WO2025090827A1 - A1at modulators - Google Patents

Abstract

Provided herein are compounds of Formula (I) and pharmaceutical compositions thereof that are useful in the treatment of alpha-1 antitrypsin deficiency. Also provided herein are pharmaceutical compositions and kits comprising compounds of Formula (I), as well as methods of treating alpha-1 antitrypsin deficiency.

Description

Attorney Docket No.063251-503001WO Client Docket No. Sub21-3.WO1 A1AT MODULATORS CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of priority under 35 U.S.C § 119(e) to U.S. Provisional Application Serial No.63/593,681 filed October 27, 2023, the disclosure of which is incorporated herein by reference in its entirety. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT [0002] NOT APPLICABLE REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK [0003] NOT APPLICABLE BACKGROUND [0004] Alpha-1 antitrypsin deficiency (AATD) is a disease characterized by subjects who have an absent or mutant form of the Alpha-1 antitrypsin (AAT) protein, and thereby do not have sufficient amounts of this protein to maintain normal biological functions. [0005] AAT is produced in the liver and passes through the blood stream into the lungs. Accordingly, AAT deficiency (AATD) primarily affects two organs: the liver and the lungs. [0006] In the lungs, AAT normally functions to protect the lungs by inhibiting elastase, thereby limiting elastin break down within the lung. Over time, the absence of AAT or the presence of suboptimal mutant forms of AAT can damage alveoli causing them to lose their shape, which limits gas exchange and breathing capacity. For example, neutrophils are recruited to sites of infections where they release neutrophil elastase. Neutrophil elastase breaks down elastin proteins in bacteria which helps fight infections; however, if not properly regulated, neutrophil elastase can also damage elastin in the lung. Continued degradation of lung elastin causes structural shifts where the alveolus is not able to maintain its shape. [0007] In addition to functionally protecting the lungs via its antiprotease activity, AAT also has immune-regulatory and anti-inflammatory activities (Cosio, M.G.; Bazzan, E.; Rigobello, C.; Tine, M.; Turato, G.; Baraldo, S.; Saetta, M. Ann. Am. Thorac. Soc.2016 Aug:13). For example, AAT can modulate neutrophil migration by inhibiting serine protease activity and modulating IL-8, and can therefore limit the effects of reactive oxygen species produced by inflammatory stimuli. AAT’s immunomodulatory activities include, for example, regulation of proinflammatory cytokines and promotion of anti-inflammatory mediators, as well as control of antigen presentation via prevention of dendritic cell maturation. Individuals with AATD may also have an adaptive immune inflammatory responses to inflammatory stimuli in the lungs, similar to that observed in subjects with chronic obstructive pulmonary disease (COPD). [0008] AATD may be attributed to a mutation in the SERPINA1 gene that encodes the AAT protein. Substitution of lysine for glutamic acid at the 342 amino acid (E342K mutation) is the mutation most commonly associated with AATD and is often referred to as the “Z mutation” or “Z allele.” This mutation leads to AAT misfolding, which can result in AAT dysfunction and polymerization. Circulating AAT levels for subjects homozygous for the Z mutation (PiZZ) may be notably reduced relative to that for healthy human subjects. Instead, polymerized Z-AAT and other mutant forms of AAT can accumulate in otherwise normally functioning hepatocytes, resulting in cytotoxicity that may lead to cirrhosis, liver cancer, or other liver disease. PiZZ individuals may have sever liver issues, as well as significant lung disease. Individuals with other AAT mutations or with absent AAT may have less severe disease manifestation in the liver and/or lungs. [0009] Although the etiology of AATD is relatively well characterized, current standards of care generally treat symptoms that stall or delay further disease progression. For example, some treatments include IV infusions of wild type AAT from donors. IV treatments have a number of drawbacks including regular (often weekly) medical appointments and a duration of time for IV administration. This form of therapy also does not address any impacts to the liver. Various additional therapies are currently under investigation. For example, Vertex Pharmaceuticals is developing small molecule therapeutics for use in the treatment of AATD. Vertex has recent patent publications describing small molecule compounds with AAT modulatory activity (e.g., International Patent Publications Nos. WO2020/081257, WO2020/247160, WO2022/104353, WO2022/026372, WO2021/20302, WO2021/203014, and WO2022/109553). It is unclear if any such compound will successfully provide clinical relief to patients in need thereof. [0010] With the known issues related to AATD and current limitations of standard treatments, there remains a need for effective treatments for AATD. The present disclosure addresses these needs and provides related advantages as well. BRIEF SUMMARY [0011] In an aspect, the present disclosure provides a compound of Formula (I): I), or a salt (e.g., pharmaceuticall ereoisomer, zwitterion, or

prodrug thereof, wherein: Z¹, Z², or Z³ the dashed bonds between Z¹, Z², and Z³, Y¹, Y², R¹, R², R³, and R⁴ are as defined herein. [0012] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. [0013] The present disclosure provides compounds that have alpha-1 antitrypsin (AAT) modulatory activity. The compounds provided herein may inhibit misfolding and/or facilitate proper folding of AAT, such as the “Z allele” AAT (Z-AAT). Such compounds may be considered chaperone molecules and/or correctors. The present disclosure also provides methods of treating AAT deficiency (AATD) and/or symptoms thereof. For example, the methods may comprise administering one or more compounds provided herein, or one or more compositions (e.g., pharmaceutical compositions) comprising the same. Performance of the methods provided herein may be useful in the treatment of AATD for subjects with one or more SERPINA1 mutations, such as the so-called “Z mutation” (PiZZ subjects). Performance of the methods provided herein may improve, delay progression of, ameliorate, treat, or reduce the severity of AATD and/or symptoms thereof, such as in the lungs or liver of the subject. [0014] Accordingly, in some aspects, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy. [0015] In another aspect, provided herein is a method of treating alpha-1 antitrypsin deficiency (AATD) in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. [0016] In another aspect, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of alpha-1 antitrypsin deficiency (AATD). [0017] In another aspect, provided herein is the use of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment of alpha-1 antitrypsin deficiency (AATD). [0018] In another aspect, provided are intermediates useful in the preparation of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, as defined herein. [0019] In another aspect, provided are methods of synthesizing a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, as defined herein. [0020] In another aspect, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt, prepared by a method of synthesis as defined herein. [0021] Other objects, features, and advantages of the present disclosure will be apparent to one of skill in the art from the following detailed description and figures. BRIEF DESCRIPTION OF THE DRAWINGS [0022] NOT APPLICABLE DETAILED DESCRIPTION OF THE INVENTION I. General [0023] Provided herein are compounds with AAT modulatory activity that that are useful in the treatment of alpha-1 antitrypsin deficiency (AATD). Without being bound to any particular theory, it is believed that the currently disclosed compounds act as chaperones, facilitating the proper folding of AAT and thus stimulating the secretion of functional AAT monomers. This chaperone activity is particularly advantageous for subjects who have one or more mutations that destabilize AAT and alter the usual folding pathway of this protein. Therefore, in some embodiments, the activity of the compounds provided herein correct the folding of, facilitate proper folding of, and/or inhibit misfolding of AAT. II. Abbreviation and Definitions [0024] As used herein, the term "about" means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In some embodiments, the term "about" means within a standard deviation using measurements generally acceptable in the art. In some embodiments, about means a range extending to +/- 10% of the specified value. In some embodiments, about means the specified value. [0025] “Alkyl” refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. Alkyl can include any number of carbons, such as C1-2, C_1-3, C_1-4, C_1-5, C_1-6, C_1-7, C_1-8, C_1-9, C_1-10, C_2-3, C_2-4, C_2-5, C_2-6, C_3-4, C_3-5, C_3-6, C_4-5, C_4-6 and C5-6. For example, C1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. [0026] “Alkoxy” refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. As for alkyl group, alkoxy groups can have any suitable number of carbon atoms, such as C_1-6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. [0027] “Halo” or “halogen” refers to fluorine, chlorine, bromine and iodine. [0028] “Haloalkyl” refers to alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms. For example, haloalkyl includes trifluoromethyl, flouromethyl, etc. In some instances, the term “perfluoro” can be used to define a compound or radical where all the hydrogens are replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl. [0029] "Hydroxyalkyl" refers to an alkyl group, as defined above, having the indicated number of carbon atoms (e.g., C_1-6 or C_1-8) and which is substituted with one or two hydroxy (OH) groups. [0030] “Cycloalkyl” refers to a saturated or partially unsaturated monocyclic ring assembly containing from 3 to 8 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as C3-6, C4-6, C5-6, C3-7 and C3-8. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring, but cycloalkyl groups are not aromatic. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl (1,3- and 1,4-isomers), cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl (1,3-, 1,4- and 1,5-isomers). When cycloalkyl is a C3-6 monocyclic cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexadienyl (1,3- and 1,4-isomers). [0031] “Heterocycloalkyl” refers to a saturated or partially unsaturated monocyclic, ring assembly having from 3 to 8 ring members with from 1 to 4 heteroatoms of N, O and S. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), tetrahydropyridine, oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. [0032] The heterocycloalkyl groups can be linked via any position on the ring. For example, aziridine can be 1- or 2-aziridine, azetidine can be 1- or 2- azetidine, pyrrolidine can be 1-, 2- or 3-pyrrolidine, piperidine can be 1-, 2-, 3- or 4-piperidine, pyrazolidine can be 1-, 2-, 3-, or 4-pyrazolidine, imidazolidine can be 1-, 2-, 3- or 4-imidazolidine, piperazine can be 1-, 2-, 3- or 4-piperazine, tetrahydrofuran can be 1- or 2-tetrahydrofuran, oxazolidine can be 2-, 3-, 4- or 5-oxazolidine, isoxazolidine can be 2-, 3-, 4- or 5-isoxazolidine, thiazolidine can be 2-, 3-, 4- or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4- or 5- isothiazolidine, and morpholine can be 2-, 3- or 4-morpholine. [0033] “Aryl” refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, or 12 ring atoms, as well as from 6 to 10, or 6 to 12 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl. [0034] “Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 12 ring atoms, where from 1 to 6 of the ring atoms are a heteroatom such as N, O or S. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 5 to 8, 5 to 9, 5 to 10, 5 to 12, or 9 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, 5, or 6, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 3 to 4, 3 to 5, or 3 to 6. Heteroaryl groups can have from 5 to 8 ring members with from 1 to 4 heteroatoms, or from 5 to 8 ring members with from 1 to 3 heteroatoms, or from 5 to 6 ring members with from 1 to 4 heteroatoms, or from 5 to 6 ring members with from 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. [0035] The heteroaryl groups can be linked via any position on the ring. For example, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3- and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazole includes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and 5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5- and 6- pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-, 5- and 6-triazine, 1,3,5-triazine includes 2-triazine, thiophene includes 2- and 3-thiophene, furan includes 2- and 3-furan. [0036] “Pharmaceutically acceptable excipient” refers to a substance that aids the formulation and/or administration of an active agent to a subject. Pharmaceutical excipients useful in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure. [0037] “Subject” refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In some embodiments, the subject is a human. The terms “subject” and “patient” are used interchangeably herein. [0038] “Administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject. [0039] “Treat,” “treating,” and “treatment” refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition. The treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination. [0040] The compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or salts thereof may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present disclosure. The scope of the present disclosure includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. Unless otherwise indicated, when a stereochemical depiction is shown, it is meant that the isomer with the depicted stereochemistry is present and substantially free of the other isomer(s). “Substantially free of” another isomer indicates at least an 80/20 ratio of the two isomers, more preferably 90/10, or 95/5 or more. [0041] Likewise, it is understood that a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or salts thereof may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present disclosure. [0042] The compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present disclosure, such as a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Isotopically labeled compounds (e.g., those labeled with ³H and ¹⁴C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in the compounds disclosed herein, including in Table 1 below one or more hydrogen atoms are replaced by ²H or ³H, or one or more carbon atoms are replaced by ¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁵F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. III. Description of the Embodiments A. Compounds [0043] The present disclosure provides compounds and forms (e.g., salts, tautomers, stereoisomers, zwitterions, and prodrugs) thereof, which compounds may be useful in the treatment of a disease, disorder, or condition such as alpha-1 antitrypsin deficiency (AATD). [0044] In an aspect, the present disclosure provides a compound of Formula (I): I), or a pharmaceutically accepta Z¹, Z², or Z³

are each independently CHR^Z1, CR^Z1, N, or NR^Z2, provided that at least one of Z¹, Z², or Z³ is N or NR^Z2, and (i) the dashed bond between Z¹ and Z² is a double bond and the dashed bond between Z² and Z³ is a single bond; or (ii) the dashed bond between Z² and Z³ is a double bond and the dashed bond between Z¹ and Z² is a single bond; R^Z1 is H, C_1-6 alkyl, halo, C_1-6 haloalkyl, or phenyl; R^Z2 is H, C1-6 alkyl, or C1-6 haloalkyl; Y¹ is CR^Y1, or N; Y² is CR^Y2 or N; R^Y1 is H, C1-6 alkyl, halo, or C1-6 haloalkyl; R^Y2 is H, C_1-6 alkyl, halo, or C_1-6 haloalkyl; R¹ is C3-6 cycloalkyl, heterocycloalkyl, C6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; each heteroaryl has 5 to 10 ring members with 1 to 4 heteroatom ring vertices, each independently N, O, or S; and wherein each C3-6 cycloalkyl, heterocycloalkyl, C6-12 aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^1a; each R^1a is independently C1-6 alkyl, C1-6 alkoxy, –OH, C1-6 haloalkyl, halo, or C1-6 haloalkoxy; R² and R³ are each independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; each heteroaryl has 5 to 10 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; and wherein each C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^2a, and each C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C_1-6 haloalkoxy is unsubstituted or substituted with 1 to 3 R^2c; or R² and R³ combine with the sulfur atom to which they are attached to form a heterocycloalkyl having 3 to 7 ring members with 0 to 2 additional heteroatom ring vertices, each independently N, O, or S, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 3 R^2b; each R^2a is independently C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halo, C1-6 haloalkoxy, cyano, –C(O)OH, or –C(O)OC1-6 alkyl; each R^2c is independently –NR^2c1R^2c2, –C(O)OH, or –C(O)OC1-6 alkyl; each R^2c1 and R^2c2 are independently H, C1-6 alkyl, or C1-6 haloalkyl; each R^2b is independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, halo, C_1-6 haloalkoxy, or heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; or two R^2b moieties on adjacent ring vertices combine with the atoms to which each is attached to form a phenyl ring; or two R^2b moieties on the same ring vertex combine with the atom to which each is attached to form a heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; or two R^2b moieties on non-adjacent ring vertices combine to form NH; and R⁴ is C1-6 alkyl, C1-6 hydroxyalkyl, –C1-6 alkyl–C(O)H, C3-6 cycloalkyl, –C1-6 alkyl–C3-6 cycloalkyl, heterocycloalkyl, or –C1-6 alkyl–heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, S, S(O), or S(O)2. [0045] In an aspect, the present disclosure provides a compound of Formula (I): I), or a salt (e.g., pharmaceuticall ereoisomer, zwitterion, or

prodrug thereof, wherein: Z¹, Z², or Z³ are each independently CH₂, CH, N, or NH, provided that at least one of Z¹, Z², or Z³ is N or NH, and (i) the dashed bond between Z¹ and Z² is a double bond and the dashed bond between Z² and Z³ is a single bond; or (ii) the dashed bond between Z² and Z³ is a double bond and the dashed bond between Z¹ and Z² is a single bond; Y¹ is CH or N; Y² is CH; R¹ is C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; each heteroaryl has 5 to 10 ring members with 1 to 4 heteroatom ring vertices, each independently N, O, or S; and wherein each C3-6 cycloalkyl, heterocycloalkyl, C6-12 aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^1a; each R^1a is independently C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halo, or C1-6 haloalkoxy; R² and R³ are each independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_3-6 cycloalkyl, heterocycloalkyl, C6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; each heteroaryl has 5 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; and wherein each C_3-6 cycloalkyl, heterocycloalkyl, C6-12 aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^2a; or R² and R³ combine with the sulfur atom to which they are attached to form a heterocycloalkyl having 3 to 6 ring members with 0 to 2 additional heteroatom ring vertices, each independently N, O, or S, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 3 R^2b; each R^2a and R^2b is independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, halo, –C(O)OH, or –C(O)OC_1-6 alkyl; and R⁴ is C1-6 alkyl, C1-6 hydroxyalkyl, C3-6 cycloalkyl, or heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S. [0046] In some embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof. [0047] In some embodiments, at least one of Z¹, Z², or Z³ is NH, and the remaining two moieties are each independently CH or N. In some embodiments, Z¹ is NH, Z² is CH, and Z³ is CH. In some embodiments, Z¹ is NH, Z² is CH, and Z³ is N. In some embodiments, Z¹ is NH, Z² is N, and Z³ is CH. In some embodiments, Z¹ is NH, Z² is N, and Z³ is N. In some embodiments, Z² is NH, Z¹ is CH, and Z³ is CH. In some embodiments, Z² is NH, Z¹ is CH, and Z³ is N. In some embodiments, Z² is NH, Z¹ is N, and Z³ is CH. In some embodiments, Z² is NH, Z¹ is N, and Z³ is N. In some embodiments, Z³ is NH, Z² is CH, and Z¹ is CH. In some embodiments, Z³ is NH, Z² is CH, and Z¹ is N. In some embodiments, Z³ is NH, Z² is N, and Z¹ is CH. In some embodiments, Z³ is NH, Z² is N, and Z¹ is N. In some embodiments, Z¹ is NH, Z² is NH, and Z³ is NH. In some embodiments, Z¹ is NH, Z² is NH, and Z³ is N. In some embodiments, Z¹ is NH, Z² is NH, and Z³ is CH. In some embodiments, Z¹ is NH, Z² is N, and Z³ is NH. In some embodiments, Z¹ is NH, Z² is CH, and Z³ is NH. In some embodiments, Z¹ is CH, Z² is NH, and Z³ is NH. In some embodiments, Z¹ is N, Z² is NH, and Z³ is NH. [0048] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is a compound of Formula (Ia): a).

[0049] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is a compound of Formula (Ib): b). [0050] In some embodiments,

rmaceutically acceptable salt thereof, is a compound of Formula (Ic): c). [0051] In some embodiments,

rmaceutically acceptable salt thereof, is a compound of Formula (Id): d). [0052] In some embodiments, t

p , p armaceutically acceptable salt thereof, is a compound of Formula (Ie): e). [0053] In some embodiments, t

he compound, or the pharmaceutically acceptable salt thereof, is a compound of Formula (If): f). [0054] In some embodiments, t

armaceutically acceptable salt thereof, is a compound of Formula (Ig): g). [0055] In some embodiments, t

armaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R¹ is cyclopropyl, tetrahydropiperidinyl, phenyl, naphthyl, pyrazolyl, pyridyl, [1,2,4]triazolo[1,5- a]pyridinyl, benzothiopheneyl, or isoquinolinyl, each of which is unsubstituted or substituted with 1 to 3 R^1a. [0056] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R¹ is C6-12 aryl unsubstituted or substituted with 1 to 3 R^1a. [0057] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R¹ is phenyl unsubstituted or substituted with 1 to 3 R^1a. [0058] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R¹ is heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S, and wherein the heteroaryl is unsubstituted or substituted with 1 to 3 R^1a. [0059] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R¹ is pyridyl unsubstituted or substituted with 1 to 3 R^1a. [0060] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein each R^1a is independently C1-6 alkyl, C1-6 haloalkyl, or halo. [0061] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein each R^1a is independently methyl, trifluoromethyl, or fluoro. [0062] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein each R^1a is independently methyl. [0063] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein each R^1a is independently fluoro. [0064] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R¹ is

[0065] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R¹ is , ,

[0066] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R¹ is , any of which

[0067] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R¹ is ,

, any of which is optionally

^1a. [0068] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R² is C_1-6 alkyl; and R³ is C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S, each heteroaryl has 5 to 10 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S, wherein each C3-6 cycloalkyl, heterocycloalkyl, C6-12 aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^2a, and each C_1-6 alkyl, C_1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy is unsubstituted or substituted with 1 to 3 R^2c. [0069] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R² is C_1-6 alkyl; and R³ is C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, C6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S, each heteroaryl has 5 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S, wherein each C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^2a. [0070] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R² is C1-4 alkyl; and R³ is C_1-4 alkyl, C_1-4 haloalkyl, phenyl, or pyridyl, wherein the phenyl or pyridyl is unsubstituted or substituted with 1 to 3 R^2a. [0071] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein each R^2a is independently C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, or halo. [0072] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein each R^2a is independently methyl, methoxy, trifluoromethyl, fluoro, or chloro. [0073] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R² and R³ are each C_1-4 alkyl. [0074] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R² and R³ are each methyl. [0075] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R² and R³ combine with the sulfur atom to which they are attached to form a heterocycloalkyl having 4 to 7 ring members with 0 to 1 additional heteroatom ring vertex, independently N, O, or S, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 2 R^2b. [0076] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R² and R³ combine with the sulfur atom to which they are attached to form a heterocycloalkyl having 4 to 6 ring members with 0 to 1 additional heteroatom ring vertex, independently N, O, or S, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 2 R^2b. [0077] It is understood that when R² and R³ combine with the sulfur atom to which they are attached to form a heterocycloalkyl, reference to unsubstituted or substituted with R^2b does not include the oxo moiety that is shown in Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig). Accordingly, the oxo moiety shown in Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig) is present when R² and R³ combine with the sulfur atom to which they are attached to form an unsubstituted heterocycloalkyl. [0078] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein each R^2b is independently C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halo, or heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S. [0079] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein each R^2b is independently C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, or halo. [0080] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein each R^2b is independently methoxy or piperazine. [0081] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein each R^2b is independently methyl or methoxy. [0082] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein two R^2b moieties on adjacent ring vertices combine with the atoms to which each is attached to form a phenyl ring. [0083] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein two R^2b moieties on the same ring vertex combine with the atom to which each is attached to form a heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S. [0084] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein two R^2b moieties on the same ring vertex combine with the atom to which each is attached to form azetidinyl or oxetanyl. [0085] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein two R^2b moieties on non-adjacent ring vertices combine to form NH. [0086] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R² and R³ are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, , ,

,

, [

, , thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R² and R³ are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, ,

with the sulfur atom to which they are attached to form , any of which is optio

. [0088] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R² and R³ are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, or sec-butyl. [0089] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R² and R³ are each independently methyl. [0090] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R⁴ is C1-4 alkyl or C3-6 cycloalkyl. [0091] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R⁴ is , [

, , thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R⁴ is . [0093] In some

em o ments, t e compoun , or t e p armaceut ca y acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R⁴ is isopropyl. [0094] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein R⁴ is cyclopropyl. [0095] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), wherein Z¹ is N, N–H, or N–CH3; Z² is C–H, C–CH₃, or N; Z³ is C–H, C–CH₃, C–I, C–phenyl, N–H, or N–CH₃, provided that at least one of Z¹, Z², or Z³ is N, N–H, or N–CH3; Y¹ is C–H, C–F, or N; Y² is C–H or N; R¹ is , , , R² and

tert- butyl, methoxy, , ,

, R² and

, R⁴ is

, [0096]

n some emo ments, te compoun s seecte rom a compoun scosed in Table 1. Table 1: Selected Compounds of the Present Disclosure

Compound Compound Structure Structure No. No.

