EP4100124A1

EP4100124A1 - Heterocyclic compounds as dihydroorotate dehydrogenase inhibitors

Info

Publication number: EP4100124A1
Application number: EP21704615.0A
Authority: EP
Inventors: Scott Kuduk; Xuqing Zhang
Original assignee: Janssen Biotech Inc
Current assignee: Janssen Biotech Inc
Priority date: 2020-02-04
Filing date: 2021-02-04
Publication date: 2022-12-14
Also published as: AU2021216714A1; CA3170111A1; CN115427109A; BR112022015351A2; KR20220137709A; MX2022009535A; WO2021156787A1; JP2023513496A

Abstract

Disclosed are compounds, compositions and methods for treating diseases, disorders, or medical conditions that are affected by the modulation of DHODH. Embodiments of such compounds are represented by Formula (I) and Formula (II) as follows: and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X¹, X², X³, X⁴, Y and Z, are defined herein.

Description

HETEROCYCLIC COMPOUNDS AS DIHYDROOROTATE DEHYDROGENASE INHIBITORS

CROSS REFERENCE TO RELATED APPLICATIONS This application is entitled to priority pursuant to 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62/969,688, filed on 4 February 2020, the disclosure of which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel compounds that are dihydroorotate dehydrogenase (DHODH) inhibitors. These compounds may be useful for the treatment of a disease, disorder, or medical condition where there is an advantage in inhibiting DHODH. The invention also relates to pharmaceutical compositions comprising one or more of such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the method of treatment of cancer, and autoimmune and inflammatory diseases, syndromes, and disorders.

BACKGROUND OF THE INVENTION Acute myelogenous leukemia (AML) is a clonal disease of the blood and bone marrow resulting from mutations that occur in normal hematopoietic stem cells. AML is a heterogenous disease in that it presents with a range of cytogenetic, morphological and immunophenotypic features, and is characterized by an accumulation of clonal, abnormal myeloid progenitor cells, known as myeloblasts. These cells demonstrate disruption of normal myeloid differentiation and excessive proliferation, resulting in the decreased formation of hematopoietic cells. Disease remission can be achieved with standard induction chemotherapy, but refractory and relapsed disease remains a challenge due to persistence of leukemic stem cells. Therefore, AML represents an unmet medical need with >20,000 new cases per year in the US with 5 -year overall survival below 30% (Stein ET et al., Health Qual Life Outcomes 16: 193, 2018). Differentiation therapy is considered an attractive approach to AML treatment based on the knowledge that differentiation and loss of stem cell self-renewal are coupled in normal cells. Treatment of acute promyelocytic leukemia, which represents 10-15% of all AML, with all-trans retinoic acid is the paradigm for differentiation therapy. Retinoic acid targets the promyelocytic leukemia protein (PML)-retinoic acid receptor-α (RAR-α) fusion protein encoded by at(15,17) chromosomal translocation. Targeting PML-RAR specifically lifts the transcriptionally mediated differentiation block induced by the fusion protein and early clinical trials with single agent ATRA demonstrated complete hematologic remission in all treated patients (McCulloch D et al. Onco Targets Ther 2017; 10: 1585-1601; Nowak D et al. Blood 113: 3655, 2009).

Although differentiation therapy is successful, it is only applicable to a small population of AML patients. Research efforts have aimed at identifying additional differentiation inducing agents, but with limited success. Recently dihydroorotate dehydrogenase (DHODH) emerged as a potentially more broadly applicable differentiation target in a phenotypic screen aimed at identifying small molecules that overcome blockade of the maturation of primary murine bone marrow cells expressing the homeobox protein HoxA9. This protein is a key transcription factor involved in balancing stem cell maintenance/differentiation and is normally expressed in hematopoietic progenitor cells and downregulated upon induction of differentiation and has been found to be widely overexpressed in AML (Sykes et al., Cell 167: 171, 2016).

DHODH is a flavin mononucleotide (FMN) flavoprotein located in the inner mitochondrial membrane that catalyzes the oxidation of dihydroorotate to orotate, the fourth step in the de novo pyrimidine biosynthesis pathway. Inhibition of DHODH leads to decreased pyrimidine synthesis important precursors for nucleotide synthesis, but also glycoprotein and phospholipid biosynthesis (Reis RAG et al., Archives Biochem Biophysics 632: 175, 2017; Vyas VK et al., Mini Rev Med Chem 11: 1039, 2011). DHODH is a validated target for the treatment of autoimmune diseases with the FDA approved small molecule DHODH inhibitors leflunomide and teriflunomide for rheumatoid arthritis and multiple sclerosis, respectively (Lolli ML et al., Recent patents on Anti-Cancer Drug Discovery 13: 86, 2018).

Since the first observation by Sykes et al. demonstrating that DHODH inhibition drives AML differentiation in vitro, as evidenced by upregulation of the differentiation markers CD lib and CD 14, and results in dose dependent anti -leukemic effects, decreased leukemic stem cells and prolonged survival in vivo, additional evidence emerged demonstrating that small molecule DHODH inhibitors mediate antiproliferative activity against AML cells with concomitant cell cycle arrest, upregulation of CD11b and CD14, and induction of apoptosis (Wu D et al.. Haematologica 103: 1472, 2018; Sainas S et al., J Med Chem 61: 6034, 2018; Cao L et al., Mol Cancer Ther, October 23rd Epub ahead of print). Moreover, preclinical solid tumor in vitro and in vivo models demonstrated effectiveness of DHODH inhibition and DHODH was identified as a synthetic lethality in PTEN and KRAS mutant solid tumors (Pharmacology and Therapeutics, Epub October 19th, 2018; Mathur D et al., Cancer Discovery 7: 1, 2017; Cell Chemical Biology 25: 1, 2018).

There remains a need for DHODH inhibitors that provide a therapeutic benefit to patients suffering from cancer and/or inflammatory and immunological diseases.

SUMMARY OF THE INVENTION

Embodiments of the present invention relate to compounds, pharmaceutical compositions containing them, methods of making and purifying them, methods of using them as inhibitors of DHODH enzymatic activity and methods for using them in the treatment of a subject suffering from or diagnosed with a disease, disorder, or medical condition such as autoimmune or inflammatory disorders, or diseases such as cancer.

Embodiments of this invention are compounds of Formula (I),

wherein

X¹ and X² are each independently CH or N;

Y is O, NH or S; R¹ is selected from the group consisting of: C_1-6alkyl; C_1-6alkyl substituted with OH, or OCH₃; C_2-6alkenyl; C_1-6haloalkyl; C_1-6haloalkyl substitu ted with OH, or OCH₃; C_3-6Cyeloalkyl; C_3-6heterocycloalkyl; and phenyl; wherein R^b is C_1-6alkyl substituted with a member selected from the group consisting of:

OH, halo, CN, OC_1-6alkyl, OC_1-6haloalkyl and OC_3-6Cyeloalkyl;

R^c is selected from the group consisting of: C_1-6alkyl, C_1-6haloalkyl, and C_3-6Cyeloalkyl;

R³ is H, Cl or F; R⁴ is selected from the group consisting of:

(a) C_1-6alkyl; C_1-6alkyl substituted with one or two substituents each independently selected from the group consisting of OH and OCH₃; tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH₃; cyclohexyl substituted with CH₃; and tetrahydro-2H-thiopyran 1,1-dioxide; and (b)

wherein

R^d is independently selected from the group consisting of: H; halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH, OCH₃, SCH₃, and OCF₃; C_1-6haloalkyl; C_1-6haloalkyl substituted with a member selected from the group consisting of: OH, and OCH₃; CN; OH; CO₂H; N(CH₃)₂; (C=O)NH-CH₂CH₂OH; NHSO₂CH₃; OC_1-6alkyl; and OC_1-6alkyl substituted with a member selected from the group consisting of: OH, and OCH₃; R^e is selected from the group consisting of: halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH, OCH₃, SCH₃, and OCF₃; OC_1-6alkyl; C_1-6haloalkyl; C_1-6haloalkyl substituted with a member selected from the group consisting of: OH, and OCH₃; and n is 1 or 2; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- oxide thereof.

Embodiments of this invention are compounds of Formula (II), wherein X³ and X⁴ are each independently CH or N; wherein when X³ is N, X⁴ is CH and wherein when X³ is CH, X⁴ is N;

Z is O, S, or NH;

R⁵ is selected from the group consisting of: C_1-6alkyl; C_1-6alkyl substituted with OH, or OCH₃; C_1-6haloalkyl; C_1-6haloalkyl substituted with OH, or OCH₃; and C_3-6Cyeloalkyl; wherein

R^f is independently selected from the group consisting of: H; halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH, and OCH₃; CN; OH; CO₂H; N(CH₃)₂; (C=O)NH-CH₂CH₂OH; NHSO₂CH₃; and OC_1-6alkyl; R^g is selected from the group consisting of: halo, C_1-6alkyl and OC_1-6alkyl; and m is 1 or 2; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. The present invention further provides methods for treating or ameliorating a disease, syndrome, condition, or disorder in a subject, including a mammal and/or human in which the disease, syndrome, condition, or disorder is affected by the inhibition of DHODH enzymatic activity, including but not limited to, cancer and/or inflammatory or immunological diseases, using a compound of Formula (I) (as well as a compound of Formula (II)) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in art. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present invention.

The singular forms "a", "an" and "the" encompass plural references unless the context clearly indicates otherwise.

With reference to substituents, the term “independently” refers to the situation where when more than one substituent is possible, the substituents may be the same or different from each other.

The term “substituted” means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency- allowed position on the system.

Unless qualified specifically in particular instances of use, the term “alkyl” refers to a straight- or branched-chain alkyl group having from 1 to 8 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. “C_1-6alkyl” refers to straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain. “C_1-4alkyl” refers to straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain.

The term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.). The term alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain).

The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle. “ C_3-6Cycloalkyl” refers to a carbocycle having from 3 to 6 ring atoms per carbocycle. Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties:

The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine. The term “haloalkyl” refers to a straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain optionally substituting hydrogens with halogens. The term “C_1-6 haloalkyl” as used here refers to a straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain, optionally substituting hydrogens with halogens. The term “C_1-4 haloalkyl” as used here refers to a straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain, optionally substituting hydrogens with halogens. Examples of “haloalkyl” groups include trifluoromethyl (CF₃), difluoromethyl (CF₂H), monofluoromethyl (CH₂F), pentafluoroethyl (CF₂CF₃), tetrafluoroethyl (CHFCF₃), monofluoroethyl (CH₂CH₂F), trifluoroethyl (CH₂CF₃), tetrafluorotrifluoromethylethyl (CF(CF₃)₂), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.

The term “aryl” refers to a monocyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) having 6 atoms per ring. (Carbon atoms in the aryl groups are sp2 hybridized.)

The term “phenyl” represents the following moiety:

The terms "4- to 7-membered heterocycloalkyl" and "4- to 6-membered heterocycloalkyl" mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present and not excluded otherwise, a nitrogen atom. Illustrative examples of heterocycloalkyl groups include the following entities, in the form of properly bonded moieties: The term “tetrahydro-2H-thiopyran 1,1 -dioxide” represents the following moiety

The term “tetrahydrofuranyl” represents the following moiety:

The term “tetrahydropyranyl” represents the following moiety:

The term “heteroaryl” refers to a monocyclic or fused bicyclic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 9 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of heterocycloalkyl, cycloalkyl, heteroaryl and aryl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.

The term " tautomeric " or " tautomeric form " refers to structural isomers of different energies that are interconvertible through low energy barriers. For example, proton tautomers (also known as proton tautomers) include interconversions through the transfer of protons, such as keto-enol and imine-enamine isomerization. The valence tautomers include interconversions by restructuring some bond electrons.

For example, hydroxypyridine or the tautomeric pyridone is represented below.

The term “variable point of attachment” means that a group is allowed to be attached at more than one alternative position in a structure. The attachment will always replace a hydrogen atom on one of the ring atoms. In other words, all permutations of bonding are represented by the single diagram, as shown in the illustrations below.

Those skilled in the art will recognize that that if more than one such substituent is present for a given ring, the bonding of each substituent is independent of all of the others. The groups listed or illustrated above are not exhaustive. As used herein, the term "or" means "and/or" unless stated otherwise.

As used herein, the terms "including", "containing" and “comprising” are used in their open, non-limiting sense.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

As used herein, the term “treat”, “treating”, or “treatment” of any disease, condition, syndrome or disorder refers, in one embodiment, to ameliorating the disease, condition, syndrome or disorder (i.e. slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, “treat”, “treating”, or “treatment” refers to alleviating or ameliorating at least one physiological or biochemical parameter associated with or causative of the disease, condition, syndrome or disorder, including those which may not be discernible by the patient. In a further embodiment, “treat”, “treating”, or “treatment” refers to modulating the disease, condition, syndrome or disorder either physically (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In yet another embodiment, “treat”, “treating”, or “treatment” refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome or disorder.

The terms “subject” and “patient” are used interchangeably herein and may refer to an animal, preferably a mammal, most preferably a human.

As used herein, the terms active compound, pharmaceutical agent and active ingredient are used interchangeably to refer to a pharmaceutically active compound. Other ingredients in a drug composition, such as carriers, diluents or excipients, may be substantially or completely pharmaceutically inert. A pharmaceutical composition (also referred to herein as a composition or formulation) may comprise the active ingredient in combination with one or more carriers and/or one or more excipients and/or one or more diluents.

The term “therapeutically effective amount” (used interchangeably herein with “effective amount”) refers to an amount (e.g., of an active compound or pharmaceutical agent, such as a compound of the present invention), which elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, including reduction or inhibition of an enzyme or a protein activity, or ameliorating symptoms, alleviating conditions, slowing or delaying disease progression, or preventing a disease. Stated another way, the term therapeutically effective amount may refer to an amount that, when administered to a particular subject, achieves a therapeutic effect by inhibiting, alleviating or curing a disease, condition, syndrome or disorder in the subject or by prophylactically inhibiting, preventing or delaying the onset of a disease, condition, syndrome or disorder, or symptom(s) thereof. A therapeutically effective amount may be an amount which relieves to some extent one or more symptoms of a disease, condition, syndrome or disorder in a subject; and/or returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease, condition, syndrome or disorder; and/or reduces the likelihood of the onset of the disease, condition, syndrome or disorder, or symptom(s) thereof.

"Pharmaceutically acceptable" means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

A "pharmaceutically acceptable salt” is intended to mean a salt of an acid or base of a compound represented by Formula (I) (as well as compounds of Formula (IA), (IB) and (II)) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al, “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts,

Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.

Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, and mandelates. A compound of Formula (I) (as well as a compound of Formula (II)) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

Compounds of Formula (I) (as well as compounds of Formula (II)) may contain at least one nitrogen of basic character, so desired pharmaceutically acceptable salts may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents.

Compounds of Formula (I) (as well as compounds of Formula (II)) may contain a carboxylic acid moiety, a desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine, piperazine, N-methyl-glucamine and tromethamine and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

Each compound used herein may be discussed interchangeably with respect to its chemical formula, chemical name, abbreviation, etc.

Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of such formula. The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual ( R )- or (S)-stereoisomers or as mixtures thereof. Thus, any formula given herein is intended to represent a racemate, one or more of its enantiomeric forms, one or more of its diastereomeric forms, and mixtures thereof. Additionally, any formula given herein is intended to refer also to any one of: hydrates, solvates, polymorphs and of such compounds, and mixtures thereof, even if such forms are not listed explicitly. The term “R” at a stereocenter designates that the stereocenter is purely of the R-configuration as defined in the art; likewise, the term “S” means that the stereocenter is purely of the S-configuration, As used herein, the term “RS” refers to a stereocenter that exists as a mixture of the R- and S-configurations,

Compounds containing one stereocenter drawn without a stereo bond designation are a mixture of 2 enantiomers. Compounds containing 2 stereocenters both drawn without stereo bond designations are a mixture of 4 diastereomers. Compounds with 2 stereocenters both labeled “RS” and drawn with stereo bond designations are a 2-component mixture with relative stereochemistry as drawn. Unlabeled stereocenters drawn without stereo bond designations are a mixture of the R- and S-configurations. For unlabeled stereocenters drawn with stereo bond designations, the absolute stereochemistry is as depicted.

Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

Reference to a compound herein stands for a reference to any one of: (a) the recited form of such compound, and (b) any of the forms of such compound in the medium in which the compound is being considered when named. For example, reference herein to a compound such as R-COOH, encompasses reference to any one of: for example, R-COOH(s), R-COOH(sol), and R-COO-(sol). In this example, R- COOH(s) refers to the solid compound, as it could be for example in a tablet or some other solid pharmaceutical composition or preparation; R-COOH(sol) refers to the undissociated form of the compound in a solvent; and R-COO-(sol) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, whether such dissociated form derives from R- COOH, from a salt thereof, or from any other entity that yields R-COO- upon dissociation in the medium being considered. In another example, an expression such as “exposing an entity to compound of formula R-COOH” refers to the exposure of such entity to the form, or forms, of the compound R-COOH that exists, or exist, in the medium in which such exposure takes place. In still another example, an expression such as “reacting an entity with a compound of formula R-COOH” refers to the reacting of (a) such entity in the chemically relevant form, or forms, of such entity that exists, or exist, in the medium in which such reacting takes place, with (b) the chemically relevant form, or forms, of the compound R-COOH that exists, or exist, in the medium in which such reacting takes place. In this regard, if such entity is for example in an aqueous environment, it is understood that the compound R-COOH is in such same medium, and therefore the entity is being exposed to species such as R-COOH(aq) and/or R-COO-(aq), where the subscript “(aq)” stands for “aqueous” according to its conventional meaning in chemistry and biochemistry. A carboxylic acid functional group has been chosen in these nomenclature examples; this choice is not intended, however, as a limitation but it is merely an illustration. It is understood that analogous examples can be provided in terms of other functional groups, including but not limited to hydroxyl, basic nitrogen members, such as those in amines, and any other group that interacts or transforms according to known manners in the medium that contains the compound. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerism, solvolysis, including hydrolysis, solvation, including hydration, protonation, and deprotonation. No further examples in this regard are provided herein because these interactions and transformations in a given medium are known by any one of ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number in an enriched form. Examples of isotopes that can be incorporated into compounds of the invention in a form that exceeds natural abundances include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H (or chemical symbol D), ³H (or chemical symbol T), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., ²H, or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The term Cn-m alkyl refers to an aliphatic chain, whether straight or branched, with a total number N of carbon members in the chain that satisfies n ≤ N ≤ m, with m > n.

When the same plurality of substituents is assigned to various groups, the specific individual substituent assignment to each of such groups is meant to be independently made with respect to the specific individual substituent assignments to the remaining groups. By way of illustration, but not as a limitation, if each of groups Q and R can be H or F, the choice of H or F for Q is made independently of the choice of H or F for R, so the choice of assignment for Q does not determine or condition the choice of assignment for R, or vice-versa, unless it is expressly indicated otherwise. Illustrative claim recitation in this regard would read as “each of Q and R is independently H or F”, or “each of Q and R is independently selected from the group consisting of H and F”.

In another example, a zwitterionic compound would be encompassed herein by referring to a compound that is known to form a zwitterion, even if it is not explicitly named in its zwitterionic form. Terms such as zwitterion, zwitterions, and their synonyms zwitterionic compound(s) are standard IUPAC-endorsed names that are well known and part of standard sets of defined scientific names. In this regard, the name zwitterion is assigned the name identification CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities. As generally well known, a zwitterion or zwitterionic compound is a neutral compound that has formal unit charges of opposite sign. Sometimes these compounds are referred to by the term “inner salts”. Other sources refer to these compounds as “dipolar ions”, although the latter term is regarded by still other sources as a misnomer. As a specific example, aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH, and it exists in some media (in this case in neutral media) in the form of the zwitterion ⁺H₃NCH₂COO-. Zwitterions, zwitterionic compounds, inner salts and dipolar ions in the known and well-established meanings of these terms are within the scope of this invention, as would in any case be so appreciated by those of ordinary skill in the art. Because there is no need to name each and every embodiment that would be recognized by those of ordinary skill in the art, no structures of the zwitterionic compounds that are associated with the compounds of this invention are given explicitly herein. They are, however, part of the embodiments of this invention. No further examples in this regard are provided herein because the interactions and transformations in a given medium that lead to the various forms of a given compound are known by any one of ordinary skill in the art.

When referring to any formula given herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the same choice of the species for the variable appearing elsewhere. In other words, where a variable appears more than once, the choice of the species from a specified list is independent of the choice of the species for the same variable elsewhere in the formula, unless stated otherwise. By way of a first example on substituent terminology, if substituent S¹ _example is one of S₁ and S₂, and substituent S² _example is one of S₃ and S₄, then these assignments refer to embodiments of this invention given according to the choices S¹ _example is S₁ and S² _example is S₃ ; S¹ _example is S₁ and S² _example is S₄; S¹ _example is S₂ and S² _example is S₃ ; S¹ _example is S₂ and S² _example is S₄; and equivalents of each one of such choices. The shorter terminology “S¹ _example is one of S₁ and S₂, and S² _example is one of S₃ and S₄” is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing first example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein.

Furthermore, when more than one assignment is given for any member or substituent, embodiments of this invention comprise the various groupings that can be made from the listed assignments, taken independently, and equivalents thereof. By way of a second example on substituent terminology, if it is herein described that substituent S_example is one of S₁, S₂, and S₃, this listing refers to embodiments of this invention for which S_example is S₁; S_example is S₂; S_example is S₃, S_example is one of S₁ and S₂; S_example is one of S₁ and S₃; S_example is one of S₂ and S₃; S_example is one of S₁, S₂ and S₃; and S_example is any equivalent of each one of these choices. The shorter terminology “S_example is one of S₁, S₂, and S₃” is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing second example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein.

The nomenclature “C_i-C_j” with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this invention for which each and every one of the number of carbon members, from i to j including i and j, is independently realized. By way of example, the term C₁-C₃ refers independently to embodiments that have one carbon member ( C₁), embodiments that have two carbon members (C₂), and embodiments that have three carbon members (C₃).

Embodiments of this invention include compounds of Formula (I),

wherein

X¹ and X² are each independently CH or N;

Y is O, NH or S; R¹ is selected from the group consisting of: C_1-6alkyl; C_1-6alkyl substituted with OH, or OCH₃; C_2-6alkenyl; C_1-6haloalkyl; C_1-6haloalkyl substituted with OH, or OCH₃; C_3-6Cyeloalkyl; C_3-6heterocycloalkyl; and phenyl; wherein

R^b is C_1-6alkyl substituted with a member selected from the group consisting of: OH, halo, CN, OC_1-6alkyl, OC_1-6haloalkyl and OC_3-6Cyeloalkyl;

R³ is H, Cl or F;

R⁴ is selected from the group consisting of: (a) C_1-6alkyl; C_1-6alkyl substituted with one or two substituents each independently selected from the group consisting of OH and OCH₃; tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH₃; cyclohexyl substituted with CH₃; and tetrahydro-2H-thiopyran 1,1 -dioxide; and

(b)

wherein

R^d is independently selected from the group consisting of: H; halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH, OCH₃, SCH₃, and OCF₃; C_1-6haloalkyl; C_1-6haloalkyl substituted with a member selected from the group consisting of: OH, and OCH₃; CN; OH; CO₂H; N(CH₃)₂; (C=O)NH-CH₂CH₂OH; NHSO₂CH₃; OC_1-6alkyl; and OC_1-6alkyl substituted with a member selected from the group consisting of: OH, and OCH₃; R^e is selected from the group consisting of: halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH, OCH₃, SCH₃, and OCF₃; OC_1-6alkyl; C_1-6haloalkyl; C_1-6haloalkyl substituted with a member selected from the group consisting of: OH, and OCH₃; and n is 1 or 2; or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof; or pharmaceutically acceptable salts of the isotopes, N-oxides, solvates, or stereoisomers thereof.

An additional embodiment of the invention is a compound of Formula (I) wherein X¹ is CH. An additional embodiment of the invention is a compound of Formula (I) wherein X¹ is N.

An additional embodiment of the invention is a compound of Formula (I) wherein X² is CH. An additional embodiment of the invention is a compound of Formula (I) wherein X² is N.

An additional embodiment of the invention is a compound of Formula (I) wherein Y is O.

An additional embodiment of the invention is a compound of Formula (I) wherein Y is NH.

An additional embodiment of the invention is a compound of Formula (I) wherein Y is S.

An additional embodiment of the invention is a compound of Formula (I) wherein R¹ is selected from the group consisting of: C_1-6alkyl; C_1-6alkyl substituted with OH, or OCH₃; C_2-6alkenyl; C_1-6haloalkyl; C_1-6haloalkyl substituted with OH, or OCH₃; C_3-6cycloalkyl; tetrahydropyran-4-yl; and phenyl.

An additional embodiment of the invention is a compound of Formula (I) wherein R¹ is C_1-4alkyl; C_1-4alkyl substituted with OH, or OCH₃; C_1-4haloalkyl; C_1- ₄haloalkyl substituted with OH, or OCH₃; tetrahydropyran-4-yl; or C_3-6Cyeloalkyl.

An additional embodiment of the invention is a compound of Formula (I) wherein Y is O and R¹ is CH(CH₃)₂, CH(CH₃)(CF₃), cyclopropyl, cyclobutyl, or tetrahydropyranyl .

An additional embodiment of the invention is a compound of Formula (I) wherein Y is O and R¹ is CH(CH₃)₂ or CH(CH₃)(CF₃).

An additional embodiment of the invention is a compound of Formula (I) wherein

An additional embodiment of the invention is a compound of Formula (I) wherein An additional embodiment of the invention is a compound of Formula (I) wherein ; wherein

R^b is C_1-4alkyl substituted with OH, halo, CN, OC_1-4alkyl, OC_1-4haloalkyl or OC_3-6cycloalkyl; and R^c is C_1-4alkyl, C_1-4haloalkyl, or C_3-6cycloalkyl.

An additional embodiment of the invention is a compound of Formula (I) wherein

An additional embodiment of the invention is a compound of Formula (I) wherein R³ is H. An additional embodiment of the invention is a compound of Formula (I) wherein R³ is Cl.

An additional embodiment of the invention is a compound of Formula (I) wherein R³ is F.

An additional embodiment of the invention is a compound of Formula (I) wherein R⁴ is

An additional embodiment of the invention is a compound of Formula (I) wherein R^d is independently selected from the group consisting of: H; halo; CH₃; CH₂OH; CN; OH; CO₂H; N(CH₃)₂; (C=O)NH-CH₂CH₂OH; NHSO₂CH₃; OCH₃, OCH₂CH₂OH and OCH₂CH₂OCH₃;

R^e is selected from the group consisting of: Cl, F, CH₃, and OCH₃; and n is 1 or 2.

An additional embodiment of the invention is a compound of Formula (I) wherein

An additional embodiment of the invention is a compound of Formula (I) wherein wherein

R^d is independently selected from the group consisting of: H, Cl, CH₃, OH and OCH₃; R^e is F, Cl, or CH₃; and n is 1 or 2.

An additional embodiment of the invention is a compound of Formula (I) wherein

R⁴ is

An additional embodiment of the invention is a compound of Formula (I) wherein n is 1.

An additional embodiment of the invention is a compound of Formula (I) wherein n is 2. An additional embodiment of the invention is a compound of Formula (I) wherein Y is NH and R⁴ is

An additional embodiment of the invention is a compound of Formula (I) wherein Y is S and R⁴ is Further embodiments of the current invention include compounds as shown below in Table 1, and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof.

Table 1

Additional embodiments of the invention include a compound of Formula (I) having the Formula (IA), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof: Y is O, NH or S;

R¹ is selected from the group consisting of: C_1-6alkyl; C_1-6alkyl substituted with OH, or OCH₃; C_2-6alkenyl; C_1-6haloalkyl; C_1-6haloalkyl substituted with OH, or OCH₃; C_3-6cycloalkyl; C_3-6heterocycloalkyl; and phenyl; R^b is C_1-6alkyl substituted with a member selected from the group consisting of:

OH, halo, CN, OC_1-6alkyl, OC_1-6haloalkyl and OC_3-6cycloalkyl;

R^c is selected from the group consisting of: C_1-6alkyl, C_1-6haloalkyl, and C_3-6cycloalkyl;

R³ is H or F; R⁴ is selected from the group consisting of:

(a) C_1-6alkyl; C_1-6alkyl substituted with one or two substituents each independently selected from the group consisting of OH and OCH₃; tetrahydro- 2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH₃; cyclohexyl substituted with CH₃; and tetrahydro-2H-thiopyran 1,1 -dioxide; and (b)

R^d is independently selected from the group consisting of: H; halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH, and OCH₃; CN; OH; CO₂H; N(CH₃)₂; (C=O)NH-CH₂CH₂OH; NHSO₂CH₃; OC_1-6alkyl; and OC_1-6alkyl substituted with a member selected from the group consisting of: OH, and OCH₃;

R^e is selected from the group consisting of: halo, C_1-6alkyl, and OC_1-6alkyl; and n is 1 or 2. Additional embodiments of the invention include compounds of Formula (I) having the Formula (IB), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof: wherein

X¹ is CH or N;

Y is O or NH;

R¹ is selected from the group consisting of: C_1-6alkyl; C_1-6alkyl substituted with OH, or OCH₃; C_2-6alkenyl; C_1-6haloalkyl; C_1-6haloalkyl substituted with OH, or OCH₃; C_3-6cycloalkyl; C_3-6heterocycloalkyl; and phenyl;

R² is wherein

R^b is C_1-6alkyl substituted with a member selected from the group consisting of:

OH, halo, CN, OC_1-6alkyl, OC_1-6haloalkyl and OC_3-6Cyeloalkyl;

R³ is H or F;

R⁴ is selected from the group consisting of: R^d is independently selected from the group consisting of: H, Cl, and F; R^e is selected from the group consisting of: F, CH₃, and OCH₃; and n is 1 or 2.

An additional embodiment of the invention is a compound of Formula (I) having the Formula (IA), wherein Y is O.

An additional embodiment of the invention is a compound of Formula (I) having the Formula (IA), wherein R¹ is C_1-6alkyl or C_1-6haloalkyl.

An additional embodiment of the invention is a compound of Formula (I) having the Formula (IB), wherein Y is N. An additional embodiment of the invention is a compound of Formula (I) having the Formula (IB), wherein Y is O.

Embodiments of this invention also include compounds of Formula (II) and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, wherein

X³ and X⁴ are each independently CH or N; wherein when X³ is N, X⁴ is CH and wherein when X³ is CH, X⁴ is N;

Z is O, S, or NH; R⁵ is selected from the group consisting of: C_1-6alkyl; C_1-6alkyl substituted with OH, or

OCH₃; C_1-6haloalkyl; C_1-6haloalkyl substituted with OH, or OCH₃; and C_3-6Cyeloalkyl;

wherein R^f is independently selected from the group consisting of: H; halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH, and OCH₃; CN; OH; CO₂H; N(CH₃)₂; (C=O)NH-CH₂CH₂OH; NHSO₂CH₃; and OC_1-6alkyl;

R^g is selected from the group consisting of: halo, C_1-6alkyl and OC_1-6alkyl; and m is 1 or 2.

An additional embodiment of the invention is a compound of Formula (II) wherein X³ is N, X⁴ is CH. An additional embodiment of the invention is a compound of Formula (II) wherein X³ is CH, X⁴ is N.

An additional embodiment of the invention is a compound of Formula (II) wherein Z is O.

An additional embodiment of the invention is a compound of Formula (II) wherein R⁵ is C_1-6alkyl or C_1-6haloalkyl.

An additional embodiment of the invention is a compound of Formula (II) wherein R⁷ is H. An additional embodiment of the invention is a compound of Formula (I) wherein

Also within the scope of the invention are enantiomers and diastereomers of the compounds of Formula (I) (as well as Formulas (IA), (IB), and (II)). Also within the scope of the invention are the pharmaceutically acceptable salts, N-oxides or solvates of the compounds of Formula (I) (as well as Formulas (IA), (IB), and (II)). Also within the scope of the invention are the pharmaceutically acceptable prodrugs of compounds of Formula (I) (as well as Formulas (IA), (IB), and (II)), and pharmaceutically active metabolites of the compounds of Formula (I) (as well as Formulas (IA), (IB), and (II)). Also within the scope of the invention are isotopic variations of compounds of

Formula (I) ((as well as Formulas (IA), (IB), and (II)), such as, e.g., deuterated compounds of Formula (I). Also within the scope of the invention are the pharmaceutically acceptable salts, N-oxides or solvates of the isotopic variations of the compounds of Formula (I) (as well as Formulas (IA), (IB), and (II)). Also within the scope of the invention are the pharmaceutically acceptable prodrugs of the isotopic variations of the compounds of Formula (I) (as well as Formulas (IA), (IB), and (II)), and pharmaceutically active metabolites of the isotopic variations of the compounds of Formula (I) (as well as Formulas (IA), (IB), and (II)).

Even though the compounds of embodiments of the present invention (including their pharmaceutically acceptable salts and pharmaceutically acceptable solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and/or a pharmaceutically acceptable diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice. Thus, particular embodiments of the present invention are directed to pharmaceutical and veterinary compositions comprising compounds of Formula (I) (as well as compounds of Formula (II)) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or pharmaceutically acceptable diluent. By way of example, in the pharmaceutical compositions of embodiments of the present invention, the compounds of Formula (I) (as well as compounds of Formula (II)) may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), and combinations thereof.

