pd(PPh3)4 in DMF stirred at 130 °C for 2 h, followed by standard hydrogenation using Method B.

[0339] Step 4: 3-[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl]propanoic acid (143) Method D: Ester hydrolysis using LiOH. A solution of C127 (70 mg, 0.1653 mmol) dissolved in a mixture of THF (3 mL) and HO (1.5 mL) was treated with LiOH (100 mg, 2.383 mmol), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was acidified with HCl (2.5 mL of 1 M, 2.500 mmol) and extracted with EtOAc. The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give 143 (65 mg, 87%). 1 H NMR (300MHz, chloroform-d) δ7.58(s, 1H), 7.28~7.13(m, 7H), 4.06~3.98(m, 2H), 3.68(d,J=6.4Hz, 2H), 3.31 (t,J=11.7Hz, 2H), 3.08(t,J=6.1Hz, 2H), 2.85(t,J=12.0Hz, 1H), 2.32~2.18(m, 2H), 1.60~1.49(m, 2H). LCMS m / z 396.13[M+H] + .

[0340] compound 144 1-[[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-isoquinoline-1-carbonyl]amino]cyclopropanecarboxylic acid (144) [ka] Step 1: 7-benzyloxy-4-bromo-3-tetrahydropyran-4-yl-isoquinoline-1-carbonitrile (C128) To a mixture of S11 (10 g, 23.73 mmol) in ACN (150 mL) and THF (100 mL) was added TEA (8.25 mL, 59.19 mmol) and TMSCN (10 mL, 75.00 mmol) under N2. The reaction mixture was heated to 55 °C for 18 h. Additional TMSCN (10 mL, 75.00 mmol) was added and the reaction was stirred for an additional 2 days. After completion of the reaction, the mixture was concentrated to dryness. MeOH (30 mL) was added and the solid was filtered to give C128 (1400 mg, 14%). 1 H NMR (300MHz, chloroform-d) δ8.26(d,J=10.0Hz, 1H), 7.65~7.34(m, 7H), 5.30(s, 2H), 4.15(dd,J= 11.5, 4.3Hz, 2H), 3.73~3.57(m, 2H), 2.24~2.08(m, 1H), 1.78(d,J=13.4Hz, 2H), 1.28(s, 1H). LCMS m / z 423.22[M+H] + .

[0341] Steps 2-4: 4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-isoquinoline-1-carboxylic acid (C129) Conversion of intermediate C128 to C129 was achieved via standard method B using Pd(OH)2 and standard method D using NaOH, respectively.

[0342] Step 5: 1-[[[4-(4-fluorophenyl)-7-hydroxy-3-tetrahydropyran-4-yl-isoquinoline-1-carbonyl]amino]methyl]cyclopropanecarboxylic acid (144) Method E: Amide coupling method. To a mixture of C129 (40 mg, 0.1089 mmol) in DMF (2 mL) was added ethyl 1-(aminomethyl)cyclopropanecarboxylate (approximately 23.38 mg, 0.1634 mmol), T3P (approximately 138.6 μL of 50% w / v, 0.2178 mmol), and DIPEA (approximately 42.22 mg, 56.90 μL, 0.3267 mmol). The reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the mixture was concentrated to dryness and dissolved in a minimum amount of DMSO. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in HO with 5 mM HCl to give 144 (HCl salt) (5.80 mg, 11%). LCMS m / z 465.19 [M+H] + .

[0343] Compounds 145~155 Compounds 145-155 (Table 12) were prepared in five or six steps from intermediate S11 from the appropriate amine following the method described for compound 144. Any modifications to the method are described in Table 12 and the accompanying footnotes. [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] 1. KOH was added before submitting for purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: 10-100% MeCN in H2O with 0.2% formic acid.

[0344] compound 156 4-[[4-(4-fluorophenyl)-7-hydroxy-1-oxo-3-tetrahydropyran-4-yl-2-isoquinolyl]methyl]cyclohexanecarboxylic acid (156) [ka] Step 1: Methyl 5-benzyloxy-2-bromo-benzoate (C1) Method F: S using alkyl bromides N Reaction 2. To a solution of methyl 2-bromo-5-hydroxybenzoate (5.34 g, 23.113 mmol) in anhydrous DMF (60 mL) was added K2CO3 (6.45 g, 46.669 mmol), followed by benzyl bromide (4.6735 g, 3.25 mL, 27.325 mmol). The mixture was stirred at room temperature for 6 h and then diluted with EtOAc (650 mL). The organic phase was washed with 5% aqueous NaHCO3 (5 × 100 mL) and brine (2 × 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (column: 120 g Combiflash® ISCO. Gradient: 0 to 20% EtOAc in heptane) to give C1 (7.32 g, 98%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ3.85(s, 3H), 5.15(s, 2H), 7.15(dd,J=8.8, 3.1Hz, 1H), 7.26~7.50(m, 6H), 7.53(d,J=8.8Hz, 1H). LCMS m / z 321.0[M+H] + .

