Modulators of alpha-1 antitrypsin

Abstract

1H-Pyrazolo[4,3-g]isoquinoline and 1H-pyrazolo[4,3-g]quinoline derivatives as alpha-1-antitrypsin modulators for treating alpha-1-antitrypsin deficiency (AATD).

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 004,719, filed April 3, 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

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

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

[0004] The mutation most commonly associated with AATD involves a substitution of lysine for glutamic acid (E342K) in the SERPINA1 gene, which encodes the AAT protein. This mutation, known as the Z mutation or Z allele, leads to misfolding of the translated protein, so that it is not secreted into the bloodstream and can polymerize within the producing cells. As a result, circulating AAT levels in individuals homozygous for the Z allele (PiZZ) are significantly reduced, and only about 15% of the mutant Z-AAT protein is correctly folded and secreted by cells. An additional consequence of the Z mutation is that secreted Z-AAT has reduced activity compared to the wild-type protein, with 40% to 80% of the normal antiprotease activity (American thoracic society / European respiratory society, Am J Respir Crit Care Med. 2003;168(7):818-900, and Ogushi et al. J Clin Invest. 1987;80(5):1366-74). Accumulation of polymerized Z-AAT protein within hepatocytes results in gain-of-function cytotoxicity, which can lead to cirrhosis or liver cancer later in life and neonatal liver disease in 12% of patients. This accumulation can resolve spontaneously, but can be fatal in a small number of children. A lack of circulating AAT leads to unregulated protease activity, which degrades lung tissue over time and leads to emphysema, a form of chronic obstructive pulmonary disease (COPD). This effect is severe in 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. [Prior art documents] [Non-patent literature]

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

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

[0007] The current standard of care for individuals with AAT deficiency who show 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 is a compound of formula I: [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Z 1 , Z 2 , and Z 3 are each independently -N, -NH, or -CH, with the proviso that Z 1 , Z 2 , and Z 3 is N or —NH; V 1 and V 2 are each selected from C and N; W 1 and W 2 are -C=O and -CR, respectively. 2 , N, and -NR 2 is selected from W 1 Ga-CR2 When W 2 is N, W 2 Ga-CR 2 When W 1 is N or -NR 2 and W 1 When is -C=O, W 2 Ga-NR 2 and W 2 When is -C=O, W 1 Ga-NR 2 and [ka] is, for each of two occurrences, a single bond or a double bond, provided that one is a single bond and the other is a double bond; W 1 and W 2 (h) is a double bond, except that (h) is a single bond when either one of R 0 But halogen or [ka] and Ring A is C3~C 12 Carbocyclyl, 3- to 12-membered heterocyclyl, C6 or C 10 aryl, or 5- to 10-membered heteroaryl; R 1 is halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(=O)R z , -C(=O)OR z , -C(=O)NR w R x , -NR w R x , -NR w C(=O)R z , -NR w C(=O)OR z , -NR w C(=O)NR x Ry , -OR z , -OC(=O)R z , -OC(=O)NR w R x , S(=O)2R z , C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl; R 1 C1-C6 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl is -OR z , optionally substituted with 1 to 3 groups selected from C1-C3 haloalkyl, —CN, and halogen; R w , R x , R y , and R z are each independently hydrogen or C1-C4 alkyl, X 1 and X 2 are each independently hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 cycloalkyl, or 5- or 6-membered heteroaryl; R 2 But hydrogen, halogen, [ka] and T is absent, a bond, or selected from —O—, —OCH—, —NH—, —NS(═O)CH, —S—, and —CH—; Y is C1-C6 alkyl, -(CR a R a ) p COOH, -(CR a R a ) p NR b S(=O)2(CR c R c ) q OH, -(CR a R a ) p C(=O)NR b (CR c R c )q COOH, and -(CR a R a ) p (O)(CR c R c ) q COOH, R a is, for each occurrence, independently, halogen, —OH, or C1-C4 alkyl optionally substituted with 1 to 3 groups selected from halogen and —OH; or alternatively, R a is a C1-C4 alkyl for each occurrence, two R a groups together with the intervening carbon atoms form a cyclopropyl or cyclobutyl; R b and R c are, for each occurrence, independently hydrogen or C1-C2 alkyl; p and q are each independently an integer selected from 1 and 2; Ring B is C3~C 12 Carbocyclyl, 3- to 12-membered heterocyclyl, C6 or C 10 aryl, or 5- to 10-membered heteroaryl; R 3 But -C(=O)OR d and R d But -OC(O)R e , -OC(=O)OR e , or -OP(=O)OR f R f C1-C4 alkyl optionally substituted with R e is, for each occurrence, independently hydrogen, —CH3, or —C2H5; R f is, for each occurrence, independently -OH, -CH3, -C2H5, -OCH3, or -OC2H5, R k is halogen, —CN, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, or O—(C3-C6 cycloalkyl), R m is, for each occurrence, independently selected from halogen, —CN, ═O, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)R r , -C(=O)OR r , -C(=O)NR p R q , -C(=O)NR p OR r , -NR p R q , -NR p C(=O)R r , -NR p S(=O)2R r 、 -OR r , S(=O)2R r , -S(=O)2NR p R q ,-P(=O)R s R t , C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; R m C1-C6 alkyl, phenyl, or 5- or 6-membered heteroaryl is halogen, CN, —C(═O)OR r , -NR p R q , and -OR r and optionally substituted with 1 to 3 groups selected from R m C3-C6 cycloalkyl or 3-6 membered heterocyclyl is halogen, CN, =O, -C(=O)OR r , -NR p R q , and -OR r and optionally substituted with 1 to 3 groups selected from R p and R q are each independently, for each occurrence, hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 groups selected from -OH, -OCH3, -OC2H5, and -COOH; R ris, for each occurrence, independently at each occurrence, hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl; R r wherein the C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from -OH, -OCH3, -OC2H5, -CH2OH, -C(=O)OH, -(O)C(=O)OH, and -(O)P(=O)(OH)2; R s and R t is, for each occurrence, independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or —OH; k and m are each independently an integer selected from 0, 1, 2, 3, 4, and 5; The present invention provides a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, and 2.

[0009] Another aspect of the present disclosure provides compounds of Formula II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, VIIIa-c, and compounds 1-262, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts disclosed herein.

[0010] The compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c are modulators of AAT activity. In some embodiments, the compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, 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. 50In some embodiments, compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an EC of less than 0.5 μM when tested in an AAT functional assay. 50 It has.

[0011] In some embodiments, compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an IC of 5.0 μM or less when tested in a Z-AAT elastase activity assay. 50 In some embodiments, compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an IC of less than 2.0 μM when tested in a Z-AAT elastase activity assay. 50 It has.

[0012] In some embodiments, compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an EC of 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 50In some embodiments, compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an EC of less than 0.5 μM when tested in an AAT functional assay. 50 and has an IC of 5.0 μM or less when tested in the Z-AAT elastase activity assay 50 In some embodiments, compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an EC of 2.0 μM or less when tested in an AAT functional assay. 50 and has an IC of less than 2.0 μM when tested in the Z-AAT elastase activity assay 50 In some embodiments, compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an EC of less than 0.5 μM when tested in an AAT functional assay. 50 and has an IC of less than 2.0 μM when tested in the Z-AAT elastase activity assay 50 It has.

[0013] In some embodiments, compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, 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.

[0014] In one aspect of the present disclosure, compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, and compounds 1-262, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, may be employed in the treatment of AATD.

[0015] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In specific embodiments, pharmaceutical compositions can comprise a compound selected from compounds 1-262, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions can further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0016] 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 Formulas I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, a tautomer thereof, a deuterated derivative of such a compound or tautomer, and a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In a specific embodiment, the method comprises administering a compound selected from Compounds 1-262, a tautomer thereof, a deuterated derivative of such a compound or tautomer, and a pharmaceutically acceptable salt of any of the foregoing.

[0017] 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 compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions. In specific embodiments, the method comprises administering a compound selected from Compounds 1-262, tautomers thereof, deuterated derivatives of those compounds or 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 separate compositions. In some embodiments, the subject in need of treatment carries a ZZ mutation. In some embodiments, the subject in need of treatment carries an SZ mutation.

[0018] Also provided are methods for modulating AAT, comprising administering to a subject in need of AAT modulation at least one compound selected from the compounds of Formulas I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or salt. In specific embodiments, the method for modulating AAT comprises administering to a subject in need of AAT modulation a pharmaceutical composition comprising at least one compound selected from compounds 1-262, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or at least one compound, tautomer, deuterated derivative, or salt.

[0019] Also provided are compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, tautomers of these compounds, deuterated derivatives of these 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 1-262, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy.

[0020] Also provided are pharmaceutical compositions comprising a compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, or a tautomer of such a compound, a deuterated derivative of such a compound and tautomer, or a pharmaceutically acceptable salt of any of the foregoing, for use in therapy. In some embodiments, pharmaceutical compositions are provided comprising a compound selected from Compounds 1-262, a tautomer of such a compound, a deuterated derivative of such a compound and tautomer, and a pharmaceutically acceptable salt of any of the foregoing, for use in therapy.

[0021] 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.

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

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

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

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

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

[0027] The compounds of the present disclosure 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.

[0028] The term "isotopically modified" refers to a species whose chemical structure differs from a specific compound of the present disclosure only in its isotopic composition. Additionally, unless otherwise specified, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure can be modified by the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Except for the replacement of carbon with C, it is within the scope of this disclosure.

[0029] 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.

[0030] 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.

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

[0032] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ("D"). It will be recognized that some variation in natural isotopic abundance will occur in synthesized compounds depending on the 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).

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

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

[0035] 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.

[0036] 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.

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

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

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

[0040] 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.

[0041] 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.

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

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

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

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

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

[0047] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems in which at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the system contains 3 to 7 ring members, for a total of 5 to 14 ring members. In some embodiments, heteroaryl contains 6 or 10 ring atoms.

[0048] Examples of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, t-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.

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

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

[0051] The present disclosure includes pharmaceutically acceptable salts of the disclosed compounds. A salt of a compound is 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.

[0052] As used herein, the term "pharmaceutically acceptable" refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" refers to any non-toxic salt that, upon administration to a recipient, is capable of providing, 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.

[0053] 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.

[0054] 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.

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

[0056] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to that amount of a 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 an 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).

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

[0058] The terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, include a 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.

[0059] Any one or more of the compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, their tautomers, 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 specific embodiments, any one or more compounds are selected from Compounds 1-262, their tautomers, 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 the compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered once daily. In specific embodiments, a compound selected from compounds 1-262, a tautomer thereof, a deuterated derivative of the compound or tautomer, and a pharmaceutically acceptable salt of any of the foregoing are administered once daily. In some embodiments, at least one compound selected from compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, a tautomer thereof, a deuterated derivative of the compound or tautomer, and a pharmaceutically acceptable salt of any of the foregoing are administered twice daily. In specific embodiments, a compound selected from compounds 1-262, a tautomer thereof, a deuterated derivative of the compound or tautomer, and a pharmaceutically acceptable salt of any of the foregoing are administered twice daily. In some embodiments, at least one compound selected from compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered three times daily.In a specific embodiment, a compound selected from compounds 1-262, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered three times daily.

[0060] Any one or more of the compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, their tautomers, 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 specific embodiments, any one or more compounds is selected from Compounds 1-262, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

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

[0062] References herein to methods of treatment (e.g., methods of treating AATD) using one or more compounds (e.g., compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c), and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds) are intended to include, but are not limited to, methods of treating AATD. one or more compounds for use in methods of treating, for example, AATD (e.g., compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, as well as tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds), and / or It should be understood that this should also be construed as a reference to the use of one or more compounds (e.g., compounds of Formulas I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c), as well as tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds) in the manufacture of a medicament for treating, for example, AATD.

[0063] Exemplary embodiments: Some non-limiting embodiments of the present disclosure include the following: 1. A compound represented by formula I: [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Z 1 , Z 2 , and Z 3 are each independently -N, -NH, or -CH, with the proviso that Z 1 , Z 2 , and Z 3 is N or —NH; V 1 and V 2 are each selected from C and N; W 1 and W 2 are -C=O and -CR, respectively. 2 , N, and -NR 2 is selected from W 1 Ga-CR 2 When W 2 is N, W 2 Ga-CR 2 When W 1 is N or -NR 2 and W 1 When is -C=O, W 2 Ga-NR 2 and W2 When is -C=O, W 1 Ga-NR 2 and [ka] is, for each of two occurrences, a single bond or a double bond, provided that one is a single bond and the other is a double bond; W 1 and W 2 (h) is a double bond, except that (h) is a single bond when either one of R 0 But halogen or [ka] and Ring A is C3~C 12 Carbocyclyl, 3- to 12-membered heterocyclyl, C6 or C 10 aryl, or 5- to 10-membered heteroaryl; R 1 is halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(=O)R z , -C(=O)OR z , -C(=O)NR w R x , -NR w R x , -NR w C(=O)R z , -NR w C(=O)OR z , -NR w C(=O)NR x R y , -OR z , -OC(=O)R z , -OC(=O)NR w R x , S(=O)2R z , C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl; R 1 C1-C6 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl is -OR z , optionally substituted with 1 to 3 groups selected from C1-C3 haloalkyl, —CN, and halogen; R w , R x , R y , and R z are each independently hydrogen or C1-C4 alkyl, X 1 and X 2 are each independently hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 cycloalkyl, or 5- or 6-membered heteroaryl; R 2 But hydrogen, halogen, [ka] and T is absent, a bond, or selected from —O—, —OCH—, —NH—, —NS(═O)CH, —S—, and —CH—; Y is C1-C6 alkyl, -(CR a R a ) p COOH, -(CR a R a ) p NR b S(=O)2(CR c R c ) q OH, -(CR a R a ) p C(=O)NR b (CR c R c ) q COOH, and -(CR a R a ) p (O)(CR c R c ) q COOH, R ais, for each occurrence, independently, halogen, —OH, or C1-C4 alkyl optionally substituted with 1 to 3 groups selected from halogen and —OH; or alternatively, R a is a C1-C4 alkyl for each occurrence, two R a groups together with the intervening carbon atoms form a cyclopropyl or cyclobutyl; R b and R c are, for each occurrence, independently hydrogen or C1-C2 alkyl; p and q are each independently an integer selected from 1 and 2; Ring B is C3~C 12 Carbocyclyl, 3- to 12-membered heterocyclyl, C6 or C 10 aryl, or 5- to 10-membered heteroaryl; R 3 But -C(=O)OR d and R d But -OC(O)R e , -OC(=O)OR e , or -OP(=O)OR f R f C1-C4 alkyl optionally substituted with R e is, for each occurrence, independently hydrogen, —CH3, or —C2H5; R f is, for each occurrence, independently -OH, -CH3, -C2H5, -OCH3, or -OC2H5, R k is halogen, —CN, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, or O—(C3-C6 cycloalkyl), R m is, for each occurrence, independently selected from halogen, —CN, ═O, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)R r , -C(=O)OR r , -C(=O)NR p Rq , -C(=O)NR p OR r , -NR p R q , -NR p C(=O)R r , -NR p S(=O)2R r 、 -OR r , S(=O)2R r , -S(=O)2NR p R q , -P(=O)R s R t , C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; R m C1-C6 alkyl, phenyl, or 5- or 6-membered heteroaryl is halogen, CN, -C(=O)OR r , -NR p R q , and -OR r and optionally substituted with 1 to 3 groups selected from R m C3-C6 cycloalkyl or 3-6 membered heterocyclyl is halogen, CN, =O, -C(=O)OR r , -NR p R q , and -OR r and optionally substituted with 1 to 3 groups selected from R p and R q are each independently, for each occurrence, hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 groups selected from -OH, -OCH3, -OC2H5, and -COOH; R r is, for each occurrence, independently at each occurrence, hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl; R r C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl is -OH, -OCH3, -OC2H5, -CH2OH, -C(=O)OH, optionally substituted with 1 to 3 groups selected from —(O)C(═O)OH, and —(O)P(═O)(OH); R s and R t is, for each occurrence, independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or —OH; k and m are each independently an integer selected from 0, 1, 2, 3, 4, and 5; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, wherein n is an integer selected from 0, 1, and 2. 2.Z 1 , Z 2 , and Z 3 are N or —NH; n is an integer selected from 0 and 1; and all other variables not specifically defined in this embodiment are as defined in the preceding embodiments. 3. Represented by formula II: [ka] During the ceremony, R 3 But -C(=O)OR d and R d But -OC(O)R e , -OC(=O)OR e , or -OC(=O)OR f R f C1-C4 alkyl optionally substituted with R e is, for each occurrence, independently hydrogen or —CH; R f is, for each occurrence, independently -OH, -CH3, or -OCH3; n is an integer selected from 0 and 1; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1 or 2, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 4. Represented by IIIa, IIIb, IIIc, or IIId; [ka] [ka] During the ceremony, Ring A is R k wherein Ring A is a 5- or 6-membered carbocyclyl, phenyl, or 5- or 6-membered heteroaryl; R 1 C1-C6 alkyl, C1-C6 alkoxyC(=O)OR z , -C(=O)NR w R x , -NR w R x , -OR z , -S(=O)2R z , C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl; R 1 C1-C6 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl is -OR z and halogen, R w , R x , R y , and R z are each independently hydrogen or C1-C4 alkyl, X 1 and X 2 are each independently hydrogen, halogen, —CN, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, or C3-C4 cycloalkyl; R 2 but [ka] and ring B is R m R is optionally substituted with, except when Ring B is C4-C9 carbocyclyl, phenyl, 4- to 9-membered heterocyclyl, or 5- to 6-membered heteroaryl. 2is as defined in embodiment 1; R 3 is absent or is —C(═O)O(CH)(O)P(═O)(OH), R k is halogen, —CN, —CH3, C1 haloalkyl, or —OCH3; n is an integer selected from 0 and 1; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-3, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 5. Represented by formula IVa, IVb, or IVc, [ka] In the formula, X 1 is hydrogen, halogen, —CH, —CHF, —CHF, or —OCH; and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 6. Represented by formula Va, Vb, or Vc, [ka] During the ceremony, R 1 is C1-C4 alkyl, C1-C4 alkoxy, -C(=O)OR z , -C(=O)NR w R x , -NR w R x , -OR z , -S(=O)2R z , cyclopropyl, cyclobutyl, or 5- or 6-membered heterocyclyl; R 1 C1-C4 alkyl, cyclopropyl, or 5- or 6-membered heterocyclyl is -OR z and halogen, R w , R x , R y , and R z are each independently hydrogen or C1-C2 alkyl, T is absent or selected from —O—, —OCH—, —NH—, and —CH—; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-5, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 7. Ring A is R k and Ring A is phenyl, cyclohexenyl, 3,6-dihydro-2H-pyranyl, pyridinyl, pyridazinyl, thiophenyl, or pyrazolyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 8. Ring A is R k and ring A is optionally substituted with [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 9. Ring A is R k and ring A is optionally substituted with [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 10.R 2 but [ka] When ring B is R m and Ring B is selected from isoindolinyl, azaspiro[3.4]octanyl, spiro[3.3]heptanyl, azaspiro[3.3]heptanyl, oxaspiro[3.3]heptanyl, azabicyclo[3.2.0]heptanyl, phenyl, cyclohexenyl, cyclohexyl, pyridinyl, piperidinyl, morpholinyl, tetrahydro-2H-pyranyl, thiazolyl, pyrazolyl, furanyl, tetrahydrofuranyl, cyclopentyl, bicyclo[1.1.1]pentanyl, pyrrolidinyl, cyclobutyl, azetidinyl, and cyclopropyl; and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 11.R 2 but, [ka] and Ring B is R m and ring B is [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 12.R 2 but, [ka] and Ring B is R m and ring B is [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 13.R m is, for each occurrence, independently selected from halogen, —CN, ═O, C1-C6 alkyl, C1-C4 alkoxy, —C(═O)R r , -C(=O)OR r , -C(=O)NR p R q , -C(=O)NR p OR r , -NR p R q , -NR p C(=O)R r , -NR p S(=O)2R r 、 -OR r , S(=O)2R r , -S(=O)2NR p R q , -P(=O)R s R t or 5- or 6-membered heterocyclyl; R m wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups selected from -C(=O)OH, -C(=O)OCH3, -C(=O)OC2H5, -OH, -OCH3, and -OC2H5; R m wherein the 5- or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from halogen, ═O, —C(═O)OH, and —OH; R p and R q is, for each occurrence, independently, hydrogen or C1-C3 alkyl optionally substituted with 1 to 3 groups selected from -OH, -OCH3, and -C(=O)OH; R r is, for each occurrence, independently at each occurrence, hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl; R rwherein the C1-C2 alkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from -OH, -OCH3, -OC2H5, -C(=O)OH, -(O)C(=O)OH, and -(O)P(=O)(OH)2; R s and R t is, for each occurrence, independently, hydrogen, C1-C2 alkyl, C1-C2 alkoxy, or —OH; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-12, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 14.R m is, for each occurrence, independently selected from halogen, CN, ═O, C1-C4 alkyl, C1-C4 alkoxy, —C(═O)R r , -C(=O)OR r , -C(=O)NR p R q , -C(=O)NR p OR r , -NR p R q , -NR p C(=O)R r , -NR p S(=O)2R r 、 -OR r , S(=O)2R r , -S(=O)2NR p R q , -P(=O)R s R t , imidazolidinyl, or morpholinyl; R m wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from -C(=O)OH, -C(=O)OCH3, -C(=O)OC2H5, -OH, -OCH3, and -OC2H5; R m wherein the imidazolidinyl or morpholinyl is optionally substituted with 1 to 3 groups selected from oxo (=O) and -OH; R p and Rq is, for each occurrence, independently, hydrogen or C1-C3 alkyl optionally substituted with 1 to 3 groups selected from -OH, -OCH3, and -C(=O)OH; R r is, for each occurrence, independently at each occurrence, hydrogen, C1-C2 alkyl, cyclopropyl, oxetanyl, or azetidinyl; R r C1-C2 alkyl, cyclopropyl, oxetanyl, or azetidinyl is -OH, -CH2OH, optionally substituted with 1 to 3 groups selected from -C(=O)OH, and -(O)P(=O)(OH); R s and R t But for each occurrence, independently, -CH3, -OCH3, or -OH; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-13, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 15.R m But for each occurrence, independently, -COOH, -C(=O)CH(OH)CH3, F, -CH3, -C(=O)NH2, -C(=O)NH(OCH3), S(=O)2NH2, -NHS(=O)2CH3, =O, -OH, -P(=O)(CH3)2, -P(=O)(OH)2, -P(=O)(OCH3)2, -OH, imidazolidin-4-yl, -CH2OH, -NHCH3, morpholin-4-yl, -(C=O)NHCH(CH3)CH2OH, -C(=O)N(CH3)CH(CH3)CH2OH, -NCH3C(=O)CH(OH)CH3, -C(=O)CH(CH3)CH2OH, -C(=O)CH(OH)CHOH, -C(=O)(hydroxymethyl)oxetan-3-yl, -C(=O)(hydroxy)cyclopropyl, -C(=O)CH(OH)CH3, -C(=O)OCH3, -OCH3, -CH2COOH, -CN, -OCH2COOH, -OCH(CH3)COOH, -CH(CH3)COOH, Cl, S(=O)2CH3, S(=O)2NHCH3, -CH2C(=O)OC2H5, -C(=O)OCH2(O)P(=O)(OH)2, -C(=O)NHCH(CH3)COOH, The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-14, wherein: -C(=O)NHCH3, -C=O(3-hydroxyazetidin-1-yl), and -C(=O)(morpholin-4-yl), and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 16.R m At least one occurrence of -COOH, -CH2COOH, -OCH2COOH, -OCH(CH3)COOH, -CH(CH3)COOH, The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-15, wherein: —C(═O)OCH(O)P(═O)(OH) or —C(═O)NHCH(CH)COOH; and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 17. Represented by formula VIa, VIb, or VIc, [ka] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-16, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 18.R 1 is C1-C3 alkyl, C1-C3 alkoxy, -C(=O)OR z , -C(=O)NR w R x , -NR w R x , -OR z , -S(=O)2R z, cyclopropyl, cyclobutyl, or 6-membered heterocyclyl; R 1 C1-C3 alkyl, cyclopropyl, cyclobutyl, or tetrahydro-2H-pyran-4-yl is -OH, -OCH3, C1-C2 haloalkyl, optionally substituted with 1 to 3 groups selected from —CN and halogen; R w , R x , R y , and R z are each independently hydrogen or —CH3; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-17, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 19.R 1 is -C(CH3)2, -CF3, -CH2C(CH3)2OCH3, -C(CH3)2CH2OH, -OCH3, -O(C)(CH3)2, -C(=O)OCH3, -C(=O)N(CH3)2, N(CH3)2, -S(=O)2CH3, S(=O)2C2H5, -S(=O)2CH(CH3)2, tetrahydro-2H-pyran-4-yl, cyclopropyl, or cyclobutyl; R 1 cyclopropyl or cyclobutyl of A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-18, optionally substituted with —OH, —OCH3, or —CF3, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 20. Represented by formula VIIa, VIIb, VIIc, VIId, VIIe, or VIIf, [ka] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-19, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 21. Represented by formula VIIIa, VIIIb, or VIIIc, [ka] During the ceremony, Ring A is R k and Ring A is phenyl or 5- or 6-membered heteroaryl; T is absent or selected from —O—, —NH—, and —CH—; Z is C1-C2 alkyl, -(CR a R a ) p COOH, -(CR a R a ) p NR b S(=O)2(CR c R c ) q OH, -(CR a R a ) p C(=O)NR b (CR c R c ) q COOH, or -(CR a R a ) p (O)(CR c R c ) q COOH, R a is, for each occurrence, independently hydrogen, —OH, —CH3, or -CHOH, R b and R c is, for each occurrence, independently hydrogen or —CH; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-5, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5. twenty two. [ka] But -NHCH3, -CH2COOH, -(CH2)2COOH, -CH(CH3)CH2COOH, -NHCH(CH3)COOH, -OCH2COOH, -O(CH2)2(O)CH2COOH, -CH2CH(CH3)COOH, -OCH(CH3)C(=O)NHCH2COOH, or The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-5 and 21, wherein —OCH(CHOH)CHNHS(═O)(CH)OH, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5 and 21. 23. Ring A is R k and wherein ring A is phenyl or pyridinyl, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5, 21, and 22. 24. Ring A is R k and ring A is optionally substituted with [ka] and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5 and 21-23, or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof. 25. Ring A is [ka] is selected from The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-5 and 21-23, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5 and 21-23. 26. Ring A is [ka] and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5 and 21-23. 27.R 1 is halogen, -CN, C1-C3 alkyl, C1-C3 alkoxy, -NR w R x , -OR z , C3-C6 cycloalkyl, or 5- or 6-membered heterocyclyl; R 1 wherein the C1-C3 alkyl, C3-C6 cycloalkyl, or 5- or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from -OH, -OCH3, C1-C2 haloalkyl, -CN, and halogen; R w , R x , R y , and R z are each independently hydrogen or —CH3; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-5 and 21-26, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5 and 21-26. 28.R 1 is C1-C3 alkyl or 5- or 6-membered heterocyclyl; R 1wherein the C1-C3 alkyl or 5- or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from -OH, -OCH3, C1-C2 haloalkyl, and halogen; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-5 and 21-26, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5 and 21-26. 29.R 1 is —C(CH3)2 or tetrahydro-2H-pyran-4-yl, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5 and 21-26. 30.R 1 but, [ka] and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5 and 21-26. 31.R 1 but, [ka] and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5 and 21-26. 32.R 2 but, [ka] and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5 and 21-31. 33.R 2 but, [ka] and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5 and 21-31. 34. X 1 is hydrogen, F, or -CH3, R k is F, Cl, -CH3, or -OCH3; k is an integer selected from 0, 1, and 2; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-32, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 35. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-34, wherein the compound is selected from the compounds of Table I. 36. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-35, and a pharmaceutically acceptable carrier. 37. A method for modulating alpha-1 antitrypsin (AAT) activity in a subject, comprising administering a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 35, or a pharmaceutical composition of embodiment 36. 38. Use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 35 in the manufacture of a medicament for modulating AAT activity. 39. The pharmaceutical composition according to embodiment 36 for use in modulating AAT activity. 40. A method for treating alpha-1 antitrypsin deficiency (AATD) in a subject, comprising administering a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 35, or a pharmaceutical composition of embodiment 36. 41. Use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-35 in the manufacture of a medicament for treating AATD. 42. The pharmaceutical composition according to embodiment 36 for use in the treatment of AATD.

[0064] 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, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once daily, twice daily, or three times daily. In certain 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 1-262, a tautomer thereof, a deuterated derivative of the compound or tautomer, and a pharmaceutically acceptable salt of any of the foregoing is administered once daily, twice daily, or three times daily.

[0065] 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).

[0066] II. Compounds and Compositions Some embodiments of the present disclosure include compounds represented by formula I: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Z 1 , Z 2 , and Z 3 are each independently -N, -NH, or -CH, with the proviso that Z 1 , Z 2 , and Z 3 is N or —NH; V 1 and V 2 are each selected from C and N; W 1 and W 2 are -C=O and -CR, respectively. 2 , N, and -NR 2 is selected from W 1 Ga-CR 2 When W 2 is N, W 2 Ga-CR 2 When W 1 is N or -NR 2 and W 1 When is -C=O, W 2Ga-NR 2 and W 2 When is -C=O, W 1 Ga-NR 2 and [ka] is, for each of two occurrences, a single bond or a double bond, provided that one is a single bond and the other is a double bond; W 1 and W 2 (h) is a double bond, except that (h) is a single bond when either one of R 0 But halogen or [ka] and Ring A is C3~C 12 Carbocyclyl, 3- to 12-membered heterocyclyl, C6 or C 10 aryl, or 5- to 10-membered heteroaryl; R 1 is halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(=O)R z , -C(=O)OR z , -C(=O)NR w R x , -NR w R x , -NR w C(=O)R z , -NR w C(=O)OR z , -NR w C(=O)NR x R y , -OR z , -OC(=O)R z , -OC(=O)NR w R x , S(=O)2R z , C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl; R 1C1-C6 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl is -OR z , optionally substituted with 1 to 3 groups selected from C1-C3 haloalkyl, —CN, and halogen; R w , R x , R y , and R z are each independently hydrogen or C1-C4 alkyl, X 1 and X 2 are each independently hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 cycloalkyl, or 5- or 6-membered heteroaryl; R 2 But hydrogen, halogen, [ka] and T is absent, a bond, or selected from —O—, —OCH—, —NH—, —NS(═O)CH, —S—, and —CH—; Y is C1-C6 alkyl, -(CR a R a ) p COOH, -(CR a R a ) p NR b S(=O)2(CR c R c ) q OH, -(CR a R a ) p C(=O)NR b (CR c R c ) q COOH, and -(CR a R a ) p (O)(CR c R c ) q COOH, R ais, for each occurrence, independently, halogen, —OH, or C1-C4 alkyl optionally substituted with 1 to 3 groups selected from halogen and —OH; or alternatively, R a is a C1-C4 alkyl for each occurrence, two R a groups together with the intervening carbon atoms form a cyclopropyl or cyclobutyl; R b and R c are, for each occurrence, independently hydrogen or C1-C2 alkyl; p and q are each independently an integer selected from 1 and 2; Ring B is C3~C 12 Carbocyclyl, 3- to 12-membered heterocyclyl, C6 or C 10 aryl, or 5- to 10-membered heteroaryl; R 3 But -C(=O)OR d and R d But -OC(O)R e , -OC(=O)OR e , or -OP(=O)OR f R f C1-C4 alkyl optionally substituted with R e is, for each occurrence, independently hydrogen, —CH3, or —C2H5; R f is, for each occurrence, independently -OH, -CH3, -C2H5, -OCH3, or -OC2H5, R k is halogen, —CN, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, or O—(C3-C6 cycloalkyl), R m is, for each occurrence, independently selected from halogen, —CN, ═O, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)R r , -C(=O)OR r , -C(=O)NR p Rq , -C(=O)NR p OR r , -NR p R q , -NR p C(=O)R r , -NR p S(=O)2R r 、 -OR r , S(=O)2R r , -S(=O)2NR p R q , -P(=O)R s R t , C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; R m C1-C6 alkyl, phenyl, or 5- or 6-membered heteroaryl is halogen, —CN, -C(=O)OR r , -NR p R q , and -OR r and optionally substituted with 1 to 3 groups selected from R m C3-C6 cycloalkyl or 3-6 membered heterocyclyl is halogen, CN, =O, -C(=O)OR r , -NR p R q , and -OR r and optionally substituted with 1 to 3 groups selected from R p and R q are each independently, for each occurrence, hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 groups selected from -OH, -OCH3, -OC2H5, and -COOH; R r is, for each occurrence, independently at each occurrence, hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl; R r C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl is -OH, -OCH3, -OC2H5, -CH2OH, -C(=O)OH, optionally substituted with 1 to 3 groups selected from —(O)C(═O)OH, and —(O)P(═O)(OH); R s and R t is, for each occurrence, independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or —OH; k and m are each independently an integer selected from 0, 1, 2, 3, 4, and 5; The present invention provides a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, and 2.

[0067] In some embodiments, Z 1 , Z 2 , and Z 3 are N or —NH in the compound of Formula I, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt, and n is an integer selected from 0 and 1.

[0068] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, R 0 is Cl.

[0069] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula II: [ka] During the ceremony, R 3 is -C(=O)OR d and R d is -OC(O)R e , -OC(=O)OR e , or -OC(=O)OR f R f C1-C4 alkyl optionally substituted with R e is, for each occurrence, independently hydrogen or —CH; R fis, for each occurrence, independently -OH, -CH3, or -OCH3; n is an integer selected from 0 and 1; All other variables not specifically defined herein are as defined for Formula I.

[0070] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula IIIa, Formula IIIb, Formula IIIc, or Formula IIId ("Formulas IIIa-d"): [ka] [ka] During the ceremony, Ring A is R k and Ring A is a 5- or 6-membered carbocyclyl, phenyl, or 5- or 6-membered heteroaryl; R 1 is C1-C6 alkyl, C1-C6 alkoxyC(=O)OR z , -C(=O)NR w R x , -NR w R x , -OR z , -S(=O)2R z , C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl; R 1 C1-C6 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl is -OR z and halogen, R w , R x , R y , and R z are each independently hydrogen or C1-C4 alkyl, X 1 and X 2are each independently hydrogen, halogen, —CN, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, or C3-C4 cycloalkyl; R 2 is as defined for formula I, except that R 2 but [ka] When the ring B is R m and Ring B is C4-C9 carbocyclyl, phenyl, 4- to 9-membered heterocyclyl, or 5- to 6-membered heteroaryl; R 3 is absent or is —C(═O)O(CH)(O)P(═O)(OH), R k is halogen, —CN, —CH3, C1 haloalkyl, or —OCH3; n is an integer selected from 0 and 1; All other variables not specifically defined herein are as defined for Formula I or Formula II.

[0071] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula IVa, Formula IVb, or Formula IVc ("Formulas IVa-c"): [ka] In the formula, X 1 is hydrogen, halogen, —CH, —CHF, —CHF, or —OCH, and all other variables not specifically defined herein are as defined for Formula I, Formula II, or Formula IIIa-d.

[0072] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula Va, Formula Vb, or Formula Vc ("Formula Va c"): [ka] During the ceremony, R 1 is C1-C4 alkyl, C1-C4 alkoxy, -C(=O)OR z , -C(=O)NR w R x , -NR w R x , -OR z , -S(=O)2R z , cyclopropyl, cyclobutyl, or 5- or 6-membered heterocyclyl; R 1 C1-C4 alkyl, cyclopropyl, or 5- or 6-membered heterocyclyl is -OR z and halogen, R w , R x , R y , and R z are each independently hydrogen or C1-C2 alkyl, T is absent or selected from —O—, —OCH—, —NH—, and —CH—; All other variables not specifically defined herein are as defined for Formula I, Formula II, Formula IIIa-d, or Formula IVa-c.