An embodiment of the invention relates to a pharmaceutical composition comprising an effective amount of at least one compound selected from compounds of Formula (I) (as well as compounds of Formula (II)), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, in accordance with any embodiment described herein; and at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceutical composition comprising:

(A) an effective amount of at least one compound selected from compounds of Formula (I) wherein X¹ and X² are each independently CH or N;

Y is O, NH or S;

R¹ is selected from the group consisting of: C_1-6alkyl; C_1-6alkyl substituted with OH, or OCH₃; C_2-6alkenyl; C_1-6haloalkyl; C_1-6haloalkyl substituted with OH, or OCH₃; C_3-6cycloalkyl; C_3-6heterocycloalkyl; and phenyl; wherein

OH, halo, CN, OC_1-6alkyl, OC_1-6haloalkyl and OC_3-6cycloalkyl;

R³ is H, Cl orF;

R⁴ is selected from the group consisting of:

(a) C_1-6alkyl; C_1-6alkyl substituted with one or two substituents each independently selected from the group consisting of OH and OCH₃; tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH₃; cyclohexyl substituted with

CH₃; and tetrahydro-2H-thiopyran 1,1 -dioxide; and

(b) wherein R^d is independently selected from the group consisting of: H; halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH, OCH₃, SCH₃, and OCF₃; C_1-6haloalkyl; C_1-6haloalkyl substituted with a member selected from the group consisting of: OH, and OCH₃; CN; OH; CO₂H; N(CH₃)₂; (C=O)NH-CH₂CH₂OH; NHSO₂CH₃; OC_1-6alkyl; and OC_1-6alkyl substituted with a member selected from the group consisting of: OH, and

OCH₃; R^e is selected from the group consisting of: halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH, OCH₃, SCH₃, and OCF₃; OC_1-6alkyl; C_1-6haloalkyl; C_1-6haloalkyl substituted with a member selected from the group consisting of: OH, and OCH₃; and n is 1 or 2; or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers of a compound of Formula (I); and (B) at least one pharmaceutically acceptable excipient.

(A) an effective amount of at least one compound selected from compounds of Formula (II) wherein X³ and X⁴ are each independently CH or N; wherein when X³ is N, X⁴ is CH and wherein when X³ is CH, X⁴ is N;

Z is O, S, or NH;

R⁵ is selected from the group consisting of: C_1-6alkyl; C_1-6alkyl substituted with OH, or OCH₃; C_1-6haloalkyl; C_1-6haloalkyl substituted with OH, or OCH₃; and C_3-6cycloalkyl;

R⁷ is H or F; wherein

R^f is independently selected from the group consisting of: H; halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH, and OCH₃; CN; OH; CO₂H; N(CH₃)₂; (C=O)NH-CH₂CH₂OH; NHSO₂CH₃; and

OC_1-6alkyl;

R^g is selected from the group consisting of: halo, C_1-6alkyl and OC_1-6alkyl; and m is 1 or 2; or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers of a compound of Formula (II); and (B) at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceutical composition comprising an effective amount of a compound shown in Table 1 (e.g., a compound selected from Examples 1-78), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer of the compound of Table 1, a pharmaceutically acceptable prodrug of the compound of Table 1, or a pharmaceutically active metabolite of the compound of Table 1 ; and at least one pharmaceutically acceptable excipient.

Solid oral dosage forms such as, tablets or capsules, containing one or more compounds of the present invention may be administered in at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.

Additional oral forms in which the present inventive compounds may be administered include elixirs, solutions, syrups, and suspensions; each optionally containing flavoring agents and coloring agents.

Alternatively, one or more compounds of Formula (I) (as well as compounds of Formula (II)) can be administered by inhalation (intratracheal or intranasal) or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between about 1 % and about 10 % by weight of the cream, into an ointment comprising, consisting of, and/or consisting essentially of a wax or soft paraffin base together with any stabilizers and preservatives as may be required. An alternative means of administration includes transdermal administration by using a skin or transdermal patch.

The pharmaceutical compositions of the present invention (as well as the compounds of the present invention alone) can also be injected parenterally, for example, intracavemosally, intravenously, intramuscularly, subcutaneously, intradermally, or intrathecally. In this case, the compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.

For parenteral administration, the pharmaceutical compositions of the present invention are best used in the form of a sterile aqueous solution that may contain other substances, for example, enough salts and monosaccharides to make the solution isotonic with blood.

For buccal or sublingual administration, the pharmaceutical compositions of the present invention may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.

By way of further example, pharmaceutical compositions containing at least one of the compounds of Formula (I) (as well as compounds of Formula (II)) as the active ingredient can be prepared by mixing the compound(s) with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques. The carrier, excipient, and diluent may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral, etc.). Thus, for liquid oral preparations such as, suspensions, syrups, elixirs and solutions, suitable carriers, excipients and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations such as, powders, capsules, and tablets, suitable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations also may be optionally coated with substances such as, sugars, or be enterically coated so as to modulate the major site of absorption and disintegration. For parenteral administration, the carrier, excipient and diluent will usually include sterile water, and other ingredients may be added to increase solubility and preservation of the composition. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives such as, solubilizers and preservatives.

According to particular embodiments, a therapeutically effective amount of a compound of Formula (I) (as well as compounds of Formula (II)) or a pharmaceutical composition thereof may comprise a dose range from about 0.1 mg to about 3000 mg, or any particular amount or range therein, in particular from about 1 mg to about 1000 mg, or any particular amount or range therein, or, more particularly, from about 10 mg to about 500 mg, or any particular amount or range therein, of active ingredient in a regimen of about 1 to about (4x) per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for a compound of Formula (I) (as well as compounds of Formula (II)) will vary as will the diseases, syndromes, conditions, and disorders being treated.

For oral administration, a pharmaceutical composition may be provided in the form of one or more tablets containing about 1.0, about 10, about 50, about 100, about 150, about 200, about 250, or about 500 milligrams of a compound of Formula (I). An embodiment of the present invention is directed to a pharmaceutical composition for oral administration, comprising a compound of Formula (I) (as well as compounds of Formula (II)) in an amount of from about 1 mg to about 500 mg.

Advantageously, a compound of Formula (I) (as well as compounds of Formula (II)) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three and (4x) daily.

Optimal dosages of a compound of Formula (I) (as well as compounds of Formula (II)) to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease, syndrome, condition or disorder. In addition, factors associated with the particular subject being treated, including subject gender, age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level and desired therapeutic effect. The above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.

Compounds of Formula (I) (as well as compounds of Formula (II)) may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of a compound of Formula (I) (as well as compounds of Formula (II)) is administered to a subject in need thereof.

According to particular embodiments, one or more compounds of Formula (I) (as well as compounds of Formula (II)) are useful in methods for treating, ameliorating and / or preventing a disease, a syndrome, a condition or a disorder that is affected by the inhibition of DHODH enzymatic activity.

An additional embodiment of the invention relates to the use of compounds of Formula (I), e.g., by inhibiting dihydroorotate oxygenase enzyme activity, in treating disorders like inflammatory disorders, autoimmune disorders, or cancer;

wherein

X¹ and X² are each independently CH or N;

R³ is H, Cl or F;

(b)

wherein

R^d is independently selected from the group consisting of: H; halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH,

OCH₃, SCH₃, and OCF₃; C_1-6haloalkyl; C_1-6haloalkyl substituted with a member selected from the group consisting of: OH, and OCH₃ CN; OH; CO₂H; N(CH₃)₂; (C=O)NH-CH₂CH₂OH; NHSO₂CH₃; OC_1-6alkyl; and OC_1-6alkyl substituted with a member selected from the group consisting of: OH, and OCH₃; is selected from the group consisting of: halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH, OCH₃, SCH₃, and OCF₃; OC_1-6alkyl; C_1-6haloalkyl; C_1-6haloalkyl substituted with a member selected from the group consisting of: OH, and OCH₃; and n is 1 or 2; or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof.

An additional embodiment of the invention relates to the use of compounds of Formula (II), e.g., by inhibiting dihydroorotate oxygenase enzyme activity, in treating disorders like inflammatory disorders, autoimmune disorders, or cancer; wherein

Z is O, S, or NH; R⁵ is selected from the group consisting of: C_1-6alkyl; C_1-6alkyl substituted with OH, or OCH₃; C_1-6haloalkyl; C_1-6haloalkyl substituted with OH, or OCH₃; and C_3-6cycloalkyl;

R⁶ is

R⁷ is H or F; wherein

R^f is independently selected from the group consisting of: H; halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH, and OCH₃; CN; OH; CO₂H; N(CH₃)₂; (C=O)NH-CH₂CH₂OH; NHSO₂CH₃; and OC_1-6alkyl;

R^g is selected from the group consisting of: halo, C_1-6alkyl and OC_1-6alkyl; and m is 1 or 2; or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof. In a further aspect the present invention provides a method for inhibiting or altering Dihydroorotate Dehydrogenase (DHODH) enzymatic activity, the method comprising contacting DHODH with any compound of Formula (I) (as well as compounds of Formula (II)), aspect or embodiment disclosed herein, thereby inhibiting or otherwise altering DHODH enzymatic activity. An additional embodiment of the present invention provides methods for treating diseases, disorders, or medical conditions mediated or otherwise affected by dihydroorotate dehydrogenase (DHODH) enzyme activity comprising administering a compound of Formula (I) (as well as compounds of Formula (II)) to a subject in need thereof.

As used herein, the term "DHODH inhibitor" may refer to an agent that inhibits or reduces DHODH activity.

In one embodiment, the term “therapeutically effective amount” (or “effective amount”) refers to the amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent, and/ or ameliorate a condition, or a disorder or a disease (i) mediated by DHODH enzymatic activity; or (ii) associated with DHODH enzymatic activity; or (iii) characterized by activity (normal or abnormal) of DHODH enzyme; or (2) reduce or inhibit the activity of DHODH enzyme; or (3) reduce or inhibit the expression of DHODH; or (4) modify the protein levels of DHODH. Without being bound by a particular theory, DHODH inhibitors are believed to act by inhibiting nucleic acid synthesis, cell cycle arrest or altering post-translational glycosylation of proteins involved in regulating myeloid differentiation within progenitor tumor cells.

An additional embodiment of the invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated or otherwise affected by DHODH enzymatic activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from: compounds of Formula (I) (as well as Formulas (IA), (IB), and (II) such as a compound of Table 1), enantiomers and diastereomers of the compounds of Formula (I) (as well as Formulas (IA), (IB), and (II) such as a compound of Table 1), isotopic variations of the compounds of Formula (I) (as well as Formulas (IA), (IB), and (II) such as a compound of Table 1), and pharmaceutically acceptable salts of all of the foregoing. Stated another way, according to an embodiment, a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition, such as cancer, comprises administering to the subject an effective amount of at least one compound selected from: compounds of Formula (I) (as well as Formulas (IA), (IB), and (II) such as a compound of Table 1), and pharmaceutically acceptable salts of all the foregoing (e.g., by inhibiting or otherwise altering dihydroorotate oxygenase enzyme activity in the subject).

In another embodiment, inhibitors of DHODH of the present invention may be used for the treatment of immunological diseases including, but not limited to, autoimmune and inflammatory disorders, e.g. arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus- host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjogren’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune -complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including edema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

As used herein, unless otherwise noted, the term “affect” or “affected” (when referring to a disease, disorder, or medical condition that is affected by the inhibition or alteration of DHODH enzymatic activity) includes a reduction in the frequency and / or severity of one or more symptoms or manifestations of said disease, syndrome, condition or disorder; and / or includes the prevention of the development of one or more symptoms or manifestations of said disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder. An additional embodiment of the invention provides a method of treatment of cancer comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I) (as well as compounds of Formula (II)), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. According to an embodiment, the cancer is selected from but not limited to, lymphomas, leukemias, carcinomas, and sarcomas.

An additional embodiment of the invention provides the use of a compound of Formula (I) (as well as compounds of Formula (II)), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, for the treatment of one or more cancer types.

According to particular embodiments, the uses and methods of treatment described herein are directed to the treatment of cancer, wherein the cancer is selected from but not limited to: leukemias including but not limited to acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and also myelodysplastic syndrome (MDS), which can develop into an acute myeloid leukemia,

lymphomas including but not limited to AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma and double-expressor lymphoma; anaplastic large cell lymphoma, marginal B cell lymphoma and primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL); T-cell NHL such as precursor T- lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma sarcomas including but not limited to sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma; and other cancers, such as solid tumors, including but not limited to breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma and sarcoma.

In an embodiment, cancers that may benefit from a treatment with inhibitors of DHODH of the present invention include, but are not limited to, lymphomas, leukemias, carcinomas, and sarcomas, e.g. non-Hodgkin’s lymphoma, diffuse large B- cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, brain (gliomas), glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head & neck cancer, testicular cancer, Ewing’s sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor).

In another embodiment of the present invention, the compounds of the present invention may be employed in combination with one or more other medicinal agents, more particularly with one or more anti-cancer agents, e.g. chemotherapeutic, anti- proliferative or immunomodulating agents, or with adjuvants in cancer therapy, e.g. immunosuppressive or anti-inflammatory agents. Additional non-limiting examples of anti-cancer agents that may be administered in combination with a compound of the present invention include biologic compounds, such as monoclonal antibodies (e.g., that mediate effector function upon binding to cancer cell-associated antigens, or block interaction of a receptor expressed on cancer cells with a soluble or cell bound ligand), bispecific antibodies that mediate immune cell redirection, etc. According to an embodiment, a method of treating cancer comprises administering an effective amount of a compound of the present invention (e.g., selected from compounds of Formula (I) (as well as compounds of Formula (II)), such as a compound shown in Table 1, pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof) and an effective amount of one or more additional anti-cancer agents, wherein the method comprises administering the compound of the present invention and the additional anti -cancer agent(s) either simultaneously (e.g., as part of the same pharmaceutical composition) or sequentially. According to an embodiment, a pharmaceutical composition comprises an effective amount of a compound of the present invention (e.g., selected from compounds of Formula (I) (as well as compounds of Formula (II)), such as a compound shown in Table 1, pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof), an effective amount of one or more additional anti -cancer agents, and optionally one or more excipients.

An additional embodiment of the invention provides the use of a compound of Formula (I) (as well as compounds of Formula (II)), or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof, as part of chemotherapeutic regimens for the treatment of cancers, lymphomas and leukemias alone or in combination with classic antitumoral compounds well known by the one skilled in the art.

GENERAL SYNTHETIC METHODS

Exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables are as defined above in reference to Formula (I) (as well as compounds of Formula (II)). Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0 °C and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent. Abbreviations used in the instant specification, particularly the schemes and examples, are as follows:

ACN acetonitrile

AcOH glacial acetic acid aq. aqueous

Bn or Bzl benzyl Boc tert-butyloxy carbonyl cone. concentrated

DCC N,N'-dicyclohexyl-carbodiimide

DCM dichloromethane

DIPEA or DIEA diisopropyl-ethyl amine DMA dimethylaniline

DMAP 4-dimethylaminopyridine

DME dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide EA ethyl acetate

EDCI 1 -ethyl-3-(3 -dimethylaminopropyl) carbodiimide

ESI electrospray ionization

EtOAc or EA ethyl acetate

EtOH ethanol GCMS gas chromatography-mass spectrometry h or hr(s) hour or hours

HPLC high performance liquid chromatography

KHMDS Potassium bis(trimethylsilyl)amide LiHMDS Lithium bis(trimethylsilyl)amide

MeOH methanol MHz megahertz min minute or minutes MS mass spectrometry

NaHMDS Sodium bis(trimethylsilyl)amide

NMR nuclear magnetic resonance

PE petroleum ether

RP reverse-phase rt or RT room temperature R_t retention time Sec second or seconds

TBDPS tert-Butyldiphenylchlorosilane TBS tert-Butyldimethylsilyl TES triethylsilane TIPS triisopropylsilane

TEA or Et₃N triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran TLC thin layer chromatography

PREPARATIVE EXAMPLES

Exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples to follow.

SCHEME 1

According to SCHEME 1, a 1,2,4-triazol-5(4H)-one compound of formula (V), where PG is Bn, is prepared from ethyl 2-(benzyloxy)acetate in three steps. In a first step 2-(benzyloxy)acetohydrazide is prepared by the reaction of ethyl 2- (benzyloxy)acetate with hydrazine hydrate, in a suitable solvent such as EtOH, and the like; at temperatures ranging from 70-85 °C. Reaction of the hydrazide with an isocyanate of formula R^c-NCO, where R^c is C_1-6alkyl, in a suitable solvent such as water, and the like; provides the corresponding semicarbazide. Subsequent cyclization of the semicarbazide with a suitable base such as NaOH, in a suitable solvent such as water, provides a compound of formula (V), where PG is Bn.

Protecting group exchange of a compound of formula (V), where PG is Bn to a compound of formula (V) where PG is TBDPS, is achieved in two steps employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999. In a first step, deprotection of benzyl group is achieved under hydrogenolytic conditions known to one skilled in the art provides the alcohol. For example, deprotection is achieved employing a palladium catalyst such Pd/C, and the like; under H₂; in a suitable solvent such as EtOH, MeOH, EtOAc, or a mixture thereof, preferably EtOH; with or without the presence HCl; for a period of 4 to 72 hrs. In a second step, protection of the corresponding alcohol as the silyl ether, is achieved with tert-butyldimethylsilyl chloride, a suitable base such as imidazole, dimethylaminopyridine, pyridine, and the like; in a solvent such as DMF, DCM, and the like; at temperatures ranging from 0 °C to room temperature; affords a compound of formula (V) where PG is TBDPS.