Compound Compound Structure Structure No. No.

Compound Compound Structure Structure No. No.

Compound Compound Structure Structure No. No.

Compound Compound Structure Structure No. No.

Compound Compound Structure Structure No. No.

Compound Compound Structure Structure No. No.

Compound Compound Structure Structure No. No.

Compound Compound Structure Structure No. No.

Compound Compound Structure Structure No. No.

Compound Compound Structure Structure No. No.

Compound Compound Structure Structure No. No.

Compound Compound Structure Structure No. No.

Compound Compound Structure Structure No. No.

B. Pharmaceutical Compositions & Routes of Administration [0097] Also provided herein are pharmaceutical compositions that comprise a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a salt, tautomer, stereoisomer, zwitterion, or prodrug thereof, with a pharmaceutically acceptable diluent or carrier. [0098] The compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, dispersible powders, syrups, emulsions, or granules), for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, intramuscular, intraperitoneal, subcutaneous, or intramuscular dosing), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or topical use (for example as gels, creams, ointments, or aqueous or oily solutions or suspensions) or as a suppository for rectal administration of the drug. [0099] The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. [0100] In using a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof for therapeutic or prophylactic purposes it will generally be administered so that a total daily dose in the range, for example, 0.01 mg/kg to 100 mg/kg body weight is received. Oral administration may also be suitable, particularly in tablet form. [0101] Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily, three times daily, or less is preferred, with a dosage regimen of once daily or 2 times daily being particularly preferred. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e., other drugs being administered to the patient), the severity of the particular disease undergoing therapy, and other factors, including the judgment of the prescribing medical practitioner. C. Methods of Treatment [0102] In some embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy. [0103] In an aspect, provided herein is a method of treating alpha-1 antitrypsin deficiency (AATD) in a subject in need of such treatment, the methods comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. [0104] In an aspect, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of alpha-1 antitrypsin deficiency (AATD). [0105] In an aspect, provided herein is the use of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment of alpha-1 antitrypsin deficiency (AATD). [0106] In an aspect, provided herein is a method of modulating alpha-1 antitrypsin (AAT) activity. In some embodiments, the method comprises contacting AAT with a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. In some embodiments, the AAT is located within a cell. In some embodiments, the cell is located within a subject. In some embodiments, the subject is a human. Accordingly, in some embodiments, the method is a method of modulating ATT activity in a subject in need of such treatment, the methods comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. In some embodiments, modulating AAT comprises correcting the folding of, facilitating proper folding of, and/or inhibiting misfolding of AAT. [0107] In an aspect, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the modulation of alpha-1 antitrypsin (AAT) activity. In some embodiments, modulation of AAT comprises correcting the folding of, facilitating proper folding of, and/or inhibiting misfolding of AAT. [0108] In an aspect, provided herein is the use of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in modulation of alpha-1 antitrypsin (AAT) activity. In some embodiments, modulation of AAT comprises correcting the folding of, facilitating proper folding of, and/or inhibiting misfolding of AAT. [0109] In an aspect, provided herein is a method of correcting the folding of, facilitating proper or beneficial folding of, and/or inhibiting misfolding of alpha-1 antitrypsin (AAT) in a subject in need of such treatment, the methods comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. [0110] In an aspect, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in correcting the folding of, facilitating proper or beneficial folding of, and/or inhibiting misfolding of alpha-1 antitrypsin (AAT). [0111] In an aspect, provided herein is the use of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in correcting the folding of, facilitating proper or beneficial folding of, and/or inhibiting misfolding of alpha-1 antitrypsin (AAT). [0112] In an aspect, provided herein is a method of modulating AAT in vitro, ex vivo, or in vivo, the methods comprising contacting a sample with an effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. [0113] In some embodiments, modulation of AAT activity takes place in vivo. In some embodiments, modulation of AAT activity takes place ex vivo and the AAT is from a biological sample obtained from a human subject. In some embodiments, the methods of modulating AAT take place in vitro and the AAT is from a biological sample obtained from a human subject. In some embodiments, the biological sample comprises tissue or fluid. In some embodiments, the biological sample is a blood sample. In some embodiments, the biological sample is a sample taken from a liver biopsy or lung biopsy. [0114] In some embodiments of any of the preceding aspects, the subject has been diagnosed with, or is suspected of having, chronic obstructive pulmonary disease (COPD). In some embodiments, the subject has not been diagnosed with, or is not suspected of having, COPD. [0115] In some embodiments of any of the preceding aspects, the subject has been identified as having, or is suspected of having, liver cirrhosis. In some embodiments, the subject has not been identified as having, or is not suspected of having, liver cirrhosis. [0116] In some embodiments of any of the preceding aspects, the subject has two copies of the M allele of the SERPINA1 gene (e.g., MM or PiMM type). In some embodiments, the subject has two copies of the S allele of the SERPINA1 gene (e.g., SS or PiSS type). In some embodiments, the subject has one copy of the M allele and one copy of the S allele of the SERPINA1 gene (e.g., MS or PiMS type). In some embodiments, the subject has one copy of the M allele and one copy of the Z allele of the SERPINA1 gene (e.g., MZ or PiMZ type). In some embodiments, the subject has one copy of the Z allele and one copy of the S allele of the SERPINA1 gene (e.g., SZ or PiSZ type). In some embodiments, the subject has two copies of the Z allele of the SERPINA1 gene (e.g., ZZ or PiZZ type). A subject having the PiMM is homozygous for the M allele of the AAT protein and may produce normal levels of AAT. A subject having the PiSS, PiMS, or PiMZ genotype may have lower than normal serum levels of AAT, but may in some instances produce sufficient levels of AAT to protect the lungs. A subject having the PiSZ genotype may have lower than normal serum levels of AAT, and may have or be at risk of developing lung disease and/or one or more symptoms or manifestations of AATD in the lungs. A subject having the PiZZ genotype may have lower than normal serum levels of AAT and may have or be at risk of developing lung disease and/or liver disease, and/or one or more symptoms or manifestations of AATD in the lungs and/or liver. [0117] In some embodiments of any of the preceding aspects, the subject carries the SZ mutation (e.g., has the PiSZ genotype). [0118] In some embodiments of any of the preceding aspects, the subject carries the ZZ mutation (e.g., has the PiZZ genotype). [0119] In some embodiments of any of the preceding aspects, the subject has or is at risk of developing lung disease. In some embodiments, the subject has or is at risk of developing one or more symptoms or manifestations of AATD in the lungs. In some embodiments, the subject has or is at risk of developing liver disease. In some embodiments, the subject has or is at risk of developing one or more symptoms or manifestations of AATD in the liver. In some embodiments, the subject has or is at risk of developing lung disease and/or liver disease. In some embodiments, the subject has or is at risk of developing one or more symptoms or manifestations of AATD in the lungs and/or liver. In some embodiments, the subject has or is at risk of developing lung disease and liver disease. In some embodiments, the subject has or is at risk of developing one or more symptoms or manifestations of AATD in the lungs and liver. In some embodiments, the subject has one or more symptoms or manifestations of AATD selected from the group consisting of shortness of breath following mild activity, wheezing, reduced ability to exercise, unintentional weight loss, recurring respiratory infections, fatigue, emphysema, difficulty breathing, hacking cough, barrel shaped chest, jaundice, cirrhosis of the liver, swollen abdomen, liver cancer (e.g., hepatocellular carcinoma), and a combination thereof. D. Intermediates and Methods of Synthesis [0120] The present disclosure also provides methods of making a compound of Formula (I) (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof. The examples section of this application, for example, provides illustrative methods of how to prepare compounds of Formula I, including generic methods A, B, C, and D. Accordingly, in an aspect, the present disclosure provides a method of making a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof. [0121] The pharmaceutical compositions and units dosage forms described herein can be prepared using standard techniques known in the art. [0122] In some embodiments, the present disclosure provides one or more intermediates useful in the preparation of compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig). Certain intermediates useful in the preparation of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) can be found, for example, in the Examples section of the current disclosure. E. Kits [0123] The present disclosure contemplates kits comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof. The kits are generally in the form of a physical structure housing various components, as described below, and can be utilized, for example, in practicing the methods described above. Accordingly, in an aspect, the present disclosure provides a kit comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the kit comprises one or more additional components as described herein, such as a label or packaging insert including identifying information for the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredient(s), including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). [0124] In some embodiments, labels or inserts can include manufacturer information such as lot numbers and expiration dates. The label or packaging insert may be, e.g., integrated into the physical structure housing the components, contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampule, tube or vial). [0125] In some embodiments, labels or inserts additionally include, or are incorporated into, a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory-type cards. In some embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g., via the internet, are provided. [0126] A kit can include one or more of the compounds disclosed herein (provided in, e.g., a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. The compounds described herein can be provided in a form that is ready for use (e.g., a tablet, capsule, syringe) or in a form requiring, for example, reconstitution or dilution (e.g., a powder) prior to administration. When the compounds described herein are in a form that needs to be reconstituted or diluted by a user, the kit may also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, and the like, packaged with or separately from the compounds described herein. Each component of the kit can be enclosed within an individual container, and all of the various containers can be within a single package. A kit of the present disclosure can be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing). F. Combination Therapy [0127] In some aspects, the uses and methods provided herein include administration of an additional therapeutic agent. The additional therapeutic agent can be administered simultaneously, separately, or sequentially. [0128] In some embodiments, the additional therapeutic agent is in a separate pharmaceutical composition. In some embodiments, the additional therapeutic agent is in the same pharmaceutical composition as the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof. [0129] 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. [0130] In some embodiments, the additional therapeutic agent is selected the group consisting of alpha-1 antitrypsin protein (AAT) from the blood plasma of healthy human donors and recombinant AAT. As used herein, “AAT augmentation therapy” refers to the use of AAT from the blood plasma of healthy human donors to augment (increase) the alpha- 1 antitrypsin levels circulating in the blood. “AAT replacement therapy” refers to administration of recombinant AAT. [0131] Accordingly, in some embodiments, the additional active agent is AAT augmentation therapy (AAT from the blood plasma of healthy human donors). In some embodiments, the additional active agent is AAT replacement therapy (administration of recombinant AAT). [0132] In some embodiments, the additional therapeutic agent is an agent used for the treatment of chronic obstructive pulmonary disease (COPD). [0133] In some embodiments, the additional therapeutic agent is a corticosteroid. [0134] In some embodiments, the additional therapeutic agent is a bronchodilator inhaler. In some embodiments, the additional therapeutic agent is a breztri inhaler. In some embodiments, the additional therapeutic agent is supplemental oxygen. [0135] In some embodiments, the additional therapeutic agent is an agent used for the treatment of liver cirrhosis. In some embodiments, the additional therapeutic agent is lactulose. In some embodiments, the additional therapeutic agent is ursodiol. G. Non-Limiting Embodiments [0136] Embodiment 1. A compound having Formula (I) I), or a pharmaceutically accepta

Z¹, Z², or Z³ are each independently CH₂, CH, N, or NH, provided that at least one of Z¹, Z², or Z³ is N or NH, and (i) the dashed bond between Z¹ and Z² is a double bond and the dashed bond between Z² and Z³ is a single bond; or (ii) the dashed bond between Z² and Z³ is a double bond and the dashed bond between Z¹ and Z² is a single bond; Y¹ is CH or N; Y² is CH; R¹ is C3-6 cycloalkyl, heterocycloalkyl, C6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; each heteroaryl has 5 to 10 ring members with 1 to 4 heteroatom ring vertices, each independently N, O, or S; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^1a; each R^1a is independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, halo, or C_1-6 haloalkoxy; R² and R³ are each independently C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; each heteroaryl has 5 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^2a; or R² and R³ combine with the sulfur atom to which they are attached to form a heterocycloalkyl having 3 to 6 ring members with 0 to 2 additional heteroatom ring vertices, each independently N, O, or S, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 3 R^2b; each R^2a and R^2b is independently C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halo, C(O)OH, or C(O)OC_1-6 alkyl; and R⁴ is C1-6 alkyl, C1-6 hydroxyalkyl, C3-6 cycloalkyl, or heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S. [0137] Embodiment 2. The compound of embodiment 1, wherein at least one of Z¹, Z², or Z³ is NH, and the remaining two moieties are each independently CH or N. [0138] Embodiment 3. The compound of embodiment 1, having the Formula (Ia) a). [0139] Embodiment 4. The

p ent 1, having the Formula (Ib) b). [0140] Embodiment 5. The

compound of embodiment 1, having the Formula (Ic) c).

[0141] Embodiment 6. The compound of embodiment 1, having the Formula (Id) d). [0142] Embodiment 7. Th

ent 1, having the Formula (Ie) e). [0143] Embodiment 8. Th

f embodiments 1 to 7, wherein R¹ is cyclopropyl, tetrahydropiperidinyl, phenyl, naphthyl, pyrazole, pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzothiopheneyl, or isoquinolinyl, each of which is unsubstituted or substituted with 1 to 3 R^1a. [0144] Embodiment 9. The compound of any one of embodiments 1 to 7, wherein R¹ is C_6-12 aryl unsubstituted or substituted with 1 to 3 R^1a. [0145] Embodiment 10. The compound of any one of embodiments 1 to 7, wherein R¹ is phenyl unsubstituted or substituted with 1 to 3 R^1a. [0146] Embodiment 11. The compound of any one of embodiments 1 to 7, wherein R¹ is heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S, and wherein the heteroaryl is unsubstituted or substituted with 1 to 3 R^1a. [0147] Embodiment 12. The compound of any one of embodiments 1 to 7, wherein R¹ is pyridyl unsubstituted or substituted with 1 to 3 R^1a. [0148] Embodiment 13. The compound of any one of embodiments 1 to 12, wherein each R^1a is independently C1-6 alkyl, C1-6 haloalkyl, or halo. [0149] Embodiment 14. The compound of any one of embodiments 1 to 12, wherein each R^1a is independently methyl, trifluoromethyl, or fluoro. [0150] Embodiment 15. The compound of any one of embodiments 1 to 12, wherein each R^1a is independently methyl. [0151] Embodiment 16. The compound of any one of embodiments 1 to 12, wherein each R^1a is independently fluoro. [0152] Embodiment 17. The compound of embodiment 1, wherein R¹ is , [0

153] Embodiment 18. The compound of any one of embodiments 1 to 17, wherein R² is C_1-6 alkyl, and R³ is C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_3-6 cycloalkyl, heterocycloalkyl, C6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S, each heteroaryl has 5 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^2a. [0154] Embodiment 19. The compound of any one of embodiments 1 to 17, wherein R² is C1-4 alkyl, and R³ is C1-4 alkyl, C1-4 haloalkyl, phenyl, or pyridyl, wherein the phenyl or pyridyl is unsubstituted or substituted with 1 to 3 R^2a. [0155] Embodiment 20. The compound of any one of embodiments 1 to 19, wherein each R^2a is independently C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, or halo. [0156] Embodiment 21. The compound of any one of embodiments 1 to 19, wherein each R^2a is independently methyl, methoxy, trifluoromethyl, fluoro, or chloro. [0157] Embodiment 22. The compound of any one of embodiments 1 to 17, wherein R² and R³ are each C1-4 alkyl. [0158] Embodiment 23. The compound of any one of embodiments 1 to 17, wherein R² and R³ are each methyl. [0159] Embodiment 24. The compound of any one of embodiments 1 to 17, wherein R² and R³ combine with the sulfur atom to which they are attached to form a heterocycloalkyl having 4 to 6 ring members with 0 to 1 additional heteroatom ring vertex, independently N, O, or S, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 2 R^2b. [0160] Embodiment 25. The compound of any one of embodiments 1 to 17 or 24, wherein each R^2b is independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, or halo. [0161] Embodiment 26. The compound of any one of embodiments 1 to 17 or 24, wherein each R^2b is independently methyl, or methoxy. [0162] Embodiment 27. The compound of any one of embodiments 1 to 17, wherein R² and R³ are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, , R² an

.

[0163] Embodiment 28. The compound of any one of embodiments 1 to 27, wherein R⁴ is C1-4 alkyl or C3-6 cycloalkyl. [0164] Embodiment 29. The compound of any one of embodiments 1 to 27, wherein R⁴ is . [0165] Embodi s ⁴

1 to 29, wherein R is isopropyl. [0166] Embodiment 31. The compound of any one of embodiments 1 to 29, wherein R⁴ is cyclopropyl. [0167] Embodiment 32. The compound of embodiment 1, wherein the compound is selected from the compounds included in Table 1. [0168] Embodiment 33. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 32 and a pharmaceutically acceptable excipient. IV. Examples [0169] The following examples are offered to illustrate, but not to limit the claimed invention. A. Synthetic Examples [0170] Compounds within the scope of this invention can be synthesized as described below, using a variety of reactions known to the skilled artisan. One skilled in the art will also recognize that alternative methods may be employed to synthesize the target compounds of this invention, and that the approaches described within the body of this document are not exhaustive, but do provide broadly applicable and practical routes to compounds of interest. [0171] Those skilled in the art will also recognize that during standard work up procedures in organic chemistry, acids and bases are frequently used. Salts of the parent compounds are sometimes produced, if they possess the necessary intrinsic acidity or basicity, during the experimental procedures described within this patent. Compound 1 Method A: Synthesis of ((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)(phenyl)- λ⁶-sulfanone. O N S H N N CuI