[0073] In some embodiments, ring A in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of Formulas I, II, IIIa-d, IVa-c, and Va-c is R k and is selected from phenyl, cyclohexenyl, 3,6-dihydro-2H-pyranyl, pyridinyl, pyridazinyl, thiophenyl, and pyrazolyl.

[0074] In some embodiments, ring A in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of Formulas I, II, IIIa-d, IVa-c, and Va-c is R k optionally replaced by [ka] is selected from.

[0075] In some embodiments, ring A in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of Formulas I, II, IIIa-d, IVa-c, and Va-c is R k optionally replaced by [ka] is selected from.

[0076] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of Formulas I, II, IIIa-d, IVa-c, and Va-c is 2 teeth, [ka] and ring B is R m and Ring B is selected from isoindolinyl, azaspiro[3.4]octanyl, spiro[3.3]heptanyl, azaspiro[3.3]heptanyl, oxaspiro[3.3]heptanyl, azabicyclo[3.2.0]heptanyl, phenyl, cyclohexenyl, cyclohexyl, pyridinyl, piperidinyl, morpholinyl, tetrahydro-2H-pyranyl, thiazolyl, pyrazolyl, furanyl, tetrahydrofuranyl, cyclopentyl, bicyclo[1.1.1]pentanyl, pyrrolidinyl, cyclobutyl, azetidinyl, and cyclopropyl.

[0077] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of Formulas I, II, IIIa-d, IVa-c, and Va-c is 2 teeth, [ka] and ring B is R m and ring B is optionally substituted with [ka] is selected from.

[0078] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of Formulas I, II, IIIa-d, IVa-c, and Va-c is 2 teeth, [ka] and ring B is R m and ring B is optionally substituted with [ka] is selected from.

[0079] In some embodiments of Formulas I, II, IIIa-d, IVa-c, and Va-c, for each occurrence in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, R m are independently halogen, -CN, =O, C1-C6 alkyl, C1-C4 alkoxy, -C(=O)R r , -C(=O)OR r , -C(=O)NR p R q , -C(=O)NR p OR r , -NR p R q , -NR p C(=O)R r , -NR p S(=O)2R r 、 -OR r , S(=O)2R r , -S(=O)2NR p R q , -P(=O)R s R t and 5- and 6-membered heterocyclyl; R mThe C1-C6 alkyl in R is optionally substituted with 1 to 3 groups selected from -C(=O)OH, -C(=O)OCH3, -C(=O)OC2H5, -OH, -OCH3, and -OC2H5; m wherein the 5- or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from halogen, ═O, —C(═O)OH, and —OH; R p and R q are each independently, for each occurrence, hydrogen or C1-C3 alkyl optionally substituted with 1 to 3 groups selected from -OH, -OCH3, and -C(=O)OH; R r are, for each occurrence, independently at each occurrence, hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl; R r wherein the C1-C2 alkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from -OH, -OCH3, -OC2H5, -C(=O)OH, -(O)C(=O)OH, and -(O)P(=O)(OH)2; R s and R t is, for each occurrence, independently at each occurrence, hydrogen, C1-C2 alkyl, C1-C2 alkoxy, or —OH.

[0080] In some embodiments of Formulas I, II, IIIa-d, IVa-c, and Va-c, for each occurrence in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, R m are independently halogen, -CN, =O, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)R r , -C(=O)OR r , -C(=O)NR p R q , -C(=O)NR p OR r , -NR p R q , -NR p C(=O)R r , -NR p S(=O)2R r、 -OR r , S(=O)2R r , -S(=O)2NR p R q , -P(=O)R s R t , imidazolidinyl, and morpholinyl; R m The C1-C4 alkyl in R is optionally substituted with 1 to 3 groups selected from -C(=O)OH, -C(=O)OCH3, -C(=O)OC2H5, -OH, -OCH3, and -OC2H5; m wherein the imidazolidinyl or morpholinyl is optionally substituted with 1 to 3 groups selected from oxo (=O) and -OH; R p and R q are each independently, for each occurrence, hydrogen or C1-C3 alkyl optionally substituted with 1 to 3 groups selected from -OH, -OCH3, and -C(=O)OH; R r are, for each occurrence, independently hydrogen, C1-C2 alkyl, cyclopropyl, oxetanyl, or azetidinyl; R r C1-C2 alkyl, cyclopropyl, oxetanyl, or azetidinyl is —OH, —CH2OH, optionally substituted with 1 to 3 groups selected from -C(=O)OH, and -(O)P(=O)(OH); R s and R t are, for each occurrence, independently: -CH3, -OCH3, or -OH.

[0081] In some embodiments of Formulas I, II, IIIa-d, IVa-c, and Va-c, for each occurrence in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, R m are independently -COOH, -C(=O)CH(OH)CH3, F, -CH3, -C(=O)NH2, -C(=O)NH(OCH3), S(=O)2NH2, -NHS(=O)2CH3, =O, -OH, -P(=O)(CH3)2, -P(=O)(OH)2, -P(=O)(OCH3)2, -OH, imidazolidin-4-yl, -CH2OH, -NHCH3, morpholin-4-yl, -(C=O)NHCH(CH3)CH2OH, -C(=O)N(CH3)CH(CH3)CH2OH, -NCH3C(=O)CH(OH)CH3, -C(=O)CH(CH3)CH2OH, -C(=O)CH(OH)CH2OH, -C(=O)(hydroxymethyl)oxetan-3-yl, -C(=O)(hydroxy)cyclopropyl, -C(=O)CH(OH)CH3, -C(=O)OCH3, -OCH3, -CH2COOH, -CN, -OCH2COOH,-OCH(CH3)COOH, -CH(CH3)COOH, Cl, S(=O)2CH3, S(=O)2NHCH3, -CH2C(=O)OC2H5, -C(=O)OCH2(O)P(=O)(OH)2, -C(=O)NHCH(CH3)COOH, -C(=O)NHCH3, -C=O(3-hydroxyazetidin-1-yl), and -C(=O)(morpholin-4-yl).

[0082] In some embodiments of Formulas I, II, IIIa-d, IVa-c, and Va-c, for each occurrence in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, R m are independently -COOH, -CH2COOH, -OCH2COOH, -OCH(CH3)COOH, is selected from -CH(CH3)COOH, -C(=O)OCH2(O)P(=O)(OH)2, and -C(=O)NHCH(CH3)COOH.

[0083] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula VIa, Formula VIb, or Formula VIc ("Formulas VIa-c"): [ka] All other variables not specifically defined herein are as defined in any one of Formulas I, II, IIIa-d, IVa-c, and Va-c.

[0084] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, Va-c, and VIa-c 1 is C1-C3 alkyl, C1-C3 alkoxy, -C(=O)OR z , -C(=O)NR w R x , -NR w R x , -OR z , -S(=O)2R z cyclopropyl, cyclobutyl, and 6-membered heterocyclyl; R 1 C1-C3 alkyl, cyclopropyl, cyclobutyl, or tetrahydro-2H-pyran-4-yl is optionally substituted with 1 to 3 groups selected from -OH, -OCH3, C1-C2 haloalkyl, and halogen; R w , R x , R y , and R z are each independently hydrogen or —CH3.

[0085] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, Va-c, and VIa-c 1 -C(CH3)2, -CF3, -CH2C(CH3)2OCH3, -C(CH3)2CH2OH, -OCH3, -O(C)(CH3)2, is selected from —C(═O)OCH3, —C(═O)N(CH3)2, N(CH3)2, —S(═O)2CH3, S(═O)2C2H5, —S(═O)2CH(CH3)2, tetrahydro-2H-pyran-4-yl, cyclopropyl, and cyclobutyl; R 1 The cyclopropyl or cyclobutyl is optionally substituted with -OH, -OCH3, or -CF3.

[0086] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula VIIa, Formula VIIb, Formula VIIc, Formula VIId, Formula VIIe, or Formula VIIe ("Formulas VIIa-f"), [ka] All other variables not specifically defined herein are as defined in any one of Formulas I, II, IIIa-d, IVa-c, Va-c, and VIa-c.

[0087] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I is a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula VIIIa, Formula VIIIb, or Formula VIIIc ("Formulas VIIIa-c"): [ka] During the ceremony, Ring A is R k and Ring A is phenyl or 5- or 6-membered heteroaryl; T is absent or selected from —O—, —NH—, and —CH—; Z is C1-C2 alkyl, -(CR a R a ) p COOH, -(CR a R a ) p NR b S(=O)2(CR c R c )q OH, -(CR a R a ) p C(=O)NR b (CR c R c ) q COOH, or -(CR a R a ) p (O)(CR c R c ) q COOH, R a is, for each occurrence, independently hydrogen, -OH, -CH3, or -CHOH, R b and R c is, for each occurrence, independently hydrogen or —CH; All other variables not specifically defined herein are as defined in any one of Formulas I, II, IIIa-d, and IVa-c.

[0088] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, or VIIIa-c, [ka] are -NHCH3, -CH2COOH, -(CH2)2COOH, -CH(CH3)CH2COOH, -NHCH(CH3)COOH, -OCH2COOH, -O(CH2)2(O)CH2COOH, -CH2CH(CH3)COOH, -OCH(CH3)C(=O)NHCH2COOH, and -OCH(CH2OH)CH2NHS(=O)2(CH2)2OH.

[0089] In some embodiments, ring A in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, or Va-c is R k is phenyl or pyridinyl optionally substituted with

[0090] In some embodiments, ring A in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, or Va-c is R k optionally replaced with [ka] is.

[0091] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, or VIIIa-c is 1 is halogen, -CN, C1-C3 alkyl, C1-C3 alkoxy, -NR w R x , -OR z , C3-C6 cycloalkyl, and 5- or 6-membered heterocyclyl; R 1 wherein the C1-C3 alkyl, C3-C6 cycloalkyl, or 5- or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from -OH, -OCH3, C1-C2 haloalkyl, -CN, and halogen; R w , R x , R y , and R z are each independently hydrogen or —CH3.

[0092] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, or VIIIa-c is 1 is C1-C3 alkyl or 6-membered heterocyclyl, R 1 The C1-C3 alkyl or 5- or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from -OH, -OCH3, C1-C2 haloalkyl, and halogen.

[0093] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, or VIIIa-c is 1 is —C(CH 3 ) 2 or tetrahydro-2H-pyran-4-yl.

[0094] In some embodiments of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, X 1 is hydrogen, F, or -CH3, R k is F, Cl, -CH3, or -OCH3, k is an integer selected from 0, 1, and 2.

[0095] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c is selected from compounds 1-262 set forth in Table I below. [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 Table 1-25 [Table 1-26]

[0096] Some embodiments of the present disclosure include derivatives of compounds 1-262 or compounds of Formulas I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c. In some embodiments, the derivatives are silicon derivatives in which at least one carbon atom in compounds 1-262 or compounds selected from compounds of Formulas I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c is replaced by silicon. In some embodiments, the derivatives are boron derivatives in which at least one carbon atom in compounds 1-262 or compounds selected from compounds of Formulas I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c is replaced by boron. In some embodiments, the derivative is a phosphorus derivative in which at least one carbon atom in compounds 1-262 or a compound selected from compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c 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.

[0097] In some embodiments, the derivative is a silicon derivative in which one carbon atom in compounds 1-262 or a compound selected from compounds of Formulae I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c 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 in 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 in a tert-butyl moiety where a carbon is replaced by silicon can be replaced by deuterium. In other embodiments, the silicon derivative of compounds 1-262 or a compound selected from compounds of Formulae I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c can have silicon incorporated into a heterocyclic ring.

[0098] Another aspect of the present disclosure provides pharmaceutical compositions comprising a compound according to any formula selected from Formulas I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, as well as compounds 1-262, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound selected from compounds of Formulas I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, as well as compounds 1-262, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered to a patient in need thereof.

[0099] 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.

[0100] 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 another active therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, their tautomers, deuterated derivatives of these compounds or 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 other active therapeutic agent. In some embodiments, a pharmaceutical composition comprising at least one compound selected from Compounds 1-262, their tautomers, deuterated derivatives of these compounds or 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 other active therapeutic agent.

[0101] In some embodiments, a compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, or VIIIa-c, a tautomer of these compounds, a deuterated derivative of these compounds and tautomers, or a pharmaceutically acceptable salt of any of the foregoing, is 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 compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, or VIIIa-c, a tautomer of these compounds, a deuterated derivative of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing are in separate pharmaceutical compositions. In some embodiments, when used simultaneously, the compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, or VIIIa-c, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, or pharmaceutically acceptable salts of any of the foregoing, and at least one additional active agent are together in the same pharmaceutical composition. In some embodiments, the compound is a compound selected from Compounds 1-262, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0102] In some embodiments, a compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, or VIIIa-c, a tautomer of these compounds, a deuterated derivative of these compounds and tautomers, or a pharmaceutically acceptable salt of any of the foregoing is provided for use in a method of treating AATD, the method 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 1-262, a tautomer of these compounds, a deuterated derivative of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing.

[0103] In some embodiments, a compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, or VIIIa-c, a tautomer of these compounds, a deuterated derivative of these compounds and tautomers, or a pharmaceutically acceptable salt 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 1-262, a tautomer of these compounds, a deuterated derivative of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing.

[0104] 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), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), or (VIIa)-(VIIe), a tautomer of the compound, a deuterated derivative of the compound and tautomer, or a pharmaceutically acceptable salt 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 1-262, a tautomer of the compound, a deuterated derivative of the compound and tautomer, and a pharmaceutically acceptable salt of any of the foregoing.

[0105] In some embodiments, a compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, or VIIIa-c, a tautomer of the compound, a deuterated derivative of the compound and tautomer, or a pharmaceutically acceptable salt of any of the foregoing is provided for use in a method of treating AATD, wherein the compound is prepared for administration in combination with an additional active agent. 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 1-262, a tautomer of the compound, a deuterated derivative of the compound and tautomer, and a pharmaceutically acceptable salt of any of the foregoing.

[0106] In some embodiments, a compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, or VIIIa-c, a tautomer of the compound, a deuterated derivative of the compound and tautomer, or a pharmaceutically acceptable salt 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 1-262, a tautomer of the compound, a deuterated derivative of the compound and tautomer, and a pharmaceutically acceptable salt of any of the foregoing.

[0107] 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, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, or VIIIa-c, a tautomer of these compounds, a deuterated derivative of these compounds and tautomers, or a pharmaceutically acceptable salt 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 1-262, a tautomer of these compounds, a deuterated derivative of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound of any one of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c is selected from compounds 1-262, tautomers thereof, deuterated derivatives of these compounds or 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.

[0112] Another aspect of the present disclosure provides a method of modulating alpha-1 antitrypsin activity, comprising contacting the alpha-1 antitrypsin with at least one compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, a tautomer thereof, a deuterated derivative of the compound or tautomer, and a pharmaceutically acceptable salt 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 1-262, a tautomer thereof, a deuterated derivative of the compound or tautomer, and a pharmaceutically acceptable salt of any of the foregoing.

[0113] 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.

[0114] III. Compound Preparation All generic, subgeneric, and specific compound formulas disclosed herein are considered part of the present invention.

[0115] A. Compounds of Formula I The compounds of the present disclosure can be made according to standard chemical practices or as described herein. Throughout the synthetic schemes below, the following abbreviations are used in describing the preparation of compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, as well as compounds 1-262, their tautomers, deuterated derivatives of the compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing: Abbreviation BrettPhos Pd G1 = chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) or (BrettPhos)palladium(II) phenethylamine chloride 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 CBzCl = benzyl chloroformate Chos = 2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMAP = dimethylaminopyridine DMF = dimethylformamide DMSO = dimethyl sulfoxide EtOAc = ethyl acetate HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphorus hexafluoride ion) IPA = Isopropyl alcohol 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 Pd(dppf)2Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(PPh3)2 = bis(triphenylphosphine) palladium(II) dichloride PTSA = p-toluenesulfonic acid monohydrate SFC = Supercritical Fluid Chromatography 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 TFA = trifluoroacetic acid THF = tetrahydrofuran THP = tetrahydropyran 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

[0116] In some embodiments, the process for preparing a compound of Formula I, a tautomer, a pharmaceutically acceptable salt of the compound or tautomer, or a deuterated derivative of any of the foregoing comprises reacting a compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIa-c, and compounds 1-262, a tautomer thereof, a deuterated derivative of the compound or tautomer, and a pharmaceutically acceptable salt of any of the foregoing. General synthetic scheme [ka]

[0117] Scheme 1 refers to the preparation of compounds of formula IIIa'.

[0118] Definition:PG 1 is a suitable nitrogen atom protecting group such as THP. 1 can also be Cbz, pivalolyl, tosyl, phenylsulfonyl.

[0119] Compounds of formula IIIa' can be prepared from compounds of formula 1-1 using any suitable method for removal of a nitrogen protecting group. 1 is THP. In some embodiments, a reagent such as trifluoroacetic acid may be used. [ka]

[0120] Scheme 2 shows a process for the preparation of compounds of formula 1-1. Definition:Y1 is a halogen (e.g., I, Br, or Cl). 11 is any alkyl group such as Me, Et, or tBu. 1 is H or SiMe3. PG 1 is defined as above. R 11 is OH, alkyl, or cyclic alkyl; R 11 The groups are linked by carbon-carbon bonds.

[0121] Compounds of formula 2-2 can be prepared from 2-1 using a suitable method for adding a protecting group on the nitrogen atom. For example, PG 1 When is a THP group, treatment with dihydropyran and p-toluenesulfonic acid provides a compound of formula 2-2. Compounds of formula 2-3 can be prepared from formula 2-3 using any suitable method for the reduction of esters to alcohols (e.g., DiBALH or LiAlH). Oxidation of compounds of formula 2-3 to aldehydes of formula 2-4 can be carried out using any suitable oxidation reagent. In some embodiments, 4-acetamido-TEMPO and NaHCO3 can be used. Sonogashira coupling of compounds of formula 2-4 with alkynes of formula 2-5 using a reagent system such as Pd(PPh3)2Cl2, CuI, and an amine base such as NEt3. Compounds of formula 2-7 can be prepared from compounds of formula 2-6 by a condensation reaction with hydroxylamine in the presence of a base such as pyridine. Compounds of formula 2-8 can be prepared from compounds 2-7 by intramolecular cyclization of the amine group on the alkyne. In some embodiments, a reagent such as molecular iodine in the presence of a base such as K2CO3 can be used. Compounds of formula 2-10 can be prepared from 2-8 by Suzuki coupling with a boronic acid or ester of formula 2-9. Compounds 2-11 can be prepared by any suitable method for the preparation of aryl chlorides. For example, reagents such as POCl or oxalyl chloride and iPrNH can be used. Compounds of formula 1-1 can be prepared using any suitable conditions for coupling an organometallic reagent (e.g., boronic ester, alkyl zinc) 2-12 with an aryl chloride 2-11. [ka]

[0122] Scheme 3 provides a process for the preparation of compounds of formula 2-10.

[0123] Definition:Y 3 is a halogen such as Br or I. PG 1 is defined as above.

[0124] Allylation of a compound of formula 3-2 with an aryl halide of formula 3-1 provides a compound of formula 3-3. In some embodiments, palladium-catalyzed coupling conditions, such as Pd(dppf)Cl and cesium carbonate, were used. Compounds of formula 2-10 can be prepared from compound 3-3 by treatment with NHOH. [ka]

[0125] Scheme 4 depicts a process for preparing a compound of formula 4-1 from a compound of formula 2-10. In some embodiments, a reagent such as DABCO in the presence of TFAA is used. A solvent such as dichloromethane can be used. [ka]

[0126] Scheme 5 shows one possible method for preparing compounds of formula 5-3. Compounds of formula 5-2 can be prepared from aryl chlorides of formula 2-11 and alcohols of formula 5-1. In some embodiments, bases such as NaH, Cs2CO3, or K2CO3 can be used. Solvents such as DMSO can be used. The reaction can be carried out in the presence of heat (e.g., 50°C).

[0127] Definition: R 12 can be alkyl or aryl.

[0128] Compounds of formula 5-3 can be prepared from 5-2 using any suitable conditions for removal of the nitrogen protecting group, for example, trifluoroacetic acid can be used. [ka]

[0129] Scheme 6 depicts a process for the preparation of compound 6-3. Definitions: R 13 OMe, halogens, phosphonates, phosphites, -CO2R 50 In some embodiments, compounds of formula 6-2 can be prepared from compounds of formula 2-10 and 6-1 by treatment with 2-isopropoxyphosphonoyloxypropane, DIPEA. Solvent systems such as CCl4 and MeCN can be used. The reaction can be carried out in the presence of additional heat (e.g., 40°C). Compounds of formula 6-3 can be prepared from PG 1 It can be prepared from 6-2 using a suitable reagent for the removal of PG. 1 If is a THP group, TFA in dichloromethane can be used. [ka]

[0130] A process for the preparation of compounds of formula 7-4 is shown in Scheme 7.

[0131] Definition: R 14 = alkyl such as Me, Et, tBu, etc., L 1 = any straight chain, branched, or cyclic alkyl.

[0132] Compounds of formula 7-2 can be prepared from compounds of formula 2-10 and amines of formula 7-1 using suitable reagents for coupling amines to pyridine N-oxide compounds. For example, in some embodiments, PyBrop and DIPEA can be used. Compounds of formula 7-3 can be prepared from 7-2 using any suitable method for hydrolysis of esters. For example, a base such as NaOH in a solvent such as MeOH can be used. Compounds of formula 7-4 can be prepared using any suitable conditions for removal of a nitrogen protecting group (e.g., THP) from the nitrogen atom. [ka]

[0133] Compounds of formula 8-2 can be prepared from intermediate 4-1 and an alcohol of formula 8-1 using a suitable base (e.g., NaH). A solvent such as DMSO can be used. Compounds of formula 8-3 can be prepared from 8-2 by any suitable method for the hydrolysis of an ester. Compounds of formula 8-4 can be prepared from 8-3 by treatment with a suitable reagent for the removal of the nitrogen protecting group.

[0134] Definition: R 15 = alkyl such as Me, Et or tBu. 2 = any straight-chain, branched, or cyclic alkyl or aryl group. [ka]

[0135] Scheme 9 illustrates the preparation of compounds of formula IIIb' from compounds of formula 9-1, and PG 1 is a suitable nitrogen protecting group as defined above. Any suitable method for the removal of a nitrogen protecting group may be used. For example, PG 1 When is a tosyl group, removal can be achieved by treatment with a base such as NaOH or LiOH in a solvent such as THF and water with heating. For example, in some embodiments, the reaction can be carried out at 50° C. [ka]

[0136] Scheme 10 provides a method for the preparation of compounds of formula IIIb' and formula 9-1 from compounds of formula 10-1.

[0137] Definition:Y 4 = halogen (e.g., Cl).

[0138] Compounds of formula IIIb' can be prepared by reacting aryl halides 10-1 with compounds of formula R 2 Compounds of formula 9-1 can be prepared from 10-1 by any method known to those skilled in the art for coupling with organometallic reagents of -[M]. Compounds of formula 9-1 can be prepared by coupling an organometallic reagent with compounds of formula 10-2. [ka]

[0139] Scheme 11 refers to a method for preparing compounds of formula 10-1 from compounds of formula 11-1. Compounds of formula 11-1 can be converted to compounds of formula 11-2 using any suitable method for the reduction of esters to alcohols. In some embodiments, this can be carried out using NaBH4 in the presence of a reagent such as ethyl chloroformate. Compounds of formula 11-3 can be prepared by oxidation of compounds of formula 11-2 using a suitable reagent system for the oxidation of alcohols to aldehydes. In some examples, oxalyl chloride, NEt3 in DMSO can be used. Compounds of formula 11-4 can be prepared using any suitable reagent for the reaction of ortho-halogen-substituted aryl aldehydes 11-3 to form five-membered heterocycles. For example, Z 1 and Z 2 is a nitrogen atom, and Z 3In some embodiments, where is CH, hydroxylamine and K2CO3, followed by hydrazine, can be used to give compounds of formula 11-4. Compounds of formula 11-5 can be prepared from 11-4 by treatment with an oxidation reagent such as mCPBA. Compounds of formula 10-1 can be prepared by treatment with any suitable reagent for the conversion of pyridyl N-oxides to aryl halides. For example, POCl3 can be used.

[0140] Definition: R 16 is alkyl (e.g., Me, Et, tBu). Y 5 is a halogen such as F. Y 4 = Cl or Br. [ka]

[0141] Scheme 12 depicts a process for preparing compounds of formula 12-3 and 12-6 from amines of formula 11-5 and formulas 12-1 and 12-4. Any suitable method for the addition of an amine to an N-oxide can be used in the preparation of compounds 12-2 and 12-5. In some embodiments, PyBrop and DIPEA in a solvent such as dichloromethane can be used. Compounds of formula 12-3 can be prepared from 12-2 by any suitable method for ester hydrolysis. In some embodiments, a base such as NaOH or LiOH can be used. Solvents such as THF or MeOH can be used. Compound 12-6 can be prepared from 12-5 using any method suitable for the hydrolysis of alkyl esters.

[0142] Definition: R 17 = alkyl group (e.g., Me, Et, tBu). L 3 , L 4 and L 5 is an optional alkyl linker group. [ka]

[0143] Scheme 13 refers to a method for the preparation of compounds of formula 13-10 from compounds of formula 13-1. Compounds of formula 13-3 can be prepared from 13-1 using any suitable method for amide formation. In some embodiments, reaction of an acyl halide of formula 13-2 in the presence of a base such as DIPEA can be used. Compounds of formula 13-5 can be prepared from 13-3 by reaction with compounds of formula 13-4. Reagent systems such as ammonium sulfoxyhydrogen sulfate and Pd(TFA)2 can be used. Compounds of formula 13-5 can be converted to compounds of formula 13-6 by treatment with any suitable reagent to effect intramolecular condensation onto a ketone. For example, in some embodiments, a base such as LiOMe in a solvent such as DMF can be used. Additional heat (e.g., 80°C) can be applied. Compounds of formula 13-7 can be prepared from 13-6 by treatment with a reagent such as POCl3 at elevated temperatures (e.g., 100°C). Compounds of formula 13-8 can be prepared by treating compounds of formula 13-7 with a halogenating reagent such as N-bromosuccinimide in CCl4 in the presence of a compact fluorescent lamp. Compounds of formula 13-8 can be prepared from 13-9 by any method suitable for the conversion of benzyl halides to aldehydes. For example, N-methylmorpholine oxide in the presence of 4A molecular sieves can be used. The reaction can be carried out in a solvent such as MeCN. Compounds of formula 13-10 can be prepared by treating compounds of formula 13-9 with a reagent such as tosylhydrazine and Cu2O. The reaction can be carried out in a solvent such as tBuOH at elevated temperatures (e.g., 130 °C).

[0144] Definition:Y 6 , Y 7 = halogens such as F, Cl or Br. PG 2 =Ts. Y 8 =Cl. [ka]

[0145] Scheme 14 shows a method for the preparation of compounds of formula 14-5.

[0146] Definition:Y 6 is defined as above. Y 8 is a halogen such as Cl.

[0147] PG 3 L can be tosyl or any suitable nitrogen protecting group. 6 = alkyl or aryl. Compounds of formula 14-2 can be prepared by the addition of an alcohol of formula 14-1 to a compound of formula 13-9. A base such as K0tBu, K2CO3, or NaH can be used. A solvent such as THF or DMF can be used. Compounds of formula 14-4 can be prepared from 14-2 and an N-protected hydrazine of formula 14-3 in the presence of Cu2O in a solvent such as EtOH. The reaction can be carried out in the presence of heat (e.g., 130 °C). Compounds of formula 14-4 can be converted to compounds of formula 14-5 using any suitable conditions for the simultaneous removal of the N-tosyl protecting group and hydrolysis of the ester. In some embodiments, the reaction is carried out in the presence of a base such as LiOH in a solvent such as MeOH, THF, and water. The reaction can be carried out in the presence of additional heat (e.g., at 50 °C). [ka]

[0148] Scheme 15 depicts a process for the preparation of compounds of formula 15-8.

[0149] Definition:Y 9 = halogen (e.g., Cl, Br, I). R 19 = alkyl group.

[0150] R 20 is any suitable group (e.g., H or alkyl) that forms a suitable boronic ester or acid. 4 is a THP group. E as defined above 1Compounds of formula 15-2 can be prepared from 3-1 by Sonogashira coupling of alkynes of formula 15-1 using methods known to those skilled in the art. Compounds of formula 15-3 can be prepared from 15-2 by treatment with a reagent system such as molecular iodine and a base such as NaHCO3. A solvent such as dichloromethane can be used. Compounds of formula 15-5 can be prepared by Suzuki coupling of compounds of formula 15-3 with boronic acid or ester 15-4. Any suitable method for Suzuki coupling can be used. For example, a RuPhos Pd G4 catalyst system with a mixture of K3PO4 and NaOH as a base can be used. Compounds of formula 15-7 can be prepared by treatment of 15-5 with an amine such as 15-6 with pyridine and molecular sieves. PG 4 When is a group such as THP, compounds of formula 15-8 can be prepared by treating compounds of formula 15-7 with an acid such as HCl or p-toluenesulfonic acid, followed by ester hydrolysis with a base such as LiOH. [ka]

[0151] Scheme 16 describes a process for the preparation of compounds of formula 16-4 and 16-7. Definitions: L 8 is an alkyl group. 22 is any suitable alkyl (e.g., Me, Et, tBu). 4 is defined as above.

[0152] Compounds of formula 16-1 can be prepared from 15-5 by treatment with a base such as NaOH in a solvent such as EtOH at reflux temperature. Compounds of formula 16-3 or 16-6 can be prepared from 16-1 by coupling of an appropriate amine such as 16-2 or 16-5 using an amide coupling reagent such as HATU in the presence of an organic base (e.g., DIPEA). A solvent such as DMF can be used. Compounds of formula 16-4 can be prepared from 16-3 in two steps using a reagent for removal of the nitrogen atom protecting group and then a suitable reagent for ester hydrolysis. For example, in some embodiments, treatment of 16-3 with p-toluenesulfonic acid at elevated temperature (e.g., 65 °C), followed by hydrolysis with a base such as NaOH, provides compounds of formula 16-4. Compounds of formula 16-7 can be prepared from compounds of formula 16-6 by treatment with an acid such as p-toluenesulfonic acid or HCl. [ka]

[0153] Synthesis of starting materials The following describes synthetic routes to intermediates used in the synthesis of compounds 1-262.

[0154] Preparation of S1 5-Iodo-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S1) [ka] Step 1. Synthesis of methyl 5-bromo-1-tetrahydropyran-2-yl-indazole-6-carboxylate (C2) To a solution / suspension of methyl 5-bromo-1H-indazole-6-carboxylate (200 g, 784.1 mmol) in dichloromethane (2.4 L) in a 5 L three-neck flask at room temperature, DHP (92 mL, 1.008 mol) was added, followed by 4-methylbenzenesulfonic acid monohydrate (1.8 g, 9.463 mmol). After approximately 20 minutes, the suspension was consumed and a clear solution was achieved. The reaction was allowed to stir overnight at room temperature. The mixture was washed with saturated aqueous NaHCO (2 × 1 L), then brine (1 L), dried over (MgSO), filtered, and concentrated to give the product. 5-Bromo-1-tetrahydropyran-2-yl-indazole-6-carboxylate (266 g, 100%). 1 H NMR (300MHz, chloroform-d)δ 8.04(t,J=0.7Hz, 1H), 8.02(d,J=0.5Hz, 1H), 8.00(d,J=0.9Hz, 1H), 5.74(dd,J=9.0, 2.7Hz, 1H), 4.04~ 3.96(m, 1H), 3.98(s, 3H), 3.83~3.67(m, 1H), 2.62~2.43(m, 1H), 2.22~2.02(m, 2H), 1.87~1.62(m, 3H).

[0155] Step 2. Synthesis of (5-bromo-1-tetrahydropyran-2-yl-indazol-6-yl)methanol (C3) DIBALH (50 mL of 1 M, 50.00 mmol) was added via syringe over 15 minutes to a solution of methyl 5-bromo-1-tetrahydropyran-2-yl-indazole-6-carboxylate (6.5 g, 19.16 mmol) in dichloromethane (60 mL) at −78° C. After 1 hour, the mixture was quenched by the addition of ethyl acetate (10 mL) and saturated Rochelle's salt (100 mL). The mixture was warmed to room temperature and stirred vigorously until the layers became clear (approximately 2 hours). The layers were separated, and the aqueous layer was re-extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give (5-bromo-1-tetrahydropyran-2-yl-indazol-6-yl)methanol (5.81 g, 97%) as an off-white solid. 1H NMR (300MHz, chloroform-d) δ7.96(d,J=0.9Hz, 1H), 7.91(s, 1H), 7.77~7.66(m, 1H), 5.72(dd,J=9.5, 2.6Hz, 1H), 4.83(d,J= 1.2Hz, 2H), 4.11~3.95(m, 1H), 3.85~3.70(m, 1H), 2.66~2.48(m, 1H), 2.40(s, 1H), 2.25~1.98(m, 2H), 1.89~1.41(m, 3H). LCMS m / z 311.2[M+H] + .

[0156] Step 3. Synthesis of 5-bromo-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde (C4) In a 12 L three-neck flask equipped with a temperature probe and mechanical stirrer, water (750 mL) was added to a solution of (5-bromo-1-tetrahydropyran-2-yl-indazol-6-yl)methanol (100 g, 321.4 mmol) in dichloromethane (2.75 L) at 3 °C (ice-water bath), followed by NaHCO (44.5 g, 529.7 mmol), NaBr (2.08 g, 20.22 mmol), and 4-acetamido-TEMPO, free radical (1.05 g, 4.923 mmol). To the resulting stirred biphasic mixture was added sodium hypochlorite (250 mL of 2 M, 500.0 mmol) (10-15% aqueous solution, 2 M used as the approximate concentration) dropwise over 20 min via an addition funnel. A mild exotherm occurred, with the internal temperature rising to 6 °C. The mixture was stirred in an ice-water bath for an additional hour to achieve an internal temperature of 2°C. The layers were separated and the aqueous layer was extracted with dichloromethane (500 mL). The combined dichloromethane layers were dried (MgSO), filtered, and concentrated to give the product as a yellow / brown solid. 5-Bromo-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde (99 g, 100%) 1H NMR (400 MHz, chloroform-d) δ 10.55 (s, 1H), 8.25 (t, J = 0.8 Hz, 1H), 8.06 (d, J = 1.0 Hz, 1H), 8.04 (d, J = 0.6 Hz, 1H), 5.79 (dd, J = 9.6, 2.6 Hz, 1H), 4.12–4.03 (m, 1H), 3.86–3.75 (m, 1H), 2.63–2.48 (m, 1H), 2.25–2.06 (m, 2H), 1.89–1.59 (m, 3H).

