Alpha-1-antitrypsin modulators

Abstract

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

Description

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

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

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

[0004] The most common mutation associated with AATD involves a substitution of glutamic acid with lysine (E342K) in the SERPINA1 gene, which encodes the AAT protein. This mutation, known as the Z mutation or Z allele, causes the translated protein to misfold and therefore not be secreted into the blood, and to aggregate within the producing cells. Consequently, circulating AAT levels are significantly reduced in individuals homozygous for the Z allele (PiZZ); only approximately 15% of the mutant Z-AAT protein is correctly folded and secreted by cells. Another consequence of the Z mutation is that the secreted Z-AAT has reduced activity compared to the wild-type protein, ranging from 40% to 80% of the normal antiprotease activity (American Thoracic Society / European Respiratory Society, Am J Respir Crit Care Med. 2003; 168(7): 818-900; and Ogushi et al. J Clin Invest. 1987; 80(5): 1366-74).

[0005] The accumulation of polymerized Z-AAT protein within liver cells leads to gain-of-function cytotoxicity, which can lead to cirrhosis or liver cancer later in life in 12% of patients and neonatal liver disease. This accumulation may resolve spontaneously but is fatal in a small number of children. The lack of circulating AAT leads to unregulated protease activity, which degrades lung tissue over time, resulting in a form of chronic obstructive pulmonary disease (COPD), namely emphysema. This effect is severe in PiZZ individuals and usually manifests in middle age, leading to a decreased quality of life and a shortened lifespan (average 68 years) (Tanash et al. Int J Chron Obstruct Pulm Dis. 2016; 11: 1663-9). The effect is even more pronounced in PiZZ individuals who smoke, leading to a further shortened lifespan (58 years). (Piitulainen and Tanash, COPD 2015; 12(1): 36-41). PiZZ individuals account for the majority of patients with clinically relevant AATD lung disease. Therefore, additional effective treatments for AATD are needed.

[0006] A milder form of AATD is associated with the SZ genotype, in which the Z allele combines with the S allele. The S allele is associated with decreased circulating AAT levels but does not cause hepatocyte cytotoxicity. The result is clinically significant lung disease rather than liver disease (Fregonese and Stolk, Orphanet J Rare Dis. 2008;33:16). As with the ZZ genotype, the lack of circulating AAT in subjects with the SZ genotype leads to unregulated protease activity that degrades lung tissue over time and can cause emphysema, particularly in smokers.

[0007] For individuals with AAT deficiency who have or show signs of developing significant lung or liver disease, the current standard of care is intensive therapy or protein replacement therapy. Intensive therapy involves administering human AAT protein concentrate purified from pooled donor plasma to enhance the missing AAT. Although plasma protein transfusion has been shown to improve survival or slow the rate of progression of emphysema, intensive therapy is often insufficient in challenging conditions, such as during active lung infections. Similarly, although protein replacement therapy has shown promise in slowing disease progression, intensive therapy does not restore the normal physiological regulation of AAT in patients, and its efficacy is difficult to demonstrate. In addition, intensive therapy requires weekly treatment follow-up, and intensive therapy cannot address liver disease driven by the toxic gain of function of the Z allele. Therefore, there is a continuing need for new and more effective AATD treatments.

[0008] One aspect of the present disclosure provides a compound of Formula I:

[0009]

[0010] or a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0011] Z 1 , Z 2 and Z 3 are each independently N, -NH or -CH; provided that Z 1 , Z 2 and Z 3 At least one of is N or -NH;

[0012] V 1 and V 2 are each selected from C and N;

[0013] W 1 and W 2 Each selected from -C=O, -CR 2 , N and -NR 2 ,in:

[0014] When W 1 -CR 2 When W 2 is N;

[0015] When W 2 -CR 2 When W 1 N or -NR 2 ;

[0016] When W 1 When -C=O, then W 2 -NR 2 ;and

[0017] When W 2 When -C=O, then W 1 -NR 2 ;

[0018] For each of the two cases, a single bond or a double bond, provided that one is a single bond and the other is a double bond;

[0019] (h) is a double bond, the difference is that when W 1 and W 2 When any one of is -C=O, (h) is a single bond;

[0020] R 0 Halogen or in:

[0021] Ring A is C3-C 12Carbocyclic group, 3 to 12 membered heterocyclic group, C6 or C 10 aryl or 5- to 10-membered heteroaryl;

[0022] 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 heterocyclic group; wherein:

[0023] R 1 The C1-C6 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from the following: -OR z , C1-C3 haloalkyl, -CN and halogen; and

[0024] R w 、R x 、R y and R z Each is independently hydrogen or C1-C4 alkyl;

[0025] X 1 and X 2 Each is 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;

[0026] R 2 For hydrogen, halogen, in:

[0027] T is absent or a bond, or is selected from -O-, -OCH2-, -NH-, -NS(=O)2CH3, -S-, and -CH2-;

[0028] Y is selected from C1-C6 alkyl, -(CRa 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; of which:

[0029] R a is independently at each occurrence hydrogen, halogen, -OH or C1-C4 alkyl optionally substituted with 1 to 3 groups selected from halogen and -OH;

[0030] Or alternatively, when R a When each occurrence is C1-C4 alkyl, the two R a The groups together with their intervening carbon atoms form a cyclopropyl or cyclobutyl group;

[0031] R b and R c is independently hydrogen or C1-C2 alkyl at each occurrence; and

[0032] p and q are each independently an integer selected from 1 and 2;

[0033] Ring B is C3-C 12 Carbocyclic group, 3 to 12 membered heterocyclic group, C6 or C 10 aryl or 5- to 10-membered heteroaryl;

[0034] R 3 -C(=O)OR d ; where R d is optionally -OC(O)R e 、-OC(=O)OR e OR-OP(=O)OR f R f Substituted C1-C4 alkyl; wherein:

[0035] R eis independently at each occurrence hydrogen, -CH3 or -C2H5;

[0036] R f is independently at each occurrence -OH, -CH3, -C2H5, -OCH3 or -OC2H5;

[0037] R k is halogen, -CN, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy or O-(C3-C6 cycloalkyl);

[0038] R m is independently at each occurrence 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 heterocyclic group, phenyl or 5 or 6-membered heteroaryl,

[0039] where R m The C1-C6 alkyl, phenyl or 5- or 6-membered heteroaryl is optionally substituted by 1 to 3 groups selected from the following: halogen, CN, -C(=O)OR r 、-NR p R q AND-OR r ;and

[0040] where R m The C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted by 1 to 3 groups selected from the group consisting of halogen, CN, ═O, —C(═O)OR r 、-NR p R q AND-OR r ;

[0041] where R p and Rq is independently at each occurrence hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 groups selected from the group consisting of: -OH, -OCH3, -OC2H5 and -COOH;

[0042] where R r Each occurrence is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or 3 to 6 membered heterocyclyl; wherein R r The C1-C4 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from the group consisting of -OH, -OCH3, -OC2H5, -CH2OH, -C(=O)OH, -(O)C(=O)OH and -(O)P(=O)(OH)2; and

[0043] where R s and R t is independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy or -OH at each occurrence;

[0044] k and m are each independently an integer selected from 0, 1, 2, 3, 4 and 5; and

[0045] n is an integer selected from 0, 1 and 2.

[0046] Other aspects of the present disclosure provide compounds of Formula II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, VIIIa-c and compounds 1-262 disclosed herein, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts.

[0047] 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, compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, have an EC of 2.0 μM or less when tested in an AAT functional 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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, have an EC of less than 0.5 μM when tested in an AAT functional assay. 50 .

[0048] In some embodiments, compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these 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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, have an IC of less than 2.0 μM when tested in a Z-AAT elastase activity assay. 50 .

[0049] In some embodiments, compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these 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 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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these 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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these 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 less than 2.0 μM 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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these 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 less than 2.0 μM when tested in the Z-AAT elastase activity assay 50 .

[0050] In some embodiments, compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives are provided for use in treating AATD.

[0051] In one aspect of the present disclosure, compounds of Formula I, 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 of any of the foregoing can be used to treat AATD.

[0052] In some embodiments, the disclosure provides pharmaceutical compositions comprising at least one compound selected from the group consisting of: 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, the pharmaceutical compositions may comprise compounds selected from the group consisting of: compounds 1-262, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0053] Another aspect of the present disclosure provides a method for treating AATD, comprising administering to a subject in need thereof at least one compound selected from the group consisting of 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 pharmaceutically acceptable salt. In specific embodiments, the method comprises administering a compound selected from the group consisting of Compounds 1-262, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0054] In some embodiments, the treatment method comprises administering to a subject in need thereof at least one additional active agent in the form of a single pharmaceutical composition with at least one compound selected from the group consisting 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 thereof, or in the form of separate compositions. In specific embodiments, the method comprises administering to a subject in need thereof at least one additional active agent in the form of a single pharmaceutical composition with at least one compound selected from the group consisting of Compounds 1-262, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts thereof, or in the form of 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.

[0055] Also provided are methods for regulating AAT, comprising administering to a subject in need thereof at least one compound selected from the group consisting of 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 methods for regulating AAT comprise administering at least one compound selected from the group consisting of compounds 1-262, 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.

[0056] Also provided are compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, or VIIIa-c, as well as tautomers of these compounds, deuterated derivatives and tautomers of these compounds, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a compound 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 is provided for use in therapy.

[0057] Also provided are pharmaceutical compositions for use in therapy comprising a compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, or VIIIa-c, tautomers thereof, deuterated derivatives thereof, and tautomers thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, pharmaceutical compositions for use in therapy comprising a compound selected from Compounds 1-262, tautomers thereof, deuterated derivatives thereof and tautomers thereof, and a pharmaceutically acceptable salt thereof are provided.

[0058] definition

[0059] As used herein, the term "AAT" means alpha-1 antitrypsin or a mutation thereof, including but not limited to AAT gene mutations, such as the Z mutation. As used herein, "Z-AAT" means an AAT mutant having the Z mutation.

[0060] As used herein, "mutation" can refer to the effect of a mutation or gene sequence change in the SERPINA1 gene (a gene encoding AAT) on AAT protein. "SERPINA1 gene mutation" refers to a mutation in the SERPINA1 gene, and "AAT protein mutation" refers to a mutation that produces a change in the amino acid sequence of the AAT protein. A change in the nucleotides in a gene defect or mutation or gene typically produces a mutation in the AAT protein translated from this gene.

[0061] As used herein, a patient who is "homozygous" for a particular gene mutation has the same mutation on each allele.

[0062] As used herein, a patient with the PiZZ genotype is a patient who is homozygous for the Z mutation in the AAT protein.

[0063] As used herein, the term "AATD" means alpha-1 antitrypsin deficiency, a genetic disorder characterized by low circulating levels of AAT.

[0064] 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 specified 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 there may be isotopic differences between the constituent atoms of the molecule. Thus, it will be clear to those skilled in the art that a compound represented by a specific chemical structure containing an indicated deuterium atom will also contain a smaller amount of isotopologues having hydrogen atoms at one or more designated deuterium positions in the structure. The relative amount of such isotopologues in the compounds of the present disclosure will depend on many factors, including the isotopic purity of the reagents used to prepare the compound and the incorporation efficiency of the isotopes in the various synthetic steps used to prepare the compound. However, as explained above, the relative amount of all such isotopologues will be less than 49.9% of the compound. In other embodiments, the relative amount of all such isotopologues 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.

[0065] The compounds of the present disclosure may optionally be substituted with one or more substituents. It should be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". Generally speaking, the term "substituted", whether or not preceded by the term "optionally", refers to the replacement of hydrogen groups in a given structure with a group of a specific 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 by more than one substituent selected from a specified group, the substituent at each position may be the same or different. The combination of substituents contemplated by the present disclosure is a combination of substituents that results in the formation of stable or chemically feasible compounds.

[0066] The term "isotopologue" refers to a substance whose chemical structure differs from a specific compound of the present disclosure only in its isotopic composition. Additionally, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium, or replacing 13 C or 14 Compounds having the present structures except for the substitution of C for a carbon are within the scope of this disclosure.

[0067] Unless otherwise indicated, structures depicted herein are also intended to include all isomeric forms of the structures, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the compounds of the present invention are within the scope of this disclosure. Unless otherwise indicated, all tautomeric forms of the compounds of the present disclosure are within the scope of this disclosure.

[0068] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by migration of atoms or groups within the molecule.

[0069] "Stereoisomers" refers to both enantiomers and diastereomers.

[0070] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound but in which one or more hydrogen atoms are replaced by a deuterium atom ("D"). It will be recognized that, depending on the source of the chemical materials used in the synthesis, there is some variation in natural isotopic abundance in the synthesized compounds. Despite this variation, the concentration of the naturally abundant stable hydrogen isotope is small and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described herein. Therefore, unless otherwise indicated, when referring to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen is replaced by deuterium at a level well above its natural isotopic abundance (typically about 0.015%). In some embodiments, the deuterated derivatives of the present disclosure have an isotopic enrichment factor per 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).

[0071] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0072] As used herein, the term "alkyl" means a straight (i.e., straight or unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or may contain one or more saturated units, but is not fully aromatic. Unless otherwise indicated, an alkyl group contains 1-12 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-10 aliphatic carbon atoms. In other embodiments, an alkyl group contains 1-8 aliphatic carbon atoms. In other embodiments, an alkyl group contains 1-6 alkyl carbon atoms, in other embodiments, an alkyl group contains 1-4 alkyl carbon atoms, and in other embodiments, an alkyl group contains 1-3 alkyl carbon atoms.

[0073] As used herein, the term "heteroalkyl" refers to an aliphatic group in which one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus or silicon. The heteroalkyl group may be substituted or unsubstituted, branched or unbranched.

[0074] As used herein, the term "alkenyl" means a straight chain (ie, linear or unbranched), branched, substituted or unsubstituted hydrocarbon chain containing one or more carbon-carbon double bonds.

[0075] The terms "cycloalkyl", "carbocycle" and "cyclic alkyl" refer to fused, spirocyclic, monocyclic or bridged monocyclic C 3-9 hydrocarbon, or fused, spiro, bicyclic, bridged bicyclic, tricyclic or bridged tricyclic C 8-14 Hydrocarbon, it is fully saturated or contains one or more unsaturated units, but is not fully aromatic, wherein any single ring in the bicyclic system has 3-9 members. Usually, cycloalkyl is fully saturated, and carbocyclic ring can contain one or more unsaturated units, but is not aromatic. In some embodiments, cycloalkyl or carbocyclic group contains 3 to 12 carbon atoms. In some embodiments, cycloalkyl or carbocyclic group contains 3 to 8 carbon atoms. In some embodiments, cycloalkyl or carbocyclic group contains 3 to 6 carbon atoms.

[0076] 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, one or more of which 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, the heterocyclyl group contains 3 to 12 ring member atoms. In some embodiments, the heterocyclyl group contains 3 to 8 ring member atoms. In some embodiments, the heterocyclyl group contains 3 to 6 ring member atoms.

[0077] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; a quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0078] As used herein, the term "alkoxy" refers to an alkyl group as defined above, wherein one of the carbon atoms of the alkyl group is replaced by an oxygen ("alkoxy") atom, provided that the oxygen atom is attached between two carbon atoms. "Cyclic alkoxy" refers to a monocyclic, fused, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon ring 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.

[0079] The terms "haloalkyl" and "haloalkoxy" refer to an alkyl or alkoxy group, as the case may be, substituted with one or more halogen atoms. The term "halogen" may refer to F, Cl, Br, or I. In some embodiments, halogen is selected from F, Cl, and Br. Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CF2-, and perhaloalkyl groups, such as -CF2CF3.

[0080] As used herein, "=0" refers to an oxo group.

[0081] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0082] As used herein, "hydroxy" refers to -OH.

[0083] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system having a delocalized π electron orbital consisting of [4n+2]p orbital electrons, where n is an integer from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl.

[0084] The term "aryl" refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, an aryl group contains 6 or 10 carbon atoms. A non-limiting example of an aryl group is a benzene ring.

[0085] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, the heteroaryl group contains 6 or 10 ring atoms.

[0086] Examples of useful protecting groups for nitrogen-containing groups such as amidos include, for example, tert-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylamine, and p-toluenesulfonamide. Methods for adding (commonly referred to as the process of "protection") and removing (commonly referred to as the process of "deprotection") such amine protecting groups are well known in the art and can be obtained in, for example, PJ Kocienski, Protecting Groups, Thieme, 1994, which is incorporated herein by reference in its entirety, and in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition (John Wiley & Sons, New York, 1999).

[0087] Examples of suitable solvents that can be used in the present disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CH2Cl2), 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 (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0088] 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 (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropylethylamine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).

[0089] The present disclosure includes pharmaceutically acceptable salts of the disclosed compounds.Salts of a compound are formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.

[0090] As used herein, the term "pharmaceutically acceptable" refers to a composition that is suitable for contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. "Pharmaceutically acceptable salt" means any non-toxic salt that, when administered to a recipient, is capable of providing, directly or indirectly, a compound of the present disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge et al. J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0091] 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, ditartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Thus, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propionates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioic acid, Pharmaceutically acceptable acid addition salts include, but are not limited to, 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 inorganic acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0092] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4alkyl) 4 salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Other 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, low-carbon alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0093] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0094] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of a compound that produces the desired effect for which the compound is administered (e.g., improving AATD or AATD symptoms, reducing the severity of AATD or AATD symptoms, and / or reducing the onset or incidence of AATD or AATD symptoms). The exact amount of an effective dose will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0095] As used herein, the term "treating" and its cognates refer to improving a subject's AATD or a symptom thereof, delaying the onset of a subject's AATD or a symptom thereof, or reducing the severity of a subject's AATD or a symptom thereof. As used herein, "treating" and its cognates include, but are not limited to, improving liver and / or spleen function, reducing jaundice, improving lung function, reducing lung disease and / or lung exacerbation (e.g., emphysema), reducing skin diseases (e.g., necrotizing panniculitis), increasing growth in children, improving appetite, and reducing fatigue. The improvement of any of these symptoms or the reduction of their severity can be readily assessed according to methods and techniques known in the art or subsequently developed.

[0096] When used in conjunction with the dose, amount, or weight percentage of an ingredient of a composition or dosage form, the terms "about" and "approximately" include a value of a specified dose, amount, or weight percentage, or a range of such doses, amounts, or weight percentages, that one of ordinary skill in the art would recognize as providing a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percentage. Typically, the term "about" refers to a variation of up to 10%, up to 5%, or up to 2% of a given value.

[0097] 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 a specific embodiment, a compound selected from Compound 1-262, its tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered once a day. In some embodiments, at least one compound selected from Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, its tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered twice a day. In a specific embodiment, a compound selected from Compound 1-262, its tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered twice a day. In some embodiments, at least one compound selected from Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c, its tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered three times a day. In a specific embodiment, a compound selected from Compound 1-262, a tautomer thereof, a deuterated derivative of these compounds or tautomers, and a pharmaceutically acceptable salt of any of the foregoing is administered three times daily.

[0098] 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 are selected from Compounds 1-262, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0099] 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) the level of alpha-1 antitrypsin circulating in the blood. "AAT replacement therapy" refers to the administration of recombinant AAT.

[0100] It should be understood that 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), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds) should also be construed as references to:

[0101] - one or more compounds (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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds) for use in a method of treating, for example, AATD; and / or

[0102] - Use of one or more compounds (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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds) in the preparation of a medicament for treating, for example, AATD.

[0103] Example implementation:

[0104] Some non-limiting embodiments of the present disclosure include:

[0105] 1. A compound represented by formula I

[0106]

[0107] (I)

[0108] or a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0109] Z 1 , Z 2 and Z 3 are each independently -N, -NH or -CH; provided that Z 1 , Z 2 and Z 3 At least one of is N or -NH;

[0110] V 1 and V 2 are each selected from C and N;

[0111] W 1 and W 2 Each selected from -C=O, -CR 2 , N and -NR 2 ,in:

[0112] When W 1 -CR 2 When W 2 is N;

[0113] When W 2 -CR 2 When W 1 N or -NR 2 ;

[0114] When W 1 When -C=O, then W 2 -NR 2 ;and

[0115] When W 2 When -C=O, then W 1 -NR 2 ;

[0116] For each of the two cases, a single bond or a double bond, provided that one is a single bond and the other is a double bond;

[0117] (h) is a double bond, the difference is that when W 1 and W 2 When any one of is -C=O, (h) is a single bond;

[0118] R 0 Halogen or in:

[0119] Ring A is C3-C 12 Carbocyclic group, 3 to 12 membered heterocyclic group, C6 or C 10 aryl or 5- to 10-membered heteroaryl;

[0120] R 1 is halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(=O)R z ,

[0121] -C(=O)OR z 、-C(=O)NR w R x 、-NR w Rx 、-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 heterocyclic group; wherein:

[0122] R 1 The C1-C6 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from the following:

[0123] -OR z , C1-C3 haloalkyl, -CN and halogen; and

[0124] R w 、R x 、R y and R z Each is independently hydrogen or C1-C4 alkyl;

[0125] X 1 and X 2 Each is 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;

[0126] R 2 For hydrogen, halogen, in:

[0127] T is absent or a bond, or is selected from -O-, -OCH2-, -NH-, -NS(=O)2CH3, -S- and -CH2-;

[0128] Y is selected from 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,

[0129] -(CRa 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; of which:

[0130] R a is independently at each occurrence hydrogen, halogen, -OH or C1-C4 alkyl optionally substituted with 1 to 3 groups selected from halogen and -OH;

[0131] Or alternatively, when R a When each occurrence is C1-C4 alkyl, the two R a The groups together with their intervening carbon atoms form a cyclopropyl or cyclobutyl group;

[0132] R b and R c is independently hydrogen or C1-C2 alkyl at each occurrence; and

[0133] p and q are each independently an integer selected from 1 and 2;

[0134] Ring B is C3-C 12 Carbocyclic group, 3 to 12 membered heterocyclic group, C6 or C 10 aryl or 5- to 10-membered heteroaryl;

[0135] R 3 -C(=O)OR d ; where R d is C1-C4 alkyl, which is optionally substituted with -OC(O)R e 、-OC(=O)OR e OR-OP(=O)OR f R f Replace; of which:

[0136] R e is independently at each occurrence hydrogen, -CH3 or -C2H5;

[0137] R f is independently at each occurrence -OH, -CH3, -C2H5, -OCH3 or

[0138] -OC2H5;

[0139] R kis halogen, -CN, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy or O-(C3-C6 cycloalkyl);

[0140] R m is independently at each occurrence 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 heterocyclic group, phenyl or 5 or 6-membered heteroaryl,

[0141] where R m The C1-C6 alkyl, phenyl or 5- or 6-membered heteroaryl is optionally substituted by 1 to 3 groups selected from the following: halogen, CN, -C(=O)OR r 、-NR p R q AND-OR r ;and

[0142] where R m The C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted by 1 to 3 groups selected from the group consisting of halogen, CN, ═O, —C(═O)OR r 、-NR p R q AND-OR r ;

[0143] where R p and R q is independently at each occurrence hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 groups selected from the group consisting of: -OH, -OCH3, -OC2H5 and -COOH;

[0144] where R rEach occurrence is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or 3 to 6 membered heterocyclyl; wherein R r The C1-C4 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from the group consisting of -OH, -OCH3, -OC2H5, -CH2OH, -C(=O)OH, -(O)C(=O)OH and -(O)P(=O)(OH)2; and

[0145] where R s and R t is independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy or -OH at each occurrence;

[0146] k and m are each independently an integer selected from 0, 1, 2, 3, 4 and 5; and

[0147] n is an integer selected from 0, 1 and 2.