[0345] Step 2: Methyl 5-benzyloxy-2-(2-tetrahydropyran-4-ylethynyl)benzoate (C130) Sonogashira coupling procedure. To a mixture of C1 (8 g, 24.91 mmol) and TEA (35 mL, 251.1 mmol) in DMF (50 mL) was added CuI (474 ​​mg, 2.489 mmol), TBAF.3HO (12 mL, 34.34 mmol), and TMS-alkyne (C71) (5.94 g, 32.58 mmol). The mixture was purged with N for 5 min, and then PdCl(PPh) (873 mg, 1.244 mmol) was added. The mixture was purged again with N for 5 min and then heated to 80 °C for 18 h. The reaction mixture was cooled to room temperature, concentrated, diluted with water (500 mL), and extracted with EtOAc (450 mL). The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (Column: 120 g Combiflash® ISCO. Gradient: 0-40% EtOAc in heptane) to give C130 (6 g, 69%). 1 H NMR (300MHz, chloroform-d) δ7.56~7.31(m, 7H), 7.06(dd,J=8.6, 2.8Hz, 1H), 5.11(s, 2H), 4.00(ddd,J=11.5, 5.9, 3.6Hz, 2H), 3.93 (s, 3H), 3.59(ddd,J=11.5, 8.2, 3.1Hz, 2H), 2.93(tt,J=8.3, 4.1Hz, 1H), 1.95(ddt,J=13.4, 6.5, 3.7Hz, 2H), 1.88~1.73(m, 2H).

[0346] Step 3: 7-Benzyloxy-4-iodo-3-tetrahydropyran-4-yl-isochromen-1-one (C131) Electrophilic cyclization of alkynes (I2-promoted). To a solution of C130 (1.54 g, 4.390 mmol) in anhydrous dichloromethane (20 mL) was slowly added a solution of I2 (1.23 g, 4.846 mmol) in anhydrous dichloromethane (24 mL) over 30 minutes at room temperature. The reaction mixture was stirred at room temperature for an additional 20 minutes, and then EtOAc (100 mL) was added. The organic phase was washed with a mixture of 5% aqueous NaHCO3, brine (3 x 100 mL, 90 / 10 ratio), followed by additional brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure, whereupon a white precipitate formed. Filtration of the precipitate afforded C131 (1.76 g, 87%) as a white solid. 1 H NMR (300MHz, chloroform-d) δ7.79(d,J=2.7Hz, 1H), 7.71(d,J=8.9Hz, 1H), 7.52~7.33(m, 7H), 5.20(s, 2H) ), 4.11(dd,J=11.7, 4.3Hz, 2H), 3.61~3.34(m, 3H), 2.24~1.95(m, 2H), 1.75(dq,J=12.9, 1.9Hz, 2H).

[0347] Steps 4-6: 4-[[4-(4-fluorophenyl)-7-hydroxy-1-oxo-3-tetrahydropyran-4-yl-2-isoquinolyl]methyl]cyclohexanecarboxylic acid (156) Conversion of C131 to C133 was achieved via standard method C using RuPhos Pd G4 and K3PO4 in toluene stirred at 70 °C for 2 hours, followed by standard method D using NaOH on C132. C133 underwent standard method E using HATU and DIPEA in DMF, followed by MsOH-mediated cyclization in dichloromethane, then standard method B using LiCl and standard method D, respectively, to form 156. 1H NMR (300MHz, methanol-d4) δ7.57(d,J=2.7Hz, 1H), 7.24~7.10(m, 4H), 6.94(dd,J=8.9, 2.7Hz, 1H), 6.58(d,J=9.0Hz) , 1H), 3.76(d,J=11.5Hz, 2H), 3.04(s, 2H), 2.28~2.09(m, 1H), 1.67(dd,J=41.7, 31.8Hz, 7H), 1.29~1.18(m, 5H). LCMS m / z 480.47[M+H] +

[0348] Compounds 157~159 Compounds 157-159 (Table 13) were prepared in four steps from intermediate C133 using the appropriate amine following the method described for compound 156. Any modifications to the method are described in Table 13 and the accompanying footnotes. [Table 14-1] [Table 14-2]

[0349] compound 160 4-(4-Fluorophenyl)-7-hydroxy-2-(3-hydroxypropyl)-3-tetrahydropyran-4-yl-isoquinolin-1-one (160) [ka] Compound 160 was obtained directly from the reaction of C132 with 3-aminopropanol, followed by MsOH-mediated cyclization, and finally by standard method B and standard method D. 1 H NMR (300MHz, DMSO-d6) δ9.94(s, 1H), 7.59(d,J=2.7Hz, 1H), 7.40~7.24(m, 4H), 7.03(dd,J=8.8, 2.8Hz, 1H), 6.56(s, 1H), 4.73(s, 1H), 4.23(s, 2H), 3.56(d,J=5.4Hz, 2H), 1.85(s, 2H), 1.56(d,J=12.4Hz, 2H). LCMS m / z actual value 398.38[M+H]+ .