[0157] Step 4. Synthesis of 1-tetrahydropyran-2-yl-5-(2-tetrahydropyran-4-ylethynyl)indazole-6-carbaldehyde (C5) A solution of 5-bromo-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde (5 g, 16.17 mmol) and trimethyl(2-tetrahydropyran-4-ylethynyl)silane (3.1 mL, 16.83 mmol) in triethylamine (70 mL), 1,4-dioxane (8 mL), and water (580 μL, 32.19 mmol) was sparged with nitrogen for 15 minutes at 50 °C. Pd(PPh)Cl (552 mg, 0.7864 mmol) and CuI (226 mg, 1.187 mmol) were added, followed by the addition of TBAF (18 mL of 1 M, 18.00 mmol) in THF via syringe over 2 minutes. The mixture darkened. The mixture was sparged with nitrogen for 5 minutes, and the flask was placed under nitrogen and stirred at 50 °C for 6 hours. The reaction was cooled and most of the solvent was removed in vacuo. The residue was dissolved in EtOAc, washed with 1M HCl (2x) and ammonium chloride solution (1x) and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to a dark oil. The residue was dissolved in dichloromethane (ca. 15 mL), IPA (50 mL) was added, and the mixture was then concentrated in vacuo to ca. 25 mL. The solution was seeded with crystals, and crystallization was induced by scraping the flask with a spatula. After 1 h, the solid was collected by vacuum filtration, washed with cold IPA, and dried under vacuum to give 3.3 g as a tan solid. The residue was concentrated and purified by flash chromatography on silica gel (gradient: 5–30% EtOAc / heptane) to give an additional 1.1 g of product. 1-Tetrahydropyran-2-yl-5-(2-tetrahydropyran-4-ylthinyl)indazole-6-carbaldehyde (4.4 g, 80%). 1H NMR (300 MHz, chloroform-d) δ 10.71 (s, 1H), 8.20 (s, 1H), 8.08 (d, J = 0.9 Hz, 1H), 7.94 (d, J = 0.7 Hz, 1H), 5.79 (dd, J = 9.7, 2.5 Hz, 1H), 4.14 to 3.92 (m, 3H), 3.80 (ddd, J = 13.4 , 10.6, 3.0Hz, 1H), 3.60(ddd,J=11.7, 8.7, 3.0Hz, 2H), 2.96(tt,J=8.6, 4.2Hz, 1H) , 2.67~2.42(m, 1H), 2.25~1.92(m, 4H), 1.80(dddd,J=21.2, 18.3, 9.9, 5.4Hz, 5H). LCMS m / z 339.0[M+H] + .

[0158] Step 5. Synthesis of (6E)-1-tetrahydropyran-2-yl-5-(2-tetrahydropyran-4-ylethynyl)indazole-6-carbaldehyde oxime (C6) A solution of hydroxylamine (hydrochloride) (1.4 g, 20.15 mmol) in pyridine (10 mL, 123.6 mmol) was added over 2 minutes to a solution of 1-tetrahydropyran-2-yl-5-(2-tetrahydropyran-4-ylethynyl)indazole-6-carbaldehyde (2.23 g, 6.590 mmol) in acetonitrile (30 mL) at room temperature. After stirring for 1 hour at room temperature, the mixture was concentrated in vacuo to remove acetonitrile, and the residue was partitioned between EtOAc and water. The organic layer was washed with water (3×), 1 M HCl (1×), and brine, dried over sodium sulfate, filtered, and concentrated to give the product. (6E)-1-tetrahydropyran-2-yl-5-(2-tetrahydropyran-4-ylthynyl)indazole-6-carbaldehyde oxime (2.32 g, 100%) as a tan solid, which was used without further purification. LCMS m / z 354.0[M+H] + .

[0159] Step 6. Synthesis of 5-iodo-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S1) (6E)-1-tetrahydropyran-2-yl-5-(2-tetrahydropyran-4-ylthinyl)indazole-6-carbaldehyde oxime (790 mg, 2.235 mmol) (as a solution in 15 mL of dichloromethane) was added to a mixture of molecular iodine (1.56 g, 6.146 mmol) and K2CO3 (940 mg, 6.801 mmol) in dry dichloromethane (20 mL) over 30 minutes at room temperature. After stirring for an additional 30 minutes at room temperature, the reaction was quenched by the addition of sodium bicarbonate and sodium thiosulfate solution (4:1). The layers were separated, the aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (gradient: 0 to 5% MeOH in dichloromethane, then isocratic 5% methanol in dichloromethane) to give the product as a dark brown solid: 5-iodo-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (740 mg, 69%). 1 H NMR (300 MHz, chloroform-d) δ 8.83 (s, 1H), 8.61 (s, 1H), 8.34 (d, J = 1.1 Hz, 1H), 7.77 (s, 1H), 5.85 (dd, J = 9.1, 2.5 Hz, 1H), 4.18 (dd, J = 11.2, 4.4 Hz, 2H), 4.06 (dd, J = 12.0, 4.2 Hz, 1H), 3.84(ddd,J=11.4, 9.4, 3.5Hz, 1H), 3.61(t,J=11.8Hz, 2H), 3.24(s, 2H), 2. 73~2.51(m, 1H), 2.18(d, J=12.6Hz, 2H), 1.94~1.70(m, 3H), 1.62(d,J=13.1Hz, 3H). LCMS m / z 480.0[M+H] + .

[0160] Preparation of S2 and S3 5-(2-methyl-4-pyridyl)-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S2) and 8-chloro-5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S3) [ka] Step 1. Synthesis of 5-(2-methyl-4-pyridyl)-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S2) Sodium carbonate (6 mL of 2 M, 12.00 mmol) was added to a solution of 5-iodo-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (3 g, 6.259 mmol) and (2-methyl-4-pyridyl)boronic acid (1.3 g, 9.493 mmol) in DMSO (60 mL) at room temperature. Nitrogen was bubbled through the mixture for 5 minutes, then Pd(dppf)Cl (280 mg, 0.3429 mmol) was added, and the reaction was heated at 100 °C for 2 hours. The mixture was cooled, diluted with EtOAc, and washed with water (3x). The organic layer was then extracted with 2 M HCl (3x), the aqueous layer was washed with EtOAc (1x), and then carefully basified with solid potassium carbonate. The mixture was extracted with dichloromethane (2x). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-5% MeOH in dichloromethane) afforded the product. 5-(2-methyl-4-pyridyl)-7-oxide-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (1.9 g, 68%) as a tan solid. LCMS m / z 445.0 [M+H] + .

[0161] Step 2. Synthesis of 8-chloro-5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S3) A solution of 5-(2-methyl-4-pyridyl)-7-oxide-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (660 mg, 1.485 mmol), DIPEA (950 μL, 5.454 mmol) in dichloromethane (10 mL) at -78 °C was treated with a solution of oxalyl dichloride (1 mL of 2 M, 2.000 mmol) over 10 min. The reaction was stirred at -78 °C for 1 h, then quenched with 5 mL of MeOH and concentrated. Purification by silica gel chromatography (gradient: 0-8% MeOH in dichloromethane). 8-Chloro-5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (520 mg, 76%). 1 H NMR (400MHz, chloroform-d) δ8.75(d,J=5.0Hz, 1H), 8.61(q,J=1.1Hz, 1H), 8.27~8.16(m, 1H), 7.68(d,J=1.0Hz, 1H), 7.21~7.05(m, 2H), 5.96(ddd,J=9.0, 2.8, 1.0Hz, 1H), 4.25~3.96(m, 1H), 3.96~3.72(m, 1H), 3.45~3.23(m, 2H), 2 .84~2.51(m, 6H), 2.41~2.11(m, 5H), 1.97~1.66(m, 2H), 1.61~1.37(m, 2H). LCMS m / z 463.0[M+H] + .

[0162] Preparation of S4 8-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S4) [ka] Step 1. Synthesis of 5-(3,4-difluorophenyl)-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (C7) To a mixture of 5-iodo-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (460 mg, 0.9348 mmol), (3,4-difluorophenyl)boronic acid (295 mg, 1.868 mmol), and Pd(PPh) (63 mg, 0.05452 mmol) in DMF (10 mL) under nitrogen, NaCO (2.5 mL of 2 M, 5.000 mmol) was added. The reaction mixture was heated in a microwave at 125 °C for 60 min. Water was added, and the mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, and dried. Silica gel chromatography (gradient: 0-10% MeOH in dichloromethane) afforded the product. 5-(3,4-Difluorophenyl)-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (386 mg, 89%). 1 H NMR (300 MHz, chloroform-d) δ 8.99 (s, 1H), 8.14 (d, J = 0.9 Hz, 1H), 7.87 (d, J = 1.3 Hz, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.50–7.37 (m, 1H), 7.18 (ddd, J = 10.0, 7.4, 2.1 Hz, 1H), 7.08 (ddd, J = 8.3, 4.0, 1H). .8Hz, 1H), 5.84(dd,J=9.1, 2.5Hz, 1H), 4.03(t,J=12.3Hz, 3H), 3.91~3.73(m, 1H), 3.32(q,J =11.0Hz, 3H), 2.94~2.37(m, 3H), 2.15(d,J=15.9Hz, 2H), 1.96~1.70(m, 3H), 1.49(s, 2H)ppm. LCMS m / z 466.33[M+H] + .

[0163] Step 2. Synthesis of 8-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S4) To a solution of 5-(3,4-difluorophenyl)-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (200 mg, 0.4297 mmol) and 1,4-diazabicyclo[2.2.2]octane (250 mg, 2.229 mmol) in CHCl (5 mL) at 0° C. was added TFAA (366 mg, 1.743 mmol). The reaction was then stirred at 0° C. for 1 hour, then allowed to warm to room temperature, and stirring was continued for an additional 3 hours. The reaction mixture was concentrated in vacuo to provide the product, which was used in the next reaction without further purification. 8-(4-Aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (trifluoroacetic acid (3)) (388 mg, 100%) LCMS m / z 560.84 [M+H] + .

[0164] Preparation of S5 and S6 8-(4-Aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinoline (S5) and 8-chloro-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S6) [ka] Step 1. Synthesis of 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinoline (S5) To a solution of 5-(3,4-difluorophenyl)-7-oxide-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-7-ium (hydrochloride) (254 mg, 0.5268 mmol) and 1,4-diazabicyclo[2.2.2]octane (300 mg, 2.674 mmol) in dichloromethane (2 mL) was added TFAA (300 μL, 2.158 mmol) at room temperature. The mixture was allowed to stir for 1 h. The mixture was concentrated and dissolved in DMSO. Reverse-phase chromatography (column: C18; gradient: 10–100% MeCN in water with 0.1% trifluoroacetic acid) afforded the product. 8-(4-Aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinoline (trifluoroacetic acid (2)) (321 mg, 85%). LCMS m / z 476.38 [M+H] + .

[0165] Step 2. Synthesis of 8-chloro-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S6) A solution of 5-(3,4-difluorophenyl)-7-oxide-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (1.9 g, 4.082 mmol), DIPEA (2.85 mL, 16.36 mmol) in dichloromethane (20 mL) at −78° C. was treated with a dropwise solution of oxalyl dichloride (4.2 mL of 2 M, 8.400 mmol) over 1 minute. The reaction was stirred at −78° C. for 1 hour and then at 0° C. for 1 hour. The mixture was quenched with MeOH (5 mL) and concentrated. The residue was treated with MeOH (5 mL), sonicated for 1 minute to form a suspension, and then filtered. The collected solid was washed with MeOH (3×1 mL) and then dried under vacuum for 30 minutes. The solid was transferred to a 250 mL flask and then dried on a rotovap (65 °C, 3 mbar) for 1 h. 10 mL of cold MeOH was added to the crude residue, and the solution was filtered. The resulting brown solid was washed with ice-cold MeOH and dried under vacuum to give 8-chloro-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (1.2 g, 61%). 1 H NMR (300MHz, DMSO-d6) δ8.65(d,J=1.0Hz, 1H), 8.46(d,J=0.9Hz, 1H), 7.85(d,J=1.0H z, 1H), 7.78~7.50(m, 2H), 7.28(d,J=5.1Hz, 1H), 6.20(dd,J=9.3, 2.3Hz, 1H), 3.88(d, J=7.3Hz, 4H), 3.22(td,J=11.4, 6.5Hz, 2H), 2.81~2.63(m, 1H), 2.43(d,J=9.3Hz, 1H) , 2.00(td,J=13.9, 9.0Hz, 4H), 1.82(d,J=11.5Hz, 1H), 1.57(dd,J=23.8, 10.2Hz, 4H). LCMS m / z 484.19[M+H] + .

[0166] Preparation of S7 and S8 5-(4-Fluorophenyl)-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S7) and 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(4-fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S8) [ka] Compounds S7 and S8 were prepared as described from S1 using the method described for the preparation of S4.

[0167] 5-(4-Fluorophenyl)-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S7) 1 H NMR (400MHz, chloroform-d) δ8.97(s, 1H), 8.10(d,J=0.9Hz, 1H), 7.84(d,J=1.1Hz, 1H), 7.52(t,J=1.0Hz, 1H), 7.29(m, 4H), 5.82(dd,J=9.1, 2.7Hz, 1H), 4.0 4(d,J=11.4Hz, 1H), 4.00~3.90(m, 2H), 3.87~3.74(m, 1H), 3.28(m, 3H), 2.98 ~2.36(m, 3H), 2.26~2.06(m, 2H), 1.93~1.67(m, 3H), 1.46(d,J=12.5Hz, 2H). LCMS m / z 448.25[M+H] + .

[0168] 8-(4-Aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(4-fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S8) LCMS m / z 542.0 [M+H] + .

[0169] Preparation of S9 8-chloro-5-(4-fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S9) [ka] Step 1. Synthesis of 8-chloro-5-(4-fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S9) A solution of 5-(4-fluorophenyl)-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (500 mg, 1.117 mmol), DIPEA (600 μL, 3.445 mmol) in dichloromethane (5 mL) at −78° C. was treated with a dropwise solution of oxalyl dichloride (1.15 mL of 2 M, 2.300 mmol) over 10 minutes. The reaction was stirred at −78° C. for 1 hour. The reaction was quenched with MeOH (5 mL) and concentrated. Purification by silica gel chromatography (gradient: 0 to 10% EtOAc in dichloromethane) afforded the product. 8-Chloro-5-(4-fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (390 mg, 75%). 1 H NMR (400MHz, chloroform-d) δ8.58(t,J=1.1Hz, 1H), 8.20(d,J=0.9Hz, 1H), 7.74(d,J=1.0Hz, 1H), 7.32~7.20(m, 3H), 5.95(dd,J=9.3, 2.7Hz, 1H), 4.23~ 4.01(m, 3H), 3.98~3.81(m, 1H), 3.44~3.23(m, 2H), 2.91~2.58(m, 2H), 2. 39~2.14(m, 3H), 2.00~1.70(m, 4H), 1.63~1.44(m, 2H), 1.31~1.19(m, 1H). LCMS m / z 466.0[M+H] + .

[0170] Preparation of S10 and S11 5-(4-Fluorophenyl)-6-isopropyl-7-oxido-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S10) and 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinoline (S11) [ka] Step 1. Synthesis of 5-(3-methylbut-1-ynyl)-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde (C9) In a 3 L four-neck flask (equipped with a mechanical stirrer, temperature probe, and heating jacket), a solution of 5-bromo-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde (113 g, 365.5 mmol) in DMF (1.1 L) was bubbled with nitrogen for 15 minutes, and then diisopropylamine (103 mL, 734.9 mmol) was added. Nitrogen bubbling was continued for 15 minutes, and then 3-methylbut-1-yne (54 mL, 554.9 mmol) was added, followed by Pd(PPh3)2Cl2 (8.0 g, 11.40 mmol) and CuI (4.18 g, 21.95 mmol). The mixture was placed under a slight positive pressure of nitrogen and then heated to 50 °C for 3 hours. The mixture was cooled to 25 °C, and then water (1 L) was added with stirring. The internal temperature rose to 41 °C and a precipitate was observed. The mixture was extracted with EtOAc (2 x 1.5 L). The combined EtOAc extracts were washed successively with 1:1 water:saturated brine, 1:1 saturated aqueous NH4Cl:saturated aqueous NaHCO3, 0.3 M aqueous HCl, and brine (1.5 L each). The organic layer was dried (MgSO4), filtered, and concentrated. 1H NMR (200MHz, chloroform-d) δ10.71(s, 1H), 8.19(t,J=0.9Hz, 1H), 8.07(d,J=1.0Hz, 1H), 7.91(d,J=0.7Hz, 1H), 5.78(dd,J=9.7, 2.6Hz, 1H), 4.08(ddt,J=11.8, 3.8, 1.9Hz, 1H), 3.85~3.75(m, 1H), 2.88(hept,J=6.9Hz, 1H), 2.56(dddd,J=13.7, 11 .9, 9.8, 4.0Hz, 1H), 2.24~2.05(m, 2H), 1.88~1.64(m, 3H), 1.34(d,J=6.9Hz, 6H). LCMS m / z 297.03[M+H] + Melting point = 100°C.

[0171] Step 2. Synthesis of (6E)-5-(3-methylbut-1-ynyl)-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde oxime (C10) In a 5 L three-neck flask equipped with mechanical stirring, a temperature probe, and a heating jacket, pyridine (550 mL, 6.800 mol) was added to a suspension of hydroxylamine (hydrochloride) (70.0 g, 1.007 mol) in MeCN (1.0 L) at room temperature. The mixture was heated to 50 °C, and then a solution of 5-(3-methylbut-1-ynyl)-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde (100 g, 337.4 mmol) in dichloromethane (750 mL) was added. The mixture was stirred at 50 °C for 1 hour and then concentrated. The residue was dissolved in EtOAc (2 L), washed successively with water (2x) and then brine (1.5 L each), dried (MgSO), filtered, and concentrated. The residue was concentrated from a solution of EtOAc / heptane to give a dark solid. The solid was treated with MTBE (200 mL) and heated to reflux for 5 minutes to form a homogeneous suspension, then treated with heptane (500 mL). The resulting suspension was allowed to stand at room temperature for 18 hours. The crystals were isolated via filtration, washed with heptane (3 × 100 mL), and then dried under vacuum for 30 minutes and then on a rotovap (65 °C, 3 mbar) for 1 hour to give the product (6E)-5-(3-methylbut-1-ynyl)-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde oxime (92.7 g, 88%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 8.82–8.75 (m, 1H), 8.07 (s, 1H), 8.00 (d, J = 0.9 Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.62 (s, 1H), 5.74 (dd, J = 9.7, 2.7 Hz, 1H), 4.07 (dd, J = 11.5, 3 .0Hz, 1H), 3.78(td,J=11.1, 3.0Hz, 1H), 2.87(hept,J=6.9Hz, 1H), 2.64~2.51(m, 1 H), 2.12(ddd,J=31.8, 11.3, 4.1Hz, 2H), 1.87~1.57(m, 3H), 1.33(d,J=6.9Hz, 6H). LCMS m / z 312.1[M+H] + .

[0172] Step 3. Synthesis of 5-iodo-6-isopropyl-7-oxido-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (C11) Compound C11 was prepared from C10 by iodination as described for the preparation of S1.

[0173] 5-Iodo-6-isopropyl-7-oxide-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (1.2 g, 84%) as a yellow foam. H NMR (400 MHz, chloroform-d) δ 8.82 (s, 1H), 8.60 (s, 1H), 8.34 (d, J = 1.0 Hz, 1H), 7.77 (q, J = 0.9 Hz, 1H), 5.85 (dd, J = 9.1, 2.6 Hz, 1H), 4.22 (s, 1H), 4.12–4.00 (m, 1H), 3.90–3.78 (m, 1H), 2.62 (qd, J = 9.5, 5.2 Hz, 1H), 2.29–2.11 (m, 2H), 1.93–1.69 (m, 3H), 1.62 (d, J = 6.9 Hz, 6H). LCMS m / z 438.03 [M+1] + .

[0174] Step 4. Synthesis of 5-(4-fluorophenyl)-6-isopropyl-7-oxide-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S10) Compound S10 was prepared from C11 by Suzuki coupling with 4-fluorophenylboronic acid as described in the preparation of compound S2. Pd(PPh3)4 was used as the catalyst in this example. Purification by silica gel chromatography (gradient: 0-10% EtOAc in dichloromethane) gave the product, which was used in the subsequent reaction without further purification. 5-(4-fluorophenyl)-6-isopropyl-7-oxido-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium. LCMS m / z 406.08 [M+1] + .

[0175] Step 5. Synthesis of 5-(4-fluorophenyl)-6-isopropyl-7-oxide-1H-pyrazolo[4,3-g]isoquinolin-7-ium (C12) 5-(4-Fluorophenyl)-6-isopropyl-7-oxide-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (1050 mg, 2.590 mmol) was treated with hydrogen chloride (30 mL of 4 M, 120.0 mmol) at room temperature. The reaction mixture was stirred for 18 hours. The solvent was removed to give 5-(4-fluorophenyl)-6-isopropyl-7-oxide-1H-pyrazolo[4,3-g]isoquinolin-7-ium (830 mg, 100%). LCMS m / z 322.37 [M+H] + .

[0176] Step 6. Synthesis of 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinoline (S11) To a solution of 5-(4-fluorophenyl)-6-isopropyl-7-oxide-1H-pyrazolo[4,3-g]isoquinolin-7-ium (830 mg, 2.583 mmol) and 1,4-diazabicyclo[2.2.2]octane (2.6 mg, 23.18 mmol) in CHCl (22 mL) at 0° C. was added TFAA (2.5 mL, 17.99 mmol). The reaction was stirred at 0° C. for 1 hour, then allowed to warm to ambient temperature and stirred for an additional 3 hours. The reaction mixture was concentrated in vacuo. The crude product was triturated with EtOAc to provide the product. 8-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinoline(trifluoroacetic acid) (3.2 g, 96%). 1H NMR (300 MHz, chloroform-d): 14.16 (s, 1H), 10.13 (s, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.32 (d, J = 7.0 Hz, 4H), 4.38 (t, J = 7.4 Hz, 6H), 3.71 (t, J = 7.4 Hz, 6H), 3.03 (q, J = 6.7 Hz, 1H), 1.25 (d, J = 6.7 Hz, 6H) ppm. LCMS m / z 416.28 [M+H] + .

[0177] Preparation of S12 and S13 8-chloro-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S12) and 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S13) [ka] Preparation of 8-chloro-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S12) Compound S12 was prepared from S10 using the method described for the preparation of S10 to give the product: 8-chloro-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (5.3 g, 82%). LCMS m / z 424.14 [M+H] + .

[0178] Preparation of 8-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S13) Compound S10 was prepared from S13 using the method described for the preparation of S8. 8-(4-Aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline(trifluoroacetic acid) (374 mg, 100%). LCMS m / z 500.9 [M+H] + .

[0179] Preparation of S14 and S15 6-Isopropyl-5-(2-methyl-4-pyridyl)-7-oxido-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S14) and 8-chloro-6-isopropyl-5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S15) [ka] Synthesis of 6-isopropyl-5-(2-methyl-4-pyridyl)-7-oxide-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S14) Compound S14 was prepared from C11 by Suzuki coupling with 2-methyl-4-pyridylboronic acid using the method described for the preparation of S2. 6-Isopropyl-5-(2-methyl-4-pyridyl)-7-oxide-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (900 mg, 65%) as a tan solid. LCMS m / z 403.0 [M+H] + .

[0180] Synthesis of 8-chloro-6-isopropyl-5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S15) Compound S15 was prepared from S14 using the method described for the preparation of S3. 8-Chloro-6-isopropyl-5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (280 mg, 77%). LCMS m / z 421.0 [M+H] + .

[0181] Preparation of S16 8-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-6-isopropyl-5-(2-methoxy-4-pyridyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S16) [ka] Step 1. Synthesis of 6-isopropyl-5-(2-methoxy-4-pyridyl)-7-oxido-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (C13) Compound C13 was prepared by Suzuki coupling with C11 and 2-methoxy-4-pyridylboronic acid using the method described for the preparation of S2. Purification by silica gel chromatography (gradient: 0-5% MeOH in dichloromethane) afforded the product as a pale red solid. 6-Isopropyl-5-(2-methoxy-4-pyridyl)-7-oxide-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (168.5 mg, 92%). 1 H NMR (400MHz, chloroform-d) δ8.87(s, 1H), 8.31(m, 1H), 8.04(d,J=1.0Hz, 1H), 7.77(s, 1H), 7.49(s, 1H), 6.79(m, 1H), 6.69~6.65(m, 1H), 5.75(dd,J =9.1, 2.7Hz, 1H), 4.00(m, 4H), 3.81~3.70(m, 1H), 3.25~3.00(m, 1H), 2. 59~2.47(m, 1H), 2.19~2.01(m, 2H), 1.71(m, 3H), 1.39(d,J=6.9Hz, 6H). LCMS m / z 419.26[M+H] + .

[0182] Step 2. Synthesis of 8-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-6-isopropyl-5-(2-methoxy-4-pyridyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S16) Compound S16 was prepared from C13 using the method described for the preparation of compound S4. Reverse-phase chromatography (column: C18. Gradient: 0-50% MeCN in water containing 0.1% trifluoroacetic acid) yielded the product. 8-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-6-isopropyl-5-(2-methoxy-4-pyridyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline(trifluoroacetic acid) (182 mg, 74%). LCMS m / z 513.43 [M+H] +

[0183] Preparation of S17 8-(4-Aza-1-azonibicyclo[2.2.2]octan-1-yl)-6-(1-benzyloxycyclopropyl)-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinoline (S17) [ka] Step 1. Synthesis of 6-(1-benzyloxycyclopropyl)-5-(4-fluorophenyl)-7-oxido-1H-pyrazolo[4,3-g]isoquinolin-7-ium (C17) Part A. To a 20 mL vial was added 5-bromo-6-(1,3-dioxolan-2-yl)-1-tetrahydropyran-2-yl-indazole (1.15 g, 3.256 mmol), CsCO (2.44 g, 7.489 mmol), and Pd(dppf)Cl (212 mg, 0.3253 mmol). The vial was sealed and flushed with nitrogen. THF (7.9 mL) was added, followed by 1-(1-benzyloxycyclopropyl)-2-(4-fluorophenyl)ethanone (1.2 g, 4.221 mmol). The reaction mixture was heated to 70 °C overnight, then cooled to room temperature and diluted with EtOAc. The organic solution was washed with brine, dried over NaSO, and concentrated in vacuo. The mixture was then purified by silica gel chromatography (Gradient: 10-25% EtOAc in heptane) to afford C16.

[0184] Part B. Hydroxylamine (hydrochloride) (1.13 g, 16.26 mmol) in EtOH (14.5 mL) / HO (1.5 mL) was added to the product of Part A (C16). The reaction mixture was heated at 90 °C in a microwave for 2 hours. The reaction was concentrated, and the product was purified by silica gel chromatography (gradient: 30 to 80% EtOAc in heptane) to give 6-(1-benzyloxycyclopropyl)-5-(4-fluorophenyl)-7-oxide-1H-pyrazolo[4,3-g]isoquinolin-7-ium (600 mg, 43%). LCMS m / z 426.21 [M+H] + .

[0185] Step 2. Synthesis of 8-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-6-(1-benzyloxycyclopropyl)-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinoline (S17) To a solution of 6-(1-benzyloxycyclopropyl)-5-(4-fluorophenyl)-7-oxide-1H-pyrazolo[4,3-g]isoquinolin-7-ium (hydrochloride) (600 mg, 1.299 mmol) and DABCO (1.29 g, 11.50 mmol) in dichloromethane (12 mL) was added TFAA (1.24 mL, 8.921 mmol) dropwise over 1 minute at room temperature. The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo to provide a dark brown solid. Reverse-phase chromatography (column: C18; gradient: 0-100% MeCN in water with 0.1% TFA) afforded the product. 8-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-6-(1-benzyloxycyclopropyl)-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinoline (trifluoroacetic acid (2)) (620 mg, 63%) LCMS m / z 520.3 [M+H] + .

[0186] S18 Preparation of 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-6-(1-benzyloxycyclopropyl)-5-(3,4-difluorophenyl)-1H-pyrazolo[4,3-g]isoquinoline (S18) [ka] Compound S18 was prepared from C14 and 1-(1-benzyloxycyclopropyl)-2-(3,4-difluorophenyl)ethanone using the method described for compound S17. Reverse-phase chromatography (column: C18; gradient: 0-100% MeCN in water with 0.1% TFA) afforded the product. 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-6-(1-benzyloxycyclopropyl)-5-(3,4-difluorophenyl)-1H-pyrazolo[4,3-g]isoquinoline(trifluoroacetic acid (2)) (122 mg, 51%) LCMS m / z 538.55 [M+H] + .

[0187] S19 Preparation of 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(3,4-difluorophenyl)-6-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazolo[4,3-g]isoquinoline (S19) [ka] Compound S19 was prepared from C14 and C18 using the method described for the preparation of S17. Reverse-phase chromatography (column: C18; gradient: 0-100% MeCN in water with 0.1% trifluoroacetic acid) afforded the product. 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(3,4-difluorophenyl)-6-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazolo[4,3-g]isoquinoline (trifluoroacetate salt) (91 mg, 52%) LCMS m / z 500.49 [M+H] + .

[0188] Preparation of S20 6-(1,1-difluoroethyl)-5-(4-fluorophenyl)-7-oxide-1H-pyrazolo[4,3-g]isoquinolin-7-ium (S20) [ka] S20 was prepared from C14 and 3,3-difluoro-1-(4-fluorophenyl)butan-2-one (160 mg, 0.7914 mmol) as described for the preparation of C20. The reaction was concentrated and the product purified by ISCO (40 g silica, 100% EtOAc in heptane) to give 6-(1,1-difluoroethyl)-5-(4-fluorophenyl)-7-oxide-1H-pyrazolo[4,3-g]isoquinolin-7-ium (100 mg, 50%). LCMS m / z 344.18 [M+H] + .

[0189] Preparation of S21 5-(3,4-Difluorophenyl)-6-(1-methoxycyclobutyl)-7-oxido-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S21) [ka] Compound S21 was prepared from 2-(3,4-difluorophenyl)-1-(1-methoxycyclobutyl)ethanone and C14 as described for the preparation of compound S17. The THP protecting group remained during the cyclization step. 1 H NMR (300 MHz, chloroform-d) δ 8.92 (s, 1H), 8.16 (d, J = 0.9 Hz, 1H), 7.87 (d, J = 1.3 Hz, 1H), 7.73 (d, J = 1.1 Hz, 1H), 7.40-7.23 (m, 3H), 7.18 (dq, J = 8.5, 2.3, 1.9 Hz, 1H), 5.84 (dd, J = 9.1, 2.5 Hz, 1H). 4.09~3.99(m, 1H), 3.89~3.76(m, 1H), 3.48(s, 3H), 2.69~2.50(m, 1H), 2.36(dt,J=10.9, 8.5H z, 2H), 2.25~2.09(m, 1H), 2.04~1.88(m, 1H), 1.88~1.67(m, 1H), 1.58(dt,J=11.4, 8.9Hz, 1H). LCMS m / z 563.09[M+H] + .

[0190] Preparation of S22 8-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-5-(3,4-difluorophenyl)-6-(2-methoxy-2-methyl-propyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S22) [ka] Compound S22 was prepared from 1-(3,4-difluorophenyl)-4-methoxy-4-methyl-pentan-2-one and C14 as described for the preparation of S22. 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(3,4-difluorophenyl)-6-(2-methoxy-2-methyl-propyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline(trifluoroacetic acid (3)) (160 mg, 56%) LCMS m / z 563.09 [M+1] + .

[0191] Preparation of S23 [6-(2-benzyloxy-1,1-dimethyl-ethyl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]trifluoromethanesulfonate (S23) [ka] Step 1. Synthesis of 6-(2-benzyloxy-1,1-dimethyl-ethyl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-7H-pyrazolo[4,3-g]isoquinolin-8-one (C23) Part A. To a 20 mL vial was added methyl 5-bromo-1-tetrahydropyran-2-yl-indazole-6-carboxylate (1.23 g, 3.626 mmol), Cs2CO3 (2.72 g, 8.348 mmol), and Pd(dppf)Cl2 (236 mg, 0.3621 mmol). The vial was sealed and flushed with nitrogen. THF (10 mL) was added, followed by 4-benzyloxy-1-(3,4-difluorophenyl)-3,3-dimethyl-butan-2-one (1.5 g, 4.712 mmol), both via syringe. The reaction mixture was heated to 70 °C overnight. The reaction was cooled to room temperature and diluted with dichloromethane. The organic solution was washed with brine, dried over Na2SO4, and concentrated in vacuo. The reaction mixture was then purified by silica gel chromatography (gradient: 10% to 25% EtOAc in heptane) and the product was used in the subsequent reaction.

[0192] Part B. To the product from Part A was added NH3 in methanol (10 mL of 7 M, 70.00 mmol) in a 10-20 mL microwave vial. The reaction mixture was heated at 120 °C in a microwave for 5 h. The reaction was concentrated, and the product was purified by silica gel chromatography (gradient: 30-80% EtOAc in heptane) to give 6-(2-benzyloxy-1,1-dimethyl-ethyl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-7H-pyrazolo[4,3-g]isoquinolin-8-one (850 mg, 43%). 1 H NMR (300 MHz, chloroform-d) δ 10.23 (s, 1H), 8.73 (q, J = 1.0 Hz, 1H), 8.06 (d, J = 0.9 Hz, 1H), 7.48–7.20 (m, 7H), 7.10–6.94 (m, 2H), 5.87 (dd, J = 9.9, 2.4 Hz, 1H), 4.65 (s, 2H) H), 4.16~4.02(m, 1H), 3.83(td, J=11.1, 2.9Hz, 1H), 3.47(t,J=1.7Hz, 2H), 2.71 ~2.53(m, 1H), 2.27~2.01(m, 2H), 1.88~1.63(m, 3H), 1.12(dd,J=6.3, 4.3Hz, 6H). LCMS m / z 577.44[M+H] + .

[0193] Step 2. Synthesis of [6-(2-benzyloxy-1,1-dimethyl-ethyl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]trifluoromethanesulfonate (S23) To a solution of 6-(2-benzyloxy-1,1-dimethyl-ethyl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-7H-pyrazolo[4,3-g]isoquinolin-8-one (200 mg, 0.3652 mmol) and pyridine (100 μL, 1.236 mmol) in dichloromethane (2.8 mL) was added trifluoromethylsulfonyl trifluoromethanesulfonate (90 μL, 0.5349 mmol) at 0° C. The reaction was stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. The reaction was quenched with NaHCO3, washed with dichloromethane, concentrated, and purified by silica gel chromatography (gradient: 0 to 30% EtOAc in heptane) to give [6-(2-benzyloxy-1,1-dimethyl-ethyl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]trifluoromethanesulfonate (220 mg, 89%). LCMS m / z 676.25 [M+H] + .

[0194] Exemplary Compounds 1-262 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.

[0195] All specific and generic compounds, and intermediates disclosed for making those compounds, are considered to be part of the disclosure disclosed herein.

[0196] compound 1 3-[[5-(4-chlorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (1) [ka] Step 1. Synthesis of 5-(4-chlorophenyl)-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (C24) In a microwave vial, 5-iodo-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (500 mg, 0.9994 mmol), (4-chlorophenyl)boronic acid (310 mg, 1.982 mmol), and Pd(PPh3)4 (70 mg, 0.060 mmol) were dissolved in DMF (7 mL). Na2CO3 (2 mL of 2 M, 4.000 mmol) was added. The reaction mixture was heated under microwave conditions at 125 °C for 1 hour. Water and dichloromethane were added to the reaction. The mixture was extracted with dichloromethane (×3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. Purification by silica gel chromatography (gradient: 0-5% MeOH in dichloromethane) afforded the product. 5-(4-Chlorophenyl)-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (390 mg, 84%). 1 H NMR (400 MHz, chloroform-d) δ 8.91 (s, 1H), 8.04 (d, J = 0.9 Hz, 1H), 7.78 (m, 1H), 7.55–7.48 (m, 2H), 7.44 (t, J = 1.0 Hz, 1H), 7.21–7.16 (m, 3H), 5.75 (dd, J = 9.1 Hz, 1H), 2.77–2.78 (m, 2H). H), 4.02~3.94(m, 1H), 3.91(dd,J=11.3, 4.1Hz, 2H), 3.75(m, 1H), 3.22(m, 3H), 2 .93~2.27(m, 3H), 2.18~2.00(m, 2H), 1.83~1.64(m, 3H), 1.39(d,J=12.5Hz, 2H). LCMS m / z 444.24[M+H] + .