[0148] 2. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to embodiment 1, wherein Z 1 , Z 2 and Z 3 Wherein both are N or -NH; n is an integer selected from 0 and 1; and wherein all other variables not specifically defined herein are as defined in the previous embodiment.

[0149] 3. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to embodiment 1 or embodiment 2, which is represented by formula II

[0150]

[0151] in:

[0152] R 3 -C(=O)OR d ; where R d is C1-C4 alkyl, which is optionally substituted with -OC(O)R e 、-OC(=O)OR e OR-OC(=O)OR f R f Replace; of which:

[0153] R e is independently hydrogen or -CH3 at each occurrence;

[0154] R f is independently at each occurrence -OH, -CH3 or -OCH3;

[0155] n is an integer selected from 0 and 1;

[0156] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0157] 4. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 3, which is represented by formula IIIa, IIIb, IIIc or IIId

[0158]

[0159] in:

[0160] Ring A is optionally replaced by R k substituted and Ring A is a 5- or 6-membered carbocyclyl, phenyl, or a 5- or 6-membered heteroaryl;

[0161] R 1 C1-C6 alkyl, C1-C6 alkoxy-C(=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 heterocyclic group; wherein:

[0162] R 1 The C1-C6 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from the following: -OR z and halogens; and

[0163] R w 、R x 、R y and R z Each is independently hydrogen or C1-C4 alkyl;

[0164] X 1 and X 2 Each is independently hydrogen, halogen, -CN, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy or C3-C4 cycloalkyl;

[0165] R 2 As defined in embodiment 1, except that when R 2 for When ring B is optionally replaced by R m substituted and Ring B is C4-C9 carbocyclyl, phenyl, 4- to 9-membered heterocyclyl, or 5- to 6-membered heteroaryl;

[0166] R 3Absent or -C(=O)O(CH2)2(O)P(=O)(OH)2;

[0167] R k is halogen, -CN, -CH3, C1 haloalkyl or -OCH3;

[0168] n is an integer selected from 0 and 1;

[0169] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0170] 5. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 4, which is represented by Formula IVa, IVb or IVc

[0171]

[0172] where X 1 is hydrogen, halogen, -CH3, -CHF2, -CH2F, or -OCH3; and wherein all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0173] 6. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of Embodiments 1 to 5, which is represented by Formula Va, Vb or Vc:

[0174]

[0175] in:

[0176] R 1 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 heterocyclic group; wherein:

[0177] R 1 The C1-C4 alkyl, cyclopropyl, cyclobutyl or 5- or 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from the following: -OR z and halogens; and

[0178] R w 、R x 、R y and R z Each is independently hydrogen or C1-C2 alkyl;

[0179] T is absent or selected from -O-, -OCH2-, -NH- and -CH2-;

[0180] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0181] 7. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 6, wherein Ring A is optionally replaced by R k substituted, and Ring A is phenyl, cyclohexenyl, 3,6-dihydro-2H-pyranyl, pyridinyl, pyridazinyl, thienyl, or pyrazolyl; and wherein all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0182] 8. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 7, wherein Ring A is optionally replaced by R k is substituted, and Ring A is selected from:

[0183] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0184] 9. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 8, wherein Ring A is optionally replaced by R k substituted, and ring A is selected from And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0185] 10. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 9, wherein when R 2 for When ring B is optionally replaced by R m substituted, and Ring B is selected from the group consisting of 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 wherein all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0186] 11. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 10, wherein

[0187] R 2 for

[0188] Ring B is optionally replaced by R m substituted, and ring B is selected from

[0189] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0190] 12. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 11, wherein

[0191] R 2 for

[0192] Ring B is optionally replaced by R m substituted, and ring B is selected from

[0193] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0194] 13. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 12, wherein R m is independently at each occurrence 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 a 5- or 6-membered heterocyclic group; wherein:

[0195] R m The C1-C6 alkyl group is optionally substituted by 1 to 3 groups selected from the group consisting of: -C(=O)OH, -C(=O)OCH3, -C(=O)OC2H5, -OH, -OCH3, and -OC2H5; and R m The 5- or 6-membered heterocyclyl is optionally substituted by 1 to 3 groups selected from the group consisting of halogen, ═O, —C(═O)OH, and —OH; wherein:

[0196] R p and R q is independently at each occurrence hydrogen or C1-C3 alkyl optionally substituted with 1 to 3 groups selected from the group consisting of: -OH, -OCH3 and -C(=O)OH;

[0197] R r Each occurrence is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl; wherein R r The C1-C2 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from the group consisting of -OH, -OCH3, -OC2H5, -C(=O)OH, -(O)C(=O)OH and -(O)P(=O)(OH)2; and

[0198] R s and R t is independently at each occurrence hydrogen, C1-C2 alkyl, C1-C2 alkoxy or -OH;

[0199] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0200] 14. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 13, wherein R m is independently at each occurrence 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; wherein:

[0201] R m The C1-C4 alkyl group is optionally substituted by 1 to 3 groups selected from the group consisting of: -C(=O)OH, -C(=O)OCH3, -C(=O)OC2H5, -OH, -OCH3, and -OC2H5; and R m The imidazolidinyl or morpholinyl group is optionally substituted with 1 to 3 groups selected from the group consisting of oxo (=O) and -OH; wherein:

[0202] R p and R q is independently at each occurrence hydrogen or C1-C3 alkyl optionally substituted with 1 to 3 groups selected from the group consisting of: -OH, -OCH3 and -C(=O)OH;

[0203] R r is independently hydrogen, C1-C2 alkyl, cyclopropyl, oxetanyl or azetidinyl at each occurrence; wherein R r The C1-C2 alkyl, cyclopropyl, oxetanyl or azetidine group is optionally substituted with 1 to 3 groups selected from the group consisting of -OH, -CH2OH, -C(=O)OH and -(O)P(=O)(OH)2; and

[0204] R s and R t Each time it occurs, it is independently

[0205] -CH3, -OCH3 or -OH;

[0206] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0207] 15. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 14, wherein R m In each occurrence, independently

[0208] -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)oxy -C(=O)(hydroxy)azetidin-3-yl, -C(=O)(hydroxy)cyclopropyl, -C(=O)CH(OH)CH, -C(=O)OCH, -OCH, -CHCOOH, -CN, -OCHCOOH, -OCH(CH)COOH, -CH(CH)COOH, Cl, S(=O)CH, S(=O)NHCH, -CHC(=O)OCH, -C(=O)OCH(O)P(=O)(OH), -C(=O)NHCH(CH)COOH, -C(=O)NHCH, -C=O(3-hydroxyazetidin-1-yl), and -C(=O)(morpholin-4-yl; and wherein all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0209] 16. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 15, wherein at least one occurrence of R m is -COOH, -CH2COOH, -OCH2COOH, -OCH(CH3)COOH, -CH(CH3)COOH, -C(=O)OCH2(O)P(=O)(OH)2, or -C(=O)NHCH(CH3)COOH; and wherein all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0210] 17. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of Embodiments 1 to 16, which is represented by Formula VIa, VIb or VIc

[0211]

[0212] All other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0213] 18. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 17, wherein R 1 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 heterocyclic group; wherein:

[0214] R 1 The C1-C3 alkyl, cyclopropyl, cyclobutyl or tetrahydro-2H-pyran-4-yl is optionally substituted with 1 to 3 groups selected from the group consisting of -OH, -OCH3, C1-C2 haloalkyl, -CN and halogen;

[0215] R w 、R x 、R y and R z are each independently hydrogen or -CH3;

[0216] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0217] 19. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 18, wherein 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; wherein R 1 The cyclopropyl or cyclobutyl is optionally substituted with -OH, -OCH 3 or -CF 3 ; and wherein all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0218] 20. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of Embodiments 1 to 19, which is represented by Formula VIIa, VIIb, VIIc, VIId, VIIe or VIIf

[0219]

[0220]

[0221] All other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0222] 21. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 5, which is represented by Formula VIIIa, VIIIb or VIIIc

[0223]

[0224] in:

[0225] Ring A is optionally replaced by R k substituted and Ring A is phenyl or a 5- or 6-membered heteroaryl;

[0226] T is absent or selected from -O-, -NH- and -CH2-;

[0227] 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; wherein:

[0228] R a is independently at each occurrence hydrogen, -OH, -CH3 or -CH2OH; and

[0229] R b and R c is independently hydrogen or -CH3 at each occurrence;

[0230] and wherein all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5.

[0231] 22. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1 to 5 and 21, wherein is -NHCH3,

[0232] -CH2COOH, -(CH2)2COOH, -CH(CH3)CH2COOH, -NHCH(CH3)COOH, -OCH2COOH, -O(CH2)2(O)CH2COOH, -CH2CH(CH3)COOH, -OCH(CH3)C(=O)NHCH2COOH or

[0233] -OCH(CH2OH)CH2NHS(=O)2(CH2)2OH; and wherein all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5 and 21.

[0234] 23. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 5, 21 and 22, wherein Ring A is optionally replaced by R k substituted, and Ring A is phenyl or pyridinyl; and wherein all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5, 21 and 22.

[0235] 24. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 5 and 21 to 23, wherein Ring A is optionally replaced by R k substituted, and Ring A is And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5 and 21 to 23.

[0236] 25. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 5 and 21 to 23, wherein ring A is selected from

[0237]

[0238] And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5 and 21 to 23.

[0239] 26. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 5 and 21 to 23, wherein ring A is selected from

[0240] And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5 and 21 to 23.

[0241] 27. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 5 and 21 to 26, wherein R 1 Halogen, -CN, C1-C3 alkyl, C1-C3 alkoxy, -NR w R x 、-OR z , C3-C6 cycloalkyl or 5- or 6-membered heterocyclic group; wherein:

[0242] R 1 The C1-C3 alkyl, C3-C6 cycloalkyl or 5- or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from the group consisting of -OH, -OCH3, C1-C2 haloalkyl, -CN and halogen; and

[0243] R w 、R x 、R y and R z are each independently hydrogen or -CH3;

[0244] And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5 and 21 to 26.

[0245] 28. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 5 and 21 to 26, wherein R 1 is a C1-C3 alkyl group or a 6-membered heterocyclic group; wherein:

[0246] R 1 The C1-C3 alkyl or 5- or 6-membered heterocyclyl is optionally substituted by 1 to 3 groups selected from the group consisting of -OH, -OCH3, C1-C2 haloalkyl and halogen;

[0247] And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5 and 21 to 26.

[0248] 29. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 5 and 21 to 26, wherein R 1 is -C(CH3)2 or tetrahydro-2H-pyran-4-yl; and wherein all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5 and 21 to 26.

[0249] 30. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 5 and 21 to 26, wherein R 1 Selected from

[0250] All other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5 and 21 to 26.

[0251] 31. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 5 and 21 to 26, wherein R 1 Selected from

[0252] And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5 and 21 to 26.

[0253] 32. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 5 and 21 to 31, wherein R 2 Selected from

[0254] And wherein all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5 and 21 to 31.

[0255] 33. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 5 and 21-31, wherein R 2 Selected from And wherein all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5 and 21 to 31.

[0256] 34. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Embodiments 1 to 32, wherein:

[0257] X 1 is hydrogen, F or -CH3;

[0258] R k is F, Cl, -CH3 or -OCH3; and

[0259] k is an integer selected from 0, 1 and 2.

[0260] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0261] 35. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Embodiments 1 to 34, wherein the compound is selected from the compounds of Table 1.

[0262] 36. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of Embodiments 1 to 35 and a pharmaceutically acceptable carrier.

[0263] 37. A method of modulating alpha-1 antitrypsin (AAT) activity in a subject comprising administering a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 35, or a pharmaceutical composition according to Embodiment 36.

[0264] 38. Use of a compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 35 for the preparation of a medicament for modulating AAT activity.

[0265] 39. The pharmaceutical composition according to embodiment 36, which is used for modulating AAT activity.

[0266] 40. A method of treating alpha-1 antitrypsin deficiency (AATD) in a subject comprising administering a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 35, or a pharmaceutical composition according to Embodiment 36.

[0267] 41. Use of a compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 35 for the preparation of a medicament for treating AATD.

[0268] 42. The pharmaceutical composition according to embodiment 36, for use in the treatment of AATD.

[0269] 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, tautomers thereof, 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 specific 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 Compound 1-262, a tautomer thereof, a deuterated derivative of these compounds or tautomers, and a pharmaceutically acceptable salt of any of the foregoing is administered once a day, twice a day, or three times a day.

[0270] Those skilled in the art will recognize that when disclosing the amount of a compound, the relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the free base concentration of the compound. Note that the disclosed amounts of the compounds, tautomers, deuterated derivatives, and pharmaceutically acceptable salts disclosed herein are based on the free base form of the reference compound. For example, "10 mg of at least one compound selected from the group consisting of compounds of formula (I) and pharmaceutically acceptable salts 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).

[0271] II. Compounds and compositions

[0272] Some embodiments of the present disclosure provide compounds represented by Formula I:

[0273]

[0274] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0275] Z 1 , Z 2 and Z 3 are each independently N, -NH or -CH; provided that Z 1 , Z 2 and Z 3 At least one of is N or -NH;

[0276] V 1 and V2 are each selected from C and N;

[0277] W 1 and W 2 Each selected from -C=O, -CR 2 , N and -NR 2 ,in:

[0278] When W 1 -CR 2 When W 2 is N;

[0279] When W 2 -CR 2 When W 1 N or -NR 2 ;

[0280] When W 1 When -C=O, then W 2 -NR 2 ;and

[0281] When W 2 When -C=O, then W 1 -NR 2 ;

[0282] For each of the two cases, a single bond or a double bond, provided that one is a single bond and the other is a double bond;

[0283] (h) is a double bond, the difference is that when W 1 and W 2 When any one of is -C=O, (h) is a single bond;

[0284] R 0 Halogen or in:

[0285] Ring A is C3-C 12 Carbocyclic group, 3 to 12 membered heterocyclic group, C6 or C 10 aryl or 5- to 10-membered heteroaryl;

[0286] 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 、-NRw 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 heterocyclic group; wherein:

[0287] R 1 The C1-C6 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from the following: -OR z , C1-C3 haloalkyl, -CN and halogen; and

[0288] R w 、R x 、R y and R z Each is independently hydrogen or C1-C4 alkyl;

[0289] X 1 and X 2 Each is 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;

[0290] R 2 For hydrogen, halogen, in:

[0291] T is absent or a bond, or is selected from -O-, -OCH2-, -NH-, -NS(=O)2CH3, -S- and -CH2-;

[0292] Y is selected from 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 -(CRa R a ) p (O)(CR c R c ) q COOH; wherein:

[0293] R a is independently at each occurrence hydrogen, halogen, -OH or C1-C4 alkyl optionally substituted with 1 to 3 groups selected from halogen and -OH;

[0294] Or alternatively, when R a When each occurrence is C1-C4 alkyl, the two R a The groups together with their intervening carbon atoms form a cyclopropyl or cyclobutyl group;

[0295] R b and R c is independently hydrogen or C1-C2 alkyl at each occurrence; and

[0296] p and q are each independently an integer selected from 1 and 2;

[0297] Ring B is C3-C 12 Carbocyclic group, 3 to 12 membered heterocyclic group, C6 or C 10 aryl or 5- to 10-membered heteroaryl;

[0298] R 3 -C(=O)OR d ; where R d is C1-C4 alkyl, which is optionally substituted with -OC(O)R e 、-OC(=O)OR e OR-OP(=O)OR f R f Replace; of which:

[0299] R e is independently at each occurrence hydrogen, -CH3 or -C2H5;

[0300] R f is independently at each occurrence -OH, -CH3, -C2H5, -OCH3 or -OC2H5;

[0301] R k is halogen, -CN, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy or O-(C3-C6 cycloalkyl);

[0302] R m is independently at each occurrence halogen, -CN, ═O, C1-C6 alkyl, C1-C6 alkoxy, -C(═O)Rr 、-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 heterocyclic group, phenyl or 5 or 6-membered heteroaryl,

[0303] where R m The C1-C6 alkyl, phenyl or 5- or 6-membered heteroaryl is optionally substituted by 1 to 3 groups selected from the following: halogen, -CN, -C(=O)OR r 、-NR p R q AND-OR r ;and

[0304] where R m The C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted by 1 to 3 groups selected from the group consisting of halogen, CN, ═O, —C(═O)OR r 、-NR p R q AND-OR r ;

[0305] where R p and R q is independently at each occurrence hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 groups selected from the group consisting of: -OH, -OCH3, -OC2H5 and -COOH;

[0306] where R r Each occurrence is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or 3 to 6 membered heterocyclyl; wherein R r The C1-C4 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from the group consisting of -OH, -OCH3, -OC2H5, -CH2OH, -C(=O)OH, -(O)C(=O)OH and -(O)P(=O)(OH)2; and

[0307] where R s and R t is independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy or -OH at each occurrence;

[0308] k and m are each independently an integer selected from 0, 1, 2, 3, 4 and 5; and

[0309] n is an integer selected from 0, 1 and 2.

[0310] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, Z 1 , Z 2 and Z 3 Both of them are N or -NH, and n is an integer selected from 0 and 1.

[0311] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, R 0 It's Cl.

[0312] 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:

[0313]

[0314] in:

[0315] R 3 -C(=O)OR d ; where R d is C1-C4 alkyl optionally substituted -OC(O)R e 、-OC(=O)OR e OR-OC(=O)OR f R f ;in:

[0316] R e is independently hydrogen or -CH3 at each occurrence;

[0317] R f is independently at each occurrence -OH, -CH3 or -OCH3;

[0318] n is an integer selected from 0 and 1;

[0319] And all other variables not specifically defined herein are as defined for Formula I.

[0320] 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 (“Formula IIIa-d”):

[0321]

[0322] in:

[0323] Ring A is optionally replaced by R k substituted and Ring A is a 5- or 6-membered carbocyclyl, phenyl, or a 5- or 6-membered heteroaryl;

[0324] R 1 C1-C6 alkyl, C1-C6 alkoxy-C(=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 heterocyclic group; wherein:

[0325] R 1 The C1-C6 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from the following: -OR z and halogens; and

[0326] R w 、R x 、R y and R z Each is independently hydrogen or C1-C4 alkyl;

[0327] 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;

[0328] R 2 As defined in formula I, but when R 2 for When ring B is optionally replaced by R m substituted and Ring B is selected from C4-C9 carbocyclyl, phenyl, 4- to 9-membered heterocyclyl, and 5- to 6-membered heteroaryl;

[0329] R 3 Absent or -C(=O)O(CH2)2(O)P(=O)(OH)2;

[0330] Rk is halogen, -CN, -CH3, C1 haloalkyl or -OCH3;

[0331] n is an integer selected from 0 and 1;

[0332] And all other variables not specifically defined herein are as defined for Formula I or Formula II.

[0333] 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 (“Formula IVa-c”):

[0334]

[0335] where X 1 is hydrogen, halogen, -CH3, -CHF2, -CH2F, or -OCH3; and wherein all other variables not specifically defined herein are as defined for Formula I, Formula II, or Formula IIIa-d.

[0336] 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 Vac”):

[0337]

[0338] in:

[0339] R 1 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 heterocyclic group; wherein:

[0340] R 1 The C1-C4 alkyl, cyclopropyl, cyclobutyl or 5- or 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from the following: -OR z and halogens; and

[0341] R w 、R x 、R y and R z Each is independently hydrogen or C1-C2 alkyl;

[0342] T is absent or selected from -O-, -OCH2-, -NH- and -CH2-;

[0343] And all other variables not specifically defined herein are as defined for Formula I, Formula II, Formula IIIa-d, or Formula IVa-c.

[0344] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Formulas I, II, IIIa-d, IVa-c, and Va-c, Ring A is optionally replaced by R k substituted and selected from phenyl, cyclohexenyl, 3,6-dihydro-2H-pyranyl, pyridyl, pyridazinyl, thienyl and pyrazolyl.

[0345] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Formulas I, II, IIIa-d, IVa-c, and Va-c, Ring A is optionally replaced by R k Replaced and selected from:

[0346]

[0347] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Formulas I, II, IIIa-d, IVa-c, and Va-c, Ring A is optionally replaced by R k Replaced and selected from:

[0348]

[0349] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Formulas I, II, IIIa-d, IVa-c, and Va-c, R 2 for

[0350]

[0351] Ring B is optionally replaced by R m is substituted and Ring B is selected from the group consisting of isoindolinyl, azaspiro[3.4]octanyl, spiro[3.3]heptyl, azaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, azabicyclo[3.2.0]heptyl, phenyl, cyclohexenyl, cyclohexyl, pyridinyl, piperidinyl, morpholinyl, tetrahydro-2H-pyranyl, thiazolyl, pyrazolyl, furanyl, tetrahydrofuranyl, cyclopentyl, bicyclo[1.1.1]pentyl, pyrrolidinyl, cyclobutyl, azetidinyl and cyclopropyl.

[0352] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Formulas I, II, IIIa-d, IVa-c, and Va-c, R 2 for

[0353]

[0354] Ring B is optionally replaced by R m substituted, and ring B is selected from

[0355]

[0356] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Formulas I, II, IIIa-d, IVa-c, and Va-c, R 2 for

[0357]

[0358] Ring B is optionally replaced by R m substituted, and ring B is selected from

[0359]

[0360] 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 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 and 5-membered and 6-membered heterocyclic groups; wherein:

[0361] R mThe C1-C6 alkyl group is optionally substituted by 1 to 3 groups selected from the group consisting of: -C(=O)OH, -C(=O)OCH3, -C(=O)OC2H5, -OH, -OCH3, and -OC2H5; and R m The 5- or 6-membered heterocyclyl is optionally substituted by 1 to 3 groups selected from the group consisting of halogen, ═O, —C(═O)OH, and —OH; wherein:

[0362] R p and R q is independently at each occurrence hydrogen or C1-C3 alkyl optionally substituted with 1 to 3 groups selected from the group consisting of: -OH, -OCH3 and -C(=O)OH;

[0363] R r Each occurrence is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl; wherein R r The C1-C2 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from the group consisting of -OH, -OCH3, -OC2H5, -C(=O)OH, -(O)C(=O)OH and -(O)P(=O)(OH)2; and

[0364] R s and R t Each occurrence is independently hydrogen, C1-C2 alkyl, C1-C2 alkoxy or -OH.

[0365] 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 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 Rt , imidazolidinyl and morpholinyl; wherein:

[0366] R m The C1-C4 alkyl group is optionally substituted by 1 to 3 groups selected from the group consisting of: -C(=O)OH, -C(=O)OCH3, -C(=O)OC2H5, -OH, -OCH3, and -OC2H5; and an imidazolidinyl or morpholinyl group R m is optionally substituted with 1 to 3 groups selected from oxo (=O) and -OH; wherein:

[0367] R p and R q is independently at each occurrence hydrogen or C1-C3 alkyl optionally substituted with 1 to 3 groups selected from the group consisting of: -OH, -OCH3 and -C(=O)OH;

[0368] R r is independently hydrogen, C1-C2 alkyl, cyclopropyl, oxetanyl or azetidinyl at each occurrence; wherein R r The C1-C2 alkyl, cyclopropyl, oxetanyl or azetidine group is optionally substituted with 1 to 3 groups selected from the group consisting of -OH, -CH2OH, -C(=O)OH and -(O)P(=O)(OH)2; and

[0369] R s and R t Each time it occurs, it is independently

[0370] -CH3, -OCH3 or -OH.