[0350] Compounds 161~165 Compounds 161-165 (Table 14) were prepared in 3-5 steps from intermediate C132 using the appropriate amine following the method described for compound 160. Any modifications to the method are described in Table 14 and the accompanying footnotes. [Table 15-1] [Table 15-2] 1. Oxidation to the aldehyde was carried out using Dess-Martin periodinane and NaHCO3. Further oxidation to the carboxylic acid was achieved via treatment with NaClO2 and 2-methylbut-2-ene and Na3PO4. The product was obtained via standard method E using NH3, HATU, and DIPEA before proceeding to standard method B. 2. An additional Mitsunobu reaction with the appropriate amine, PPh3, and ethyl N-ethoxycarbonyliminocarbamate was carried out before proceeding to standard method B.

[0351] Compounds 166~167 Compounds 166-167 (Table 15) were prepared in two steps from intermediate S14 using the appropriate alcohol following the method described for compound 116. Any modifications to the method are described in Table 15 and the accompanying footnotes. [Table 16]

[0352] compound 168 (S)-2-((3-ethyl-4-(4-fluorophenyl)-7-hydroxyisoquinolin-1-yl)oxy)propanoic acid methyl ester (168) [ka] Step 1: 3-ethyl-4-(4-fluorophenyl)-7-methoxy-2H-isoquinolin-1-one (C134) Formation of isoquinolinone using nitrile. LDA (300 μL of 2 M, 0.6000 mmol) was added dropwise to a solution of S15 (126 mg, 0.3995 mmol) in THF (3 mL) at 0 °C. The clear, colorless solution was stirred at the same temperature for 1 h until it turned red and the temperature warmed to 0 °C. To this, propanenitrile (50 μL, 0.7008 mmol) was added dropwise, and the reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was quenched with 1 N HCl (200 μL), and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (column: 4 g Combiflash® ISCO. Gradient: 10–100% EtOAc in hexanes) to give C134 (34 mg, 29%) as an off-white solid. 1 H NMR (400MHz, chloroform-d) δ7.77(d,J=2.8Hz, 1H), 7.19~7.14(m, 2H), 7.14~7.03(m, 3H) ), 6.92(d,J=8.9Hz, 1H), 3.86(s, 3H), 2.37(q,J=7.6Hz, 2H), 1.14(t,J=7.6Hz, 3H). LCMS m / z 298.12[M+H] + .

[0353] Step 2: (2S)-2-[[3-ethyl-4-(4-fluorophenyl)-7-methoxy-1-isoquinolyl]oxy]-methyl propanoate (C135) CsF-mediated displacement using a tosylate. In a round-bottom flask, CsF (60 mg, 0.3950 mmol) was heated under vacuum at 200 °C for 15 min. The flask was then cooled to room temperature and purged with N2. C134 (35 mg, 0.1174 mmol) and DMF (1 mL) were added sequentially to the flask. After the mixture was stirred for 5 min, methyl (2R)-2-(p-tolylsulfonyloxy)propanoate (33 mg, 0.1278 mmol) was added. The reaction mixture was heated at 50 °C and stirred for 12 h. The mixture was quenched with ice water and air-dried. The solid was purified by silica gel chromatography (column: 4 g Combiflash® ISCO, gradient: 0-50% EtOAc in hexanes) to give C135 (17 mg, 33%) as a clear, colorless oil. 1 H NMR (400 MHz, chloroform-d): δ 7.52 (t, J = 1.6 Hz, 1H), 7.16–7.05 (m, 6H), 5.42 (q, J = 7.0 Hz, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 2.47–2.31 (m, 2H), 1.69 (d, J = 7.1 Hz, 3H), 1.05 (t, J = 7.5 Hz, 3H). LCMS m / z 714.03 [M+H] + .

[0354] Step 3: (2S)-2-[[3-ethyl-4-(4-fluorophenyl)-7-hydroxy-1-isoquinolyl]oxy]propanoic acid (168) Method G: Demethylation Reaction. To a solution of C135 (17 mg, 0.04434 mmol) in EtSH (250 μL) was added AlBr3 (70 mg, 0.2625 mmol) at 0 °C. The reaction was stirred for 1 h. Additional AlBr3 (70 mg, 0.2625 mmol) was added to drive the reaction to completion. After an additional 1 h, the reaction was dried under air and the crude product was dissolved in a minimal amount of ACN (0.5 mL). The residue was purified by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: 0 to 70% MeCN in HO with 0.2% formic acid to give 168 (3 mg, 19%). 1H NMR (400 MHz, chloroform-d) δ 7.73–7.66 (m, 0H), 7.63–7.57 (m, 1H), 7.24–7.14 (m, 6H), 5.53–5.41 (m, 1H), 3.22 (q, J = 7.1 Hz, 1H), 2.60–2.43 (m, 2H), 1.79 (dd, J = 6.9, 5.6 Hz, 3H), 1.16 (td, J = 7.5, 1.8 Hz, 3H). LCMS m / z 356.19 [M+H] + .