[0197] Step 2. Synthesis of 8-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-5-(4-chlorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (C25) 5-(4-Chlorophenyl)-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (281 mg, 0.6057 mmol) and 1,4-diazabicyclo[2.2.2]octane (340 mg, 3.031 mmol) were suspended in CHCl (6.5 mL) and the reaction was cooled to 0 °C. (2,2,2-Trifluoroacetyl) 2,2,2-trifluoroacetate (250 μL, 1.799 mmol) was added and the reaction was stirred at 0 °C for 1 h. Volatiles were evaporated in vacuo. Purification was performed by flash column chromatography (gradient: 0 to 50% CHCN in water with 0.1% TFA). The product fractions were concentrated and the acetonitrile was removed in vacuo. The water was removed by lyophilization to give the product as a pale yellow solid: 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(4-chlorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (trifluoroacetate) (385 mg, 94%). LCMS m / z 558.35 [M+H] +

[0198] Step 3. Synthesis of 3-[5-(4-chlorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (C26) In a vial, 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-5-(4-chlorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (trifluoroacetate salt) (250 mg, 0.3714 mmol) and 3-hydroxycyclobutanecarboxylic acid (130 mg, 1.120 mmol) were dissolved in DMSO (3.7 mL). Then, NaH (90 mg of 60% w / w, 2.250 mmol) was added at room temperature under nitrogen. The reaction was stirred for 2 hours. Purification by reverse-phase chromatography (column: C18, gradient: 0-100% MeCN in water with 0.1% trifluoroacetic acid) afforded the product. Product-containing fractions were pooled, and the acetonitrile was evaporated in vacuo. The aqueous mixture was extracted with CHCl3:IPA (3:1). The organic phases were combined, dried over MgSO4, and the volatiles were evaporated in vacuo to give the product: 3-[5-(4-chlorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (161.1 mg, 77%). LCMS m / z 562.26 [M+H] + .

[0199] Step 4. Synthesis of 3-[[5-(4-chlorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (1) In a vial, 3-[5-(4-chlorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (160 mg, 0.2847 mmol) was dissolved in dichloromethane (1.5 mL). Octane-1-thiol (108 μL, 0.6223 mmol) was then added. In a separate vial, AlCl (76 mg, 0.5700 mmol) was dissolved in CH NO (1.5 mL) and added to the mixture. The reaction was stirred at room temperature for 1 hour. Saturated NaHCO was added, and the mixture was extracted with dichloromethane. The organic phases were combined, filtered through a phase separator, and the volatiles were evaporated in vacuo. The crude mixture was purified by flash column chromatography (gradient: 0–5% MeOH in dichloromethane). The purification was repeated twice as impurities co-eluted with the product. The crude material was then purified by reverse-phase chromatography (Column: C18. Gradient: 5 to 100% CH3CN in water with 0.1% TFA) to give the product: 3-[[5-(4-chlorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (32 mg, 23%). 1 H NMR (400MHz, DMSO-d6) δ13.35(s, 1H), 12.38(s, 1H), 8.35(s, 1H), 8.32(s, 1H), 7.63(d,J=7.9Hz, 2H), 7.58(s, 1H), 7.38(d,J=7.9Hz, 2H), 5.58 (m, 1H), 3.88(dd,J=11.7, 4.2Hz, 2H), 3.19(t,J=11.9Hz, 3H), 2.88~2.75(m, 2H), 2.69~2.57(m, 3H), 2.03(m, 2H), 1.47(dd,J=13.1, 3.3Hz, 2H). LCMS m / z 478.27[M+H] + .

[0200] compound 2 3-[[5-(4-Fluoro-3-methoxy-phenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (2) [ka] Compound 2 was prepared from S1 and (4-fluoro-3-methoxy-phenyl)boronic acid as described for compound 1. HCl was used for the final THP deprotection step. 3-[[5-(4-Fluoro-3-methoxy-phenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (80.7 mg). 1 H NMR (400 MHz, methanol-d4:chloroform-d 3:1) δ 8.41 (s, 1H), 8.12 (d, J = 1.2 Hz, 1H), 7.64 (d, J = 1.1 Hz, 1H), 7.22 (dd, J = 11.3, 8.1 Hz, 1H), 6.93 (dd, J = 8.2, 2.0 Hz, 1H), 6.83 (m, 1H), 5.74–5.62 (p, J = 8.0 Hz, 1H), 3.97(m, 2H), 3.84(s, 3H), 3.42~3.33(m, 2H), 3.24(tt,J=9.6, 4.1Hz, 1H), 2 .94(m, 2H), 2.75(tt,J=11.5, 3.7Hz, 1H), 2.65(m, 2H), 2.21(m, 2H), 1.51(m, 2H). LCMS m / z 492.27[M+H] +

[0201] compound 3 3-[[5-(3-chloro-4-fluoro-phenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (3) [ka] Compound 3 was prepared from S1 and 4-fluoro,3-chlorophenylboronic acid as described for compound 1. Purification by reverse-phase chromatography (column: C18, gradient: 5 to 100% MeCN in water with 0.1% trifluoroacetic acid) afforded the product. A pale yellow solid, 3-[[5-(3-chloro-4-fluoro-phenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (75.3 mg, 48%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ13.37(s, 1H), 12.38(s, 1H), 8.36(s, 1H), 8.33(s, 1H), 7.69~7.55(m, 3H), 7.38(m, 1H), 5.59 (m, 1H), 3.97~3.81(m, 2H), 3.28~3.11(m, 3H), 2.90~2.71(m, 2H), 2.62(m, 3H), 2.12~1.92(m, 2H), 1.58~1.40(m, 2H). LCMS m / z 496.23[M+H] + .

[0202] compound 4 3-[[5-(4-chloro-3-fluoro-phenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (4) [ka] Compound 4 was prepared from S1 and 4-fluoro,3-chlorophenylboronic acid as described for compound 1. Purification by reverse-phase chromatography (Column: C18 column; Gradient: 0 to 50% MeCN in water with 0.2% formic acid) afforded the product. A pale yellow solid, 3-[[5-(4-chloro-3-fluoro-phenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (33.3 mg, 24%) was obtained. 1H NMR (400 MHz, methanol-d4:chloroform-d 3:1)δ8.43(t,J=1.1Hz, 1H), 8.14(d,J=1.2Hz, 1H), 7.65~7.56(m, 2H), 7.16(dd,J=9.6, 1.9Hz, 1H), 7.09(dd,J=8.0, 1.9Hz, 1H), 5.68(p,J=6.8H) z, 1H), 3.97(d,J=11.5Hz, 2H), 3.37(m, 2H), 3.20~3.27(m, 1H), 3.01~2. 87(m, 2H), 2.77~2.59(m, 3H), 2.29~2.24(m, 2H), 1.50(d,J=13.5Hz, 2H). LCMS m / z 496.23[M+H] + .

[0203] compound 5 1-[5-(5-fluoro-3-pyridyl)-8-[1-[(2S)-2-hydroxypropanoyl]azetidin-3-yl]oxy-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-1-yl]-2-hydroxy-propan-1-one (5) [ka] Step 1. Synthesis of 5-(5-fluoro-3-pyridyl)-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (C25) A mixture of 5-iodo-7-oxido-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (1 g, 1.997 mmol), (5-fluoro-3-pyridyl)boronic acid (360 mg, 2.555 mmol), and Pd(dppf)Cl (100 mg, 0.1225 mmol) in DMSO (10 mL) was bubbled with nitrogen. NaCO (2 mL of 2 M, 4.000 mmol) was added, and the mixture was stirred at 90 °C overnight. The mixture was diluted with EtOAc, washed with HO, dried over NaSO, and then concentrated. Purification by silica gel chromatography (gradient: 0-10% MeOH / dichloromethane) gave the product, which was used in the next step without further purification. 5-(5-Fluoro-3-pyridyl)-7-oxide-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (850 mg, 61%). The product was carried on to the next step. LCMS m / z 449.0 [M+H] + .

[0204] Step 2. Synthesis of 8-chloro-5-(5-fluoro-3-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (C26) To a solution of 5-(5-fluoro-3-pyridyl)-7-oxide-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (850 mg, 1.895 mmol) in dichloromethane (20 mL) was added DIPEA (1 mL, 5.741 mmol) and oxalyl chloride (2 mL of 2 M, 4.0 mmol) at 0 °C. The mixture was stirred for 1 hour and then concentrated. Purification by silica gel chromatography (gradient: 0 to 10% MeOH in dichloromethane) afforded the product. 8-Chloro-5-(5-fluoro-3-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (500 mg, 57%). LCMS m / z 467.0[M+H] + .

[0205] Step 3. Synthesis of 8-(azetidin-3-yloxy)-5-(5-fluoro-3-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (C27) Part A. A solution of benzyl 3-hydroxyazetidine-1-carboxylate (90 mg, 0.4343 mmol) in DMSO (1 mL) was added to KOtBu (48 mg, 0.4278 mmol) and stirred for 10 minutes. To the mixture was added 8-chloro-5-(5-fluoro-3-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (100 mg, 0.2142 mmol) and stirred at 50° C. for 30 minutes. The reaction was then diluted with EtOAc, washed with HO, dried over NaSO, and concentrated. Purification by silica gel chromatography (gradient: 0-10% MeOH in dichloromethane) afforded the product: benzyl 3-[5-(5-fluoro-3-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyazetidine-1-carboxylate (130 mg, 95%). LCMS m / z 638.0 [M+H] + .

[0206] Part B. To a solution of benzyl 3-[5-(5-fluoro-3-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyazetidine-1-carboxylate (130 mg, 95%) in methanol (5 mL) was added Pd / C (70 mg of 10% w / w, 0.06578 mmol) and stirred under a H2 balloon for 1 hour. The mixture was filtered through a layer of Celite® and the filtrate was concentrated. 8-(azetidin-3-yloxy)-5-(5-fluoro-3-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (90 mg, 83%), LCMS m / z 504.0 [M+H] + .

[0207] Step 4. Synthesis of (2S)-1-[3-[[5-(5-fluoro-3-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]azetidin-1-yl]-2-hydroxy-propan-1-one (5) Part A. To a mixture of 8-(azetidin-3-yloxy)-5-(5-fluoro-3-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (90 mg, 0.1787 mmol), (2S)-2-hydroxypropanoic acid (25 mg, 0.2775 mmol) in DMF (1 mL) was added HATU (100 mg, 0.2630 mmol) and DIPEA (75 μL, 0.4306 mmol). The mixture was stirred for 30 min. Purification by reverse-phase chromatography (column: C18, gradient: 0 to 100% MeCN in water with 0.2% formic acid) afforded the product, which was used in Part B. (2S)-1-[3-[5-(5-Fluoro-3-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyazetidin-1-yl]-2-hydroxy-propan-1-one (65 mg, 63%). LCMS m / z 576.0 [M+H] + .

[0208] Part B. To a solution of (2S)-1-[3-[3-[5-(5-fluoro-3-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyazetidin-1-yl]-2-hydroxy-propan-1-one (65 mg) in dichloromethane (5 mL) was added TFA (200 μL, 2.596 mmol). The mixture was stirred at room temperature for 2 hours. Purification by reverse-phase chromatography (column: C18. Gradient: 10-100% MeCN in water with 0.1% formic acid) followed by silica gel chromatography (gradient: 0-15% MeOH in dichloromethane). (2S)-1-[3-[[5-(5-fluoro-3-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]azetidin-1-yl]-2-hydroxy-propan-1-one (14.1 mg, 16%). 1 H NMR (400 Hz, methanol-d4) δ 8.67 (d, J = 2.7 Hz, 1H), 8.50 (t, J = 1.1 Hz, 1H), 8.38 (q, J = 1.8 Hz, 1H), 8.22 (d, J = 1.1 Hz, 1H), 7.78–7.69 (m, 1H), 7.64 (d, J = 1.1 Hz, 1H), 5.74 (tq, J = 6.6, 4.3 Hz, 1H), 5.01 (tdd, J = 11.1, 6.6, 1H). .6Hz, 1H), 4.75~4.55(m, 2H), 4.43~4.19(m, 3H), 3.98(dd,J=11.5, 4.2Hz, 2H), 3.39~3.33(m, 2H), 2.73~2 .54(m, 1H), 2.21(tdd,J=12.8, 10.5, 8.3, 5.2Hz, 2H), 1.54(dd,J=11.3, 5.0Hz, 2H), 1.38(d,J=6.7Hz, 3H). LCMS m / z 492.0[M+H] + .

[0209] compound 6 3-Fluoro-4-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (6) [ka] Step 1. Synthesis of 3-fluoro-4-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (C28) To a mixture of methyl 3-fluoro-4-hydroxybenzoate (30 mg, 0.1763 mmol), CCl (150 μL, 1.554 mmol), DIPEA (40 μL, 0.2296 mmol), 5-(2-methyl-4-pyridyl)-7-oxide-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium, and 5-(2-methyl-4-pyridyl)-7-oxide-2-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (50 mg, 0.1125 mmol) in MeCN (2 mL) was added 2-isopropoxyphosphonoyloxypropane (38 mg, 0.2287 mmol). The reaction mixture was stirred at 40° C. overnight. The mixture was diluted with dichloromethane and washed with HO. Purification by silica gel chromatography (gradient: 0-8% MeOH in dichloromethane) afforded the product. Methyl 3-fluoro-4-[5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-benzoate (32 mg, 48%). LCMS m / z 597.0 [M+H] + .

[0210] Step 2. Synthesis of methyl 3-fluoro-4-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoate (C29) To a solution of methyl 3-fluoro-4-[5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxybenzoate (32 mg, 48%) in dichloromethane (3 mL), TFA (800 μL, 10.38 mmol) was added and stirred for 1 hour. The mixture was concentrated to give the product. methyl 3-fluoro-4-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoate (25 mg, 43%). LCMS m / z 513.0 [M+H] + .

[0211] Step 3. Synthesis of 3-fluoro-4-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (6) To a solution of methyl 3-fluoro-4-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoate (25 mg, 43%) in MeOH (5 mL) was added NaOH (300 μL of 6 M, 1,800 mmol) and stirred at 40 °C for 1 h. The pH of the mixture was adjusted to pH = 3 by addition of 1 M HCl and then concentrated. Purification by reverse-phase chromatography (column: C18. Gradient: 10 to 100% MeCN in water with 0.1% formic acid) afforded the product. 3-Fluoro-4-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (18.8 mg, 32%). 1H NMR (400MHz, methanol-d4) δ8.69~8.54(m, 2H), 8.27(d,J=1.1Hz, 1H), 8.12(s, 2H), 8.05~7.96(m, 1 H), 7.92(dd,J=10.9, 2.0Hz, 1H), 7.74(d,J=1.1Hz, 1H), 7.56(dd,J=8.4, 7.5Hz, 1H), 7.40~7.34 (m, 1H), 7.29(ddd,J=5.2, 1.7, 0.7Hz, 1H), 3.83(dd,J=11.6, 4.3Hz, 2H), 3.27~3.18(m,1H), 2.6 6(s, 3H), 2.49~2.39(m, 1H), 1.90~1.60(m, 2H), 1.44(d,J=13.4Hz, 2H), 0.81~0.67(m, 1H), LCMS m / z 499.0[M+H] + .

[0212] Compounds 7~24 Compounds 7-24 (Table 1) were prepared from S2 and the appropriate aryl alcohol following the method described for the preparation of compound 6. The ester hydrolysis step was omitted where appropriate. Modifications to this procedure are described in the table footnotes. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] *Phosphonates were hydrolyzed by treatment with TMSBr in dichloromethane at room temperature.

[0213] Compounds 25-29 Compounds 25-29 were prepared from aryl chloride S3 by addition of the appropriate alcohol reagent using KOtBu in DMSO. The THP group was deprotected with TFA in dichloromethane. Modifications to this procedure are described in the table footnotes. [Table 3-1] [Table 3-2] *Acetonide deprotection occurred during THP deprotection with TFA. Trifluoroacetate esters of products 25 and 29 were also observed upon acetonide deprotection. These esters were converted to products 25 and 29 by hydrolysis with NaOH. **The Boc group was removed during THP deprotection with TFA. ***Methyl ester hydrolysis was carried out by treatment with NaOH prior to the THP deprotection step.

[0214] compound 30 N-[(1S)-2-Hydroxy-1-methyl-ethyl]-3-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxamide (30) [ka] Compound 30 was prepared in two steps from C30.

[0215] Part A. To a mixture of 3-[5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (15 mg, 0.02764 mmol), (2S)-2-aminopropan-1-ol (3 mg, 0.03994 mmol) in DMF (0.5 mL) was added HATU (15 mg, 0.03945 mmol) and DIPEA (20 μL, 0.1148 mmol). The mixture was stirred for 1 h. Purification by reverse-phase chromatography (column: C18; gradient: 0 to 100% MeCN in water with 0.1% formic acid) afforded the product. N-[(1S)-2-Hydroxy-1-methyl-ethyl]-3-[5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-cyclobutanecarboxamide (8 mg, 48%), LCMS m / z 600.0 [M+H] + .

[0216] Part B. To a solution of N-[(1S)-2-hydroxy-1-methyl-ethyl]-3-[5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-cyclobutanecarboxamide (8 mg) in dichloromethane (2 mL) was added TFA (200 μL, 2.596 mmol). The mixture was stirred for 1 h. Purification by reverse-phase chromatography (column: C18. Gradient: 10-100% MeCN in water with 0.1% formic acid) afforded the product. N-[(1S)-2-hydroxy-1-methyl-ethyl]-3-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxamide (3.0 mg, 20%), 1H NMR (400 MHz, methanol-d4) δ 8.59 (dd, J = 5.1, 0.9 Hz, 1H), 8.46 (dt, J = 3.7, 1.1 Hz, 1H), 8.38 (s, 1H), 8.19 (t, J = 1.2 Hz, 1H), 7.61 (d, J = 1.1 Hz, 1H), 7.39-7.31 (m, 1H), 7.30-7.20 (m, 1H), 5.48 (q, J = 7.2 , 6.7Hz, 1H), 4.07~3.88(m, 3H), 3.59~3.43(m, 2H), 3.36(d,J=11.9Hz, 2H), 2.98~2.76(m, 4H), 2. 76~2.48(m, 6H), 2.25(dq,J=12.1, 6.4, 6.0Hz, 2H), 1.55(d,J=13.0Hz, 2H), 1.16(d,J=6.8Hz, 4H). LCMS m / z 516.0[M+H] + .

[0217] compound 31 N-(2-hydroxy-1-methyl-ethyl)-N-methyl-3-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxamide (31) [ka] Compound 31 was prepared from C30 and 2-(methylamino)propan-1-ol according to the method described for the preparation of compound 30. N-(2-hydroxy-1-methyl-ethyl)-N-methyl-3-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxamide (2.7 mg, 17%). 1H NMR (400 MHz, methanol-d4) δ 8.59 (d, J = 5.0 Hz, 1H), 8.44 (t, J = 1.1 Hz, 1H), 8.28 (s, 2H), 8.24–8.09 (m, 1H), 7.61 (d, J = 1.1 Hz, 1H), 7.33 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 5.52 (q, J = 7.5H) z, 1H), 4.75~4.63(m, 2H), 4.19~3.98(m, 4H), 3.69~3.47(m, 2H), 3.35~3.30(m, 2H), 2.96 (m, 3H), 2.83~2.43(m, 6H), 2.42~2.21(m, 2H), 1.55(d,J=12.9Hz, 2H), 1.23~1.03(m, 3H). LCMS m / z 530.0[M+H] + .

[0218] compound 32 (2S)-2-Hydroxy-N-methyl-N-[3-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutyl]propanamide (32) [ka] Compound 32 was prepared from C31 and (2S)-2-hydroxypropanoic acid according to the method described for compound 30. (2S)-2-hydroxy-N-methyl-N-[3-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutyl]propanamide (11.4 mg, 40%). 1H NMR (400 MHz, methanol-d4) δ 8.60 (dd, J = 5.1, 0.8 Hz, 1H), 8.51 (t, J = 1.1 Hz, 1H), 8.20 (d, J = 1.1 Hz, 1H), 8.11 (s, 2H), 7.63 (d, J = 1.1 Hz, 1H), 7.35 (s, 1H), 7.27 (d, J = 5.1 Hz, 1H), 5.63 (d, J = 7.7 Hz, 1H), 4 .71~4.51(m, 1H), 4.02~3.92(m, 2H), 3.36(d,J=11.9Hz, 2H), 3.23~3.09(m, 3H), 3.10~2.85(m, 3H) ), 2.80~2.62(m, 5H), 2.23(tt,J=12.6, 7.0Hz, 2H), 1.54(d,J=13.3Hz, 2H), 1.33(t,J=7.4Hz, 3H). LCMS m / z 516.0[M+H] + .

[0219] compound 33 2-Hydroxy-N-[3-hydroxy-2-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]propyl]ethanesulfonamide (33) [ka] Step 1. Synthesis of benzyl 3-[5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyazetidine-1-carboxylate To a solution of benzyl 3-hydroxyazetidine-1-carboxylate (150 mg, 0.7238 mmol) in DMSO (2 mL) was added KOtBu (82 mg, 0.7308 mmol), and the mixture was stirred for 10 minutes. The mixture was added to a vial of 8-chloro-5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (170 mg, 0.3672 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was diluted with EtOAc, washed with HO, dried over NaSO, and concentrated. Purification by silica gel chromatography (gradient: 0-5% MeOH in dichloromethane) afforded the product. Benzyl 3-[5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyazetidine-1-carboxylate (222 mg, 95%) LCMS m / z 634.0 [M+H] + .

[0220] Step 2. Synthesis of 8-(azetidin-3-yloxy)-5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (C32) A solution of benzyl 3-[5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyazetidine-1-carboxylate (222 mg, 0.3503 mmol) in MeOH (5 mL) and EtOAc (5 mL) was added to Pd / C (120 mg of 10% w / w, 0.1128 mmol) and stirred under a hydrogen balloon for 1 h. The Pd catalyst was filtered, and the filtrate was concentrated. Purification by silica gel chromatography (gradient: 0 to 20% MeOH in dichloromethane) afforded the product. 8-(azetidin-3-yloxy)-5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (132 mg, 75%), LCMS m / z 500.0 [M+H]+ . 1 H NMR (400MHz, methanol-d4) δ8.74~8.50(m, 2H), 8.21(d,J=0.9Hz, 1H), 7.65(d,J=1.1Hz, 1H), 7.32(d, J=2.0Hz, 2H), 7.24(dt,J=5.1, 1.6Hz, 1H), 6.03(dd,J=9.5, 2.6Hz, 1H), 5.82(p,J=6.3Hz, 1H), 4.70 (dd,J=12.3, 6.9Hz, 2H), 4.45(dt,J=12.4, 6.8Hz, 2H), 4.04~3.81(m, 5H), 3.42~3.34(m, 2H), 2.81~ 2.44(m, 4H), 2.29~2.02(m, 4H), 2.00~1.83(m, 1H), 1.73(dq,J=9.1, 4.3Hz, 2H), 1.65~1.48(m, 2H).

[0221] Step 3. Synthesis of 2-hydroxy-N-[3-hydroxy-2-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]propyl]ethanesulfonamide (33) Part A. To a solution of 8-(azetidin-3-yloxy)-5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (20 mg, 0.04003 mmol) in DMF (0.5 mL) was added DIPEA (15 μL, 0.08612 mmol) and 2-hydroxyethanesulfonyl chloride (10 mg, 0.06917 mmol). The mixture was stirred for 30 minutes and then concentrated. Purification by reverse-phase chromatography (column: C18; gradient: 0-100% MeCN in water with 0.2% formic acid) afforded the product. 2-[3-[5-(2-Methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyazetidin-1-yl]sulfonylethanol (21 mg, 86%). LCMS m / z 608.0 [M+H] + .

[0222] Parts B and C. To a solution of 2-[3-[5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyazetidin-1-yl]sulfonylethanol (21 mg, 86%) in dichloromethane (2 mL) was added TFA (100 μL, 1.298 mmol). The mixture was stirred overnight. The mixture was concentrated, then diluted with MeOH (2 mL), and NaOH (400 μL of 1 M, 0.4000 mmol) was added and stirred for 130 minutes. Purification by reverse-phase chromatography (column: C18; gradient: 10 to 100% MeCN in water with 0.2% formic acid) afforded the product. 2-hydroxy-N-[3-hydroxy-2-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]propyl]ethanesulfonamide (8.8 mg, 39%), 1 H NMR (400MHz, methanol-d4) δ8.65~8.53(m, 2H), 8.14(s, 1H), 8.09(t,J=0.9Hz, 1H), 7.42~7.35(m, 1H), 7.34~7.23(m, 1H), 7.15(s, 1H), 4.54(dd,J =14.1, 3.8Hz, 1H), 4.41~4.18(m, 3H), 3.98(t,J=6.1Hz, 2H), 3.90~3.73(m, 2H), 3.34(m, 5H), 2.66(d,J=2.1Hz, 3H), 1.77(m, 2H), 1.61(m, 2H). LCMS m / z 542.0[M+H] + .

[0223] compound 34 3-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]azetidine-1-carboxamide (34) [ka] To a solution of 8-(azetidin-3-yloxy)-5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (10 mg, 0.02002 mmol) in dichloromethane (1 mL) was added DIPEA (20 μL, 0.1148 mmol) and isocyanato(trimethyl)silane (10 μL, 0.07387 mmol). The mixture was stirred for 1 h and then concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-10% MeOH in dichloromethane) afforded the product. 3-[5-(2-Methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyazetidine-1-carboxamide (7 mg, 64%). LCMS m / z 543.0 [M+H] + . To a solution of 3-[5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyazetidine-1-carboxamide (7 mg, 64%) in dichloromethane (2 mL) was added TFA (200 μL, 2.596 mmol), stirred for 1 h, and then placed under vacuum. Purification by reverse-phase chromatography (column: C18. Gradient: 10 to 100% MeCN in water with 0.2% formic acid) afforded the product: 3-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]azetidine-1-carboxamide (4.2 mg, 43%). 1H NMR (400MHz, methanol-d4) δ8.77~8.66(m, 2H), 8.40(d,J=1.1Hz, 1H), 8.10(s, 2H), 7.78(s, 1H), 7.43(s, 1H), 7.35(d,J=4.9Hz, 1H), 5.81(t,J= 8.4Hz, 1H), 5.32(t,J=10.5Hz, 1H), 5.15(t,J=9.1Hz, 1H), 4.04~3.76(m, 3H), 3.31(m, 2H), 3.18(m, 2H), 2.68(d,J=18.1Hz, 4H), 1.77(s, 3H). LCMS m / z 459.0[M+H] + .

[0224] compound 35 3-Hydroxy-2-methyl-1-[3-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]azetidin-1-yl]propan-1-one (35) [ka] Compound 35 was prepared from C32 as described for compound 32. 3-hydroxy-2-methyl-1-[3-[[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]azetidin-1-yl]propan-1-one (2.0 mg, 13%). 1H NMR (400 MHz, methanol-d4) δ 8.61 (d, J = 5.1 Hz, 1H), 8.51 (dt, J = 7.0, 1.1 Hz, 1H), 8.21 (t, J = 1.3 Hz, 1H), 7.66 (t, J = 1.2 Hz, 1H), 7.36 (d, J = 4.2 Hz, 1H), 7.28 (t, J = 4.5 Hz, 1H), 5.82-5.67 (m, 1H), 4.75-4.40 (m, 2H), 4.33~4.17(m, 1H), 4.02~3.93(m, 2H), 3.80~3.63(m, 1H), 3.54(ddd,J=10.6, 8.5, 5.4Hz, 1H), 3. 37(d,J=12.2Hz, 2H), 2.67(s, 5H), 2.21(s, 3H), 1.56(d,J=13.2Hz, 2H), 1.07(dd,J=10.1, 6.8Hz, 3H). LCMS m / z 502.0[M+H] + .

[0225] Compounds 36~41 Compounds 36-41 (Table 3) were prepared from C32 using the method described for the preparation of compound 32. [Table 4-1] [Table 4-2] [Table 4-3]

[0226] compound 42 4-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (42) [ka] Compound 42 was prepared from S4 by treatment with 4-hydroxy-benzoic acid and sodium hydride, followed by THP deprotection with HCl as described for the preparation of compound 1. 1H NMR (300 MHz, chloroform-d + methanol-d) δ 8.62 (d, J = 1.2 Hz, 1H), 8.28–8.11 (m, 3H), 7.71 (d, J = 1.1 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.42–7.34 (m, 2H), 7.18 (ddd, J = 10.4 Hz, 2H), 7.62–7.64 (m, 3H). 1Hz, 1H), 7.13~7.04(m, 1H), 3.90(d,J=11.5Hz, 2H), 3.29(dt,J=11.1, 5.7Hz, 2H), 2. 69(ddd,J=11.5, 7.7, 3.8Hz, 1H), 1.94(q,J=12.3Hz, 2H), 1.44(d,J=13.3Hz, 2H)ppm. LCMS m / z 502.29[M+H] + .

[0227] Compounds 43 and 44 4-[[5-(3,4-Difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-3-fluoro-2-methoxy-benzoic acid (43) and 4-[[5-(3,4-Difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-3-fluoro-2-hydroxy-benzoic acid methyl ester (44) [ka] Step 1. 4-[5-(3,4-Difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-3-fluoro-2-hydroxy-benzoic acid (C33), 4-[5-(3,4-Difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-3-fluoro-2-methoxy-benzoic acid (C34-A), and methyl 4-[5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-3-fluoro-2-hydroxy-benzoate (C34-B) To a mixture of 8-chloro-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (99 mg, 0.2046 mmol) and methyl 3-fluoro-4-hydroxy-2-methoxybenzoate (140 mg, 0.6994 mmol) in dry DMF (4 mL) at room temperature under nitrogen, CsCO (539 mg, 1.654 mmol) was added. The reaction mixture was heated in a microwave oven at 150 °C under nitrogen for 20 hours. The reaction mixture was quenched with water (1 mL) and 1 M HCl (approximately 2 mL until pH = 6 was achieved). The desired product was extracted with EtOAc, washed with water, saturated NaCl, and dried. Purification by silica gel chromatography (gradient: 0-10% MeOH in dichloromethane, then 0-20% MeOH in dichloromethane) gave the product: 4-[5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-3-fluoro-2-methoxy-benzoic acid C34-A (60 mg, 46%). LCMS m / z 634.11 [M+H] + was obtained as an inseparable mixture with a small amount of methyl 4-[5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-3-fluoro-2-hydroxy-benzoate (C34-B).

[0228] Compound C33 was isolated as a single compound. 4-[5-(3,4-Difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-3-fluoro-2-hydroxy-benzoic acid C33 (10 mg, 8%). LCMS m / z 620.16 [M+H] + .

[0229] Step 2. Synthesis of 4-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-3-fluoro-2-methoxy-benzoic acid (43) and methyl 4-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-3-fluoro-2-hydroxy-benzoate (44) A mixture of 4-[5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-3-fluoro-2-methoxy-benzoic acid C34-A (60 mg, 0.09469 mmol) containing a trace impurity of C34-B was dissolved in dichloromethane (4 mL). The mixture was treated with TFA (2 mL, 25.96 mmol) for 90 minutes. Excess solvent was removed, and the mixture was purified by reverse-phase HPLC. (Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in HO with 0.2% formic acid.)

[0230] Product A: 4-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-3-fluoro-2-methoxy-benzoic acid (hydrochloride) (44) (15 mg, 26%). 1 H NMR (300 MHz, chloroform-d + methanol-d) δ 8.64 (t, J = 1.1 Hz, 1H), 8.22 (d, J = 1.1 Hz, 1H), 7.84 (dd, J = 8.8, 2.1 Hz, 1H), 7.73 (d, J = 1.1 Hz, 1H), 7.38 (dd, J = 10.3, 8.3 Hz, 1H), 7.31–7.14 (m, 2H) , 7.09(ddd,J=8.6, 4.4, 1.8Hz, 1H), 4.08(d,J=1.2Hz, 3H), 3.88(d,J=11.3Hz, 2H), 3.29(dt ,J=9.9, 5.8Hz, 2H), 2.74~2.62(m, 1H), 1.89(q,J=12.2Hz, 2H), 1.43(d,J=13.3Hz, 2H)ppm. LCMS m / z 550.21[M+H]+ .

[0231] Product B: methyl 4-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-3-fluoro-2-hydroxybenzoate (3 mg, 5%) (43). 1 H NMR (300 MHz, chloroform-d + -methanol-d4)δ8.63(t,J=1.1Hz, 1H), 8.21(d,J=1.1Hz, 1H), 7.87~7.66(m, 2H), 7.40(dt,J=10.4, 8.3Hz, 1H), 7.28~7.05(m, 2H), 7.00(dd,J=8. ppm LCMS m / z 550.21[M+H] + .

[0232] Compounds 45~64 Compounds 45-62 were prepared from S5 by treatment with NaH and the appropriate alcohol reagent as described for the preparation of compound 42. Compounds 62-64 were prepared from S4 by treatment with NaH and the appropriate alcohol reagent, followed by treatment with HCl to remove the THP protecting group. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] *Compound 62 was prepared from S4 and 4-(hydroxymethyl)pyrrolidin-2-one to yield the intermediate 4-[[5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxymethyl]pyrrolidin-2-one. Alkylation of this intermediate with benzyl 2-bromoacetate yielded benzyl 2-[4-[[5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxymethyl]-2-oxo-pyrrolidin-1-yl]acetate. THP deprotection with HCl followed by hydrogenation yielded compound 62.

[0233] compound 65 4-[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-3-fluorobenzoic acid (65) [ka] Step 1. Synthesis of 4-[5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]-3-fluoro-benzoic acid (C35) To a mixture of 8-chloro-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline S6 (95 mg, 0.1786 mmol), 4-borono-3-fluorobenzoic acid (50 mg, 0.2718 mmol), and Pd(PPh3)4 (15 mg, 0.01298 mmol) in DMF (4 mL) under nitrogen, Na2CO3 (600 μL of 2 M, 1.200 mmol) was added. The reaction mixture was heated in a microwave oven at 130 °C for 2 hours. Water was added, the mixture was extracted with EtOAc, and the combined organic layers were washed with water, saturated NaCl, and dried over Na2SO4. Purification by silica gel chromatography (gradient: 0-10% MeOH in dichloromethane) followed by reverse-phase HPLC (method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in HO with 0.2% formic acid) afforded the product: 4-[5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]-3-fluoro-benzoic acid (100 mg, 95%) LCMS m / z 588.28 [M+H] + .

[0234] Step 2. Synthesis of 4-[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-3-fluoro-benzoic acid (65) 4-[5-(3,4-Difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]-3-fluoro-benzoic acid (100 mg, 0.1702 mmol) was treated with HCl in 1,4-dioxane (4.5 mL of 4 M, 18.00 mmol). The reaction mixture was microwaved at 80° C. for 50 minutes. Excess solvent was removed and the mixture was purified by reverse-phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in HO with 0.2% formic acid to afford the product. 4-[5-(3,4-Difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-3-fluoro-benzoic acid (trifluoroacetate) (62 mg, 56%). 1 H NMR (300MHz, methanol-d4) δ8.22(d,J=1.0Hz, 1H), 8.09(dd,J=7.8, 1.5Hz, 1H), 8.03~7.89(m, 2H), 7.87~7.64(m, 2H), 7.51~7.41(m, 1H), 7.30~7.09(m , 2H), 4.10(d,J=11.0Hz, 1H), 3.95(d,J=9.9Hz, 1H), 3.51~3.38(m, 2H), 2 .88(d,J=12.0Hz, 1H), 2.33(d,J=13.4Hz, 2H), 1.72~1.46(m, 2H)ppm.LCMS m / z 504.15[M+H] + .