Step A: Preparation of methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6- carboxylate: [0172] The methyl 5-bromo-1H-indazole-6-carboxylate (25.0 g, 98.0 mmol) was dissolved in DCM (325 mL) under nitrogen atmosphere then 3,4-Dihydro-2H-pyran (11.6 mL, 127 mmol) and 4-methylbenzenesulfonic acid monohydrate (0.205 g, 1.08 mmol) were added and the reaction mixture was stirred at rt overnight. The resulting mixture was diluted with DCM, washed with a saturated solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0 to100% of EtOAc in hexane to afford the title compound as an off-white solid (30.0 g, 90 %). [0173] ¹H NMR (300 MHz, CDCl3): δ 8.06 – 8.03 (m, 1H), 8.00 (dt, J = 1.2, 4.2 Hz, 2H), 5.73 (dd, J = 2.6, 9.2 Hz, 1H), 4.04 – 3.98 (m, 1H), 3.98 (s, 3H), 3.82 – 3.68 (m, 1H), 2.61 – 2.42 (m, 1H), 2.23 – 2.07 (m, 2H), 1.81 – 1.67 (m, 3H). Step B: Preparation of (5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl) methanol: [0174] The methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carboxylate (30.0 g, 88.4 mmol) was dissolved in DCM (270 mL) under nitrogen atmosphere and the solution mixture was cooled down to -78 ^°C. To the previous mixture was added a 1M solution of DIBAL-H in THF (230 mL, 230 mmol) dropwise. The mixture was warmed to 0 °C and stirred for 2 h. The resulting mixture was diluted with EtOAc (46 mL) and DCM (250 mL) then a solution of 0.5 M solution of Rochelle’salt (460 mL) was added and the mixture was stirred at rt for 1 h. The organic layer was separated and washed with water, brine, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the title compound as a white solid (25.0 g, 91 %). [0175] ¹H NMR (300 MHz, CDCl3): δ 7.96 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.73 (s, 1H), 5.71 (d, J = 9.6 Hz, 1H), 4.84 (d, J = 4.2 Hz, 2H), 4.04 (d, J = 11.5 Hz, 1H), 3.85 – 3.66 (m, 1H), 2.66 – 2.46 (m, 1H), 2.34 – 2.23 (m, 1H), 2.18 – 2.00 (m, 2H), 1.80 – 1.63 (m, 3H). Step C: Preparation of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde: [0176] The (5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl) methanol (24.0 g, 77.0 mmol) was dissolved in DCM (650 mL) then the solution was cooled down to 0 ^oC. To the previous mixture water (180 mL), NaHCO3 (10.3 g, 123 mmol), NaBr (0.480 g, 5.00 mmol) and TEMPO (0.240 g, 1.00 mmol) and sodium hypochlorite solution (57.8 mL, 116 mmol) were added and the reaction mixture was stirred at 0 ^oC for 1 h. The reaction was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound as an off-white solid (22.5 g, 94 %). [0177] ¹H NMR (300 MHz, CDCl₃): δ 10.52 (s, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 8.01 (s, 1H), 5.77 (dd, J = 2.5, 9.6 Hz, 1H), 4.09 – 4.00 (m, 1H), 3.85 – 3.70 (m, 1H), 2.62 – 2.43 (m, 1H), 2.22 – 2.00 (m, 2H), 1.84 – 1.68 (m, 3H). Step D: Preparation of 5-(3-methylbut-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- 6-carbaldehyde: [0178] The 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (15.0 g, 48.5 mmol) was dissolved in DMF (160 mL) then diisopropylamine (14.0 mL, 97.0 mmol) was added and the reaction mixture was stirred and degassed with argon for 5 min. To the previous solution CuI (0.554 g, 2.91 mmol), Pd(PPh3)2Cl2 (1.02 g, 1.45 mmol) and 3-Methyl- 1-butyne (7.50 mL, 72.8 mmol) were added and the mixture was purged with argon for another 5 min then stirred at 50 ^oC for 16 h. The resulting mixture was cooled to rt, diluted with EtOAc, and washed with water, brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0 to 100% of EtOAc in hexane, to afford the title compound as an off-white solid (10.7 g, 74%). [0179] ¹H NMR (300 MHz, CDCl₃): δ 10.69 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 5.76 (dd, J = 2.5, 9.8 Hz, 1H), 4.14 – 4.00 (m, 1H), 3.86 – 3.70 (m, 1H), 2.93 – 2.74 (m, 1H), 2.68 – 2.42 (m, 1H), 2.22 – 2.03 (m, 2H), 1.85 – 1.63 (m, 3H), 1.31 (d, J = 6.9 Hz, 6H). Step E: Preparation of (E)-5-(3-methylbut-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole-6-carbaldehyde oxime: [0180] The 5-(3-methylbut-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6- carbaldehyde (22.0 g, 0.0741 mol) was dissolved in DCM (165 mL) then added dropwise to a heated (50 ^oC) stirring solution of hydroxylamine hydrochloride (15.5 g, 0.222 mol) and pyridine (119 mL, 1.48 mol) in acetonitrile (220 mL). The reaction mixture was stirred at the same temperature for 1 h then cooled down to rt and the solvent was removed in vacuo. The resulting residue was diluted with EtOAc and water and the layers were separated. The aqueous phase was extracted again with EtOAc and the combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0% to 100% of EtOAc in hexane, to afford the title compound as a solid (20.0 g, 87%). [0181] ¹H NMR (300 MHz, CDCl₃): δ 8.76 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.65 (s, 1H), 5.71 (dd, J = 2.5, 9.7 Hz, 1H), 4.05 (d, J = 11.7 Hz, 1H), 3.81 – 3.70 (m, 1H), 2.90 – 2.78 (m, 1H), 2.63 – 2.48 (m, 1H), 2.19 – 1.97 (m, 2H), 1.87 – 1.55 (m, 3H), 1.31 (d, J = 6.9 Hz, 6H). MS (ES+) m/z 310.14 [M-H]-. Step F: Preparation of 5-iodo-6-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-g] isoquinoline 7-oxide: [0182] The (E)-5-(3-methylbut-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6- carbaldehyde oxime (21.5 g, 69.0 mmol) was dissolved in DCM (428 mL) under argon then iodine (23.6 g, 93.2 mmol) and potassium carbonate (29.5 g, 214 mmol) were added and the reaction mixture was stirred at rt for 4 h. The resulting mixture was diluted with DCM and quenched with a saturated aqueous sodium thiosulfate solution. The mixture was stirred for 5 min then the organic layer was separated and washed with a saturated solution of NaHCO₃, water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0 to 5% of MeOH in DCM to afford the title compound as a brown solid (17.1 g, 57%). [0183] ¹H NMR (300 MHz, CDCl3): δ 8.79 (s, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 7.74 (s, 1H), 5.82 (dd, J = 2.4, 9.1 Hz, 1H), 4.27 – 4.14 (m, 1H), 4.09 – 3.97 (m, 1H), 3.89 – 3.73 (m, 1H), 2.68 – 2.51 (m, 1H), 2.25 – 2.09 (m, 2H), 1.85 – 1.70 (m, 3H), 1.59 (d, J = 6.5 Hz, 6H). Step G: Preparation of 5-(4-fluorophenyl)-6-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[4,3-g] isoquinoline 7-oxide: [0184] To a solution of 5-iodo-6-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3- g] isoquinoline 7-oxide (2.00 g, 5.00 mmol) in DMSO (45 mL) were added 4- (fluorophenyl)boronic acid (0.96 g, 7.0 mmol) and 2 M aqueous solution of Na2CO3 (4.60 mL, 9.00 mmol). The mixture was degassed with argon for 5 min then Pd(PPh₃)₄ (0.264 g, 1.00 mmol) was added at rt and purged another time with argon. The reaction was stirred at 100 °C for 2 h then cooled to rt. Water was added to the mixture and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient of 0- 100% of EtOAc in hexane, to afford the title compound as a brown solid (1.0 g, 54%). [0185] ¹H NMR (300 MHz, CDCl₃): δ 8.94 (s, 1H), 8.07 (d, J = 1.0 Hz, 1H), 7.82 (s, 1H), 7.49 (t, J = 1.0 Hz, 1H), 7.34 – 7.11 (m, 4H), 5.78 (dd, J = 2.6, 9.2 Hz, 1H), 4.05 – 3.96 (d, J = 11.4 Hz, 1H), 3.89 – 3.68 (m, 1H), 2.62 – 2.59 (m, 1H), 2.24 – 2.03 (m, 2H), 1.92 – 1.70 (m, 4H), 1.40 (d, J = 6.9 Hz, 6H). MS (ES+) m/z 406.26 [M+H]⁺ and 428.35 [M+Na]⁺. Step H: Preparation of 8-chloro-5-(4-fluorophenyl)-6-isopropyl-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazolo[4,3-g] isoquinoline: [0186] The 5-(4-fluorophenyl)-6-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3- g] isoquinoline 7-oxide (0.750 g, 2.00 mmol) was dissolved in DCM (17 mL) under argon atmosphere then ethylbis(propan-2-yl)amine (0.967 mL, 6.00 mmol) was added dropwise at rt and the mixture was cooled to 0 °C. To the previous solution oxalyl chloride (0.333 mL, 4.00 mmol) in DCM (12 mL) was added dropwise and the mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with a saturated aqueous NaHCO₃ solution and extracted twice with DCM. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0% to100% of EtOAc in hexane, to afford the title compound as a white solid (0.440 g, 56 %). [0187] ¹H NMR (300 MHz, CDCl₃): δ 8.56 (s, 1H), 8.19 (s, 1H), 7.72 (s, 1H), 7.33 – 7.27 (m, 4H), 5.94 (dd, J = 2.7, 9.3 Hz, 1H), 4.16 – 4.02 (m, 1H), 3.93 – 3.79 (m, 1H), 2.94 (sept, J = 6.7 Hz, 1H), 2.79 – 2.59 (m, 1H), 2.31 – 2.00 (m, 2H), 2.00 – 1.69 (m, 3H), 1.27 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 424.04 [M+H]⁺. Step I: Preparation of ((5-(4-fluorophenyl)-6-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[4,3-g]isoquinolin-8-yl)imino)(methyl)(phenyl)- λ⁶-sulfanone: [0188] 8-chloro-5-(4-fluorophenyl)-6-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[4,3-g] isoquinoline (50.0 mg, 0.120 mmol) was dissolved in 1,4-dioxane (0.780 mL) under argon then imino(methyl)(phenyl)- λ⁶-sulfanone (22.0 mg, 0.142 mmol) and Xantphos (7.00 mg, 0.01 mmol) were added at rt. The resulting mixture was degassed with argon for 5 min then Pd2(dba)3 (5.00 mg, 6.00 mmol) and cesium carbonate (58.2 mg, 0.177 mmol) were added and the mixture was purged again with argon and stirred at 100 °C for 8 h. The resulting mixture was cooled to rt then water was added. The aqueous solution was extracted twice with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0% to 100% of EtOAc in hexane, to afford the title compound as a yellow solid (45.0 mg, 70%). [0189] ¹H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 8.16 – 8.06 (m, 3H), 7.65 – 7.54 (m, 3H), 7.52 (s, 1H), 7.24 – 7.10 (m, 4H), 5.94 (t, J = 8.2 Hz, 1H), 4.10 – 4.01 (m, 1H), 3.85 (t, J = 10.6 Hz, 1H), 3.54 (d, J = 17.2 Hz, 3H), 2.76 – 2.57 (m, 2H), 2.27– 2.07 (m, 2H), 1.91 – 1.62 (m, 3H), 1.05 (t, J = 5.3 Hz, 3H), 0.54 (dd, J = 4.4, 6.7 Hz, 3H). MS (ES+) m/z 543.30 [M+H]⁺. Step J: Preparation of ((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)(phenyl)- λ⁶-sulfanone (1): [0190] ((5-(4-fluorophenyl)-6-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3- g]isoquinolin-8-yl)imino)(methyl)(phenyl)-λ⁶-sulfanone (40.0 mg, 0.0740 mmol) was dissolved in DCM (4.40 mL) under nitrogen atmosphere then triisopropylsilane (0.030 mL, 0.15 mmol) and TFA (0.370 mL, 4.84 mmol) were add and the reaction mixture was stirred at rt for 3 h. The resulting mixture was diluted with more DCM and quenched by adding a saturated aqueous solution of NaHCO₃ dropwise. The two phases were stirred for 10 min then separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, brine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0% to 100% of EtOAc in hexane, to afford the title compound as an off-white solid (12.0 mg, 35%). [0191] ¹H NMR (300 MHz, DMSO-d6): δ 13.24 (s, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 8.07 (d, J = 7.0 Hz, 2H), 7.73 – 7.64 (m, 3H), 7.47 (s, 1H), 7.39 – 7.24 (m, 4H), 3.65 (s, 3H), 2.61 – 2.54 (m, 1H), 1.00 (d, J = 6.6 Hz, 3H), 0.50 (d, J = 6.6 Hz, 3H). MS (ES+) m/z 458.97 [M+H]⁺ and 481.06 [M+Na]⁺ . Compound 2 ethyl((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(methyl)- λ⁶-sulfanone [0192] Compound 2 was synthesiz

hod A described for the preparation of Compound 1 where imino(methyl)(phenyl)-λ⁶-sulfanone is replaced with ethyl(imino)(methyl)-l6-sulfanone in Step I. [0193] ¹H NMR (300 MHz, CDCl₃): δ 10.44 (s, 1H), 8.72 (s, 1H), 8.12 (s, 1H), 7.55 (s, 1H), 7.28 – 7.11 (m, 4H), 3.94 – 3.65 (m, 2H), 3.51 (s, 3H), 2.97 – 2.77 (m, 1H), 1.53 (t, J = 7.4 Hz, 3H), 1.20 (dd, J = 3.1, 6.8 Hz, 6H). MS (ES+) m/z 433.15 [M+Na]⁺. Compound 3 ((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl-λ⁶- sulfanone [0194] Compound 3 was synthesiz hod A described for the preparation of

Compound 1. [0195] ¹H NMR (300 MHz, CDCl₃): δ 10.13 (s, 1H), 8.67 (s, 1H), 8.13 (s, 1H), 7.56 (s, 1H), 7.29 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 8.4 Hz, 2H), 3.56 (s, 6H), 2.90 (sept, J = 6.7 Hz, 1H), 1.21 (d, J = 6.4 Hz, 6H). MS (ES+) m/z 397.28 [M + H]⁺ and 419.10 [M+Na]⁺. Compound 4 diethyl((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)-λ⁶- sulfanone [0196] Compound 4 was synthesiz

hod A described for the preparation of Compound 1. [0197] ¹H NMR (300 MHz, CDCl₃): δ 10.40 (s, 1H), 8.74 (s, 1H), 8.12 (s, 1H), 7.55 (s, 1H), 7.30 – 7.14 (m, 4H), 3.96 – 3.76 (m, 2H), 3.76 – 3.56 (m, 2H), 2.97 – 2.78 (m, 1H), 1.50 (t, J = 7.5 Hz, 6H), 1.18 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 447.19 [M+Na]⁺. Compound 5 (R)-((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)(phenyl)-λ⁶-sulfanone [0198] Compound 5 was synthesi od A described for the preparation of

Compound 1. Compound 1 was submitted to chiral separation, after purification, peak at RT: 3.761 min was designated as a compound 5 (99.98% ee, Absolute configuration is not known). [0199] ¹H NMR (300 MHz, CDCl₃): δ 8.74 (s, 1H), 8.18 – 8.10 (m, 3H), 7.67 – 7.54 (m, 4H), 7.24 – 7.12 (m, 4H), 3.55 (s, 3H), 2.75 – 2.61 (m, 1H), 1.08 (d, J = 6.6 Hz, 3H), 0.62 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 481.13 [M+Na]⁺. Compound 6 (S)-((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)(phenyl)-λ⁶-sulfanone [0200] Compound 6 was synthes

od A described for the preparation of Compound 1. Compound 1 was submitted to chiral separation, after purification peak at RT: 4.183 min was designated as a compound 6 (99.84% ee, Absolute configuration is not known). [0201] ¹H (300 MHz, CDCl3): δ 8.75 (s, 1H), 8.19 – 8.09 (m, 3H), 7.66 – 7.55 (m, 4H), 7.24 – 7.12 (m, 4H), 3.55 (s, 3H), 2.76 – 2.60 (m, 1H), 1.08 (d, J = 6.6 Hz, 3H), 0.62 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 481.13 [M+Na]⁺. Compound 7 ((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(isopropyl)(methyl)-λ⁶-sulfanone [0202] Compound 7 was synthesiz hod A described for the preparation of

Compound 1. [0203] ¹H (300 MHz, CDCl3): δ 10.24 (s, 1H), 8.67 (s, 1H), 8.12 (s, 1H), 7.55 (s, 1H), 7.39 – 7.08 (m, 4H), 4.09 – 3.96 (m, 1H), 3.50 (s, 3H), 2.97 – 2.76 (m, 1H), 1.63 (d, J = 6.8 Hz, 3H), 1.57 (d, J = 6.9 Hz, 3H), 1.19 (dd, J = 6.7, 9.0 Hz, 6H). MS (ES+) m/z 425.23 [M+H]⁺. Compound 8 ethyl((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(isopropyl)- λ⁶-sulfanone [0204] Compound 8 was synthesiz

hod A described for the preparation of Compound 1. [0205] ¹H NMR (300 MHz, CDCl3): δ 8.72 (d, J = 1.1 Hz, 1H), 8.12 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 1.1 Hz, 1H), 7.31 – 7.26 (m, 2H), 7.20 (t, J = 8.9 Hz, 2H), 4.27 – 4.11 (m, 1H), 4.12 – 3.93 (m, 1H), 3.76 – 3.61 (m, 1H), 3.07 – 2.76 (m, 1H), 1.57 – 1.53 (m, 4H), 1.49 – 1.36 (m, 5H), 1.22 – 1.12 (m, 6H). MS (ES+) m/z 461.24 [M+Na]⁺ Compound 9 sec-butyl((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)-λ⁶-sulfanone [0206] Compound 9 was synthesiz hod A described for the preparation of

Compound 1. [0207] ¹H NMR (300 MHz, CDCl₃): δ 10.29 (s, 1H), 8.67 (d, J = 5.5 Hz, 1H), 8.12 (s, 1H), 7.55 (s, 1H), 7.28 – 7.14 (m, 4H), 4.06 – 3.80 (m, 1H), 3.48 (d, J = 6.6 Hz, 3H), 2.88 (sept, J = 6.2 Hz, 1H), 2.45 – 2.20 (m, 1H), 1.88 – 1.69 (m, 1H), 1.58 (dd, J = 6.9, 16.2 Hz, 3H), 1.22 – 1.01 (m, 9H). MS (ES+) m/z 439.24 [M+H]⁺. Compound 10 cyclopropyl((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)-λ⁶-sulfanone [0208] Compound 10 was synthes

thod A described for the preparation of Compound 1. [0209] ¹H NMR (300 MHz, CDCl3): δ 10.46 (s, 1H), 8.68 (s, 1H), 8.12 (s, 1H), 7.55 (s, 1H), 7.38 – 7.09 (m, 4H), 3.67 (s, 3H), 3.46 – 3.29 (m, 1H), 2.90 (sept, J = 6.7 Hz, 1H), 1.70 – 1.45 (m, 2H), 1.27 – 1.13 (m, 8H). MS (ES+) m/z 423.22 [M+H]⁺. Compound 11 1-((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)tetrahydro-1H- 1 λ⁶ -thiophene 1-oxide [0210] Compound 11 was synthesi thod A described for the preparation of

Compound 1. [0211] ¹H NMR (300 MHz, CDCl3): δ 8.65 (s, 1H), 8.13 (s, 1H), 7.56 (s, 1H), 7.26 – 7.20 (m, 5H), 4.01 – 3.83 (m, 2H), 3.52 – 3.38 (m, 2H), 2.88 (sept, J = 6.8 Hz, 1H), 2.45 – 2.26 (m, 4H), 1.22 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 423.26 [M+H]⁺. Compound 12 1-((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)-1 λ⁶- thiomorpholine 1-oxide [0212] Compound 12 was synthe

hod A described for the preparation of Compound 1. [0213] ¹H NMR (300 MHz, acetone-d6): δ 12.37 (s, 1H), 8.74 (s, 1H), 8.19 (s, 1H), 7.56 (s, 1H), 7.50 – 7.23 (m, 4H), 4.05 (q, J = 7.1 Hz, 2H), 3.52 – 3.39 (m, 4H), 3.39 – 3.26 (m, 2H), 2.83 – 2.79 (m, 1H), 1.18 (d, J = 6.7 Hz,6H). MS (ES+) m/z 460.18 m/z [M+Na]⁺. Compound 13 ((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)(piperidin-4-yl)-λ⁶-sulfanone [0214] Compound 13 was synth od A described for the preparation of

Compound 1. [0215] ¹H NMR (300 MHz, CD₃OD): δ 8.64 (s, 1H), 8.14 (s, 1H), 7.57 (s, 1H), 7.36 – 7.23 (m, 4H), 4.19 – 4.04 (m, 1H), 3.62 (s, 3H), 3.60 – 3.44 (m, 2H), 3.09 – 2.92 (m, 2H), 2.95 – 2.80 (m, 1H), 2.59 – 2.42 (m, 2H), 2.30 – 2.09 (m, 2H), 1.23 (dd, J = 1.9, 6.7 Hz, 6H). MS (ES+) m/z 466.60 [M+H]⁺. Compound 14 (4-chlorophenyl)((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)-λ⁶-sulfanone [0216] Compound 14 was synth

od A described for the preparation of Compound 1. [0217] ¹H NMR (300 MHz, CDCl3): δ 10.41 (s, 1H), 8.73 (s, 1H), 8.14 (s, 1H), 8.06 (d, J = 8.7 Hz, 2H), 7.57 (s, 2H), 7.54 (s, 1H), 7.24 – 7.11 (m, 4H), 3.54 (s, 3H), 2.70 (sept, J = 6.7 Hz, 1H), 1.07 (d, J = 6.7 Hz, 3H), 0.64 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 515.15 and 517.13 [M+Na]⁺. Compound 15 (4-fluorophenyl)((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)-λ⁶-sulfanone [0218] Compound 15 was synth od A described for the preparation of

Compound 1. [0219] ¹H NMR (300 MHz, DMSO-d6): δ 13.23 (s, 1H), 8.63 (s, 1H), 8.24 (s, 1H), 8.19 – 8.05 (m, 2H), 7.49 (dd, J = 7.8, 16.8 Hz, 3H), 7.41 – 7.16 (m, 4H), 3.64 (s, 3H), 2.64 – 2.51 (m, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.50 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 499.15 [M+Na]⁺. Compound 16 ((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(4- methoxyphenyl)(methyl)-λ⁶-sulfanone [0220] Compound 16 was syn

d A described for the preparation of Compound 1. [0221] ¹H NMR (300 MHz, CDCl3): δ 10.14 (s, 1H), 8.73 (t, J = 1.2 Hz, 1H), 8.13 (d, J = 1.2 Hz, 1H), 8.10 – 8.03 (m, 2H), 7.57 (d, J = 1.1 Hz, 1H), 7.25 – 7.13 (m, 4H), 7.10 – 7.03 (m, 2H), 3.89 (s, 3H), 3.58 (s, 3H), 2.80 – 2.65 (m, 1H), 1.11 (d, J = 6.6 Hz, 3H), 0.78 (d, J = 6.6 Hz, 3H). MS (ES+) m/z 489.26 [M+H]⁺ and 511.21 [M+Na]⁺. Compound 17 4-(N-(5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)-S- methylsulfonimidoyl)benzoic acid [0222] Compound 17 was syn A described for the preparation of

Compound 1. [0223] ¹H NMR (300 MHz, CD3OD): δ 8.76 (s, 1H), 8.22 (d, J = 8.3 Hz, 2H), 8.17 – 8.10 (m, 3H), 7.55 (s, 1H), 7.27 – 7.17 (m, 4H), 3.57 (s, 3H), 2.61 (p, J = 6.7 Hz, 1H), 1.04 (d, J = 6.6 Hz, 3H), 0.48 (d, J = 6.7 Hz, 3H). MS (ES-) m/z 501.31 [M-H]-. Compound 18 methyl 4-(N-(5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)-S- methylsulfonimidoyl)benzoate [0224] Compound 18 was syn

A described for the preparation of Compound 1. [0225] ¹H NMR (300 MHz, CDCl3): δ 8.74 (s, 1H), 8.29 – 8.11 (m, 5H), 7.57 (d, J = 1.0 Hz, 1H), 7.23 – 7.12 (m, 4H), 3.97 (s, 3H), 3.53 (s, 3H), 2.76 – 2.55 (m, 1H), 1.05 (d, J = 6.7 Hz, 3H), 0.53 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 539.19 [M+Na]⁺. Compound 19 ((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(methyl)(4- (trifluoromethyl)phenyl)-λ⁶-sulfanone [0226] Compound 19 was synt d A described for the preparation of

Compound 1. [0227] ¹H NMR (300 MHz, CDCl3): δ 8.72 (s, 1H), 8.24 (d, J = 8.2 Hz, 2H), 8.15 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.58 (s, 1H), 7.23 – 7.14 (m, 4H), 3.53 (s, 4H), 2.77 – 2.57 (m, 1H), 1.03 (d, J = 6.7 Hz, 3H), 0.47 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 549.17 [M+Na]⁺. Compound 20 (2-fluorophenyl)((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)-λ⁶-sulfanone [0228] Compound 20 was synthe

hod A described for the preparation of Compound 1. [0229] ¹H NMR (300 MHz, CDCl₃): δ 10.13 (s, 1H), 8.70 (s, 1H), 8.27 (t, J = 7.4 Hz, 1H), 8.12 (s, 1H), 7.61 (q, J = 6.1 Hz, 1H), 7.55 (s, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.24 – 7.10 (m, 5H), 3.65 (s, 3H), 2.67 (sept, J = 6.4 Hz, 1H), 1.06 (d, J = 6.7 Hz, 3H), 0.58 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 477.19 [M+H]⁺. Compound 21 ((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)(naphthalen-1-yl)-λ⁶-sulfanone [0230] Compound 21 was synth od A described for the preparation of

Compound 1. [0231] ¹H NMR (300 MHz, CDCl₃): δ 10.31 (s, 1H), 8.77 (d, J = 13.4 Hz, 2H), 8.14 (s, 1H), 8.10 – 7.96 (m, 3H), 7.93 (d, J = 9.3 Hz, 1H), 7.72 – 7.59 (m, 2H), 7.56 (s, 1H), 7.25 – 7.07 (m, 4H), 3.63 (s, 3H), 2.75 – 2.55 (m, 1H), 1.06 (d, J = 6.7 Hz, 3H), 0.47 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 509.20 [M+H]⁺. Compound 22 ((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)(pyridin-4-yl)-λ⁶-sulfanone [0232] Compound 22 was synth

hod A described for the preparation of Compound 1. [0233] ¹H NMR (300 MHz, CDCl₃): δ 10.36 (s, 1H), 8.90 (d, J = 6.2 Hz, 2H), 8.73 (s, 1H), 8.15 (s, 1H), 7.97 (d, J = 6.2 Hz, 2H), 7.58 (s, 1H), 7.23 – 7.14 (m, 4H), 3.50 (s, 3H), 2.75 – 2.56 (m, 1H), 1.03 (d, J = 6.7 Hz, 3H), 0.45 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 482.05 [M+Na]⁺. Compound 23 ((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)(pyridin-2-yl)-λ⁶-sulfanone [0234] Compound 23 was synthe hod A described for the preparation of