[0371] 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 mindependently selected from -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).

[0372] 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 Independently selected from -COOH, -CH2COOH, -OCH2COOH, -OCH(CH3)COOH, -CH(CH3)COOH, -C(=O)OCH2(O)P(=O)(OH)2 and -C(=O)NHCH(CH3)COOH.

[0373] 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 (“Formula VIa-c”):

[0374]

[0375] All other variables not specifically defined herein are as defined in any of Formulas I, II, IIIa-d, IVa-c, and Va-c.

[0376] In some embodiments, R in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Formula I, II, IIIa-d, IVa-c, Va-c, and VIa-c is 1 Selected from 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 heterocyclic group; wherein:

[0377] R 1 The C1-C3 alkyl, cyclopropyl, cyclobutyl or tetrahydro-2H-pyran-4-yl is optionally substituted with 1 to 3 groups selected from the group consisting of -OH, -OCH3, C1-C2 haloalkyl and halogen;

[0378] R w 、R x 、R y and R z are each independently hydrogen or -CH3.

[0379] In some embodiments, R in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Formula I, II, IIIa-d, IVa-c, Va-c, and VIa-c is 1 is selected from -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 and cyclobutyl; wherein R 1 The cyclopropyl or cyclobutyl groups are optionally substituted by -OH, -OCH3 or -CF3.

[0380] 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 Vila, Formula VIIb, Formula VIIc, Formula VIId, Formula VIIe, or Formula VIIf (“Formula Vila-f”):

[0381]

[0382]

[0383] All other variables not specifically defined herein are as defined in any of Formulas I, II, IIIa-d, IVa-c, Va-c, and VIa-c.

[0384] 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 (“Formula VIIIa-c”):

[0385]

[0386] in:

[0387] Ring A is optionally replaced by R k substituted and Ring A is phenyl or a 5- or 6-membered heteroaryl;

[0388] T is absent or selected from -O-, -NH- and -CH2-;

[0389] 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; wherein:

[0390] R a is independently at each occurrence hydrogen, -OH, -CH3 or -CH2OH; and

[0391] R b and R c is independently hydrogen or -CH3 at each occurrence;

[0392] And all other variables not specifically defined herein are as defined in any of Formulas I, II, IIIa-d, and IVa-c.

[0393] In some embodiments, the compound of Formula I, II, IIIa-d, IVa-c, or VIIIa-c, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof is Selected from -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.

[0394] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, or VIIIa-c, Ring A is optionally replaced by R k substituted phenyl or pyridyl.

[0395] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, or VIIIa-c, Ring A is Optionally R k replace.

[0396] In some embodiments, R in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, or VIIIa-c is 1 Selected from halogen, -CN, C1-C3 alkyl, C1-C3 alkoxy, -NR w R x 、-OR z , C3-C6 cycloalkyl and 5- or 6-membered heterocyclic group; wherein:

[0397] R 1 The C1-C3 alkyl, C3-C6 cycloalkyl or 5- or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from the group consisting of -OH, -OCH3, C1-C2 haloalkyl and halogen; and

[0398] R w 、R x 、R y and R z are each independently hydrogen or -CH3.

[0399] In some embodiments, R in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, or VIIIa-c is 1is a C1-C3 alkyl group or a 6-membered heterocyclic group; wherein:

[0400] 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.

[0401] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula I, II, IIIa-d, IVa-c, or VIIIa-c, R 1 It is -C(CH3)2 or tetrahydro-2H-pyran-4-yl.

[0402] In some embodiments of the compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f and VIIIa-c, tautomers, deuterated derivatives, or pharmaceutically acceptable salts:

[0403] X 1 is hydrogen, F or -CH3;

[0404] R k is F, Cl, -CH3 or -OCH3; and

[0405] k is an integer selected from 0, 1 and 2.

[0406] 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 as described in Table I below.

[0407] Table I. Compounds 1-262

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431] Some disclosed embodiments include derivatives of compounds 1-262 or compounds of formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c. In some embodiments, the derivative is a silicon derivative, wherein at least one carbon atom selected from the group consisting of compounds 1-262 or compounds of formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c has been replaced by silicon. In some embodiments, the derivative is a boron derivative, wherein at least one carbon atom selected from the group consisting of compounds 1-262 or compounds of formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c has been replaced by boron. In other embodiments, the derivative is a phosphate derivative, wherein at least one carbon atom selected from the group consisting of compounds 1-262 or compounds of formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c has been replaced by phosphorus. Because the general properties of silicon, boron, and phosphorus are similar to those of carbon, replacement of carbon with silicon, boron, or phosphorus can produce compounds with similar biological activity as the original carbon-containing compound.

[0432] In some embodiments, the derivative is a silicon derivative, wherein one carbon atom in a compound selected from compound I-262 or formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f and VIIIa-c has been 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, the quaternary carbon atom of the tert-butyl moiety can be replaced by silicon. In certain embodiments, the silicon derivative of the present disclosure can include one or more hydrogen atoms replaced by deuterium. For example, one or more hydrogens (wherein carbon has been replaced by silicon) of the tert-butyl moiety can be replaced by deuterium. In other embodiments, the silicon derivative of a compound selected from compound I-262 or formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f and VIIIa-c can have silicon incorporated into a heterocycle.

[0433] Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound selected from any one of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c and compound 1-262, its tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any one of the foregoing. In some embodiments, at least one compound selected from Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, and VIIIa-c and compound 1-262, its tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any one of the foregoing are administered to a patient in need thereof.

[0434] 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, a disintegrant, a surfactant, a binder, and a lubricant.

[0435] It should also be understood that the pharmaceutical compositions of the present disclosure can be used in combination therapies; that is, the pharmaceutical compositions described herein may further comprise another active therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one 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 can be administered as a separate composition simultaneously with, before, or after a composition comprising at least one other active agent. In a specific embodiment, a pharmaceutical composition comprising at least one compound selected from compound 1-262, tautomers thereof, 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, before, or after a composition comprising at least one other active agent.

[0436] In some embodiments, a compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, or VIIIa-c, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, or pharmaceutically acceptable salts of any of the foregoing are combined with at least one additional active agent for simultaneous, separate, or sequential use in the treatment of AATD. In some embodiments, when used simultaneously, a compound of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f, or VIIIa-c, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing and at least one additional active agent are in separate pharmaceutical compositions. In some embodiments, when used simultaneously, 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 a tautomer, or a pharmaceutically acceptable salt of any of the foregoing, and at least one additional active agent are present together in the same pharmaceutical composition. In some embodiments, the compound is a compound selected from Compounds 1-262, a tautomer of these compounds, a deuterated derivative of these compounds and a tautomer, and a pharmaceutically acceptable salt of any of the foregoing.

[0437] 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 for treating AATD, wherein the method comprises 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, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing.

[0438] In some embodiments, a compound of Formula, 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 a method of treating AATD. In some embodiments, the compound and the additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are co-administered simultaneously. In some embodiments, the compound and the additional active agent are co-administered sequentially. In some embodiments, the compound is selected from Compounds 1-262, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing.

[0439] In some embodiments, an additional active agent is provided for use in a method of treating AATD, wherein the method comprises co-administering an additional active agent and a compound of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), or (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives 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 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, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0440] 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 for 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 a separate pharmaceutical composition. 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 continuous co-administration. In some embodiments, the compound is selected from Compounds 1-262, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing.

[0441] In some embodiments, a compound of Formula, 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 a method 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 continuous co-administration. In some embodiments, the compound is selected from Compound 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.

[0442] In some embodiments, an additional active agent is provided for use in a method for treating AATD, wherein the additional active agent is prepared for administration in combination with a compound of 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 a tautomer, 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 a separate pharmaceutical composition. 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 continuous co-administration. In some embodiments, the compound is selected from compound 1-262, a tautomer of these compounds, a deuterated derivative of these compounds and a tautomer, and a pharmaceutically acceptable salt of any of the foregoing.

[0443] In some embodiments, the additional active agent is selected from the group consisting of alpha-1 antitrypsin protein (AAT) from the plasma of a healthy human donor and recombinant AAT. In some embodiments, the additional active agent is alpha-1 antitrypsin protein (AAT) from the plasma of a healthy human donor. In some embodiments, the additional active agent is alpha-1 antitrypsin protein (AAT) from the plasma of a healthy human donor.

[0444] As mentioned above, the pharmaceutical composition disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. At least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, dispersing aids, suspending aids, surfactants, isotonic 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, edited by D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York discloses various carriers for preparing pharmaceutical compositions and known techniques for preparing them. Unless any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, its use is contemplated to be within the scope of the present disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), mixtures of saturated plant fatty acid partial glycerides, water salts and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl acetate, cellulose acetate, cellulose glycol ...

[0014] The compositions herein include, but are not limited to, cellulose acetate and cellulose cellulose powder, tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), 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, ethanol, phosphate buffer, nontoxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants.

[0445] 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 carries a ZZ mutation. In some embodiments, the subject in need of treatment with the compounds and compositions of the present disclosure carries an SZ mutation.

[0446] In some embodiments, the methods of the present disclosure include administering to a patient in need thereof a compound selected from the group consisting of: any one 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 compound 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 the Z mutation in the alpha-1 antitrypsin gene.

[0447] Another aspect of the present disclosure provides a method for modulating the activity of alpha-1 antitrypsin, 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, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In a specific embodiment, the method for modulating the activity of alpha-1 antitrypsin comprises contacting the alpha-1 antitrypsin with at least one compound selected from compound 1-262, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0448] In some embodiments, the method for modulating alpha-1 antitrypsin activity is performed in vivo. In some embodiments, the method for 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 for 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 taken from a liver biopsy.

[0449] III. Preparation of compounds

[0450] All genera, subgenera, and specific compound formulae disclosed herein are considered to be part of this disclosure.

[0451] A. Compounds of Formula I

[0452] The compounds of the present disclosure can be prepared according to standard chemical practices or as described herein. In the following synthetic schemes and in the description of the preparation of compounds of Formula I, II, IIIa-d, IVa-c, Va-c, VIa-c, VIIa-f and VIIIa-c and compounds 1-262, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, the following abbreviations are used:

[0453] abbreviation

[0454] 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)phenylethylamine chloride

[0455] 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

[0456] CBzCl = benzyl chloroformate

[0457] Cphos=2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl

[0458] DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine

[0459] DMAP = dimethylaminopyridine

[0460] DMF = dimethylformamide

[0461] DMSO = dimethyl sulfoxide

[0462] EtOAc = Ethyl acetate

[0463] HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphorus hexafluoride ion)

[0464] IPA = Isopropyl alcohol

[0465] MeOH = methanol

[0466] MP-TMT Scavenger Resin = Macroporous polystyrene bound trimercaptotriazine, resin bound 2,4,6-trimercaptotriazine (TMT) equivalent.

[0467] MTBE = methyl tert-butyl ether

[0468] Pd(dppf)2Cl2=[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0469] PdCl2(PPh3)2=Bis(triphenylphosphine)palladium(II) dichloride

[0470] PTSA = p-toluenesulfonic acid monohydrate

[0471] SFC = Supercritical Fluid Chromatography

[0472] TBAF = Tetrabutylammonium fluoride

[0473] 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) phenylethylamine chloride

[0474] tBuXPhos Pd G3=[(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II)

[0475] TFA = trifluoroacetic acid

[0476] THF = Tetrahydrofuran

[0477] THP = Tetrahydropyran

[0478] XPhos Pd G1 = (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride or (XPhos)palladium(II)phenylethylamine chloride

[0479] In some embodiments, a method of preparing a compound of Formula I, a tautomer, a pharmaceutically acceptable salt of such compounds or tautomers, 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 with compound 1-262, a tautomer thereof, a deuterated derivative of such compounds or tautomers, and a pharmaceutically acceptable salt of any of the foregoing:

[0480] General synthetic scheme

[0481]

[0482] Scheme 1 relates to the preparation of compounds of formula IIIa'.

[0483] Definition: PG 1 is a suitable nitrogen protecting group, such as THP. PG 1 It may also be Cbz, pivaloyl, toluenesulfonyl, or phenylsulfonyl.

[0484] Compounds of Formula IIIa' can be prepared by removing the nitrogen protecting group from compounds of Formula I-1 using any suitable method. 1 In the case of THP, a reagent such as trifluoroacetic acid can be used.

[0485] Solution 1

[0486]

[0487] Scheme 2 relates to a method for preparing compounds of formula 1-1.

[0488] Definition: Y 1 is halogen (such as Br, Cl or I). 11 is any alkyl group such as Me, Et or tBu. 1 It is H or SiMe3. PG 1 As defined above. 11 is OH, alkyl or cycloalkyl, where R 11 The groups are linked via carbon-carbon bonds.

[0489] Compounds of formula 2-2 can be prepared from 2-1 by adding a protecting group to the nitrogen atom using suitable methods. For example, when PG 1When it is THP, it is treated with dihydropyran and p-toluenesulfonic acid to obtain a compound of Formula 2-2. Compounds of Formula 2-3 can be prepared from Formula 2-3 using any suitable method for reducing esters to alcohols (e.g., DiBALH or LiAlH4). Compounds of Formula 2-3 can be oxidized to aldehydes of Formula 2-4 using any suitable oxidizing agent. In some embodiments, 4-acetamido-TEMPO and NaHCO3 can be used. Compounds of Formula 2-4 are Sonagashira coupled 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 condensation reaction with hydroxylamine in the presence of a base such as pyridine. Compounds of Formula 2-8 can be prepared from compound 2-7 by intramolecular cyclization of the amine group on the alkyne. In some embodiments, reagents such as molecular iodine can be used in the presence of a base such as K2CO3. Compounds of formula 2-10 can be prepared from 2-8 by Suzuki coupling with boronic acids or esters of formula 2-9. Compound 2-11 can be prepared by any suitable method for preparing aryl chlorides. For example, reagents such as POCl3 or oxalyl chloride and iPr2NH can be used. Compounds of formula 1-1 can be prepared using any suitable conditions for coupling organometallic reagents (e.g., borate esters, alkyl zinc) 2-12 with aryl chloride 2-11.

[0490] Option 2

[0491]

[0492] Scheme 3 provides a method for preparing compounds of formula 2-10.

[0493] Definition: Y 3 is a halogen such as Br or I. PG 1 As defined above.

[0494] Arylation of the compound of formula 3-2 with an aryl halide of formula 3-1 yields a compound of formula 3-3. In some embodiments, palladium-catalyzed coupling conditions are used, such as Pd(dppf)Cl2 and cesium carbonate. Compounds of formula 2-10 can be prepared from compound 3-3 by treatment with NH2OH.

[0495] Option 3

[0496]

[0497] Scheme 4 describes a method for preparing compounds of Formula 4-1 from compounds of Formula 2-10. In some embodiments, a reagent such as DABCO is used in the presence of TFAA. A solvent such as dichloromethane can be used.

[0498] Option 4

[0499]

[0500] 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, a base such as NaH, Cs2CO3, or K2CO3 can be used. A solvent such as DMSO can be used. The reaction can be carried out in the presence of additional heat (e.g., 50°C).

[0501] Definition: R 12 It can be an alkyl or aryl group.

[0502] Compounds of formula 5-3 can be prepared from 5-2 using any suitable nitrogen protecting group removal conditions. For example, trifluoroacetic acid can be used.

[0503] Option 5

[0504]

[0505] Scheme 6 depicts a method for preparing compound 6-3. Definition: R 13 It can be OMe, halogen, phosphonate, phosphite, -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-isopropoxyphosphonooxypropane DIPEA. A solvent system such as CCl4 and MeCN can be used. The reaction can be carried out in the presence of additional heat (e.g., 40°C). PG can be removed using a suitable reagent. 1 The compound of formula 6-3 can be prepared from 6-2. 1 In the case of a THP group, a dichloromethane solution of TFA can be used.

[0506] Option 6

[0507]

[0508] The method for preparing the compound of formula 7-4 is shown in Scheme 7.

[0509] Definition: R 14 = alkyl such as Me, Et, tBu; L 1 = any linear, branched or cyclic alkyl group.

[0510] A compound of formula 7-2 can be prepared from a compound of formula 2-10 and an amine of formula 7-1 using a suitable reagent for coupling an amine to a pyridine N-oxide compound. For example, in some embodiments, PyBrop and DIPEA can be used. A compound of formula 7-3 can be prepared from 7-2 using any suitable ester hydrolysis method. For example, a base such as NaOH in a solvent such as MeOH can be used. A compound of formula 7-4 can be prepared by removing a protecting group (e.g., THP) from a nitrogen atom using any suitable method.

[0511] Option 7

[0512]

[0513] 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 ester hydrolysis method. Compounds of formula 8-4 can be prepared from 8-3 by treatment with a suitable reagent to remove the nitrogen protecting group.

[0514] Definition: R 15 = alkyl such as Me, Et or tBu. L 2 = any linear, branched or cyclic alkyl or aryl group.

[0515] Option 8

[0516]

[0517] Scheme 9 describes the preparation of compounds of Formula IIIb' from compounds of Formula 9-1, wherein PG 1 is a suitable nitrogen protecting group as defined above. Any suitable method for removing nitrogen protecting groups may be used. For example, when PG 1 In the case of 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 the application of additional heat. For example, in some embodiments, the reaction can be carried out at 50°C.

[0518] Option 9

[0519]

[0520] Scheme 10 provides a method for preparing compounds of Formula IIIb' and Formula 9-1 from compounds of Formula 10-1.

[0521] Definition: Y 4 =halogen (eg Cl).

[0522] Aryl halide 10-1 can be reacted with a halogenated aryl halide of formula R by methods known to those skilled in the art. 2Compounds of Formula IIIb' can be prepared from 10-1 by any method of coupling an organometallic reagent with a compound of Formula 10-2.

[0523] Plan 10

[0524]

[0525] Scheme 11 relates to a method for preparing a compound of formula 10-1 from a compound of formula 11-1. The compound of formula 11-1 can be converted to a compound of formula 11-2 using any suitable method for reducing an ester to an alcohol. In some embodiments, this can be performed using NaBH4 in the presence of a reagent such as ethyl chloroformate. The compound of formula 11-3 can be prepared by oxidizing the compound of formula 11-2 using a suitable reagent system for oxidizing an alcohol to an aldehyde. In some examples, oxalyl chloride, NEt3 in DMSO can be used. The compound of formula 11-4 can be prepared using any reagent suitable for reacting the ortho-halogen substituted aryl aldehyde 11-3 to form a five-membered heterocycle. For example, in Z 1 and Z 2 is a nitrogen atom and Z 3 In some embodiments where CH is CH, hydroxylamine and KCO can be used sequentially to obtain compounds of formula 11-4. Compounds of formula 11-5 can be prepared from 11-4 by treating with an oxidizing agent such as mCPBA. Compounds of formula 10-1 can be prepared by converting a pyridyl N-oxide to an aryl halide by treatment with any suitable reagent. For example, POCl can be used.

[0526] Definition: R 16 Y is an alkyl group (e.g., Me, Et, tBu). 5 is a halogen such as F. Y 4 =Cl or Br.

[0527] Plan 11

[0528]

[0529] Scheme 12 depicts a method for preparing compounds of Formula 12-3 and 12-6 from amines of Formula 11-5 and Formulas 12-1 and 12-4. Compounds 12-2 and 12-5 can be prepared using any suitable method for adding amines to N-oxides. 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 ester hydrolysis method. 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 alkyl ester hydrolysis.

[0530] Definition: R 17 = alkyl (e.g. Me, Et, tBu). 3 、L 4 and L 5 is any alkyl linking group.

[0531] Plan 12

[0532]

[0533] Scheme 13 relates to a method for preparing a compound of formula 13-10 from a compound of formula 13-1. A compound of formula 13-3 can be prepared from 13-1 using any suitable method for forming an amide. In some embodiments, the reaction of an acyl halide of formula 13-2 in the presence of a base such as DIPEA can be used. A compound of formula 13-5 can be prepared from 13-3 by reacting it with a compound of formula 13-4. A reagent system such as ammonium bisulfate and Pd(TFA)2 can be used. A compound of formula 13-5 can be converted to a compound of formula 13-6 by treating it with any suitable reagent to perform an intramolecular condensation with 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 added. A compound of formula 13-7 can be prepared from 13-6 by treating it with a reagent such as POCl3 at an elevated temperature (e.g., 100°C). The compound of formula 13-8 can be prepared by treating the compound of formula 13-7 with a halogenating reagent such as N-bromosuccinimide in CCl4 in the presence of a compact fluorescent. The compound of formula 13-8 can be prepared by 13-9 by any method suitable for converting benzyl halide into aldehyde. For example, N-methylmorpholine oxide can be used in the presence of 4A molecular sieves. The reaction can be carried out in a solvent such as MeCN. The compound of formula 13-10 can be prepared by treating the compound 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 high temperature (e.g., 130°C).

[0534] Definition: Y 6 、Y 7 = halogen such as F, Cl or Br. PG 2 =Ts. Y 8 =Cl.

[0535] Plan 13

[0536]

[0537] Scheme 14 shows a method for preparing compounds of formula 14-5.

[0538] Definition: Y 6 As defined above.8 is a halogen such as Cl.

[0539] PG 3 It can be tosyl or any suitable nitrogen protecting group. 6 = alkyl or aryl. The compound of formula 14-2 can be prepared by adding the alcohol of formula 14-1 to the compound of formula 13-9. A base such as KOtBu, K2CO3 or NaH can be used. A solvent such as THF or DMF can be used. The compound of formula 14-4 can be prepared by the N-protected hydrazine of 14-2 and formula 14-3 in the presence of Cu2O in a solvent such as EtOH. The reaction can be carried out in the presence of additional heat (e.g., 130°C). Using any suitable conditions for simultaneously removing the N-tosyl protecting group and ester hydrolysis, the compound of formula 14-4 can be converted into a compound of formula 14-5. In some embodiments, the reaction is carried out in a solvent such as MeOH, THF and water in the presence of a base such as LiOH. The reaction can be carried out in the presence of additional heat (e.g., at 50°C).

[0540] Plan 14

[0541]

[0542] Scheme 15 shows a method for preparing compounds of formula 15-8.

[0543] Definition: Y 9 = halogen (e.g. Cl, Br, I). R 19 =alkyl.

[0544] R 20 is any suitable group (eg H or alkyl) that forms a suitable borate ester or acid. PG 4 It is a THP group. 1 As defined above. Using methods known to those skilled in the art, compounds of formula 15-2 can be prepared from 3-1 by Sonagashira coupling of alkynes of formula 15-1. 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 boric acid ester 15-4. Any suitable method for carrying out the Suzuki coupling can be used. For example, a RuPhos Pd G4 catalyst system can be used with a mixture of K3PO4 and NaOH as a base. Compounds of formula 15-7 can be prepared by treating 15-5 with an amine such as 15-6 and pyridine and molecular sieves. When PG 4When 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.

[0545] Plan 15

[0546]

[0547] Scheme 16 describes a method for preparing compounds of formula 16-4 and 16-7. Definition: L 8 is an alkyl group. 22 is any suitable alkyl group (eg, Me, Et, tBu). PG 4 As defined above.