SCHEME 2

According to SCHEME 2, commercially available or synthetically accessible 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one is reacted with sodium azide; in the presence of a suitable acid such as methylsulfonic acid (MSA), and the like; in a suitable solvent such as THF, and the like; at temperatures ranging from 0 °C to 50 °C; to provide 6-bromo-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one. 6-Bromo-8-fluoro-3,4- dihydroisoquinolin-1(2H)-one is treated with a commercially available or synthetically accessible alcohol of formula R¹OH. where R¹ is C_1-6alkyl; C_1-6alkyl substituted with OH, or OCH₃; C_2-6alkenyl; C_1-6haloalkyl; C_1-6haloalkyl substituted with OH, or OCH₃; C_3-6cycloalkyl; C_3-6heterocycloalkyl; and phenyl; in the presence of a suitable base such as NaH, and the like; in an aprotic solvent such as DMF, and the like; at temperatures ranging from 0 °C to 100 °C, preferably 30 °C; to provide a compound of formula (VI).

A compound of formula (VI) is oxidized with a suitable oxidant such as MnO₂, DDQ and the like; in a suitable solvent such as dioxane, toluene and the like; at temperatures ranging from 60 °C to 120 °C, preferably 100 °C; to afford a compound of formula (VII). A compound of formula (VII) is coupled with a commercially available or synthetically accessible compound of formula (VIII), where R^b is C_1-6alkyl substituted with O-PG, where PG is a suitable alcohol protecting group such as Bn, allyl, p-methoxy-Bn (PMB), TBDMS, methoxymethyl (MOM), 2- methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM); under Ullman N-arylation conditions; with a suitable catalyst such as Cul, Cu(acac)₂, CuO, and the like; a suitable base such a K₃PO₄, Cs₂CO₃, t-BuOK and the like; with or without a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane- 1,2-diamine, dimethylglycine and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; at temperatures ranging from 80 °C to about 120 °C; to provide a compound of formula (IX). A compound of formula (IX) is reacted with a chlorinating agent such as POCl₃, SOCl₂ and the like; at temperatures ranging from 60 °C to about 100 °C; to afford a compound of formula (X).

SCHEME 3

According to SCHEME 3, commercially available or synthetically accessible 2,6- dichloro-4-methylnicotinonitrile is coupled with a commercially available or synthetically accessible compound of formula (VIII), where R^b is C_1-6alkyl substituted with O-PG, where PG is a suitable alcohol protecting group; in the presence of a suitable base such as NaH, Cs₂CO₃ and the like; in an aprotic solvent such as DMF, DMSO and the like; at temperatures ranging from 60 °C to about 120 °C, preferably 80 °C; to afford a compound of formula (XI). A compound of formula (XI) is treated with a commercially available or synthetically accessible alcohol of formula R¹OH: employing conditions previously described to provide a compound of formula (XII).

A compound of formula (XIII) is prepared in two steps from a compound of formula (XII). In a first step, a compound of formula (XII) is hydrolyzed with a suitable oxidant such as H₂O₂, NaCIO and the like; with a suitable base such a K₂CO₃, Cs₂CO₃ and the like; in a solvent such as DMSO, dioxane, THF and the like; at temperatures ranging from 0 to 60 °C. Subsequent coupling with commercially available 1,1-dimethoxy-N,N-dimethylmethanamine; ; at temperatures ranging from 80 °C to about 120 °C, affords a compound of formula (XIII).

A compound of formula (XIII) is treated with a suitable base such as NaH, t- BuOK, LiHMDS and the like; in an aprotic solvent such as THF, dioxane and the like; at temperatures ranging from 0 °C to about 80 °C; to afford a compound of formula (XIV). A compound of formula (XIV) is reacted with a chlorinating agent such as POCl₃, SOCl₂ and the like; at temperatures ranging from 60 °C to about 100 °C; to afford a compound of formula (XV).

SCHEME 4

According to SCHEME 4, 5,7-dichloropyrido[3,4-d]pyridazin-4(3H)-one (a commercially available compound (or synthesized according to methods described in Vasudevan, A. et al, Bicyclic heterocycles as ALK inhibitors and their preparation and use for the treatment of cancer. Patent Application No. US 2014/0155389Al) is coupled with a commercially available or synthetically accessible alcohol of formula R¹OH: according to methods previously described affords a compound of formula (XVI). A compound of formula (XVI) is reacted with a commercially available or synthetically accessible compound of formula (VIII); employing methods previously described affords a compound of formula (XVII). A compound of formula (XVII) is reacted with a chlorinating agent employing methods previously described to afford a compound of formula (XVIII).

SCHEME 5

According to SCHEME 4, 5,7-dichloro-1,6-naphthyridin-4(1H)-one (a commercially available compound (or synthesized according to Long, Y. et al, Pyrido- azaheterocyclic compound and preparation method and use thereof, Patent Application No. US 2018/0244667 Al) is coupled with a commercially available or synthetically accessible alcohol of formula R¹OH: according to methods previously described affords a compound of formula (XIX). A compound of formula (XIX) is reacted with a commercially available or synthetically accessible compound of formula (VIII); under Ullman N-arylation conditions; employing a suitable catalyst such as Cul, Cu(acac)₂, CuO, and the like; a suitable base such a K₃PO₄, Cs₂CO₃, t-BuOK and the like; with or without a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane-1,2- diamine, dimethylglycine and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; to afford a compound of formula (XX). A compound of formula (XX) is reacted with a chlorinating agent employing methods previously described to afford a compound of formula (XXI).

SCHEME 6

According to SCHEME 6, a compound of formula (VII) is reacted with a chlorinating agent employing conditions previously described to afford a compound of formula (XXII). A compound of formula (XXII) is reacted a commercially available or synthetically accessible compound of formula R⁴-Y¹, where R⁴ is a suitably substituted aryl or five or six membered heteroaryl ring and Y¹ is OH, SH, or NH₂; under nucleophilic substitution conditions, with a suitable base such a KOH, Cs₂CO₃, t- BuOK and the like; without or in a suitable solvent such as NMP, DMF, DMSO, and the like; to provide a compound of formula (XXIII). A compound of formula compound (XXIII) was reacted with diphenylmethanimine under Buchwald-Hartwig amination conditions, in the presence of a suitable catalyst such as Pd(Ph₃P)₄, Pd₂(dba)₃, PdCl₂(Ph₃P)₂, and the like; with a suitable base such a K₃PO₄, Cs₂CO₃, t-BuOK and the like; with a suitable ligand such as Xantphos (4,5-bis(diphenylphosphino)-9,9- dimethylxanthene), CPhos (2-dicyclohexylphosphino-2',6'-bis( N,N- dimethylamino)biphenyl), BINAP and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; at temperatures ranging from 60 °C to about 120 °C; to provide a compound of formula compound (XXIV). A compound of formula (XXIV) is deprotected with an acidic agent such as TFA, HCl and H₂SO₄ the like; in a suitable solvent such as dioxane, THF, DCM, and the like; at temperatures ranging from 0 °C to about 80 °C; to provide a compound of formula (XXV).

A compound of formula compound (XXV) is reacted with phenyl carbonochloridate; a suitable base such a TEA, DIPEA, pyridine and the like; in a suitable solvent such as dioxane, THF, DCM, and the like; at temperatures ranging from 0 °C to about 60 °C, to provide a compound of formula compound (XXVI).

SCHEME 7 According to SCHEME 7, commercially available 2-amino-4-bromo-6- fluorobenzonitrile is hydrolyzed to under a base such as K₂CO₃, and the like; in a protonic solvent such as water, and the like; at temperatures ranging from 80 °C to aboutl60 °C; employing conventional heating or microwave irradiation; to afford 2- amino-4-bromo-6-fluorobenzamide. 2-Amino-4-bromo-6-fluorobenzamide is treated with a formylating agent such as DMF, and the like; in the presence of an acid such as pTSA, MSA and the like; at temperatures ranging from 60 °C to about 140 °C; to afford 7 -bromo-5 -fluoroquinazolin-4(3H)-one . 7-Bromo-5 -fluoroquinazolin-4(3H)-one is coupled with a commercially available or synthetically accessible alcohol of formula R¹OH: employing conditions previously described to afford a compound of formula (XXVII). A compound of formula (XXVII) is reacted with a commercially available or synthetically accessible compound of formula (VIII); under Ullman N-arylation conditions, under a suitable catalyst such as Cul, Cu(acac)₂, CuO, and the like; with a suitable base such a K₃PO₄, Cs₂CO₃, t-BuOK and the like; with or without a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane- 1,2-diamine, dimethylglycine and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; to afford a compound of formula (XXVIII). A compound of formula (XXVIII) is reacted with a chlorinating agent such as POCl₃, SOCl₂ and the like; employing conditions previously described to provide a compound of formula (XXIX).

SCHEME 8

According to SCHEME 8, commercially available methyl 4-bromo-2- fluorobenzoate is coupled with a commercially available or synthetically accessible alcohol of formula R¹OH: employing conditions previously described affords a compound of formula (XXX). A compound of formula (XXX) is hydrolyzed in the presence of a suitable base such as NaOH, LiOH and the like; in a suitable solvent such as THF, MeOH, water and the like; at temperatures ranging from 20 °C to about 80 °C; to afford a compound of formula (XXXI). A compound of formula (XXXI) is annulated employing a suitable catalyst such as Pd(OAc)₂, Pd₂(dba)₃, and the like; with a suitable base such a K₃PO₄, Cs₂CO₃, K₂CO₃ and the like; with a suitable electrophile such as 1,2-employing conventional heating or under micro wave irradiation; at temperatures ranging from 100 °C to about 160 °C, to afford a compound of formula (XXXII). A compound of formula (XXXII) is reacted halogenated with a bromine source such as NBS, Bn, and the like; with a suitable radical initiator such as BPO, AIBN and the like; in a suitable solvent such as DCE, CCl₄, and the like; at temperatures ranging from 70 °C to about 120 °C, to afford a compound of formula (XXXIII). A compound of formula (XXXIII) is reacted with hydrazine in a suitable solvent such as EtOH, dioxane, and the like; at temperatures ranging from 80 °C to about 120 °C, to afford a compound of formula (XXXIV). A compound of formula (XXXIV) is reacted with a chlorinating agent according to methods previously described to afford a compound of formula (XXXV).

According to SCHEME 9, commercially available 2,6-dichloro-5- fluoronicotinic acid is treated with a suitable base such as LDA, LiHMDS, and the like; in a solvent such as THF, ether, and the like; at temperatures ranging from -78 °C to about 0 °C, for example at about -40°C; followed by reaction with a formyl source such as DMF, and the like; to afford 4,6-dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridin- 3(1H)-one. 4,6-Dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridin-3(1H)-one is reacted with hydrazine in a suitable solvent such as THF, MeOH, EtOH and the like; at temperatures ranging from 20 °C to about 80 °C; to afford 5,7-dichloro-8- fluoropyrido [3 ,4-d]pyridazin-4(3H)-one . 5 ,7-Dichloro-8-fluoropyrido [3 ,4-d]pyridazin- 4(3H)-one is coupled with a commercially available or synthetically accessible alcohol of formula R¹OH: according to methods previously described to provide a compound of formula (XXXVI). A compound of formula (XXXVI) is reacted with a commercially available or synthetically accessible compound of formula (VIII); under Ullman N- arylation conditions, according to methods previously described to provide a compound of formula (XXXVII). A compound of formula (XXXVII) is reacted with a chlorinating agent such as POCl₃, SOCl₂ and the like; employing methods previously described to provide a compound of formula (XXXVIII).

SCHEME 10 According to SCHEME 10, commercially available 2,6-dichloro-5- fluoronicotinic acid is treated with a suitable base such as LDA, LiHMDS, and the like; in a solvent such as THF, ether, and the like; at temperatures ranging from -78 °C to about 0 °C, for example at about -40 °C, followed by reaction with a bromine source such as NBS, 1,2-dibromo-1,1,2,2-tetrachloroethane and the like to afford 4-bromo-2,6- dichloro-5-fluoronicotinic acid. 4-Bromo-2,6-dichloro-5-fluoronicotinic acid is reacted with a chloro source such as oxalyl chloride, thionyl chloride, and the like; in a suitable solvent such as DCM, THF, ether and the like; at temperatures ranging from 0 °C to about 80 °C, followed by reaction with t-butyl amine; in a suitable base such as TEA, DIPEA, and the like; to afford 4-bromo-N-(tert-butyl)-2,6-dichloro-5- fluoronicotinamide. 4-Bromo-N-(tert-butyl)-2,6-dichloro-5-fluoronicotinamide is coupled with commercially available or synthetically accessible (E)-2-(2-ethoxyvinyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane; under Suzuki coupling conditions, under a suitable catalyst such as Pd(OAc)₂, Pd₂(dba)₃, and the like; a suitable base such a K₃PO₄, Cs₂CO₃, t-BuOK and the like; with or without a suitable ligand such as triphenylphosphine, tricyclohexylphosphine, and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; at temperatures ranging from 80 °C to about 120 °C, to provide (E)-N-(tert-butyl)-2,6-dichloro-4-(2-ethoxyvinyl)-5- fluoronicotinamide. (E)-N-(tert-Butyl)-2,6-dichloro-4-(2-ethoxyvinyl)-5- fluoronicotinamide is annulated intramolecularly in a suitable acid such as TFA, formic acid, and the like; in a suitable solvent such as DCM, THF, ether and the like; at temperatures ranging from 20 °C to about 80 °C; to afford 6,8-dichloro-5-fluoro-2,7- naphthyridin-1(2H)-one. 6,8-Dichloro-5-fluoro-2,7-naphthyridin-1(2H)-one is coupled with a commercially available or synthetically accessible alcohol of formula R¹OH: employing conditions previously described to provide a compound of formula (XXXIX). A compound of formula (XXXIX) is reacted with a commercially available or synthetically accessible compound of formula (VIII); under Ullman N-arylation conditions, employing conditions previously described to provide a compound of formula (XL). A compound of formula (XXXXVIII) is reacted with a chlorinating agent such as POCl₃, SOCl₂ and the like; employing conditions previously described to provide a compound of formula (XLI). SCHEME 11

According to SCHEME 11, a compound of formula (XLII) which includes compounds of formulas (X), (XV), (XVII), (XXXVIII), and (XLI); is reacted with a commercially available or synthetically accessible compound of formula R⁴-Y¹. where R⁴ is C_1-6alkyl optionally substituted with one or two substituents each independently selected from the group consisting of OH and OCH₃, C_3-6cycloalkyl substituted with C_1- ₃alkyl, a suitably substituted aryl, a five or six membered heteroaryl ring, or an optionally substituted six membered heterocycloalkyl; and Y¹ is OH, SH, or NH₂; under nucleophilic substitution conditions, with a suitable base such a NaH, KOH, Cs₂CO₃, t- BuOK, DBU, and the like; without or in a suitable solvent such as NMP, DMF, DMSO, dioxane, and the like; at temperatures ranging from 0 °C to 150 °C; employing conventional or microwave heating.

When a compound of formula R⁴-Y¹ is 3,5-difluoro-4-hydroxybenzaldehyde is coupled with a compound of formula (X) employing methods described previously; the resulting aldehyde functional group is reduced to the CH₂OH functional group employing a reducing agent such as sodium borohydride, in a suitable solvent such as MeOH, at a temperature of about 0 °C.

When a compound of formula R⁴-Y¹ is 3,5-difluoro-4-hydroxybenzonitrile is coupled with a compound of formula (X) employing methods described previously; the nitrile functional group is hydrolyzed to CO₂H employing aq. NaOH, in a suitable solvent such as MeOH/THF, at a temperature of about 80 °C. Additionally, the CO₂H functional group can be further coupled with an amine such as 2-aminoethan-1-ol, under conventional amide bond forming techniques known to one skilled in the art; for example where the acid is activated with an appropriate activating reagent, for example a carbodiimide, such as N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI) optionally in the presence of hydroxybenzotriazole (HOBt) and/or a catalyst such as 4-dimethylaminopyridine (DMAP); a halotrisaminophosphonium salt such as (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP^®); a suitable pyridinium salt such as 2-chloro-1-methyl pyridinium chloride; or another suitable coupling agent such as N,N,N',N' -tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3 -triazolo [4,5 - b]pyridinium 3-oxid hexafluorophosphate (HATU), 2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphorinane-2, 4, 6-trioxide (T3P^®) and the like. Coupling reactions are conducted in a suitable solvent such as DCM, THF, DMF and the like, optionally in the presence of a tertiary amine such as N-methylmorpholine, N-ethyldiisopropylamine (DIEA, DIPEA), or triethylamine (TEA), at a temperature ranging from about 0 °C to rt.

When a compound of formula R⁴-Y¹ is 2,5-dichloropyridin-4-ol, is coupled with a compound of formula (X), employing methods described previously; the aryl chloro group is further reacted with a methylating agent such as 2,4,6-trimethyl-1,3, 5, 2,4,6- trioxatriborinane, employing an appropriate catalyst, such as (2-dicyclohexylphosphino- 2',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methane sulfonate (SPhos Pd G3), [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium (II) and the like; an inorganic base such as Cs₂CO₃, K₂CO₃ or K₃PO₄ and the like; in a suitable solvent such as DMF, dioxane, at a temperature of about 20-100 °C.