Compound 1. [0235] ¹H NMR (300 MHz, CDCl₃): δ 10.59 (s, 1H), 8.94 (s, 1H), 8.78 (d, J = 5.3 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 8.05 (t, 1H), 7.62 – 7.47 (m, 2H), 7.24 – 7.06 (m, 4H), 3.65 (s, 3H), 2.76 – 2.54 (m, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.57 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 482.17 [M+Na]⁺. Compound 24 ((6-isopropyl-5-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl-λ⁶- sulfanone [0236] Compound 24 was synthes

thod A described for the preparation of Compound 1. [0237] ¹H NMR (300 MHz, CDCl3): δ 10.16 (s, 1H), 8.65 (s, 1H), 8.16 (s, 1H), 7.86 (s, 1H), 7.67 (s, 2H), 3.55 (s, 6H), 3.13 (sept, J = 7.0 Hz, 1H), 1.23 (d, J = 6.8 Hz, 6H). MS (ES+) m/z 391.14 [M+Na]⁺. Compound 25 ((6-isopropyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl-λ⁶-sulfanone [0238] Compound 25 was synthes thod A described for the preparation of

Compound 1. [0239] ¹H NMR (300 MHz, CDCl₃): δ 10.41 (s, 1H), 8.66 (s, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 4.07 (s, 3H), 3.56 (s, 6H), 3.17 (sept, J = 6.8 Hz, 1H), 1.23 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 383.20 [M+H]⁺. Compound 26 ((6-isopropyl-5-(1-methyl-1H-indazol-5-yl)-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl-λ⁶-sulfanone [0240] Compound 26 was synthesi

thod A described for the preparation of Compound 1. [0241] ¹H NMR (300 MHz, CDCl₃): δ 10.37 (s, 1H), 8.70 (s, 1H), 8.05 (s, 2H), 7.66 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.33 (dd, J = 1.5, 8.5 Hz, 1H), 4.18 (s, 3H), 3.59 (d, J = 2.9 Hz, 6H), 2.94 (sept, J = 6.7 Hz, 1H), 1.21 (dd, J = 4.3, 6.6 Hz, 6H). MS (ES+) m/z 455.13 [M+Na]⁺. Compound 27 ((5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl-λ⁶-sulfanone [0242] Compound 27 was synthesi thod A described for the preparation of

Compound 1. [0243] ¹H NMR (300 MHz, CDCl3): δ 10.45 (s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 8.46 (s, 1H), 8.13 (s, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.58 (d, J = 1.1 Hz, 1H), 7.50 (dd, J = 1.6, 9.0 Hz, 1H), 3.58 (d, J = 4.9 Hz, 6H), 2.93 (sept, J = 6.7 Hz, 1H), 1.25 (dd, J = 6.8, 11.6 Hz, 6H). MS (ES+) m/z 420.30 [M+H]⁺. Compound 28 ((6-isopropyl-5-(naphthalen-1-yl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl-λ⁶- sulfanone [0244] Compound 28 was synthesi

thod A described for the preparation of Compound 1. [0245] ¹H NMR (300 MHz, CDCl₃): δ 10.20 (s, 1H), 8.70 (s, 1H), 8.06 – 7.88 (m, 3H), 7.62 (t, J = 7.6 Hz, 1H), 7.54 – 7.36 (m, 3H), 7.32 (s, 1H), 7.28 (s, 1H), 3.60 (d, J = 7.3 Hz, 6H), 2.75 – 2.60 (m, 1H), 1.19 (d, J = 6.7 Hz, 3H), 1.11 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 429.26 [M+H]⁺. Compound 29 ((5-(benzo[b]thiophen-3-yl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl- λ⁶-sulfanone [0246] Compound 29 was synthesi thod A described for the preparation of

Compound 1. [0247] ¹H NMR (300 MHz, CDCl3): δ 10.38 (s, 1H), 8.70 (s, 1H), 8.04 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.54 (s, 1H), 7.42 – 7.34 (m, 2H), 7.25 (d, J = 1.2 Hz, 2H), 3.60 (d, J = 7.4 Hz, 6H), 2.90 – 2.81 (m, 1H), 1.23 (d, J = 6.7 Hz, 3H), 1.16 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 435.15 [M+H]⁺. Compound 30 ((6-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl-λ⁶-sulfanone [0248] Compound 30 was synthes

thod A described for the preparation of Compound 1. [0249] ¹H NMR (300 MHz, CDCl₃): δ 8.59 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 5.79 (s, 1H), 3.94 (d, J = 3.1 Hz, 2H), 3.64 – 3.53 (m, 8H), 3.27 – 3.17 (m, 1H), 2.77 – 2.63 (m, 1H), 2.63 – 2.44 (m, 1H), 1.34 – 1.29 (m, 6H). MS (ES+) m/z 406.19 [M+Na]⁺. Compound 31 ((6-isopropyl-5-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl- λ⁶-sulfanone [0250] Compound 31 was synthesi thod A described for the preparation of

Compound 1. [0251] ¹H NMR (300 MHz, CDCl₃): δ 10.43 (s, 1H), 8.70 (s, 1H), 8.66 (d, J = 5.0 Hz, 1H), 8.14 (s, 1H), 7.53 (s, 1H), 7.15 (s, 1H), 7.10 (d, J = 5.1 Hz, 1H), 3.57 (s, 6H), 2.91 – 2.79 (m, 1H), 2.67 (s, 3H), 1.22 (dd, J = 3.8, 6.8 Hz, 6H). MS (ES+) m/z 416.21 [M+Na]⁺. Compound 32 ((6-isopropyl-5-(quinolin-4-yl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl-λ⁶- sulfanone [0252] Compound 32 was synthesi

thod A described for the preparation of Compound 1. [0253] ¹H NMR (300 MHz, CDCl3): δ 10.63 (s, 1H), 9.08 (d, J = 4.5 Hz, 1H), 8.75 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.01 (s, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.43 – 7.30 (m, 2H), 7.26 (s, 1H), 3.62 (d, J = 8.5 Hz, 6H), 2.61 (sept, J = 6.7 Hz, 1H), 1.20 (d, J = 6.7 Hz, 3H), 1.12 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 430.29 [M+H]⁺. Compound 33 ((6-isopropyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl-λ⁶-sulfanone [0254] Compound 33 was synthesi thod A described for the preparation of

Compound 1. [0255] ¹H NMR (300 MHz, CDCl3): δ 10.51 (s, 1H), 8.72 (s, 1H), 8.13 (s, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.49 (s, 1H), 7.45 (d, J = 8.1 Hz, 2H), 3.59 (s, 6H), 2.84 (sept, J = 6.6 Hz, 1H), 1.22 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 447.08 [M+H]⁺. Compound 34 ((5-(2,4-difluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl-λ⁶- sulfanone [0256] Compound 34 was synthesi

thod A described for the preparation of Compound 1. [0257] ¹H NMR (300 MHz, CDCl3): δ 10.47 (s, 1H), 8.71 (s, 1H), 8.14 (s, 1H), 7.53 (s, 1H), 7.32 – 7.19 (m, 1H), 7.11 – 6.97 (m, 2H), 3.57 (d, J = 10.7 Hz, 6H), 2.84 (sept, J = 6.3 Hz, 1H), 1.24 – 1.17 (m, 6H). MS (ES+) m/z 415.15 [M+H]⁺. Compound 35 ((5-cyclopropyl-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl-λ⁶- sulfanone O S

[0258] Compound 35 was synthesized by using Method A described for the preparation of Compound 1. [0259] ¹H NMR (300 MHz, CDCl3): δ 10.33 (s, 1H), 8.77 (s, 1H), 8.64 (s, 1H), 8.30 (s, 1H), 3.97 (sept, J = 6.7 Hz, 1H), 3.52 (s, 6H), 2.03 – 1.91 (m, 1H), 1.28 (d, J = 6.7 Hz, 6H), 1.25 – 1.18 (m, 2H), 0.71–0.60 (m, 2H). MS (ES+) m/z 343.17 [M+H]⁺. Compound 36 ((6-isopropyl-5-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)(phenyl)-λ⁶-sulfanone [0260] Compound 36 was synthe hod A described for the preparation of

Compound 1. [0261] ¹H NMR (300 MHz, CDCl3): δ 10.18 (s, 1H), 8.76 (s, 1H), 8.65 – 8.58 (m, 1H), 8.18 – 8.07 (m, 3H), 7.60 (d, J = 7.8 Hz, 3H), 7.53 (s, 1H), 7.12 – 7.01 (m, 2H), 3.54 (d, J = 3.1 Hz, 3H), 2.63 (d, J = 3.1 Hz, 4H), 1.08 (d, J = 6.8 Hz, 3H), 0.62 (dd, J = 6.7, 12.3 Hz, 3H). MS (ES+) m/z 455.9 [M+H]⁺. Compound 37 1-((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)hexahydro- 1λ⁶-thiopyran 1-oxide [0262] Compound 37 was synthesi

thod A described for the preparation of Compound 1. [0263] ¹H NMR (300 MHz, CDCl₃): δ 10.41 (s, 1H), 8.72 (s, 1H), 8.13 (s, 1H), 7.55 (s, 1H), 7.35 – 7.26 (m, 2H), 7.20 (t, J = 8.5 Hz, 2H), 4.22 (dt, J = 5.7, 13.0 Hz, 2H), 3.35 (dt, J = 5.5, 12.8 Hz, 2H), 2.88 (sept, J = 6.7 Hz, 1H), 2.23 (q, J = 6.0 Hz, 4H), 1.77 (q, J = 5.8 Hz, 2H), 1.20 (d, J = 6.6 Hz, 6H). MS (ES+) m/z 437.29 [M+H]⁺. Compound 38 ((5-(3-fluoro-4-methoxyphenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl- λ⁶-sulfanone [0264] Compound 38 was synthesi thod A described for the preparation of

Compound 1. [0265] ¹H NMR (300 MHz, CD3OD): δ 8.66 (s, 1H), 8.18 (s, 1H), 7.66 (s, 1H), 7.42 – 7.20 (m, 1H), 7.09 (d, J = 8.2 Hz, 2H), 4.01 (s, 3H), 3.65 (s, 6H), 3.08 – 2.86 (m, 1H), 1.27 (d, J = 6.3 Hz, 6H). MS (ES+) m/z 427.25 [M+H]⁺. Compound 39 ((5-(3-(difluoromethoxy)phenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl- λ⁶-sulfanone [0266] Compound 39 was synthe

hod A described for the preparation of Compound 1. [0267] ¹H NMR (300 MHz, CDCl3): δ 8.78 (s, 1H), 8.03 (s, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.41 (s, 1H), 7.28 – 7.23 (m, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.08 (s, 1H), 6.63 (t, J = 73.6 Hz, 1H), 3.78 (s, 6H), 3.01 – 2.83 (m, 1H), 1.28 – 1.21 (m, 6H). MS (ES+) m/z 445.26 [M+H]⁺. Compound 40 ((5-(2-fluoropyridin-4-yl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl- λ⁶-sulfanone [0268] Compound 40 was synthesi thod A described for the preparation of

Compound 1. [0269] ¹H NMR (300 MHz, CD₃OD): δ 8.70 (s, 1H), 8.41 (d, J = 4.2 Hz, 1H), 8.20 (s, 1H), 7.60 (s, 1H), 7.35 (d, J = 4.4 Hz, 1H), 7.14 (s, 1H), 3.66 (s, 6H), 2.98 – 2.70 (m, 1H), 1.30 – 1.22 (m, 6H). MS (ES+) m/z 398.27 [M+H]⁺. Compound 41 ((5-(cyclohex-1-en-1-yl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl-λ⁶- sulfanone O S N [0270] Compound 41 was synthesi

thod A described for the preparation of Compound 1. [0271] ¹H NMR (300 MHz, acetone-d6): δ 8.64 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 5.73 (s, 1H), 3.64 (s, 6H), 3.35 (p, J = 7.0 Hz, 2H), 2.39 – 2.21 (m, 4H), 1.87 (m, 3H), 1.28 (dd, J = 6.9, 9.2 Hz, 6H). MS (ES+) m/z 383.35 [M+H]⁺. Compound 42 ((5-(6-fluoro-5-methylpyridin-3-yl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl-λ⁶-sulfanone [0272] Compound 42 was synthesi thod A described for the preparation of

Compound 1. [0273] ¹H NMR (300 MHz, acetone-d6): δ 12.42 (s, 1H), 8.69 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.79 (d, J = 9.7 Hz, 1H), 7.57 (s, 1H), 3.63 (d, J = 3.6 Hz, 6H), 2.87 – 2.77 (m, 1H), 2.40 (s, 3H), 1.23 (t, J = 7.1 Hz, 6H). MS (ES+) m/z 434.23 [M+Na]⁺. Compound 43 ((6-isopropyl-5-(1-methyl-1H-indazol-4-yl)-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl-λ⁶-sulfanone [0274] Compound 43 was synthesi

thod A described for the preparation of Compound 1. [0275] ¹H NMR (300 MHz, acetone-d₆): δ 8.71 (s, 1H), 8.11 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.65 – 7.54 (m, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 7.11 (d, J = 6.8 Hz, 1H), 4.16 (s, 3H), 3.67 (s, 6H), 2.81 – 2.72 (m, 1H), 1.19 (dd, J = 6.7, 13.4 Hz, 6H). MS (ES+) m/z 433.29 [M+H]⁺. Compound 44 1-((6-cyclopropyl-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)tetrahydro- 1H-1λ⁶-thiophene 1-oxide [0276] Compound 44 was synthes hod A described for the preparation of

Compound 1. [0277] ¹H NMR (300 MHz, CD3OD) δ 8.66 (s, 1H), 8.20 (s, 1H), 7.70 (s, 1H), 7.51 – 7.23 (m, 4H), 3.97 – 3.80 (m, 2H), 3.79 – 3.57 (m, 2H), 2.60 – 2.32 (m, 4H), 1.98 – 1.83 (m, 1H), 1.03 – 0.73 (m, 4H). MS (ES+) m/z 421.41 [M+H]⁺ . Compound 45 ((6-cyclopropyl-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(ethyl)(methyl)- λ⁶-sulfanone [0278] Compound 45 was synthes

thod A described for the preparation of Compound 1. [0279] ¹H NMR (300 MHz, CD3OD) δ 8.64 (s, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 7.43 – 7.35 (m, 2H), 7.28 (t, J = 8.7 Hz, 2H), 3.88 – 3.74 (m, 2H), 3.58 (s, 3H), 1.88 – 1.77 (m, 1H), 1.53 (t, J = 7.4 Hz, 3H), 1.00 – 0.88 (m, 2H), 0.87 – 0.75 (m, 2H). MS (ES+) m/z 409.38 [M+H]⁺. Compound 46 ((6-cyclopropyl-5-(4-fluorophenyl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl-λ⁶- sulfanone [0280] Compound 46 was synthes hod A described for the preparation of

Compound 1. [0281] ¹H NMR (300 MHz, CD3OD): δ 8.65 (s, 1H), 8.19 (s, 1H), 7.68 (s, 1H), 7.47 – 7.38 (m, 2H), 7.31 (t, J = 8.8 Hz, 2H), 3.64 (s, 6H), 1.91 – 1.74 (m, 1H), 1.10 – 0.93 (m, 2H), 0.87 – 0.71 (m, 2H). MS (ES+) m/z 395.25 [M+H]⁺. Compound 47 ((5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl-λ⁶-sulfanone [0282] Compound 47 was synthe

hod A described for the preparation of Compound 1. [0283] ¹H NMR (300 MHz, CD₃OD): δ 8.62 (s, 1H), 8.09 (s, 1H), 7.56 (s, 1H), 7.31 – 7.19 (m, 4H), 3.98 (dd, J = 11.3, 4.3 Hz, 2H), 3.60 (s, 6H), 3.43 – 3.32 (m, 2H), 2.85 – 2.68 (m, 1H), 2.26 – 2.07 (m, 2H), 1.64 – 1.52 (m, 2H). MS (ES+) m/z 439.40 [M+H]⁺. Compound 48 ((8-(4-fluorophenyl)-7-isopropyl-1H-imidazo[4,5-g]isoquinolin-5-yl)imino)dimethyl-λ⁶- sulfanone [0284] Compound 48 was synthesi thod A from the intermediate methyl 5-

bromo-1H-benzo[d]imidazole-6-carboxylate. [0285] ¹H NMR (300 MHz, CDCl3): δ 8.80 (s, 1H), 8.20 (s, 1H), 7.36 (s, 1H), 7.30 – 7.26 (m, 1H), 7.25 – 7.24 (m, 1H), 7.17 (t, J = 8.6 Hz, 2H), 3.56 (s, 6H), 2.92 (sept, J = 6.6 Hz, 1H), 1.22 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 379.23 [M+H]⁺. Compound 49 ((8-(4-fluorophenyl)-7-isopropyl-1H-[1,2,3]triazolo[4,5-g]isoquinolin-5-yl)imino)dimethyl- λ⁶-sulfanone [0286] Compound 49 was synthes

thod A from the intermediate methyl 5- bromo-1H-benzo[d][1,2,3]triazole-6-carboxylate. [0287] ¹H NMR (300 MHz, DMSO-d₆): δ 8.98 (s, 1H), 7.60 – 7.33 (m, 4H), 7.29 (s, 1H), 3.62 (s, 6H), 3.01 – 2.70 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H). MS (ES+) m/z 398.22 [M+H]⁺. Compound 50 ((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[3,4-b][1,7]naphthyridin-8-yl)imino)dimethyl- λ⁶-sulfanone

[0288] The intermediate methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-6-carboxylate was synthesized according to procedures reported in WO2018/203235 A1. After that, we used the intermediate methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-6-carboxylate to synthesize compound 50 by following Method A. [0289] ¹H NMR (300 MHz, DMSO-d₆): δ 13.78 (s, 1H), 8.31 (s, 1H), 7.99 (s, 1H), 7.38 (d, J = 7.0 Hz, 4H), 3.58 (s, 6H), 2.82 (p, J = 6.7 Hz, 1H), 1.17 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 398.30 [M+H]⁺. Compound 51 ((5-(4-fluorophenyl)-6-isopropyl-1H-pyrrolo[3,2-g]isoquinolin-8-yl)imino)dimethyl-λ⁶- sulfanone [0290] Compound 51 was synthesi

thod A from the intermediate methyl 5- bromo-1H-indole-6-carboxylate. [0291] ¹H NMR (300 MHz, DMSO-d₆): δ 11.25 (s, 1H), 8.39 (s, 1H), 7.64 (s, 1H), 7.42 – 7.28 (m, 4H), 7.17 (s, 1H), 6.45 (s, 1H), 3.58 (s, 6H), 2.88 – 2.70 (m, 1H), 1.16 (d, J = 6.6 Hz, 6H). MS (ES+) m/z 396.35 [M+H]⁺. Compound 52 Method B: Synthesis of dibutyl((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3- g]isoquinolin-8-yl)imino)-λ⁶-sulfanone

p y [0292] To a solution of dibutylsulfane (0.050 g, 0.34 mmol) in methanol (0.684 mL) was added (diacetoxyiodo)benzene (0.275 g, 0.854 mmol) and ammonium carbonate (0.0530 g, 0.684 mmol) and the reaction mixture was stirred at rt for 3 h. The solvent was evaporated in vacuo and the resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0% to 100% of EtOAc in hexane followed by 0-30% of MeOH in EtOAc, to afford the title compound as a colourless oil (38.0 mg, 63%). [0293] ¹H NMR (300 MHz, CDCl₃): δ 3.08 – 2.88 (m, 4H), 2.56 (s, 1H), 1.91 – 1.65 (m, 4H), 1.45 (sext, J = 7.4 Hz, 4H), 0.94 (t, J = 7.3 Hz, 6H). MS (ES+) m/z 198.95 [M+Na]⁺. Step B: Preparation of dibutyl((5-(4-fluorophenyl)-6-isopropyl-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)-λ⁶-sulfanone: [0294] The 8-chloro-5-(4-fluorophenyl)-6-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[4,3-g] isoquinoline (20 mg, 0.047 mmol) was dissolved in 1,4-dioxane (0.315 mL) under nitrogen atmosphere then dibutyl(imino)-λ⁶-sulfanone (10 mg, 0.057 mmol) and Xantphos (3.0 mg, 0.0051 mmol) were added at rt and the mixture was degassed with argon for 5 min. To the previous solution Pd2(dba)3 (2 mg, 0.002 mmol) and cesium carbonate (23 mg, 0.071 mmol) were added then the mixture was purged with argon for another 5 min. The resulting reaction mixture was stirred at 100 °C for 8 h then cooled down to rt, diluted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0% to 100% of EtOAc in hexane, to afford the title compound as a yellow solid (23.0 mg, 86%). [0295] ¹H NMR (300 MHz, CDCl3): δ 8.73 (s, 1H), 8.10 (s, 1H), 7.51 (s, 1H), 7.28 – 7.12 (m, 4H), 5.92 (dd, J = 2.7, 9.9 Hz, 1H), 4.13 – 4.03 (m, 1H), 4.03 – 3.79 (m, 3H), 3.65 – 3.50 (m, 2H), 2.88 (p, J = 6.6 Hz, 1H), 2.74 – 2.55 (m, 1H), 2.17 (s, 1H), 2.06 (d, J = 10.6 Hz, 1H), 2.00 – 1.73 (m, 6H), 1.68 (s, 1H), 1.49 (h, J = 7.4 Hz, 4H), 1.17 (dd, J = 6.7, 2.9 Hz, 6H), 0.94 (td, J = 7.4, 2.0 Hz, 6H). MS (ES+) m/z 565.40 [M+H]⁺. Step C: Preparation of dibutyl((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3- g]isoquinolin-8-yl)imino)-λ⁶-sulfanone (52): [0296] The dibutyl((5-(4-fluorophenyl)-6-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[4,3-g]isoquinolin-8-yl)imino)-λ⁶-sulfanone (15 mg, 0.074 mmol) was dissolved in DCM (2.66 mL) under nitrogen atmosphere then triisopropylsilane (0.011 mL, 0.147 mmol) and TFA (0.134 mL, 4.84 mmol) were added in this order. The reaction mixture was stirred at rt for 3 h. The resulting mixture was diluted with DCM then a saturated aqueous NaHCO₃ solution was added slowly and stirred for 10 min. The two layers were separated then the aqueous layer was extracted with DCM. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0% to 100% of EtOAc in hexane, to afford the title compound as an off-white solid (12.0 mg, 94%). [0297] ¹H NMR (300 MHz, CDCl₃): δ 10.30 (s, 1H), 8.73 (s, 1H), 8.12 (s, 1H), 7.55 (s, 1H), 7.29 – 7.13 (m, 4H), 3.96 – 3.81 (m, 2H), 3.67 – 3.50 (m, 2H), 2.95 – 2.82 (m, 1H), 2.02 – 1.81 (m, 4H), 1.50 (h, J = 7.4 Hz, 4H), 1.18 (d, J = 6.7 Hz, 6H), 0.95 (t, J = 7.3 Hz, 6H). MS (ES+) m/z 481.36 [M+H]⁺. Compound 53 ((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dipropyl- λ⁶- sulfanone [0298] Compound 53 was synthes