[0235] Compounds 66 and 67 3-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylate methyl (66) and 3-[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylic acid (67) [ka] Step 1. Synthesis of methyl 3-[[5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylate (C36) To a solution of 5-(3,4-difluorophenyl)-7-oxide-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (150 mg, 0.1642 mmol), methyl 3-aminocyclobutanecarboxylate (hydrochloride) (100 mg, 0.6038 mmol), and DIPEA (750 μL, 4.306 mmol) in dichloromethane (2 mL), PyBroP (560 mg, 1.201 mmol) was added and the reaction was stirred overnight at 80° C. Additional PyBroP (560 mg, 1.201 mmol) was added and the reaction was stirred overnight at 80° C. The mixture was concentrated in vacuo and then purified by reverse phase HPLC (Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid) to give the product. Methyl 3-[[5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylate (74 mg, 62%). LCMS m / z 577.34 [M+H] + .

[0236] Synthesis of methyl 3-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylate (66) Methyl 3-[[5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylate (70 mg, 0.09635 mmol) in a solution of hydrogen chloride (5 mL of 4 M, 20.00 mmol) in 1,4-dioxane (5 mL) was stirred for 50 minutes. EtO was added and stirred for 10 minutes. The mixture was filtered, and the cake was washed with EtO and filtered. The cake was then dried under vacuum. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid. Methyl 3-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylate (trifluoroacetate) (45 mg, 72%). 1 H NMR (400MHz, methanol-d4) δ8.94(s, 1H), 8.28(d,J=1.1Hz, 1H), 7.67(d,J=1.0Hz, 1H), 7.53(dt,J=10.5 , 8.3Hz, 1H), 7.36(ddd,J=10.9, 7.6, 2.1Hz, 1H), 7.20(ddt,J=8.1, 3.8, 1.7Hz, 1H), 5.17~4.99(m, 2H) ), 4.08~3.94(m, 2H), 3.79(s, 3H), 3.36(ddd,J=12.7, 6.4, 4.1Hz, 3H), 2.97(dddd,J=12.9, 6.7, 5.1, 2.8Hz, 3H), 2.77(dtt,J=10.4, 7.1, 2.9Hz, 2H), 2.04(qd,J=12.3, 4.6Hz, 2H), 1.69(d,J=13.3Hz, 2H). LCMS m / z 493.31[M+H] + .

[0237] Synthesis of 3-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylic acid (67) NaOH (2000 μL of 2 M, 4.000 mmol) was added to a solution of methyl 3-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylate (trifluoroacetate) (45 mg, 0.06932 mmol) in MeOH (6 mL), and the mixture was allowed to stir for 30 minutes. TFA (250 μL, 3.245 mmol) was added, and the mixture was evaporated to dryness. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in HO with 0.2% formic acid gave the product. 3-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylic acid (12.8 mg, 37%) 1 H NMR (400MHz, methanol-d4) δ8.39(d,J=1.1Hz, 1H), 8.15~8.09(m, 2H), 7.54(d,J=1.0Hz, 1H), 7.41(dt,J=1 0.8, 8.4Hz, 1H), 7.20(ddd,J=11.3, 7.8, 2.1Hz, 1H), 7.07(ddd,J=8.0, 3.9, 1.9Hz, 1H), 4.95(d,J=7.9Hz , 1H), 3.97(dt,J=10.5, 4.7Hz, 2H), 3.39~3.31(m, 2H), 3.26~3.14(m, 1H), 2.88~2.77(m, 2H), 2.67(tt,J =11.6, 3.8Hz, 1H), 2.53(tdd,J=10.1, 7.4, 2.4Hz, 2H), 2.26(qt,J=12.6, 4.7Hz, 2H), 1.57~1.42(m, 2H). LCMS m / z 479.31[M+H] + .

[0238] Compounds 68~74 Compounds 68-74 were prepared from S7 according to the method described for the preparation of compound 6. Modifications to this procedure are described in the table footnotes. [Table 6-1] [Table 6-2] [Table 6-3] *Phosphonates were hydrolyzed by treatment with TMSBr in dichloromethane at room temperature.

[0239] Compounds 75~88 Compounds 75-88 (Table 6) were prepared from S8 using the method described for the preparation of compound 42. The THP protecting group was removed by treatment with TFA, HCl, or TFA. Any modifications are noted in the table footnotes. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] *Compound 87 was prepared by the addition of tert-butyl 6-hydroxy-3-azabicyclo[3.2.0]heptane-3-carboxylate to S8. The resulting Boc-protected product was treated with TFA to give 8-(3-azabicyclo[3.2.0]heptan-6-yloxy)-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinoline (trifluoroacetate). Alkylation of the amine was achieved by treatment with tert-butyl 2-bromopropanoate and K2CO3 in DMF. The tert-butyl ester group was then removed with TFA to give the product.

[0240] compound 89 [3-[[5-(4-Fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]azetidin-1-yl]-(1-hydroxycyclopropyl)methanone (89) [ka] Compound 89 was prepared from S9 using the method described for the preparation of compound 35. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in HO containing 0.2% formic acid. [3-[[5-(4-Fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]azetidin-1-yl]-(1-hydroxycyclopropyl)methanone (4.0 mg, 32%). 1 H NMR (400MHz, methanol-d4) δ8.68(s, 1H), 8.45(s, 2H), 8.23(d,J=0.9Hz, 1H), 7.53(s, 1H), 7.38(d,J=7.5Hz, 3H), 4.70(s, 1H), 4.37(d ,J=13.1Hz, 1H), 4.04~3.79(m, 3H), 3.72(d,J=13.9Hz, 1H), 3.22(d,J=27.2Hz, 2H), 1.76(d,J=12.9Hz, 1H), 1.63(d,J=13.3Hz, 1H). LCMS m / z 503.0[M+H] +

[0241] compound 90 (2R)-3-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propanoic acid (hydrochloride) (90) [ka] Step 1. Synthesis of methyl (2R)-3-[5-(4-fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propanoate (C37) To a mixture of 8-chloro-5-(4-fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (107 mg, 0.2296 mmol) and Pd(PPh3)4 (20 mg, 0.01731 mmol) in THF (2 mL) under nitrogen, bromo[(2S)-3-methoxy-2-methyl-3-oxopropyl]zinc (1.9 mL of 0.5 M, 0.9500 mmol) was added. The reaction mixture was heated at 90 °C for 4 h. The solvent was evaporated, and the residue was dissolved in dichloromethane. The organic solution was washed with NaOH (0.5 M / 6 mL), water, brine, dried over Na2SO4, and concentrated. Purification by silica gel chromatography (gradient: 10 to 100% EtOAc in heptane) gave the product. 3-[5-(4-Fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propanoate (115 mg, 94%). 1 H NMR (300 MHz, chloroform-d) δ 8.32 (dt, J = 3.7, 1.1 Hz, 1H), 8.15 (d, J = 0.9 Hz, 1H), 7.71 (d, J = 1.0 Hz, 1H), 7.28–7.17 (m, 4H), 5.95 (dd, J = 8.9, 2.7 Hz, 1H), 4.08–3.98 (m, 3H), 3.92 (dd, J = 8.1, 6.1 Hz, 1H), 3.81(s, 3H), 3.68~3.47(m, 2H), 3.43~3.27(m, 2H), 2.90~2.60(m, 2H), 2.47~2.31(m, 1H), 2.27~2.12(m, 3H), 1.99~1.69(m, 3H), 1.48(dd,J=7.0, 2.2Hz, 4H), 0.95~0.85(m, 3H)ppm. LCMS m / z 531.81[M+H] + .

[0242] Step 2. Synthesis of methyl (2R)-3-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propanoate (C37) Methyl (2R)-3-[5-(4-fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propanoate (110 mg, 0.2069 mmol) was treated with HCl in 1,4-dioxane (5 mL of 4 M, 20.00 mmol). The reaction mixture was stirred at room temperature for 1 hour. MeOH (1 mL, 24.69 mmol) was added, and the resulting clear reaction mixture was stirred at room temperature for 3 hours. Excess solvent was removed and the residue was triturated with CH3CN, water, dichloromethane, MeOH, then dried to give methyl (2R)-3-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propanoate (56 mg, 60%) LCMS m / z 447.5 [M+H] + This resulted in

[0243] Step 3. Synthesis of (2R)-3-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propanoic acid (90) A mixture of methyl (2R)-3-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methylpropanoate (55 mg, 0.1229 mmol) and LiOH.HO (135 mg, 3.217 mmol) in THF (4 mL) and HO (2 mL) was stirred for 3 h. The reaction mixture was acidified with HCl (4 mL of 1 M, 4.000 mmol) and extracted with EtOAc. The organic layer was concentrated. Purification by silica gel chromatography (gradient: 0-10% MeOH in dichloromethane) afforded the product. (2R)-3-[5-(4-Fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propanoic acid (hydrochloride) (25 mg, 41%). 1H NMR (300MHz, DMSO-d6) δ13.35(s, 1H), 12.08(s, 1H), 8.44~8.26(m, 2H), 7.67(d,J=0.9Hz, 1H), 7.50~7.29(m, 4H), 3.99 ~3.68(m, 3H), 3.55~3.36(m, 2H), 3.18(t,J=11.9Hz, 2H), 2.77~2.61(m, 1H), 2.29~2.09(m, 2H), 1.54~1.23(m, 5H)ppm. LCMS m / z 434.43[M+H] + .

[0244] compound 91 3-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]propanoic acid (91) [ka] Compound 91 was prepared from S9 as described for compound 90. tert-Butyl ester and THP deprotection was carried out by treatment of C38 with HCl. 3-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]propanoic acid (hydrochloride) (25 mg, 29%) 1 H NMR (400 MHz, chloroform-d + methanol-d) δ 8.34 (d, J = 1.2 Hz, 1H), 8.15 (d, J = 1.0 Hz, 1H), 7.74 (d, J = 1.1 Hz, 1H), 7.32–7.21 (m, 4H), 4.01 (dd, J = 11.5 Hz, 4.2 Hz, 2H), 3.41–3.34 (m, 4H), 3.09 (t, J = 6.6 Hz, 2H), 2.80 (tt, J = 11.8 Hz, 3.8 Hz, 1H), 2.32 (qd, J = 12.8 Hz, 4.5 Hz, 2H), 1.51 (d, J = 12.2 Hz, 2H) ppm. LCMS m / z 420.39 [M+H] + .

[0245] compound 92 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]benzoic acid (92) [ka] Compound 92 was prepared from S9 by Suzuki coupling with tert-butyl 4-(4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate followed by treatment with HCl: 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]benzoic acid (hydrochloride) (49 mg, 89%). 1 H NMR (400MHz, DMSO-d6) δ13.26(s, 1H), 8.39(d,J=1.0Hz, 1H), 8.26~8.18(m, 2H), 8.16(t,J=1.1Hz, 1H), 8.01~7.91(m, 2H), 7.80(d,J=1.1Hz, 1 H), 7.55~7.43(m, 4H), 3.74~3.63(m, 2H), 3.21(t,J=11.8Hz, 2H), 2.90~2.75(m, 1H), 2.13(qd,J=12.6, 4.6Hz, 2H), 1.55(d,J=12.3Hz, 2H)ppm. LCMS m / z 468.26[M+H] + .

[0246] Compounds 93~103 Compounds 93-103 (Table 7) were prepared from S11 by addition of the appropriate alcohol in the presence of NaH in DMSO. Any modifications are noted in the table footnotes. [Table 8-1] [Table 8-2] [Table 8-3] *The tert-butyl ester was removed under the reaction conditions. **The ethyl ester was removed under the reaction conditions.

[0247] Compound 102 and Compound 103 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-6-azaspiro[3.4]octan-6-yl]acetic acid [isomer-1] (102) and 2-[2-[[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-6-azaspiro[3.4]octan-6-yl]acetic acid [isomer-2] (103) [ka] Steps 1 and 2. A mixture of compounds C41 and C42 was prepared in two steps from S11 and C39 using the method described for the preparation of compound C32. Compound C43 was prepared from a mixture of C41 and C42 by reductive amination with ethyl 2-oxoacetate.

[0248] Step 3. Synthesis of ethyl 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-6-azaspiro[3.4]octan-6-yl]acetate (C43) To a solution of 8-(6-azaspiro[3.4]octan-2-yloxy)-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (67 mg, 0.1302 mmol), 8-(6-azaspiro[3.4]octan-2-yloxy)-5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinoline (50 mg, 0.1161 mmol), ethyl 2-oxoacetate (155 mg of 50% w / w, 0.7591 mmol), and acetic acid (8 μL, 0.1407 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (275 mg, 1.298 mmol). The mixture was stirred for 18 hours, then 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. Excess solvent was evaporated. Purification by silica gel chromatography (gradient: 0-100% EtOAc in heptane) afforded C43 and the THP-protected analog. Compound C43 was the first product to elute. 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-6-azaspiro[3.4]octan-6-yl]ethyl acetate (30 mg, 45%). LCMS m / z 517.5 [M+H] + 2-[2-[5-(4-Fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-6-azaspiro[3.4]octan-6-yl]ethyl acetate (43 mg, 55%). LCMS m / z 601.61 [M+H] + .

[0249] Step 4. Preparation of 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-6-azaspiro[3.4]octan-6-yl]acetic acid [isomer-1] (102) and 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-6-azaspiro[3.4]octan-6-yl]acetic acid [isomer-2] (103) A mixture of 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-6-azaspiro[3.4]octan-6-yl]ethyl acetate C43 (30 mg, 0.05807 mmol) and LiOH (25 mg, 0.5957 mmol) in water (1 mL) and THF (1 mL) was stirred at room temperature for 3 hours. The reaction mixture was treated with 1 M HCl until a pH of 7 was reached. Excess solvent was removed. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid gave two isomers, namely, Compound 102 and Compound 103.

[0250] Compound 102. 1 H NMR (300 MHz, chloroform-d + methanol-d) δ 7.52 (s, 1H), 7.48–7.45 (m, 1H), 7.35 (s, 1H), 7.20 (d, J = 7.1 Hz, 4H), 5.46 (t, J = 6.9 Hz, 1H), 4.23 (d, J = 2.1 Hz, 2H), 4.08 (s, 2H), 3.32 (s, 2H), 2.90–2.71 (m, 3H), 2.56–2.33 (m, 4H), 1.13 (d, J = 6.7 Hz, 6H) ppm. LCMS m / z 489.36 [M+H] + .

[0251] Compound 103. 1H NMR (300 MHz, chloroform-d + methanol-d) δ 8.40 (d, J = 1.1 Hz, 1H), 8.12 (d, J = 1.1 Hz, 1H), 7.62 (d, J = 1.1 Hz, 1H), 7.25 (dtd, J = 11.1, 8.6, 5.9 Hz, 4H), 5.50 (p, J = 6.9 Hz, 1H), 4.05 (s, 2H), 3.70 (d, J = 14.4 Hz, 4H), 3.10–2.77 (m, 3H), 2.54 (dd, J = 13.2, 6.5 Hz, 2H), 2.38 (t, J = 7.2 Hz, 2H), 1.18 (d, J = 6.7 Hz, 6H) ppm. LCMS m / z 489.36[M+H] + .

[0252] Compound 104 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-5-oxo-6-azaspiro[3.4]octan-6-yl]propanoic acid (104) [ka] Compound 104 was prepared from S11 and sodium 2-(2-hydroxy-5-oxo-6-azaspiro[3.4]octan-6-yl)propanoate as described for compounds 93-103. LCMS m / z 517.28 [M+H] + .

[0253] Compounds 105~128 Compounds 105-107 and 120-121 (Table 8) were prepared from S12 using the method described for compound 43. Compounds 108-119 were prepared by Suzuki or Negishi coupling onto S12 and ester deprotection, as appropriate. Any modifications are noted in the table footnotes. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] *Compound 117 was prepared by Negishi coupling as described for compound 90. The nitrile group was converted to a carboxylic acid by hydrolysis with NaOH in EtOH at 110° C. under microwave conditions. **Compound 122 was obtained as a by-product in the preparation of compound 112.

[0254] Compound 123 and Compound 124 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-5-oxo-6-azaspiro[3.4]octan-6-yl]acetic acid (hydrochloride) (123) and 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-5-oxo-6-azaspiro[3.4]octan-6-yl]acetic acid (hydrochloride) (124) [ka] Step 1. Synthesis of tert-butyl 2-[2-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-6-azaspiro[3.4]octan-6-yl]acetate (C44) To a solution of 8-(6-azaspiro[3.4]octan-2-yloxy)-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (200 mg, 0.3886 mmol), tert-butyl 2-bromoacetate (86 mg, 0.4409 mmol) in dichloromethane (4 mL) was added N,N-diethylethanamine (62 μL, 0.4448 mmol). DMSO (2 mL) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 18 h. Excess solvent was removed. Silica gel chromatography (gradient: 0-20% MeOH in dichloromethane) afforded the product. 2-[2-[5-(4-Fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-6-azaspiro[3.4]octan-6-yl]tert-butyl acetate (138 mg, 56%). LCMS m / z 629.4 [M+H] + The THP deprotected product was also observed. tert-Butyl 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-6-azaspiro[3.4]octan-6-yl]acetate (20 mg, 9%). LCMS m / z 545.23 [M+1] + .

[0255] Step 2. Synthesis of tert-butyl 2-[2-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-5-oxo-6-azaspiro[3.4]octan-6-yl]acetate (C45) To a mixture of tert-butyl 2-[2-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-6-azaspiro[3.4]octan-6-yl]acetate C44 (138 mg, 0.2195 mmol) and ethyl 2-[2-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-6-azaspiro[3.4]octan-6-yl]acetate (C47) (132 mg, 0.2197 mmol) in THF (10 mL) was added NaHCO (19 mg, 0.2262 mmol) and molecular iodine (450 mg, 1.773 mmol). The mixture was stirred for 3 hours. The reaction was quenched with saturated NaHCO (1 mL) and sodium thiosulfate (10 mL). Silica gel chromatography (gradient: 0-20% MeOH in dichloromethane) followed by (gradient: 10-50% EtOAc in hexanes) afforded the product.

[0256] tert-Butyl 2-[2-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-5-oxo-6-azaspiro[3.4]octan-6-yl]acetate C45 (36 mg, 26%) LCMS m / z 643.55 [M+H] +Ethyl 2-[2-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-5-oxo-6-azaspiro[3.4]octan-6-yl]acetate and tert-butyl 2-[2-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-7-oxo-6-azaspiro[3.4]octan-6-yl]acetate were also obtained. 2-[2-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-5-oxo-6-azaspiro[3.4]octan-6-yl]ethyl acetate (33 mg, 24%) LCMS m / z 615.52 [M+H] + 2-[2-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-7-oxo-6-azaspiro[3.4]octan-6-yl]tert-butyl acetate (10 mg, 7%) LCMS m / z 643.52 [M+H] + .

[0257] Step 3. Preparation of 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-5-oxo-6-azaspiro[3.4]octan-6-yl]acetic acid (123) and -[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-5-oxo-6-azaspiro(3.4]octan-6-yl]acetic acid (124) tert-Butyl 2-[2-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-5-oxo-6-azaspiro[3.4]octan-6-yl]acetate C45 (36 mg, 0.05601 mmol) in dichloromethane (2 mL) was treated with TFA (1 mL, 12.98 mmol) for 1 hour. Excess solvent was removed. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in HO with 0.2% formic acid gave Compound 123 and Compound 124.

[0258] Compound 123 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-5-oxo-6-azaspiro[3.4]octan-6-yl]acetic acid (hydrochloride) (123) (4 mg, 25%). 1 H NMR (300 MHz, chloroform-d + methanol-d) δ 8.44 (t, J = 1.1 Hz, 1H), 8.12 (d, J = 1.1 Hz, 1H), 7.62 (d, J = 1.1 Hz, 1H), 7.42-7.08 (m, 4H), 5.70 (q, J = 6.7 Hz, 1H), 4.10 (s, 2H), 3.51 (t, J = 6.8 Hz, 2H), 3.20-3.02 (m, 2H), 2.85 (p, J = 6.7 Hz, 1H), 2.54-2.20 (m, 4H), 1.19 (d, J = 6.7 Hz, 6H). LCMS m / z 503.14 [M+H] + .

[0259] Compound 124 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-5-oxo-6-azaspiro[3.4]octan-6-yl]acetic acid (hydrochloride) (124) (3 mg, 19%). 1H NMR (300 MHz, chloroform-d + methanol-d) δ 8.46 (t, J = 1.1 Hz, 1H), 8.12 (d, J = 1.1 Hz, 1H), 7.61 (d, J = 1.1 Hz, 1H), 7.42–7.08 (m, 4H), 5.66 (p, J = 7.7 Hz, 1H), 4.09 (s, 2H), 3.54 (t, J = 6.8 Hz, 2H), 2.95–2.54 (m, 5H), 2.44 (t, J = 6.8 Hz, 2H), 1.20 (d, J = 6.7 Hz, 6H) ppm. LCMS m / z 503.11 [M+H] + .

[0260] Compound 125 and Compound 126 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-5-oxo-6-azaspiro[3.4]octan-6-yl]acetic acid [ENANT-1] (125) and 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-5-oxo-6-azaspiro[3.4]octan-6-yl]acetic acid [ENANT-2] (126) [ka] Compounds 125 and 126 were prepared from C41 using the methods described in the preparation of C43 and compounds 123 and 124.

[0261] Compound 125: 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-5-oxo-6-azaspiro[3.4]octan-6-yl]acetic acid [ENANT-1] (125). 1H NMR (300 MHz, chloroform-d + methanol-d) δ 8.43 (t, J = 1.1 Hz, 1H), 8.12 (d, J = 1.1 Hz, 1H), 7.62 (d, J = 1.11 Hz, 1H), 7.33–7.18 (m, 4H), 5.71 (p, J = 6.8 Hz, 1H), 4.23 (t, J = 7.2 Hz, 2H), 4.11 (s, 2H), 3.82~3.69(m, 1H), 3.49(t,J=6.8Hz, 2H), 3.22~2.99(m, 2H), 2.85(p,J=6.6Hz, 1H), 2 .48~2.40(m, 1H), 2.35(t,J=6.8Hz, 2H), 1.32(t,J=7.1Hz, 3H), 1.19(d,J=6.7Hz, 6H)ppm. LCMS m / z 530.93[M+H] + .

[0262] Compound 126: 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-5-oxo-6-azaspiro[3.4]octan-6-yl]acetic acid [ENANT-2] (126). H NMR (300 MHz, chloroform-d + methanol-d): δ 8.45 (t, J = 1.1 Hz, 1H), 8.10 (d, J = 1.1 Hz, 1H), 7.60 (d, J = 1.1 Hz, 1H), 7.37–7.10 (m, 4H), 5.65 (p, J = 7.7 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.10 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.99–2.54 (m, 5H), 2.43 (t, J = 6.8 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 6.7 Hz, 6H) ppm. LCMS m / z 531.32[M+H] +

[0263] compound 127 3-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (127) [ka] Step 1. Synthesis of 3-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (C49) In a vial, 8-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (trifluoroacetate) (350 mg, 0.5694 mmol) and 3-hydroxycyclobutanecarboxylic acid (200 mg, 1.722 mmol) were dissolved in DMSO (6 mL). Then, at room temperature under nitrogen, NaH (140 mg of 60% w / w, 3.500 mmol) was added. The reaction was stirred for 1 h. Purification by reverse-phase chromatography (column: C18, gradient: 0 to 100% MeCN in water with 0.1% trifluoroacetic acid) afforded the product. Fractions containing the product were pooled, and the acetonitrile was evaporated in vacuo. The aqueous mixture was extracted with CHCl3:IPA (3:1). The organic phases were combined, dried over MgSO4, and the volatiles were evaporated in vacuo to give a yellow solid: 3-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]-isoquinolin-8-yl]oxycyclobutanecarboxylic acid (225.8 mg, 79%). LCMS m / z 504.29 [M+H] + .

[0264] Step 2. Synthesis of 3-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (127) To a solution / suspension of 3-[[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (dicyclohexylamine) in dichloromethane (560 mL) at room temperature in a 3 L four-neck flask equipped with a mechanical stirrer and temperature probe, EtSiH (13.2 mL, 82.64 mmol) was added, followed by TFA (224 mL). The reaction mixture was stirred for 2 h and then concentrated (rotovap bath at 50 °C). The resulting thick yellow oil / paste was treated with water (850 mL), the solids scraped from the walls of the flask, and the resulting suspension was spun on a rotovap (without vacuum) with the bath set at 65 °C for 30 min. The resulting suspension was cooled to 28 °C and then filtered. The recovered solid was washed with water (500 mL), then dried under suction, then transferred to a 1 L flask, and then dissolved / suspended in AcOH (300 mL). The suspension was heated on a rotovap (no vacuum) at 75° C. for 20 minutes, resulting in a uniform suspension. The mixture was then sonicated for 2 minutes and treated with water (300 mL). The mixture was then heated on a rotovap (no vacuum) at 75° C. for 20 minutes, then cooled to 23° C. and filtered. The material was suspended in AcOH (1.5 L) and heated to 90° C. After 30 minutes at 90° C., the suspension was cooled to room temperature, treated with water (1.5 L), and then filtered. The residue was dissolved in DMSO (200 mL). Water (200 mL) was added dropwise over 15 minutes, resulting in a suspension. The mixture was stirred for an additional 20 minutes, then filtered and washed with water (200 mL). The solid was dried under suction for 30 minutes, then on a rotovap (75° C., 3 mbar) for 1 hour, and then in a vacuum oven at 75° C. for 18 hours, yielding 16.1 g of a yellow powder. 1H NMR (4MHz, DMSO-d6) δ13.34(s, 1H), 12.36(s, 1H), 8.35(t,J=1.2Hz, 1H), 8.31(d,J=1.1Hz, 1H), 7.57(d,J=1.1Hz, 1H), 7.45~7.31(m, 4H) , 5.59(p,J=7.0Hz, 1H), 3.25~3.12(m, 1H), 2.80(dd,J=13.5, 11.0, 5.3Hz, 3H), 2.59(ddt,J=10.3, 6.5, 3.1Hz, 2H), 1.16(d,J=6.7Hz, 6H). 19 F NMR (376MHz, DMSO-d6) δ-115.17. LCMS m / z 420.02[M+H] + Melting point = 311°C.

[0265] compound 128 3-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylate phosphonooxymethyl (128) [ka] Step 1. Synthesis of di-tert-butoxyphosphoryloxymethyl 3-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylate (C50) To a solution of 3-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (735 mg, 1.460 mmol) in DMF (12 mL) at room temperature was added NaI (68 mg, 0.4537 mmol), DIPEA (0.80 mL, 4.593 mmol), and di-tert-butylchloromethyl phosphate (950 mg, 3.673 mmol). The mixture was heated to 75° C. After 2.5 h, additional DIPEA (1.0 mL, 5.741 mmol) and di-tert-butylchloromethyl phosphate (800 mg, 3.093 mmol) were added. The reaction was stirred at 75° C. for an additional 2.5 h and then cooled to room temperature. The mixture was partitioned between water and EtOAc (80 mL each). The organic layer was separated, washed with 5 wt% aqueous citric acid, water, and brine (80 mL each), dried (MgSO), filtered, and concentrated. Purification by silica gel chromatography (gradient: 0 to 100% EtOAc in heptane) gave the product: di-tert-butoxyphosphoryloxymethyl 3-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylate (610 mg, 58%) as a yellow glassy solid. 1 H NMR (400MHz, chloroform-d) δ8.43(t,J=1.1Hz, 1H), 8.14(d,J=0.9Hz, 1H), 7.60(d,J=1.0Hz, 1H), 7.32~7.1 9(m, 4H), 5.94(dd,J=9.2, 2.8Hz, 1H), 5.78~5.68(m, 3H), 4.07(d,J=12.0Hz, 1H), 3.93~3.82(m, 1H), 3.4 0(tdd,J=9.8, 5.0, 4.0Hz, 1H), 3.10~2.99(m, 2H), 2.85(h,J=6.7Hz, 1H), 2.81~2.63(m, 2H), 2.31~2.20 (m, 1H), 2.15(d,J=13.6Hz, 1H), 1.96~1.68(m, 3H), 1.54(d,J=0.6Hz, 18H), 1.19(dd,J=6.7, 3.1Hz, 6H). 19 F NMR (376 MHz, chloroform-d) δ −115.36.31 P NMR (162 MHz, chloroform-d) δ -11.54. LCMS m / z 726.36 [M+1] + .

[0266] Step 2. Synthesis of phosphonooxymethyl 3-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylate (128) To a solution of ditert-butoxyphosphoryloxymethyl 3-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylate (596 mg, 0.8212 mmol) in dichloromethane (40 mL) at room temperature was added TFA (26 mL). The mixture was stirred for 2 hours and then concentrated on a rotovap (60 °C). The residue was dissolved in MeOH (5 mL) and purified. Purification by reverse-phase chromatography (column: C18, gradient: 0 to 100% MeCN in water with 0.1% trifluoroacetic acid) followed by lyophilization afforded the product. The powder was slurried in water (10 mL) for 45 minutes, then filtered and washed with water (10 mL). Drying under vacuum for 30 min and then on a rotovap (2 mbar, 60° C.) for 1 h gave phosphonooxymethyl 3-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylate (192 mg, 40%) as a yellow powder. 1 H NMR (400MHz, DMSO-d6) δ13.34(s, 1H), 8.35(t,J=1.1Hz, 1H), 8.31(d,J=1.1Hz, 1H), 7.57(d,J=1.1Hz, 1H), 7.43~7.34(m, 4H), 5.64~5.55(m, 1H), 5.57(d,J=13 .8Hz, 2H), 3.39~3.28(m, 1H), 2.88(ddq,J=11.2, 7.3, 3.8, 3.2Hz, 2H), 2.77(p, J=6.7Hz, 1H), 2.65(dddd,J=13.4, 10.3, 6.7, 2.8Hz, 2H), 1.16(d,J=6.6Hz, 6H). 19F NMR (282MHz, DMSO-d6) δ-115.18. 31 P NMR (162MHz, DMSO-d6) δ-2.56. LCMS m / z 530.14[M+H] + .

[0267] compound 129 3-[5-(4-fluorophenyl)-6-isopropyl-1-(2-phosphonooxyethoxycarbonyl)pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (129) [ka] Step 1. Synthesis of 3-[1-(2-ditert-butoxyphosphoryloxyethoxycarbonyl)-5-(4-fluorophenyl)-6-isopropyl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (C51) To a solution of 3-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (188 mg, 0.4452 mmol) in THF (10 mL) at 0 °C under nitrogen, KOtBu (1.4 mL of 1 M, 1.400 mmol) (solution in THF) was added, resulting in a suspension of a yellow solid and preventing stirring. 2-Ditert-butoxyphosphoryloxyethyl (2,5-dioxopyrrolidin-1-yl)carbonate (540 mg, 1.366 mmol) was added (as a solid), and the reaction mixture turned slightly red, consuming the yellow solid in approximately 5 minutes. After a total of 8 minutes, the reaction was quenched with saturated aqueous NH4Cl (10 mL). The mixture was partitioned between water and EtOAc (80 mL each). The organic layer was separated, washed with water, then brine (80 mL each), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (gradient: 0 to 100% EtOAc in heptane) gave the product. 3-[1-(2-ditert-butoxyphosphoryloxyethoxycarbonyl)-5-(4-fluorophenyl)-6-isopropyl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (245 mg, 79%) as a light yellow / green oil. LCMS m / z 700.19 [M+1] + .

[0268] Step 2. Synthesis of 3-[5-(4-fluorophenyl)-6-isopropyl-1-(2-phosphonooxyethoxycarbonyl)-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (129) To a solution of 3-[1-(2-ditert-butoxyphosphoryloxyethoxycarbonyl)-5-(4-fluorophenyl)-6-isopropyl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (240 mg, 0.3430 mmol) in DCM (10 mL) at room temperature was added TFA (3 mL). The reaction mixture was stirred at room temperature for 45 minutes and then concentrated. Purification by reverse-phase chromatography (column: C18. Gradient: 0 to 100% MeCN in water with 0.1% trifluoroacetic acid) afforded the product. 3-[5-(4-fluorophenyl)-6-isopropyl-1-(2-phosphonooxyethoxycarbonyl)pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (trifluoroacetic acid (0.5)) (70 mg, 31%) was obtained as a pale yellow solid. 1 H NMR (400MHz, methanol-d4) δ9.08(t,J=1.0Hz, 1H), 8.45(d,J=0.9Hz, 1H), 7.73(d,J=1.0Hz, 1H), 7.38~7.28(m, 4H), 5.80~5.69(m, 1H), 4 .84~4.77(m, 2H), 4.50~4.41(m, 2H), 3.31~3.23(m, 1H), 3.00~2.86(m, 3H), 2.72(dtd,J=13.4, 6.7, 2.7Hz, 2H), 1.24(d,J=6.6Hz, 6H). LCMS m / z 587.96[M+H] + .

[0269] compound 130 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]ethoxy]acetic acid (130) [ka] Compound 130 was prepared in two steps from S13 following the method described for the preparation of compound 2 (addition of tert-butyl 2-(2-hydroxyethoxy)acetate to S13 using NaH, followed by tandem THP deprotection and ester hydrolysis with HCl): 2-[2-[[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]ethoxy]acetic acid (8.4 mg, 37%). 1 H NMR (400MHz, methanol-d4) δ8.47(t,J=1.1Hz, 1H), 8.13(d,J=1.1Hz, 1H), 7.59(d,J=1.1Hz, 1H), 7.33~ 7.25(m, 4H), 4.84~4.77(m, 2H), 4.24(s, 2H), 4.15~4.06(m, 2H), 2.83(m, 1H), 1.20(d,J=6.7Hz, 6H). LCMS m / z 424.26[M+H] + .

[0270] compound 131 (2S,4R)-1-Acetyl-4-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]pyrrolidine-2-carboxylic acid (131) [ka] Compound 131 was prepared in two steps from S13 according to the method described for the preparation of compound 2(2S,4R)-1-acetyl-4-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]pyrrolidine-2-carboxylic acid (20.3 mg, 55%). 1H NMR (400MHz, methanol-d4) δ8.35(m, 1H), 8.13(d,J=1.1Hz, 1H), 7.61(m, 1H), 7.35~7.18(m, 4H), 6.06~5.84(m, 1H), 4.86~4 .61(m, 1H), 4.23(dd, J=11.6, 4.9Hz, 1H), 4.14~3.94(m, 1H), 2.94~2.72(m, 2H), 2.57(m, 1H), 2.13(m, 3H), 1.21(m, 6H). LCMS m / z 477.33[M+H] +

[0271] compound 132 2-[3-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarbonyl]amino]propanoic acid (132) [ka] Compound 132 was prepared from compound 127 by HATU coupling in two steps using the method described for the preparation of compound 30. In the second step, the ethyl ester group was removed by hydrolysis with NaOH. 2-[[3-[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarbonyl]amino]propanoic acid (43 mg, 54%) was obtained as a colorless solid. 1 H NMR (300MHz, methanol-d4) δ8.44(t,J=1.1Hz, 1H), 8.13(d,J=1.1Hz, 1H), 7.61(d,J=1.0Hz, 1H), 7.39~7.14(m, 4H), 5.81~5.60(m, 1H), 4.49(qd,J=7.3, 2.7Hz, 1H), 3.31~3.21(m, 1H), 3.05~2.74(m, 3H), 2.74~2.51(m, 2H), 1.44(d,J=7.4Hz, 3H), 1.19(d,J=6.7Hz, 6H). LCMS m / z 491.0[M+H] + .