When a compound of formula R⁴-Y¹ is 5-chloro-2-methoxypyridin-4-ol, is coupled with a compound of formula (X), where R³ is H; employing methods described previously; further chlorination proceeds by reacting a chlorinating agent such as N- chloro-succinimide (NCS) or Palau'Chlor^® (2-chloro-1,3- bis(methoxycarbonyl)guanidine) and the like; in a suitable solvent such as ACN, THF, at a temperature of about 20-60 °C, to provide a compound where R³ is Cl.

When a compound of formula R⁴-Y⁴ is 5-chloro-2-methoxypyridin-4-ol is coupled with a compound of formula (X), where R³ is H, employing methods described previously; de-methylation of the 5-chloro-2-methoxypyridine is achieved by reaction with trimethylsilyl iodide (TMSI) (prepared by mixing trimethylsilyl chloride (TMSCl) and sodium iodide; in a suitable solvent such as ACN, THF, at a temperature of about 10-50 °C).

When a compound of formula R⁴-Y¹ is 2-chloro-6-fluoro-3-(2- methoxyethoxy)phenol is coupled with a compound of formula is achieved employing boron tribromide (BBr₃; in a suitable solvent such as DCM, THF, at a temperature of about 0-35 °C.

When a compound of formula R⁴-Y¹ is methyl 2-chloro-4-fluoro-3- hydroxybenzoate is coupled with a compound of formula (X) employing methods described previously; the carboxylate functional group is hydrolyzed to CO₂H employing aq. LiOH, in a suitable solvent such as MeOH/THF, at a temperature of about 50-80°C. Additionally, the CO₂H functional group is further transformed to aNH₂ group by the treatment with diphenylphosphoryl azide (DPPA) and an organic base such as TEA or DIPEA, in a suitable alcohol solvent such as t-BuOH at a temperature of 60- 100°C; followed by hydrolysis in an acidic solvent such as HCl/dioxane solution at a temperature of 20-30°C; the amino group is alkylated to provide the dimethylamino group (NMe₂) employing formaldehyde, an acid such as acetic acid and a reducing agent such as NaBH₃CN. in a suitable solvent such as MeOH or THF, at a temperature of about 0-50°C. In an alternate method, the amino group is also reacted with methane sulfonyl chloride to provide a compound where the amine is substituted with SO₂CH₃.

Alternatively, a compound of formula (XLII) is reacted a commercially available or synthetically accessible compound of formula R⁴-Y¹. where R⁴ is a suitably substituted aryl or five or six membered heteroaryl ring and Y¹ is OH, SH, or NH₂; under Ullman arylation conditions; employing a suitable catalyst such as Cul,

Cu(acac)₂, CuO, and the like; a suitable base such a K₃PO₄, Cs₂CO₃, t-BuOK and the like; with or without a suitable ligand such as picolinic acid, trans-N,N- dimethylcyclohexane- 1,2-diamine, dimethylglycine and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; at temperatures ranging from 80 °C to about 120 °C.

Deprotection of PG is achieved according to procedures known to one skilled in the art and employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999. For example, when PG is benzyl, deprotection is achieved employing Pd/C; under an H₂; in a suitable solvent such as EtOH, MeOH, EtOAc, or a mixture thereof, preferably EtOH; with or without the presence HCl, preferably 0.75 equiv for 4 to 72 hrs, to provide a compound of Formula (I). Additionally, when PG is benzyl, deprotection can be employed using trifluoroacetic acid as solvent; or by treatment with BCl₃; in a suitable solvent such as DCM, toluene, and the like; at reduced temperatures ranging from -78 °C to rt; for a period of about 1 to 4 hrs. Additionally, where PG is TBDPS, is deprotected employing conditions known to one skilled in the art, preferably with TBAF in a suitable solvent such as THF, and the like; to afford a compound of Formula (I).

SCHEME 12 According to SCHEME 12, a compound of formula (XLIII) (which includes compounds of formulas (XXI), and (XXIX)), where R⁵ is C_1-6alkyl or C_1-6haloalkyl, R⁷ is H or F, X³ is CH or N, and X⁴ is CH or N; is reacted a commercially available or synthetically accessible compound of formula R⁸-Z, where R⁸ is a suitably substituted aryl or five or six membered heteroaryl ring and Z is OH, SH, or NH₂; under nucleophilic substitution conditions, with a suitable base such a KOH, Cs₂CO₃, t-BuOK and the like; without or in a suitable solvent such as NMP, DMF, DMSO, and the like.

Alternatively, a compound of formula (XLIII) is reacted a commercially available or synthetically accessible compound of formula R⁸-Z, where R⁸ is a suitably substituted aryl or five or six membered heteroaryl ring and Z is OH, SH, or NH₂; under Ullman arylation conditions; employing a suitable catalyst such as Cul, Cu(acac)₂,

CuO, and the like; a suitable base such a K₃PO₄, Cs₂CO₃, t-BuOK and the like; with or without a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane- 1,2- diamine, dimethylglycine and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; at temperatures ranging from 80 °C to about 120 °C.

Deprotection of PG is achieved according to procedures known to one skilled in the art and employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999. For example, when PG is benzyl, deprotection is achieved employing Pd/C; under an H₂; in a suitable solvent such as EtOH, MeOH, EtOAc, or a mixture thereof, preferably EtOH; with or without the presence HCl, preferably 0.75 equiv for 4 to 72 hrs, to provide a compound of Formula (II). Additionally, when PG is benzyl, deprotection can be employed using trifluoroacetic acid as solvent. Additionally, where PG is TBDPS, is deprotected employing conditions known to one skilled in the art, preferably with TBAF in a suitable solvent such as THF, and the like; to afford a compound of Formula (II).

SCHEME 13

According to SCHEME 13, a compound of formula (XXVI), where R¹ is C₁-

₆alkyl or C_1-6haloalkyl and Y is O, is reacted with a commercially available or synthetically accessible primary or secondary amine, where the amine is substituted with one or two C_1-6alkyl or C_1-6haloalkyl members such as; under nucleophilic displacement conditions. For example, N-methylethanamine is reacted with a compound of formula (XXVI), employing a suitable base such a TEA or DIPEA and the like; in a suitable solvent such as DCM, THF, and the like at a temperature ranging from 0-30 to provide a compound of Formula (I), where R² is and R³ is H.

According to SCHEME 14, a compound of formula (XXXV) is reacted with a commercially available or synthetically accessible compound of formula R⁴-Y¹, where R⁴ is C_1-6alkyl optionally substituted with one or two substituents each independently selected from the group consisting of OH and OCH₃ C_3-6cycloalkyl substituted with C₁- 3alkyl; suitably substituted aryl; a five or six membered heteroaryl ring; or an optionally substituted six membered heterocycloalkyl; and Y¹ is OH, SH, or ME; under nucleophilic substitution conditions, with a suitable base such aNaH, KOH, Cs₂CO₃, t- BuOK, DBU, and the like; without or in a suitable solvent such as NMP, DMF, DMSO, dioxane, and the like; at temperatures ranging from 0 °C to 150 °C; employing conventional or microwave heating. A compound of formula (XLIV) is coupled with a commercially available or synthetically accessible compound of formula (VIII), where R^b is C_1-6alkyl substituted with O-PG, where PG is a suitable alcohol protecting group as previously described; under Ullman N-arylation conditions; with a suitable catalyst such as Cul, Cu(acac)₂, CuO, and the like; a suitable base such a K₃PO₄, Cs₂CO₃, t- BuOK and the like; with or without a suitable ligand such as picolinic acid, trans-N,N- dimethylcyclohexane- 1,2-diamine, dimethylglycine and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; at temperatures ranging from 80 °C to about 120 °C; to provide a compound of formula (XLV).

Deprotection of PG is achieved according to procedures known to one skilled in the art and employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999. For example, when PG is benzyl, deprotection is achieved employing Pd/C; under an H₂; in a suitable solvent such as EtOH, MeOH, EtOAc, or a mixture thereof, preferably EtOH; with or without the presence HCl, preferably 0.75 equiv for 4 to 72 hrs, to provide a compound of Formula (II). Additionally, when PG is benzyl, deprotection can be employed using trifluoroacetic acid as solvent. Additionally, where PG is TBDPS, is deprotected employing conditions known to one skilled in the art, preferably with TBAF in a suitable solvent such as THF, and the like; to afford a compound of Formula (I).

Compounds of Formula (I) (as well as compounds of Formula (II)) may be converted to their corresponding salts using methods known to one of ordinary skill in the art. For example, an amine of Formula (I) is treated with trifluoroacetic acid, HCl, or citric acid in a solvent such as Et₂O, CH₂Cl₂, THF, MeOH, chloroform, or isopropanol to provide the corresponding salt form. Alternately, trifluoroacetic acid or formic acid salts are obtained as a result of reverse phase HPLC purification conditions. Crystalline forms of pharmaceutically acceptable salts of compounds of Formula (I) may be obtained in crystalline form by recrystallization from polar solvents (including mixtures of polar solvents and aqueous mixtures of polar solvents) or from non-polar solvents (including mixtures of non-polar solvents).

Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

Compounds prepared according to the schemes described above may be obtained as single forms, such as single enantiomers, by form-specific synthesis, or by resolution. Compounds prepared according to the schemes above may alternately be obtained as mixtures of various forms, such as racemic (1:1) or non-racemic (not 1:1) mixtures. Where racemic and non-racemic mixtures of enantiomers are obtained, single enantiomers may be isolated using conventional separation methods known to one of ordinary skill in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation. Where regioisomeric or diastereomeric mixtures are obtained, as applicable, single isomers may be separated using conventional methods such as chromatography or crystallization.

The following specific examples are provided to further illustrate the invention and various preferred embodiments.

EXAMPLES

In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated. Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Where solutions were “dried,” they were generally dried over a drying agent such asNa₂SO₄ or MgSO₄. Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure.

Normal-phase silica gel chromatography (FCC) was performed on silica gel (SiO₂) using prepacked cartridges.

Preparative reverse-phase high performance liquid chromatography (RP HPLC) was performed on either:

METHOD A. A Gilson GX-281 semi-prep-HPLC with Phenomenex Synergi C18(10μm, 150 x 25mm), or Boston Green ODS C18 (5μm, 150 x 30mm) , and mobile phase of 5-99% ACN in water (with 0.225%FA) over 10 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min. or

METHOD B. A Gilson GX-281 semi-prep-HPLC with Phenomenex Synergi C18(10μm, 150 x 25mm) , or Boston Green ODS C18 (5μm, 150 x 30mm) , and mobile phase of 5-99% ACN in water(0.1%TFA) over 10 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min. or

METHOD C. A Gilson GX-281 semi-prep-HPLC with Phenomenex Synergi C18(10μm, 150 x 25mm), or Boston Green ODS C18 (5μm, 150 x 30mm) , and mobile phase of 5-99% ACN in water(0.05%HCl) over 10 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min. or METHOD D. a Gilson GX-281 semi-prep-HPLC with Phenomenex Gemini C18 (10μm, 150 x 25mm), AD(10μm, 250mm x 30mm), or Waters XBridge C18 column (5μm, 150 x 30mm), mobile phase of 0-99% ACN in water (with 0.05% ammonia hydroxide v/v) over 10 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min. or

METHOD E. a Gilson GX-281 semi-prep-HPLC with Phenomenex Gemini Cl 8 (10μm, 150 x 25mm), or Waters XBridge C18 column (5μm, 150 x 30mm), mobile phase of 5-99% ACN in water(10mM NH₄HCO₃) over 10 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min.

Preparative supercritical fluid high performance liquid chromatography (SFC) was performed either on a Thar 80 Prep-SFC system, or Waters 80Q Prep-SFC system from Waters. The ABPR was set to 100bar to keep the CO2 in SF conditions, and the flow rate may verify according to the compound characteristics, with a flow rate ranging from 50g/min to 70g/min. The column temperature was ambient temperature

Mass spectra (MS) were obtained on a SHIMADZU LCMS-2020 MSD or Agilent 1200\G6110A MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model AVIII 400 spectrometers. Definitions for multiplicity are as follows: s = singlet, d = doublet, t= triplet, q = quartet, m = multiplet, br = broad. It will be understood that for compounds comprising an exchangeable proton, said proton may or may not be visible on an NMR spectrum depending on the choice of solvent used for running the NMR spectrum and the concentration of the compound in the solution.

Chemical names were generated using ChemDraw Ultra 17.1 (Cambridge Soft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

Compounds designated as R* or S* are enantiopure compounds where the absolute configuration was not determined. Intermediate 1: 4-Chloro-2-methylpyridin-3-ol.

To a solution of 4-chloro-3-methoxy-2-methylpyridine (300 mg, 1.90 mmol) in dichloromethane (DCM) (2 mL) was added BBr₃ (1.43 g, 5.71 mmol, 550.26 μL) at - 78 °C under N₂. The mixture was stirred at 15 °C for 12 h. The reaction mixture was quenched by addition of MeOH (2 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. Purification (FCC, SiO₂, DCM/ MeOH; 100/1 to 10/1) afforded the title compound (270 mg, 1.88 mmol, 99% yield) as yellow solid. ¹H NMR (400 MHz, CD₃OD) δ = 8.17 (d, J= 6.4 Hz, 1H), 7.93 (d, J= 6.3 Hz, 1H), 2.69 (s, 3H).

Intermediate 2: 3.5-Dimethylisoxazol-4-ol. To a solution of (3,5-dimethylisoxazol-4-yl)boronic acid (300 mg, 2.13 mmol) in tetrahydrofuran (THF) (5 mL) and H₂O (5 mL) was added sodium perborate tetrahydrate (1.31 g, 8.51 mmol, 1.64 mL). The reaction mixture was stirred at 15 °C for 12 h. The reaction mixture was quenched by addition ofNa₂SO₃ (20 mL), and then diluted with 1N HCl (30 mL) and extracted with EtOAc (40 mL × 2). The combined organic layers were washed with brine (60 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, petroleum ether/ethyl acetate: 1/0 to 1/1) afforded the title compound (70 mg, 29.1% yield) as white solid. ¹H NMR (400 MHz, CDCl₃) δ = 2.31 (s, 3H), 2.21 (s, 3H). Intermediate 3: 1,3-Dimethyl-1H-pyrazol-4-ol.

To a stirred solution of l,3-dimethyl-1H-pyrazole-4-carbaldehyde (0.3 g, 2.42 mmol) in CHCl₃ (8 mL) was added meta-chloroperoxybenzoic acid (m-CPBA) (1.47 g, 7.25 mmol, 85% purity) at 16 °C, and the resulting mixture was stirred at 16 °C for 15 hrs. The reaction mixture was poured into sat.Na₂SO₃ (40 mL) and extracted with DCM (40 mL x 2). The combined organic phase was washed with brine (50 mL × 2), dried with anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give 1,3- dimethyl- 1H-pyrazol-4-yl formate. 1,3-Dimethyl- 1H-pyrazol-4-yl formate was used crude in the next step without further purification. To a solution of 0.5N NaOH aq. solution: MeOH (3 mL, 1: 1) was added 1, 3-dimethyl- 1H-pyrazol-4-yl formate and the reaction mixture was stirred at 16 °C for 1 hr. The reaction mixture was concentrated under reduced pressure. Purification (prep-TLC SiO₂, dichloromethane: methanol= 10:1) afforded 130 mg impure product, which was re-purified by prep-HPLC

(METHOD A) to give the title compound (55 mg, 20.3%) as a white solid. MS (ESI): mass calcd for C₅H₈N₂O, 112.1; m/z found, 113.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ = 8.03 (s, 1H), 7.04 (s, 1H), 3.59 (s, 3H), 1.98 (s, 3H). Intermediate 4: 2-Chloro-6-fluoro-3-(2-methoxyethoxy)phenol. Step A. 2-Chloro-4-fluoro- 1 -(2-methoxyethoxy)benzene. To a solution of 2-chloro-4- fluoro-phenol (5 g, 34.12 mmol) and 1-bromo-2-methoxy-ethane (5.69 g, 40.94 mmol, 3.85 mL) in MeCN (100 mL) was added K₂CO₃ (9.43 g, 68.24 mmol). The reaction mixture was stirred at 80 °C for 12 hrs. The reaction mixture was cooled and diluted with H₂O (50 mL), and then diluted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, Petroleum ether/Ethyl acetate=1/0 to 20/1) afforded the title compound (6.9 g, 98%) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ = 7.14 - 7.12 (m, 1H), 6.93 - 6.91 (m, 2H), 4.15 (t, J= 4.8 Hz,

2H), 3.78 (t, J= 4.8 Hz, 2H), 3.18 (s, 3H).