hod B described for the preparation of compound 52. [0299] ¹H NMR (300 MHz, CDCl3): δ 10.09 (s, 1H), 8.70 (s, 1H), 8.12 (s, 1H), 7.55 (s, 1H), 7.36 – 7.27 (m, 2H), 7.24 – 7.16 (m, 2H), 3.93 – 3.73 (m, 2H), 3.66 – 3.47 (m, 2H), 2.97 – 2.80 (m, 1H), 2.04 – 1.92 (m, 4H), 1.19 (d, J = 6.7 Hz, 6H), 1.10 (t, J = 7.5 Hz, 6H). MS (ES+) m/z 475.20 [M+Na]⁺. Compound 54 butyl(ethyl)((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)- λ⁶- sulfanone [0300] Compound 54 was synthe

hod B described for the preparation of compound 52. [0301] ¹H NMR (300 MHz, CDCl3): δ 10.10 (s, 1H), 8.72 (s, 1H), 8.13 (s, 1H), 7.56 (s, 1H), 7.31 – 7.28 (m, 2H), 7.24 – 7.17 (m, 2H), 3.94 – 3.81 (m, 2H), 3.71 – 3.57 (m, 2H), 2.99 – 2.82 (m, 1H), 2.00 – 1.87 (m, 2H), 1.54 – 1.45 (m, 5H), 1.18 (d, J = 6.7 Hz, 6H), 0.96 (t, J = 7.3 Hz, 3H). MS (ES+) m/z 453.18 [M+H]⁺. Compound 55 1-((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)-3-methoxy-1 λ⁶-thietane 1-oxide [0302] Compound 55 was synthe od B described for the preparation of

compound 52. [0303] ¹H NMR (300 MHz, CDCl₃): δ 10.22 (s, 1H), 8.60 (s, 1H), 8.14 (s, 1H), 7.59 (s, 1H), 7.34 – 7.15 (m, 4H), 5.02 (dd, J = 14.7, 7.1 Hz, 2H), 4.51 – 4.38 (m, 1H), 4.31 (dd, J = 14.7, 4.2 Hz, 2H), 3.41 (s, 3H), 2.89 (sept, J = 6.7 Hz, 1H), 1.21 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 461.19 [M+Na]⁺. Compound 56 1-((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)-3-methoxy-1 λ⁶-thietane 1-oxide [0304] Compound 56 was synthe

od B described for the preparation of compound 52. [0305] ¹H NMR (300 MHz, CDCl3): δ 10.20 (s, 1H), 8.60 (s, 1H), 8.13 (s, 1H), 7.58 (s, 1H), 7.33 – 7.16 (m, 4H), 4.78 – 4.46 (m, 5H), 3.36 (s, 3H), 2.87 (sept, J = 6.6 Hz, 1H), 1.21 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 461.19 [M+Na]⁺. Compound 57 Method C: ((5-(4-fluorophenyl)-6-(2-hydroxyethyl)-1H-benzo[f]indazol-8- yl)imino)dimethyl-l6-sulfanone

Step A: 5-(4-hydroxybut-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6- carbaldehyde: [0306] In a sealed tube was added 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6- carbaldehyde (1.00 g, 3.23 mmol) followed by DMF (10.8 mL) and diisopropylamine (0.914 mL, 6.47 mmol). The mixture was degassed with argon for 5 min followed by the addition of 3-butyn-1-ol (0.340 g, 4.85 mmol), CuI (0.037 g, 0.19 mmol) and Pd(PPh3)2Cl2 (0.068 g, 0.096 mmol). The reaction mixture was purged with argon for 5 min then heated at 50 ^oC for 16 h. The resulting mixture was cooled to rt, diluted with EtOAc and washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0% to 100% of EtOAc in hexane, to afford the title compound as an off-white solid (0.850 g, 88 %). [0307] ¹H NMR (300 MHz, CDCl₃): δ 10.62 (d, J = 1.1 Hz, 1H), 8.18 (q, J = 1.1 Hz, 1H), 8.09 (q, J = 0.9 Hz, 1H), 7.94 (t, J = 1.0 Hz, 1H), 5.79 (dd, J = 2.5, 9.6 Hz, 1H), 4.14 – 4.02 (m, 1H), 3.91 (q, J = 6.2 Hz, 2H), 3.86 – 3.70 (m, 1H), 2.80 (td, J = 6.2, 1.7 Hz, 2H), 2.72 – 2.42 (m, 1H), 2.42 – 1.96 (m, 3H), 1.98 – 1.69 (m, 3H). MS (ES+) m/z 321.12 [M+Na]⁺. Step B: Preparation of 5-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole-6-carbaldehyde: [0308] To a solution of 5-(4-hydroxybut-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole-6-carbaldehyde (0.410 g, 1.37 mmol) in DCM (5.7 mL) were added imidazole (0.139 g, 2.04 mmol) and tert-butylchlorodimethylsilane (0.246 g, 1.63 mmol) at rt under nitrogen atmosphere. After stirred for 1 h at rt, the reaction mixture was diluted with DCM and water. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0% to 50% EtOAc in hexane, to afford the title compound (0.318 g, 56 %). [0309] ¹H NMR (300 MHz, CDCl₃): δ 10.68 (s, 1H), 8.17 (d, J = 0.9 Hz, 1H), 8.06 (d, J = 1.0 Hz, 1H), 7.96 – 7.74 (m, 1H), 5.76 (dd, J = 2.5, 9.7 Hz, 1H), 4.13 – 3.99 (m, 1H), 3.86 (t, J = 6.9 Hz, 2H), 3.84 – 3.64 (m, 1H), 2.71 (t, J = 6.9 Hz, 2H), 2.65 – 2.46 (m, 1H), 2.36 – 1.94 (m, 2H), 1.94 – 1.63 (m, 3H), 0.91 (s, 9H), 0.10 (s, 6H). MS (ES+) m/z 435.99 [M+Na]⁺. Step C: Preparation of (E)-5-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazole-6-carbaldehyde oxime: [0310] A mixture of hydroxylamine hydrochloride (0.161 g, 2.31 mmol) and pyridine (1.2 mL, 14.9 mmol) in acetonitrile (2.30 mL) was heated at 50 ^oC then was added a solution of 5- (4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6- carbaldehyde (0.318 g, 0.771 mmol) in DCM (1.70 mL) dropwise. The reaction mixture was stirred at the same temperature for 1 h then cooled to rt and diluted with DCM and water. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0% to 100 % EtOAc in hexane, to afford the title compound as an off-white solid (0.260 g, 79 %). [0311] ¹H NMR (300 MHz, CDCl₃): δ 8.76 (s, 1H), 8.04 (s, 1H), 7.98 (d, J = 0.9 Hz, 1H), 7.82 (s, 1H), 7.42 (s, 1H), 5.71 (dd, J = 2.6, 9.6 Hz, 1H), 4.12 – 3.99 (m, 1H), 3.85 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 11.0 Hz, 1H), 2.69 (t, J = 7.0 Hz, 2H), 2.52 (m, 1H), 2.09 (m, 2H), 1.84 – 1.62 (m, 3H), 0.91 (s, 9H), 0.10 (s, 6H). MS (ES+) m/z 450.20 [M+Na]⁺. Step D: Preparation of 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-iodo-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazolo[4,3-g]isoquinoline 7-oxide: [0312] To a solution of (E)-5-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazole-6-carbaldehyde oxime (0.260 g, 0.608 mmol) in DCM (2.0 mL) were added iodine (0.208 g, 0.819 mmol) and potassium carbonate (0.260 g, 1.88 mmol) and stirred at rt for 1 h. The resulting mixture was diluted with DCM and then quenched with a saturated aqueous sodium thiosulfate solution and stirred for 5 min. The organic layer was separated, and washed with a saturated solution of NaHCO3, water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0 % to 100% EtOAc in hexane, to afford the title compound as a brown solid (0.165 g, 49 %). [0313] ¹H NMR (300 MHz, CDCl₃): δ 8.89 (s, 1H), 8.56 (s, 1H), 8.35 (s, 1H), 7.80 (s, 1H), 5.86 (d, J = 9.6 Hz, 1H), 4.09 (m, 3H), 3.84 (m, 3H), 2.62 (m, 1H), 2.20 (m, 2H), 2.12 – 1.67 (m, 3H), 0.87 (s, 9H), 0.04 (s, 6H). MS (ES+) m/z 554.17 [M+Na]⁺. Step E: Preparation of 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4-fluorophenyl)-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-g]isoquinoline 7-oxide: [0314] To a solution of 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-iodo-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazolo[4,3-g]isoquinoline 7-oxide (0.165 g, 0.298 mmol) in DMSO (3.0 mL) were added in this order 4-(fluorophenyl)boronic acid (0.063 g, 0.450 mmol) and 2 M aqueous solution of Na2CO3(0.298 mL, 0.596 mmol). The mixture was purged with nitrogen for 5 minutes followed by the addition of Pd(PPh₃)₄(0.017 g, 0.015 mmol). The mixture was heated at 100 °C for 2 h then diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0% to 100 % EtOAc in hexane, to afford the title compound as a yellow solid (0.110 g, 71%). [0315] ¹H NMR (300 MHz, CDCl₃): δ 9.02 (s, 1H), 8.14 (d, J = 1.0 Hz, 1H), 7.89 (s, 1H), 7.62 (s, 1H), 7.40 – 7.24 (m, 4H), 5.99 – 5.48 (m, 1H), 4.11 (m, 1H), 4.02 (t, J = 6.8 Hz, 2H), 3.85 (t, J = 9.1 Hz, 1H), 3.12 (t, J = 6.7 Hz, 2H), 2.63 (m, 1H), 2.16 (m, 2H), 1.98 – 1.69 (m, 3H), 0.81 (s, 9H) -0.03 (s, 6H). MS (ES+) m/z 522.38 [M+H]⁺. Step F: Preparation 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-chloro-5-(4-fluorophenyl)-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-g]isoquinoline : [0316] To a solution of 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4-fluorophenyl)-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-g]isoquinoline 7-oxide (0.110 g, 0.210 mmol) in DCM (2.0 mL), was added ethylbis(propan-2-yl)amine (0.110 mL, 0.631 mmol). The reaction mixture was cooled to 0 °C and oxalyl chloride (0.038 mL, 0.443 mmol) in DCM (0.5 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min then diluted with DCM and a saturated aqueous NaHCO3 solution. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0% to 100 % EtOAc in hexane, to afford the title compound as a white solid (0.060 g, 53 %). [0317] ¹H NMR (300 MHz, CDCl3): δ 8.57 (m, 1H), 8.21 (d, J = 1.1 Hz, 1H), 7.80 (d, J = 1.1 Hz, 1H), 7.51 – 7.19 (m, 4H), 5.95 (dd, J = 2.5, 9.5 Hz, 1H), 4.18 – 3.96 (m, 3H), 3.89 (t, J = 10.8 Hz, 1H), 2.89 (t, J = 6.5 Hz, 2H), 2.76 – 2.59 (m, 1H), 2.18 (m, 2H), 1.99 – 1.76 (m, 3H), 0.78 (s, 9H), -0.07 (s, 6H). MS (ES+) m/z 540.30 [M+H]⁺ and 562.25 [M+Na]⁺. Step G: Preparation of ((6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4-fluorophenyl)-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl-λ⁶- sulfanone: [0318] To a solution of 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-chloro-5-(4- fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-g]isoquinoline (0.060 g, 0.110 mmol) in 1,4-dioxane (0.80 mL) were added iminodimethyl-λ⁶-sulfanone (0.012 g, 0.19 mmol) and Xantphos (0.006 g, 0.01 mmol) at rt. The mixture was degassed with argon for 5 min followed by the addition of Pd2(dba)3 (0.005 g, 0.006 mmol) and cesium carbonate (0.054 g, 0.165 mmol) and the resulting mixture was purged with argon for another 5 min. The reaction mixture was heated at 100 °C for 8 h then cooled to rt, diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0% to 100 % EtOAc in hexane, to afford the title compound as a yellow solid (0.050 g, 75 %). [0319] ¹H NMR (300 MHz, CDCl3): δ 8.67 (s, 1H), 8.13 (s, 1H), 7.59 (s, 1H), 7.31 – 7.03 (m, 4H), 5.93 (d, J = 8.0 Hz, 1H), 4.09 (d, J = 11.9 Hz, 1H), 3.95 (t, J = 7.5 Hz, 2H), 3.86 (m, 1H), 3.59 (s, 3H), 3.56 (s, 3H), 2.83 (t, J = 7.4 Hz, 2H), 2.69 (m, 1H), 2.30 – 2.04 (m, 2H), 1.77 (m, 3H), 0.83 (s, 9H), -0.03 (s, 6H). MS (ES+) m/z 597.36 [M+H]⁺ and 619.44 [M+Na]⁺. Step H: Preparation of ((5-(4-fluorophenyl)-6-(2-hydroxyethyl)-1H-benzo[f]indazol-8- yl)imino)dimethyl-λ⁶-sulfanone (57): [0320] To a solution of ((6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4-fluorophenyl)-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl-λ⁶-sulfanone (0.011 g, 0.018 mmol) in DCM (1.0 mL) was added in this order triisopropylsilane and of TFA (0.55 mL) at rt under nitrogen atm. The reaction mixture was stirred for 3 h at rt then diluted with DCM and quenched slowly with a saturated aqueous solution of NaHCO3. The two phases reaction mixture was stirred for 10 min then the layers were separated, and the aqueous phase was extracted with DCM. The combined organic layers were washed with water, and brine solution, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient from 0 % to 5 % of MeOH in DCM, to afford the title compound as a yellow solid (8.0 mg, 75%). [0321] ¹H NMR (300 MHz, CD₃OD): δ 8.65 (s, 1H), 8.17 (d, J = 1.1 Hz, 1H), 7.63 (s, 1H), 7.56 – 6.84 (m, 4H), 3.92 (t, J = 6.4 Hz, 2H), 3.62 (s, 6H), 2.79 (t, J = 6.4 Hz, 2H). MS (ES+) m/z 421.04 [M+Na]⁺ . Compound 58 1-((5-(4-fluorophenyl)-6-(2-hydroxyethyl)-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)tetrahydro-1H-1λ⁶-thiophene 1-oxide [0322] Compound 58 was synth hod C described for the preparation of

compound 57. [0323] ¹H NMR (300 MHz, CD3OD): δ 8.85 (d, J = 1.1 Hz, 1H), 8.30 (d, J = 1.1 Hz, 1H), 7.79 (d, J = 1.0 Hz, 1H), 7.60 – 6.98 (m, 4H), 4.02 (m, 2H), 3.92 (t, J = 5.6 Hz, 2H), 3.77 (m, 2H), 2.83 (t, J = 5.7 Hz, 2H), 2.53 (m, 4H). MS (ES+) m/z 425.24 [M+H]⁺. Compound 59 ethyl((5-(4-fluorophenyl)-6-(2-hydroxyethyl)-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)-λ⁶-sulfanone [0324] Compound 59 was synthe

hod C described for the preparation of compound 57. [0325] ¹H NMR (300 MHz, CD3OD): δ 8.85 (d, J = 1.1 Hz, 1H), 8.31 (d, J = 1.1 Hz, 1H), 7.80 (d, J = 1.0 Hz, 1H), 7.63 – 6.93 (m, 4H), 4.03 – 3.93 (m, 2H), 3.90 (t, J = 5.6 Hz, 2H), 3.77 (s, 3H), 2.81 (t, J = 5.5 Hz, 2H), 1.65 (t, J = 7.4 Hz, 3H). MS (ES+) m/z 413.32 [M+H]⁺. Compound 60 ((5-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl-λ⁶-sulfanone

[0326] Compound 60 was synthesized using Method C described for the preparation of compound 57. In step B, the alcohol was protected with a SEM group instead of TBS group using standard conditions. [0327] ¹H NMR (300 MHz, DMSO-d6): δ 13.26 (s, 1H), 8.54 (t, J = 1.1 Hz, 1H), 8.26 (t, J = 1.3 Hz, 1H), 7.48 (s, 1H), 7.41 – 7.27 (m, 4H), 5.52 (s, 1H), 3.57 (s, 6H), 2.59 (s, 2H), 1.01 (s, 6H). MS (ES+) m/z 427.31 [M+H]⁺. Compound 61 ethyl((5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)- λ⁶-sulfanone [0328] Compound 61 was synthe

hod A described for the preparation of Compound 1. [0329] ¹H NMR (300 MHz, CD3OD): δ 8.64 (s, 1H), 8.12 (s, 1H), 7.56 (s, 1H), 7.35 – 7.24 (m, 4H), 3.97 (dd, J = 11.4, 4.3 Hz, 2H), 3.83 (q, J = 7.4 Hz, 2H), 3.55 (s, 3H), 3.40 – 3.31 (m, 2H), 3.31 – 3.23 (m, 2H), 2.83 – 2.67 (m, 1H), 2.29 – 2.10 (m, 2H), 1.54 (s, 3H). MS (ES+) m/z 475.37 [M+Na]⁺. Compound 62 1-((5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)tetrahydro-1H- λ⁶-thiophene 1-oxide [0330] Compound 62 was synthe

hod A described for the preparation of Compound 1. [0331] ¹H NMR (300 MHz, CD₃OD): δ 8.62 (s, 1H), 8.13 (s, 1H), 7.58 (s, 1H), 7.42 – 7.22 (m, 4H), 4.00 – 3.83 (m, 4H), 3.64 – 3.51 (m, 2H), 3.39 – 3.32 (m, 2H), 2.81 – 2.71 (m, 1H), 2.51 – 2.17 (m, 6H), 1.62 – 1.49 (m, 2H). MS (ES+) m/z 465.45 [M+H]⁺. Compound 63 cyclopentyl((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)- λ⁶-sulfanone [0332] Compound 63 was synthes hod A described for the preparation of

Compound 1. [0333] ¹H NMR (300 MHz, CDCl₃): δ 8.74 (s, 1H), 7.54 (s, 1H), 7.36 – 7.11 (m, 7H), 3.60 (s, 3H), 2.99 – 2.80 (m, 1H), 2.43 – 2.28 (m, 2H), 2.28 – 2.17 (m, 1H), 1.99 – 1.71 (m, 6H), 1.25 – 1.19 (m, 6H). MS (ES+) m/z 451.23 [M+H]⁺. Compound 64 cyclohexyl((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)- λ⁶-sulfanone [0334] Compound 64 was synthes

hod A described for the preparation of Compound 1. [0335] ¹H NMR (300 MHz, CDCl₃): δ 10.32 (s, 1H), 8.70 (s, 1H), 8.12 (s, 1H), 7.54 (s, 1H), 7.31 – 7.24 (m, 4H), 3.59 – 3.35 (m, 2H), 3.01 – 2.77 (m, 1H), 2.37 – 2.29 (m, 1H), 2.01 – 1.90 (m, 1H), 1.88 – 1.75 (m, 2H), 1.75 – 1.58 (m, 6H), 1.48 – 1.32 (m, 2H), 1.25 – 1.13 (m, 6H). MS (ES+) m/z 465.32 [M+H]⁺. Compound 65 ethyl((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[3,4-b][1,7]naphthyridin-8- yl)imino)(methyl)- λ⁶-sulfanone [0336] The intermediate methyl 5- olo[3,4-b]pyridine-6-carboxylate was

synthesized according to procedures reported in WO2018/203235 A1. After that, The intermediate methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-6-carboxylate was used to synthesize compound 65 following Method A. [0337] ¹H NMR (300 MHz, DMSO-d6): δ 13.78 (s, 1H), 8.31 (d, J = 1.0 Hz, 1H), 7.99 (s, 1H), 7.38 (d, J = 7.4 Hz, 4H), 3.80 (dt, J = 8.8, 6.4 Hz, 2H), 3.49 (s, 3H), 2.81 (sept, J = 6.6 Hz, 1H), 1.38 (t, J = 7.4 Hz, 3H), 1.16 (dd, J = 6.7, 3.6 Hz, 6H).¹⁹F NMR (283 MHz, DMSO-d6): δ -115.09. MS (ES+) m/z 412.23 [M+H]⁺. Compound 66 ethyl((8-(4-fluorophenyl)-7-isopropyl-1H-[1,2,3]triazolo[4,5-g]isoquinolin-5- yl)imino)(methyl)- λ⁶-sulfanone [0338] Compound 66 was synthes

thod A from the intermediate methyl 5- bromo-1H-benzo[d][1,2,3]triazole-6-carboxylate. [0339] ¹H NMR (300 MHz, DMSO-d₆): δ 9.02 (s, 1H), 7.54 – 7.34 (m, 4H), 7.30 (s, 1H), 3.80 (q, J = 7.4 Hz, 2H), 3.57 (s, 3H), 2.89 – 2.73 (m, 1H), 1.43 (t, J = 7.3 Hz, 3H), 1.16 (d, J = 2.4 Hz, 6H). MS (ES+) m/z 412.30 [M+H]⁺. Compound 67 diethyl((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[3,4-b][1,7]naphthyridin-8-yl)imino)- λ⁶-sulfanone [0340] The intermediate methyl 5- olo[3,4-b]pyridine-6-carboxylate was

synthesized according to procedures reported in WO2018/203235 A1. After that, the intermediate methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-6-carboxylate was used to synthesize compound 67 following Method A. [0341] ¹H NMR (300 MHz, DMSO-d6): δ 13.76 (s, 1H), 8.31 (d, J = 1.2 Hz, 1H), 7.99 (s, 1H), 7.38 (d, J = 7.3 Hz, 4H), 3.75 (q, J = 7.4 Hz, 4H), 2.80 (sept, J = 6.6 Hz, 1H), 1.35 (t, J = 7.4 Hz, 6H), 1.15 (d, J = 6.7 Hz, 6H).¹⁹F NMR (283 MHz, DMSO-d6): δ -115.09. MS (ES+) m/z 426.38 [M+H]⁺. Compound 68 1-((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[3,4-b][1,7]naphthyridin-8- yl)imino)tetrahydro-1H-1 λ⁶-thiophene 1-oxide [0342] The intermediate methyl 5-

olo[3,4-b]pyridine-6-carboxylate was synthesized according to procedures reported in WO2018/203235 A1. After that, the intermediate methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-6-carboxylate was used to synthesize compound 68 following Method A. [0343] ¹H NMR (300 MHz, DMSO-7₆): δ 13.79 (s, 1H), 8.32 (d, 7 = 1.1 Hz, 1H), 8.01 (s, 1H), 7.40 - 7.37(m, 4H), 3.82 - 3.73 (m, 2H), 3.55 - 3.46 (m, 2H), 2.83 - 2.76 (m, 1H), 2.33 - 2.23 (m, 2H), 2.20 - 2.16 (m, 2H), 1.17 (d, 7 = 6.6 Hz, 6H). ¹⁹F NMR (283 MHz, DMSO- d₆): δ -115.07. MS (ES+) m/z 424.23 [M+H]⁺.