[0355] Compounds 169~172 Compounds 169-172 (Table 16) were prepared in three steps from intermediate S15 using the appropriate nitrile and alcohol according to the method described for compound 168. Any modifications to the method are described in Table 16 and the accompanying footnotes. [Table 17-1] [Table 17-2] 1, Benzyl 3-(p-tolylsulfonyloxy)cyclobutanecarboxylate was used as a reactant in the second step.

[0356] compound 175 4-(4-Fluorophenyl)-7-hydroxy-3-isopropyl-isoquinoline-1-carbonitrile (175) [ka] Step 1: 7-benzyloxy-4-(4-fluorophenyl)-3-isopropyl-isoquinoline-1-carbonitrile (C136) DBU (85 μL, 0.5684 mmol) and TMSCN (42 μL, 0.3150 mmol) were added to a suspension of C21 (100 mg, 0.2581 mmol) in dry THF (1.5 mL) at room temperature. The mixture was heated at 50 °C, and after stirring for 15 min, the mixture became homogeneous. After stirring for 3 h, a precipitate formed, and the reaction mixture was diluted with EtOAc and washed with 1 M HCl. The organic layer was washed with NH OH and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography (column: 4 g Combiflash® ISCO. Gradient: 0-20% EtOAc in heptane) to give C136 (40 mg, 39%) as a colorless solid. 1 H NMR (300MHz, chloroform-d) δ7.63 (dd, J=2.3, 0.8Hz, 1H), 7.58~7.49 (m, 2H), 7.49~7.31 (m, 5H), 7.25 (m, 4H), 5.29 (s, 2H), 3.00 (hept,J=6.8Hz, 1H), 1.24 (d,J=6.7Hz, 6H).

[0357] Step 2: 4-(4-fluorophenyl)-7-hydroxy-3-isopropyl-isoquinoline-1-carbonitrile (175) Compound C136 was subjected to standard method B to provide 175. 1 H NMR (300 MHz, chloroform-d) δ 7.68 (dd, J = 2.4, 0.7 Hz, 1H), 7.44–7.16 (m, 6H), 6.40 (s, 1H), 3.00 (h, J = 6.7 Hz, 1H), 1.24 (d, J = 6.8 Hz, 6H). LCMS m / z 307.58 [M+H] + .

[0358] compound 176 2-[[3-(Dimethylamino)-4-(4-fluorophenyl)-7-methoxy-1-isoquinolyl]oxy]acetic acid (176) [ka] Step 1: Methyl 2-[(3-chloro-7-methoxy-1-isoquinolyl)oxy]acetate (C137) Method H: Nucleophilic substitution using an alcohol. To a mixture of C22 (5.09 g, 22.32 mmol) and methyl 2-hydroxyacetate (1.8 mL, 23.32 mmol) in THF (100 mL) was added dropwise KOtBu (25 mL of 1 M, 25.00 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. Additional methyl 2-hydroxyacetate (1.8 mL, 23.32 mmol) and KOtBu (25 mL of 1 M, 25.00 mmol) were added to drive the reaction to completion. Saturated NH4Cl was added to the reaction mixture, which was extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and water (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (Column: 120 g gold Combiflash® ISCO. Gradient: 0-100% EtOAc in heptane) to yield C137 (3560 mg, 55%). 1 H NMR (400 MHz, chloroform-d) δ 7.61–7.50 (m, 2H), 7.33 (dt, J = 9.0, 1.9 Hz, 1H), 7.24 (s, 1H), 5.12 (d, J = 1.4 Hz, 2H), 3.95 (d, J = 1.4 Hz, 3H), 3.82 (d, J = 1.4 Hz, 3H). LCMS m / z 282.18 [M+H] + .

[0359] Step 2: Methyl 2-[[3-(dimethylamino)-7-methoxy-1-isoquinolyl]oxy]acetate (C138) Method I: Buchwald Coupling Method. A suspension of C137 (70 mg, 0.2401 mmol), N-methylmethanamine (HCl salt) (25 μL, 0.2876 mmol), CsCO (300 mg, 0.9208 mmol), and dioxane (3 mL) was purged under N for 5 minutes. To this, RuPhos Pd G (10 mg, 0.01287 mmol) was added, and the mixture was purged under N for an additional 5 minutes. The reaction mixture was heated to 80 °C and stirred for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in a minimal amount of DMSO (2 mL) and purified by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: 2 to 98% MeCN in HO with 0.2% formic acid to give C138 (32 mg, 41%). LCMS m / z 290.91[M+H] + .

[0360] Steps 3-5: 2-[[3-(dimethylamino)-4-(4-fluorophenyl)-7-methoxy-1-isoquinolyl]oxy]acetic acid (C139) Compound C138 then underwent bromination with NBS in dichloromethane. Further conversion to C139 was achieved following standard method B using 4-fluorophenylboronic acid followed by standard method D using NaOH.

[0361] Step 6: 2-[[3-(dimethylamino)-4-(4-fluorophenyl)-7-methoxy-1-isoquinolyl]oxy]acetic acid (176) Compound 176 was obtained following standard procedure G. 1 H NMR (400MHz, methanol-d4) δ8.09(s, 2H), 7.54(d,J=2.5Hz, 1H), 7.41~7.34(m, 2H), 7.30~7. 23(m, 2H), 7.20(d,J=9.1Hz, 1H), 7.13(dd,J=9.1, 2.6Hz, 1H), 5.04(s, 2H), 2.80(s, 6H). LCMS m / z 357.27[M+H] + .