[0548] Compounds of formula 16-1 can be prepared by treating 15-5 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 a suitable amine such as 16-2 or 16-5 using an amide coupling agent such as HATU in the presence of an organic base (such as DIPEA). A solvent such as DMF can be used. Compounds of formula 16-4 can be prepared from 16-3 in two steps, wherein the nitrogen atom protecting group is first removed with a reagent, and then the ester is hydrolyzed with a suitable reagent. For example, in some embodiments, 16-3 is treated with p-toluenesulfonic acid at an elevated temperature (e.g., 65° C.), followed by hydrolysis with a base such as NaOH, to obtain 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.

[0549] Plan 16

[0550]

[0551] Synthesis starting materials

[0552] The following describes synthetic routes to intermediates used in the synthesis of compounds 1-262.

[0553] Preparation S1

[0554] 5-Iodo-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S1)

[0555]

[0556] Step 1. Synthesis of 5-bromo-1-tetrahydropyran-2-yl-indazole-6-carboxylic acid methyl ester (C2)

[0557] 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-necked flask at room temperature was added DHP (92 mL, 1.008 mol) followed by 4-methylbenzenesulfonic acid monohydrate (1.8 g, 9.463 mmol). After approximately 20 minutes, the suspension was consumed, yielding a clear solution. The mixture was stirred at room temperature overnight. The mixture was washed with saturated aqueous NaHCO₃ (2 x 1 L) and then with brine (1 L), dried over MgSO₄, filtered, and concentrated to yield the product: methyl 5-bromo-1-tetrahydropyran-2-yl-indazole-6-carboxylate (266 g, 100%). 1 H NMR (300 MHz, CHLOROFORM-d) δ 8.04 (t, J = 0.7 Hz, 1H), 8.02 (d, J = 0.5 Hz, 1H), 8.00 (d, J = 0.9 Hz, 1H), 5.74 (dd, J = 9.0, 2.7 Hz, 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).

[0558] Step 2. Synthesis of (5-bromo-1-tetrahydropyran-2-yl-indazol-6-yl)methanol (C3)

[0559] At -78°C, DIBALH (50 mL of 1 M, 50.00 mmol) was added via syringe to a solution of 5-bromo-1-tetrahydropyran-2-yl-indazole-6-carboxylic acid methyl ester (6.5 g, 19.16 mmol) in dichloromethane (60 mL) over 15 minutes. After one 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 extracted again with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford (5-bromo-1-tetrahydropyran-2-yl-indazole-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] + .

[0560] Step 3. Synthesis of 5-bromo-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde (C4)

[0561] In a 12-L three-necked flask equipped with a temperature probe and a mechanical stirrer, at 3°C (ice-water bath), to a solution of (5-bromo-1-tetrahydropyran-2-yl-indazol-6-yl)methanol (100 g, 321.4 mmol) in dichloromethane (2.75 L) was added water (750 mL), followed by NaHCO (44.5 g, 529.7 mmol), NaBr (2.08 g, 20.22 mmol), 4-acetamido-TEMPO, and a free radical (1.05 g, 4.923 mmol). Sodium hypochlorite (250 mL of 2 M, 500.0 mmol) (10-15% aqueous solution, 2 M is used as an approximate concentration) was added dropwise via an addition funnel to the resulting stirred biphasic mixture over 20 minutes. 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, allowing the internal temperature to reach 2°C. The layers were separated and the aqueous layer was extracted with dichloromethane (500 mL). The combined dichloromethane layers were dried (MgSO4), filtered and concentrated to afford the product as a yellow / brown solid. 5-Bromo-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde (99 g, 100%) 1 H 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).

[0562] Step 4. Synthesis of 1-tetrahydropyran-2-yl-5-(2-tetrahydropyran-4-ylethynyl)indazole-6-carbaldehyde (C5)

[0563] 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 at 50° C. for 15 minutes. Pd(PPh 3 ) 2 Cl 2 (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 turned dark. After sparging the mixture with nitrogen for 5 minutes, 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 give a dark oil. The residue was dissolved in dichloromethane (~15 mL), IPA (50 mL) was added, and the mixture was concentrated in vacuo to ~25 mL. The solution was seeded with crystals and the flask was scraped with a spatula to induce crystallization. After standing for 1 hour, the solid was collected by vacuum filtration, washed with cold IPA, and dried in vacuo to give 3.3 g of 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-ylethynyl)indazole-6-carbaldehyde (4.4 g, 80%). 1 H NMR (300MHz, chloroform-d) δ10.71(s,1H),8.20(s,1H),8.08(d,J=0.9Hz,1H),7.94(d,J =0.7Hz,1H),5.79(dd,J=9.7,2.5Hz,1H),4.14-3.92(m,3H),3.80(ddd,J=13.4,1 0.6,3.0Hz,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] + .

[0564] Step 5. Synthesis of (6E)-1-tetrahydropyran-2-yl-5-(2-tetrahydropyran-4-ylethynyl)indazole-6-carbaldehyde oxime (C6)

[0565] A solution of hydroxylamine (hydrochloride) (1.4 g, 20.15 mmol) in pyridine (10 mL, 123.6 mmol) was added over two 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 at room temperature for 1 hour, the mixture was concentrated in vacuo to remove the acetonitrile, and the residue was partitioned between EtOAc and water. The organic layer was washed with water (3x), 1M HCl (1x), and brine, dried over sodium sulfate, filtered, and concentrated to afford the product. (6E)-1-tetrahydropyran-2-yl-5-(2-tetrahydropyran-4-ylethynyl)indazole-6-carbaldehyde oxime (2.32 g, 100%) was obtained as a tan solid that was used without further purification. LCMS m / z 354.0[M+H] + .

[0566] Step 6. Synthesis of 5-iodo-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S1)

[0567] (6E)-1-tetrahydropyran-2-yl-5-(2-tetrahydropyran-4-ylethynyl)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 KCO (940 mg, 6.801 mmol) in anhydrous dichloromethane (20 mL) at room temperature over 30 minutes. After stirring at room temperature for an additional 30 minutes, the reaction was quenched by the addition of a solution of sodium bicarbonate and sodium thiosulfate (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: 0-5% MeOH in dichloromethane, then isocratic 5% MeOH / dichloromethane) to afford the product as a dark brown solid. 5-Iodo-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (740 mg, 69%). 1H 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),2.7 3-2.51(m,1H),2.18(d,J=12.6Hz,2H),1.94-1.70(m,3H),1.62(d,J=13.1Hz,3H). LCMS m / z480.0[M+H] + .

[0568] Preparation of S2 and S3

[0569] 5-(2-methyl-4-pyridinyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S2) and 8-chloro-5-(2-methyl-4-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S3)

[0570]

[0571] Step 1. Synthesis of 5-(2-methyl-4-pyridyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S2)

[0572] Sodium carbonate (6 mL of 2M, 12.00 mmol) was added to a solution of 5-iodo-7-oxo-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. The mixture was sparged with nitrogen for 5 minutes, then Pd(dppf)Cl2 (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 2M HCl (3x), and 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 layers were combined and dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-5% MeOH / dichloromethane) gave the product. 5-(2-methyl-4-pyridinyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (1.9 g, 68%) was obtained as a tan solid. LCMS m / z 445.0 [M+H] + .

[0573] 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)

[0574] A solution of 5-(2-methyl-4-pyridinyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (660 mg, 1.485 mmol) and DIPEA (950 μL, 5.454 mmol) in dichloromethane (10 mL) was treated with oxalyl chloride solution (1 mL of 2 M, 2.000 mmol) for 10 minutes at -78°C. The reaction was stirred at -78°C for 1 hour, then quenched with 5 mL of MeOH and concentrated. The product was purified by silica gel chromatography (gradient: 0-8% MeOH / dichloromethane). 8-Chloro-5-(2-methyl-4-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (520 mg, 76%) was obtained. 1H 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] + .

[0575] Preparation of S4

[0576] 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)

[0577]

[0578] Step 1. Synthesis of 5-(3,4-difluorophenyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (C7)

[0579] To a mixture of 5-iodo-7-oxo-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 was added NaCO (2.5 mL of 2M, 5.000 mmol). The reaction mixture was microwaved at 125°C for 60 minutes. 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 / dichloromethane) provided the product. 5-(3,4-Difluorophenyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (386 mg, 89%). 1H 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, 1.8 Hz ,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] + .

[0580] 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)

[0581] To a solution of 5-(3,4-difluorophenyl)-7-oxo-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 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 to give the product, which was used in the next reaction without further purification. 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 (trifluoroacetic acid (3)) (388 mg, 100%) LCMS m / z 560.84 [M+H] + .

[0582] Preparation of S5 and S6

[0583] 8-(4-Aza-1-azoniabicyclo[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)

[0584]

[0585] Step 1. Synthesis of 8-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinoline (S5)

[0586] To a solution of 5-(3,4-difluorophenyl)-7-oxo-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 stirred for 1 hour. The mixture was concentrated and dissolved in DMSO. The product was purified by reverse phase chromatography (column: C18, gradient: 10-100% MeCN / water with 0.1% trifluoroacetic acid) to afford the product. 8-(4-Aza-1-azoniabicyclo[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] + .

[0587] Step 2. Synthesis of 8-chloro-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S6)

[0588] A solution of 5-(3,4-difluorophenyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (1.9 g, 4.082 mmol) and DIPEA (2.85 mL, 16.36 mmol) in dichloromethane (20 mL) was treated dropwise with a solution of oxalyl chloride (4.2 mL, 2 M, 8.400 mmol) at -78°C for 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) and sonicated for 1 minute to give a suspension, which was then filtered. The collected solid was washed with MeOH (3 x 1 mL) and then dried under suction for 30 minutes. The solid was transferred to a 250 mL flask and dried on a rotary evaporator (65°C, 3 mbar) for 1 hour. To the crude residue was added 10 mL of cold MeOH, 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] + .

[0589] Preparation of S7 and S8

[0590] 5-(4-Fluorophenyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S7) and 8-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-5-(4-fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S8)

[0591]

[0592] Compounds S7 and S8 were prepared from S1 using the method described for the preparation of S4.

[0593] 5-(4-Fluorophenyl)-7-oxo-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),4.04( 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] + .

[0594] 8-(4-Aza-1-azoniabicyclo[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] + .

[0595] Preparation of S9

[0596] 8-Chloro-5-(4-fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S9)

[0597]

[0598] Step 1. Synthesis of 8-chloro-5-(4-fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (S9)

[0599] A solution of 5-(4-fluorophenyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (500 mg, 1.117 mmol) and DIPEA (600 μL, 3.445 mmol) in dichloromethane (5 mL) was treated dropwise with oxalyl chloride (1.15 mL of 2 M, 2.300 mmol) at -78°C for 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: 0-10% EtOAc / 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),2.3 9-2.14(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] + .

[0600] Preparation of S10 and S11

[0601] 5-(4-Fluorophenyl)-6-isopropyl-7-oxo-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S10) and 8-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinoline (S11)

[0602]

[0603] Step 1. Synthesis of 5-(3-methylbut-1-ynyl)-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde (C9)

[0604] In a 3L four-necked flask (equipped with a mechanical stirrer, temperature probe, and heating jacket), a solution of 5-bromo-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde (113g, 365.5mmol) in DMF (1.1L) was bubbled with nitrogen for 15 minutes, followed by the addition of diisopropylamine (103mL, 734.9mmol). Nitrogen bubbling continued for 15 minutes, followed by the addition of 3-methylbut-1-yne (54mL, 554.9mmol), followed by Pd(PPh3)2Cl2 (8.0g, 11.40mmol) and CuI (4.18g, 21.95mmol). The mixture was placed under a slight positive nitrogen pressure and then heated to 50°C for 3 hours. The mixture was cooled to 25°C, and then water (1L) was added with stirring. The internal temperature rose to 41°C, and precipitation was observed. The mixture was extracted with EtOAc (2×1.5L). The combined EtOAc extracts were washed sequentially with 1:1 water:saturated brine, 1:1 saturated aqueous NH4Cl:saturated aqueous NaHCO3, 0.3M aqueous HCl, and brine (1.5 L each). The organic layer was dried (MgSO4), filtered, and concentrated. 1 H NMR (200 MHz, chloroform-d) δ 10.71 (s, 1H), 8.19 (t, J = 0.9 Hz, 1H), 8.07 (d, J = 1.0 Hz, 1H), 7.91 (d, J = 0.7 Hz, 1H), 5.78 (dd, J = 9.7, 2.6 Hz, 1H), 4.08 (ddt, J = 11.8, 3.8, 1.9 Hz, 1H), 3.85-3.75 (m, 1H), 2.88 (septet, J = 6.9 Hz, 1H), 2.56 (dddd, J = 13.7, 11.9, 9.8, 4.0 Hz, 1H), 2.24-2.05 (m, 2H), 1.88-1.64 (m, 3H), 1.34 (d, J = 6.9 Hz, 6H). LCMS m / z 297.03[M+H] + Melting point = 100°C.

[0605] Step 2. Synthesis of (6E)-5-(3-methylbut-1-ynyl)-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde oxime (C10)

[0606] In a 5L three-necked flask equipped with mechanical stirring, a temperature probe, and a heating jacket, pyridine (550mL, 6.800mol) was added to a suspension of hydroxylamine (hydrochloride) (70.0g, 1.007mol) in MeCN (1.0L) at room temperature. The mixture was heated to 50°C, followed by the addition of a solution of 5-(3-methylbut-1-ynyl)-1-tetrahydropyran-2-yl-indazole-6-carbaldehyde (100g, 337.4mmol) in dichloromethane (750mL). The mixture was stirred at 50°C for 1 hour and then concentrated. The residue was dissolved in EtOAc (2L), washed sequentially with water (2x), then with brine (1.5L each), dried (MgSO4), filtered, and concentrated. The residue was concentrated from the EtOAc / heptane solution to give a black solid. The solid was treated with MTBE (200 mL) and heated at reflux for 5 minutes to give a homogeneous suspension, which was then treated with heptane (500 mL). The resulting suspension was allowed to stand at room temperature for 18 hours. The crystals were isolated by filtration, washed with heptane (3 × 100 mL), and then dried under suction for 30 minutes and then on a rotary evaporator (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, 3.0 Hz, 1H), 3.78 (td, J = 11.1, 3.0 Hz, 1H), 2.87 (septet, J = 6.9 Hz, 1H), 2.64-2.51 (m, 1H), 2.12 (ddd, J = 31.8, 11.3, 4.1 Hz, 2H), 1.87-1.57 (m, 3H), 1.33 (d, J = 6.9 Hz, 6H). LCMS m / z 312.1[M+H] + .

[0607] Step 3. Synthesis of 5-iodo-6-isopropyl-7-oxo-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (C11)

[0608] Compound C11 was prepared from C10 by iodination as described for the preparation of S1.

[0609] 5-Iodo-6-isopropyl-7-oxo-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (1.2 g, 84%) as a yellow foam. 1H NMR (400MHz, chloroform-d) δ8.82(s,1H),8.60(s,1H),8.34(d,J=1.0Hz,1H),7.77(q,J=0.9Hz,1H),5.85(dd,J=9.1,2.6Hz,1H),4.22(s,1 H),4.12-4.00(m,1H),3.90-3.78(m,1H),2.62(qd,J=9.5,5.2Hz,1H),2.29-2.11(m,2H),1.93-1.69(m,3H),1.62(d,J=6.9Hz,6H). LCMS m / z 438.03[M+1] + .

[0610] Step 4. Synthesis of 5-(4-fluorophenyl)-6-isopropyl-7-oxo-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S10)

[0611] 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 / dichloromethane) gave the product, which was used in subsequent reactions without further purification. 5-(4-Fluorophenyl)-6-isopropyl-7-oxo-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium. LCMS m / z 406.08 [M+1] + .

[0612] Step 5. Synthesis of 5-(4-fluorophenyl)-6-isopropyl-7-oxo-1H-pyrazolo[4,3-g]isoquinolin-7-ium (C12)

[0613] 5-(4-Fluorophenyl)-6-isopropyl-7-oxo-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (1050 mg, 2.590 mmol) was treated with hydrogen chloride (30 mL of 4M, 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-oxo-1H-pyrazolo[4,3-g]isoquinolin-7-ium (830 mg, 100%). LCMS m / z 322.37 [M+H] + .

[0614] Step 6. Synthesis of 8-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinoline (S11)

[0615] To a solution of 5-(4-fluorophenyl)-6-isopropyl-7-oxo-1H-pyrazolo[4,3-g]isoquinolin-7-ium (830 mg, 2.583 mmol) and 1,4-diazabicyclo[2.2.2]octane (2.6 g, 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 afford 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%). 1 H NMR (300MHz, chloroform-d) δ14.16(s,1H),10.13(s,1H),8.22(s,1H),7.92(s,1H),7.32(d,J=7.0Hz,4H), 4.38(t,J=7.4Hz,6H),3.71(t,J=7.4Hz,6H),3.03(q,J=6.7Hz,1H),1.25(d,J=6.7Hz,6H)ppm.LCMS m / z 416.28[M+H] + .

[0616] Preparation of S12 and S13

[0617] 8-Chloro-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S12) and 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)

[0618]

[0619] Preparation of 8-chloro-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S12)

[0620] 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] + .

[0621] Preparation of 8-(4-aza-1-azoniabicyclo[2.2.2]oct-1-yl)-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S13)

[0622] Compound S10 was prepared from S13 using the method described for the preparation of S8. 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(trifluoroacetic acid) (374 mg, 100%). LCMS m / z 500.9 [M+H] + .

[0623] Preparation of S14 and S15

[0624] 6-Isopropyl-5-(2-methyl-4-pyridyl)-7-oxo-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)

[0625]

[0626] Synthesis of 6-isopropyl-5-(2-methyl-4-pyridyl)-7-oxo-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S14)

[0627] Compound S14 was prepared from C11 by Suzuki coupling with 2-methyl-4-pyridinylboronic acid using the method described for the preparation of S2. 6-Isopropyl-5-(2-methyl-4-pyridinyl)-7-oxo-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (900 mg, 65%) was obtained as a tan solid. LCMS m / z 403.0 [M+H] + .

[0628] Synthesis of 8-chloro-6-isopropyl-5-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S15)

[0629] Compound S15 was prepared from S14 using the method described for the preparation of compound S3. 8-Chloro-6-isopropyl-5-(2-methyl-4-pyridinyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (280 mg, 77%). LCMS m / z 421.0 [M+H] + .

[0630] Preparation of S16

[0631] 8-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-6-isopropyl-5-(2-methoxy-4-pyridinyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S16)

[0632]

[0633] Step 1. Synthesis of 6-isopropyl-5-(2-methoxy-4-pyridyl)-7-oxo-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (C13)

[0634] Compound C13 was prepared by Suzuki coupling with C11 and 2-methoxy-4-pyridinylboronic acid using the method described for the preparation of S2. Purification by silica gel chromatography (gradient: 0-5% MeOH / dichloromethane) gave the product as a light red solid. 6-Isopropyl-5-(2-methoxy-4-pyridinyl)-7-oxo-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),2.5 9-2.47(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] + .

[0635] Step 2. Synthesis of 8-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-6-isopropyl-5-(2-methoxy-4-pyridinyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (S16)

[0636] Compound S16 was prepared from C13 using the method described for the preparation of compound S4. Purification by reverse phase chromatography (column: C18. Gradient: 0-50% MeCN / water with 0.1% trifluoroacetic acid) gave the product. 8-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-6-isopropyl-5-(2-methoxy-4-pyridinyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinoline (trifluoroacetate) (182 mg, 74%). LCMS m / z 513.43 [M] + .

[0637] Preparation of S17

[0638] 8-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-6-(1-benzyloxycyclopropyl)-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinoline (S17)

[0639]

[0640] Step 1. Synthesis of 6-(1-benzyloxycyclopropyl)-5-(4-fluorophenyl)-7-oxo-1H-pyrazolo[4,3-g]isoquinolin-7-ium (C17)

[0641] 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 / heptane) to afford C16.

[0642] Part B. A solution of hydroxylamine (hydrochloride) (1.13 g, 16.26 mmol) in EtOH (14.5 mL) / H2O (1.5 mL) was added to the product of Part A (C16). The reaction mixture was heated at 90°C under microwave for 2 hours. The reaction was concentrated, and the product was purified by silica gel chromatography (Gradient: 30-80% EtOAc / heptane) to afford 6-(1-benzyloxycyclopropyl)-5-(4-fluorophenyl)-7-oxo-1H-pyrazolo[4,3-g]isoquinolin-7-ium (600 mg, 43%). LCMS m / z 426.21 [M+H] + .

[0643] 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)

[0644] To a solution of 6-(1-benzyloxycyclopropyl)-5-(4-fluorophenyl)-7-oxo-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 afford a dark brown solid. The product was purified by reverse phase chromatography (column: C18, gradient: 0-100% MeCN / water with 0.1% TFA) to afford 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] + .

[0645] Preparation of S188-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)-6-(1-benzyloxycyclopropyl)-5-(3,4-difluorophenyl)-1H-pyrazolo[4,3-g]isoquinoline (S18)

[0646]

[0647] Compound S18 was prepared from C14 and 1-(1-benzyloxycyclopropyl)-2-(3,4-difluorophenyl)ethanone using the method described for compound S17. Purification by reverse phase chromatography (column: C18. Gradient: 0-100% MeCN / water with 0.1% TFA) gave the product. 8-(4-Aza-1-azoniabicyclo[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] + .

[0648] Preparation of S198-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-5-(3,4-difluorophenyl)-6-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazolo[4,3-g]isoquinoline (S19)

[0649]

[0650] Compound S19 was prepared from C14 and C18 using the method described for the preparation of S17. Purification by reverse phase chromatography (column: C18. Gradient: 0-100% MeCN / water with 0.1% trifluoroacetic acid) gave the product. 8-(4-Aza-1-azoniabicyclo[2.2.2]octan-1-yl)-5-(3,4-difluorophenyl)-6-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazolo[4,3-g]isoquinoline (trifluoroacetate) (91 mg, 52%) LCMS m / z 500.49 [M+H] + .

[0651] Preparation of S20

[0652] 6-(1,1-difluoroethyl)-5-(4-fluorophenyl)-7-oxo-1H-pyrazolo[4,3-g]isoquinolin-7-ium (S20)

[0653]

[0654] 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 was purified by ISCO (40 g silica, 100% EtOAc / heptane) to give 6-(1,1-difluoroethyl)-5-(4-fluorophenyl)-7-oxo-1H-pyrazolo[4,3-g]isoquinolin-7-ium (100 mg, 50%). LCMS m / z 344.18 [M+H] + .

[0655] Preparation of S21

[0656] 5-(3,4-Difluorophenyl)-6-(1-methoxycyclobutyl)-7-oxo-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-7-ium (S21)

[0657]

[0658] Compound S21 was prepared from 2-(3,4-difluorophenyl)-1-(1-methoxycyclobutyl)ethanone and C 14 as described for the preparation of compound S 17. The THP protecting group was retained 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=10.9,8.5Hz ,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 / z563.09[M+H] + .

[0659] Preparation of S22

[0660] 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)

[0661]

[0662] 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-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 (trifluoroacetic acid (3)) (160 mg, 56%) LCMS m / z 563.09 [M+1] + .

[0663] Preparation of S23

[0664] [6-(2-Benzyloxy-1,1-dimethyl-ethyl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl] trifluoromethanesulfonate (S23)

[0665]

[0666] 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)

[0667] 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 added via syringe. The reaction mixture was heated to 70°C overnight. The reaction was cooled to room temperature and diluted with EtOAc. The organic solution was washed with brine, dried over Na2SO4, and concentrated in vacuo. The reaction was then purified by silica gel chromatography (Gradient: 10% to 25% EtOAc / heptane), and the product was used in subsequent reactions.