[0272] compound 133 3-[[5-(3,4-difluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (133) [ka] Compound 133 was prepared from C11 using the method described for the preparation of compound 1. Purification by reverse-phase chromatography (column: C18. Gradient: 0 to 100% MeCN in water with 0.2% formic acid) afforded the product. A pale yellow solid was obtained: 3-[[5-(3,4-difluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (22.7 mg, 35%). 1 H NMR (400 MHz, methanol-d4:chloroform-d 3:1) δ 8.46 (s, 1H), 8.18 (s, 1H), 7.64 (s, 1H), 7.42 (q, J = 9.0 Hz, 1H), 7.21 (t, J = 9.4 Hz, 1H), 7.12 (m, 1H), 5.74 (q, J = 6.9 Hz, 1H), 3.26 (m, 1H), 3.02–2.90 (m, 2H), 2.85 (p, J = 6.6 Hz, 1H), 2.67 (m, 2H), 1.23 (m, 6H). LCMS m / z 438.21 [M+H] + .

[0273] compound 134 3-[[6-Isopropyl-5-(2-methyl-4-pyridyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (134) [ka] Compound 134 was prepared from S15 and 3-hydroxycyclobutanecarboxylate as described for the preparation of compound 27. KOtBu was used as the base in the substitution reaction. NaOH was used for hydrolysis of the methyl ester, followed by TFA deprotection of the THP group to afford the product. 1H NMR (400 MHz, methanol-d4) δ 8.58 (dd, J = 5.1, 0.8 Hz, 1H), 8.45 (dt, J = 2.9, 1.1 Hz, 1H), 8.25 (s, 1H), 8.18 (t, J = 1.2 Hz, 1H), 7.60 (d, J = 1.1 Hz, 1H), 7.38–7.31 (m, 1H), 7 .24(dd,J=5.2, 1.7Hz, 1H), 5.52~5.40(m, 1H), 3.08~2.87(m, 4H), 2.85~2.71(m, 1H), 2.65(s, 3H), 2.53(dd,J=8.3, 2.7Hz, 1H), 1.23(ddd,J=6.6, 3.9, 2.5Hz, 6H). LCMS m / z 417.05[M+H] +

[0274] compound 135 4-[[6-Isopropyl-5-(2-methyl-4-pyridyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (135) [ka] Compound 135 was prepared from S14 and hydroxylbenzoic acid using the method described for compound 6. 1 H NMR (300MHz, methanol-d4) δ8.68~8.54(m, 2H), 8.30~8.11(m, 4H), 7.72(d,J=1.1Hz, 1H), 7.54~7.43(m, 2H), 7.40~ 7.32(m, 1H), 7.32~7.24(m, 1H), 6.89~6.74(m, 1H), 2.83~2.70(m, 1H), 2.66(s, 3H), 1.05(dd,J=6.6, 1.2Hz, 6H). LCMS m / z 439.0[M+H] + .

[0275] compound 136 3-[[6-Isopropyl-5-(2-methoxy-4-pyridyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (136) [ka] Compound 136 was prepared by the addition of 3-hydroxycyclobutanecarboxylate to S16 using NaH in DMSO. 1 H NMR (400MHz, methanol-d4) δ8.42(t,J=1.1Hz, 1H), 8.25(dd,J=5.2, 0.7Hz, 1H), 8.12(d,J=1.1Hz, 1H), 7.61(d,J=1.1Hz, 1H), 6.90(dd,J=5.2, 1.4H) z, 1H), 6.75(t,J=1.0Hz, 1H), 5.75~5.57(m, 1H), 3.99(s, 3H), 3.23(m, 1 H), 2.92(m, 2H), 2.80(p, J=6.6Hz, 1H), 2.70~2.58(m, 2H), 1.18(m, 6H). LCMS m / z 433.26[M+H] + .

[0276] compound 137 3-[[5-(4-fluorophenyl)-6-(1-hydroxycyclopropyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (137) [ka] Compound 137 was prepared by the addition of 3-hydroxycyclobutanecarboxylate to S17 using NaH in DMSO. The benzyl ester was removed by hydrogenation using a Pd(OH) catalyst. LCMS m / z 434.09 [M+H] +

[0277] compound 138 4-[[5-(4-fluorophenyl)-6-(1-hydroxycyclopropyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (138) [ka] Compound 138 was prepared by the addition of 3-hydroxycyclobutanecarboxylate to S17 using NaH in DMSO. The benzyl ester was removed by hydrogenation using a Pd(OH) catalyst. LCMS m / z 458.04 [M+H] +

[0278] compound 139 3-[[5-(3,4-difluorophenyl)-6-(1-hydroxycyclopropyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (139) [ka] Compound 139 was prepared by the addition of 3-hydroxycyclobutanecarboxylate to S18 using NaH in DMSO. The benzyl ester was removed by hydrogenation using a Pd(OH) catalyst.

[0279] 1 H NMR (300MHz, methanol-d4) δ8.45(t,J=1.1Hz, 1H), 8.21(d,J=1.1Hz, 1H), 7.81(d,J=1.1Hz, 1H), 7.45~7.27(m, 3H), 7.24~7.13( m, 1H), 5.79~5.61(m, 1H), 3.27~3.12(m, 1H), 2.90(dddd,J=11.2, 7.0, 4.0, 2.6Hz, 2H), 2.70~2.57(m, 1H), 1.00~0.80(m, 4H). LCMS m / z 452.47[M+H] + .

[0280] compound 140 3-[[5-(3,4-difluorophenyl)-6-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (140) [ka] Compound 140 was prepared by the addition of 3-hydroxycyclobutanecarboxylate to S19 using NaH in DMSO. 1 H NMR (300MHz, acetone-d6) δ8.56(t,J=1.1Hz, 1H), 8.30(d,J=1.1Hz, 1H), 7.77(d,J=1.1Hz, 1H), 7.55(dt,J=10.8, 8.5Hz, 1H), 7.40(ddd,J=1 0.5, 7.8, 2.1Hz, 1H), 7.30~7.21(m, 1H), 5.80~5.62(m, 1H), 3.32~3.22(m, 2H), 3.04~2.75(m, 2H), 2.73~2.59(m, 2H), 1.21~1.12(m, 2H). LCMS m / z 504.39[M+H] + .

[0281] compound 141 3-[[6-(1,1-difluoroethyl)-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (141) [ka] Compound 141 was prepared in two steps from S20. Compound S20 was converted to 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-6-(1,1-difluoroethyl)-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinoline by treatment with DABCO and TFAA. 3-Hydroxycyclobutanecarboxylic acid was added to 8-(4-aza-1-azonibicyclo[2.2.2]octan-1-yl)-6-(1,1-difluoroethyl)-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinoline using NaH in DMSO to give the product. 3-[[6-(1,1-difluoroethyl)-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid. 1H NMR (300MHz, methanol-d4) δ8.47(q, J=1.2Hz, 1H), 8.22(d,J=1.1Hz, 1H), 7.72(d,J=1.0Hz, 1H), 7.35~7.16(m, 4H), 5.75~5 .60(m, 1H), 3.24(dtt,J=9.3, 4.0, 1.7Hz, 1H), 2.97~2.84(m, 2H), 2.67(dtd,J=13.4, 6.6, 2.7Hz, 2H), 2.07~1.88(m, 3H). LCMS m / z 442.33[M+H] + .

[0282] compound 142 3-[[5-(3,4-difluorophenyl)-6-(1-methoxycyclobutyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (142) [ka] Compound 142 was prepared from S21 and 3-hydroxycyclobutanecarboxylic acid as described for the preparation of compound 127. HCl was used in the THP deprotection step. 1 H NMR (400 MHz, methanol-d4) δ 8.47 (t, J = 1.1 Hz, 1H), 8.22 (d, J = 1.1 Hz, 1H), 7.76 (d, J = 1.1 Hz, 1H), 7.36 (dt, J = 10.7, 8.4 Hz, 1H), 7.25 (ddd, J = 11.4, 7.8, 2.1 Hz, 1H), 7.16–7.09 (m, 1H) ), 5.74~5.62(m, 1H), 3.29~3.19(m, 1H), 3.06(s, 3H), 2.91(dddd,J=12.6, 5.4, 4.0, 2.0H z, 2H), 2.70~2.54(m, 3H), 2.54~2.46(m, 1H), 2.04~1.85(m, 3H), 1.71~1.57(m, 1H).LCMS m / z 480.42[M+H] + .

[0283] compound 143 3-[[5-(3,4-difluorophenyl)-6-(2-methoxy-2-methyl-propyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (143) [ka] Compound 143 was prepared from S22 and 3-hydroxycyclobutanecarboxylic acid as described for the preparation of compound 127. HCl was used in the THP deprotection step. 1 H NMR (300MHz, methanol-d4) δ8.45(t,J=1.1Hz, 1H), 8.19(d,J=1.1Hz, 1H), 7.65(d,J=1.1Hz, 1H), 7.44(dt,J=10.7, 8.4Hz, 1H), 7.26(ddd,J=11.3, 7.7, 2.1H z, 1H), 7.13(ddd,J=8.6, 4.4, 1.9Hz, 1H), 5.78~5.68(m, 1H), 3.18(s, 3H), 2 .95~2.80(m, 4H), 2.64(dtd,J=13.3, 6.5, 2.8Hz, 2H), 1.21(d,J=3.6Hz, 6H). LCMS m / z 482.49[M+H] + .

[0284] compound 144 4-[[5-(3,4-difluorophenyl)-6-(2-hydroxy-1,1-dimethyl-ethyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (144) [ka] Step 1. Synthesis of ethyl 4-[5-(3,4-difluorophenyl)-6-(2-hydroxy-1,1-dimethyl-ethyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxybenzoate (C42) To a vial was added ethyl 4-hydroxybenzoate (73.8 mg, 0.4441 mmol), [6-(2-benzyloxy-1,1-dimethyl-ethyl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]trifluoromethanesulfonate (100 mg, 0.1480 mmol), Pd(OAc) (3.32 mg, 0.01479 mmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (9.43 mg, 0.02221 mmol), and KPO (94.2 mg, 0.4438 mmol). The vial was sealed and flushed with nitrogen. Toluene (1.2 mL) was added, and the reaction was stirred at 100 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc and washed with saturated NH4Cl solution. Purification by silica gel chromatography (gradient: 0-30% EtOAc in heptane) afforded the product. Ethyl 4-[6-(2-benzyloxy-1,1-dimethyl-ethyl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxybenzoate (33 mg, 30%) LCMS m / z 691.78 [M+H] + .

[0285] Step 2. Synthesis of ethyl 4-[5-(3,4-difluorophenyl)-6-(2-hydroxy-1,1-dimethyl-ethyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxybenzoate (C43) Ethyl 4-[6-(2-benzyloxy-1,1-dimethyl-ethyl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxybenzoate was dissolved in MeOH (5 mL). The solution was transferred to a vial containing Pd (7.87 mg, 0.007395 mmol). The vial was flushed with H2, and the reaction was stirred at room temperature overnight. The reaction mixture was filtered through a Celite® plug, concentrated, and purified (gradient: 0 to 30% EtOAc in heptane) to give the product. Ethyl 4-[5-(3,4-difluorophenyl)-6-(2-hydroxy-1,1-dimethyl-ethyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxybenzoate (17 mg, 19%) LCMS m / z 602.13 [M+H] + .

[0286] Step 3. Synthesis of 4-[[5-(3,4-difluorophenyl)-6-(2-hydroxy-1,1-dimethyl-ethyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (144) To the vial was added ethyl 4-[5-(3,4-difluorophenyl)-6-(2-hydroxy-1,1-dimethyl-ethyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxybenzoate (15 mg, 0.02191 mmol), followed by the addition of HCl (1000 μL of 4 M, 4.000 mmol) in 1,4-dioxane (500 μL). The reaction was stirred at room temperature for 2 hours. The reaction mixture was poured into water and neutralized with saturated NaHCO solution. The product was extracted with EtOAc. The reaction was concentrated in vacuo and purified by silica gel chromatography (gradient: 0 to 10% MeOH in dichloromethane) to give ethyl 4-[[5-(3,4-difluorophenyl)-6-(2-hydroxy-1,1-dimethyl-ethyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoate.

[0287] To a solution of ethyl 4-[[5-(3,4-difluorophenyl)-6-(2-hydroxy-1,1-dimethyl-ethyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoate in THF (1.2 mL) / MeOH (0.4 mL) / HO (0.4 mL) was added LiOH (5.25 mg, 0.2192 mmol). The reaction was stirred at room temperature for 3 h. The reaction mixture was diluted with HO and acidified with 1 N aqueous HCl. The product was extracted with EtOAc and concentrated to give 4-[[5-(3,4-difluorophenyl)-6-(2-hydroxy-1,1-dimethyl-ethyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (8.2 mg, 69%). 1 H NMR (300MHz, methanol-d4), 8.60(t,J=1.1Hz, 1H), 8.23(d,J=1.1Hz, 1H), 8.21~8.12(m, 2H), 7.57(d,J=1.1Hz, 1H), 7.51~7.37 (m, 3H), 7.31(ddd,J=11.2, 7.7, 2.1Hz, 1H), 7.17(ddt,J=6.8, 4.9, 1.9Hz, 1H), 3.45(d,J=2.4Hz, 2H), 0.97(d,J=3.5Hz, 7H). LCMS m / z 490.14[M+H] + .

[0288] Preparation of T1 and T2 5-(4-fluorophenyl)-6-isopropyl-8-oxide-1H-pyrazolo[4,3-g]quinolin-8-ium (T1) and 7-chloro-5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]quinolone (T2) [ka] [ka] Step 1. Synthesis of methyl 4-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methylamino]-2-fluoro-benzoate A suspension of 2,2-dimethyl-1,3-dioxane-4,6-dione (25.562 g, 177.36 mmol), trimethoxymethane (18.821 g, 177.36 mmol), and methyl 4-amino-2-fluorobenzoate (25 g, 147.80 mmol) in ethanol (50 mL) was refluxed for 3 hours and then stirred at room temperature for an additional 2 hours. The resulting solid precipitate was filtered and washed with ethanol to give the product: methyl 4-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methylamino]-2-fluorobenzoate (45 g, 92%). 1 H NMR (400MHz, DMSO-d6) δ11.29(s, 1H), 8.66(s, 1H), 7.92(t,J=8.3Hz, 1H), 7.73 (dd,J=12.9, 2.2Hz, 1H), 7.54(dd,J=8.7, 2.2Hz, 1H), 3.85(s, 3H), 1.68(s, 6H). LCMS m / z 324.1[M+H] + .

[0289] Step 2. Synthesis of methyl 5-fluoro-4-oxo-1H-quinoline-6-carboxylate and methyl 7-fluoro-4-oxo-1H-quinoline-6-carboxylate To Dowtherm A (200 mL) at 220 °C was added methyl 4-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methylamino]-2-fluorobenzoate (45 g, 139.20 mmol) in portions. After the bubbling subsided, the mixture was heated for an additional 10 minutes and then allowed to cool to room temperature. The mixture was diluted with hexane, and the resulting solid was collected by filtration and washed with additional hexane to give the product as a regioisomeric mixture of methyl 7-fluoro-4-oxo-1H-quinoline-6-carboxylate D3 (25 g, 81%) and methyl 5-fluoro-4-oxo-1H-quinoline-6-carboxylate D4 (52:41 by LCMS). The mixture was carried on to the next step without separation. LCMS m / z 221.96 [M+H] + .

[0290] Step 3. Synthesis of methyl 3-bromo-7-fluoro-4-oxo-1H-quinoline-6-carboxylate and methyl 3-bromo-5-fluoro-4-oxo-1H-quinoline-6-carboxylate (D5) A regioisomeric mixture of methyl 7-fluoro-4-oxo-1H-quinoline-6-carboxylate (29 g, 115.38 mmol) D3 and methyl 5-fluoro-4-oxo-1H-quinoline-6-carboxylate D4 (29.000 g, 115.38 mmol) in DMF (200 mL) was cooled to 0 °C, and 1-bromopyrrolidine-2,5-dione (20.536 g, 115.38 mmol) was added in portions. The reaction was stirred overnight at room temperature. The reaction was quenched with ice-cold water under stirring conditions. The solid was filtered and washed with cold water. The compound was dried in vacuo to give methyl 3-bromo-7-fluoro-4-oxo-1H-quinoline-6-carboxylate D5 (32 g, 49%) LCMS m / z 300.0 [M+H]. + and methyl 3-bromo-5-fluoro-4-oxo-1H-quinoline-6-carboxylate (32 g, 39%), a mixture of regioisomers was obtained. LCMS m / z 302.0 [M+H] + The mixture was used in the subsequent step without separation.

[0291] Step 4. Synthesis of methyl 3-bromo-4-chloro-7-fluoro-quinoline-6-carboxylate and methyl 3-bromo-4-chloro-5-fluoro-quinoline-6-carboxylate (D6) A regioisomeric mixture of methyl 3-bromo-7-fluoro-4-oxo-1H-quinoline-6-carboxylate (30 g, 89.976 mmol) and methyl 3-bromo-5-fluoro-4-oxo-1H-quinoline-6-carboxylate (30.000 g, 89.976 mmol) was cooled to 0 °C, and thionyl chloride (107.05 g, 65.635 mL, 899.76 mmol) was added dropwise, followed by DMF (6.58 g, 6.97 mL, 89.976 mmol). The mixture was refluxed for 4 hours. The mixture was concentrated in vacuo, neutralized with a saturated solution of NaHCO3, and extracted with dichloromethane (100 mL × 3). The combined organic phase was dried over Na2SO4 and concentrated. The mixture was purified by silica gel chromatography (gradient: 3% EtOAc in hexanes) to give methyl 3-bromo-4-chloro-7-fluoro-quinoline-6-carboxylate D6 (8.5 g, 28%). 1 H NMR (400MHz, DMSO-d6) δ9.20(s, 2H), 8.74(d,J=7.4Hz, 2H), 8.06(d,J=11.6Hz, 2H), 3.96(s, 6H), 0.84(s, 1H). LCMS m / z 317.8[M+H] + .

[0292] Elution with 4% EtOAc in hexanes afforded the second regioisomer, methyl 3-bromo-4-chloro-5-fluoro-quinoline-6-carboxylate (17 g, 59%). 1 H NMR (400MHz, DMSO-d6) δ9.22(s, 1H), 8.18(dd,J=8.9, 7.0Hz, 1H), 8.01(d,J=8.9Hz, 1H), 3.94(s, 3H), 0.84(s, 1H). LCMS m / z 320.0[M+H] + .

[0293] Step 5. Synthesis of methyl 4-chloro-7-fluoro-3-isopropenyl-quinoline-6-carboxylate (D7) A stirred solution of methyl 3-bromo-4-chloro-7-fluoro-quinoline-6-carboxylate D6 (8.45 g, 26.528 mmol), K3PO4 (11.262 g, 53.056 mmol), and potassium trifluoro(isopropenyl)boranide (4.3181 g, 29.181 mmol) in 1,4-dioxane (90 mL) and HO (9 mL) was purged with Ar gas for 10 minutes. Pd(dppf)Cl2.CHCl2 (2.1664 g, 2.6528 mmol) was then added. The reaction mixture was heated at 100 °C overnight. The reaction mixture was filtered over Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo. Purification by column chromatography (gradient: 5-8% EtOAc / hexanes) afforded the product. Methyl 4-chloro-7-fluoro-3-isopropenyl-quinoline-6-carboxylate (4.5 g, 60%). 1 H NMR (400MHz, DMSO-d6) δ8.90(s, 2H), 8.78(d,J=7.6Hz, 2H), 8.00(d,J=11.7Hz, 2H), 6.96(dd,J=18.3, 8.8Hz, 1H), 5.55(s, 2H), 5.22(s, 2H) ), 3.96(s, 7H), 2.29~2.20(m, 1H), 2.21(s, 1H), 2.18(s, 6H), 2.17~2.06(m, 2H), 1.23(s, 2H), 1.14(q,J=7.6Hz, 1H), 0.85(t,J=6.6Hz, 1H). LCMS m / z 280.1[M+H] + .

[0294] Step 6. Synthesis of 7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-quinoline-6-carboxylic acid (D8) Methyl 4-chloro-7-fluoro-3-isopropenyl-quinoline-6-carboxylate (7 g, 25.0 mmol) and (4-fluorophenyl)boronic acid (6.3 g, 45.05 mmol) were dissolved in 1,4-dioxane (70 mL) and aqueous KPO (10.63 g, 50.0 mmol) (6 mL). The reaction mixture was purged with nitrogen for 10 minutes, and then Pd(PPh) (2.89 g, 2.50 mmol) and tricyclohexylphosphine (701.8 mg, 2.5 mmol) were added. Finally, the reaction mixture was heated to 90 °C for 12 hours. After completion, the reaction mixture was passed through Celite® and washed with EtOAc. The combined organic layers were evaporated under reduced pressure. Purification was carried out by flash chromatography on silica gel (100-200 mesh) using (5-10% EtOAc in hexanes) to give the product. 7-Fluoro-4-(4-fluorophenyl)-3-isopropenyl-quinoline-6-carboxylate (5.5 g, 64%). 1 H NMR (400MHz, DMSO-D6): δ8.96(s, 1H), 7.10(d,1H,J=7.8Hz), 7.95(d,1H,J=11 .88), 7.48~7.39(m, 4H), 5.24(s, 1H), 5.10(s, 1H), 3.92(s, 3H), 1.69(s, 3H). LCMS m / z 340.0 0[M+H]+.

[0295] Step 7: Synthesis of [7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-6-quinolyl]methanol (D9) To a solution of 7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-quinoline-6-carboxylic acid (1 g, 3.0740 mmol) in THF (15 mL) was added EtN (373 mg, 0.5141 mL, 3.69 mmol) and ethyl chloroformate (400 mg, 0.35 mL, 3.69 mmol) and stirred for 1 h. The reaction mixture was filtered, and to the filtrate was added a solution of NaBH (232 mg, 6.15 mmol) in HO (3.5 mL) and stirred for 3 h. The reaction mixture was carefully quenched with 1 N HCl and extracted with EtOAc. The extract was washed with saturated NaHCO, brine, dried over MgSO, filtered, and concentrated. Purification by silica gel chromatography (gradient: 30-50% EtOAc in hexanes) gave the product [7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-6-quinolyl]methanol (800 mg, 80%) as a white solid. LCMS m / z 312.0 [M+1] + .

[0296] Step 7. Synthesis of [7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-6-quinolyl]methanol (D9) To an ice-cooled stirred solution of LiAlH (201.33 mg, 0.2196 mL, 5.3045 mmol) in THF (20 mL) was added dropwise a solution of methyl 7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-quinoline-6-carboxylate (1.2 g, 3.53 mmol) in THF (10 mL). After complete addition, the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was cooled to 0° C. and quenched with the dropwise addition of water (0.2 mL), 15% NaOH (0.2 mL), and water (0.6 mL). The reaction mixture was filtered through a bed of Celite and washed with EtOAc (20 mL). The filtrate was concentrated and the crude material was purified by column chromatography (silica gel 100-200 mesh) using 30-40% EtOAc / hexanes to give the desired product [7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-6-quinolyl]methanol (800 mg, 66%). LCMS m / z 312.0 [M+1] + .

[0297] Step 8. Synthesis of [7-fluoro-4-(4-fluorophenyl)-3-isopropyl-6-quinolyl]methanol (D10) A stirred solution of [7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-6-quinolyl]methanol (1 g, 3.2121 mmol) in ethanol (10 mL) was degassed, and Pd / C (500 mg, 4.6984 mmol) was added. The mixture was stirred at room temperature under balloon pressure under hydrogen for 12 hours. The reaction was filtered, washed with EtOAc (30 mL), and concentrated. Purification by silica gel chromatography (gradient: 0 to 30% EtOAc in heptane) gave the product. [7-fluoro-4-(4-fluorophenyl)-3-isopropyl-6-quinolyl]methanol (975 mg, 93%). 1 H NMR (400MHz, DMSO-d6) δ9.02(s, 1H), 7.74(d,J=11.4Hz, 1H), 7.47~7.34(m, 4H), 5.34(t,J=5.5Hz, 1H), 4.61(d,J=5.7Hz, 2H), 1.23(d,J=7.0Hz, 6H). LCMS m / z 313.7[M+H] + .

[0298] Step 9. Synthesis of 7-fluoro-4-(4-fluorophenyl)-3-isopropyl-quinoline-6-carbaldehyde (D11) To a stirred solution of oxalyl chloride (785.85 mg, 0.5401 mL, 6.1914 mmol) in dichloromethane (10 mL) at −78° C., DMSO (967.54 mg, 0.8788 mL, 12.383 mmol) was added, followed 15 minutes later by a solution of [7-fluoro-4-(4-fluorophenyl)-3-isopropyl-6-quinolyl]methanol (970 mg, 3.0957 mmol) in dichloromethane (3 mL). The reaction mixture was then stirred at −78° C. for 2 hours. Triethylamine (1.5662 g, 2.1573 mL, 15.478 mmol) was added, and the reaction was stirred at −78° C. for 30 minutes. The reaction mixture was then partitioned between water (10 mL) and dichloromethane (20 mL x 2), and the combined organic fractions were washed with brine, dried (Na2SO4), filtered, and the solvent removed in vacuo.

[0299] Purification by silica gel chromatography (gradient: 0-10% EtOAc in heptane) gave the product: 7-fluoro-4-(4-fluorophenyl)-3-isopropyl-quinoline-6-carbaldehyde (785 mg, 80%). 1 H NMR (400MHz, DMSO-d6) δ10.20(s, 1H), 9.20(s, 1H), 7.96(d,J=11.8Hz, 1H), 7.80( d,J=7.7Hz, 1H), 7.50~7.40(m, 4H), 2.82(p,J=7.0Hz, 1H), 1.25(d,J=7.0Hz, 7H). LCMS m / z 312.03[M+H] + .

[0300] Step 10. Synthesis of 5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]quinolone (D12) In a sealed tube, 7-fluoro-4-(4-fluorophenyl)-3-isopropyl-quinoline-6-carbaldehyde (2.8 g, 8.9938 mmol), O-methylhydroxylamine hydrochloride (901.40 mg, 10.793 mmol), and K2CO3 (1.4917 g, 10.793 mmol) were mixed in DME (20 mL) at 40 °C for 4 h. The reaction mixture was filtered, concentrated in vacuo, and the volume reduced to 10 mL. Hydrazine hydrate (2.2512 g, 2.1920 mL of 65% w / v, 44.969 mmol) was added to the concentrated oxime solution, and the mixture was refluxed for 3 days. The reaction mixture was concentrated and partitioned between EtOAc (30 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (gradient: 0-50% EtOAc in heptane) gave the product: 5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]quinoline (1.4 g, 50%) 1 H NMR (400MHz, DMSO-d6) δ13.19(s, 1H), 9.03(s, 1H), 8.31(s, 1H), 8.11(s, 1H), 7. 69(s, 1H), 7.43(dd,J=7.4, 3.6Hz, 4H), 2.84~2.75(m, 1H), 1.25(d,J=7.0Hz, 7H). LCMS m / z 306.11[M+H] + .

[0301] Step 11. Synthesis of 5-(4-fluorophenyl)-6-isopropyl-8-oxide-1H-pyrazolo[4,3-g]quinolin-8-ium (T1) In a vial, 5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]quinoline (200 mg, 0.6550 mmol) in dichloromethane (20 mL) was cooled in an ice bath. The vial was placed in an ice bath, and mCPBA (225 mg, 1.304 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction was worked up by the addition of saturated NaHCO3 solution and CHCl3:IPA. The mixture was extracted with CHCl3:IPA (3:1) (x3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo to give the product. 5-(4-fluorophenyl)-6-isopropyl-8-oxide-1H-pyrazolo[4,3-g]quinolin-8-ium (205 mg, 97%). 1 H NMR (400MHz, DMSO-d6) δ13.51(s, 1H), 8.79(s, 1H), 8.72(d,J=1.1Hz, 1H), 8.40(t,J=1.3Hz, 1H) , 7.81(d,J=0.8Hz, 1H), 7.46(s, 2H), 7.44(s, 2H), 2.77(h,J=6.9Hz, 1H), 1.20(d,J=7.0Hz, 6H). LCMS m / z 322.12[M+H] + .

[0302] Step 12. Synthesis of 7-chloro-5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]quinolone (T2) 5-(4-Fluorophenyl)-6-isopropyl-8-oxide-1H-pyrazolo[4,3-g]quinolin-8-ium (790 mg, 2.458 mmol) was weighed into a vial and suspended in POCl3 (14 mL, 150.2 mmol). The reaction was stirred at room temperature for 20 minutes. The reaction was worked up by evaporating the volatiles in vacuo. The residue was suspended in ice / water, then filtered, and the collected solid was washed with cold water to give the product. 7-Chloro-5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]quinoline (867 mg, 93%). 1H NMR (400MHz, DMSO-d6) δ13.33(s, 1H), 8.35(d,J=1.1Hz, 1H), 8.05(t,J=1.1Hz, 1H ), 7.61(d,J=1.0Hz, 1H), 7.48~7.43(m, 4H), 3.15(br, 1H), 1.30(d,J=5.6Hz, 6H). LCMS m / z 340.03[M+H] + .

[0303] Preparation of T3 7-Bromo-2-chloro-4-(4-fluorophenyl)-3-isopropyl-quinoline-6-carbaldehyde (T3) [ka] Step 1. Synthesis of N-(3-bromo-4-methyl-phenyl)-3-methyl-butanamide (D14) A solution of 3-bromo-4-methyl-aniline (83 g, 446.1 mmol) and DIPEA (165 mL, 947.3 mmol) in dichloromethane (500 mL) was cooled on an ice bath. 3-Methylbutanoyl chloride (60 mL, 492.1 mmol) was added in portions. After the addition, the cooling bath was removed and the mixture was allowed to stir for 30 minutes. After 2 hours, the mixture was washed with brine, 1N HCl (70 mL), and aqueous saturated sodium bicarbonate. The aqueous washes were re-extracted with dichloromethane (2 x 500 mL). The dichloromethane phase was dried over NaSO, filtered, and evaporated. 10 g of this material was retained. The remaining product was suspended in heptane + approximately 5% MTBE with stirring for 1 hour. Purification by silica gel chromatography (gradient: 0 to 50% EtOAc in heptane) afforded the product. N-(3-Bromo-4-methyl-phenyl)-3-methyl-butanamide (118 g, 93%). 1 H NMR (300 MHz, chloroform-d): δ 7.80 (d, J = 2.2 Hz, 1H), 7.56 (s, 1H), 7.39 (dd, J = 8.3, 2.2 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 2.35 (s, 3H), 2.30-2.11 (m, 3H), 1.15-0.80 (m, 6H). LCMS m / z 270.08 [M+H] +.

[0304] Step 2. Synthesis of N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]-3-methyl-butanamide (D16) A suspension of N-(3-bromo-4-methyl-phenyl)-3-methyl-butanamide (35.1 g, 129.9 mmol), 2-(4-fluorophenyl)-2-oxo-acetic acid (24.3 g, 144.5 mmol), and Pd(TFA) (2.53 g, 7.610 mmol) in diglyme (420 mL) was stirred for 5 min. Ammonium sulfoxyhydrogen sulfate (60 g, 262.9 mmol) was added. The mixture was bubbled with nitrogen and heated at 50 °C (internal temperature) for 7 h. The solvent was distilled under high vacuum. The residue was partitioned between EtOAc and aqueous sodium bicarbonate and extracted with EtOAc (3x). The organic phase was washed with aqueous sodium bicarbonate and brine, dried over Na SO , filtered, and evaporated. Purification by silica gel chromatography (gradient: 0-30% EtOAc in dichloromethane, then 0-20% EtOAc in dichloromethane) gave the product: N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]-3-methyl-butanamide (39.56 g, 78%). 1 H NMR (300MHz, chloroform-d) δ10.60(s, 1H), 8.98(s, 1H), 7.74(dd,J=8.8, 5.3Hz, 2H), 7.36(d,J =0.8Hz, 1H), 7.21(t,J=8.6Hz, 2H), 2.36(s, 3H), 2.32~2.12(m, 3H), 1.03(d,J=6.3Hz, 6H). LCMS m / z 392.24[M+H] + .

[0305] Step 3. Synthesis of 7-bromo-4-(4-fluorophenyl)-3-isopropyl-6-methyl-1H-quinolin-2-one (D17) To a solution of N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]-3-methyl-butanamide (18.39 g, 46.88 mmol) in DMF (320 mL) was added LiOMe (7.12 g, 187.5 mmol). The mixture was heated at 80° C. (internal) for 19 hours. The mixture was cooled in an ice bath, poured into water (500 mL), and acidified with 6 M HCl (30 mL). The mixture was diluted to 2 L with water and filtered. The resulting solid was washed with water (2×) and then with heptane. The aqueous filtrate and heptane washes were discarded. The solid was dried under vacuum at 50° C. overnight to give the product. 7-Bromo-4-(4-fluorophenyl)-3-isopropyl-6-methyl-1H-quinolin-2-one (13.8 g, 79%) 1 H NMR (300MHz, DMSO-d6) δ11.76(s, 1H), 7.56(s, 1H), 7.46~7.34(m, 2H), 7.30(dd,J=8. 6, 5.7Hz, 2H), 6.65(s, 1H), 2.59(q,J=7.0Hz, 1H), 2.19(s, 3H), 1.19(d,J=6.9Hz, 6H). LCMS m / z 374.23[M+H] + .

[0306] Step 4. Synthesis of 7-bromo-2-chloro-4-(4-fluorophenyl)-3-isopropyl-6-methyl-quinoline (D18) A suspension of 7-bromo-4-(4-fluorophenyl)-3-isopropyl-6-methyl-1H-quinolin-2-one (13.8 g, 36.87 mmol) in phosphorus oxychloride (102.6 mL, 1.101 mol) was heated at 100° C. (sand bath) for 5 h. The mixture was distilled under vacuum and co-distilled with toluene (100 mL) to dryness. The residue was suspended in ice water. Aqueous sodium bicarbonate was added until the pH was about 8 and extracted with dichloromethane (3×). The organic phase was dried over Na2SO4, filtered, and evaporated. The residue was crystallized from dichloromethane / MTBE. The resulting solid was collected by filtration. The solid was washed with water (2×) and dried under high vacuum. The solid (approximately 10 g) was purified by silica gel chromatography (gradient: 0-100% EtOAc in heptane) to give the product in two batches, 4.04 g (batch 1) and 5.67 g (batch 2), both as a white solid. The filtrate (3.2 g) was purified by silica gel chromatography (gradient: 0-100% dichloromethane in heptane) to give an additional 1.47 g of product as a white solid.

[0307] 7-Bromo-2-chloro-4-(4-fluorophenyl)-3-isopropyl-6-methyl-quinoline (11.18 g, 77%). 1 H NMR (300 MHz, chloroform-d): δ 8.17 (s, 1H), 7.30–7.03 (m, 4H), 6.89 (d, J = 1.1 Hz, 1H), 3.12 (br.s, 1H), 2.33 (d, J = 0.9 Hz, 3H), 1.25 (d, J = 7.2 Hz, 6H). LCMS m / z 392.15 [M+H] + .

[0308] A by-product of this reaction is 7-bromo-2-chloro-3-isopropyl-4-(4-methoxyphenyl)-6-methyl-quinoline (D61), which was also isolated: 7-bromo-2-chloro-3-isopropyl-4-(4-methoxyphenyl)-6-methyl-quinoline (170 mg, 1%). 1H NMR (300 MHz, chloroform-d): δ 8.14 (s, 1H), 7.10–6.88 (m, 5H), 3.85 (s, 3H), 3.18 (s, 1H), 2.32 (d, J = 0.9 Hz, 3H), 1.24 (d, J = 7.2 Hz, 6H). LCMS m / z 404.22 [M+1] + .