[0362] Compounds 177~181 Compounds 177-181 (Table 17) were prepared in five steps from intermediate C137 using the appropriate amine following the method described for compound 176. Any modifications to the method are described in Table 17 and the accompanying footnotes. [Table 18-1] [Table 18-2] 1. (4-Fluoro-3-methyl-phenyl)boronic acid was used in the fourth step. 2. MOM deprotection was achieved using HCl instead of standard method G. 3. Reaction with BBr3 resulted in F displacement to form the product.

[0363] Compounds 182~184 Compounds 182-184 (Table 18) were prepared in two or three steps from intermediate S16 using 3-hydroxycyclobutanecarboxylic acid according to the method described for compound 116. Any modifications to the method are described in Table 18 and the accompanying footnotes. [Table 19] 1. Pd-catalyzed transfer hydrogenation of compound 182 in MeOH also resulted in the formation of compound 179. 2. Compound 184 was synthesized from further treatment of compound 182 with NH 4 Cl, HATU, and DIPEA according to standard method E.

[0364] compound 185 3-[[7-Hydroxy-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (185) [ka] Step 1: 7-benzyloxy-4-(2-methyl-4-pyridyl)-2-oxide-3-tetrahydropyran-4-yl-isoquinolin-2-ium (C34) C34 was synthesized according to standard method C.

[0365] Step 2: 1-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-7-benzyloxy-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-isoquinoline (S20) Method J: Amination of N-oxide using TFAA and DABCO. A solution of C34 (513 mg, 1.203 mmol) and DABCO in dichloromethane (10 mL) was cooled to 0 °C, to which was added TFAA (450 μL, 3.237 mmol). The mixture was allowed to warm to room temperature and then stirred for 1 h. The reaction mixture was concentrated, dissolved in a minimal amount of DMSO, and purified by reverse-phase HPLC (C18, 10-100% MeCN in HO with 0.1% trifluoroacetic acid) to give S20 (trifluoroacetate salt) as an off-white solid (930 mg, 99%). LCMS m / z 521.35 [M+H] + .

[0366] Steps 3 and 4: 3-[[7-hydroxy-4-(2-methyl-4-pyridyl)-3-tetrahydropyran-4-yl-1-isoquinolyl]oxy]cyclobutanecarboxylic acid (185) S20 was then subjected to standard method A followed by standard method B to form 185. 1 H NMR (300MHz, chloroform-d and methanol-d4) δ8.54 (dd, J=5.2, 0.8Hz, 1H), 7.57 (dd,J=2.6, 0.5Hz, 1H), 7.20~6.98 (m, 4H), 5.71~5.56 (m, 1H), 3.99(d,J=11.1Hz, 2H), 3.35~3.09(m, 2H), 3.00~2.86(m, 2H), 2.73~2.49(m, 6H), 2.36~1.97(m, 3H), 1.48(d,J=13.0Hz, 2H). LCMS m / z 435.37[M+H] + .

[0367] Compounds 186~190 Compounds 186-190 (Table 19) were prepared in four or five steps from intermediate S11 using the appropriate boronic acid or ester following the method described for compound 185. Any modifications to the method are described in Table 19 and the accompanying footnotes. [Table 20-1] [Table 20-2] [Table 20-3]

[0368] Compound 191 3-[(4-cyclopropyl-7-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl)oxy]cyclobutanecarboxylic acid (191) [ka] Steps 1 and 2: 3-[(7-benzyloxy-4-bromo-3-tetrahydropyran-4-yl-1-isoquinolyl)oxy]cyclobutanecarboxylic acid (C142) C142 was synthesized following standard method J using S11 followed by standard method A to C141.

[0369] Step 3: 3-[(7-benzyloxy-4-cyclopropyl-3-tetrahydropyran-4-yl-1-isoquinolyl)oxy]cyclobutanecarboxylic acid (C143) Negishi coupling method. A suspension of C142 (20 mg, 0.03751 mmol), bromo(cyclopropyl)zinc (400 μL of 0.5 M, 0.200 mmol), and THF (1 mL) was purged under N for 5 minutes. To this, Cphos Pd G3 (10 mg, 0.0124 mmol) and DavePhos (5 mg, 0.01271 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (100 g C18, 10-100% MeCN in HO with 0.1% trifluoroacetic acid) to give C143 (10 mg, 55%). LCMS m / z 474.31 [M+H] + .