[0668] Part B. To the product from Part A was added NH3 (10 mL of 7 M, 70.00 mmol) in methanol in a 10-20 mL microwave vial. The reaction mixture was heated at 120°C under microwave conditions for 5 hours. The reaction was concentrated, and the product was purified by silica gel chromatography (Gradient: 30-80% EtOAc / heptane) to afford 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%). 1HNMR (300MHz, chloroform-d) δ10.23(s,1H),8.73(q,J=1.0Hz,1H),8.06(d,J=0.9Hz,1H ),7.48-7.20(m,7H),7.10-6.94(m,2H),5.87(dd,J=9.9,2.4Hz,1H),4.65(s,2H ),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] + .

[0669] 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)

[0670] 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 triflate (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: 0-30% EtOAc / 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] + .

[0671] Exemplary Compounds 1-262

[0672] In order to more fully understand the disclosure described herein, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the disclosure in any way.

[0673] All specific and generic compounds and intermediates disclosed for the preparation of those compounds are considered to be part of the disclosure disclosed herein.

[0674] Compound 1

[0675] 3-[[5-(4-Chlorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (1)

[0676]

[0677] Step 1. Synthesis of 5-(4-chlorophenyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (C24)

[0678] In a microwave vial, 5-iodo-7-oxo-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 2M, 4.000 mmol) was added. The reaction mixture was heated at 125°C under microwave conditions for 1 hour. Water and dichloromethane were added to the reaction. The mixture was extracted with dichloromethane (x 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 / dichloromethane) gave the product. 5-(4-Chlorophenyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (390 mg, 84%). %. 1 H NMR (400MHz, chloroform-d) δ8.91 (s, 1H), 8.04 (d, J = 0.9Hz, 1H), 7.78 (m, 1H), 7.55-7.4 8(m,2H),7.44(t,J=1.0Hz,1H),7.21-7.16(m,3H),5.75(dd,J=9.1,2.7Hz,1H) ,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] + .

[0679] 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)

[0680] 5-(4-Chlorophenyl)-7-oxo-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 hour. The volatiles were evaporated in vacuo. Purification was performed by flash column chromatography (gradient: 0-50% CHCN in water with 0.1% TFA). The product fractions were concentrated and the acetonitrile was removed in vacuo. The water was removed by freeze drying to yield the product as a light yellow solid. 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 (trifluoroacetate) (385 mg, 94%). LCMS m / z 558.35 [M] + .

[0681] 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)

[0682] In a vial, 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 (trifluoroacetate) (250 mg, 0.3714 mmol) and 3-hydroxycyclobutanecarboxylic acid (130 mg, 1.120 mmol) were dissolved in DMSO (3.7 mL). NaH (90 mg of 60% w / w, 2.250 mmol) was then added at room temperature under nitrogen. The reaction was stirred for 2 hours. Purification by reverse phase flash chromatography (column: C18, gradient: 0-100% MeCN / water with 0.1% trifluoroacetic acid) gave the product. Fractions containing the product were combined 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] + .

[0683] Step 4. Synthesis of 3-[[5-(4-chlorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (1)

[0684] In a small 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). Then, octane-1-thiol (108 μL, 0.6223 mmol) was added. In a separate vial, AlCl₃ (76 mg, 0.5700 mmol) was dissolved in CH₃NO₂ (1.5 mL) and added to the mixture. The reaction was stirred at room temperature for 1 hour. Saturated NaHCO₃ 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 / dichloromethane). The purification was repeated twice, and the impurities co-eluted with the product. The crude product was then purified by reverse phase chromatography (column: C18. Gradient: 5-100% 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%). 1H 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 / z478.27[M+H] + .

[0685] Compound 2

[0686] 3-[[5-(4-Fluoro-3-methoxy-phenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (2)

[0687]

[0688] 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) was added. 1 H NMR (400 MHz, methanol-d4: chloroform-d 3:1) δ8.41(s,1H),8.12(d,J=1.2Hz,1H),7.64(d,J=1.1Hz,1H),7.22(dd,J=11. 3,8.1Hz,1H),6.93(dd,J=8.2,2.0Hz,1H),6.83(m,1H),5.74-5.62(p,J=8.0Hz, 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] +

[0689] Compound 3

[0690] 3-[[5-(3-Chloro-4-fluoro-phenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (3)

[0691]

[0692] 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: 5-100% MeCN / water with 0.1% trifluoroacetic acid) afforded the product. 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 as a light yellow solid. 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 / z496.23[M+H] + .

[0693] Compound 4

[0694] 3-[[5-(4-Chloro-3-fluoro-phenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (4)

[0695]

[0696] Compound 4 was prepared from S1 and 4-chloro, 3-fluorophenylboronic acid as described for compound 1. Purification by reverse phase chromatography (column: C18, gradient: 0-50% MeCN / water containing 0.2% formic acid) afforded the product. 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 as a light yellow solid. 1H NMR (400 MHz, methanol-d4:chloroform-d3:1) δ 8.43 (t, J = 1.1 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.65-7.56 (m, 2H), 7.16 (dd, J = 9.6, 1.9 Hz, 1H), 7.09 (dd, J = 8.0, 1.9 Hz, 1H), 5.68 (p, J = 6.8 Hz, 1H), 3.97 (d, J = 11.5 Hz, 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 = 13.5 Hz, 2H). LCMS m / z 496.23[M+H] + .

[0697] Compound 5

[0698] 1-[5-(5-Fluoro-3-pyridinyl)-8-[1-[(2S)-2-hydroxypropionyl]azetidin-3-yl]oxy-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-1-yl]-2-hydroxy-propan-1-one (5)

[0699]

[0700] Step 1. Synthesis of 5-(5-fluoro-3-pyridyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (C25)

[0701] A mixture of 5-iodo-7-oxo-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)Cl2 (100 mg, 0.1225 mmol) in DMSO (10 mL) was sparged with nitrogen. Na2CO3 (2 mL of 2M, 4.000 mmol) was added, and the mixture was stirred at 90°C overnight. The mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, 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-pyridinyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium (850 mg, 61%). The product was used in the next step. LCMS m / z 449.0 [M+H] + .

[0702] 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)

[0703] To a solution of 5-(5-fluoro-3-pyridinyl)-7-oxo-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 2M, 4.0 mmol) at 0°C. The mixture was stirred for 1 hour and then concentrated. Purification by silica gel chromatography (gradient: 0-10% MeOH / dichloromethane) gave the product: 8-chloro-5-(5-fluoro-3-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (500 mg, 57%). LCMS m / z 467.0 [M+H] + .

[0704] Step 3. Synthesis of 8-(azetidin-3-yloxy)-5-(5-fluoro-3-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (C27)

[0705] Part A. To a solution of benzyl 3-hydroxyhydroxyazetidine-1-carboxylate (90 mg, 0.4343 mmol) in DMSO (1 mL) was added KOtBu (48 mg, 0.4278 mmol) and stirred for 10 minutes. 8-Chloro-5-(5-fluoro-3-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (100 mg, 0.2142 mmol) was added to the mixture and stirred at 50° C. for 30 minutes. The reaction was then diluted with EtOAc, washed with H 2 O, dried over Na 2 SO 4 and concentrated.

[0706] Purification by silica gel chromatography (gradient: 0-10% MeOH / dichloromethane) gave the product: benzyl-3-[5-(5-fluoro-3-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyhydroxyazetidine-1-carboxylate (130 mg, 95%). LCMS m / z 638.0 [M+H] + .

[0707] Part B. To a solution of benzyl 3-[5-(5-fluoro-3-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyhydroxyazetidine-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 balloon of H2 for 1 hour. The mixture was heated at The mixture was filtered through the upper layer and the filtrate was concentrated. 8-(azetidin-3-yloxy)-5-(5-fluoro-3-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (90 mg, 83%), LCMS m / z 504.0 [M+H] + .

[0708] 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)

[0709] Part A. To a mixture of 8-(azetidin-3-yloxy)-5-(5-fluoro-3-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (90 mg, 0.1787 mmol) and (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 minutes. Purification by reverse phase chromatography (column: C18. Gradient: 0-100% MeCN / water with 0.2% formic acid) gave the product, which was used in Part B. (2S)-1-[3-[5-(5-fluoro-3-pyridinyl)-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] + .

[0710] Part B. To a solution of (2S)-1-[3-[5-(5-fluoro-3-pyridinyl)-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 was performed by reverse phase chromatography (column: C18. Gradient: 10-100% MeCN / water with 0.1% formic acid) followed by silica gel chromatography (gradient: 0-15% MeOH / dichloromethane). (2S)-1-[3-[[5-(5-Fluoro-3-pyridinyl)-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 MHz, 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, 1. 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] + .

[0711] Compound 6

[0712] 3-Fluoro-4-[[5-(2-methyl-4-pyridinyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (6)

[0713]

[0714] Step 1. Synthesis of 3-fluoro-4-[[5-(2-methyl-4-pyridinyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (C28)

[0715] To a mixture of 3-fluoro-4-hydroxy-benzoic acid methyl ester (30 mg, 0.1763 mmol), CCl4 (150 μL, 1.554 mmol), DIPEA (40 μL, 0.2296 mmol), 5-(2-methyl-4-pyridinyl)-7-oxo-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-7-ium; 5-(2-methyl-4-pyridinyl)-7-oxo-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-isopropoxyphosphoryloxypropane (38 mg, 0.2287 mmol). The mixture was stirred at 40° C. overnight. The mixture was diluted with dichloromethane and washed with H2O. Purification by silica gel chromatography (gradient: 0-8% MeOH / dichloromethane) gave the product: 3-fluoro-4-[5-(2-methyl-4-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-benzoic acid methyl ester (32 mg, 48%). LCMS m / z 597.0 [M+H] + .

[0716] Step 2. Synthesis of methyl 3-fluoro-4-[[5-(2-methyl-4-pyridinyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoate (C29)

[0717] To a solution of 3-fluoro-4-[5-(2-methyl-4-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxy-benzoic acid methyl ester (32 mg, 48%) in dichloromethane (3 mL) was added TFA (800 μL, 10.38 mmol) and stirred for 1 hour. The mixture was concentrated to give the product: 3-fluoro-4-[[5-(2-methyl-4-pyridinyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid methyl ester (25 mg, 43%). LCMS m / z 513.0 [M+H] + .

[0718] 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)

[0719] To a solution of methyl 3-fluoro-4-[[5-(2-methyl-4-pyridinyl)-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 hour. The pH of the mixture was adjusted to pH 3 by adding 1 M HCl and then concentrated. Purification by reverse phase chromatography (column: C18, gradient: 10-100% MeCN / water with 0.1% formic acid) afforded the product: 3-fluoro-4-[[5-(2-methyl-4-pyridinyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (18.8 mg, 32%). 1 H NMR (400 MHz, methanol-d4) δ 8.69-8.54 (m, 2H), 8.27 (d, J = 1.1 Hz, 1H), 8.12 (s, 2H), 8.05-7.96 (m, 1H), 7.92 (dd, J = 10.9, 2.0 Hz, 1H), 7.74 (d, J = 1.1 Hz, 1H), 7.56 (dd, J = 8.4, 7.5 Hz, 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] + .

[0720] Compound 7-24

[0721] Compounds 7-24 (Table 1) were prepared from S2 and the appropriate aryl alcohol according to the procedure described for compound 6. The ester hydrolysis step was omitted as appropriate. Modifications to the procedure are noted in the table footnotes.

[0722] Table 1. Preparation method, structure and physicochemical data of compounds 7-24

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729] *Phosphonates were hydrolyzed by treatment with TMSBr in dichloromethane at room temperature.

[0730] Compounds 25-29

[0731] 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 noted in the table footnotes.

[0732] Table 2. Preparation methods, structures and physicochemical data of compounds 25-29

[0733]

[0734]

[0735] *Acetonide deprotection occurred during THP deprotection with TFA. Trifluoroacetate esters of products 25 and 29 were also observed during acetonide deprotection. These esters were converted to products 25 and 29 by hydrolysis with NaOH.

[0736] **During the deprotection of THP with TFA, the Boc group was removed.

[0737] ***Methyl ester hydrolysis was performed by treatment with NaOH prior to the THP deprotection step.

[0738] 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)

[0739]

[0740] Compound 30 was prepared from C30 in two steps.

[0741] Part A. To a mixture of 3-[5-(2-methyl-4-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (15 mg, 0.02764 mmol) and (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 hour. Purification by reverse phase chromatography (column: C18. Gradient: 0-100% MeCN / water with 0.1% formic acid) gave the product. N-[(1S)-2-Hydroxy-1-methyl-ethyl]-3-[5-(2-methyl-4-pyridinyl)-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] + .

[0742] Part B. To a solution of N-[(1S)-2-hydroxy-1-methyl-ethyl]-3-[5-(2-methyl-4-pyridinyl)-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 hour. Purification by reverse phase chromatography (column: C18. Gradient: 10-100% MeCN / water with 0.1% formic acid) gave the product. N-[(1S)-2-hydroxy-1-methyl-ethyl]-3-[[5-(2-methyl-4-pyridinyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxamide (3.0 mg, 20%), 1H NMR (400MHz, methanol-d4) δ8.59 (dd, J=5.1, 0.9Hz, 1H), 8.46 (dt, J=3.7, 1.1Hz, 1H), 8.38 (s, 1H), 8.1 9(t,J=1.2Hz,1H),7.61(d,J=1.1Hz,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),2.7 6-2.48(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] + .

[0743] Compound 31

[0744] 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)

[0745]

[0746] Compound 31 was prepared from C30 and 2-(methylamino)propan-1-ol according to the method described for compound 30. N-(2-Hydroxy-1-methyl-ethyl)-N-methyl-3-[[5-(2-methyl-4-pyridinyl)-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 = 7.5 Hz, 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] + .

[0747] Compound 32

[0748] (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]propionamide (32)

[0749]

[0750] Compound 32 was prepared from C31 and (2S)-2-hydroxypropionic acid according to the method described for compound 30. (2S)-2-Hydroxy-N-methyl-N-[3-[[5-(2-methyl-4-pyridinyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutyl]propanamide (11.4 mg, 40%). 1H NMR (400MHz, methanol-d4) δ8.60(dd,J=5.1,0.8Hz,1H),8.51(t,J=1.1Hz,1H),8.20(d,J=1.1Hz,1H), 8.11(s,2H),7.63(d,J=1.1Hz,1H),7.35(s,1H),7.27(d,J=5.1Hz,1H),5.63(d,J=7.7Hz,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). LCMSm / z 516.0[M+H] + .

[0751] Compound 33

[0752] 2-Hydroxy-N-[3-hydroxy-2-[[5-(2-methyl-4-pyridinyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]propyl]ethanesulfonamide (33)

[0753]

[0754] Step 1. Synthesis of 3-[5-(2-methyl-4-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyhydroxyazetidine-1-carboxylic acid benzyl ester

[0755] To a solution of benzyl 3-hydroxyhydroxyazetidine-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-pyridinyl)-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 H2O, dried over Na2SO4, and concentrated. Purification by silica gel chromatography (gradient with 0-5% MeOH / dichloromethane) gave the product. Benzyl 3-[5-(2-methyl-4-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyhydroxyazetidine-1-carboxylate (222 mg, 95%) LCMS m / z 634.0 [M+H] + .

[0756] Step 2. Synthesis of 8-(azetidin-3-yloxy)-5-(2-methyl-4-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (C32)

[0757] To a solution of benzyl 3-[5-(2-methyl-4-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyhydroxyazetidine-1-carboxylate (222 mg, 0.3503 mmol) in MeOH (5 mL) and EtOAc (5 mL) was added Pd / C (120 mg of 10% w / w, 0.1128 mmol) and stirred under a hydrogen balloon for 1 hour. The Pd catalyst was filtered off and the filtrate was concentrated. Purification by silica gel chromatography (gradient: 0-20% MeOH / dichloromethane) gave the product. 8-(Azetidin-3-yloxy)-5-(2-methyl-4-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinoline (132 mg, 75%), LCMS m / z 500.0 [M+H] + . 1H 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(d d,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).

[0758] Step 3. Synthesis of 2-hydroxy-N-[3-hydroxy-2-[[5-(2-methyl-4-pyridinyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]propyl]ethanesulfonamide (33)

[0759] Part A. To a solution of 8-(azetidin-3-yloxy)-5-(2-methyl-4-pyridinyl)-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 / water with 0.2% formic acid) gave the product. 2-[3-[5-(2-methyl-4-pyridinyl)-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] + .

[0760] Part B and Part C. To a solution of 2-[3-[5-(2-methyl-4-pyridinyl)-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 1M, 0.4000 mmol) was added and stirred for 130 minutes. Purification by reverse phase chromatography (column: C18, gradient: 10% to 100% MeCN / water with 0.2% formic acid) gave the product. 2-Hydroxy-N-[3-hydroxy-2-[[5-(2-methyl-4-pyridinyl)-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] + .

[0761] Compound 34

[0762] 3-[[5-(2-methyl-4-pyridinyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]hydroxyazetidine-1-carboxamide (34)

[0763]

[0764] To a solution of 8-(azetidin-3-yloxy)-5-(2-methyl-4-pyridinyl)-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 hour and then concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-10% MeOH / dichloromethane) gave the product. 3-[5-(2-Methyl-4-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyhydroxyazetidine-1-carboxamide (7 mg, 64%). LCMS m / z 543.0 [M+H] + .

[0765] To a solution of 3-[5-(2-methyl-4-pyridinyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxyhydroxyazetidine-1-carboxamide (7 mg, 64%) in dichloromethane (2 mL) was added TFA (200 μL, 2.596 mmol) and stirred for 1 hour before being placed under vacuum. Purification by reverse phase chromatography (column: C18, gradient: 10-100% MeCN / water with 0.2% formic acid) afforded the product: 3-[[5-(2-methyl-4-pyridinyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]hydroxyazetidine-1-carboxamide (4.2 mg, 43%). 1 HNMR (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] + .

[0766] Compound 35

[0767] 3-Hydroxy-2-methyl-1-[3-[[5-(2-methyl-4-pyridinyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]azetidin-1-yl]propan-1-one (35)

[0768]

[0769] Compound 35 was prepared from C32 as described for compound 32. 3-Hydroxy-2-methyl-1-[3-[[5-(2-methyl-4-pyridinyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]azetidin-1-yl]propan-1-one (2.0 mg, 13%). 1 H NMR (400MHz, methanol-d4) δ8.61(d,J=5.1Hz,1H),8.51(dt,J=7.0,1.1Hz,1H),8.21(t,J=1.3Hz,1H),7.6 6(t,J=1.2Hz,1H),7.36(d,J=4.2Hz,1H),7.28(t,J=4.5Hz,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),3.3 7(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] + .

[0770] Compounds 36-41

[0771] Compounds 36-41 (Table 3) were prepared from C32 using the method described for the preparation of compound 32.

[0772] Table 3. Preparation methods, structures and physicochemical data of compounds 36-41

[0773]

[0774]

[0775]

[0776] Compound 42

[0777] 4-[[5-(3,4-Difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (42)

[0778]

[0779] 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. 1 H NMR (300 MHz, chloroform-d + methanol-d4) 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, 7.6, 2.1 Hz, 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(dd d,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] + .

[0780] Compounds 43 and 44

[0781] 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)

[0782]

[0783] Step 1. Synthesis 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-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 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 methyl ester (C34-B)

[0784] 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 3-fluoro-4-hydroxy-2-methoxy-benzoic acid methyl ester (140 mg, 0.6994 mmol) in anhydrous DMF (4 mL) was added CsCO (539 mg, 1.654 mmol) at room temperature under nitrogen. The reaction mixture was microwaved at 150°C under nitrogen for 20 hours. The reaction mixture was quenched with water (1 mL) and 1M HCl (~2 mL, until pH = 6). The desired product was extracted with EtOAc, washed with water, saturated NaCl, and dried. Purification by silica gel chromatography (gradient: 0-10% MeOH / dichloromethane, then 0-20% MeOH / 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] + Obtained as an inseparable mixture with a small amount 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-hydroxy-benzoic acid methyl ester (C34-B).

[0785] 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] + .

[0786] 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 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)

[0787] 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 small amount of C34-B impurity 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 x 150 mm, 5 micron). Gradient: MeCN / H2O containing 0.2% formic acid)

[0788] 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-d4) 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 / z550.21[M+H] + .

[0789] Product B: 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 (3 mg, 5%) (43). 1H 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=8.9,6 .5Hz,1H),4.04(s,3H),3.90(d,J=11.5Hz,2H),3.33-3.19(m,2H),2.73-2.62(m,1H),1.90(q,J=12.0Hz,2H),1.43(d,J=13.1Hz,2H)ppm.LCMS m / z 550.21[M+H] + .

[0790] Compounds 45-64

[0791] Compounds 45-62 were prepared by treating S5 with NaH and an appropriate alcohol reagent as described for compound 42. Compounds 62-64 were prepared from S4 by treatment with NaH and an appropriate alcohol reagent followed by removal of the THP protecting group with HCl.

[0792] Table 4. Preparation methods, structures and physicochemical data of compounds 45-64

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800] *Compound 62 was prepared from S4 and 4-(hydroxymethyl)pyrrolidin-2-one to provide 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. This intermediate was alkylated with benzyl 2-bromoacetate to provide 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 provided compound 62.

[0801] Compound 65

[0802] 4-[5-(3,4-Difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-3-fluoro-benzoic acid (65)

[0803]

[0804] 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)

[0805] 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-dihydroxyborono-3-fluoro-benzoic acid (50 mg, 0.2718 mmol), and Pd(PPh) (15 mg, 0.01298 mmol) in DMF (4 mL) was added NaCO (600 μL of 2M, 1.200 mmol) under nitrogen. The reaction mixture was microwaved 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 NaSO. Purification by silica gel chromatography (Gradient: 0-10% MeOH / dichloromethane) followed by reverse phase HPLC (Method C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN / H2O 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] + .

[0806] 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)

[0807] 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 (4.5 mL of 4M, 18.00 mmol) in 1,4-dioxane. 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 x 150 mm, 5 micron). Gradient: MeCN / H2O (containing 0.2% formic acid) to obtain 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] + ..

[0808] Compounds 66 and 67

[0809] Methyl 3-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylate (66) and 3-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylate (67)

[0810]

[0811] 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)

[0812] To a solution of 5-(3,4-difluorophenyl)-7-oxo-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) was added PyBroP (560 mg, 1.201 mmol) and the reaction was stirred at 80° C. overnight. Additional PyBrop (560 mg, 1.201 mmol) was added and the reaction was stirred at 80° C. overnight. The mixture was concentrated in vacuo and then purified by reverse phase HPLC (Method C18 Waters Sunfire column (30×150 mm, 5 micron) gradient: MeCN / H 2 O with 0.1% trifluoroacetic acid) to give the product. 3-[[5-(3,4-Difluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylic acid methyl ester (74 mg, 62%). LCMS m / z 577.34 [M+H] + .

[0813] Synthesis of methyl 3-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylate (66)

[0814] 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) was stirred in a solution of hydrogen chloride (5 mL of 4 M, 20.00 mmol) in 1,4-dioxane (5 mL) for 50 minutes. Et2O was added and stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with Et2O and filtered. The filter cake was then dried under vacuum. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN / H2O (containing 0.1% trifluoroacetic acid) to obtain the product. Methyl 3-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylate (trifluoroacetate) (45 mg, 72%). 1H NMR (400 MHz, methanol-d4) δ 8.94 (s, 1H), 8.28 (d, J = 1.1 Hz, 1H), 7.67 (d, J = 1.0 Hz, 1H), 7.53 (dt, J = 10.5, 8.3 Hz, 1H), 7.36 (ddd, J = 10.9, 7.6, 2.1 Hz, 1H), 7.20 (ddt, J = 8.1, 3.8, 1.7 Hz, 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 / z493.31[M+H] + .