[0309] Step 5. Synthesis of 7-bromo-6-(bromomethyl)-2-chloro-4-(4-fluorophenyl)-3-isopropyl-quinoline 7-bromo-2-chloro-4-(4-fluorophenyl)-3-isopropyl-quinoline-6-carbaldehyde (T3) A solution of 7-bromo-2-chloro-4-(4-fluorophenyl)-3-isopropyl-6-methyl-quinoline (11.07 g, 28.19 mmol), 1-bromopyrrolidine-2,5-dione (6.5 g, 36.52 mmol), and AIBN (630 mg, 3.837 mmol) in 2-dichloroethane (110 mL) was heated at reflux under air for 3 hours. The mixture was concentrated. Purification by silica gel chromatography (gradient: 0 to 100% dichloromethane in heptane) afforded the product. 7-Bromo-6-(bromomethyl)-2-chloro-4-(4-fluorophenyl)-3-isopropyl-quinoline (12.4 g, 40%). LCMS m / z 469.92 [M+H] + .

[0310] 7-Bromo-6-(bromomethyl)-2-chloro-4-(4-fluorophenyl)-3-isopropyl-quinoline was dissolved in CH3CN (110 mL). The resulting suspension was stirred at room temperature for 10 minutes using 4 Å molecular sieves (4 g) activated at 150 °C. 4-Methyl-4-oxide-morpholin-4-ium (6.60 g, 56.34 mmol) was added. The mixture was stirred at 50 °C for 1 hour. The mixture was filtered through Celite. The filtrate was evaporated. Purification by silica gel chromatography (gradient: 0 to 20% EtOAc in heptane) gave the product. 7-Bromo-2-chloro-4-(4-fluorophenyl)-3-isopropyl-quinoline-6-carbaldehyde (6.36 g, 56%).1 H NMR (300 MHz, chloroform-d) δ 10.32 (s, 1H), 8.25 (s, 1H), 7.71 (s, 1H), 7.29–6.98 (m, 4H), 3.17 (br.s, 1H), 1.26 (d, J = 7.2 Hz, 6H). LCMS m / z 405.98 [M+H] + LCMS m / z 406.2 [M+H] + .

[0311] Preparation of T4 7-chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolone (T4) [ka] Step 1. Synthesis of 7-methyl-1H-indazol-6-amine (D20) In a flask, palladium on carbon (750 mg of 10% w / w, 0.7048 mmol) was suspended in EtOH (10 mL). A solution of 7-methyl-6-nitro-1H-indazole (5000 mg, 28.22 mmol) in EtOH (200 mL) was then added. The flask was purged with nitrogen and then with hydrogen. The reaction was stirred at room temperature for 18 hours. The mixture was filtered through a glass fiber membrane and the volatiles were evaporated in vacuo to give a cream-colored solid. 7-Methyl-1H-indazol-6-amine (4.120 g, 99%). 1 H NMR (400MHz, DMSO-d6) δ12.38(s, 1H), 7.73(s, 1H), 7.22(d,J=8.5Hz, 1H), 6.54(d,J=8.6Hz, 1H), 4.95(s, 2H), 2.18(s, 3H). LCMS m / z 148.13[M+H] + .

[0312] Step 2. Synthesis of methyl 3-methyl-2-[(7-methyl-1H-indazol-6-yl)carbamoyl]butanoate 3-Methyl-2-[(7-methyl-1H-indazol-6-yl)carbamoyl]butanoic acid (D22) Part A: HATU (13.1 g, 34.45 mmol) was added to a stirred solution of 7-methyl-1H-indazol-6-amine (4 g, 27.18 mmol), 2-methoxycarbonyl-3-methyl-butanoic acid (6.53 g, 40.77 mmol), and DIPEA (12 mL, 68.89 mmol) in DMF (30 mL). The solution was stirred at room temperature for 24 hours. The solution was poured into water (50 mL), and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried and concentrated under reduced pressure to give a yellow solid. The solid was suspended in ether (200 ml) and filtered. The solid was washed with additional ether and dried in vacuo to give ethyl 3-methyl-2-[(7-methyl-1H-indazol-6-yl)carbamoyl]butanoate (7.5 g, 95%). LCMS m / z 290.6[M+H] + .

[0313] Part B: LiOH (6.5 g, 271.4 mmol) was added to a stirred solution of methyl 3-methyl-2-[(7-methyl-1H-indazol-6-yl)carbamoyl]butanoate (6 g) in MeOH (70 mL), THF (20 mL), and water (10 mL). The solution was stirred at room temperature for 3 hours, and the solvent was removed under reduced pressure. The crude product was dissolved in water (50 mL) and acidified with 6 M HCl. The white precipitate was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried and concentrated under reduced pressure to give 3-methyl-2-[(7-methyl-1H-indazol-6-yl)carbamoyl]butanoic acid (7 g, 91%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ13.14(s, 1H), 9.83(s, 1H), 8.03(d,J=1.3Hz, 1H), 7.52(d,J =8.5Hz, 1H), 6.97(d,J=8.5Hz, 1H), 3.68(m, 4H), 2.35(m, 4H), 0.99(t,J=6.6Hz, 6H).

[0314] Step 3. Synthesis of 6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinoline-5,7-diol (D23) 3-Methyl-2-[(7-methyl-1H-indazol-6-yl)carbamoyl]butanoic acid (650 mg, 2.361 mmol) was suspended in Eaton's reagent (6 mL, 37.81 mmol), and the mixture was heated at 150°C for 3 hours. The solution was poured into ice / water and slowly basified with 6N NaOH. A brown precipitate formed and was collected by filtration. The brown solid was dried at 60°C for 2 hours to give 6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinoline-5,7-diol (590 mg, 93%) as a brown powder. 1 H NMR (400MHz, DMSO-d6) δ13.03(s, 1H), 10.12(s, 1H), 9.91(s, 1H), 8.17(s, 1H), 3.44(p,J=6.9Hz, 1H), 2.56(s, 3H), 1.30(d,J=6.9Hz, 6H). LCMS m / z 258.18[M+H] + .

[0315] Step 4. Synthesis of 7-chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolone (T4) Part A. 6-Isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinoline-5,7-diol (1.00 g, 3.887 mmol) was weighed into a flask and dissolved in a mixture of dichloromethane (15 mL) and DMF (5 mL). EtN (650 μL, 4.664 mmol) was then added, followed by 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.460 g, 4.087 mmol). The reaction was stirred for 2 hours. Water and dichloromethane were added. The mixture was extracted three times with dichloromethane. The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. The crude mixture was triturated with cold water to give a gray solid. (7-Hydroxy-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolin-5-yl)trifluoromethanesulfonate (1.4082 g, 72%) LCMS m / z 390.23 [M+H] + .

[0316] Part B. (7-Hydroxy-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolin-5-yl)trifluoromethanesulfonate was added to a vial along with (4-fluorophenyl)boronic acid (1.010 g, 7.218 mmol), Pd(PPh3)4 (418 mg, 0.3617 mmol), and sodium carbonate (1.150 g, 10.85 mmol). The solid was suspended in a mixture of 1,4-dioxane (8 mL) and DMF (8 mL). The mixture was heated at 160 °C for 60 minutes. The volatiles were evaporated in vacuo. Water was then added to the solution, causing the product to precipitate. The solid was filtered and triturated with cold water to give the product 5-(4-fluorophenyl)-6-isopropyl-9-methyl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (1199 mg, 99%). LCMS m / z 336.25 [M+H] + .

[0317] Part C. 5-(4-Fluorophenyl)-6-isopropyl-9-methyl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one was suspended in phosphorus oxychloride (24.0 mL, 257.5 mmol). The suspension was heated at 100° C. for 20 minutes. Water and NaOH were added and the pH was adjusted to about 7. The mixture was extracted three times with dichloromethane. The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. The product was obtained as a yellow-green solid and was used without further purification. 7-Chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinoline (760 mg, 49%). LCMS m / z 354.26 [M+H] + .

[0318] Preparation of T5 and T6 5,7-dichloro-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolone (T5) and 1-[7-chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-pyrazolo[4,3-g]quinolin-1-yl]-2,2-dimethyl-propan-1-one (T6) [ka] Step 1. Synthesis of 5,7-dichloro-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolone (T5) 6-Isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinoline-5,7-diol (2 g, 7.773 mmol) was suspended in POCl3 (30 mL, 321.9 mmol). The brown suspension was heated at 150°C for 3 hours and cooled to room temperature. The solvent was removed under reduced pressure. The crude product was suspended in water (50 mL) and basified with 6N NaOH. The precipitate was collected by filtration. The wet mixture was lyophilized for 24 hours to give 5,7-dichloro-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinoline (2 g, 81%) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ13.65(s, 1H), 8.68(s, 1H), 8.57(s, 1H), 2.96(d,J=0.9Hz, 3H), 1.56(d,J=7.2Hz, 6H). LCMS m / z 294.05[M+H] + .

[0319] Step 2. Synthesis of 5-chloro-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolin-7-ol HCl (25 mL of 12 M, 300.0 mmol) was added to a stirred yellow suspension of 5,7-dichloro-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinoline (3.5 g, 11.13 mmol) in 1,4-dioxane (100 mL). The solution was heated at 100° C. for 2 hours and then poured into ice / water, forming a white precipitate. The precipitate was filtered and washed with ether. The solid was lyophilized for 24 hours to form 5-chloro-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolin-7-ol (2.8 g, 86%) as a brown solid. LCMS m / z 276.14 [M+H] + .

[0320] Step 3. Synthesis of 5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolin-7-ol (D25) Pd(PPh3)4 (250 mg, 0.2163 mmol) was added to a nitrogen-purged suspension of 5-chloro-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolin-7-ol (300 mg, 1.088 mmol), (4-fluorophenyl)boronic acid (380 mg, 1.086 mmol), and solid Na2CO3 (485 mg, 4.57 mmol) in DMF (2 mL) and 1,4-dioxane (8 mL). The solution was heated at 160 °C for 45 min under microwave conditions. The mixture was diluted with water (10 mL) and EtOAc (10 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried and concentrated under reduced pressure. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in H2O with 0.2% formic acid gave the product: 5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolin-7-ol (220 mg, 56%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ13.28(s, 1H), 10.83(s, 1H), 8.29(s, 1H), 8.26(d,J=1.2Hz, 1H), 3.83~3.53(m, 1H), 2.67(s, 3H), 1.37(d,J=7.0Hz, 6H). LCMS m / z 336.55[M+H] + .

[0321] Step 4. Synthesis of 7-chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolone (T4) A solution of 5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolin-7-ol (220 mg, 0.6560 mmol) in POCl3 (5 mL, 53.64 mmol) was heated at 150 °C for 2 h, and the reaction was cooled. POCl3 was removed under reduced pressure, and the brown solid was suspended in water (5 mL) and EtOAc (10 mL). The organic layer was dried and concentrated under reduced pressure. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in HO with 0.2% formic acid afforded the product. 7-Chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinoline (90 mg, 38%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ13.42(s, 1H), 8.32(d,J=1.4Hz, 1H), 7.54~7.22(m, 5H), 3.13(m, 1H), 2.92(d,J=0.8Hz, 3H), 1.30(d,J=7.0Hz, 6H). LCMS m / z 354.11[M+H] + .

[0322] Step 5. Synthesis of 1-[7-chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-pyrazolo[4,3-g]quinolin-1-yl]-2,2-dimethyl-propan-1-one (T6) In a flask, 7-chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinoline (120 mg, 0.3392 mmol) was dissolved in THF (3 mL). DIPEA (180 μL, 1.033 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. 2,2-Dimethylpropanoyl chloride (130 μL, 1.057 mmol) was then added dropwise. The reaction was stirred at room temperature for 20 hours. The reaction was worked up by evaporating the volatiles in vacuo. Water and dichloromethane were added, and the mixture was extracted with dichloromethane (×3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. Purification by silica gel chromatography (gradient: 0-2% EtOAc in heptane) afforded the product. 1-[7-Chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-pyrazolo[4,3-g]quinolin-1-yl]-2,2-dimethyl-propan-1-one (143.7 mg, 97%). LCMS m / z 438.35 [M+H] + .

[0323] Preparation of T7 9-Fluoro-5-hydroxy-6-isopropyl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (T7) [ka] Step 1. Synthesis of 6-azido-7-fluoro-1H-indazole (D27) In a microwave vial, 6-bromo-7-fluoro-1H-indazole (1000 mg, 4.651 mmol), NaN (605 mg, 9.306 mmol), CuI (90 mg, 0.4726 mmol), and (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (sodium salt) (45 mg, 0.2272 mmol) were dissolved in degassed EtOH (7 mL) / water (3 mL) containing N1,N2-dimethylcyclohexane-1,2-diamine (100 mg, 0.7030 mmol). The vial was sealed and heated at 80 °C for 4 h. Water and dichloromethane were added. The mixture was extracted with dichloromethane (×3). The organic phases were combined, dried over MgSO4, filtered, and the volatiles were evaporated in vacuo. Purification by reverse-phase chromatography (column: C18. Gradient: 0-100% MeCN in water with 0.2% formic acid) afforded the product: 6-azido-7-fluoro-1H-indazole (650 mg, 79%). 1 H NMR (400 MHz, methanol-d₄) δ 8.05 (d, J = 3.4 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 6.91 (dd, J = 8.6, 6.8 Hz, 1H). LCMS m / z 178.12 [M+H] + .

[0324] Step 2. Synthesis of 7-fluoro-1H-indazol-6-amine (D28) 6-Azido-7-fluoro-1H-indazole (120 mg, 0.6774 mmol) was weighed into a flask and dissolved in ethanol (7 mL). Palladium on carbon (36 mg, 0.03383 mmol) was then added. The flask was purged with nitrogen three times and then placed under a hydrogen atmosphere. The reaction was stirred at room temperature for 16 hours. The reaction was worked up by filtering the mixture through a short pad of Celite® and removing the volatiles in vacuo. The product was used without further purification. 7-Fluoro-1H-indazol-6-amine (100 mg, 98%). LCMS m / z 152.09 [M+H] + .

[0325] Step 3. Synthesis of methyl 2-[(7-fluoro-1H-indazol-6-yl)carbamoyl]-3-methyl-butanoate (D29) In a flask, 7-fluoro-1H-indazol-6-amine (90 mg, 0.5955 mmol) was suspended in dichloromethane (6 mL). 2-Methoxycarbonyl-3-methyl-butanoic acid (160 mg, 0.8991 mmol) was then added, followed by HATU (270 mg, 0.7101 mmol), and finally DIPEA (300 μL, 1.722 mmol). The mixture was stirred at room temperature for 30 minutes. The reaction was worked up by the addition of water and dichloromethane, followed by extraction with dichloromethane (×3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. The crude material was purified by flash column chromatography on silica gel (gradient: 0-7% MeOH in dichloromethane) to give the product. Methyl 2-[(7-fluoro-1H-indazol-6-yl)carbamoyl]-3-methyl-butanoate (224.2 mg, 90%, purity 70%). LCMS m / z 282.05 [M+H] + .

[0326] Step 4. Synthesis of 2-[(7-fluoro-1H-indazol-6-yl)carbamoyl]-3-methyl-butanoic acid (D30) In a flask, methyl 2-[(7-fluoro-1H-indazol-6-yl)carbamoyl]-3-methyl-butanoate (1350 mg, 3.237 mmol) and KOH (545 mg, 9.714 mmol) were added and dissolved in EtOH (27 mL) and HO (3 mL). The reaction was stirred at room temperature for 16 hours. The reaction was worked up by evaporating the volatiles and then adding water to bring the pH to 2. The mixture was extracted with CHCl:IPA (×3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo to give the product as a white solid. 2-[(7-fluoro-1H-indazol-6-yl)carbamoyl]-3-methyl-butanoic acid (875 mg, 97%). LCMS m / z 280.15 [M+H]+ .

[0327] Step 5. Synthesis of 9-fluoro-5-hydroxy-6-isopropyl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (D31) 2-[(7-Fluoro-1H-indazol-6-yl)carbamoyl]-3-methyl-butanoic acid (135 mg, 0.4834 mmol) was weighed into a vial and suspended in Eaton's reagent (2000 μL, 12.60 mmol). The reaction was heated at 80 °C for 96 h (decarboxylation prevails over cyclization when heated at higher temperatures). The reaction was worked up by adding brine, adjusting the pH to 7 with aqueous 6 M NaOH, and sequentially extracting with CHCl3:IPA. The organic phases were combined, dried over MgSO4, filtered, and the volatiles were evaporated in vacuo. Purification by silica gel chromatography (gradient: 0-5% dichloromethane in MeOH) afforded the product. 9-Fluoro-5-hydroxy-6-isopropyl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (46.4 mg, 37%). 1 H NMR (400MHz, DMSO-d6) δ13.50(s, 1H), 11.00(s, 1H), 10.14(s, 1H), 8.28(dd,J =3.4, 1.5Hz, 1H), 8.17(s, 1H), 3.43(septet, J=6.9Hz, 1H), 1.30(d,J=7.0Hz, 6H). LCMS m / z 262.19[M+H] + .

[0328] Step 6. Synthesis of (9-fluoro-6-isopropyl-7-oxo-1,8-dihydropyrazolo[4,3-g]quinolin-5-yl)trifluoromethanesulfonate (D32) In a flask, 9-fluoro-5-hydroxy-6-isopropyl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (210 mg, 0.7835 mmol) was dissolved in DMF (6 mL). EtN (130 μL, 0.9327 mmol) was then added, followed by PhN(SOCF) (330 mg, 0.9237 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was worked up by the addition of water and dichloromethane. The mixture was extracted with dichloromethane (×3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. Purification by silica gel chromatography (gradient: 0–5% dichloromethane in MeOH) gave the product as a white solid. (9-Fluoro-6-isopropyl-7-oxo-1,8-dihydropyrazolo[4,3-g]quinolin-5-yl)trifluoromethanesulfonate (255.5 mg, 92%). 1 H NMR (400MHz, DMSO-d6) δ13.83(s, 1H), 12.13(s, 1H), 8.45(dd,J=3.3, 1.3Hz, 1H), 7.93(s, 1H), 3.28~3.12(m, 1H), 1.39(d,J=6.9Hz, 6H). LCMS m / z 394.23[M+H] + .

[0329] Step 7. Synthesis of 9-fluoro-5-(4-fluorophenyl)-6-isopropyl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (D33) In a vial, (9-fluoro-6-isopropyl-7-oxo-1,8-dihydropyrazolo[4,3-g]quinolin-5-yl)trifluoromethanesulfonate (276 mg, 0.70 mmol), 4-fluorophenylboronic acid (300 mg, 2.14 mmol), Na2CO3 (225 mg, 2.123 mmol), and Pd(PPh3)4 (80 mg, 0.069 mmol) were suspended in 1,4-dioxane (4.5 mL). The reaction was heated at 160 °C for 2 h. The volatiles were evaporated in vacuo, and then water and dichloromethane were added. The mixture was extracted with dichloromethane (×3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. Purification by silica gel chromatography (gradient: 0–5% dichloromethane in MeOH) afforded the product as a pale orange solid. 9-Fluoro-5-(4-fluorophenyl)-6-isopropyl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (72.9 mg, 31%). LCMS m / z 340.26 [M+H] + .

[0330] Step 8. Synthesis of 7-chloro-9-fluoro-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]quinolone (T7) Part A. 9-Fluoro-5-(4-fluorophenyl)-6-isopropyl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (78 mg, 0.2299 mmol) was weighed into a vial and suspended in phosphorus oxychloride (1.0 mL, 10.73 mmol). The reaction was heated at 100° C. for 5 hours. The reaction was worked up by the addition of water and dichloromethane. The mixture was extracted with dichloromethane (×3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. The crude material was used without further purification. LCMS m / z 358.22 [M+H] + .

[0331] Part B. In a flask, the crude material from Part A was resuspended in dichloromethane (2.5 mL). 3,4-Dihydro-2H-pyran (105 μL, 1.15 mmol) was then added, followed by 4-methylbenzenesulfonic acid monohydrate (2.5 mg, 0.01314 mmol). The reaction was stirred at room temperature for 30 minutes. Water and dichloromethane were added. The mixture was extracted with dichloromethane (×3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. Purification by silica gel column chromatography (gradient: 0-20% EtOAc in heptane) afforded the product. 7-Chloro-9-fluoro-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]quinoline (103.4 mg, 100%) LCMS m / z 442.35 [M+H] + .

[0332] Preparation of T8 and T9 7-Bromo-2-chloro-4-(4-fluorophenyl)-6-methyl-3-tetrahydropyran-4-yl-quinoline (T8) and 7-Bromo-6-(bromomethyl)-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinoline (T9) [ka] Step 1. N-(3-Bromo-4-methyl-phenyl)-2-tetrahydropyran-4-yl-acetamide (D34) In a flask containing 3-bromo-4-methyl-aniline (1.78 g, 9.376 mmol) in DMF (21.6 mL), 2-tetrahydropyran-4-ylacetic acid (1.38 g, 9.381 mmol), HATU (4.26 g, 11.20 mmol), and DIPEA (5.6 mL, 32.15 mmol) were added. The solution was then stirred overnight at room temperature, quenched with a large amount of water, and diluted with AcOEt. The phases were separated, and the aqueous phase was extracted twice with AcOEt. The combined organic layers were dried over Na2SO4, filtered, and evaporated. Purification by silica gel chromatography (gradient: 0-100% EtOAc / heptane) gave N-(3-bromo-4-methyl-phenyl)-2-tetrahydropyran-4-yl-acetamide (2.52 g, 85%). NMR (400MHz, DMSO-d6) δ9.99(s, 1H), 7.98(d,J=2.1Hz, 1H), 7.38(dd,J=8.3, 2.1Hz, 1H), 7.25(d,J=8.7Hz, 1H), 3.81(dd,J=11.4, 2.5Hz, 2H), 3.29 (td,J=11.7, 2.1Hz, 2H), 2.27(s, 3H), 2.22(d,J=7.2Hz, 2H), 1.97(dtq,J =14.9, 7.4, 3.7Hz, 1H), 1.62~1.51(m, 2H), 1.22(qd,J=12.1, 4.6Hz, 2H). ESI-MS m / z calculated 311.0521, observed 312.04 (M+1) +

[0333] Step 2. N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]-2-tetrahydropyran-4-yl-acetamide (D35) A vial was charged with N-(3-bromo-4-methyl-phenyl)-2-tetrahydropyran-4-yl-acetamide (886 mg, 2.838 mmol), 2-(4-fluorophenyl)-2-oxo-acetic acid (716 mg, 4.259 mmol), bis[(2,2,2-trifluoroacetyl)oxy]palladium (94 mg, 0.2827 mmol), and ammonium sulfoxyhydrogen sulfate (1.3 g, 5.697 mmol). The vial was sealed and purged with one vacuum / N cycle, then diglyme (9.5 mL) was added and the reaction was stirred at 70 °C for 3 h. The mixture was evaporated under high vacuum at 80 °C, and the residue was suspended in DCM, filtered through Celite, and evaporated to dryness. Purification by silica gel chromatography (gradient: 0-100% EtOAc / heptane) gave N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]-2-tetrahydropyran-4-yl-acetamide (1.23 g, 100%). 1 H NMR (400MHz, chloroform-d) δ10.62(s, 1H), 8.92(s, 1H), 7.76~7.68(m, 2H), 7.34(s, 1H), 7.22~7.15(m, 2H), 3.94(dd,J=10. 7, 3.6Hz, 2H), 3.42(td,J=12.0, 2.2Hz, 2H), 2.36~2.31(m, 5H), 2.22~2.05(m, 1H), 1.73~1.65(m, 2H), 1.47~1.32(m, 2H). ESI-MS m / z calculated value 433.06888, measured value 434.1(M+1) +

[0334] Step 3. Synthesis of 7-bromo-4-(4-fluorophenyl)-6-methyl-3-tetrahydropyran-4-yl-1H-quinolin-2-one (D36) To a solution of N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]-2-tetrahydropyran-4-yl-acetamide (1.23 g, 2.832 mmol) in DMF (9.4 mL) was added LiOMe (419 mg, 11.03 mmol).

[0335] The mixture was heated at 80°C overnight. The mixture was cooled to room temperature and poured into saturated aqueous NH4Cl (400 mL), forming a yellow precipitate. The solid was collected by filtration and washed with water and heptane. The solid was solubilized in dichloromethane, and the solution was dried over sodium sulfate, filtered, and evaporated to give the product: 7-bromo-4-(4-fluorophenyl)-6-methyl-3-tetrahydropyran-4-yl-1H-quinolin-2-one (1.027 g, 78%). 1 H NMR (400MHz, DMSO-d6) δ11.87(s, 1H), 7.56(s, 1H), 7.40(t,J=8.8Hz, 2H), 7.35~7.29(m, 2H), 6.66(s, 1H), 3.79 (d,J=10.5Hz, 2H), 3.04~2.95(m, 2H), 2.47~2.40(m, 2H), 2.20(s, 3H), 2.16(t,J=5.9Hz, 1H), 1.28~1.19(m, 2H). LCMS m / z 416.06[M+H] + .

[0336] Step 4. Synthesis of 7-bromo-2-chloro-4-(4-fluorophenyl)-6-methyl-3-tetrahydropyran-4-yl-quinoline (D37) A suspension of 7-bromo-4-(4-fluorophenyl)-6-methyl-3-tetrahydropyran-4-yl-1H-quinolin-2-one (3.9 g, 9.163 mmol) in phosphorus oxychloride (12.8 mL, 137.3 mmol) was heated at 100 °C for 3 h. The mixture was evaporated to dryness and coevaporated twice with toluene. The residue was solubilized in dichloromethane and an excess of a saturated solution of NaHCO was added. The biphasic solution was stirred for 15 min, and the pH was checked to ensure that the aqueous phase remained basic. The phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were dried over NaSO, filtered, and evaporated to give the product. 7-Bromo-2-chloro-4-(4-fluorophenyl)-6-methyl-3-tetrahydropyran-4-yl-quinoline (3.89 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.49–7.35 (m, 4H), 7.05 (s, 1H), 3.90–3.77 (m, 2H), 3.16–2.92 (m, 3H), 2.38 (s, 3H), 1.46 (d, J = 11.5 Hz, 2H). (2H corresponds to CH2 from the THP ring.) 1 (Missing in H NMR). LCMS m / z 434.05 [M+H] + .

[0337] Step 5. Synthesis of 7-bromo-6-(bromomethyl)-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinoline (D38) 7-Bromo-2-chloro-4-(4-fluorophenyl)-6-methyl-3-tetrahydropyran-4-yl-quinoline (1 g, 2.169 mmol), CBr (71 mg, 0.2141 mmol), and N-bromosuccinimide (425 mg, 2.388 mmol) were added to a vial. The vial was sealed and purged with one vacuum / nitrogen cycle. CCl (21.7 mL) was added, and the reaction was stirred under a compact fluorescent white light for 1 hour. The solvent was evaporated to dryness. Purification by silica gel chromatography (gradient: 0-100% EtOAc in dichloromethane) gave the product 7-bromo-6-(bromomethyl)-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinoline (966 mg, 72%). LCMS m / z 511.88 [M+H] + .

[0338] Step 6. Synthesis of 7-bromo-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinoline-6-carbaldehyde (T8) To a solution of 7-bromo-6-(bromomethyl)-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinoline (906 mg, 1.376 mmol) in acetonitrile (13.8 mL) was added six activated molecular sieves and 4-methylmorpholine N-oxide (322 mg, 2.749 mmol). The reaction was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated and purified by silica gel chromatography (gradient: 0 to 100% EtOAc in dichloromethane) to give the product: 7-bromo-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinoline-6-carbaldehyde (644 mg, 99%). LCMS m / z 448.13 [M+H] + .

[0339] Step 7. Synthesis of 7-chloro-5-(4-fluorophenyl)-1-(p-tolylsulfonyl)-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]quinolone (T9) To a solution of 7-bromo-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinoline-6-carbaldehyde (215 mg, 0.4552 mmol) in ethanol (2.3 mL) was added 4-methylbenzenesulfonohydrazide (87 mg, 0.4531 mmol) and acetic acid (26 μL, 0.4572 mmol).

[0340] The reaction was heated at 50° C. for 1 hour. LCMS showed the formation of the desired N-[(E)-[7-bromo-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-6-quinolyl]methyleneamino]-4-methyl-benzenesulfonamide (280 mg, 100%). LCMS m / z 616.13 [M+1] + The reaction was evaporated to dryness and traces of acetic acid were removed by coevaporating with toluene.

[0341] The white solid was transferred to a vial containing cuproxycopper (33 mg, 0.2306 mmol). The vial was sealed and purged with one vacuum / N2 cycle. 3-Methylbutan-1-ol (4.6 mL) was added and the reaction was heated to 130 °C for 30 minutes. The reaction was cooled to room temperature and directly purified by silica gel chromatography (gradient: 0 to 100% EtOAc / heptane) to give 7-chloro-5-(4-fluorophenyl)-1-(p-tolylsulfonyl)-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]quinoline (198 mg, 77%). 1 H NMR (400MHz, chloroform-d) δ8.85(s, 1H), 8.25(d, J=1.0Hz, 1H), 7.92~7.87(m, 2H), 7.53(s, 1H), 7.30~7.27(m, 2H) ), 7.25~7.14(m, 4H), 4.04~3.91(m, 2H), 3.37~3.15(m, 3H), 2.33(s, 3H), 1.49~1.37(m, 2H), 1.34~1.16(m, 2H). LCMS m / z 536.09[M+H] + .

[0342] Preparation of T10 7-chloro-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]quinoline-6-carboxylic acid (T10) [ka] Step 1. Synthesis of N-(1H-indazol-6-yl)acetamide (D40) To a suspension of 1H-indazol-6-amine (100.2 g, 752.53 mmol) in anhydrous THF (1 L) at room temperature in a three-neck flask equipped with an addition funnel and a temperature probe, acetic anhydride (78.986 g, 73 mL, 773.70 mmol) was added dropwise over 2.25 h. The mixture was stirred at room temperature for an additional 20 h. Then, a solution of sodium hydroxide (32.98 g, 824.56 mmol) in water (500 mL) was added over 15 min at room temperature. The mixture was stirred vigorously for 30 min. The THF was removed under reduced pressure. Additional water (180 mL) was added, and the suspension was stirred at 0 °C for 1 h. The solid was filtered, washed with water (2 × 100 mL), and dried under vacuum to give N-(1H-indazol-6-yl)acetamide (128.82 g, 98%) as a beige solid.

[0343] Note: The acetic anhydride was added dropwise over 2.25 hours. During this addition, the internal temperature rose from 18° C. to 29° C. During the addition of aqueous NaOH, the internal temperature reached 33° C. 1 H NMR (300MHz, DMSO-d6): δ12.86(s, 1H), 10.08(s, 1H), 8.16(s, 1H), 7.94(s, 1H), 7.63(d,J=8.6Hz, 1H), 7.04(dd,J=8.6, 1.6Hz, 1H), 2.07(s, 3H). LCMS m / z 176.2[M+H] + .

[0344] Step 2. Synthesis of N-[1-(benzenesulfonyl)indazol-6-yl]acetamide (D41) To a suspension of N-(1H-indazol-6-yl)acetamide (31.8 g, 181.52 mmol) in anhydrous dichloroethane (400 mL) was added anhydrous pyridine (29.340 g, 30 mL, 370.92 mmol) and benzenesulfonyl chloride (33.216 g, 24 mL, 188.06 mmol) at room temperature. The mixture was heated to 25-27 °C and maintained at this temperature for 72 h. Additional benzenesulfonyl chloride (6.2280 g, 4.5 mL, 35.3 mmol) was added, and after an additional 24 h at 25-27 °C, the solvent was removed under reduced pressure. The solid was triturated in water (1 × 250 mL) at 0 °C for 20 min, then filtered, washed with water (3 × 75 mL), and dried under vacuum. The residue was triturated in MTBE (1×125 mL) and in a mixture of MTBE and THF (125 mL / 10 mL), filtered, and dried to give N-[1-(benzenesulfonyl)indazol-6-yl]acetamide (56.04 g, 96%) as a pink solid. 1 H NMR (300MHz, DMSO-d6) δ10.40(br s, 1H), 8.69~8.64(m, 1H), 8.43(d,J=0.9Hz, 1H), 7.90~7.83(m, 2H), 7.78~7. 67(m, 2H), 7.64~7.55(m, 2H), 7.51(dd,J=8.7, 1.7Hz, 1H), 2.12(s, 3H), LCMS m / z 316.1[M+H] + .

[0345] Step 3. Synthesis of N-[1-(benzenesulfonyl)-5-(4-fluorobenzoyl)indazol-6-yl]acetamide (D42) N-[1-(benzenesulfonyl)indazol-6-yl]acetamide (8.3 g, 26.32 mmol), 2-(4-fluorophenyl)-2-oxoacetic acid (5.300 g, 31.52 mmol), bis[(2,2,2-trifluoroacetyl)oxy]palladium (1.750 g, 5.264 mmol), and ammonium sulfoxyhydrogen sulfate (24.00 g, 105.2 mmol) were added to a flask and suspended in 1-methoxy-2-(2-methoxyethoxy)ethane (110 mL). The reaction was stirred at 65° C. for 5 hours. An additional 0.2 equivalents of catalyst was added, and the reaction was allowed to stir for an additional 40 hours.

[0346] The reaction was worked up by the addition of water and dichloromethane. The mixture was extracted three times with dichloromethane. The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. The crude was triturated with cold water, cold methanol, and heptane. A brown solid was obtained. N-[1-(benzenesulfonyl)-5-(4-fluorobenzoyl)indazol-6-yl]acetamide (12.59 g, 77%). LCMS m / z 438.3 [M+H] + .

[0347] Step 4. Synthesis of (6-amino-1H-indazol-5-yl)-(4-fluorophenyl)methanone (D43) To a suspension of N-[1-(benzenesulfonyl)-5-(4-fluorobenzoyl)indazol-6-yl]acetamide (2.45 g, 5.5335 mmol) in water (20 mL) was added concentrated hydrogen chloride (40 mL of 12 M, 480.00 mmol) (12 M solution in water). The mixture was heated to 85°C for 17 hours. After cooling to room temperature, additional concentrated hydrogen chloride (15 mL of 12 M, 180.00 mmol) (12 M solution in water) was added. The mixture was heated to 95°C and maintained at this temperature for 7 hours. It was cooled to room temperature and stirred overnight. After cooling to 0-5°C, the pH was adjusted to approximately pH 6-7 by dropwise addition of 25% w / w aqueous NaOH followed by 1 N aqueous NaOH. The precipitated solid was filtered, washed with water (3×15 mL), and then dried under vacuum to give (6-amino-1H-indazol-5-yl)-(4-fluorophenyl)methanone (1.41 g, 100%) as a brown solid. 1 H NMR (300MHz, DMSO-d6) δ12.56(br s, 1H), 7.90(s, 1H), 7.77(s, 1H), 7.74~7.64(m, 2H), 7.42~7.29(m, 2H), 6.79~6.58(m, 3H), 19F NMR (282MHz, DMSO-d6)δ-108.7~-109.0(m, 1F), LCMS m / z 256.1[M+H] + .

[0348] Step 5. Synthesis of methyl 5-(4-fluorophenyl)-7-oxo-1,8-dihydropyrazolo[4,3-g]quinoline-6-carboxylate (D44) Part A. (6-Amino-1H-indazol-5-yl)-(4-fluorophenyl)methanone (2000 mg, 7.555 mmol) was weighed into a vial and suspended in dichloromethane (30 mL). Pyridine (610 μL, 7.542 mmol) was then added, and the mixture was stirred at room temperature for 5 minutes. After this time, methyl 3-chloro-3-oxopropanoate (1.550 g, 11.35 mmol) was added dropwise. The reaction was stirred for 1 hour. An additional equivalent of acyl chloride was added. The reaction was stirred for an additional hour at room temperature. The reaction was worked up by the addition of water and CHCl3:IPA (3:1). The mixture was extracted with CHCl3:IPA (3:1) (×3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. The crude product was used in the next step without further purification.