[0370] Step 4: 3-[(4-cyclopropyl-7-hydroxy-3-tetrahydropyran-4-yl-1-isoquinolyl)oxy]cyclobutanecarboxylic acid (191) Compound 191 was synthesized according to standard method B. 1 H NMR (400MHz, methanol-d4) δ8.24(d,J=9.1Hz, 1H), 7.43(d,J=2.6Hz, 1H), 7.23(dd,J=9.1, 2.7Hz, 1H), 5.58~5.46(m, 1H), 4.06(dd,J=11.4, 4.3Hz, 2H), 3.76(tt,J=11.6, 3.7Hz, 1H), 3.61(ddd,J=13.1, 11.4, 1.9Hz, 2H), 3.24~3.11( m, 1H), 2.84(dddd,J=11.4, 7.3, 4.1, 2.5Hz, 2H), 2.52(dtd,J=13.5, 6.6, 2.8Hz, 2H), 2.16(qd,J=12.8, 4.5Hz, 2H) , 1.88(tt,J=8.3, 5.6Hz, 1H), 1.53(ddd,J=12.9, 3.9, 1.8Hz, 2H), 1.25~1.15(m, 2H), 0.53(td,J=5.9, 4.1Hz, 2H). LCMS m / z 384.24[M+H] + .

[0371] Compounds 192~194 Compounds 192-194 (Table 20) were prepared in three or four steps from intermediate S11 using the appropriate alkylzinc reagent or amine following the method described for compound 191. Any modificati...

Claims

1. A compound of formula I, 【Chemistry 153】 Deuterated derivatives of compounds of formula I, and / or pharmaceutically acceptable salts of any of the foregoing, wherein: R １ and R １’ is hydrogen, halogen, —OH, —O(benzyl), and —NH ２ and R １ and R １’ one of which is -OH, -O(benzyl), or NH ２ and the other is hydrogen or halogen; W １ and W ２ are respectively -CR ｘ and R ｘ is hydrogen or halogen, X is -C=O, -CR ２ , N, and -NR ３ is selected from Y is -C=O, -CR ２ , N, and -NR ３ is selected from When X is —C═O, Y is —NR ３ and X is -CR ２ when Y is N; When X is N, Y is -CR ２ and X is -NR ３ when Y is —C═O, (z) is a double bond unless X or Y is C=O, and when X or Y is C=O, (z) is a single bond; R ２ is -CN, -C(=O)OH, -C(=O)NH ２ , -C(=O)NHR ７ , -C(=O)NHCH ２ R ７ , -OCH ２ R ７ , -OR ７ , -NHR ７ , -NHCH ２ R ７ , C ６ or C １０ Aryl, 5- to 10-membered heteroaryl, C １ ~C ８ Alkyl, C ３ ~C ８ Cycloalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ heteroalkyl, and 3- to 10-membered heterocyclyl; The R ２ wherein the alkyl, heteroalkyl, alkenyl, heterocyclyl, aryl, or heteroaryl is independently selected from halogen, —C(═O)OH, C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, C ６ or C １０ Aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl (halogen, —OH, —OCH ３ and / or —C(═O)OH), and C ３ ~C ６ Cycloalkyl (halogen, -OH, -OCH ３ and / or —C(═O)OH), The R ２ wherein the heteroalkyl contains 1 to 3 heteroatoms selected from N, O, and S; R ３ But hydrogen, C ６ or C １０ Aryl, C １ ~C ８ Alkyl, and C ３ ~C ８ cycloalkyl; R ３ are independently ═O, —OH, —CH ２ OH, -C(=O)OH, NH ２ , C ３ ~C ６ Cycloalkyl (=O, -CH ２ 3- to 6-membered heterocyclyl (optionally substituted with -OH, and / or -C(=O)OH), and 3- to 6-membered heterocyclyl (=O, -CH ２ optionally substituted with 1 to 3 groups selected from -OH, and / or -C(=O)OH; The R ３ the heterocyclyl contains 1 to 3 nitrogen atoms, R ３ But C ３ ~C ６ optionally fused to a cycloalkyl; R ４ but, 【Chemistry 169】 is selected from R ５ But C ６ or C １０ aryl, —O(phenyl), and 5- or 6-membered heteroaryl, wherein said heteroaryl contains 1 to 3 nitrogen atoms; R ５ However, (R ６ ) ｎ and n is 1, 2 or 3; However, R ５ is not imidazolyl, R ６ are each independently a halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ３ haloalkoxy; R ７ But C １ ~C ８ Alkyl, C ３ ~C ８ Cycloalkyl, C ６ or C １０ Aryl, C ２ ~C ８ selected from heteroalkyl, 3- to 8-membered heterocyclyl, and 5- to 8-membered heteroaryl; R ７ are independently halogen, ═O, —OH, —OCH ３ , -CH ３ , -C(=O)OH, -C(=O)NR ８ , -CN, -NH ２ , C １ ~C ６ Alkyl (=O, -OH, -CN, -C(=O)OH, and -NH ２ optionally substituted with 1 to 3 groups selected from ３ ~C ６ Cycloalkyl (=O, -OH, -CN, -C(=O)OH, and -NH ２ optionally substituted with 1 to 3 groups selected from ６ or C １０ Aryl (=O, -OH, -CN, -C(=O)OH, and -NH ２ optionally substituted with 1 to 3 groups selected from ２ ~C ６ Heteroalkyl (=O, -OH, -CN, -C(=O)OH, and -NH ２ and 3- to 6-membered heterocyclyl (=O, -OH, -CN, -COOH, and -NH ２ optionally substituted with 1 to 3 groups selected from: 5- or 6-membered heteroaryl (═O, —OH, —CN, —COOH, and —NH ２ optionally substituted with 1 to 3 groups selected from The R ７ wherein the heteroalkyl, heterocyclyl, or heteroaryl of the formula (I) contains 1 to 3 atoms selected from N, O, and S; R ８ But C １ ~C ６ Alkyl and C ６ or C １０ aryl, R ８ is optionally substituted with halogen and / or —OH, or a deuterated derivative or pharmaceutically acceptable salt thereof.