Step B, 2-Chloro-6-fluoro-3-(2-methoxyethoxy)benzaldehyde. To a solution of 2- chloro-4-fluoro-1-(2-methoxyethoxy)benzene (2 g, 9.70 mmol) in THF (20 mL) was added n-BuLi (2.5 M in hexane, 4.65 mL) slowly at -78°C. The reaction mixture was stirred at -78°C for 1 hr, and then DMF (1.06 g, 14.54 mmol, 1.12 mL) was added to the mixture. The reaction mixture was stirred at -78 °C for 1 hr, then warmed to 10 °C for 2 hrs, and then stirred at 15°C for 12 hrs. The reaction mixture was poured into HCl (0.5 N, 50 mL), and then extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, Petroleum ether/Ethyl acetate = 80/1 to 10/1) afforded the title compound (1.9 g, 83%) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ = 10.47 (s, 1H), 7.21 - 7.17 (m, 1H), 7.05 (t, J = 9.2 Hz, 1H), 4.19 (t, J= 8.4 Hz, 2H), 3.81 (t, J= 4.8 Hz, 2H), 3.48 (s, 3H).

Step C. 2-Chloro-6-fluoro-3-(2-methoxyethoxy)phenyl formate.

To a solution of 2-chloro-6-fluoro-3-(2-methoxyethoxy)benzaldehyde (1.9 g, 8.08 mmol) in DCM (30 mL) was added m-CPBA (3.28 g, 16.17 mmol, 85% purity) at 0 °C. The reaction mixture was stirred at 40 °C for 16 hrs. The reaction mixture was then quenched by sat. aq. NaHCO₃ (40 mL) at room temperature, and then extracted with EtOAc (50 mL × 6). The combined organic layers were washed with sat. aq. Na2S03 (50 mL x 2) and brine (50 mL × 2), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound (2.1 g) without further purification.

Step D. 2-Chloro-6-fluoro-3-(2-methoxyethoxy)phenol. 2-Chloro-6-fluoro-3-(2- methoxyethoxy)phenyl formate (2.1 g) was dissolved in MeOH (30 mL). Then aq.

NaOH (0.5 M, 40.42 mL) was added. The mixture was stirred at 15°C for 16 hrs. The reaction mixture was adjusted to pH to 1 with HCl (1 N), and then diluted with H₂O (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. Purification (column chromatography (SiO₂, Petroleum ether/Ethyl acetate = 20/1 to 10/1), following by reversed-phase HPLC (0.1% FA condition) afforded the title compound (1.05 g, 57% yield,) as white solid. ¹H NMR (400 MHz, CDCl₃) δ = 6.96 (t, J= 9.6 Hz, 1H), 6.48 - 6.45 (m, 1H), 5.57 (m, 1H), 4.15 (t, J= 4.8 Hz, 2H), 3.80 (t, J= 4.8 Hz, 2H), 3.46 (s, 3H).

Intermediate 5: 3 -Chloro-1 -methyl- 1H-pyrazol-4-ol.

Step A. 3-Chloro-1-methyl-1H-pyrazole-4-carbaldehyde. To stirred dry DMF (4.47 g, 61.16 mmol, 4.71 mL) at -15 °C was added dropwise POCl₃ (21.88 g, 142.71 mmol, 13.26 mL). 1-Methylpyrazol-3-ol (2.0 g, 20.39 mmol) was then added, and the solution was stirred at 90 °C for 12 hrs. After cooling to room temperature, the reaction was quenched with H₂O (80 ml), and the mixture was basified with 1 N NaOH solution to pH 8. The phases were separated, and the aqueous layer was further extracted with CH₂Cl₂ (8 × 60 mL). The organic layers were combined, dried over NaSO₄, and filtered, and the solvents were removed under reduced pressure. Purification (column chromatography (SiO₂, Petroleum ether/Ethyl acetate = 2/1) afforded the title compound (740 mg, 25%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ = 9.83 (s, 1H), 7.87 (s, 1H), 3.92 (s, 3H).

Step B, 3-Chloro-1-methyl-1H-t)yrazol-4-ol. To a solution of 3 -chloro-1 -methyl - pyrazole-4-carbaldehyde (500 mg, 3.46 mmol) in DCM (5 mL) was added m-CPBA (1.40 g, 6.92 mmol, 85% purity) at 0 °C. Then the reaction mixture was warmed to 25 °C and stirred for 12 hrs. The reaction mixture was quenched with sat. aq. Na₂SO₃ (3 mL), filtered and the solvent was removed under reduced pressure and used crude in the next step. Then MeOH (10 mL) and TEA (2.18 g, 21.55 mmol, 3 mL) were added to the reaction mixture and the reaction mixture was stirred at 25 °C for 2 h. The solvent was removed under reduced pressure. Purification (column chromatography, SiO₂, Petroleum ether/Ethyl acetate = 3/1 to 1/1) afforded the title compound (330 mg, 72%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ = 7.07 (s, 1H), 4.34 (br s, 1H), 3.78 (s, 3H).

Intermediate 6: 3.6-Dichloropyridin-2(1H)-one.

To a solution of 2,3,6-trichloropyridine (1 g, 5.48 mmol) in DMSO (4 mL) was added NaOH (600 mg, 15.00 mmol) in H₂O (4 mL). The mixture was stirred at 110 °C for 1 h. The reaction was cooled down and HCl (I N) was added to adjust pH = 7 and filtered. The filter cake was purified by prep-HPLC (METHOD A) to give the title compound (300 mg, 34% yield) as a white solid. MS (ESI): mass calcd. Lor C₅H₃Cl₂NO, 163.0; m/z found, 164.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 7.62 (d, J= 8.0 Hz, 1H), 6.58 (d, J= 8.0 Hz, 1H). Intermediate 7: 3-Chloro-2-methoxy-5-methylpyridin-4-ol.

Step A. 2-Chloro-4-methoxy-5-methylpyridine To a solution of 2,4-dichloro-5-methyl- pyridine (13 g, 80.24 mmol) in MeOH (195 mL) was added NaOH (3.59 g, 89.87 mmol) under N₂. The mixture was stirred at 70 °C for 24 hours. The mixture was cooled down and concentrated in vacuum. Purification (silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate = 100/1 to 50/1) afforded the title compound (11 g, 87% ) as white solid. MS (ESI): mass calcd. for C₇H₈CINO, 157.0; m/z found, 158.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 7.99 (s, 1H), 6.74 (s, 1H), 3.87 (s, 3H), 2.17 - 2.07 (m, 3H).

Step B, 2-Chloro-5-methylpyridin-4-ol. To a mixture of 2-chloro-4-methoxy-5- methylpyridine (3 g, 19.04 mmol) in 1,2-dichloroethane (DCE) (30 mL) was added BBr₃ (28.61 g, 114.22 mmol, 11.01 mL) in one portion at 0 °C under N₂. The mixture was stirred at 80 °C for 12 hours. The mixture was cooled down and quenched with MeOH (250 mL) and basified with K₂CO₃ to pH = 8, then filtered and concentrated in vacuum. Purification (silica gel chromatography (1000 mesh silica gel, dichloromethane : methanol=50/1 to 10/1) afforded the title compound (2.4 g, 86%) as white solid. MS (ESI): mass calcd. for C₆H₅ClNO, 143.0; m/z found, 144.2 [M+H]⁺. Step C. 2.3-Dichloro-5-methylpyridin-4-ol. To a mixture of 2-chloro-5-methylpyridin- 4-ol (1 g, 6.97 mmol) in MeCN (12 mL) was added N-chlorosuccinimide (NCS)

(930.09 mg, 6.97 mmol) in one portion under N₂. The mixture was stirred at 75 °C for 1 hours. The mixture was cooled down and filtered and concentrated in vacuum. Purification (reverse-phase flash (0.1% TEA) afforded the title compound (400 mg,

32%) as white solid. MS (ESI): mass calcd. for C₆H₅ClNO, 176.9; m/z found, 178.0 [M+H]⁺. Step D. 3-Chloro-2-methoxy-5-methylpyridin-4-ol. To a mixture of 2,3-dichloro-5- methylpyridin-4-ol (300 mg, 1.69 mmol) in N-methyl-2-pyrrolidone (NMP) (10 mL) was added CH₃ONa (1.82 g, 33.70 mmol) in one portion under N₂. The reaction mixture was heated to 180 °C and stirred for 12 hours. The reaction mixture was cooled down and poured into water (40 mL). To the resulting mixture was added

AcOH to adjust pH = 7. The aqueous phase was extracted with ethyl acetate (20 mL × 4). The combined organic phase was washed with brine (15 mL × 2), dried with anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resulting product was purified by prep-TLC (Petroleum ether/ethyl acetate=3/l) to give the title compound (240 mg, 80%) as white solid. MS (ESI): mass calcd. for C₇H₈CINO₂, 173.0; m/z found, 174.0 [M+H]⁺.

Intermediate 8: 3-Chloro-2-methoxynyridin-4-ol. Step A, 4-(Benzyloxy)-2.3-dichloropyridine. To a solution ofNaH (876.94 mg, 21.93 mmol, 60% purity) in DMF (20 mL) was dropwise added benzyl alcohol (BnOH) (1.19 g, 10.96 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. 2,3,4- Trichloropyridine (2 g, 10.96 mmol) was added to the reaction mixture and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water (100 mL), then the mixture was filtered and extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with brine (200 mL × 4), dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, petroleum ether: ethyl acetate = 100: 1 to 10: 1) afforded the title compound (1.5 g, 53%) as a white solid. MS (ESI): mass calcd. for C₁₂H₉Cl₂NO, 253.0; m/z found, 254.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.15-8.14 (d, J= 5.6 Hz, 1H), 7.45-7.27 (m = 13.6 Hz, 5H), 6.86-6.84 (d, J= 1.5 Hz, 1H), 5.27 (s, 1H). Step B. 4-(Benzyloxy)-3-chloro-2-methoxypyridine. To a mixture of 4-(benzyloxy)- 2,3-dichloropyridine (1.4 g, 5.51 mmol) in toluene (20 mL) was added Cul (209.85 mg, 1.10 mmol), N,N,N',N'-tetramethylmethanediamine (506.64 mg, 4.96 mmol) and sodium methoxide (NaOMe) (595.27 mg, 11.02 mmol). The reaction mixture was purged with nitrogen for three times and then heated at 100 °C for 12 hours. The reaction mixture was cooled down and diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. Purification (prep-HPLC (0.1% FA condition) afforded the title compound (800 mg, 58% ) as a brown solid. MS (ESI): mass calcd. for C₁₃H₁₂CINO₂, 249.0; m/z found,

249.8 [M+H]⁺.

Step C. 3-Chloro-2-methoxypyridin-4-ol. To a solution of 4-(benzyloxy)-3-chloro-2- methoxypyridine (400 mg, 1.60 mmol) in DCM (5 mL) was added BCl₃ (1 M in DCM, 4.81 mL). The reaction mixture was stirred at -78 °C for 1 hr. The reaction mixture was warmed up to room temperature and quenched by addition H₂O (5 mL), and then the mixture was partitioned between DCM and water. The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. Purification (prep-TLC (SiO₂, DCM: MeOH = 11: 1)) afforded title compound (105 mg, 41% yield) as a yellow solid. MS (ESI): mass calcd. for C₆H₅CINO₂, 159.0; m/z found, 160.0 [M+H]⁺.

Intermediate 9: 5-Chloro-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-r)yrazol-4- ol. Step A: 5-Chloro-3-methyl-1H-pyrazole-4-carbaldehyde. POCl₃ (62.52 g, 407.73 mmol, 37.89 mL) was added to DMF (14.90 g, 203.87 mmol, 15.69 mL) dropwise at - 15 °C. 3 -Methyl- 1,4-dihydropyrazol-5 -one (5.0 g, 50.97 mmol) was added to the reaction mixture. The resulting reaction mixture was heated to 80 °C and stirred for 12 hrs. The reaction mixture was cooled to 25 °C and poured into ice-H₂O (300 ml). Then the mixture was adjusted pH = 8 by 2 N NaOH solution. The aqueous layer was extracted with ethyl acetate (80 ml × 6). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, petroleum ether/ethyl acetate=3/l) afforded the title compound (1.5 g,

20%) as a yellow solid. MS (ESI): mass calcd. for C₅H₅ClN₂O, 144.01, m/z found, 145.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl3) δ = 12.51 (s, 1H), 9.94 (s, 1H), 2.68 (s, 3H).

Step B : 5-Chloro-3-methyl- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazolc-4- carbaldehyde. To a suspension ofNaH (719.36 mg, 17.99 mmol, 60% purity) in THF (13 mL) was added a solution of 5-chloro-3-methyl-1H-pyrazole-4-carbaldehyde (1.3 g, 8.99 mmol) in THF (13 mL) at 0 °C. The resulting suspension was stirred at 25 °C for 1 h. 2-(Trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (2.25 g, 13.49 mmol, 2.39 mL) was added to this reaction mixture at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 2 hrs. The mixture was poured into H₂O ( 200 mL) and the aqueous layer was extracted with ethyl acetate (50 ml × 4). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Purification (FCC, SiO₂, petroleum ether/ethyl acetate =10/1) afforded the title compound (2.0 g, 78%) as a light yellow oil. MS (ESI): mass calcd. for C₁₁H₁₉ClN₂O₂Si, 274.0, m/z found, 275.1 [M+H]⁺.

Step C: 5-Chloro-3-methyl- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-4-ol. To a solution of 5-chloro-3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-4- carbaldehyde (2.0 g, 7.28 mmol) in DCM (20 mL) was added m-CPBA (2.95 g, 14.56 mmol, 85% purity) at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 12 hrs. The reaction mixture was diluted with DCM (20 ml) and washed with Na₂SO₃ (10 mL×2. sat. aq.). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure and used crude in the next step. The resulting residue was re- dissolved with MeOH (10 mL). TEA (7.27 g, 71.85 mmol, 10.00 mL) was added. The resulting reaction mixture was stirred at 25 °C for 2 hrs. The solvent was removed under reduced pressure. Purification (FCC, SiO₂, petroleum ether/ethyl acetate = 10/1) afforded the title compound (710 mg, 36%) as a light yellow oil. MS (ESI): mass calcd. for C₁₀H₁₉ClN₂O₂Si, 262.0, m/z found, 262.8 [M+H]⁺.

Intermediate 10: 3-Chloro-2.5-dimethyk)yridin-4-ol. Step A, 2.5-Dimethylpyridin-4-ol. A mixture of 2-chloro-5-methylpyridin-4-ol (1 g, 6.97 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.27 g, 9.05 mmol), K₂CO₃ (2.89 g, 20.90 mmol), 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (Pd(dppf)Cl₂) (509.65 mg, 696.52 μmol) in dioxane (20 mL) and H₂O (2 mL) was degassed and purged with N₂ for 3 times. The mixture was stirred at 120 °C for 12 hrs under N₂ atmosphere. The reaction mixture was cooled down and filtered and washed with ethyl acetate (100 mL) and MeOH (20 mL). The filtrate was concentrated under reduced pressure. Purification (FCC, SiO₂, DCM\MeOH = 50/1 to 5/1) afforded crude product (0.9 g). The crude product (0.9 g) was purified by prep-HPLC (METHOD A) to give the title compound (0.6 g, 67%) as a white solid. MS (ESI): mass calcd. for C₇H₉NO, 123.0; m/z found, 124.1[M+H]⁺. Step B. 3-Chloro-2.5-dimethylpyridin-4-ol. To a solution of 2,5-dimethylpyridin-4-ol (0.55 g, 4.47 mmol) in MeCN (5.5 mL) was added NCS (715.63 mg, 5.36 mmol). The reaction mixture was stirred at 75 °C for 12 hr. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO₂, DCM/MeOH = 30/1 to 20/1) afforded the title compound (0.38 g, 52%) as yellow solid. MS (ESI): mass calcd. for C₇H₈ClNO, 157.0; m/z found, 157.9 [M+H]⁺.

Intermediate 11: 3-Chloro-6-methoxypyridin-2( 1H)-one. Step A, 5-Chloro-2-methoxyt)yridine 1-oxide. To a solution of 5-chloro-2-methoxy- pyridine (2 g, 13.93 mmol) in DCM (30 mL) was added m-CPBA (12.02 g, 55.72 mmol). The reaction mixture was stirred at 20 °C for 16 hr. The mixture was concentrated and under reduced pressure and purified (FCC, SiO₂, DCM: MeOH =0/1 to 10 /l) to give the title compound (1.4 g, 58%) as a white solid. MS (ESI): mass calcd. for C₆H₆CINO₂, 159.01; m/z found, 160.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.36 (d, J= 2.4 Hz, 1H), 7.31 (dd, J= 4.8 Hz, 2.4 Hz, 1H), 6.85 (d, J= 4.8 Hz, 1H), 4.08 (s, 3H).

Step B, 3-Chloro-6-methoxynyridin-2( I H)-one. To a solution of 5-chloro-2-methoxy-1- oxido-pyridin-1-ium (1.3 g, 7.50 mmol) in THF (30 mL) was added triethylamine (TEA) (3.79 g, 37.48 mmol, 5.22 mL) and trifluoroacetic anhydride (TFAA) (2.05 g, 9.74 mmol, 1.36 mL) at 0-10 °C. The reaction mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO₂, petroleum ether/ethyl acetate=10/l to 0/1) and then trituration with a mixture of petroleum ether/ethyl acetate (5 mL/1 mL) afforded the title compound (380 mg, 31%) as a yellow solid. MS (ESI): mass calcd. for C₆H₆CINO₂, 159.01; m/z found, 160.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 7.55 (d, J= 8.0 Hz, 1H), 5.65 (d, J= 8.4 Hz, 1H), 3.87 (s, 3H).