[0815] Synthesis of 3-[[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]amino]cyclobutanecarboxylic acid (67)

[0816] 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 stirred for 30 minutes. TFA (250 μL, 3.245 mmol) was added, and the mixture was evaporated to dryness. Purification by reverse phase HPLC was performed using a C18 Waters Sunfire column (30 x 150 mm, 5 micron). A gradient of MeCN / H2O containing 0.2% formic acid was used to obtain 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%) 1H NMR (400 MHz, methanol-d4) δ 8.39 (d, J = 1.1 Hz, 1H), 8.15-8.09 (m, 2H), 7.54 (d, J = 1.0 Hz, 1H), 7.41 (dt, J = 10.8, 8.4 Hz, 1H), 7.20 (ddd, J = 11.3, 7.8, 2.1 Hz, 1H), 7.07 (ddd, J = 8.0, 3.9, 1.9 Hz, 1H), 4.95 (d, J = 7.9 Hz, 1 H),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] + .

[0817] Compounds 68-74

[0818] Compounds 68-74 (Table 5) were prepared from S7 according to the procedure described for compound 6. Modifications to the procedure are noted in the table footnotes.

[0819] Table 5. Preparation methods, structures and physicochemical data of compounds 68-74

[0820]

[0821]

[0822]

[0823] *Phosphonates were hydrolyzed by treatment with TMSBr in dichloromethane at room temperature.

[0824] Compounds 75-88

[0825] Compounds 75-88 (Table 6) were prepared from S8 using the method described for compound 42. The THP protecting group was removed by treatment with TFA, HCl, or TFA. Any modifications are noted in the table footnotes.

[0826] Table 6. Preparation methods, structures and physicochemical data of compounds 75-88

[0827]

[0828]

[0829]

[0830]

[0831]

[0832] *Compound 87 was prepared by 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 yield 8-(3-azabicyclo[3.2.0]hept-6-yloxy)-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinoline (trifluoroacetate). The amine was alkylated by treatment with tert-butyl 2-bromopropionate and K2CO3 in DMF. The tert-butyl ester group was then removed with TFA to yield the product.

[0833] Compound 89

[0834] [3-[[5-(4-Fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]azetidin-1-yl]-(1-hydroxycyclopropyl)methanone (89)

[0835]

[0836] Compound 89 was prepared from S9 according to the method described for compound 35. Purification was by reverse phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN / H2O with 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] +

[0837] Compound 90

[0838] (2R)-3-[5-(4-Fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propionic acid (hydrochloride) (90)

[0839]

[0840] Step 1. Synthesis of (2R)-3-[5-(4-fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propionic acid methyl ester (C37)

[0841] 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(PPh) (20 mg, 0.01731 mmol) in THF (2 mL) under nitrogen was added bromo-[(2S)-3-methoxy-2-methyl-3-oxo-propyl]zinc (1.9 mL of 0.5 M, 0.9500 mmol). The reaction mixture was heated at 90°C for 4 hours to evaporate the solvent, and the residue was dissolved in dichloromethane. The organic solution was washed with NaOH (0.5 M / 6 mL), water, brine, dried over NaSO, and concentrated. Purification by silica gel chromatography (gradient: 10-100% EtOAc / 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-propionic acid methyl ester (115 mg, 94%). 1 H NMR (300MHz, chloroform-d) δ8.32(dt,J=3.7,1.1Hz,1H),8.15(d,J=0.9Hz,1H),7.71(d,J=1.0Hz,1H) ,7.28-7.17(m,4H),5.95(dd,J=8.9,2.7Hz,1H),4.08-3.98(m,3H),3.92(dd,J=8.1,6.1Hz,1 H),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] + .

[0842] Step 2. Synthesis of (2R)-3-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propionic acid methyl ester (C37)

[0843] (2R)-3-[5-(4-Fluorophenyl)-1-tetrahydropyran-2-yl-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propionic acid methyl ester (110 mg, 0.2069 mmol) was treated with HCl (5 mL of 4M, 20.00 mmol) in 1,4-dioxane. 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 and then dried to give (2R)-3-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propionic acid methyl ester (56 mg, 60%) LCMS m / z 447.5 [M+H] + .

[0844] Step 3. Synthesis of (2R)-3-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propionic acid (90)

[0845] A mixture of (2R)-3-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propionic acid methyl ester (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 hours. 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 / dichloromethane) gave the product. (2R)-3-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]-2-methyl-propionic 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 / z434.43[M+H] + .

[0846] Compound 91

[0847] 3-[5-(4-Fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]propanoic acid (91)

[0848]

[0849] Compound 91 was prepared from S9 as described for compound 90. Tert-butyl ester and THP deprotection were performed by treating 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-d4) 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, 4.2 Hz, 2H), 3.41-3.34 (m, 4H), 3.09 (t, J = 6.6 Hz, 2H), 2.80 (tt, J = 11.8, 3.8 Hz, 1H), 2.32 (qd, J = 12.8, 4.5 Hz, 2H), 1.51 (d, J = 12.2 Hz, 2H) ppm. LCMS m / z 420.39 [M+H] + .

[0850] Compound 92

[0851] 4-[5-(4-Fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]benzoic acid (92)

[0852]

[0853] Compound 92 was prepared from S9 by Suzuki coupling with tert-butyl 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,1H) ,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 / z468.26[M+H] + .

[0854] Compounds 93-103

[0855] 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.

[0856] Table 7. Preparation methods, structures and physicochemical data of compounds 93-103

[0857]

[0858]

[0859]

[0860]

[0861] *The tert-butyl ester is removed under the reaction conditions.

[0862] **Ethyl ester was removed under reaction conditions.

[0863] Compound 102 and Compound 103

[0864] 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)

[0865]

[0866] Steps 1 and 2.

[0867] A mixture of compounds C41 and C42 was prepared in two steps from S11 and C39 using the procedure described for the preparation of compound C32. Compound C43 was prepared from the mixture of C41 and C42 by reductive amination with ethyl 2-oxoacetate.

[0868] 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)

[0869] 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 NaHCO (50 mL). After separation, the organic layer was washed with water, saturated NaCl and dried. Excess solvent was pumped off. Purification by silica gel chromatography (gradient: 0-100% EtOAc / heptane) gave C43 and the THP-protected analog. Compound C43 was the first eluting product. 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 (30 mg, 45%). LCMS m / z 517.5 [M+H] +.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 (43 mg, 55%). LCMS m / z 601.61 [M+H] + .

[0870] 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)

[0871] A mixture 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 (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 pH = 7. Excess solvent was removed. Purification by reverse phase HPLC was performed using a C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN / H2O (containing 0.1% trifluoroacetic acid) to afford two isomers, Compound 102 and Compound 103.

[0872] Compound 102. 1 H NMR (300 MHz, chloroform-d + methanol-d4) 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] + .

[0873] Compound 103. 1H NMR (300 MHz, chloroform-d + methanol-d4) 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] + .

[0874] 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)

[0875]

[0876] 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] + .

[0877] Compounds 105-128

[0878] 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 to S12 and appropriate ester deprotection. Any modifications are noted in the table footnotes.

[0879] Table 8. Preparation methods, structures and physicochemical data of compounds 105-128

[0880]

[0881]

[0882]

[0883]

[0884]

[0885] *Compound 117 was prepared by Negishi coupling as described for compound 90. The nitrile group was converted to the carboxylic acid by hydrolysis with NaOH in EtOH at 110 °C under microwave conditions.

[0886] **Compound 122 was obtained as a by-product in the preparation of compound 112.

[0887] Compound 123 and Compound 124

[0888] 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

[0889] 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)

[0890]

[0891] 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)

[0892] 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) and tert-butyl 2-bromoacetate (86 mg, 0.4409 mmol) in dichloromethane (4 mL) was added N,N-diethanolamine (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 hours. Excess solvent was removed. Purification by silica gel chromatography (gradient: 0-20% MeOH / dichloromethane) afforded the product. 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 (138 mg, 56%). LCMS m / z 629.4 [M+H] +The THP deprotected product was also observed. 2-[2-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]-6-azaspiro[3.4]octan-6-yl]acetate tert-butyl ester (20 mg, 9%). LCMS m / z 545.23 [M+1] + .

[0893] 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)

[0894] 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 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 (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 reaction mixture was stirred for 3 hours. The reaction was quenched with saturated NaHCO3 (1 mL) and sodium thiosulfate (10 mL). Silica gel chromatography (gradient: 0-20% MeOH / dichloromethane) followed by (gradient: 10-50% EtOAc / hexanes) provided the product.

[0895] Also obtained was 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] +.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 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. 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 (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]acetic acid tert-butyl ester (10 mg, 7%) LCMS m / z 643.52 [M+H] + .

[0896] 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)

[0897] A solution 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 (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 was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN / H2O (containing 0.2% trifluoroacetic acid) to provide Compound 123 and Compound 124.

[0898] 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%). 1H NMR (300 MHz, chloroform-d + methanol-d4) 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] + .

[0899] 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%). 1 H NMR (300 MHz, chloroform-d + methanol-d4) 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] + .

[0900] Compound 125 and Compound 126

[0901] 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)

[0902]

[0903] Compounds 125 and 126 were prepared from C41 using the procedures described for the preparation of C43 and compounds 123 and 124.

[0904] 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). 1 H NMR (300 MHz, chloroform-d + methanol-d4) δ8.43 (t, J = 1.1 Hz, 1H), 8.12 (d, J = 1.1 Hz, 1H), 7.62 (d, J = 1.1 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] + .

[0905] 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).1H NMR (300 MHz, chloroform-d + methanol-d4) 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] +

[0906] Compound 127

[0907] 3-[[5-(4-Fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (127)

[0908]

[0909] Step 1. Synthesis of 3-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (C49)

[0910] 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). NaH (140 mg of 60% w / w, 3.500 mmol) was then added at room temperature under nitrogen. The reaction was stirred for 1 hour. Purification by reverse phase chromatography (column: C18, gradient: 0-100% MeCN / water with 0.1% trifluoroacetic acid) gave the product. Fractions containing the product were combined 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 obtain 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%) was obtained. LCMS m / z 504.29 [M+H] + .

[0911] Step 2. Synthesis of 3-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (127)

[0912] In a 3 L four-necked flask equipped with a mechanical stirrer and a temperature probe, 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) (28.2 g, 41.17 mmol) in dichloromethane (560 mL) was added Et3SiH (13.2 mL, 82.64 mmol) followed by TFA (224 mL) at room temperature. The reaction mixture was stirred for 2 hours and then concentrated (50°C rotary evaporation bath). The resulting thick yellow oil / paste was treated with water (850 mL), the solids were scraped off the sides of the flask, and the resulting suspension was rotated on a rotary evaporator (no vacuum) for 30 minutes with the bath set at 65°C. The resulting suspension was cooled to 28°C and then filtered. The collected solid was washed with water (500mL), then suction dried, then transferred to a 1L flask and then dissolved / suspended in AcOH (300mL). The suspension was heated at 75°C for 20 minutes on a rotary evaporator (non-vacuum) to obtain a uniform suspension. The mixture was then ultrasonicated for 2 minutes and treated with water (300mL). The mixture was then heated at 75°C for 20 minutes on a rotary evaporator (non-vacuum), then cooled to 23°C and filtered. The material was suspended in AcOH (1.5L) and heated to 90°C. After 30 minutes at 90°C, the suspension was cooled to room temperature, treated with water (1.5L), and then filtered. The residue was dissolved in DMSO (200mL). Water (200mL) was added dropwise over 15 minutes to obtain a suspension. The mixture was stirred for another 20 minutes, then filtered and washed with water (200mL). The solid was dried under suction for 30 minutes, then on a rotary evaporator (75° C., 3 mbar) for 1 hour and then in a vacuum oven at 75° C. for 18 hours. 16.1 g of a yellow powder were obtained. 1 H 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(ddt,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.

[0913] Compound 128

[0914] 3-[[5-(4-Fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid phosphonooxymethyl ester (128)

[0915]

[0916] Step 1. Synthesis of di-tert-butyloxyphosphoryloxymethyl 3-[5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylate (C50)

[0917] 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-butyl chloromethyl phosphate (950 mg, 3.673 mmol). The mixture was heated to 75°C. After 2.5 hours, additional DIPEA (1.0 mL, 5.741 mmol) and di-tert-butyl chloromethyl phosphate (800 mg, 3.093 mmol) were added. The reaction was stirred at 75°C for an additional 2.5 hours and then cooled to room temperature. The mixture was partitioned between water and EtOAc (80 mL each). The organic layer was separated and washed with 5 wt% aqueous citric acid, water, and brine (80 mL each), dried (MgSO₄), filtered, and concentrated. Purification by silica gel chromatography (Gradient: 0-100% EtOAc / heptane) afforded the product: di-tert-butyloxyphosphoryloxymethyl 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. 1H 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),7.32-7.19(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),3.40( 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] + .

[0918] Step 2. Synthesis of phosphonooxymethyl 3-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylate (128)

[0919] To a solution of di-tert-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 rotary evaporator (60°C). The residue was dissolved in MeOH (5 mL) and purified. The product was obtained by reverse phase chromatography (column: C18. Gradient: 0-100% MeCN / water with 0.1% trifluoroacetic acid) and then lyophilized. The powder was slurried in water (10 mL) for 45 minutes, then filtered and washed with water (10 mL). Drying under suction for 30 minutes and then on a rotary evaporator (2 mbar, 60° C.) for 1 hour 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. 1H 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). 19 FNMR(282MHz,DMSO-d6)δ-115.18. 31 P NMR(162MHz,DMSO-d6)δ-2.56.LCMS m / z 530.14[M+H] + .

[0920] Compound 129

[0921] 3-[5-(4-Fluorophenyl)-6-isopropyl-1-(2-phosphonooxyethoxycarbonyl)pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (129)

[0922]

[0923] Step 1. Synthesis of 3-[1-(2-di-tert-butoxyphosphoryloxyethoxycarbonyl)-5-(4-fluorophenyl)-6-isopropyl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (C51)

[0924] 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 was added KOtBu (1.4 mL of 1 M, 1.400 mmol) (solution in THF) to give a suspension of a yellow solid with hindered stirring. 2-di-tert-butoxyphosphoryloxyethyl (2,5-dioxypyrrolidin-1-yl) carbonate (540 mg, 1.366 mmol) (as a solid) was added, and the reaction mixture turned light red in color, and the yellow solid was consumed after approximately 5 minutes. After a total of 8 minutes, the reaction was quenched with saturated aqueous NH4Cl solution (10 mL). The mixture was partitioned between EtOAc and water (80 mL each). The organic layer was separated, washed with water, then with brine (80 mL each), dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (gradient: 0-100% EtOAc / heptane) afforded the product, 3-[1-(2-di-tert-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] + .

[0925] Step 2. Synthesis of 3-[5-(4-fluorophenyl)-6-isopropyl-1-(2-phosphonooxyethoxycarbonyl)-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (129)

[0926] To a solution of 3-[1-(2-di-tert-butoxyphosphoryloxyethoxycarbonyl)-5-(4-fluorophenyl)-6-isopropyl-pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (240 mg, 0.3430 mmol) in DCM (10 mL) was added TFA (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 45 minutes and then concentrated. Purification by reverse phase chromatography (column: C18, gradient: 0-100% MeCN / water with 0.1% trifluoroacetic acid) afforded the product. 3-[5-(4-fluorophenyl)-6-isopropyl-1-(2-phosphoryloxyethoxycarbonyl)pyrazolo[4,3-g]isoquinolin-8-yl]oxycyclobutanecarboxylic acid (trifluoroacetic acid (0.5%)) (70 mg, 31%) was obtained as a light yellow solid. 1H 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),4.8 4-4.77(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] + .

[0927] Compound 130

[0928] 2-[2-[[5-(4-Fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]ethoxy]acetic acid (130)

[0929]

[0930] Compound 130 was prepared in two steps from S13 according to the method described for the preparation of compound 2 (tert-butyl 2-(2-hydroxyethoxy)acetate was added 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 HNMR (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] + .

[0931] Compound 131

[0932] (2S,4R)-1-Acetyl-4-[[5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]pyrrolidine-2-carboxylic acid (131)

[0933]

[0934] 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%). 1 H 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 / z477.33[M+H] +

[0935] Compound 132

[0936] 2-[[3-[[5-(4-Fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarbonyl]amino]propionic acid (132)

[0937]

[0938] Compound 132 was prepared from compound 127 by a two-step HATU coupling using the method described for 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). LCMSm / z 491.0[M+H] + .

[0939] Compound 133

[0940] 3-[[5-(3,4-Difluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (133)

[0941]

[0942] Compound 133 was prepared from C11 using the method described for compound 1. Purification by reverse phase chromatography (column: C18, gradient: 0-100% MeCN / water with 0.2% formic acid) afforded the product. A light 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-d3:1) 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] + .

[0943] Compound 134

[0944] 3-[[6-Isopropyl-5-(2-methyl-4-pyridyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (134)

[0945]

[0946] Compound 134 was prepared from S15 and methyl 3-hydroxycyclobutanecarboxylate as described for compound 27. KOtBu was used as the base in the displacement reaction. Hydrolysis of the methyl ester using NaOH followed by TFA deprotection of the THP group afforded the product. 1HNMR (400MHz, methanol-d4) δ8.58 (dd, J=5.1, 0.8Hz, 1H), 8.45 (dt, J=2.9, 1.1Hz, 1H), 8.25(s,1H),8.18(t,J=1.2Hz,1H),7.60(d,J=1.1Hz,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,1 H), 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] +

[0947] Compound 135

[0948] 4-[[6-Isopropyl-5-(2-methyl-4-pyridyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (135)

[0949]

[0950] Compound 135 was prepared from S14 and a hydroxybenzoate using the procedure 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] + .

[0951] Compound 136

[0952] 3-[[6-Isopropyl-5-(2-methoxy-4-pyridinyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (136)

[0953]

[0954] Compound 136 was prepared by adding 3-hydroxycyclobutanecarboxylate to S16 using NaH in DMSO. 1HNMR (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=5.2,1.4Hz ,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] + .

[0955] Compound 137

[0956] 3-[[5-(4-Fluorophenyl)-6-(1-hydroxycyclopropyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (137)

[0957]

[0958] Compound 137 was prepared by adding 3-hydroxycyclobutanecarboxylate to S17 using NaH in DMSO. The benzyl ester was removed by hydrogenation using a Pd(OH)2 catalyst. LCMS m / z 434.09 [M+H] +

[0959] Compound 138

[0960] 4-[[5-(4-Fluorophenyl)-6-(1-hydroxycyclopropyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (138)

[0961]

[0962] Compound 138 was prepared by adding 3-hydroxycyclobutanecarboxylate to S17 using NaH in DMSO. The benzyl ester was removed by hydrogenation using a Pd(OH)2 catalyst. LCMS m / z 458.04 [M+H] +

[0963] Compound 139

[0964] 3-[[5-(3,4-Difluorophenyl)-6-(1-hydroxycyclopropyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (139)

[0965]

[0966] Compound 139 was prepared by adding 3-hydroxycyclobutanecarboxylate to S18 using NaH in DMSO. The benzyl ester was removed by hydrogenation using a Pd(OH)2 catalyst.

[0967] 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 / z452.47[M+H] + .

[0968] Compound 140

[0969] 3-[[5-(3,4-Difluorophenyl)-6-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (140)

[0970]

[0971] Compound 140 was prepared by adding 3-hydroxycyclobutanecarboxylate to S19 using NaH in DMSO. 1 HNMR (300 MHz, acetone-d6) δ 8.56 (t, J = 1.1 Hz, 1H), 8.30 (d, J = 1.1 Hz, 1H), 7.77 (d, J = 1.1 Hz, 1H), 7.55 (dt, J = 10.8, 8.5 Hz, 1H), 7.40 (ddd, J = 10.5, 7.8, 2.1 Hz, 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] + .

[0972] Compound 141

[0973] 3-[[6-(1,1-difluoroethyl)-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (141)

[0974]

[0975] Compound 141 was prepared in two steps starting from S20. Compound S20 was converted to 8-(4-aza-1-azoniabicyclo[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-azoniabicyclo[2.2.2]octan-1-yl)-6-(1,1-difluoroethyl)-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinoline using NaH in DMSO to afford the product: 3-[[6-(1,1-difluoroethyl)-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid. 1 H 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),5.75-5.6 0(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] + .

[0976] Compound 142

[0977] 3-[[5-(3,4-Difluorophenyl)-6-(1-methoxycyclobutyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (142)

[0978]

[0979] 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. 1H 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. 0Hz,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] + .

[0980] Compound 143

[0981] 3-[[5-(3,4-Difluorophenyl)-6-(2-methoxy-2-methyl-propyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]cyclobutanecarboxylic acid (143)

[0982]

[0983] 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=11.3,7.7,2.1Hz ,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] + .

[0984] Compound 144

[0985] 4-[[5-(3,4-Difluorophenyl)-6-(2-hydroxy-1,1-dimethyl-ethyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoic acid (144)

[0986]

[0987] 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)

[0988] 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)2 (3.32 mg, 0.01479 mmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (9.43 mg, 0.02221 mmol), and K3PO4 (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 a saturated solution of NH4Cl. The product was purified by silica gel chromatography (gradient: 0-30% EtOAc / heptane). 4-[6-(2-Benzyloxy-1,1-dimethyl-ethyl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxybenzoic acid ethyl ester (33 mg, 30%) LCMS m / z 691.78 [M+H] + .

[0989] 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)

[0990] 4-[6-(2-Benzyloxy-1,1-dimethyl-ethyl)-5-(3,4-difluorophenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]isoquinolin-8-yl]oxybenzoic acid ethyl ester was dissolved in MeOH (5 mL). The solution was transferred into 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 small column, concentrated, and purified (gradient: 0-30% EtOAc / heptane) to afford 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] + .

[0991] 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)

[0992] To a 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 a solution 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 a saturated solution of NaHCO₃. The product was extracted with EtOAc. The reaction was concentrated in vacuo and purified by silica gel chromatography (Gradient: 0-10% MeOH / dichloromethane) to provide ethyl 4-[[5-(3,4-difluorophenyl)-6-(2-hydroxy-1,1-dimethyl-ethyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl]oxy]benzoate.

[0993] 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) / H₂O (0.4 mL) was added LiOH (5.25 mg, 0.2192 mmol). The reaction was stirred at room temperature for 3 hours. The reaction mixture was diluted with H₂O and acidified with 1N aqueous HCl. The product was extracted with EtOAc and concentrated to yield 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%). 1H NMR (300MHz, methanol-d4) δ8.60(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] + .

[0994] Preparation of T1 and T2

[0995] 5-(4-Fluorophenyl)-6-isopropyl-8-oxo-1H-pyrazolo[4,3-g]quinolin-8-ium (T1) and 7-chloro-5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]quinolone (T2)

[0996]

[0997]

[0998] Step 1. Synthesis of methyl 4-[(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methylamino]-2-fluoro-benzoate

[0999] 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-fluoro-benzoate (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 yield the product: methyl 4-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methylamino]-2-fluoro-benzoate (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 / z324.1[M+H] + .