2. Compounds of formula Ia(i), Ia(ii), Ia(iii), Ia(iv), Ia(v), and Ia(vi), 【Chemistry 154】 selected from deuterated derivatives of formula Ia(i), Ia(ii), Ia(iii), Ia(iv), Ia(v), and Ia(vi), and pharmaceutically acceptable salts of any of the foregoing; In the formula, R １’ is selected from hydrogen and halogen, and R ２ , R ３ , R ４ , R ５ , R ６ and n is as defined in claim 1, a deuterated derivative, or a pharmaceutically acceptable salt of the compound of claim 1.

3. Compounds of formula Ib(i), Ib(ii), Ib(iii), Ib(iv), Ib(v), and Ib(vi), 【Chemistry 155】 selected from deuterated derivatives of formula Ib(i), Ib(ii), Ib(iii), Ib(iv), Ib(v), and Ib(vi), and pharmaceutically acceptable salts of any of the foregoing; In the formula, R １’ is selected from hydrogen and halogen, and R ２ , R ３ , R ４ , R ５ , R ６ and n is as defined in claim 1, a deuterated derivative, or a pharmaceutically acceptable salt of the compound of claim 1.

4. Compounds of formula Ic(i), Ic(ii), Ic(iii), Ic(iv), Ic(v), and Ic(vi), 【Chemistry 156】 selected from deuterated derivatives of formula Ic(i), Ic(ii), Ic(iii), Ic(iv), Ic(v), and Ic(vi), and pharmaceutically acceptable salts of any of the foregoing; In the formula, R １ is selected from hydrogen and halogen, and R ２ , R ３ , R ４ , R ５ , R ６ and n is as defined in claim 1, a deuterated derivative, or a pharmaceutically acceptable salt of the compound of claim 1.

5. Compounds of formula Id(i), Id(ii), Id(iii), Id(iv), Id(v), and Id(vi), 【Chemistry 157】 selected from deuterated derivatives of formulae Id(i), Id(ii), Id(iii), Id(iv), Id(v), and Id(vi), and pharmaceutically acceptable salts of any of the foregoing; In the formula, R １ is selected from hydrogen and halogen, and R ２ , R ３ , R ４ , R ５ , R ６ and n is as defined in claim 1, a deuterated derivative, or a pharmaceutically acceptable salt of the compound of claim 1.

6. R １ 2. The compound, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein: is -OH.

7. R １’ 2. The compound, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein: is -OH.

8. R １ But -NH ２ 2. The compound, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein:

9. R １’ But -NH ２ 2. The compound, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein:

10. R ３ phenyl and C ３ ~C ８ cycloalkyl; -R ３ are independently ═O, —OH, —CH ２ OH, -C(=O)OH, -NH ２ , C ３ ~C ６ Cycloalkyl (independently: ═O, —CH ２ and 3- to 6-membered heterocyclyl (independently selected from ═O, —CH ２ optionally further substituted with 1 to 3 groups selected from —OH, and —C(═O)OH; - said 3- to 6-membered heterocyclyl contains 1 to 2 nitrogen atoms, -R ３ But C ３ ~C ６ 10. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 9, optionally fused to a cycloalkyl.

11. R ３ are independently ═O, —OH, —CH ２ OH, -C(=O)OH, -NH ２ , C ３ ~C ６ Cycloalkyl (independently: ═O, —CH ２ and 3- to 6-membered heterocyclyl (independently selected from ═O, —CH ２ -C(═O)-, ... １ ~C ６ alkyl, - said 3- to 6-membered heterocyclyl contains 1 to 2 nitrogen atoms, -R ３ But C ３ ~C ６ 10. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 9, optionally fused to a cycloalkyl.

12. R ３ are independently ═O, —OH, —CH ２ OH, —C(═O)OH, and —NH ２ C optionally substituted with 1 to 2 groups selected from ４ Cyclic alkyl and C ８ 10. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 9, selected from spirocyclic alkyls.