Intermediate 12: l-(Benzyloxy)-3-methoxypropan-2-ol.

To a solution of 2-((benzyloxy)methyl)oxirane (10 g, 60.90 mmol) in MeOH (10 mL) was added solution ofNaOMe (2.4 g, 44.42 mmol) in MeOH (10 mL). The reaction mixture was stirred at 50 °C for 1.5 hr. The reaction mixture was cooled down and quenched by addition NaHC03 at 0 °C adjust pH to 7-9, and then diluted with H₂O (10 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification (FCC, petroleum ether/Ethyl acetate=20: 1 to 2: 1) afforded the title compound (9.32 g, 45.12 mmol) as yellow oil. MS (ESI): mass calcd. for C₁₁H₁₆O₃, 196.1; m/z found, 197.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 7.27 (s, 5H), 4.49 (s, 2H), 3.97 - 3.88 (m, 1H), 3.51 - 3.34 (m, 4H), 3.33 - 3.29 (m, 3H),

2.52 (d, J= 4.3 Hz, 1H).

Intermediate 13, 2-Methoxy-3.5-dimethylt)yridin-4-ol. NaNO₂ (759 mg, 11.00 mmol) was slowly added into the solution of 2-methoxy-3,5- dimethylpyridin-4-amine (1.4 g, 9.17 mmol) in H₂SO₄/H₂O (v/v, 3/1, 15 mL) at ice- water bath to keep the temperature below 5 °C. After addition is complete, the reaction mixture was stirred at 0 °C for 1 hour. The mixture was diluted by ethyl acetate (20 mL) and sat. aq. Na₂CO₃ (15 mL). The mixture was separated and the organic layer was washed by brine (10 mL), dried byNa₂SO₄, filtered and evaporated. Purification (FCC, SiO₂, gradient elution: 0 - 100% ethyl acetate in petroleum ether) afforded the title compound (1.2 g, 7.83 mmol, 85.45% yield) as light yellow solid. MS (ESI): mass calcd. for C₈H₁₁NO₂, 153.1; m/z found, 153.8 [M+H]⁺.

Intermediate 14: 6-Chloro-5-fluoro-8-((1,1,1-trifluoropropan-2-yl)oxy)-2.7- naphthyridin- 1 (2H1 -one . Step A. 4-Bromo-2.6-dichloro-5-fluoronicotinic acid. Diisopropylamine (1.47 mL. 10.5 mmol) in THF (10 mL) was treated with n-BuLi (3.81 mL, 2.5 M, 9.52 mmol) at -78°C for 10 min. 2,6-Dichloro-5-fluoronicotinic acid (1.0 g, 4.76 mmol) in THF (5 mL) was dropwise added into the reaction and stirring was kept for another 30 min. 1,2-dibromo- 1,1,2,2-tetrachloroethane (3.1 g, 9.52 mmol) in THF (5 mL) was dropwise added into the reaction at -78 °C and stirring was kept for another 2 hours. The reaction was then warmed to room temperature and quenched with IN HCl. The reaction mixture was then partitioned between citric acid solution and DCM/MeOH (10: 1) solution. The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated to give crude product. It was then purified by flash system using silica gel at 5: 1 DCM: MeOH to give the title product as an off-yellow solid (650 mg, 47.2%). MS (ESI): mass calcd. for C₆HBrCl₂FNO₂: m/z found, 288.9; m/z found, 289.8 [M+H]⁺.

Step B, 4-Bromo-N-(tert-butyl)-2.6-dichloro-5-fluoronicotinamide. 4-Bromo-2.6- dichloro-5-fluoronicotinic acid (300 mg, 1.04 mmol) was treated with thionyl chloride (2 mL) at 70 °C for 2 hours. The solvent was cooled down and removed in vacuum. The residue was re-dissolved in DCM (5 mL) was treated with triethylamine (0.3 mL, 2.08 mmol) followed by t-butylamine (0.13 mL, 1.25 mmol) at 0 °C. The reaction was slowly warmed to room temperature over 2 hours. The solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated to give crude product. It was then purified by flash system using silica gel at 10-60% ethyl acetate in heptanes to give the title product as an off- white foam (310 mg, 87%). MS (ESI): mass calcd. for C₁₀H₁₀BrCl₂FN₂O: m/z found, 344.0; m/z found, 345.2 [M+H]⁺.

Step C. (E)-N-(tert -Butyl)-2.6-dichloro-4-(2-ethoxyv inyl)-5-fluoronicotinamide. 4- Bromo-N-(tert-butyl)-2,6-dichloro-5-fluoronicotinamide (200 mg, 0.58 mmol), Pd₂(dba)₃ (53 mg, 0.058 mmol), tricyclohexylphosphine (16 mg, 0.058 mmol), (E)-2- (2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (172 mg, 0.87 mmol), sodium carbonate (184 mg, 1.74 mmol) in dioxane (10 mL) and water (1 mL) were heated at 100 °C for 2 hours. The solution was cooled down and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated to give crude product. Purification (flash system using silica gel at 0-50% ethyl acetate in heptanes) afforded the title product as an off-yellow oil (160 mg, 84%). MS (ESI): mass calcd. for C₁₄H₁₇CI₂FN₂O₂; m/z found, 335.2; m/z found, 336.2 [M+H]⁺.

Step D. 6.8-Dichloro-5-fluoro-2.7-naphthyridin-1(2H)-one. (E)-N-(tert-Butyl)-2.6- dichloro-4-(2-ethoxyvinyl)-5-fluoronicotinamide (100 mg, 0.30 mmol) in DCM (2.5 mL) and TFA (2.5 mL) was heated at 60 °C in a seal tube overnight. The reaction was cooled down and the solvent was removed. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated to give crude product.

Purification (flash system using silica gel at 20-80% ethyl acetate in heptanes) afforded the title product as an off-white solid (50 mg, 72%). MS (ESI): mass calcd. for C₈H₃CI₂FN₂O; m/z found, 232.9; m/z found, 233.7 [M+H]⁺. Step E. 6-Chloro-5-fluoro-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)-2.7-naphthyridin- 1(2H)- one. To a solution of 1,1,1-trifluoropropan-2-ol (1.14 mL, 10.8 mmol) in DMF (10 mL) was added sodium hydride (60%, 430 mg, 10.8 mmol) portion wise at 0 °C in 10 min. After addition, the mixture was stirred for another 30 min. To the reaction mixture was added 6,8-dichloro-5-fluoro-2,7-naphthyridin-1(2H)-one (1.21 g, 5.2 mmol) in DMF (5 mL) at 0 °C. The reaction was then warmed to room temperature over 2 hours. The reaction solution was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column on an Agilent purification system using 20-60% ethyl acetate in heptanes to give the title product (1.05 g, 75.8%) as a white solid. MS (ESI): mass calcd. for C₁₁H₇ClF₄N₂O₂; m/z found, 310.6; m/z found, 311.5 [M+H]⁺.

Intermediate 15: 7-Chloro-8-fluoro-5-(( 1.1.1 -trifluoropropan-2-yl)oxy )pyridol 3,4-

Step A, 4.6-Dichloro-7-fluoro-1-hydroxyfuro[3.4-clpyridin-3( 1H)-one. To a mixture of diisopropylamine (13.01 g, 128.58 mmol) in THF (50 mL) was added n-BuLi (2.5 M in THF, 42.86 mL) dropwise at -78 °C under N₂. The mixture was stirred at -78 °C for 1 hr. And then to the mixture was added a mixture of 2,6-dichloro-5-fluoronicotinic acid (10 g, 47.62 mmol) in THF (25 mL) dropwise at -78 °C and the mixture was stirred at - 78 °C for 1 hr. DMF (19.00 g, 259.94 mmol) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 3 hrs. The mixture was warmed to room temperature and poured into water (200 mL) and adjusted to pH 4~5 with 1 N HCl. Then the mixture was extracted with ethyl acetate (150 mL × 2). The combined organic phase was washed with brine (150 mL × 2), dried with anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give title compound (11.64 g, 41.57 mmol, 87.30% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ = 8.82 (s, 1H), 6.85(s, 1H).

Step B, 5.7-Dichloro-8-fluoropyridor3.4-dlpyridazin-4-ol. To a solution of 4,6- dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridin-3(1H)-one (11.5 g, 41.07 mmol) and hydrazine sulfuric acid (13.36 g, 102.68 mmol) in H₂O (100 mL) was added sodium acetate (10.11 g, 123.21 mmol). The mixture was stirred at 105 °C for 1 hr. The mixture was cooled down and poured into water (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phase was washed with NaHCO₃ (500 mL, sat.) and brine (500 mL/2). dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Purification (re-crystallization from mixed solvent of petroleum ether/ethyl acetate(2/l, 100 mL) at 20 °C afforded title compound (9.26 g, 95.50%) as yellow solid. MS (ESI): mass calcd. for C₇H₂Cl₂FN₃O; m/z found, 232.9; m/z found, 233.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 13.31 (s, 1H), 8.50 (s, 1H).

Step C. 7-Chloro-8-fluoro-5-(( 1.1.1 -trifluoropropan-2-yl)oxy)pyrido|3.4-d|pyridazin-4- pL To amixture of 1,1,1-trifluoropropan-2-ol (1.5 g, 13.13 mmol) in DMF (10 mL) was added NaH (500 mg, 12.5 mmol, 60% purity) in one portion at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. The mixture was added to a solution of 5,7-dichloro-8- fluoropyrido[3,4-d]pyridazin-4-ol (1.46 g, 6.26 mmol) in DMF (5 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 hrs. The mixture was warmed up to room temperature and poured into IN HCl (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (200 mL × 2), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give title compound (2.07 g, 56%) as yellow solid. MS (ESI): mass calcd. for C₁₀H₅CIF₄N₃O₂; m/z found, 311.0; m/z found, 312.4 [M+H]⁺. Intermediate 16: (S)-7-Chloro-8-fluoro-5-(( 1.1.1 -trifluoropropan-2-yl)oxy)pyridol3.4- dlpvridazin-4-ol.

The title compound was prepared in a manner analogous to Intermediate 15, Step C; using (S)-1,1,1-trifluoropropan-2-ol and 5,7-dichloro-8-fluoropyrido[3,4-d]pyridazin-4- ol (Intermediate 15, product from Step B). MS (ESI): mass calcd. for C₁₀H₆CIF₄N₃O₂; m/z found, 311.0; m/z found, 312.4 [M+H]⁺.

Intermediate 17: 3-1 (Benzyloxy)methyl)- 1 -(4-chloro-8-fluoro-5 -((1.1.1 -trifluoropropan- 2-yl)oxy)pyridol3.4-dlpyridazin-7-yl)-4-ethyl-1H-1.2.4-triazol-5(4H)-one.

Step A, 3-((Benzyloxy)methyl)-4-ethyl-1-(8-fluoro-4-hydroxy-5-((1,1,1- trifluoropropan-2-yl)oxylpyrido 13.4-dlpyridazin-7 -yl)- 1H- 1.2.4-triazol-5(4H)-one . To a mixture of 7-chloro-8-fluoro-5-(( 1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4- d]pyridazin-4-ol (Intermediate 15, 1.7 g, 2.84 mmol) and 3-(benzyloxymethyl)-4-ethyl- 1H-1,2,4-triazol-5-one (1.99 g, 8.52 mmol) in dioxane (30 mL) was added Cs₂CO₃ (3.33 g, 10.22 mmol), KI (942.89 mg, 5.68 mmol), (1S,2S)-N1,N2 - dimethylcyclohexane- 1,2-diamine (646.35 mg, 4.54 mmol) followed by Cul (1.08 g, 5.68 mmol) under N₂. The mixture was stirred at 110 °C for 16 hours. And then the reaction was cooled down and was added 3-(benzyloxymethyl)-4-ethyl-1H- 1,2,4- triazol-5-one (1.99 g, 8.52 mmol), Cs₂CO₃ (3.33 g, 10.22 mmol), KI (942.89 mg, 5.68 mmol), (1S,2S)-N1,N2 -dimethylcyclohexane- 1,2-diamine (646.35 mg, 4.54 mmol) followed by Cul (1.08 g, 5.68 mmol) under N₂. The reaction mixture was stirred at 110 °C for another 16 hours. The mixture was cooled down and poured into water (150 mL). The aqueous phase was extracted with ethyl acetate (150 mL × 2). The combined organic phase was washed with brine (30 mL × 2), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Purification (silica gel chromatography, 1000 mesh silica gel, petroleum ether/Ethyl acetate=10/l to 1/1) afforded title compound (400 mg, 26%) as yellow solid. MS (ESI): mass calcd. for C₂₂H₂₀F₄N₆O₄; m/z found, 508.1; m/z found, 509.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 13.11 (s, 1H), 8.45 (s, 1H), 7.38-7.31(m, 5H), 5.88-5.84 (m, 1H), 4.61-4.59 (m, 4 H), 3.78-3.75(m, 2H), 1.53(d, J= 6.8 Hz, 3H), 1.53 (t, J= 7.2 Hz, 3H).

Step B, 3-((Benzyloxy)methyl)- 1 -(4-chloro-8-fluoro-5-(( 1.1.1 -trifluoropropan-2- yl)oxylpyrido 13.4-dlpyridazin-7 -yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-one . To a solution of 3 -((benzyloxy)methyl)-4-ethyl- 1 -(8-fluoro-4-hydroxy-5 -((1,1,1 -trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-1H-1,2,4-triazol-5(4H)-one (50 mg, 98.34 μmol) in POCl₃ (1 mL) was stirred at 90 °C for 1 h. The reaction mixture was cooled down, filtered and concentrated under reduced pressure. Toluene (20 mL) was added and the mixture was concentrated under reduced pressure, and then another batch of toluene (20 mL) was added and the mixture was concentrated under reduced pressure one more time. The title compound was obtained as a yellow oil (52 mg), which was used directly in next step. MS (ESI): mass calcd. for C₂₂H₁₉CIF₄N₆O₃; m/z found, 526.1; m/z found, 527.1 [M+H]⁺.

Intermediate 18: (S)-3-((Benzyloxy)methyl)- 1 -(4-chloro-8-fluoro-5-(( 1.1.1- trifluoropropan-2-yl)oxy)pyridor3.4-dlpyridazin-7-yl)-4-ethyl-1H-1.2.4-triazol-5(4H)- one.

Step A. (S)-3-((Benzyloxy)methyl)-4-ethyl- 1-(8-fluorc)-4-hydro\y-5-(( 1.1.1- trifluoropropan-2-yl)oxy)pyrido [ 3.4-d]pyridazin-7 -y l)- 1H- 1.2.4-triazol-5(4H)-one . The title compound was prepared in a manner analogous to Intermediate 17, Step A, using (S)-7-chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-4-ol (Intermediate 16). MS (ESI): mass calcd. for C₂₂H₂₀F₄N₆O₄; m/z found, 508.1; m/z found, 509.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 13.11 (s, 1H), 8.45 (s, 1H), 7.38-7.31 (m, 5H), 5.88-5.84 (m, 1H), 4.61-4.59 (m, 4 H), 3.78-3.75 (m, 2H), 1.53 (d, J = 6.8 Hz, 3H), 1.53 (t, J= 7.2 Hz, 3H). Step B, (S)-3-((Benzyloxy)methyl)- 1 -(4-chloro-8-fluoro-5-(( 1.1.1 -trifluoropropan-2- yl)oxy)pyridol3.4-dlpyridazin-7-yl)-4-ethyl-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Intermediate 17, Step B. MS (ESI): mass calcd. for C₂₂H₁₉CIF₄N₆O₃; m/z found, 526.1; m/z found, 527.1 [M+H]⁺. Intermediate 19: 5-((Benzyloxy)methyl)-2-(8-chloro-4-fluoro-1-((l.1, 1-trifluoropropan-

2-yl)oxy)-2.7-naphthyridin-3-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one. Step A. 6-(3-( (Benzyloxy)methyl)-4-ethyl-5 -oxo-4.5 -dihydro- 1H- 1.2.4-triazol- 1 -ylI-5 - fluoro-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)-2.7-naphthyridin- 1(2H)-one. The title compound was prepared in a manner analogous to Intermediate 17, Step A, using 6- chloro-5-fluoro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)-2,7-naphthyridin- l(2H)-one (Intermediate 14). MS (ESI): mass calcd. for C₂₃H₂₁F₄N₅O₄; m/z found, 507.5; m/z found, 508.5 [M+H]⁺.

Step B, 5-((Benzyloxy)methyl)-2-(8-chloro-4-fluoro- 1 -(( 1 , 1 , 1 -trifluoropropan-2- yl)oxyl-2.7-naphthyridin-3-yl)-4-ethyl-24-dihydro-3H-1.2.4-triazol-3-one. The title compound was prepared in a manner analogous to Intermediate 17, Step B. MS (ESI): mass calcd. for C₂₃H₂₀CIF₄N₅O₃; m/z found, 525.2; m/z found, 526.5 [M+H]⁺.