[1000] Step 2. Synthesis of 5-fluoro-4-oxo-1H-quinoline-6-carboxylic acid methyl ester 7-fluoro-4-oxo-1H-quinoline-6-carboxylic acid methyl ester

[1001] At 220 0 To Dowtherm A (200 mL) at 7°C was added portionwise 4-[(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methylamino]-2-fluoro-benzoic acid methyl ester (45 g, 139.20 mmol). After bubbling subsided, the mixture was heated for an additional 10 minutes and then cooled to room temperature. The mixture was diluted with hexanes, and the resulting solid was collected by filtration and washed with hexanes to give the product as a regioisomer mixture of 7-fluoro-4-oxo-1H-quinoline-6-carboxylic acid methyl ester D3 (25 g, 81%) and 5-fluoro-4-oxo-1H-quinoline-6-carboxylic acid methyl ester D4 (52:41, determined by LCMS). The mixture was carried on to the next step without separation. LCMS m / z 221.96 [M+H] + .

[1002] Step 3. Synthesis of 3-bromo-7-fluoro-4-oxo-1H-quinoline-6-carboxylic acid methyl ester and 3-bromo-5-fluoro-4-oxo-1H-quinoline-6-carboxylic acid methyl ester (D5)

[1003] A mixture of regioisomers of 7-fluoro-4-oxo-1H-quinoline-6-carboxylic acid methyl ester (29 g, 115.38 mmol) D3 and 5-fluoro-4-oxo-1H-quinoline-6-carboxylic acid methyl ester 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 portionwise. The reaction was stirred at room temperature overnight. The reaction was quenched with ice-cold water under stirring. The solid was filtered and washed with cold water. The compound was dried under vacuum to give 3-bromo-7-fluoro-4-oxo-1H-quinoline-6-carboxylic acid methyl ester D5 (32 g, 49%). LCMS m / z 300.0 [M+H] + A mixture of regioisomers and methyl 3-bromo-5-fluoro-4-oxo-1H-quinoline-6-carboxylate (32 g, 39%). LCMS m / z 302.0 [M+H] + The mixture was used in the subsequent step without separation.

[1004] Step 4. Synthesis of 3-bromo-4-chloro-7-fluoro-quinoline-6-carboxylic acid methyl ester and 3-bromo-4-chloro-5-fluoro-quinoline-6-carboxylic acid methyl ester (D6)

[1005] A regioisomer 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 saturated NaHCO₃ solution, and extracted with dichloromethane (100 mL x 3). The combined organic phases were dried over Na₂SO₄ and concentrated. The mixture was purified by silica gel chromatography (Gradient: 3% EtOAc / hexanes) to give 3-bromo-4-chloro-7-fluoro-quinoline-6-carboxylic acid methyl ester 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 / z317.8[M+H] + .

[1006] Elution with 4% EtOAc / hexanes afforded the second regioisomer, 3-bromo-4-chloro-5-fluoro-quinoline-6-carboxylic acid methyl ester (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] + .

[1007] Step 5. Synthesis of 4-chloro-7-fluoro-3-isopropenyl-quinoline-6-carboxylic acid methyl ester (D7)

[1008] A stirred solution of 3-bromo-4-chloro-7-fluoro-quinoline-6-carboxylic acid methyl ester D6 (8.45 g, 26.528 mmol), K3PO4 (11.262 g, 53.056 mmol) and potassium trifluoro(isopropenyl)borate (4.3181 g, 29.181 mmol) in 1,4-dioxane (90 mL) and H2O (9 mL) was purged with Ar gas for 10 minutes. Then, Pd(dppf)Cl2.CH2Cl2 (2.1664 g, 2.6528 mmol) was added. The reaction mixture was heated at 100°C overnight. The reaction mixture was stirred for 10 minutes. The mixture was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo. Purification by column chromatography (gradient: 5-8% EtOAc / hexanes) gave the product: 4-chloro-7-fluoro-3-isopropenyl-quinoline-6-carboxylic acid methyl ester (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] + .

[1009] Step 6. Synthesis of 7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-quinoline-6-carboxylic acid (D8)

[1010] 4-Chloro-7-fluoro-3-isopropenyl-quinoline-6-carboxylic acid methyl ester (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 K3PO4 (10.63 g, 50.0 mmol) aqueous solution (6 mL) was added thereto. The reaction mixture was purged with nitrogen for 10 minutes, and then Pd(PPh3)4 (2.89 g, 2.50 mmol) and tricyclohexylphosphine (701.8 mg, 2.5 mmol) were added thereto, and finally the reaction mixture was heated to 90 ° C and continued for 12 hours. After completion, the reaction mixture was passed through The mixture was washed with EtOAc. The combined organic layers were evaporated under reduced pressure. Purification by flash chromatography on silica gel (100-200 mesh) using 5-10% EtOAc / hexanes gave 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]+.

[1011] Step 7: Synthesis of [7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-6-quinolyl]methanol (D9)

[1012] To a solution of 7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-quinoline-6-carboxylic acid (1g, 3.0740mmol) in THF (15mL) was added Et3N (373mg, 0.5141mL, 3.69mmol) and ethyl chloroformate (400mg, 0.35mL, 3.69mmol) and stirred for 1 hour. The reaction mixture was filtered out and a solution of NaBH4 (232mg, 6.15mmol) in H2O (3.5mL) was added to the filtrate and stirred for 3 hours. The reaction mixture was carefully quenched with 1N HCl and extracted with EtOAc. The extract was washed with saturated NaHCO3 brine, dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (Gradient: 30-50% EtOAc / hexanes) gave the product as a white solid [7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-6-quinolinyl]methanol (800 mg, 80%). LCMS m / z 312.0 [M+1] + .

[1013] Step 7. Synthesis of [7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-6-quinolyl]methanol (D9)

[1014] To an ice-cold stirred solution of LiAlH4 (201.33 mg, 0.2196 mL, 5.3045 mmol) in THF (20 mL) was added dropwise a solution of 7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-quinoline-6-carboxylic acid methyl ester (1.2 g, 3.53 mmol) in THF (10 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was cooled to 0 ° C and quenched by 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 celite bed and washed with EtOAc (20 mL). The filtrate was concentrated and the crude product was purified by column chromatography (silica gel 100-200 mesh) using 30%-40% EtOAc / hexane to give the desired product [7-fluoro-4-(4-fluorophenyl)-3-isopropenyl-6-quinolinyl]methanol (800 mg, 66%). LCMS m / z 312.0 [M+1] + .

[1015] Step 8. Synthesis of [7-fluoro-4-(4-fluorophenyl)-3-isopropyl-6-quinolyl]methanol (D10)

[1016] 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 hydrogen under balloon pressure for 12 hours. The reaction was filtered, washed with EtOAc (30 mL), and concentrated. Purification by silica gel chromatography (gradient: 0-30% EtOAc / 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] + .

[1017] Step 9. Synthesis of 7-fluoro-4-(4-fluorophenyl)-3-isopropyl-quinoline-6-carbaldehyde (D11)

[1018] After 15 minutes, DMSO (967.54 mg, 0.8788 mL, 12.383 mmol) was added to a stirred solution of oxalyl chloride (785.85 mg, 0.5401 mL, 6.1914 mmol) in dichloromethane (10 mL) at -78°C. A solution of [7-fluoro-4-(4-fluorophenyl)-3-isopropyl-6-quinolinyl]methanol (970 mg, 3.0957 mmol) in dichloromethane (3 mL) was added. 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.

[1019] Purification by silica gel chromatography (Gradient: 0-10% EtOAc / heptane) afforded the product: 7-fluoro-4-(4-fluorophenyl)-3-isopropyl-quinoline-6-carbaldehyde (785 mg, 80%). 1H 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] + .

[1020] Step 10. Synthesis of 5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]quinolone (D12)

[1021] 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) in a sealed tube were mixed in DME (20 mL) at 40 ° for 4 hours. The reaction mixture was filtered and concentrated in vacuo to reduce the volume (10 mL). Hydrazine hydrate (2.2512 g, 2.1920 mL 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 distributed 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 / 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] + .

[1022] Step 11. Synthesis of 5-(4-fluorophenyl)-6-isopropyl-8-oxo-1H-pyrazolo[4,3-g]quinolin-8-ium (T1)

[1023] In a vial, a solution of 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 warmed to room temperature and stirred for 16 hours. The reaction was treated by adding saturated NaHCO3 solution and CHCl3:IPA. The mixture was extracted with CHCl3:IPA (x 3). 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-oxo-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] + .

[1024] Step 12. Synthesis of 7-chloro-5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]quinolone (T2)

[1025] In a small vial, 5-(4-fluorophenyl)-6-isopropyl-8-oxo-1H-pyrazolo[4,3-g]quinolin-8-ium (790 mg, 2.458 mmol) was weighed 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 recovered solid was washed with cold water to yield the product: 7-chloro-5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]quinoline (867 mg, 93%). 1 H 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). LCMSm / z 340.03[M+H] + .

[1026] Preparation of T3

[1027] 7-Bromo-2-chloro-4-(4-fluorophenyl)-3-isopropyl-quinoline-6-carbaldehyde (T3)

[1028]

[1029] Step 1. Synthesis of N-(3-bromo-4-methyl-phenyl)-3-methyl-butyramide (D14)

[1030] 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 in an ice bath. 3-Methylbutyryl chloride (60 mL, 492.1 mmol) was added portionwise. After addition, the cooling bath was removed and the mixture was stirred for 30 minutes. After 2 hours, the mixture was washed with brine, 1N HCl (70 mL), and saturated aqueous sodium bicarbonate solution. The aqueous washings were re-extracted with dichloromethane (2 x 500 mL). The dichloromethane phase was dried over Na₂SO₄, filtered, and evaporated. 10 g of this material was set aside. The remaining product was suspended in heptane plus approximately 5% MTBE and stirred for 1 hour. Purification by silica gel chromatography (gradient: 0-50% EtOAc / heptane) afforded the product: N-(3-bromo-4-methyl-phenyl)-3-methyl-butyramide (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] + .

[1031] Step 2. Synthesis of N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]-3-methyl-butyramide (D16)

[1032] A suspension of N-(3-bromo-4-methyl-phenyl)-3-methyl-butyramide (35.1 g, 129.9 mmol), 2-(4-fluorophenyl)-2-oxo-acetic acid (24.3 g, 144.5 mmol) and Pd(TFA)2 (2.53 g, 7.610 mmol) in diethylene glycol dimethyl ether (420 mL) was stirred for 5 minutes. Sulfoxyammonium hydrogen sulfate (60 g, 262.9 mmol) was added. The mixture was bubbled with nitrogen and heated at 50°C (internal temperature) for 7 hours. The solvent was distilled off under high vacuum. The residue was partitioned between EtOAc and aqueous sodium bicarbonate solution and extracted with EtOAc (3x). The organic phase was washed with aqueous sodium bicarbonate solution and brine, dried over Na2SO4, filtered and evaporated. Purification by silica gel chromatography (gradient: 0-30% EtOAc / dichloromethane, then 0-20% EtOAc / dichloromethane) gave the product, N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]-3-methyl-butyramide (39.56 g, 78%). 1 HNMR (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] + .

[1033] Step 3. Synthesis of 7-bromo-4-(4-fluorophenyl)-3-isopropyl-6-methyl-1H-quinolin-2-one (D17)

[1034] To a solution of N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]-3-methyl-butyramide (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 6M HCl (30 mL). The mixture was diluted to 2 L with water and filtered. The resulting solid was washed with water (2x) 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%) 1H 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] + .

[1035] Step 4. Synthesis of 7-bromo-2-chloro-4-(4-fluorophenyl)-3-isopropyl-6-methyl-quinoline (D18)

[1036] 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 hours. 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 solution was added to pH ~8 and extracted with dichloromethane (3x). The organic phase was dried over Na2SO4, filtered and evaporated. The residue was crystallized from dichloromethane / MTBE. The resulting precipitate was collected by filtration. The solid was washed with water (2x) and dried under high vacuum. The solid (~10 g) was purified by silica gel chromatography (gradient: 0-100% EtOAc / heptane) to obtain two batches of product, 4.04 g (batch 1) and 5.67 g (batch 2), both as white solids. The filtrate (3.2 g) was purified by silica gel chromatography (Gradient: 0-100% dichloromethane / heptane) to provide 1.47 g of additional product as a white solid.

[1037] 7-Bromo-2-chloro-4-(4-fluorophenyl)-3-isopropyl-6-methyl-quinoline (11.18 g, 77%). 1 H NMR (300MHz, chloroform-d) δ8.17 (s, 1H), 7.30-7.03 (m, 4H), 6.89 (d, J = 1.1Hz, 1H), 3.12 (br.s, 1H), 2.33 (d, J = 0.9Hz, 3H), 1.25 (d, J = 7.2Hz, 6H). LCMS m / z 392.15[M+H] + .

[1038] Also isolated as a by-product of the reaction was 7-bromo-2-chloro-3-isopropyl-4-(4-methoxyphenyl)-6-methyl-quinoline (D61). 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] + .

[1039] 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)

[1040] 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 under reflux for 3 hours under air. The mixture was concentrated. Purification by silica gel chromatography (gradient: 0-100% dichloromethane / heptane) gave 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] + .

[1041] 7-Bromo-6-(bromomethyl)-2-chloro-4-(4-fluorophenyl)-3-isopropyl-quinoline was dissolved in CH3CN (110 mL). The resulting suspension was mixed with Activated molecular sieves (4 g) were stirred at room temperature for 10 minutes at 150°C. 4-Methyl-4-oxomorpholinium (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: 0-20% EtOAc / heptane) gave the product. 7-Bromo-2-chloro-4-(4-fluorophenyl)-3-isopropyl-quinoline-6-carbaldehyde (6.36 g, 56%). 1 H NMR (300MHz, 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 = 7.2Hz, 6H). LCMS m / z405.98[M+H] + .LCMS m / z 406.2[M+H] + .

[1042] Preparation of T4

[1043] 7-Chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolone (T4)

[1044]

[1045] Step 1. Synthesis of 7-methyl-1H-indazol-6-amine (D20)

[1046] In a flask, carbon / palladium (750 mg of 10% w / w, 0.7048 mmol) was suspended in EtOH (10 mL). Then, a solution of 7-methyl-6-nitro-1H-indazole (5000 mg, 28.22 mmol) in EtOH (200 mL) was added. The flask was purged with nitrogen and then 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 obtain a paste solid. 7-Methyl-1H-indazole-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 / z148.13[M+H] + .

[1047] Step 2. Synthesis of methyl 3-methyl-2-[(7-methyl-1H-indazol-6-yl)carbamoyl]butanoate

[1048] 3-Methyl-2-[(7-methyl-1H-indazol-6-yl)carbamoyl]butanoic acid (D22)

[1049] 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 x 10 mL). The combined organic layers were dried and concentrated under reduced pressure to give a yellow solid. The solid was suspended in diethyl ether (200 ml) and filtered. The solid was washed with additional diethyl ether and dried under vacuum to give methyl 3-methyl-2-[(7-methyl-1H-indazol-6-yl)carbamoyl]butanoate (7.5 g, 95%). LCMS m / z 290.6 [M+H] + .

[1050] 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 x 100 mL). The combined organic layers were dried and concentrated under reduced pressure to afford 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).

[1051] Step 3. Synthesis of 6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinoline-5,7-diol (D23)

[1052] 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) δ 13.03 (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] + .

[1053] Step 4. Synthesis of 7-chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolone (T4)

[1054] Part A. In a flask, 6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinoline-5,7-diol (1.00 g, 3.887 mmol) was weighed and dissolved in a mixture of dichloromethane (15 mL) and DMF (5 mL). Et3N (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 under vacuum. 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] + .

[1055] 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 under vacuum. Water was then added to the solution to precipitate the product. 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] + .

[1056] 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 to adjust the pH to ~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 green-yellow solid, which 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] + .

[1057] Preparation of T5 and T6

[1058] 5,7-Dichloro-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolone (T5) and

[1059] 1-[7-Chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-pyrazolo[4,3-g]quinolin-1-yl]-2,2-dimethyl-propan-1-one (T6)

[1060]

[1061] Step 1. Synthesis of 5,7-dichloro-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolone (T5)

[1062] 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 then cooled to room temperature. The solvent was removed under reduced pressure. The crude product was suspended in water (50 mL) and then basified with 6N NaOH. The precipitate was collected by filtration. The wet product 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) δ 13.65 (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] + .

[1063] Step 2. Synthesis of 5-chloro-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolin-7-ol

[1064] 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 to form 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] + .

[1065] Step 3. Synthesis of 5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolin-7-ol (D25)

[1066] Pd(PPh3)4 (250 mg, 0.2163 mmol) was added to a 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) purged with nitrogen. The solution was heated at 160°C for 45 minutes 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 was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30x150 mm, 5 microns). Gradient: MeCN / H2O (containing 0.2% formic acid) to afford 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] + .

[1067] Step 4. Synthesis of 7-chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinolone (T4)

[1068] 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 hours, and the reaction was cooled. The 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 was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN / H₂O (containing 0.2% trifluoroacetic acid) to obtain the product. 7-Chloro-5-(4-fluorophenyl)-6-isopropyl-9-methyl-1H-pyrazolo[4,3-g]quinoline (90 mg, 38%) was obtained 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 / z354.11[M+H] + .

[1069] 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)

[1070] 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. Then, 2,2-dimethylpropanoyl chloride (130 μL, 1.057 mmol) was added dropwise. The reaction was stirred at room temperature for 20 hours. The reaction was post-processed by evaporating the volatiles in vacuo. Water and dichloromethane were added and the mixture was extracted with dichloromethane (x 3). The organic phase was filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. Purification by silica gel chromatography (gradient: 0-2% EtOAc / heptane) gave 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] + .

[1071] Preparation of T7

[1072] 9-Fluoro-5-hydroxy-6-isopropyl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (T7)

[1073]

[1074] Step 1. Synthesis of 6-azido-7-fluoro-1H-indazole (D27)

[1075] In a microwave vial, 6-bromo-7-fluoro-1H-indazole (1000 mg, 4.651 mmol), NaN3 (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-ol (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 hours. Water and dichloromethane were added. The mixture was extracted with dichloromethane (x 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 / water with 0.2% formic acid) gave 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] + .

[1076] Step 2. Synthesis of 7-fluoro-1H-indazol-6-amine (D28)

[1077] In a flask, 6-azido-7-fluoro-1H-indazole (120 mg, 0.6774 mmol) was weighed and dissolved in ethanol (7 mL). Then, carbon / palladium (36 mg, 0.03383 mmol) was 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 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] + .

[1078] Step 3. Synthesis of 2-[(7-fluoro-1H-indazol-6-yl)carbamoyl]-3-methyl-butyric acid methyl ester (D29)

[1079] In a flask, 7-fluoro-1H-indazol-6-amine (90 mg, 0.5955 mmol) was suspended in dichloromethane (6 mL). Then, 2-methoxycarbonyl-3-methylbutanoic acid (160 mg, 0.8991 mmol) was 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 quenched by the addition of water and dichloromethane, followed by extraction with dichloromethane (x 3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. The crude product was purified by flash column chromatography on silica gel (gradient: 0-7% MeOH / dichloromethane) to obtain the product. 2-[(7-fluoro-1H-indazol-6-yl)carbamoyl]-3-methyl-butanoic acid methyl ester (224.2 mg, 90%, 70% purity). LCMS m / z 282.05[M+H] + .

[1080] Step 4. Synthesis of 2-[(7-fluoro-1H-indazol-6-yl)carbamoyl]-3-methyl-butanoic acid (D30)

[1081] 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 H2O (3 mL). The reaction was stirred at room temperature for 16 hours. The reaction was worked up by evaporating the volatiles, then adding water and adjusting the pH to 2. The mixture was extracted with CHCl3:IPA (x 3). The organic phases were filtered through a phase separator, combined, and the volatiles evaporated in vacuo to give a white product. 2-[(7-fluoro-1H-indazol-6-yl)carbamoyl]-3-methyl-butanoic acid (875 mg, 97%). LCMS m / z 280.15 [M+H] + .

[1082] Step 5. Synthesis of 9-fluoro-5-hydroxy-6-isopropyl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (D31)

[1083] In a vial, 2-[(7-fluoro-1H-indazol-6-yl)carbamoyl]-3-methyl-butanoic acid (135 mg, 0.4834 mmol) was weighed and suspended in Eaton's reagent (2000 μL, 12.60 mmol). The reaction was heated at 80°C for 96 hours (decarboxylation outperformed cyclization when heated at higher temperatures). The reaction was worked up by adding brine, adjusting the pH to 7 with 6M aqueous NaOH, and extracting sequentially with CHCl₃:IPA. The organic phases were combined, dried over MgSO₄, filtered, and the volatiles evaporated in vacuo. Purification by silica gel chromatography (gradient: 0-5% dichloromethane / 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 (400 MHz, DMSO-d6) δ 13.50 (s, 1H), 11.00 (s, 1H), 10.14 (s, 1H), 8.28 (dd, J = 3.4, 1.5 Hz, 1H), 8.17 (s, 1H), 3.43 (septet, J = 6.9 Hz, 1H), 1.30 (d, J = 7.0 Hz, 6H). LCMS m / z 262.19 [M+H] + .

[1084] Step 6. Synthesis of (9-fluoro-6-isopropyl-7-oxo-1,8-dihydropyrazolo[4,3-g]quinolin-5-yl) trifluoromethanesulfonate (D32)

[1085] In a flask, 9-fluoro-5-hydroxy-6-isopropyl-1,8-dihydropyrazolo[4,3-g]quinoline-7-one (210 mg, 0.7835 mmol) was weighed and dissolved in DMF (6 mL). Et3N (130 μL, 0.9327 mmol) was then added, followed by PhN(SO2CF3)2 (330 mg, 0.9237 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was post-processed by adding water and dichloromethane. The mixture was extracted with dichloromethane (x 3). The organic phase was filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. Purification by silica gel chromatography (gradient: 0-5% dichloromethane / 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%). 1H 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] + .

[1086] Step 7. Synthesis of 9-fluoro-5-(4-fluorophenyl)-6-isopropyl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (D33)

[1087] 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 hours. The volatiles were evaporated in vacuo, and water and dichloromethane were added. The mixture was extracted with dichloromethane (x 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 / MeOH) gave the product as a light 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] + .

[1088] Step 8. Synthesis of 7-chloro-9-fluoro-5-(4-fluorophenyl)-6-isopropyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-g]quinolone (T7)

[1089] Part A. In a vial, 9-fluoro-5-(4-fluorophenyl)-6-isopropyl-1,8-dihydropyrazolo[4,3-g]quinolin-7-one (78 mg, 0.2299 mmol) was weighed and suspended in phosphorus oxychloride (1.0 mL, 10.73 mmol). The reaction was heated at 100°C for 5 minutes. The reaction was worked up by adding water and dichloromethane. The mixture was extracted with dichloromethane (x 3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated in vacuo. The crude product was used without further purification. LCMS m / z 358.22 [M+H] + .

[1090] Part B. In a flask, the crude product from Part A was resuspended in dichloromethane (2.5 mL). Then, 3,4-dihydro-2H-pyran (105 μL, 1.15 mmol) was 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 (x 3). The organic phases were filtered through a phase separator, combined, and the volatiles were evaporated under vacuum. Purification by silica gel column chromatography (Gradient: 0-20% EtOAc / heptane) gave 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] + .