13. R ３ but, 【Chemistry 158】 10. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 9, selected from:

14. R ３ 10. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 9, wherein is hydrogen.

15. R ４ but, [Chemical 160] 15. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 14, wherein:

16. R ４ but, 【Chemistry 161】 15. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 14, wherein:

17. R ５ is selected from phenyl and 5- or 6-membered heteroaryl; -R ５ are independently halogen and —CH ３ 17. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 16, optionally substituted with one or two groups selected from:

18. R ５ but, 【Chemistry 162】 18. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 17, selected from:

19. R ５ but, 【Chemical 163】 19. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 18, selected from:

20. R ２ But, -OR ７ 20. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 19, selected from:

21. R ２ But, -NHR ７ 20. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 19, selected from:

22. R ２ is -C(=O)NHR ７ 20. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 19, selected from:

23. R ２ But -NHCH ２ R ７ 20. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 19, selected from:

24. R ２ is -CN, -C(=O)OH, -C(=O)NH ２ , -C(=O)NHCH ２ R ７ , and -OCH ２ R ７ 20. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 19, selected from:

25. R ７ But C １ ~C ８ Alkyl and C ３ ~C ８ cycloalkyl, each of which is independently selected from Br, Cl, F, —CH ３ , -C(=O)OH, =O, -OCH ３ 25. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 20 to 24, optionally substituted with 1 to 3 groups selected from -, and -OH.

26. R ７ But C ２ ~C ８ selected from heteroalkyl and 3- to 8-membered heterocyclyl; said heteroalkyl or heterocyclyl contains 1 to 3 heteroatoms selected from N, O and S, said heteroalkyl or heterocyclyl is independently Br, Cl, F, —CH ３、 -C(=O)OH,=O,-OCH ３ 25. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 20 to 24, optionally substituted with 1 to 3 groups selected from -, and -OH.

27. R ７ is selected from aryl and 3- to 8-membered heteroaryl; said heteroalkyl or heterocyclyl contains 1 to 3 heteroatoms selected from N, O and S, said heteroalkyl or heterocyclyl is independently Br, Cl, F, —CH ３、 -C(=O)OH,=O,-OCH ３ 25. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 20 to 24, optionally substituted with 1 to 3 groups selected from -, and -OH.

28. R ７ But C １ ~C ８ Alkyl, C ３ ~C ８ Cycloalkyl, C ２ ~C ８ selected from heteroalkyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 8-membered heteroaryl; -R ７ are independently selected from halogen, ═O, —C(═O)OH, phenyl, 5- to 8-membered heteroaryl, C １ ~C ６ Alkyl (=O, OH, CN, COOH, and NH ２ optionally further substituted with 1 to 3 groups selected from ３ ~C ６ Cycloalkyl (=O, -OH, -CN, -COOH, and -NH ２ optionally further substituted with 1 to 3 groups selected from ２ ~C ６ Heteroalkyl (halogen, ═O, —OH, —CN, —COOH, and —NH ２ and 3- to 6-membered heterocyclyl (═O, —OH, —CN, —COOH, and —NH ２ optionally further substituted with 1 to 3 groups selected from - the R ７ 25. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 20-24, wherein the heteroalkyl, heterocyclyl, or heteroaryl of the formula (I) contains 1 to 3 atoms independently selected from N, O, and S.

29. R ２ but, 【Chemistry 164-1】 【Chemistry 164-2】 【Chemistry 164-3】 【Chemistry 164-4】 【Chemistry 164-5】 【Chemistry 164-6】 20. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 19, selected from:

30. R ２ but, 【Chemistry 165-1】 【Chemistry 165-2】 20. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 19, selected from:

31. R ２ but, 【Chemistry 166-1】 【Chemistry 166-2】 【Chemistry 166-3】 20. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 19, selected from:

32. R ２ but, 【Chemistry 167-1】 【Chemistry 167-2】 20. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 19, selected from:

33. A compound comprising: 【Chemistry 168-1】 【Chemistry 168-2】 【Chemistry 168-3】 【Chemistry 168-4】 【Chemistry 168-5】 【Chemistry 168-6】 【Chemistry 168-7】 【Chemistry 168-8】 【Chemistry 168-9】 【Chemistry 168-10】 【Chemistry 168-11】 【Chemistry 168-12】 【Chemistry 168-13】 【Chemistry 168-14】 【Chemistry 168-15】 【Chemistry 168-16】 【Chemistry 168-17】 【Chemistry 168-18】 【Chemistry 168-19】 【Chemistry 168-20】 【Chemistry 168-21】 【Chemistry 168-22】 【Chemistry 168-23】 【Chemistry 168-24】 A compound selected from deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing.

34. 34. A pharmaceutical composition for treating alpha-1 antitrypsin deficiency in a patient in need thereof, said pharmaceutical composition comprising at least one compound selected from the compounds of any one of claims 1 to 33, deuterated derivatives, and pharmaceutically acceptable salts.

35. 35. The pharmaceutical composition of claim 34, wherein the patient has a Z mutation in alpha-1 antitrypsin.

36. 35. The pharmaceutical composition of claim 34, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

37. 36. The pharmaceutical composition of claim 35, wherein the patient is homozygous for the Z mutation in alpha-1 antitrypsin.

38. 34. A pharmaceutical composition for modulating alpha-1 antitrypsin activity, said pharmaceutical composition comprising at least one compound selected from the compounds of any one of claims 1 to 33, deuterated derivatives, and pharmaceutically acceptable salts.

Images