Compound 69

((6-isopropyl-5-phenyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl- λ⁶-sulfanone

[0344] Compound 69 was synthesized by using Method A described for the preparation of Compound 1.

[0345] ¹H NMR (300 MHz, CDI₃): δ 10.46 (s, 1H), 8.71 (s, 1H), 8.11 (s, 1H), 7.59 (s, 1H), 7.57 - 7.43 (m, 3H), 7.33 (d, 7 = 8.1 Hz, 2H), 3.59 (s, 6H), 3.02 - 2.81 (m, 1H), 1.22 (d, 7 = 6.7 Hz, 6H). MS (ES+) m/z 401.28 [M+Na]⁺.

Compound 70

((6-isopropyl-5-(p-tolyl)-lH-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl- λ⁶-sulfanone

[0346] Compound 70 was synthesized by using Method A described for the preparation of Compound 1.

[0347] ¹H NMR (300 MHz, CDC1₃): δ 10.34 (s, 1H), 8.69 (s, 1H), 8.12 (s, 1H), 7.63 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 3.52 (s, 6H), 3.03 - 2.87 (m, 1H), 2.50 (s, 3H), 1.22 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 415.34 [M+Na]⁺.

Compound 71

((6-isopropyl-5-(4-methoxyphenyl)-lH-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl- λ⁶- sulfanone

[0348] Compound 71 was synthesized by using Method A described for the preparation of Compound 1.

[0349] ¹H NMR (300 MHz, CDC1₃): δ 10.45 (s, 1H), 8.70 (s, 1H), 8. 12 (s, 1H), 7.64 (s, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.3 Hz, 2H), 3.93 (s, 3H), 3.59 (s, 6H), 3.08 - 2.89 (m, 1H), 1.22 (d, J = 6.9 Hz, 6H). MS (ES+) m/z 431.22 [M+Na]⁺.

Compound 72 l-((5-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-177-pyrazolo[4,3-g]isoquinolin-8- yl)imino)tetrahydro- 1 H - 1 λ⁶-thiophene 1 -oxide

[0350] Compound 72 was synthesized using Method C described for the preparation of compound 57. In step B, the alcohol was protected with a SEM group instead of TBS group using standard conditions.

[0351] H NMR (300 MHz, MeOD): 5 8.85 (s, 1H), 8.29 (d, J = 1.1 Hz, 1H), 7.75 (s, 1H), 7.53 - 7.29 (m, 4H), 3.99 -3.75 (m, 2H), 3.78 - 3.53 (m, 2H), 3.36 (s, 2H), 2.51 (m, 4H), 1.23 (s, 6H). MS (ES+) m/z 475.37 [M+Na]⁺.

Compound 73

((5-(4-fluorophenyl)-6-isopropyl-l -methyl- lH-pyrrolo[3,2-g]isoquinolin-8- yl)imino)dimethyl- λ⁶-sulfanone

[0352] Compound 73 was synthesized by using Method A from the intermediate methyl 5- bromo- 177-indole-6-carboxylate.

[0353] ¹H NMR (300 MHz, CDI₃): 5 8.44 (s, 1H), 7.35 (s, 1H), 7.32 - 7.26 (m, 3H), 7.24 - 7.15 (m, 2H), 6.43 (d, J = 3.2 Hz, 1H), 3.90 (s, 3H), 3.57 (s, 6H), 2.91 (sept, J = 6.7 Hz, 1H), 1.21 (d, 7 = 6.7 Hz, 6H). MS (ES+) m/z 432.2 [M+Na]⁺.

Compound 74 l-((8-(4-fluorophenyl)-7-isopropyl-177-[l,2,3]triazolo[4,5-g]isoquinolin-5- yl)imino)tetrahydro- 1 /7- 1 λ⁶-thiophene 1 -oxide

[0354] Compound 74 was synthesized by using Method A from the intermediate methyl 5- bromo- 177-benzo[7][ 1 ,2,3]triazole-6-carboxylate.

[0355] ¹H NMR (300 MHz, DMSO-J₆): 5 15.66 (s, 1H), 9.03 (s, 1H), 7.51 - 7.33 (m, 4H), 7.33 (d, J = 14.1 Hz, 1H), 3.85 (dt, J = 13.2, 6.7 Hz, 2H), 3.52 (dt, J= 13.2, 6.5 Hz, 2H), 2.77 (dd, J = 14.5, 8.0 Hz, 1H), 2.36 - 2.18 (m, 4H), 1.17 (d, J = 6.6 Hz, 6H). MS (ES+) m/z 424.35 [M+H]⁺.

Compound 75 diethyl((5-(4-fluorophenyl)-6-isopropyl-177-pyrrolo[3,2-g]isoquinolin-8-yl)imino)- λ⁶- sulfanone

[0356] Compound 75 was synthesized by using Method A from the intermediate methyl 5- bromo- 1 H-indole-6-carboxylate.

[0357] ¹H NMR (300 MHz, CDI₃): 5 8.60 (s, 1H), 8. 19 (brs, 1H), 7.43 - 7.39 (m, 1H), 7.36 (s, 1H), 7.33 - 7.27 (m, 2H), 7.22 - 7.14 (m, 2H), 6.53 - 6.47 (m, 1H), 3.89 (dq, J =

14.9, 7.5 Hz, 2H), 3.63 (dq, 7 = 14.7, 7.4 Hz, 2H), 2.87 (sept, 7 = 6.8 Hz, 1H), 1.47 (t, 7 = 7.5 Hz, 6H), 1.17 (d, 7 = 6.7 Hz, 6H). MS (ES+) m/z 424.25 [M+H]⁺.

Compound 76

((8-(4-fluorophenyl)-7-isopropyl-l -methyl- l/f-[ 1,2, 3]triazolo[4,5-g]isoquinolin-5- yl)imino)dimethyl- λ⁶-sulfanone

[0358] Compound 76 was synthesized by using Method A from the intermediate methyl 5- bromo- 177-benzo[d] [ 1 ,2,3]triazole-6-carboxylate.

[0359] ¹H NMR (300 MHz, CDC1₃): 5 8.74 (s, 1H), 7.90 (s, 1H), 7.27 (qd, 7 = 8.6, 3.9 Hz, 4H), 4.44 (s, 3H), 3.60 (s, 6H), 3.06 - 2.86 (m, 1H), 1.24 (d, 7 = 6.7 Hz, 6H). MS (ES+) m/z

412.23 [M+H]⁺.

Compound 77

((5-(6-fluoropyridin-3-yl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl- λ⁶-sulfanone

[0360] Compound 77 was synthesized by using Method A described for the preparation of Compound 1.

[0361] ¹H NMR (300 MHz, CDC1₃): 8 10.61 (s, 1H), 8.74 (s, 1H), 8.17 (d, 7 = 11.0 Hz, 2H), 7.76 (td, J = 8.0, 2.5 Hz, 1H), 7.51 (s, 1H), 7.13 (dd, J= 8.3, 3.0 Hz, 1H), 3.59 (d, J = 7.8 Hz, 6H), 2.95 - 2.74 (m, 1H), 1.23 (dd, J = 9.3, 6.8 Hz, 6H). MS (ES+) m/z 420.12 [M+Na]⁺.

Compound 78 ethyl((5-(4-fluorophenyl)-6-isopropyl-1H -pyrrolo[3,2-g]isoquinolin-8-yl)imino)(methyl)- λ⁶- sulfanone

[0362] Compound 78 was synthesized by using Method A from the intermediate methyl 5- bromo- lH-indole-6-carboxylate.

[0363] ¹H NMR (300 MHz, CDCI3): 3 8.56 (s, 1H), 8.21 (br, 1H), 7.45 - 7.39 (m, 1H), 7.37 (s, 1H), 7.32 - 7.27 (m, 2H), 7.23 - 7.15 (m, 2H), 6.55 - 6.47 (m, 1H), 3.94 - 3.81 (m, 1H), 3.80 - 3.64 (m, 1H), 3.48 (s, 3H), 2.88 (sept, 1H), 1.50 (t, 7= 7.4 Hz, 3H), 1.24 - 1.15 (m, 6H). MS (ES+) m/z 410.12 [M+H]⁺.

Compound 79 diethyl((8-(4-fluorophenyl)-7-isopropyl-177-[l,2,3]triazolo[4,5-g]isoquinolin-5-yl)imino)- λ⁶- sulfanone

[0364] Compound 79 was synthesized by using Method A from the intermediate methyl 5- bromo- I //-benzol d | [ 1 ,2,3]triazole-6-carboxylate.

[0365] ¹H NMR (300 MHz, DMSO-d6): δ 15.68 (s, 1H), 9.04 (s, 1H), 7.55 - 7.34 (m, 4H), 7.30 (s, 1H), 3.79 (sept, J = 7.2 Hz, 4H), 3.01 - 2.65 (m, 1H), 1.54 - 1.32 (m, 6H), 1.14 (d, J = 6.6 Hz, 6H). MS (ES+) m/z 426.38 [M+H]⁺.

Compound 80

((5-(4-fluorophenyl)-6-isopropyl-lZ/-pyrrolo[3,2-g]isoquinolin-8-yl)imino)(methyl)(phenyl)- λ⁶-sulfanone

[0366] Compound 80 was synthesized by using Method A from the intermediate methyl 5- bromo-177-indole-6-carboxylate.

[0367] ¹H NMR (300 MHz, CDI₃): 3 8.60 (s, 1H), 8.21 (brs, 1H), 8.18 - 8.08 (m, 2H), 7.67 - 7.51 (m, 3H), 7.46 - 7.40 (m, 1H), 7.38 (s, 1H), 7.25 - 7.10 (m, 4H), 6.55 - 6.47 (m, 1H), 3.56 (s, 3H), 2.77 - 2.62 (m, 1H), 1.08 (d, J= 6.7 Hz, 3H), 0.66 (d, J = 6.6 Hz, 3H). MS (ES+) m/z 458.12 [M+H]⁺.

Compound 81 l-((5-(4-fluorophenyl)-6-isopropyl-177-pyrrolo[3,2-g]isoquinolin-8-yl)imino)tetrahydro- 177-1 λ⁶-thiophene 1 -oxide

[0368] Compound 81 was synthesized by using Method A from the intermediate methyl 5- bromo-177-indole-6-carboxylate.

[0369] ¹H NMR (300 MHz, CDC1₃): 6 8.52 (s, 1H), 8.23 (brs, 1H), 7.45 - 7.40 (m, 1H), 7.38 (s, 1H), 7.33 - 7.27 (m, 2H), 7.24 - 7.14 (m, 2H), 6.57 - 6.47 (m, 1H), 4.02 - 3.87 (m, 2H), 3.51 - 3.35 (m, 2H), 2.95 - 2.80 (m, 1H), 2.52 - 2.28 (m, 4H), 1.22 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 422.13 [M+H]⁺.

Compound 82 methyl N-(5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)-2- methylpropane-2-sulfonimidate

[0370] Compound 82 was synthesized by using Method B described for the preparation of compound 52.

[0371] ¹H NMR (300 MHz, MeOD): 5 8.49 (s, 1H), 8.23 (d, J = 1.1 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.44 - 7.29 (m, 4H), 3.58 (s, 3H), 3.50 - 2.96 (m, 1H), 1.62 (s, 9H), 1.25 (d, 7 = 6.9 Hz, 6H). MS (ES+) m/z 477.20 [M+Na]⁺.

Compound 83

((8-(4-fluorophenyl)-7-isopropyl-l H-imidazo[4,5-g]isoquinolin-5-yl)imino)dimethyl-λ⁶- sulfanone

/0372] Compound 83 was synthesized by using Method A from the intermediate methyl 5- bromo-177-benzo[d]imidazole-6-carboxylate.

[0373] ¹H NMR (300 MHz, CDC1₃): δ 8.85 (s, 1H), 8.21 (s, 1H), 7.27 - 7.15 (m, 5H), 4.01 - 3.88 (m, 2H), 3.56 - 3.43 (m, 2H), 2.98 - 2.84 (m, 1H), 2.52 - 2.29 (m, 4H), 1.24 (d, J = 6.6 Hz, 6H). MS (ES+) m/z 423.23 [M+H]⁺.

Compound 84

((5-(4-fluorophenyl)-3-iodo-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)dimethyl- λ⁶-sulfanone

[0374] Compound 84 was synthesized by using Method A described for the preparation of Compound 1.

[0375] ¹H NMR (300 MHz, DMSO-d6): δ 13.68 (s, 1H), 8.53 (s, 1H), 7.43 - 7.35 (m, 4H), 7.08 (s, 1H), 3.60 (s, 6H), 2.84 - 2.70 (m, 1H), 1.16 (d, 7 = 6.7 Hz, 6H). MS (ES+) m/z 523.03 [M+H]⁺.

Compound 85 methyl N-(5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8- yl)methanesulfonimidate

[0376] Compound 82 was synthesized by using Method B described for the preparation of compound 52.

[0377] ¹H NMR (300 MHz, DMSO-d6): δ 13.42 (s, 1H), 8.45 (d, J = 1.2 Hz, 1H), 8.40 (d, J = 1.2 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.51 - 7.40 (m, 4H), 3.39 (s, 3H), 3.37 (s, 3H), 2.90

(sept, J = 6.7 Hz, 1H), 1.20 (d, J = 6.6 Hz, 6H). ¹⁹F NMR (283 MHz, DMSO): 5 -114.40. MS (ES+) m/z 435.05 [M+Na]⁺.

Compound 86

((5-(4-fluorophenyl)-6-isopropyl-3-phenyl-lH-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl- λ⁶-sulfanone

[0378] Compound 86 was synthesized by using Method A described for the preparation of Compound 1.

[0379] ¹H NMR (300 MHz, DMSO-^): 5 13.47 (s, 1H), 8.56 (d, J = 1.0 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.68 (s, 1H), 7.50 - 7.42 (m, 2H), 7.42 - 7.36 (m, 5H), 3.62 (s, 6H), 2.86 - 2.74

(m, 1H), 1.17 (d, J = 6.6 Hz, 6H). MS (ES+) m/z 473.13 [M+H]⁺.

Compound 87

2,2,2-trifluoroethyl N-(5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8- yl)methanesulfonimidate

[0380] Compound 87 was synthesized by using Method B described for the preparation of compound 52.

[0381] ¹H NMR (300 MHz, MeOD): 5 8.61 (t, J = 1.1 Hz, 1H), 8.16 (d, J = 1.1 Hz, 1H), 7.63 (d, J = 1.1 Hz, 1H), 7.38 - 7.23 (m, 4H), 5.01 - 4.94 (m, 1H), 4.88 - 4.81 (m, 1H), 3.73 (s, 3H), 2.90 (sept, 7 = 6.8 Hz, 1H), 1.22 (d, 7 = 6.7 Hz, 6H). ¹⁹F NMR (283 MHz, MeOD): 5 -75.16 (s, 3F), -117.30 (s, IF). MS (ES+) m/z 481.00 [M+H]⁺.

Compound 88 methyl N-(5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[3,4- b [l,7]naphthyridin-8- yl)methanesulfonimidate

[0382] The intermediate methyl 5-bromo- l H -pyrazolo|3,4-b |pyridine-6-carboxylate was synthesized according to procedures reported in WO2018/203235 Al. After that, the intermediate methyl 5-bromo-177-pyrazolo[3,4-b ]pyridine-6-carboxylate was used to synthesize compound 88 following Method A.

[0383] ¹H NMR (300 MHz, DMSO-7₆): 5 14.03 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 7.55 - 7.38 (m, 4H), 3.63 (s, 3H), 3.52 (s, 3H), 2.94 (sept, 7 = 6.6 Hz, 1H), 1.21 (d, 7 = 6.7 Hz, 6H). MS (ES+) m/z 436.11 [M+Na]⁺.

Compound 89

((8-(4-fluorophenyl)-7-isopropyl-2-methyl-177-imidazo[4,5-g]isoquinolin-5- yl)imino)dimethyl- λ⁶-sulfanone

[0384] Compound 89 was synthesized by using Method A from the intermediate methyl 5- bromo-2-methyl-lH-benzo[d]imidazole-6-carboxylate.

[0385] ¹H NMR (300 MHz, MeOD): 8 8.73 (s, 1H), 7.40 - 7.27 (m, 5H), 3.68 (s, 6H), 3.12 - 3.07 (m, 1H), 2.76 (s, 3H), 1.26 (d, J = 6.6 Hz, 6H). MS (ES+) m/z 411.10 [M+H]⁺.

Compound 90 tert-butyl((5-(4-fluorophenyl)-6-isopropyl-l /7-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)- λ⁶-sulfanone

[0386] Compound 90 was synthesized by using Method B described for the preparation of compound 52.

[0387] ¹H NMR (300 MHz, DMSO-d6): δ 13.13 (s, 1H), 8.51 (t, J = 1.1 Hz, 1H), 8.23 (t, J = 1.2 Hz, 1H), 7.46 (d, J = 1.0 Hz, 1H), 7.44 - 7.29 (m, 4H), 3.64 (s, 3H), 2.78 (sept, J = 6.7 Hz, 1H), 1.62 (s, 9H), 1.16 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 439.06 [M+H]⁺. Compound 91

((5-(4-fluorophenyl)-6-isopropyl-177-pyrrolo[2,3-b ][l,7]naphthyridin-8-yl)imino)dimethyl- λ⁶-sulfanone

[0388] Compound 91 was synthesized by using Method A from the intermediate methyl 5- bromo- 177-pyrrolo[ 2, 3-b ]pyridine-6-carboxylate.

[0389] ¹H NMR (300 MHz, CDC1₃): 8 12.06 (s, 1H), 7.98 - 7.93 (m, 1H), 7.77 (s, 1H), 7.36 - 7.27 (m, 2H), 7.26 - 7. 18 (m, 2H), 6.47 (d, J = 3.7 Hz, 1H), 3.61 (s, 6H), 3.04 - 2.88

(m, 1H), 1.27 - 1.20 (m, 6H). MS (ES+) m/z 397.06 [M+H]⁺.

Compound 92

((5-(4-fluorophenyl)-6-isopropyl-3-methyl-177-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl- λ⁶-sulfanone

[0390] Compound 92 was synthesized by using Method D described for the preparation of Compound 1.

[0391] H NMR (300 MHz, DMSO-d6): δ 12.80 (s, 1H), 8.44 (s, 1H), 7.41 - 7.34 (m, 4H), 7.32 (s, 1H), 3.60 (s, 6H), 2.81 - 2.70 (m, 1H), 2.42 (s, 3H), 1.16 (d, 7 = 6.7 Hz, 6H). MS (ES+) m/z 411.14 [M+H]⁺.

Compound 93 ethyl((5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-6][l,7]naphthyridin-8- yl)imino)(methyl)- λ⁶-sulfanone

[0392] Compound 93 was synthesized by using Method A from the intermediate methyl 5- bromo-177-pyrrolo[2,3-b>]pyridine-6-carboxylate.

[0393] ¹H NMR (300 MHz, CDC1₃): 6 11.49 (s, 1H), 7.84 (d, 7 = 4.2 Hz, 1H), 7.76 (s, 1H), 7.34 - 7.28 (m, 2H), 7.26 - 7.17 (m, 2H), 6.46 (d, 7 = 3.6 Hz, 1H), 4.02 - 3.82 (m, 2H), 3.48 (s, 3H), 3.06 - 2.86 (m, 1H), 1.52 (t, 7 = 7.5 Hz, 3H), 1.25 (d, 7 = 3.1 Hz, 6H). MS (ES+) m/z 411.14 [M+H]⁺.

Compound 94

4-((5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)-l,4 λ⁶- oxathiane 4-oxide

[0394] Compound 94 was synthesized by using Method A described for the preparation of Compound 1.

[0395] ¹H NMR (300 MHz, CDI₃): 8 8.83 (s, 1H), 8.12 (s, 1H), 7.52 (s, 1H), 7.28 - 7.26 (m, 4H), 4.47 - 4.34 (m, 4H), 4.20 - 4.11 (m, 2H), 3.69 - 3.59 (m, 2H), 2.97 (sept, 7 = 6.9 Hz, 1H), 1.25 (d, 7= 6.8 Hz, 6H). MS (ES+) m/z 439.01 [M+H]⁺.

Compound 95 l-((5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)-4-(piperazin- l-yl)hexahydro-l λ⁶-thiopyran 1 -oxide

[0396] The intermediate 1 -(tetrahydro-277-thiopyran-4-yl)pi perazine was synthesized according to procedures reported in W02023/0010691 Al. After that, the intermediate 1- (tetrahydro-2H-thiopyran-4-yl)piperazine was used to synthesize compound 95 following Method B.

[0397] ¹H NMR (300 MHz, CD₃OD): δ 8.72 (s, 1H), 8.17 (s, 1H), 7.62 (s, 1H), 7.36 - 7.24 (m, 4H), 4.24 (d, 7 = 13.6 Hz, 2H), 3.72 - 3.58 (m, 2H), 3.24 - 3.15 (m, 4H), 2.98 - 2.81 (m, 6H), 2.41 - 2.26 (m, 4H), 1.22 (d, 7 = 6.8 Hz, 6H). MS (ES+) m/z 521.18 [M+H]⁺.

Compound 96

((5-(4-fluorophenyl)-6-isopropyl-lH-pyrazolo[4,3-/?][ 1,6 ]naphthyridin-8-yl )imi no)dimethyl- λ⁶-sulfanone

[0398] Compound 96 was synthesized by using Method A from the intermediate methyl 5- bromo-177-pyrazolo[4,3-b ]pyridine-6-carboxylate

[0399] ¹H NMR (300 MHz, DMSO-7₆): δ 13.50 (s, 1H), 8.86 (d, J = 1.2 Hz, 1H), 8.40 (d, 7 = 1.1 Hz, 1H), 7.36 - 7.25 (m, 4H), 3.62 (s, 6H), 3.02 - 2.84 (m, 1H), 1.18 (d, 7 = 6.6 Hz, 6H). MS (ES+) m/z 398.16 [M+H]⁺.