[1091] Preparation of T8 and T9

[1092] 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)

[1093]

[1094] Step 1. N-(3-Bromo-4-methyl-phenyl)-2-tetrahydropyran-4-yl-acetamide (D34)

[1095] To a flask containing 3-bromo-4-methylaniline (1.78 g, 9.376 mmol) dissolved in DMF (21.6 mL) was added 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). The solution was then stirred at room temperature overnight, 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 value 311.0521, found value 312.04 (M+1) +

[1096] Step 2. N-[5-Bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]-2-tetrahydropyran-4-yl-acetamide (D35)

[1097] 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 bisulfate (1.3 g, 5.697 mmol). The vial was sealed and purged with one vacuum / N2 cycle, then diglyme (9.5 mL) was added and the reaction was stirred at 70°C for 3 hours. 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 (400 MHz, chloroform-d) δ 10.62 (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, 3.6 Hz, 2H), 3.42 (td, J = 12.0, 2.2 Hz, 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 calcd 433.06888, found 434.1 (M+1) +

[1098] Step 3. Synthesis of 7-bromo-4-(4-fluorophenyl)-6-methyl-3-tetrahydropyran-4-yl-1H-quinolin-2-one (D36)

[1099] 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).

[1100] The mixture was heated at 80°C overnight. The mixture was cooled to room temperature and poured into saturated aqueous NH4Cl solution (400 mL), resulting in the formation of a yellow precipitate. The solid was collected by filtration and washed with water and heptane. The solid was dissolved in dichloromethane, the solution dried over sodium sulfate, filtered, and evaporated to afford 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] + .

[1101] Step 4. Synthesis of 7-bromo-2-chloro-4-(4-fluorophenyl)-6-methyl-3-tetrahydropyran-4-yl-quinoline (D37)

[1102] 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 hours. The mixture was evaporated to dryness and co-evaporated twice with toluene. The residue was dissolved in dichloromethane and an excess of saturated NaHCO₃ solution was added. The biphasic solution was stirred for 15 minutes, 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 Na₂SO₄, filtered, and evaporated to yield the product: 7-bromo-2-chloro-4-(4-fluorophenyl)-6-methyl-3-tetrahydropyran-4-yl-quinoline (3.89 g, 92%). 1 H 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 the CH2 from the THP ring 1 Missing in H NMR). LCMS m / z 434.05 [M+H] + .

[1103] Step 5. Synthesis of 7-bromo-6-(bromomethyl)-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinoline (D38)

[1104] 7-Bromo-2-chloro-4-(4-fluorophenyl)-6-methyl-3-tetrahydropyran-4-yl-quinoline (1 g, 2.169 mmol), CBr4 (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 a vacuum / nitrogen cycle. CCl4 (21.7 mL) was added, and the reaction was stirred under compact fluorescent white light for 1 hour. The solvent was evaporated to dryness. Purification by silica gel chromatography (gradient: 0-100% EtOAc / 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] + .

[1105] Step 6. Synthesis of 7-bromo-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-quinoline-6-carbaldehyde (T8)

[1106] 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) were added 6 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: 0-100% EtOAc / 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] + .

[1107] Step 7. Synthesis of 7-chloro-5-(4-fluorophenyl)-1-(p-toluenesulfonyl)-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]quinolone (T9)

[1108] 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-methylbenzenesulfonylhydrazide (87 mg, 0.4531 mmol) and acetic acid (26 μL, 0.4572 mmol).

[1109] The reaction was heated at 50°C for 1 hour. LCMS indicated the formation of the desired N-[(E)-[7-bromo-2-chloro-4-(4-fluorophenyl)-3-tetrahydropyran-4-yl-6-quinolinyl]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 co-evaporation with toluene.

[1110] The white solid was transferred to a vial containing copper oxychloride (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 at 130°C for 30 minutes. The reaction was cooled to room temperature and purified directly by silica gel chromatography (Gradient: 0-100% EtOAc / heptane) to afford 7-chloro-5-(4-fluorophenyl)-1-(tosyl)-6-tetrahydropyran-4-yl-pyrazolo[4,3-g]quinoline (198 mg, 77%). 1H NMR (400 MHz, chloroform-d) δ 8.85 (s, 1H), 8.25 (d, J = 1.0 Hz, 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] + .

[1111] Preparation of T10

[1112] 7-Chloro-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]quinoline-6-carboxylic acid (T10)

[1113]

[1114] Step 1. Synthesis of N-(1H-indazol-6-yl)acetamide (D40)

[1115] To a suspension of 1H-indazol-6-amine (100.2 g, 752.53 mmol) in anhydrous THF (1 L) in a three-necked flask equipped with an addition funnel and a temperature probe was added acetic anhydride (78.986 g, 73 mL, 773.70 mmol) dropwise over 2.25 hours at room temperature. The mixture was stirred for an additional 20 hours. A solution of sodium hydroxide (32.98 g, 824.56 mmol) in water (500 mL) was then added over 15 minutes at room temperature. The mixture was stirred vigorously for 30 minutes. The THF was removed under reduced pressure. More water (180 mL) was added, and the suspension was stirred at 0°C for 1 hour. The solid was filtered, washed with water (2 x 100 mL), and dried under vacuum to yield N-(1H-indazol-6-yl)acetamide (128.82 g, 98%) as a beige solid.

[1116] Note: The acetic anhydride was added dropwise over 2.25 hours. During this addition, the internal temperature increased from 18°C to 29°C and reached 33°C during the addition of the aqueous NaOH solution. 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] + .

[1117] Step 2. Synthesis of N-[1-(phenylsulfonyl)indazol-6-yl]acetamide (D41)

[1118] To a suspension of N-(1H-indazol-6-yl)acetamide (31.8 g, 181.52 mmol) in anhydrous dichloroethane (400 mL) at room temperature were added anhydrous pyridine (29.340 g, 30 mL, 370.92 mmol) and benzenesulfonyl chloride (33.216 g, 24 mL, 188.06 mmol). The mixture was heated to 25-27°C and maintained at this temperature for 72 hours. More benzenesulfonyl chloride (6.2280 g, 4.5 mL, 35.3 mmol) was added, and after an additional 24 hours at 25-27°C, the solvent was removed under reduced pressure. The solid was triturated in water (1 x 250 mL) at 0°C for 20 minutes, then filtered, washed with water (3 x 75 mL), and dried under vacuum. The residue was triturated in MTBE (1 x 125 mL) and in a mixture of MTBE and THF (125 mL / 10 mL), filtered and dried to give N-[1-(phenylsulfonyl)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] + .

[1119] Step 3. Synthesis of N-[1-(phenylsulfonyl)-5-(4-fluorobenzoyl)indazol-6-yl]acetamide (D42)

[1120] In a flask, N-[1-(phenylsulfonyl)indazol-6-yl]acetamide (8.3 g, 26.32 mmol), 2-(4-fluorophenyl)-2-oxo-acetic acid (5.300 g, 31.52 mmol), bis[(2,2,2-trifluoroacetyl)oxy]palladium (1.750 g, 5.264 mmol), and sulfoxyammonium hydrogensulfate (24.00 g, 105.2 mmol) were added 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 were added, and the reaction was stirred for an additional 40 hours.

[1121] The reaction was worked up by adding 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 product was triturated with cold water, cold methanol, and heptane. A brown solid was obtained. N-[1-(phenylsulfonyl)-5-(4-fluorobenzoyl)indazol-6-yl]acetamide (12.59 g, 77%). LCMS m / z 438.3 [M+H] + .

[1122] Step 4. Synthesis of (6-amino-1H-indazol-5-yl)-(4-fluorophenyl)methanone (D43)

[1123] To a suspension of N-[1-(phenylsulfonyl)-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 in water). The mixture was heated to 85°C for 17 hours. After cooling to room temperature, more concentrated hydrogen chloride (15 mL of 12 M, 180.00 mmol) (12 M 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, 25% w / w aqueous NaOH solution was added dropwise, followed by 1 N aqueous NaOH solution, and the pH was adjusted to ~pH 6-7. The precipitated solid was filtered, washed with water (3 x 15 mL), and then dried in vacuo 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(brs,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] + .

[1124] Step 5. Synthesis of methyl 5-(4-fluorophenyl)-7-oxo-1,8-dihydropyrazolo[4,3-g]quinoline-6-carboxylate (D44)

[1125] Part A. In a vial, (6-amino-1H-indazole-5-yl)-(4-fluorophenyl)methanone (2000 mg, 7.555 mmol) was weighed and suspended in dichloromethane (30 mL). Then, pyridine (610 μL, 7.542 mmol) was added and the mixture was stirred at room temperature for 5 minutes. Thereafter, 3-chloro-3-oxo-propionic acid methyl ester (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 at room temperature for another 1 hour. The reaction was treated by adding water and CHCl3:IPA (3:1). The mixture was extracted with CHCl3:IPA (3:1) (x 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.

[1126] Part B. The crude product from Part A was resuspended in DMF (30 mL) and KCO (1.360 g, 9.840 mmol) was added. The reaction was stirred at 70°C for 3 hours. Water and CHCl:IPA (3:1) were added. The mixture was extracted with CHCl:IPA (3:1) (x 3). 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 adding 1M HCl. The solid was filtered and washed with cold water. A light yellow solid was obtained. 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] + .

[1127] Step 6. Synthesis of 5-(4-fluorophenyl)-7-oxo-1,8-dihydropyrazolo[4,3-g]quinoline-6-carboxylic acid (D45)

[1128] 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). Then, NaOH (385 mg, 9.626 mmol) was added. The reaction was heated at 70 °C for 4 hours. After this time, LC-MS showed the formation of product and almost complete consumption of starting material. The mixture was concentrated in vacuo to remove volatiles. The crude product was suspended in water and precipitated by adding 1 M HCl until the pH was ~pH 2. The precipitate was filtered and triturated with cold water to give the product as a paste 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(s,1H),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] + .

[1129] Step 7. Synthesis of 7-chloro-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]quinoline-6-carboxylic acid (T10)

[1130] In a vial, 5-(4-fluorophenyl)-7-oxo-1,8-dihydropyrazolo[4,3-g]quinoline-6-carboxylic acid (100 mg, 0.2898 mmol) was weighed 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] + .

[1131] Preparation of T11

[1132] 7-Bromo-2-chloro-4-(4-fluorophenyl)-6-methyl-3-methylsulfonyl-quinoline (T11)

[1133]

[1134] Step 1. Synthesis of N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]acetamide (D47)

[1135] 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 aminosulfoxy hydrogen sulfate (125 g, 547.8 mmol) in diethylene glycol dimethyl ether (750 mL) was sparged with nitrogen. Pd(TFA)2 (5 g, 15.04 mmol) was added. The mixture was stirred at 50°C (internal temperature) and N2 for 11 hours. Saturated aqueous sodium bicarbonate solution (700 mL) was slowly added. The mixture was then extracted with EtOAc (3x). The extract was washed with aqueous sodium bicarbonate solution, then with brine, and concentrated. The residue was distilled under high vacuum to remove diethylene glycol dimethyl ether. The product was used in the subsequent steps without further purification. N-[5-Bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]acetamide (96.3 g, 100%). LCMS m / z 350.07 [M+H] + .

[1136] Step 2. Synthesis of (2-amino-4-bromo-5-methyl-phenyl)-(4-fluorophenyl)methanone (D48)

[1137] To a suspension of N-[5-bromo-2-(4-fluorobenzoyl)-4-methyl-phenyl]acetamide (1.92 g, 5.483 mmol) in EtOH (15 mL) was added aqueous HCl (10 mL, 6 M, 60.00 mmol) and the reaction was heated at 70°C (internal temperature) for 5 hours. The reaction mixture was cooled to room temperature overnight. The resulting precipitate was collected by filtration, and the solid filter 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) (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.

[1138] Step 3. Synthesis of 7-bromo-4-(4-fluorophenyl)-6-methyl-3-methylsulfonyl-1H-quinolin-2-one (D49)

[1139] 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 hour, then at 60° C. for 1 hour. The mixture was partitioned between aqueous NH 4 Cl and EtOAc, extracted with EtOAc (3×), and washed with brine. The organic phase ...

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein: Z 1 -NH, Z 2 is -N, and Z 3 is -CH; V 1 and V 2 is C; W 1 and W 2 Each independently selected from -C=O, -CR 2 , N and -NR 2 ,in: When W 1 -CR 2 When W 2 is N; When W 2 -CR 2 When W 1 is N; When W 1 When -C=O, then W 2 -NR 2 ;and When W 2 When -C=O, then W 1 -NR 2 ; Z 1 and Z 2 between is a single bond; and Z 2 and Z 3 between is a double bond; (h) is a double bond, provided that when W 1 and W 2 When any one of is -C=O, (h) is a single bond; R 0 Halogen or in: Ring A is C3-C 12 Carbocyclic group, 3 to 12 membered heterocyclic group, 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 heterocyclic group; wherein: R 1 The C1-C6 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted by 1 to 3 groups independently selected from the following: -OR z , C1-C3 haloalkyl, -CN and halogen; and R w 、R x 、R y and R z Each is independently hydrogen or C1-C4 alkyl; X 1 and X 2 Each is independently hydrogen, halogen, C1-C3 alkyl or C1-C3 haloalkyl; R 2 is independently at each occurrence hydrogen, halogen, in: T is absent or selected from -O-, -OCH2-, -NH-, -NS(=O)2CH3, -S- and -CH2-; Y is selected from 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; wherein: R a is independently at each occurrence hydrogen, halogen, -OH, or C1-C4 alkyl optionally substituted with 1 to 3 groups independently selected from halogen and -OH; Or alternatively, when R a When each occurrence is independently C1-C4 alkyl, the two R a The groups together with their intervening carbon atoms form a cyclopropyl or cyclobutyl group; R b and R c is independently hydrogen or C1-C2 alkyl at each occurrence; and p and q are each independently an integer selected from 1 and 2; Ring B is C3-C 12 Carbocyclic group, 3 to 12 membered heterocyclic group, C6 or C 10 aryl or 5- to 10-membered heteroaryl; R 3 -C(=O)OR d ; where R d is C1-C4 alkyl, which is optionally substituted with -OC(O)R e 、-OC(=O)OR e Or-OP(=O)R f R f Replace; of which: R e is independently at each occurrence hydrogen, -CH3 or -C2H5; R f is independently at each occurrence -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 independently at each occurrence 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 heterocyclic group, phenyl or 5 or 6-membered heteroaryl, where R m The C1-C6 alkyl, phenyl or 5- or 6-membered heteroaryl is optionally substituted by 1 to 3 groups independently selected from the following: halogen, CN, -C(=O)OR r 、-NR p R q AND-OR r ;and where R m The C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, CN, ═O, —C(═O)OR r 、-NR p R q AND-OR r ; where R p and R q is independently at each occurrence hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of -OH, -OCH3, -OC2H5 and -COOH; where R r Each occurrence is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or 3 to 6 membered heterocyclyl; wherein R r The C1-C4 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted by 1 to 3 groups independently selected from the group consisting of -OH, -OCH3, -OC2H5, -CH2OH, -C(=O)OH, -(O)C(=O)OH and -(O)P(=O)(OH)2; and where R s and R t is independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy or -OH at each occurrence; k and m are each independently an integer selected from 0, 1, 2, 3, 4 and 5; and n is an integer selected from 0, 1 and 2.

2. The compound or pharmaceutically acceptable salt according to claim 1, wherein n is an integer selected from 0 and 1.

3. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, which is represented by formula II in: R 3 -C(=O)OR d ; where R d is C1-C4 alkyl, which is optionally substituted with -OC(O)R e 、-OC(=O)OR e Or-OP(=O)R f R f replace; in: R e is independently hydrogen or -CH3 at each occurrence; R f is independently -OH, -CH3 or -OCH3 at each occurrence; and n is an integer selected from 0 and 1.

4. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, which is represented by formula IIIa, IIIb, IIIc or IIId in: Ring A is (R k ) k substituted and Ring A is a 5- or 6-membered carbocyclyl, phenyl, or a 5- or 6-membered heteroaryl; R 1 C1-C6 alkyl, C1-C6 alkoxy, -C(=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 heterocyclic group; wherein: R 1 The C1-C6 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted by 1 to 3 groups independently selected from the following: -OR z and halogens; and R w 、R x and R z Each is independently hydrogen or C1-C4 alkyl; X 1 and X 2 Each is independently hydrogen, halogen, C1-C2 alkyl or C1-C2 haloalkyl; R 2 As defined in claim 1, wherein when R 2 for When ring B is (R m ) m substituted and Ring B is C4-C9 carbocyclyl, phenyl, 4- to 9-membered heterocyclyl, or 5- to 6-membered heteroaryl; R 3 Absent or -C(=O)O(CH2)2(O)P(=O)(OH)2; R k is halogen, -CN, -CH3, C1 haloalkyl or -OCH3; and n is an integer selected from 0 and 1.

5. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, which is represented by formula IVa, IVb or IVc where X 1 is hydrogen, halogen, -CH3, -CHF2 or -CH2F.

6. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, which is represented by formula Va, Vb or Vc: in: R 1 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 heterocyclic group; wherein: R 1 The C1-C4 alkyl, cyclopropyl, cyclobutyl or 5- or 6-membered heterocyclyl is optionally substituted by 1 to 3 groups independently selected from the following: -OR z and halogens; and R w 、R x and R z are each independently hydrogen or C1-C2 alkyl; and T is absent or independently selected from -O-, -OCH2-, -NH- and -CH2-.

7. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein ring A is (R k ) k is substituted, and Ring A is phenyl, cyclohexenyl, 3,6-dihydro-2H-pyranyl, pyridyl, pyridazinyl, thienyl or pyrazolyl.

8. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein ring A is (R k ) k is substituted, and Ring A is selected from:

9. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein ring A is replaced by (R k ) k substituted, and ring A is selected from 10. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein when R 2 for When ring B is (R m ) m substituted, and Ring B is selected from the group consisting of 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.

11. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R 2 for Ring B is (R m ) m substituted, and ring B is selected from 12. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R 2 for Ring B is (R m ) m substituted, and ring B is selected from 13. A compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R m is independently at each occurrence 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 a 5- or 6-membered heterocyclic group; wherein: R m The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of -C(=O)OH, -C(=O)OCH3, -C(=O)OC2H5, -OH, -OCH3, and -OC2H5; and R m The 5- or 6-membered heterocyclyl is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, ═O, —C(═O)OH, and —OH; wherein: R p and R q is independently at each occurrence hydrogen or C1-C3 alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of: -OH, -OCH3 and -C(=O)OH; R r Each occurrence is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl; wherein R r The C1-C2 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups independently selected from the group consisting of -OH, -OCH3, -OC2H5, -C(=O)OH, -(O)C(=O)OH and -(O)P(=O)(OH)2; and R s and R t Each occurrence is independently hydrogen, C1-C2 alkyl, C1-C2 alkoxy or -OH.

14. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R m is independently at each occurrence 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; wherein: R m The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of -C(=O)OH, -C(=O)OCH3, -C(=O)OC2H5, -OH, -OCH3, and -OC2H5; and R m The imidazolidinyl or morpholinyl group is optionally substituted with 1 to 3 groups independently selected from the group consisting of oxo (=O) and -OH; wherein: R p and R q is independently at each occurrence hydrogen or C1-C3 alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of: -OH, -OCH3 and -C(=O)OH; R r is independently hydrogen, C1-C2 alkyl, cyclopropyl, oxetanyl or azetidinyl at each occurrence; wherein R r The C1-C2 alkyl, cyclopropyl, oxetanyl or azetidine group is optionally substituted with 1 to 3 groups independently selected from the group consisting of -OH, -CH2OH, -C(=O)OH and -(O)P(=O)(OH)2; and R s and R t Each occurrence is independently -CH3, -OCH3 or -OH.

15. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R m -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 -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).

16. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein at least one occurrence of R m It is -COOH, -CH2COOH, -OCH2COOH, -OCH(CH3)COOH, -CH(CH3)COOH, -C(=O)OCH2(O)P(=O)(OH)2 or -C(=O)NHCH(CH3)COOH.

17. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, which is represented by formula VIa, VIb or VIc 18. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R 1 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 heterocyclic group; wherein: R 1 The C1-C3 alkyl, cyclopropyl, cyclobutyl or 6-membered heterocyclyl is optionally substituted by 1 to 3 groups independently selected from the group consisting of -OH, -OCH3, C1-C2 haloalkyl, -CN and halogen; and R w 、R x and R z are each independently hydrogen or -CH3.

19. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein 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; wherein R 1 The cyclopropyl or cyclobutyl groups are optionally substituted by -OH, -OCH3 or -CF3.

20. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, which is represented by formula VIIa, VIIb, VIIc, VIId, VIIe or VIIf 21. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, which is represented by formula VIIIa, VIIIb or VIIIc in: Ring A is optionally replaced by R k substituted and Ring A is phenyl or a 5- or 6-membered heteroaryl; T is absent or selected from -O-, -NH- and -CH2-; Y 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; wherein: R a is independently hydrogen, -OH, -CH3 or -CH2OH; and R b and R c Each occurrence is independently hydrogen or -CH3.

22. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein is -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 -OCH(CH2OH)CH2NHS(=O)2(CH2)2OH.

23. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein ring A is replaced by (R k ) k substituted, and ring A is phenyl or pyridyl.

24. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein Ring A is replaced by (R k ) k substituted, and Ring A is 25. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein ring A is selected from 26. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein ring A is selected from 27. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R 1 Halogen, -CN, C1-C3 alkyl, C1-C3 alkoxy, -NR w R x 、-OR z , C3-C6 cycloalkyl or 5- or 6-membered heterocyclic group; wherein: R 1 The C1-C3 alkyl, C3-C6 cycloalkyl or 5- or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups independently selected from the group consisting of -OH, -OCH3, C1-C2 haloalkyl, -CN and halogen; and R w 、R x and R z are each independently hydrogen or -CH3.

28. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R 1 is a C1-C3 alkyl group or a 6-membered heterocyclic group; wherein: R 1 The C1-C3 alkyl or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups independently selected from the group consisting of -OH, -OCH3, C1-C2 haloalkyl and halogen.

29. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R 1 It is -C(CH3)2 or tetrahydro-2H-pyran-4-yl.

30. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R 1 Selected from 31. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R 1 Selected from 32. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R 2 independently selected at each occurrence 33. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein R 2 independently selected at each occurrence 34. The compound or pharmaceutically acceptable salt of claim 1 or claim 2, wherein: X 1 is hydrogen, F or -CH3; R k is F, Cl, -CH3 or -OCH3; and k is an integer selected from 0, 1 and 2.

35. The compound or pharmaceutically acceptable salt of claim 1 or claim 2, wherein the compound is selected from the compounds of Table I, with the proviso that the compound selected from the compounds of Table I is not 3-(6-isopropyl-8-oxo-1H-pyrazolo[4,3-g]isoquinolin-7-yl)cyclobutanecarboxylic acid.

36. A compound having the formula: or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to any one of claims 1, 2 and 36 and a pharmaceutically acceptable carrier.

38. Use of the compound or pharmaceutically acceptable salt according to any one of claims 1, 2 and 36 in the preparation of a medicament for regulating AAT activity.

39. The pharmaceutical composition according to claim 37, which is used for modulating AAT activity.

40. Use of a compound or pharmaceutically acceptable salt according to any one of claims 1, 2 and 36 in the preparation of a medicament for treating AATD.

41. The pharmaceutical composition according to claim 37, for use in treating AATD.

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