[0349] Part B. The crude product from Part A was resuspended in DMF (30 mL) and K2CO3 (1.360 g, 9.840 mmol) was added. The reaction was stirred at 70 °C for 3 h. Water and CHCl3:IPA (3:1) were added. The mixture was extracted with CHCl3:IPA (3:1) (x3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. The crude product was suspended in water and precipitated by the addition of 1 M HCl. The solid was filtered and washed with cold water to give a pale yellow solid. Methyl 5-(4-fluorophenyl)-7-oxo-1,8-dihydropyrazolo[4,3-g]quinoline-6-carboxylate (2.3972 g, 94%). 1 H NMR (400MHz, DMSO-d6) δ13.11(s, 1H), 12.12(s, 1H), 8.16(t,J=1.2Hz, 1H), 7.58(s, 1H), 7.45~7.37(m, 5H), 3.50(s, 3H). LCMS m / z 338.05[M+H] + .

[0350] Step 6. Synthesis of 5-(4-fluorophenyl)-7-oxo-1,8-dihydropyrazolo[4,3-g]quinoline-6-carboxylic acid (D45) In a vial, methyl 5-(4-fluorophenyl)-7-oxo-1,8-dihydropyrazolo[4,3-g]quinoline-6-carboxylate (650 mg, 1.912 mmol) was suspended in a mixture of EtOH (12.0 mL) and water (4 mL). NaOH (385 mg, 9.626 mmol) was then added. The reaction was heated at 70° C. for 4 hours. After this time, LC-MS indicated the formation of the product and nearly complete consumption of the starting material. The mixture was concentrated in vacuo to remove volatiles. The crude product was suspended in water and precipitated by the addition of 1 M HCl until the pH was approximately pH 2. The precipitate was filtered and triturated with cold water to give the product as a cream-colored solid. 5-(4-fluorophenyl)-7-oxo-1,8-dihydropyrazolo[4,3-g]quinoline-6-carboxylic acid (615.2 mg, 100%) 1 H NMR (400MHz, DMSO-d6) δ13.20(s, 2H), 12.19(s1H), 8.15(d,J=1.0Hz, 1H), 7.52(s, 1H), 7.47(t,J=0.9Hz, 1H), 7.46~7.36(m, 4H). LCMS m / z 324.01[M+H] + .

[0351] Step 7. Synthesis of 7-chloro-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]quinoline-6-carboxylic acid (T10) 5-(4-Fluorophenyl)-7-oxo-1,8-dihydropyrazolo[4,3-g]quinoline-6-carboxylic acid (100 mg, 0.2898 mmol) was weighed into a vial and suspended in POCl3 (1 mL, 10.73 mmol). The reaction was heated at 80°C for 2 hours. The reaction was worked up by evaporating the volatiles in vacuo. Ice was then added and allowed to melt. The solid was suspended in water and filtered. The solid was then washed with cold water to give the product, which was used without further purification. 7-Chloro-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]quinoline-6-carboxylic acid (75.6 mg, 40%) LCMS m / z 342.0 [M+H] + .

[0352] Preparation of T11 7-Bromo-2-chloro-4-(4-fluorophenyl)-6-methyl-3-methylsulfonyl-quinoline (T11) [ka] Step 1. Synthesis of N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]acetamide (D47) A suspension of N-(3-bromo-4-methyl-phenyl)acetamide (62.73 g, 275.0 mmol), 2-(4-fluorophenyl)-2-oxo-acetic acid (63.37 g, 376.9 mmol), and ammonium sulfoxyhydrogen sulfate (125 g, 547.8 mmol) in diglyme (750 mL) was bubbled with nitrogen. Pd(TFA) (5 g, 15.04 mmol) was added. The mixture was stirred under N at 50 °C (internal temperature) for 11 h. Saturated aqueous sodium bicarbonate (700 mL) was slowly added. The mixture was then extracted with EtOAc (3x). The extract was washed with aqueous sodium bicarbonate, then brine, and concentrated. The residue was distilled under high vacuum to remove diglyme. The product was used in the next step without further purification. N-[5-Bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]acetamide (96.3 g, 100%). LCMS m / z 350.07 [M+H] + .

[0353] Step 2. Synthesis of (2-amino-4-bromo-5-methyl-phenyl)-(4-fluorophenyl)methanone (D48) To a suspension of N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]acetamide (1.92 g, 5.483 mmol) in EtOH (15 mL), aqueous HCl (10 mL of 6 M, 60.00 mmol) was added and the reaction was heated at 70 °C (internal temperature) for 5 h. The reaction mixture was allowed to cool to room temperature overnight. The resulting precipitate was collected by filtration, and the solid cake was washed with water and dried under high vacuum to give the product as a yellow solid. 1.14 g. (2-amino-4-bromo-5-methyl-phenyl)-(4-fluorophenyl)methanone (hydrochloride salt) (1.70 g, 90%). LCMS m / z 308.08 [M+H] + The filtrate was basified with 1N NaOH and extracted with dichloromethane (3x). The organic phase was evaporated. 570 mg.

[0354] Step 3. Synthesis of 7-bromo-4-(4-fluorophenyl)-6-methyl-3-methylsulfonyl-1H-quinolin-2-one (D49) Part A. A solution of (2-amino-4-bromo-5-methyl-phenyl)-(4-fluorophenyl)methanone (511 mg, 1.562 mmol) and 2-methylsulfonylacetic acid (250 mg, 1.810 mmol) in DMF (5 mL) was treated with HATU (804 mg, 2.115 mmol) and DIPEA (750 μL, 4.306 mmol) at room temperature for 1 h and then at 60° C. for 1 h. The mixture was partitioned into aqueous NH4Cl and EtOAc, extracted with EtOAc (3×), and washed with brine. The organic phase was dried over Na2SO4, filtered, and evaporated. Purification by silica gel chromatography (gradient: 0 to 100% EtOAc in heptane) afforded the product. N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]-2-methylsulfonyl-acetamide (1.02 g, 32%). LCMS m / z 428.16[M+H] + .

[0355] Part B. To a solution of N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]-2-methylsulfonyl-acetamide (1.02 g, 1.089 mmol) in DMF (8 mL) was added LiOMe (86 mg, 2.265 mmol). The mixture was heated at 70 °C (internal) for 15 minutes. The mixture was evaporated to dryness under high vacuum. Aqueous saturated NH4Cl was added. A yellow precipitate formed, and the solid was collected via filtration and washed with water. Purification by silica gel chromatography (gradient: 0-30% EtOAc in dichloromethane) afforded the product. 7-Bromo-4-(4-fluorophenyl)-6-methyl-3-methylsulfonyl-1H-quinolin-2-one (356 mg, 80%) 1 H NMR (300 MHz, chloroform-d) δ 7.59 (s, 1H), 7.26–7.14 (m, 4H), 6.88 (d, J = 1.0 Hz, 1H), 3.36 (s, 3H), 2.31 (d, J = 0.8 Hz, 3H). LCMS m / z 410.11 [M+H] + .

[0356] Step 4. Synthesis of 7-bromo-2-chloro-o-4-(4-fluorophenyl)-6-methyl-3-methylsulfonyl-quinoline (D50) A suspension of 7-bromo-4-(4-fluorophenyl)-6-methyl-3-methylsulfonyl-1H-quinolin-2-one (4.83 g, 11.77 mmol) in phosphorus oxychloride (20 mL, 214.6 mmol) was heated under reflux. The suspension became a solution after about 1 h. After 3 h, the mixture was evaporated and coevaporated with toluene to dryness. The residue was suspended in ice water. Aqueous sodium bicarbonate was added until the mixture reached about pH 8, and then the mixture was extracted with dichloromethane (3×). The organic phase was dried over Na2SO4, filtered, and evaporated. Purification by silica gel chromatography (gradient: 0-50% MeOH in dichloromethane) afforded the product. 7-Bromo-2-chloro-4-(4-fluorophenyl)-6-methyl-3-methylsulfonyl-quinoline (4.16 g, 82%) 1H NMR (300MHz, DMSO-d6) δ8.43(s, 1H), 7.50~7.39(m, 2H), 7.39~7.26(m, 2H), 7.16(d,J=1.1Hz, 1H), 3.42(s, 3H), 2.41(d,J=0.9Hz, 3H). LCMS m / z 428.07[M+H] + .

[0357] Step 5. Synthesis of 7-bromo-2-chloro-4-(4-fluorophenyl)-3-methylsulfonyl-quinoline-6-carbaldehyde (T11) Part A. A solution of 7-bromo-2-chloro-4-(4-fluorophenyl)-6-methyl-3-methylsulfonyl-quinoline (2.92 g, 6.811 mmol), 1-bromopyrrolidine-2,5-dione (1.50 g, 8.428 mmol), and AIBN (150 mg, 0.9135 mmol) in 1,2-dichloroethane (60 mL) was heated at reflux under air for 23 hours. AIBN (100 mg) and N-bromosuccinimide (500 mg) were added. The mixture was heated at reflux for 24 hours. The mixture was concentrated to dryness. Purification by silica gel chromatography (gradient: 0 to 50% EtOAc / heptane) afforded 7-bromo-6-(bromomethyl)-2-chloro-4-(4-fluorophenyl)-3-methylsulfonyl-quinoline (2.91 g, 72%). The product was used in Part B without further purification. LCMS m / z 505.79 [M+H] + .

[0358] Part B. 7-Bromo-6-(bromomethyl)-2-chloro-4-(4-fluorophenyl)-3-methylsulfonyl-quinoline was dissolved in acetonitrile (50 mL), 4 Å molecular sieves (1 g) (activated at 150° C.) were added, and the mixture was stirred at room temperature for 10 minutes. 4-Methyl-4-oxide-morpholin-4-ium (1.5 g, 12.80 mmol) was added. After 10 minutes, the mixture was heated at 50° C. for 30 minutes. The reaction was cooled to room temperature, filtered through Celite®, and washed with dichloromethane. Purification by silica gel chromatography (gradient: 0 to 50% EtOAc in heptane) afforded the product. 7-Bromo-2-chloro-4-(4-fluorophenyl)-3-methylsulfonyl-quinoline-6-carbaldehyde (1.33 g, 44%) 1 H NMR (300 MHz, chloroform-d): δ 10.34 (s, 1H), 8.36 (d, J = 0.5 Hz, 1H), 7.86 (d, J = 0.5 Hz, 1H), 7.26–7.08 (m, 4H), 3.29 (s, 3H). LCMS m / z 441.88 [M+H] + .

[0359] compound 145 4-[9-Fluoro-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]quinolin-7-yl]-3-methoxy-benzoic acid (145) [ka] Step 1. Synthesis of (6-amino-7-fluoro-1H-indazol-5-yl)-(4-fluorophenyl)methanone (D52) A suspension of Selectfluor (140 mg, 0.3952 mmol) in acetic acid (3 mL) was added dropwise to a solution of 6-amino-1H-indazol-5-yl)-(4-fluorophenyl)methanone (100 mg, 0.3918 mmol) in acetic acid (3 mL). The reaction was allowed to stir at room temperature for 18 hours. The reaction was concentrated. Water and dichloromethane were added. The mixture was extracted with dichloromethane (3x). The organic phases were passed through a phase separator, combined and concentrated in vacuo. The crude material was carried on to the next step. (6-amino-7-fluoro-1H-indazol-5-yl)-(4-fluorophenyl)methanone 1 H NMR (400MHz, DMSO-d6) δ13.26(s, 1H), 8.06(d,J=3.4Hz, 1H), 7.77~7.71(m, 2H), 7.68(s, 1H), 7.42~7.35(m, 2H), 6.43(s, 2H). LCMS m / z 273.98[M+H] + .

[0360] Step 2. Synthesis of N-[7-fluoro-5-(4-fluorobenzoyl)-1-(2-tetrahydropyran-4-ylacetyl)indazol-6-yl]-2-tetrahydropyran-4-yl-acetamide (D53) (6-Amino-7-fluoro-1H-indazol-5-yl)-(4-fluorophenyl)methanone was dissolved in dichloromethane (5 mL), and then pyridine (40 μL, 0.4946 mmol) was added, followed by 2-tetrahydropyran-4-ylacetyl chloride (140 μL, 0.9746 mmol). The mixture was stirred at room temperature for 2 hours. Water and dichloromethane were added. The mixture was extracted with dichloromethane (3×). The organic phases were passed through a phase separator, combined, and concentrated in vacuo. The crude product was carried on to the next step without further purification. N-[7-Fluoro-5-(4-fluorobenzoyl)-1-(2-tetrahydropyran-4-ylacetyl)indazol-6-yl]-2-tetrahydropyran-4-yl-acetamide LCMS m / z 526.12 [M+H] + .

[0361] Step 3. Synthesis of 9-fluoro-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (D55) (6-Amino-7-fluoro-1H-indazol-5-yl)-(4-fluorophenyl)methanone was dissolved in DMF (4 mL). NaH (32 mg, 0.8001 mmol) was then added, and the reaction was heated at 70° C. for 6 hours. Water and dichloromethane were added. The mixture was extracted with dichloromethane (3×). The organic phases were passed through a phase separator, combined, and concentrated in vacuo. The crude product was purified by flash column chromatography (15.5 g C18, 0-50% CH3CN in water, additive: formic acid 0.2%) to give a pale yellow solid: 9-fluoro-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (15.2 mg, 10%). 1 H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 11.68 (s, 1H), 8.17 (s, 1H), 7.48–7.33 (m, 4H), 7.01 (s, 1H)...

Claims

1. Compounds represented by formula I 【Chemical 189】 a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Z １ , Z ２ , and Z ３ are each independently -N=, -NH-, or -CH=, with the proviso that Z １ , Z ２ , and Z ３ is —N═ or —NH—; V １ and V ２ is C, W １ and W ２ are each independently selected from —C(═O)—, —C(R 2 )=, —N=, and —N(R 2 )—; W １ When -C(R 2 )=, W ２ is -N=, W ２ When -C(R 2 )=, W １ is -N=, W １ When is —C(═O)—, W ２ is —N(R 2 )—; W ２ When is —C(═O)—, W １ is —N(R 2 )—; 【Chemistry 190】 is, for each of two occurrences, a single bond or a double bond, provided that one is a single bond and the other is a double bond; W １ and W ２ (h) is a double bond, except that (h) is a single bond when either one of R ０ But halogen or 【Chemistry 191】 and Ring A is C ３ ~C １２ Carbocyclyl, 3- to 12-membered heterocyclyl, C ６ Or C １０ aryl, or 5- to 10-membered heteroaryl; R １ But halogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, —C(═O)R ｚ , -C(=O)OR ｚ , —C(═O)NR ｗ R ｘ , -NR ｗ R ｘ , -NR ｗ C(=O)R ｚ , -NR ｗ C(=O)OR ｚ , -NR ｗ C(=O)NR ｘ R ｙ , -OR ｚ , -OC(=O)R ｚ , -OC(=O)NR ｗ R ｘ , -S(=O) ２ R ｚ , C ３ ~C ６ cycloalkyl, or 3- to 6-membered heterocyclyl; R １ The above C １ ~C ６ alkyl, the C ３ ~C ６ cycloalkyl, or the 3- to 6-membered heterocyclyl is —OR ｚ , C １ ~C ３ optionally substituted with 1 to 3 groups independently selected from haloalkyl, —CN, and halogen; R ｗ , R ｘ , R ｙ , and R ｚ are each independently hydrogen or C １ ~C ４ is alkyl, X １ and X ２ are each independently hydrogen, halogen, —CN, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, C ３ ~C ６ cycloalkyl, or 5- or 6-membered heteroaryl; R ２ For each occurrence, independently, hydrogen, halogen, 【Chemistry 192】 and T is absent or is —O—, —OCH ２ -, -NH-, 【Chemical 216】 , —S—, and —CH ２ - is selected from, Y is C １ ~C ６ Alkyl, -(CR ａ R ａ ) ｐ COOH, -(CR ａ R ａ ) ｐ NR ｂ S (= O) ２ (CR ｃ R ｃ ) ｑ OH, -(CR ａ R ａ ) ｐ C(=O)NR ｂ (CR ｃ R ｃ ) ｑ COOH, and -(CR ａ R ａ ) ｐ (O) (CR ｃ R ｃ ) ｑ COOH, R ａ is, for each occurrence, independently, C optionally substituted with 1 to 3 groups independently selected from hydrogen, halogen, —OH, or halogen and —OH; １ ~C ４ is alkyl, Or alternatively, R ａ But for each occurrence, independently, C １ ~C ４ When it is alkyl, two R ａ groups together with the intervening carbon atoms form a cyclopropyl or cyclobutyl; R ｂ and R ｃ is, for each occurrence, independently hydrogen or C １ ~C ２ is alkyl, p and q are each independently an integer selected from 1 and 2; Ring B is C ３ ~C １２ Carbocyclyl, 3- to 12-membered heterocyclyl, C ６ Or C １０ aryl, or 5- to 10-membered heteroaryl; R ３ is -C(=O)OR ｄ and R ｄ But -OC(O)R ｅ , -OC(=O)OR ｅ , or -OP(=O)R ｆ R ｆ C optionally substituted with １ ~C ４ is alkyl, R ｅ is, for each occurrence, independently, hydrogen, -CH ３ , or -C ２ H ５ and R ｆ is, for each occurrence, independently: —OH, —CH ３ , -C ２ H ５ , -OCH ３ , or -OC ２ H ５ and R ｋ But halogen, -CN, C １ ~C ２ Alkyl, C １ ~C ２ Haloalkyl, C １ ~C ２ Alkoxy, C １ ~C ２ Haloalkoxy, or O—(C ３ ~C ６ cycloalkyl), R ｍ may, for each occurrence, independently be a halogen, —CN, ═O, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, —C(═O)R ｒ , -C(=O)OR ｒ , —C(═O)NR ｐ R ｑ , —C(═O)NR ｐ OR ｒ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｒ , -NR ｐ S (= O) ２ R ｒ 、 -OR ｒ , -S(=O) ２ R ｒ , -S(=O) ２ NR ｐ R ｑ , -P(=O)R ｓ R ｔ , C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; R ｍ The above C １ ~C ６ The alkyl, the phenyl, or the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, CN, —C(═O)OR ｒ , -NR ｐ R ｑ , and -OR ｒ and optionally substituted with 1 to 3 groups independently selected from R ｍ The above C ３ ~C ６ The cycloalkyl or the 3- to 6-membered heterocyclyl is selected from the group consisting of halogen, CN, ═O, —C(═O)OR ｒ , -NR ｐ R ｑ , and -OR ｒ and optionally substituted with 1 to 3 groups independently selected from R ｐ and R ｑ are each independently for each occurrence hydrogen, or —OH, —OCH ３ , -OC ２ H ５ C optionally substituted with 1 to 3 groups independently selected from —COOH, １ ~C ４ is alkyl, R ｒ For each occurrence, each occurrence independently represents hydrogen, C １ ~C ４ Alkyl, C ３ ~C ６ cycloalkyl, or 3- to 6-membered heterocyclyl, and R ｒ The above C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl or 3- to 6-membered heterocyclyl is —OH, —OCH ３ , -OC ２ H ５ , -CH ２ OH, -C(=O)OH, -(O)C(=O)OH, and -(O)P(=O)(OH) ２ and optionally substituted with 1 to 3 groups independently selected from R ｓ and R ｔ For each occurrence, each occurrence independently represents hydrogen, C １ ~C ４ Alkyl, C １ ~C ４ alkoxy, or —OH; k and m are each independently an integer selected from 0, 1, 2, 3, 4, and 5; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, wherein n is an integer selected from 0, 1, and 2.

2. Z １ , Z ２ , and Z ３ and n is an integer selected from 0 and 1, and all other variables not specifically defined in this claim are as defined in claim 1.

3. Represented by Formula II: 【Chemistry 193】 During the ceremony, R ３ is -C(=O)OR ｄ and R ｄ But -OC(O)R ｅ , -OC(=O)OR ｅ , or -OP(=O)R ｆ R ｆ C optionally substituted with １ ~C ４ is alkyl, R ｅ is, for each occurrence, independently hydrogen or —CH ３ and R ｆ is, for each occurrence, independently: —OH, —CH ３ , or -OCH ３ and n is an integer selected from 0 and 1; 3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1 or 2, wherein all other variables not specifically defined in this claim are as defined in claim 1 or 2.

4. represented by IIIa, IIIb, IIIc, or IIId; 【Chemistry 194】 During the ceremony, Ring A is R ｋ and Ring A is a 5- or 6-membered carbocyclyl, phenyl, or 5- or 6-membered heteroaryl; R １ But C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C(=O)OR ｚ , —C(═O)NR ｗ R ｘ , -NR ｗ R ｘ , -OR ｚ , -S(=O) ２ R ｚ , C ３ ~C ６ cycloalkyl, or 3- to 6-membered heterocyclyl; R １ The above C １ ~C ６ alkyl, the C ３ ~C ６ cycloalkyl, or the 3- to 6-membered heterocyclyl is —OR ｚ and halogen; R ｗ , R ｘ , and R ｚ are each independently hydrogen or C １ ~C ４ is alkyl, X １ and X ２ are each independently hydrogen, halogen, —CN, C １ ~C ２ Alkyl, C １ ~C ２ Haloalkyl, C １ ~C ２ Alkoxy, C １ ~C ２ haloalkoxy, or C ３ ~C ４ is cycloalkyl, R ２ but 【Chemistry 195】 and ring B is R ｍ and ring B is optionally substituted with C ４ ~C ９ except when R is carbocyclyl, phenyl, 4- to 9-membered heterocyclyl, or 5- to 6-membered heteroaryl. ２ is as defined in claim 1, R ３ is not present or -C(=O)O(CH ２ ) ２ (O)P(=O)(OH) ２ and R ｋ is halogen, -CN, -CH ３ , C １ Haloalkyl, or —OCH ３ and n is an integer selected from 0 and 1; 4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 3, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 3.

5. Represented by formula IVa, IVb, or IVc: 【Chemistry 196】 In the formula, X １ is hydrogen, halogen, -CH ３ , -CHF ２ , -CH ２ F, or -OCH ３ and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 4.

6. Represented by formula Va, Vb, or Vc, 【Chemistry 197】 During the ceremony, R １ But C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, —C(═O)OR ｚ , —C(═O)NR ｗ R ｘ , -NR ｗ R ｘ , -OR ｚ , -S(=O) ２ R ｚ , cyclopropyl, cyclobutyl, or 5- or 6-membered heterocyclyl; R １ The above C １ ~C ４ alkyl, said cyclopropyl, or said 5- or 6-membered heterocyclyl is -OR ｚ and halogen; R ｗ , R ｘ , and R ｚ are each independently hydrogen or C １ ~C ２ is alkyl, T is absent or is —O—, —OCH ２ -, -NH-, and -CH ２ are independently selected from 6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 5, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 5.

7. Ring A is R ｋ and Ring A is phenyl, cyclohexenyl, 3,6-dihydro-2H-pyranyl, pyridinyl, pyridazinyl, thiophenyl, or pyrazolyl, and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 6.

8. Ring A is R ｋ and Ring A is optionally substituted with 【Chemistry 198】 and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 7.

9. Ring A is R ｋ and Ring A is optionally substituted with 【Chemistry 199】 and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 8.

10. R ２ but 【Chemistry 200】 When ring B is R ｍ and Ring B is selected from isoindolinyl, azaspiro[3.4]octanyl, spiro[3.3]heptanyl, azaspiro[3.3]heptanyl, oxaspiro[3.3]heptanyl, azabicyclo[3.2.0]heptanyl, phenyl, cyclohexenyl, cyclohexyl, pyridinyl, piperidinyl, morpholinyl, tetrahydro-2H-pyranyl, thiazolyl, pyrazolyl, furanyl, tetrahydrofuranyl, cyclopentyl, bicyclo[1.1.1]pentanyl, pyrrolidinyl, cyclobutyl, azetidinyl, and cyclopropyl, and all other variables not specifically defined in this claim are as defined in any one of claims 1-9.

11. R ２ but, 【Chemical Engineering 201】 and Ring B is R ｍ and Ring B is optionally substituted with 【Chemical Engineering 202】 and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 10.

12. R ２ but, 【Chemical 203】 and Ring B is R ｍ and Ring B is optionally substituted with 【Chemical 204】 and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 11.

13. R ｍ may, for each occurrence, independently be a halogen, —CN, ═O, C １ ~C ６ Alkyl, C １ ~C ４ Alkoxy, —C(═O)R ｒ , -C(=O)OR ｒ , —C(═O)NR ｐ R ｑ , —C(═O)NR ｐ OR ｒ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｒ , -NR ｐ S (= O) ２ R ｒ 、 -OR ｒ , -S(=O) ２ R ｒ , -S(=O) ２ NR ｐ R ｑ , -P(=O)R ｓ R ｔ or 5- or 6-membered heterocyclyl; R ｍ The above C １ ~C ６ Alkyl is -C(=O)OH, -C(=O)OCH ３ , -C(=O)OC ２ H ５ , —OH, —OCH ３ , and -OC ２ H ５ and optionally substituted with 1 to 3 groups independently selected from R ｍ wherein said 5- or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups independently selected from halogen, ═O, —C(═O)OH, and —OH; R ｐ and R ｑ are each independently for each occurrence hydrogen, or —OH, —OCH ３ and C optionally substituted with 1 to 3 groups independently selected from —C(═O)OH. １ ~C ３ is alkyl, R ｒ For each occurrence, each occurrence independently represents hydrogen, C １ ~C ４ Alkyl, C ３ ~C ６ cycloalkyl, or 4- to 6-membered heterocyclyl, and R ｒ The above C １ ~C ２ Alkyl, C ３ ~C ６ Cycloalkyl or 4- to 6-membered heterocyclyl is —OH, —OCH ３ , -OC ２ H ５ , -C(=O)OH, -(O)C(=O)OH, and -(O)P(=O)(OH) ２ and optionally substituted with 1 to 3 groups independently selected from R ｓ and R ｔ For each occurrence, each occurrence independently represents hydrogen, C １ ~C ２ Alkyl, C １ ~C ２ alkoxy, or —OH; 13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 12, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 12.

14. R ｍ may be, for each occurrence, independently, a halogen, CN, ═O, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, —C(═O)R ｒ , -C(=O)OR ｒ , —C(═O)NR ｐ R ｑ , —C(═O)NR ｐ OR ｒ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｒ , -NR ｐ S (= O) ２ R ｒ 、 -OR ｒ , -S(=O) ２ R ｒ , -S(=O) ２ NR ｐ R ｑ , -P(=O)R ｓ R ｔ , imidazolidinyl, or morpholinyl; R ｍ The above C １ ~C ４ Alkyl is -C(=O)OH, -C(=O)OCH ３ , -C(=O)OC ２ H ５ , —OH, —OCH ３ , and -OC ２ H ５ and optionally substituted with 1 to 3 groups independently selected from R ｍ wherein said imidazolidinyl or said morpholinyl is optionally substituted with 1 to 3 groups independently selected from oxo (=O) and -OH; R ｐ and R ｑ are each independently for each occurrence hydrogen, or —OH, —OCH ３ and C optionally substituted with 1 to 3 groups independently selected from —C(═O)OH. １ ~C ３ is alkyl, R ｒ For each occurrence, each occurrence independently represents hydrogen, C １ ~C ２ alkyl, cyclopropyl, oxetanyl, or azetidinyl; R ｒ The above C １ ~C ２ Alkyl, cyclopropyl, oxetanyl, or azetidinyl is —OH, —CH ２ OH, -C(=O)OH, and -(O)P(=O)(OH) ２ and optionally substituted with 1 to 3 groups independently selected from R ｓ and R ｔ is, for each occurrence, independently at each occurrence, -CH ３ , -OCH ３ or —OH, 13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 12, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 12.

15. R ｍ is, for each occurrence, independently: —COOH, —C(═O)CH(OH)CH ３ , F, -CH ３ , —C(═O)NH ２ , -C(=O)NH(OCH ３ ), -S(=O) ２ NH ２ , -NHS(=O) ２ CH ３ , =O, -OH, -P(=O)(CH ３ ) ２ , -P(=O)(OH) ２ , -P(=O)(OCH ３ ) ２ , —OH, imidazolidin-4yl, —CH ２ OH, -NHCH ３ , morpholin-4-yl, -(C=O)NHCH(CH ３ ) CH ２ OH, -C(=O)N(CH ３ ) CH(CH ３ ) CH ２ OH, -NCH ３ C(=O)CH(OH)CH ３ , -C(=O)CH(CH ３ ) CH ２ OH, -C(=O)CH(OH)CH ２ OH, —C(═O)(hydroxymethyl)oxetan-3-yl, —C(═O)(hydroxy)cyclopropyl, —C(═O)CH(OH)CH ３ , -C(=O)OCH ３ , -OCH ３ , -CH ２ COOH, -CN, -OCH ２ COOH, -OCH(CH ３ )COOH, -CH(CH ３ )COOH, -Cl, -S(=O) ２ CH ３ , -S(=O) ２ NHCH ３ , -CH ２ C(=O)OC ２ H ５ , -C(=O)OCH ２ (O)P(=O)(OH) ２ , -C(=O)NHCH(CH ３ )COOH, -C(=O)NHCH ３ , —C(═O)(3-hydroxyazetidin-1-yl), and —C(═O)(morpholin-4-yl), and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 13.

16. R ｍ At least one occurrence of -COOH, -CH ２ COOH, -OCH ２ COOH, -OCH(CH ３ )COOH, -CH(CH ３ )COOH, -C(=O)OCH ２ (O)P(=O)(OH) ２ , or -C(=O)NHCH(CH ３ 16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 15, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25

17. Represented by formula VIa, VIb, or VIc: 【Chemical 205】 17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 16, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 16.

18. R １ But C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, —C(═O)OR ｚ , —C(═O)NR ｗ R ｘ , -NR ｗ R ｘ , -OR ｚ , -S(=O) ２ R ｚ , cyclopropyl, cyclobutyl, or 6-membered heterocyclyl; R １ is C １ ~C ３ alkyl, cyclopropyl, cyclobutyl, or tetrahydro-2H-pyran-4-yl, R １ -OH, -OCH ３ , C １ ~C ２ optionally substituted with 1 to 3 groups independently selected from haloalkyl, —CN, and halogen; R ｗ , R ｘ , R ｙ , and R ｚ are each independently hydrogen or —CH ３ and 4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 3, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 3.

19. R １ But -C(CH ３ ) ２ , -CF ３ , -CH ２ C(CH ３ ) ２ OCH ３ , -C(CH ３ ) ２ CH ２ OH, -OCH ３ , -O(CH)(CH ３ ) ２ , -C(=O)OCH ３ , -C(=O)N(CH ３ ) ２ , -N(CH ３ ) ２ , -S(=O) ２ CH ３ , -S(=O) ２ C ２ H ５ , -S(=O) ２ CH (CH ３ ) ２ , tetrahydro-2H-pyran-4-yl, cyclopropyl, or cyclobutyl; R １ wherein the cyclopropyl or cyclobutyl is —OH, —OCH ３ , or -CF ３ 18. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 17, optionally substituted with, and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 17.

20. Represented by formula VIIa, VIIb, VIIc, VIId, VIIe, or VIIf, 【Chemical 206】 20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 19, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 19.

21. Represented by formula VIIIa, VIIIb, or VIIIc: 【Chemical 207】 During the ceremony, Ring A is R ｋ and Ring A is phenyl or 5- or 6-membered heteroaryl; T is absent or is one of —O—, —NH—, and —CH ２ - is selected from, Y is C １ ~C ２ Alkyl, -(CR ａ R ａ ) ｐ COOH, -(CR ａ R ａ ) ｐ NR ｂ S (= O) ２ (CR ｃ R ｃ ) ｑ OH, -(CR ａ R ａ ) ｐ C(=O)NR ｂ (CR ｃ R ｃ ) ｑ COOH, or -(CR ａ R ａ ) ｐ (O) (CR ｃ R ｃ ) ｑ COOH, R ａ is, for each occurrence, independently hydrogen, —OH, —CH ３ , or -CH ２ OH, R ｂ and R ｃ is, for each occurrence, independently hydrogen or —CH ３ and 6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 5, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 5. 【Request Item 22】 【Chemistry 208】 But -NHCH ３ , -CH ２ COOH, -(CH ２ ) ２ COOH, -CH(CH ３ ) CH ２ COOH, -NHCH(CH ３ )COOH, -OCH ２ COOH, -O(CH ２ ) ２ (O)CH ２ COOH, -CH ２ CH (CH ３ )COOH, -OCH(CH ３ )C(=O)NHCH ２ COOH, or -OCH(CH ２ OH)CH ２ NHS (=O) ２ (CH ２ ) ２ 22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 5 and 21, wherein R is 0, R is 1, R is 2, R is 3, R is 4, R is 5, R is 6, R is 7, R is 8, R is 9, R is 10, R is 11, R is 12, R is 13, R is 14, R is 15, R is

23. Ring A is R ｋ and wherein ring A is phenyl or pyridinyl, and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 5, 21, and 22.

24. Ring A is R ｋ and Ring A is optionally substituted with 【Chemical Engineering 209】 and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 5 and 21 to 23.

25. Ring A is 【Chemical 210】 is selected from 24. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 5 and 21 to 23, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 5 and 21 to 23.

26. Ring A is 【Chemistry 211】 and all other variables not specifically defined in this claim are as defined in any one of claims 1-5, 21 and 22.

27. R １ But halogen, -CN, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, —NR ｗ R ｘ , -OR ｚ , C ３ ~C ６ cycloalkyl, or 5- or 6-membered heterocyclyl; R １ The above C １ ~C ３ alkyl, the C ３ ~C ６ cycloalkyl, or the 5- or 6-membered heterocyclyl is —OH, —OCH ３ , C １ ~C ２ optionally substituted with 1 to 3 groups independently selected from haloalkyl, —CN, and halogen; R ｗ , R ｘ , R ｙ , and R ｚ are each independently hydrogen or —CH ３ and 27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 5 and 21 to 26, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 5 and 21 to 26.

28. R １ But C １ ~C ３ alkyl or 6-membered heterocyclyl; R １ The above C １ ~C ３ The alkyl or the 5- or 6-membered heterocyclyl is —OH, —OCH ３ , C １ ~C ２ optionally substituted with 1 to 3 groups independently selected from haloalkyl and halogen; 27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 5 and 21 to 26, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 5 and 21 to 26.

29. R １ But -C(CH ３ ) ２ or tetrahydro-2H-pyran-4-yl, and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 5 and 21 to 26.

30. R １ but, 【Chemical Engineering 212】 and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 5 and 21 to 26.

31. R １ but, 【Chemistry 213】 and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 5 and 21 to 26.

32. R ２ But for each occurrence, independently, 【Chemical 214】 and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 5 and 23 to 31.

33. R ２ But for each occurrence, independently, 【Chemical 215】 and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 5 and 21 to 31.

34. X １ is hydrogen, —F, or —CH ３ and R ｋ is -F, -Cl, -CH ３ , or -OCH ３ and k is an integer selected from 0, 1, and 2; 33. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 32, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 32.

35. The following: Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 or a pharmaceutically acceptable salt of any of the foregoing.

36. 36. A pharmaceutical composition for modulating alpha-1 antitrypsin (AAT) activity, said pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 35.

37. 36. Use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 35 in the manufacture of a medicament for modulating AAT activity.

38. 36. A pharmaceutical composition for treating alpha-1 antitrypsin deficiency (AATD), said pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 35.

39. 36. Use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 35 in the manufacture of a medicament for treating AATD.

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