Compound 97

6-((5-(4-fluorophenyl)-6-isopropyl-lH-pyrazolo[4,3-g]isoquinolin-8-yl)imino)-2-oxa-6 λ⁶- thiaspiro[3.3]heptane 6-oxide

[0400] The intermediate 2-oxa-6-thiaspiro|3.3 |heptane was synthesized according to procedures reported in W02023/0010691 Al. After that, the intermediate 2-oxa-6- thiaspiro[3.3]heptane was used to synthesize compound 97 following Method B.

[0401] ¹H NMR (300 MHz, CDC1₃): 8 8.54 (s, 1H), 7.60 (s, 1H), 7.25 - 7.18 (m, 5H), 5.01 (d, J = 13.6 Hz, 2H), 4.96 (s, 2H), 4.89 (s, 2H), 4.52 (d, 7 = 13.7 Hz, 2H), 2.94 - 2.85 (m, 1H), 1.20 (d, 7 = 6.7 Hz, 6H). MS (ES+) m/z 451.14 [M+H]⁺.

Compound 98

(lR,3s,5S)-3-((5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)-3 λ⁶-thia-8-azabicyclo[3.2.1 ]octane 3-oxide

[0402] Compound 98 was synthesized by using Method B described for the preparation of compound 52.

[0403] ¹H NMR (300 MHz, CDI₃): 8 8.55 (s, 1H), 7.89 (s, 1H), 7.34 (s, 1H), 7.25 - 7.19 (m, 4H), 5.06 (d, 7= 14.6 Hz, 2H), 4.83 (s, 2H), 4.10 (d, 7 = 14.4 Hz, 2H), 2.97 (sept, 7 = 6.8 Hz, 1H), 2.67 - 2.59 (m, 2H), 2.54 - 2.45 (m, 2H), 1.28 (d, 7 = 6.9 Hz, 6H). MS (ES+) m/z 464.13 [M+H]⁺.

Compound 99 (lR,5R)-3-((5-(4-fluorophenyl)-6-isopropyl-l /7-pyrazolo[4,3-g]isoquinolin-8-yl)imino)-3 λ⁶- thia- 8- az abicyclo [3.2.1 ] octane 3 -oxide

[0404] Compound 99 was synthesized by using Method B described for the preparation of compound 52.

[0405] ¹H NMR (300 MHz, DMSO-rfc): 5 13.31 (s, 1H), 9.56 (s, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 7.55 (d, 7 = 1.0 Hz, 1H), 7.41 - 7.36 (m, 4H), 4.75 (d, 7 = 14.5 Hz, 2H), 4.55 (s, 2H), 3.89 (d, 7 = 14.4 Hz, 2H), 2.85 - 2.74 (m, 1H), 2.37 (d, 7 = 8.3 Hz, 2H), 2.09 - 2.01 (m, 2H), 1.15 (d, 7 = 6.6 Hz, 6H). MS (ES+) m/z 464.13 [M+H]⁺.

Compound 100

2-((5-(4-fluorophenyl)-6-isopropyl-lH-pyrazolo|4,3-g|isoquinolin-8-yl)imino)-2 λ⁶-thia-6- azaspiro[3.3]heptane 2-oxide

[0406] The intermediate 2-thia-6-azaspiro[3.3]heptane was synthesized according to procedures reported in W02023/0010691 Al. After that, the intermediate 2-thia-6- azaspiro[3.3]heptane was used to synthesize compound 100 following Method B.

[0407] ¹H NMR (300 MHz, Acetone-^): 5 8.64 (s, 1H), 8.21 (s, 1H), 7.61 (s, 1H), 7.39 - 7.33 (m, 4H), 5.37 (d, J = 24.3 Hz, 4H), 5.02 (s, 4H), 2.85 - 2.74 (m, 1H), 1.19 (d, 7 = 6.6 Hz, 6H). MS (ES+) m/z 450.14 [M+H]⁺.

Compound 101

2-(8-((dimethyl(oxo)- λ⁶-sulfaneylidene)amino)-5-(4-fluorophenyl)-lH-pyrazolo[4,3- g]isoquinolin-6-yl)acetaldehyde

[0408] Compound 101 was synthesized by using Method C described for the preparation of Compound 57.

[0409] ¹H NMR (300 MHz, CD3OD): 5 8.84 (s, 1H), 8.29 (s, 1H), 7.78 (s, 1H), 7.45 - 7.26 (m, 4H), 3.88 (t, J = 5.5 Hz, 2H), 3.82 (s, 6H). MS (ES+) m/z 397.02 [M+H]⁺.

Compound 102

((6-(1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4-fluorophenyl)-l H-pyrazolo[4,3- g]isoquinolin-8-yl)imino)dimethyl- λ⁶-siilfanone

[0410] Compound 102 was synthesized by using Method A described for the preparation of Compound 1.

[0411] ¹H NMR (300 MHz, DMSO-d₆ ): δ 13.23 (s, 1H), 8.50 (d, J = 1.2 Hz, 1H), 8.24 (s, 1H), 7.46 (s, 1H), 7.36 (d, J = 7.4 Hz, 4H), 3.60 (s, 6H), 3.20 - 2.90 (m, 6H), 2.83 - 2.67 (m, 1H), 1.95 (d, J = 13.5 Hz, 2H). MS (ES+) m/z 509.01 [M+Na]⁺. Compound 103

(2R)-2-amino-4-(N-(5-(4-fluorophenyl)-6-isopropyl-lH-pyrazolo[4,3-g]isoquinolin-8-yl)-S- methylsulfonimidoyl)butanoic acid

[0412] Compound 103 was synthesized by using Method B described for the preparation of compound 52.

[0413] ¹H NMR (300 MHz, CD₃OD): 5 8.66 (s, 1H), 8.14 (s, 1H), 7.58 (s, 1H), 7.35 - 7.24 (m, 4H), 4.21 - 3.81 (m, 3H), 3.67 (d, J= 3.7 Hz, 3H), 2.89 (sept, J = 6.7 Hz, 1H), 2.55 (q, J

= 7.2 Hz, 2H), 1.23 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 484.11 [M+H]⁺.

Compound 104

((9-fluoro-5-(4-fluorophenyl)-6-isopropyl-lH-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl- λ⁶-sulfanone

[0414] Compound 104 was synthesized by using Method A from the intermediate 6- bromo-7 -fluoro-5 -iodo- 1 H- i ndazole.

[0415] ¹H NMR (300 MHz, CDI₃): 5 10.19 (s, 1H), 8.10 (d, J = 3.4 Hz, 1H), 7.34 - 7.13 (m, 4H), 3.55 (s, 6H) 2.85 (sept, J = 6.7 Hz, 1H), 1.20 (d, J = 6.7 Hz, 6H). MS (ES+) m/z 437.06 [M+Na]⁺.

Compound 105

((5-(3 -chloro-4-fluorophenyl)-6-isopropyl- 1 H-pyrazolo [4,3 -g |i soq ui nol i n- 8- yl)imino)dimethyl- λ⁶-sulfanone

[0416] Compound 105 was synthesized by using Method A described for the preparation of Compound 1.

[0417] ¹H NMR (300 MHz, DMSO-rig): 5 13.19 (s, 1H), 8.50 (s, 1H), 8.23 (s, 1H), 7.62 - 7.49 (m, 2H), 7.45 (s, 1H), 7.36 - 7.25 (m, 1H), 3.58 (s, 6H), 2.79 - 2.66 (m, 1H), 1.15 (t, J = 6.1 Hz, 6H). MS (ES+) m/z 431.07 [M+H]⁺.

Compound 106

((5-(4-fluorophenyl)-6-(l-hydroxypropan-2-yl)-177-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl- λ⁶-sulfanone

[0418] Compound 106 was synthesized by using Method C described for the preparation of Compound 57.

[0419] ¹H NMR (300 MHz, CD₃OD): 5 8.65 (s, 1H), 8.16 (s, 1H), 7.61 (s, 1H), 7.50 - 7.25 (m, 4H), 3.88 (dd, J = 10.6, 6.4 Hz, 1H), 3.78 (m, 1H), 3.65 (s, 3H), 3.60 (s, 3H), 2.93 (q, J = 6.4 Hz, 1H), 1.25 (d, 7 = 6.8 Hz, 3H). MS (ES+) m/z 413.08 [M+H]⁺.

Compound 107

((5-(4-fluorophenyl)-6-(l-hydroxy-2-methylpropan-2-yl)-177-pyrazolo[4,3-_<g]isoquinolin-8- yl)imino)dimethyl- λ⁶-sulfanone

[0420] Compound 107 was synthesized by using Method C described for the preparation of Compound 57.

[0421] ¹H NMR (300 MHz, Acetone-d₆): 5 8.69 (d, 7 = 1.2 Hz, 1H), 8.20 (d, 7 = 1.2 Hz, 1H), 7.55 - 6.79 (m, 5H), 3.72 (s, 2H), 3.68 (s, 6H), 1.11 (s, 6H). MS (ES+) m/z 427.06 [M+H]⁺.

Compound 108

((5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)(pyrazin-2-yl)- λ⁶sulfanone

[0422] Compound 108 was synthesized by using Method B described for the preparation of Compound 52.

[0423] ¹H NMR (300 MHz, CD₃OD): δ 9.53 (d, 7 = 1.4 Hz, 1H), 8.84 (d, 7 = 2.4 Hz, 1H), 8.73 (q, 7 = 1.4 Hz, 2H), 8.11 (d, 7 = 1.2 Hz, 1H), 7.52 (d, 7 = 1.1 Hz, 1H), 7.25 - 7.16 (m, 4H), 3.62 (s, 3H), 2.62 (sept, 7 = 6.7 Hz, 1H), 1.02 (d, 7 = 6.7 Hz, 3H), 0.44 (d, 7 = 6.7 Hz, 3H). MS (ES+) m/z 461 . 13 [M+H]⁺.

Compound 109

((5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(methyl)(o- tolyl)- λ⁶-sul fanone

[0424] Compound 109 was synthesized by using Method A described for the preparation of Compound 1.

[0425] ¹H NMR (300 MHz, DMSO-ri₆): 5 13.22 (s, 1H), 8.62 (d, J = 1.1 Hz, 1H), 8.25 (d, J = 1.4 Hz, 1H), 8.20 - 8.07 (m, 1H), 7.56 (td, J = 7.0, 4.9 Hz, 2H), 7.47 (s, 1H), 7.43 - 7.23 (m, 5H), 3.61 (s, 3H), 2.57 (s, 3H), 0.96 (d, J = 6.6 Hz, 3H), 0.40 (d, 7 = 6.7 Hz, 3H). MS (ES+) m/z 495.08 [M+Na]⁺.

Compound 110

4-(N-(5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)->S- methylsulfonimidoyl)benzonitrile

[0426] Compound 110 was synthesized by using Method A described for the preparation of Compound 1.

[0427] ¹H NMR (300 MHz, DMSO-d6): δ 13.28 (s, 1H), 8.66 (d, J = 1.1 Hz, 1H), 8.26 (s, 1H), 8.19 (q, J = 8.5 Hz, 4H), 7.48 (s, 1H), 7.30 - 7.28 (m, 4H), 3.68 (s, 3H), 0.95 (d, J = 6.4 Hz, 3H), 0.36 (d, J = 6.6 Hz, 3H). MS (ES+) m/z 484.08 [M+H]⁺.

Compound 111

((5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(2- methoxyphenyl)(methyl)- λ⁶-sulf'anone

[0428] Compound 111 was synthesized by using Method A described for the preparation of Compound 1.

[0429] ¹H NMR (300 MHz, DMSO-d6): δ 13.18 (s, 1H), 8.58 (s, 1H), 8.24 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 8.1 Hz, 1H), 7.44 (s, 1H), 7.39 - 6.94 (m, 6H), 3.80 (s, 3H), 3.68 (s, 3H), 1.01 (d, J = 6.6 Hz, 3H), 0.59 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 489.17 [M+H]⁺.

Compound 112

((5-(3,4-difluorophenyl)-6-isopropyl-177-pyrazolo[4,3-_<g]isoquinolin-8-yl)imino)dimethyl- λ⁶- sulfanone

[0430] Compound 112 was synthesized by using Method A described for the preparation of Compound 1.

[0431] ¹H NMR (300 MHz, CDI₃): 6 10.18 (s, 1H), 8.68 (s, 1H), 8.15 (s, 1H), 7.59 - 7.52 (m, 1H), 7.37 - 7.28 (m, 1H), 7.20 - 7.09 (m, 1H), 7.09 - 7.01 (m, 1H), 3.56 (s, 6H), 2.97 - 2.80 (m, 1H), 1.22 (dd, J = 6.7, 2.3 Hz, 6H). MS (ES+) m/z 415.17 [M+H]⁺.

Compound 113

(2-bromophenyl)((5-(4-fluorophenyl)-6-isopropyl-lZ/-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)- λ⁶-sulfanone

[0432] Compound 113 was synthesized by using Method A described for the preparation of Compound 1.

[0433] ¹H NMR (300 MHz, MeOD): 5 8.76 (s, 1H), 8.60 - 8.32 (m, 1H), 8.15 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.73 (t, 7 = 7.4 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.28 - 7.19 (m, 4H), 3.67 (s, 3H), 2.65 - 2.52 (m, 1H), 1.31 (d, 7 = 6.6 Hz, 3H), 0.42 (bs, 3H). MS (ES+) m/z 559.11 [M+Na]⁺.

Compound 114

(3-chlorophenyl)((5-(4-fluorophenyl)-6-isopropyl-lH-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)- λ⁶-sulfanone

[0434] Compound 114 was synthesized by using Method A described for the preparation of Compound 1.

[0435] ¹H NMR (300 MHz, CDC1₃): 5 10.39 (s, 1H), 8.76 (d, 7 = 1.1 Hz, 1H), 8.53 - 8.11 (m, 2H), 8.01 (dq, J = 7.6, 1.3 Hz, 1H), 7.65 - 7.47 (m, 3H), 7.27 - 7.14 (m, 4H), 3.56 (d, J = 0.9 Hz, 3H), 2.70 (sept, J = 6.6 Hz, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.63 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 493.14 [M+H]⁺.

Compound 115

((5-(4-fluorophenyl)-6-(2-morpholinoethyl)-177-pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl- λ⁶ -sulfanone

[0436] Compound 115 was synthesized by using Method C.

[0437] ¹H NMR QOO MHz, CDI₃): 5 10.20 (s, 1H), 8.65 (d, J = 1.1 Hz, 1H), 8.14 (s, 1H), 7.60 (d, J = 1.0 Hz, 1H), 7.31 - 6.88 (m, 4H), 3.70 (bs, 4H), 3.55 (s, 6H), 2.78 (bs, 4H), 2.41 (bs, 4H). MS (ES+) m/z 468.18 [M+H]⁺.

Compound 116

(3-fluorophenyl)((5-(4-fluorophenyl)-6-isopropyl-1H-pyrazolo[4,3-_<g]isoquinolin-8- yl)imino)(methyl)- λ⁶-sulfanone

[0438] Compound 116 was synthesized by using Method A described for the preparation of Compound 1.

[0439] ¹H NMR (300 MHz, CDI₃): δ 10.18 (s, 1H), 8.74 (d, 7 = 1.2 Hz, 1H), 8.16 (d, 7 = 1.2 Hz, 1H), 7.93 (ddd, 7 = 7.9, 1.7, 1.0 Hz, 1H), 7.86 (dt, 7 = 8.1, 2.2 Hz, 1H), 7.68 - 7.54

(m, 2H), 7.41 - 7.32 (m, 1H), 7.27 - 7.13 (m, 4H), 3.56 (s, 3H), 2.71 (sept, 7 = 6.8 Hz, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.64 (d, 7 = 6.7 Hz, 3H). MS (ES+) m/z 499.15 [M+Na]⁺.

Compound 117

3-(N-(5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)->S'- methylsulfonimidoyl)benzonitrile

[0440] Compound 117 was synthesized by using Method A described for the preparation of Compound 1.

[0441] ¹H NMR (300 MHz, CDCI3): 5 8.74 (s, 1H), 8.44 (t, J = 1.7 Hz, 1H), 8.37 (dt, J = 8.0, 1.6 Hz, 1H), 8.18 (s, 1H), 8.03 - 7.87 (m, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.61 (s, 1H), 7.29 - 6.99 (m, 4H), 3.56 (s, 3H), 2.70 (sept, 7 = 6.7 Hz, 1H), 1.07 (d, 7 = 6.7 Hz, 3H), 0.53 (d, 7 = 6.7 Hz, 3H). MS (ES+) m/z 484.11 [M+H]⁺.

Compound 118

((5-(4-tluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(3- methoxyphenyl)(methyl)- λ⁶-sul fanone

[0442] Compound 118 was synthesized by using Method A described for the preparation of Compound 1.

[0443] ¹H NMR (300 MHz, CDCI3): 5 8.72 (s, 1H), 8.13 (s, 1H), 7.70 - 7.62 (m, 2H), 7.56 (s, 1H), 7.52 - 7.42 (m, 1H), 7.24 - 7.11 (m, 5H), 3.88 (s, 3H), 3.55 (s, 3H), 2.70 (s, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.67 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 489.19 [M+H]⁺.

Compound 119

((5-(4-fluorophenyl)-6-isopropyl-lH-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(methyl)(m- tolyl)- λ⁶-sul fanone

[0444] Compound 119 was synthesized by using Method A described for the preparation of Compound 1.

[0445] ¹H NMR (300 MHz, CDC1₃): 5 8.73 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.93 - 7.87 (m, 1H), 7.56 (s, 1H), 7.50 - 7.38 (m, 2H), 7.24 - 7. 12 (m, 4H), 3.54 (s, 3H), 2.75 - 2.63 (m,

1H), 2.46 (s, 3H), 1.09 (d, J = 6.6 Hz, 3H), 0.66 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 473.20 [M+H]⁺.

Compound 120

((5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)(thiophen-2-yl)- λ⁶-sullanone

[0446] Compound 120 was synthesized by using Method B described for the preparation of Compound 52.

[0447] ¹H NMR (300 MHz, CD3OD): 5 8.71 (s, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.94 - 7.80 (m, 2H), 7.57 (d, 7 = 1.2 Hz, 1H), 7.30 - 7.18 (m, 5H), 3.75 (s, 3H), 2.79 - 2.69 (m, 1H), 1.14

(d, J = 6.7 Hz, 3H), 0.85 (d, 7 = 6.7 Hz, 3H). MS (ES+) m/z 465.16 [M+H]⁺.

Compound 121

((5-(4-fluoro-3-hydroxyphenyl)-6-isopropyl-1H -pyrazolo[4,3-g]isoquinolin-8- yl)imino)dimethyl- λ⁶-sulfanone

[0448] Compound 121 was synthesized by using Method A described for the preparation of Compound 1.

[0449] ¹H NMR (300 MHz, CDI₃): 8 10.23 (bs, 1H), 8.66 (d, J = 1.1 Hz, 1H), 8.13 (s, 1H), 7.60 (d, 7 = 1.0 Hz, 1H), 7.21 (dd, 7 = 10.6, 8.2 Hz, 1H), 6.96 (dd, 7 = 8.5, 2.1 Hz, 1H),

6.80 (ddd, 7 = 8.2, 4.7, 2.1 Hz, 1H), 5.54 (bs, 1H), 3.56 (s, 6H), 2.94 (sept, 7 = 6.7 Hz, 1H), 1.21 (d, 7 = 6.6 Hz, 6H). MS (ES+) m/z 413.21 [M+H]⁺.

Compound 122

((5-(4-fluorophenyl)-6-isopropyl-lH-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(methyl)(5- methylfuran-2-yl)- λ⁶-sulfanone

[0450] Compound 122 was synthesized by using Method A described for the preparation of Compound 1.

[0451] ¹H NMR (300 MHz, CDI₃): 6 10.10 (s, 1H), 8.69 (s, 1H), 8.13 (s, 1H), 7.58 (s, 1H), 7.26 - 7.15 (m, 5H), 6.23 - 6.19 (m, 1H), 3.64 (s, 3H), 2.85 - 2.71 (m, 1H), 2.38 (s, 3H),

1.13 (dd, J = 6.7, 1 .0 Hz, 3H), 0.92 (dd, J = 6.7, 1 .0 Hz, 3H). MS (ES+) m/z 463.19 [M+H]⁺.

Compound 123

((5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(methyl)(3- methylfuran-2-yl)- λ⁶-sulfanone

[0452] Compound 123 was synthesized by using Method A described for the preparation of Compound 1.

[0453] ¹H NMR (300 MHz, CDI₃): δ 10.11 (s, 1H), 8.65 (s, 1H), 8.13 (s, 1H), 7.58 (s, 1H), 7.35 (s, 1H), 7.29 - 7.26 (m, 1H), 7.24 - 7.12 (m, 3H), 6.70 (s, 1H), 3.61 (s, 3H), 2.86 - 2.70 (m, 1H), 2.63 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 463.19 [M+H]⁺.

Compound 124

((5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(3-fluoropyridin-

4-yl)(methyl)- λ⁶-sulFfanone

[0454] Compound 124 was synthesized by using Method B described for the preparation of Compound 52.

[0455] ¹H NMR (300 MHz, CDI₃): 8 10.15 (s, 1H), 8.77 (dd, J = 5.0, 0.8 Hz, 1H), 8.69 (t, J= 1.1 Hz, 1H), 8.64 (d, J= 1.4 Hz, 1H), 8.19 (dd, J = 5.8, 4.9 Hz, 1H), 8.16 (d, J = 1.1 Hz, 1H), 7.59 (d, 7 = 1.1 Hz, 1H), 7.26 - 6.97 (m, 4H), 3.64 (s, 3H), 2.69 (sept, 7 = 6.7 Hz, 1H), 1.05 (d, 7 = 6.7 Hz, 3H), 0.49 (d, 7 = 6.7 Hz, 3H). MS (ES+) m/z 500.11 [M+Na]⁺.

Compound 125

((5-(4-fluorophenyl)-6-isopropyl-lH-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(methyl)(2- methylbenzo[d]thiazol-5-yl)- z/’-sull'anone

[0456] Compound 125 was synthesized by using Method B described for the preparation of Compound 52.

[0457] ¹H NMR (300 MHz, DMSO-rig): 5 13.27 (s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.26 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.47 (s, 1H), 7.39 - 7.22 (m, 4H), 3.74 (s, 3H), 2.86 (s, 3H), 0.98 (d, J = 6.6 Hz, 3H), 0.37 (d, J = 6.7 Hz, 3H). CH under DMSO pic. MS (ES+) m/z 530.19 [M+H]⁺.

Compound 126

((5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(methyl)(2- methylbenzo[d]thiazol-5-yl)- λ⁶-sulfanone

[0458] Compound 126 was synthesized by using Method B described for the preparation of Compound 52.

[0459] ¹H NMR (300 MHz, CDCI₃): 5 10.31 (bs, 1H), 8.84 (t, J = 1.1 Hz, 1H), 8.41 - 8.33 (m, 2H), 8.13 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 1.0 Hz, 1H), 7.44 (dd, J = 8.7, 2.9 Hz, 1H), 7.29 - 6.74 (m, 4H), 3.96 (s, 3H), 3.68 (s, 3H), 2.72 (sept, J = 6.7 Hz, 1H), 1.05 (d, J = 6.7 Hz, 3H), 0.74 (d, J = 6.7 Hz, 3H). MS (ES+) m/z 490.19 [M+H]⁺.

Compound 127

((5-chloropyridin-2-yl)((5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)- λ⁶-sulfanone

[0460] Compound 127 was synthesized by using Method B described for the preparation of Compound 52.

[0461] ¹ H NMR (300 MHz, CDI₃): 5 10.25 (br s, 1H), 8.79 (s, 1H), 8.66 (dd, J = 2.4, 0.7 Hz, 1H), 8.37 (dd, J = 8.4, 0.8 Hz, 1H), 8.12 (s, 1H), 7.98 (dd, J = 8.4, 2.4 Hz, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.24 - 7.12 (m, 4H), 3.64 (s, 3H), 2.69 (sept, 7 = 7 Hz, 1H), 0.99 (d, 7 = 6.6 Hz, 3H), 0.64 (d, 7 = 6.6 Hz, 3H). MS (ES+) m/z 494.16 [M+H]⁺.

Compound 128

((5-(4-fluorophenyl)-6-isopropyl-lH-pyrazolo[4,3-g]isoquinolin-8- yl)imino)(methyl)(pyridin-3-yl)- λ⁶-sulfanone

[0462] Compound 128 was synthesized by using Method B described for the preparation of Compound 52.

[0463] ¹H NMR (300 MHz, DMSO-rig): 5 13.25 (br s, 1H), 9.19 (d, 7 = 2.7 Hz, 1H), 8.86 (dd, 7 = 4.8, 1.5 Hz, 1H), 8.67 (s, 1H), 8.40 (dt, 7 = 7.5, 2.0 Hz, 1H), 8.26 (s, 1H), 7.71 (dd, 7 = 8.1, 4.8 Hz, 1H), 7.48 (s, 1H), 7.40 - 7.23 (m, 4H), 3.73 (s, 3H), 2.71 - 2.48 (m, 1H, portion of the peaks merged with residual proton of DMSO-d6), 0.97 (d, 7 = 6.6 Hz, 3H), 0.42 (d, 7 = 7.0 Hz, 3H). MS (ES+) m/z 460.24 [M+H]⁺.

Compound 129

((5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(furan-2- yl)(methyl)- λ⁶-sulfanone

[0464] Compound 129 was synthesized by using Method B described for the preparation of Compound 52.

[0465] ¹H NMR (300 MHz, CDI₃): 5 10.12 (s, 1H), 8.68 (s, 1H), 8.13 (s, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.33 (d, J = 3.5 Hz, 1H), 7.25 - 7.13 (m, 4H), 6.61 (s, 1H), 3.62 (s, 3H), 2.80 - 2.67 (m, 1H), 1.11 (d, J = 6.6 Hz, 3H), 0.86 (d, J= 6.6 Hz, 3H). MS (ES+) m/z 449.22 [M+H]⁺.

Compound 130

2-((5-(4-fluorophenyl)-6-isopropyl-l//-pyrazolo[4,3-g]isoquinolin-8-yl)imino)-2,3-dihydro- 1 /7-2 λ⁴-benzo|c| thiophene 2-oxide

[0466] Compound 130 was synthesized by using Method B described for the preparation of Compound 52.

[0467] ¹H NMR (300 MHz, MeOD and CDC1₃): 5 8.62 (br s, 1H), 8.03 (s, 1H), 7.50 (s, 1H), 7.36 -7.33 (m, 1H, merged with residual CHCI3 peak), 7.26 - 7.01 (m, 7H), 5.36 (d, J = 14.7 Hz, 2H), 4.56 (d, J = 16.1 Hz, 2H), 2.77 (t, J = 6.5 Hz, 1H), 0.99 (d, J = 6.9 Hz, 6H). MS (ES+) m/z 493.17 [M+Na]⁺.

Compound 131

((5-(4-fluorophenyl)-6-isopropyl-177-pyrazolo[4,3-g]isoquinolin-8-yl)imino)(methyl)(l- methyl- 1H-pyrazol-4-yl)- λ⁶-sulfanone

[0468] Compound 131 was synthesized by using Method B described for the preparation of Compound 52.

[0469] ¹H NMR (300 MHz, MeOD): 5 8.69 (t, J = 1.2 Hz, 1H), 8.33 (s, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.97 (d, J = 0.8 Hz, 1H), 7.57 (d, 7= 1.1 Hz, 1H), 7.35 - 7.19 (m, 4H), 3.97 (s, 3H), 3.72 (s, 3H), 2.84 - 2.72 (m, 1H), 1.15 (d, 7 = 6.7 Hz, 3H), 0.93 (d, 7 = 6.7 Hz, 3H). MS (ES+) m/z 463.25 [M+H]⁺.

B. Biologic Examples

Biological Example 1: Protein Thermal Shift Assay

[0470] The following example describes a protein thermal shift assay used to assess the activity of the disclosed compounds.

[0471] Reagents/plates:

Protein Thermal Shift™ Dye (ThermoFisher Scientific, Cat# 4461146) Recombinant Z-AAT expressed and purified from Sf9 cells

384-well PCR plate (MicroAmp™ EnduraPlate™ Optical 384-Well Clear Reaction Plates, ThermoFisher Scientific, Cat#: A36931)

[0472] Assay Protocol:

1. Prepare lOx compound serial dilution plate in 20% DMSO. The resulting compound concentrations are 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39, 0.2, 0.1, 0 μM

2. Prepare premix consisting of IxPBS pH 7.4, 1.1 lx Protein Thermal Shift™ Dye (ThermoFisher Scientific, Cat# 4461 146) and 222 nM Z-AAT protein.

3. Aliquot 9uL of premix per well to 384-well PCR plate

4. Using multichannel pipette to transfer 1 pl of lOx compounds serial dilution to appropriate wells in technical triplicate. 5. Seal the plate. Vortex well and spin 1 min @ 700g

6. Incubate at Room Temperature for 30 min.

7. Run the plate on Quantstudio 7 Pro using the following parameters: a. Instrument setup: Instrument: QuantStudio™ 7 Pro; Block: 384-Well; Run Mode: Standard; Analysis Module: (None); Filter: xl-m3 (Ex: 470nm, Em: 586nm) b. Run protocol: i. IOuL Reaction volume, 105°C Heated Cover Temperature ii. 1:00 min @ 25°C (1.6°C/s) iii. Ramp temperature 0.05°C/s with Data collection “On” until 99°C iv. 2:00 min @ 99°C v. Total measurement time <30min c. Analyze collected results using Protein Thermal Shift™ Software (Applied Biosciences by ThermoFisher Scientific) to derive apparent Kd.

[0473] The results of this thermal shift assay are summarized in Table 2, below. The disclosed activities are defined as follows: “+++” if Kd < 1 μM; “++” if 1 μM < Kd < 3 μM; “+” if 3 μM < Kd < 10 μM, “ND” if Kd > 10 μM. “NT” refers to compounds that have been prepared but not tested in the noted assay.

Biological Example 2: Cellular Secretion Assay

[0474] The following example describes a cellular secretion assay used to assess the activity of the disclosed compounds.

[0475] Reagents/Plates:

DMSO

CHO-NanoLuc-Z-AAT cells, created by lentiviral integration of a Doxycycline-inducible NanoLuc-Z-AAT fusion transgene into a Chinese hamster ovary (CHO) parent cell line CHO cell culture media: RPMI, 10% FBS, IX Glutamax

Doxycycline in Ultrapure water

Tissue culture treated black 96-well plate

Low bind polystyrene 384- well plate

Polystyrene white 384- well plate

[0476] Assay Protocol: Day 1 Cell culture 1. Prepare compound dilutions with Doxycycline and proper controls (final concentration of Doxycycline = 50ng/mL, final concentration of DMSO = 0.5%). 2. Harvest CHO-NanoLuc-Z-AAT cells into media and seed at 11,200 cells per well into compound dilutions, and incubate at 37°C, 5% CO2 for 24 hrs. Day 2 Collect supernatant and read out NanoLuc signal (proportional to secreted Z- AAT) 1. After the 24-hour incubation, remove 60uL of media from the cell plate and transfer to a storage plate (low bind polystyrene 384-well). 2. Perform Nano-Glo Luciferase Assay (Promega N110) according to manufacturer’s instructions using the media in the storage plate, preparing in a polystyrene white 384-well plate and reading luminescence on a BioTek Synergy Neo2 plate reader. 3. EC50 values were determined using nonlinear regression of the normalized luminescent readout via GraphPad Prism using the equation [Agonist] vs. response -- variable slope (four parameters). [0477] The results of this cellular secretion assay are summarized in Table 2, below. The disclosed activities are defined as follows: “+++” if EC50 < 1 µM; “++” if 1 µM ≤ EC50 < 10 µM; “+” if 10 µM ≤ EC₅₀ < 20 µM, “ND” if EC₅₀ ≥ 20 µM. “NT” refers to compounds that have been prepared but not tested in the noted assay. Table 2: Summary of Biological Results Synthetic Thermal Shift Cellular Synthetic Thermal Shift Cellular ay

[0478] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

WHAT IS CLAIMED IS:

1. A compound having Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

Z¹, Z², or Z³ are each independently CHR^Z1, CR^Z1, N, or NR^Z2, provided that at least one of Z¹, Z², or Z³ is N or NR^Z2, and

(i) the dashed bond between Z¹ and Z² is a double bond and the dashed bond between Z² and Z³ is a single bond; or

(ii) the dashed bond between Z² and Z³ is a double bond and the dashed bond between Z¹ and Z² is a single bond;

R^Z1 is H, C_1-6 alkyl, halo, C_1-6 haloalkyl, or phenyl;

R^Z2 is H, C_1-6 alkyl, or C_1-6 haloalkyl;

Y¹ is CR^Y1, or N;

Y² is CR^Y2 or N;

R^Y1 is H, C_1-6 alkyl, halo, or C_1-6 haloalkyl;

R^Y2 is H, C_1-6 alkyl, halo, or C_1-6 haloalkyl;

R¹ is C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; each heteroaryl has 5 to 10 ring members with 1 to 4 heteroatom ring vertices, each independently N, O, or S; and wherein each C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^1a; each R^1a is independently C_1-6 alkyl, C_1-6 alkoxy, -OH, C_1-6 haloalkyl, halo, or C_1-6 haloalkoxy;

R² and R³ are each independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; each heteroaryl has 5 to 10 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; and wherein each C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^2a, and each C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, and C_1-6 haloalkoxy is unsubstituted or substituted with 1 to 3 R^2c; or

R² and R³ combine with the sulfur atom to which they are attached to form a heterocycloalkyl having 3 to 7 ring members with 0 to 2 additional heteroatom ring vertices, each independently N, O, or S, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 3 R^2b; each R^2a is independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, halo, C_1-6 haloalkoxy, cyano, -C(O)OH, or -C(O)OCi-₆ alkyl; each R^2C is independently -NR^2clR^2c2, -C(O)OH, or -C(O)OC_1-6 alkyl; each R^2C1 and R^2c2 are independently H, C_1-6 alkyl, or C_1-6 haloalkyl; each R^2b is independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, halo, C_1-6 haloalkoxy, or heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; or two R^2b moieties on adjacent ring vertices combine with the atoms to which each is attached to form a phenyl ring; or two R^2b moieties on the same ring vertex combine with the atom to which each is attached to form a heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; or two R^2b moieties on non- adjacent ring vertices combine to form NH; and

R⁴ is C_1-6 alkyl, C_1-6 hydroxyalkyl, -C_1-6 alkyl-C(O)H, C_3-6 cycloalkyl,

- C_1-6 alky 1- C_3-6₆ cycloalkyl, heterocycloalkyl, or -C 1-6 alkyl-heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, S, S(O), or S(O)2.

2. A compound having Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

Z¹, Z², or Z³ are each independently CH2, CH, N, or NH, provided that at least one of Z¹, Z², or Z³ is N or NH, and

(i) the dashed bond between Z¹ and Z² is a double bond and the dashed bond between Z² and Z³ is a single bond; or

(ii) the dashed bond between Z² and Z³ is a double bond and the dashed bond between Z¹ and Z² is a single bond;

Y¹ is CH or N;

Y² is CH;

R¹ is C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; each heteroaryl has 5 to 10 ring members with 1 to 4 heteroatom ring vertices, each independently N, O, or S; and wherein each C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^1a; each R^1a is independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, halo, or C_1-6 haloalkoxy;

R² and R³ are each independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; each heteroaryl has 5 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S; and wherein each C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^2a; or

R² and R³ combine with the sulfur atom to which they are attached to form a heterocycloalkyl having 3 to 6 ring members with 0 to 2 additional heteroatom ring vertices, each independently N, O, or S, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 3 R^2b; each R^2a and R^2b is independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, halo, -C(O)OH, or -C(O)OC_1-6 alkyl; and

R⁴ is C_1-6 alkyl, C_1-6 hydroxyalkyl, C_3-6 cycloalkyl, or heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S.

3. The compound of claims 1 or 2, wherein at least one of Z¹, Z², or Z³ is NH, and the remaining two moieties are each independently CH or N.

4. The compound of claims 1 or 2, having the Formula (la)

5. The compound of claims 1 or 2, having the Formula (lb)

6. The compound of claims 1 or 2, having the Formula (1c)

7. The compound of claims 1 or 2, having the Formula (Id)

8. The compound of claims 1 or 2, having the Formula (le)

9. The compound of claims 1 or 2, having the Formula (If)

10. The compound of claims 1 or 2, having the Formula (Ig)

11. The compound of any one of claims 1 to 10, wherein R¹ is cyclopropyl, tetrahydropiperidinyl, phenyl, naphthyl, pyrazolyl, pyridyl, [l,2,4]triazolo[l,5- a]pyridinyl, benzo thiopheneyl, or isoquinolinyl, each of which is unsubstituted or substituted with 1 to 3 R^1a.

12. The compound of any one of claims 1 to 10, wherein R¹ is Ce-i2 aryl unsubstituted or substituted with 1 to 3 R^1a.

13. The compound of any one of claims 1 to 10, wherein R¹ is phenyl unsubstituted or substituted with 1 to 3 R^1a.

14. The compound of any one of claims 1 to 10, wherein R¹ is heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S, and wherein the heteroaryl is unsubstituted or substituted with 1 to 3 R^1a.

15. The compound of any one of claims 1 to 10, wherein R¹ is pyridyl unsubstituted or substituted with 1 to 3 R^1a.

16. The compound of any one of claims 1 to 15, wherein each R^1a is independently C_1-6 alkyl, C_1-6 haloalkyl, or halo.

17. The compound of any one of claims 1 to 15, wherein each R^1a is independently methyl, trifluoromethyl, or fluoro.

18. The compound of any one of claims 1 to 15, wherein each R^1a is independently methyl.

19. The compound of any one of claims 1 to 15, wherein each R^1a is independently fluoro.

20. The compound of any one of claims 1 to 19, wherein R¹ is

21. The compound of any one of claims 1 to 20, wherein

R² is C_1-6 alkyl; and R³ is C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S, each heteroaryl has 5 to 10 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S, wherein each C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^2a, and each C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, and C_1-6 haloalkoxy is unsubstituted or substituted with 1 to 3 R^2C.

22. The compound of any one of claims 1 to 20, wherein

R² is C_1-6 alkyl; and

R³ is C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, or heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S, each heteroaryl has 5 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S, wherein each C_3-6 cycloalkyl, heterocycloalkyl, C_6-12 aryl, and heteroaryl is unsubstituted or substituted with 1 to 3 R^2a.

23. The compound of any one of claims 1 to 20, wherein

R² is C_{1 -4} alkyl; and

R³ is C_{1 -4} alkyl, C_{1 -4} haloalkyl, phenyl, or pyridyl, wherein the phenyl or pyridyl is unsubstituted or substituted with 1 to 3 R^2a.

24. The compound of any one of claims 1 to 23, wherein each R^2a is independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, or halo.

25. The compound of any one of claims 1 to 23, wherein each R^2a is independently methyl, methoxy, trifluoromethyl, fluoro, or chloro.

26. The compound of any one of claims 1 to 20, wherein R² and R³ are each C_{1 -4} alkyl.

27. The compound of any one of claims 1 to 20, wherein R² and R³ are each methyl.

28. The compound of any one of claims 1 to 20, wherein R² and R³ combine with the sulfur atom to which they are attached to form a heterocycloalkyl having 4 to 7 ring members with 0 to 1 additional heteroatom ring vertex, independently N, O, or S, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 2 R^2b.

29. The compound of any one of claims 1 to 20, wherein R² and R³ combine with the sulfur atom to which they are attached to form a heterocycloalkyl having 4 to 6 ring members with 0 to 1 additional heteroatom ring vertex, independently N, O, or S, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 2 R^2b.

30. The compound of any one of claims 1 to 20, 28 or 29, wherein each R^2b is independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, halo, or heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S.

31. The compound of any one of claims 1 to 20 or 28 to 30, wherein each R^2b is independently C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, or halo.

32. The compound of any one of claims 1 to 20 or 28 to 31, wherein each R^2b is independently methoxy or piperazine.

33. The compound of any one of claims 1 to 20 or 28, to 32, wherein each R^2b is independently methyl or methoxy.

34. The compound of any one of claims 1 to 20, 28, or 29 two R^2b moieties on adjacent ring vertices combine with the atoms to which each is attached to form a phenyl ring.

35. The compound of any one of claims 1 to 20, 28, or 29, wherein two R^2b moieties on the same ring vertex combine with the atom to which each is attached to form a heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members with 1 to 3 heteroatom ring vertices, each independently N, O, or S.

36. The compound of claim 35, wherein two R^2b moieties on the same ring vertex combine with the atom to which each is attached to form azetidinyl or oxetanyl.

37. The compound of any one of claims 1 to 20, 28, or 29, wherein two R^2b moieties on non-adjacent ring vertices combine to form NH.

38. The compound of any one of claims 1 to 20, wherein R² and R³ are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, tert-butyl, methoxy,

R² and R³ combine with the sulfur atom to which they are attached to form

39. The compound of any one of claims 1 to 38, wherein R⁴ is C_{1 -4} alkyl or

C_3-6 cycloalkyl.

40. The compound of any one of claims 1 to 38, wherein R⁴ is

41. The compound of any one of claims 1 to 40, wherein R⁴ is isopropyl.

42. The compound of any one of claims 1 to 40, wherein R⁴ is cyclopropyl.

43. The compound of any one of claims 1 to 42, wherein

Z¹ is N, N-H, or N-CH c

Z² is C-H, C-CH₃, or N;

Z³ is C-H, C-CH₃, C-I, C-phenyl, N-H, or N-CH3, provided that at least one of Z¹, Z², or Z³ is N, N-H, or N-CH₃;

Y¹ is C-H, C-F, or N;

Y² is C-H or N;

R¹ is

R² and R³ are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, tert- butyl, methoxy,

R² and R³ combine with the sulfur atom to which they are attached to form

R⁴ is

44. The compound of claims 1 or 2, wherein the compound is selected from the compounds included in Table 1.

45. A compound shown in Table 1, or a pharmaceutically acceptable salt thereof.

46. A pharmaceutical composition comprising a compound of any one of claims 1 to 45 and a pharmaceutically acceptable excipient.

47. A method of modulating alpha- 1 antitrypsin (AAT) activity, comprising contacting AAT with a compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46.

48. The method of claim 47, wherein the AAT is located within a cell.

49. The method of claim 48, wherein the cell is located within a subject.

50. The method of claim 49, wherein the subject is a human.

51. A method of modulating alpha-1 antitrypsin (AAT) activity, comprising administering to a subject in need thereof a compound of any one of claims 1 to

45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim

46.

52. The method of claim 51 , wherein modulating AAT comprises correcting the folding of, facilitating proper folding of, and/or inhibiting misfolding of AAT.

53. A method of correcting the folding of, facilitating proper or beneficial folding of, and/or inhibiting misfolding of alpha- 1 antitrypsin (AAT) in a subject in need thereof, comprising administering to a subject in need thereof a compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46.

54. A method of treating alpha- 1 antitrypsin deficiency (AATD), comprising administering to a subject in need thereof a compound of any one of claims 1 to

45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim

46.

55. The method of any one of claims 49-54, wherein the subject has been diagnosed with, or is suspected of having, chronic obstructive pulmonary disease (COPD).

56. The method of any one of claims 49-54, wherein the subject has not been diagnosed with, or is not suspected of having, chronic obstructive pulmonary disease (COPD).

57. The method of any one of claims 49-56, wherein the subject has been diagnosed with, or is suspected of having, liver cirrhosis.

58. The method of any one of claims 49-56, wherein the subject has not been diagnosed with, or is not suspected of having, liver cirrhosis.

59. The method of any one of claims 49-58, wherein the subject has a PiSZ or PiZZ genotype.

60. The method of claim 59, wherein the subject has the PiZZ genotype.

61. The method of any one of claims 49-60, wherein the subject has or is at risk of developing lung disease.

62. The method of any one of claims 49-61, wherein the subject has or is at risk of developing one or more symptoms or manifestations of AATD in the lungs.

63. The method of any one of claims 49-62, wherein the subject has or is at risk of developing liver disease.

64. The method of any one of claims 49-63, wherein the subject has or is at risk of developing one or more symptoms or manifestations of AATD in the liver.

65. The method of any one of claims 49-64, wherein the subject has one or more symptoms or manifestations of AATD selected from the group consisting of shortness of breath following mild activity, wheezing, reduced ability to exercise, unintentional weight loss, recurring respiratory infections, fatigue, emphysema, difficulty breathing, hacking cough, barrel shaped chest, jaundice, cirrhosis of the liver, swollen abdomen, liver cancer (e.g., hepatocellular carcinoma), and a combination thereof.

66. A kit comprising a compound of any one of claims 1 to 45, or a pharmaceutical composition of claim 46, and instructions for use.