Intermediate 20: 5-((Benzyloxy)methyl)-2-( 1 -chloro-8-(( 1.1.1 -trifluoropropan-2- yl)oxy) isoauinolin-6-ylI-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one. Step A, 6-Bromo-8-fluoro-3.4-dihydroisoquinolin-1 (2H)-one. To a solution of 5- bromo-7-fluoro-2,3-dihydro-1H-inden-1-one (2.12 g, 9.26 mmol) in dichloromethane (DCM) (20 mL) was slowly added methylsulfonic acid (MSA) (11 mL, 170 mmol, 27.5 mL) at 0 °C. After 5 min, sodium azide (1.20 g, 18.5 mmol) was added into the reaction in 3 portions and kept the reaction temperature at 0 °C for another 2 hours. 20% NaOH (40 mL) was slowly added into the reaction and then the reaction was warmed to room temperature and stirred for another 15 min. The reaction mixture was extracted with DCM (3x). The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate to give the product as an off-white solid (1.95 g, 86.3%). MS (ESI): mass calcd. for C₉H₇BrFNO, 242.9; m/z found, 244.0, 246.0 [M+H]⁺. Step B, 6-Bromo-8-(( 1,1,1-trifluoropropan-2-yl)oxy)-3.4-dihydroisoquinolin-1(2H)- one. To a solution of 1,1,1-trifluoropropan-2-ol (1.14 mL, 12.3 mmol) in DMF (30 mL) was added sodium hydride (60%, 490 mg, 12.3 mmol) portion wise at 0 °C in 10 min. After addition, the mixture was stirred for another 30 min. To the reaction mixture was added 6-bromo-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one (1.0 g, 4.1 mmol) in N,N-dimethylmethanamide (DMF) (5 mL) at 0 °C. The reaction was then warmed to room temperature over 2 hours. The reaction solution was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column on an Agilent purification system using 20-60% ethyl acetate in heptanes to give the title product (1.05 g, 75.8%) as a white solid. MS (ESI): mass calcd. for C₁₂H₁₁BrF₃NO₂, 336.9; m/z found, 338.0, 340.0 [M+H]⁺.

Step C. 6-Bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)isoauinolin-1(2H)-one. 6- Bromo-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)-3 ,4-dihydroisoquinolin- 1 (2H)-one (300 mg, 0.89 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (241 mg, 1.07 mmol) in dioxane (5 mL) were heated at 120°C overnight. Extra DDQ (200 mg) was added and the reaction was heated at 120 °C for another 4 hours. The reaction was cooled down and the solvent was removed under vacuum. The residue was partitioned between ethyl acetate and IN NaOH solution. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was then concentrated and purified by silica gel cartridge on an Agilent purification system using 0-60% ethyl acetate/heptanes to give the title compound (135 mg, 45.3%) as a white solid. MS (ESI): mass calcd. for C₁₂H₉BrF₃NO₂, 334.9; m/z found, 336.0, 338.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 10.08 (s, 1H), 7.44 (d, J= 1.8 Hz, 1H), 7.17 (d, J= 1.6 Hz, 1H), 7.08 (d, J= 6.8 Hz, 1H), 6.38 (d, J= 7.1 Hz, 1H), 4.95 - 4.64 (m, 1H), 1.64 (d, J= 6.4 Hz, 3H).

Step D. 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1-yl)- 8-111 , 1 , 1 -trifluoropropan-2-yl)oxylisoquinolin- 1 (2H)-one . A mixture of 6-bromo-8- ((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one (70 mg, 0.21 mmol), 3- ((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (58 mg, 0.25 mmol), K₃PO₄ (79 mg, 0.37 mmol), KI (24 mg, 0.15 mmol), trans-N,N -dimethyl-cyclohexane- 1,2- diamine (0.02 mL, 0.12 mmol) and Cul (20 mg, 0.10 mmol) and in dioxane (5 mL) was degassed and purged with argon for (3x). The mixture was stirred at 100 °C overnight. The reaction mixture was filtered and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solution was then concentrated and purified by silica gel cartridge on an Agilent purification system using 0-100% ethyl acetate/heptanes to give the title compound (55 mg, 54%) as an off white solid. MS (ESI): mass calcd. for C₂₄H₂₃F₃N₄O₄, 488.5; m/z found, 489.2.1 [M+H]⁺.

Step E, 5-((Benzyloxy)methyl)-2-( 1-chloro-8-(( 1, 1, 1 -trifluoropropan-2-yl)oxy) isoqiiinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2,4-triazol-3-one. 6-(3- ((Benzyloxy)methyl)-4-ethyl-5 -oxo-4, 5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl)-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one (75 mg, 0.154 mmol) in POCl₃ ( 2mL) was refluxed for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturate sodium bicarbonate solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solution was then concentrated to give the crude title product as a clear oil (55 mg, 71%) without further purification. MS (ESI): mass calcd. for C₂₄H₂₂CIF₃N₄O₃, 506.9; m/z found, 507.2 [M+H]⁺.

Intermediate 21: (S)-3-((Benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1 , 1 , 1-trifluoropropan- 2- yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-one.

Step A. (S)-6-Bromo-8-(( 1, 1.1 -trifluoropropan-2-yl)oxy)-3.4-dihydroisoquinolin- 1 (2H)- one. To a mixture (2S)- 1.1. 1 -trifluoropropan-2-ol (490.74 mg, 4.30 mmol) in DMF (15 mL) was added NaH (183.54 mg, 4.59 mmol, 60% purity) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hours. Then 6-bromo-8-fluoro-3,4- dihydroisoquinolin- l(2H)-one (the product from Int. 20, step A) (0.7 g, 2.87 mmol) in DMF (8 mL) was added to the mixture and stirred at 0 °C for 2 h. The reaction mixture was stirred at 15 °C for 6 h. The mixture was poured into water (25 mL). The aqueous phase was extracted with ethyl acetate (25 mL X 2). The combined organic phase was washed with brine (10 mL X 2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. Purification silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate=10/l, 2/1) to give the title compound (850 mg, 87.7%) as white solid. MS (ESI): mass calcd. for C₁₂H₁₁BrF₃NO₂, 336.9; m/z found, 338.0, 340.0 [M+H]⁺.

Step B, (S)-6-Bromo-8-(( 1, 1.1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 (2H)-one. To a solution of (S)-6-bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)-3,4- dihydroisoquinolin- l(2H)-one (5 g, 14.79 mmol) in dioxane (160 mL) was added DDQ (10.07 g, 44.36 mmol) in one portion under N₂. The mixture was stirred at 130 °C for 24 hours.

Then additional DDQ (10.07 g, 44.36 mmol) was added and the mixture was stirred at 130 °C for another 24 hours. The mixture poured into IN NaOH (300 mL). The aqueous phase was extracted with ethyl acetate (300 mL X 2). The combined organic phase was washed with brine (100 mL X 2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. Purification (silica gel chromatography, 1000 mesh silica gel, petroleum ether/ethyl acetate=10/1, 1/1) afforded the title compound (2 g, 28.97% yield) as yellow solid. MS (ESI): mass calcd. for C₁₂H₉BrF₃NO₂, 334.9; m/z found, 336.0, 338.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 10.08 (s, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.17 (d, J= 1.6 Hz, 1H), 7.08 (d, J= 6.8 Hz, 1H), 6.38 (d, J= 7.1 Hz, 1H), 4.95 - 4.64 (m, 1H), 1.64 (d, J= 6.4 Hz, 3H).

Step C: (S)-6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1- yl)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 (2H)-one . To a mixture of (S)-6- bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin- l(2H)-one (2 g, 5.95 mmol) and 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (2.08 g, 8.93 mmol) in dioxane (150 mL) was added Cs₂CO₃ (3.49 g, 10.71 mmol), Cul (1.13 g, 5.95 mmol),

KI (987.8 mg, 6.0 mmol) and trans-N,N'-dimethylcyclohexane- 1,2-diamine (677.12 mg, 4.76 mmol) in one portion under N₂. The mixture was heated to 110 °C and stirred for 36 hours. The mixture was poured into water (60 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (30 mL x 2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum.

Purification (silica gel chromatography, 1000 mesh silica gel, petroleum ether/ethyl acetate=10/l, 1/1) afforded the title compound (1.2 g, 38.6% yield) as yellow solid.

MS (ESI): mass calcd. for C₂₄H₂₃F₃N₄O₄, 488.1; m/z found, 489.2 [M+H]⁺.

Step D. (S)-3-((Benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-one. A solution of (S)-6-(3- ((benzyloxy)methyl)-4-ethyl-5-oxo-4, 5-dihydro- 1H- 1,2, 4- triazol- l-yl)-8-(( 1,1,1 - trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one (300 mg, 411.50 μmol) in POCl₃ (8 mL) was heated to 110 °C for 2 hours. The mixture was concentrated in reduced pressure. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. Purification (silica gel chromatography, 1000 mesh silica gel, Petroleum ether/Ethyl acetate=10/l, 1/1) to give the title compound (190 mg, 86.5% yield) as yellow solid. MS (ESI): mass calcd. for C₂₄H₂₂CIF₃N₄O₃, 506.1; m/z found, 507.2 [M+H]⁺.

Intermediate 22: 3-((Benzyloxy)methyD-1-(1-chloro-8-isopropoxyisoquinolin-6-yl)-4- ethyl- 1H-1.2.4-triazol-5(4H)-one.

Step A. 6-Bromo-8-isopropoxy-3.4-dihydroisoauinolin- 1 (2H)-one. To a solution of iso- propanol (0.174 mL, 2.27 mmol) in DMF (5 mL) was added sodium hydride (60%, 90 mg, 2.27 mmol) portion wise, at 0 °C in 10 min. After the addition was complete, the mixture was stirred for another 30 min. To the reaction mixture was added 6-bromo-8- fluoro-3,4-dihydroisoquinolin-1(2H)-one (185 mg, 0.758 mmol) in 0.5 mL DMF at 0 °C. The reaction mixture was then warmed to room temperature over 2 hours. The reaction solution was partitioned between ethyl acetate and a saturated ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification (silica gel column on an Agilent purification system using 20-60% ethyl acetate in heptanes) afforded the title product (150 mg, 70%) as a white solid. MS (ESI): mass calcd. for C₁₂H₁₄BrNO₂, 283.0; m/z found, 284.3 [M+H]⁺.

Step B: 3-((Benzyloxy)methyl)-1-(1-chloro-8-isopropoxyisoquinolin-6-yl)-4-ethyl-1H-

1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Intermediate 20, Steps C-E; using 6-bromo-8-isopropoxy-3,4-dihydroisoquinolin- l(2H)-one instead of bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)-3,4- dihydroisoquinolin-1(2H)-one in Step E. MS (ESI): mass calcd. for C₂₄H₂₅CIN₄O₃, 452.9; m/z found, 453.7 [M+H]⁺. Intermediate 23: 3-((Benzyloxy)methyl)- 1 -(8-chloro- 1 -(( 1. 1.1 -trifluoropropan-2- yl)oxy)-2.7-naphthyridin-3-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-one. Step A. 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1 ,2.4-triazol- 1 -yl)-2- chloro-4-methylnicotinonitrile . To a solution of 5-((benzyloxy)methyl)-4-ethyl-2,4- dihydro-3H-1,2,4-triazol-3-one (500 mg, 2.14 mmol) in THF (5 mL) was added dropwise potassium hexamethyldisilane (KHMDS) (1.0 N, 2.4 mL, 2.36 mmol) at -78°C and the reaction was stirred for 30 min. 2,6-dichloro-4-methylnicotinonitrile (400 mg, 2.14 mmol) in tetrahydrofuran (THF) (1.5 mL) was dropwise added in the reaction and the reaction was stirred at -78 °C for another 1 hour. The reaction was slowly warmed to room temperature and quenched with saturated ammonium chloride solution. The solvent was evaporated under reduced pressure and the residue was partitioned with DCM and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification (silica gel column on Agilent purification system using 0-60% ethyl acetate in heptanes) afforded the title compound along with its regioisomer as a mixture (225 mg, 27%). MS (ESI): mass calcd. for C₁₉H₁₈CIN₅O₂, 383.1; m/z found, 384.5 [M+H]⁺.

Step B, 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1 ,2.4-triazol- 1 -yl)-4- methyl -2-1 ( 1, 1.1 -trifluoropropan-2-yl)oxy)nicotinonitri 1 e To a solution of 1 , 1 , 1 - trifluoropropan-2-ol (0.071 mL, 0.78 mmol) in THF (2 mL) was added sodium hydride (60%, 31 mg, 0.782 mmol) in several portions, at 0 °C in 10 min. After the addition of NaH was complete, the mixture was stirred for another 30 min. To the reaction mixture was added 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4, 5-dihydro- 1H-1, 2, 4- triazol-1-yl)-2-chloro-4-methylnicotinonitrile (250 mg, 0.65 mmol) in 2 mL THF at 0 °C. The reaction was then warmed to room temperature over 2 hours. The reaction solution was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification ( silica gel column on an Agilent purification system using 20-80% ethyl acetate in heptanes) afforded the title product (150 mg, 49.9%) as a yellow solid. MS (ESI): mass calcd. for C₂₂H₂₂F₃N₅O₃, 461.2; m/z found, 462.5 [M+H]⁺.

Step C. 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1-yl)-4- methyl-2-( (1.1.1 -trifluoropropan-2-yl)oxy)nicotinamide . To a solution of 6-(3- ((benzyloxy )methyl)-4-ethyl-5-oxo-4, 5-dihydro- 1H- 1 ,2,4-triazol- 1 -yl)-4-methyl-2- ((1,1,1-trifluoropropan-2-yl)oxy)nicotinonitrile (80 mg, 0.173 mmol) and K₂CO₃ (24 mg, 0.173 mmol) in ACN (5 mL) were added hydrogen peroxide (30%, 0.1 mL, 0.87 mmol) at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was partitioned between DCM and saturated sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification (silica gel column on an Agilent purification system using 20-100% ethyl acetate in heptanes) afforded the title product as an off yellow solid (55 mg, 66%). MS (ESI): mass calcd. for C₂₂H₂₄F₃N₅O₄, 479.2; m/z found, 480.4 [M+H]⁺.

Step D. 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1-yl)-N- ((dimethylamino)methylene)-4-methyl-2-((1,1,1-trifluoropropan-2-yl)oxy)nicotinamide. 6-(3 -((Benzyloxy)methyl)-4-ethyl-5-oxo-4,5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl)-4-methyl- 2-((1,1,1-trifluoropropan-2-yl)oxy)nicotinamide (100 mg, 0.21 mmol) in dioxane (5 mL) was treated with l,l-dimethoxy-N,N-dimethylmethanamine (0.12 mL, 1.04 mmol) at 80 °C for 2 hours. The solvent was removed under reduced pressure, and the residue was dried over vacuum without further purification (85 mg, 76%). MS (ESI): mass calcd. for C₂₅H₂₉F₃N₆O₄, 534.2; m/z found, 535.5 [M+H]⁺.

Step E, 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1.2.4-triazol- l-yl)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)-2.7 -naphthyridin- 1 ( 2H) -one . To a solution of 6-(3- ((benzyloxy )methyl)-4-ethyl-5-oxo-4, 5-dihydro- 1H- 1 ,2, 4-triazol- 1 -yl)-N- ((dimethylamino)methylene)-4-methyl-2-(( 1,1,1 -trifluoropropan-2-yl)oxy)nicotinamide

(100 mg, 0.187 mmol) in THF (3 mL) at room temperature was added t-BuOK (1.0 N, 0.35 mL, 0.347 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification (silica gel column on an Agilent purification system using 20-100% ethyl acetate in heptanes) afforded the title product as an off yellow solid (25 mg, 27%). MS (ESI): mass calcd. for C₂₃H₂₂F₃N₅O₄, 489.2; m/z found, 490.5 [M+H]⁺.

Step F: 3-((Benzyloxy)methyl)- 1 -(8-chloro- 1 -(( 1 , 1 , 1 -trifluoropropan-2-yl)oxy )-2.7- naphthyridin-3-yl)-4-ethyl-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Intermediate 20, Step C. MS (ESI): mass calcd. for C₂₃H₂₁CIF₃N₅O₃, 507.9; m/z found, 508.7 [M+H]⁺. Intermediate 24: 3-((Benzyloxy)methyl)- 1 -(4-chloro-5-(( 1, 1,1 -trifluoropropan-2- yl)oxy)pyrido[3.4-d]pyridazin-7-yl)-4-ethyl-1H-1.2.4-triazol-5(4H)-one. To a solution of 1.1.1 -trifluoropropan-2-ol (0.23 mL, 2.08 mmol) in DMF (2 mL) was added sodium hydride (60%, 17 mg, 0.42 mmol) in several portions at 0 °C in 10 min. After the addition of NaH was complete, the mixture was stirred for another 30 min.

To the reaction mixture was added 5,7-dichloropyrido[3,4-d]pyridazin-4(3H)-one (90 mg, 0.42 mmol) in DMF (1 mL) at 0 °C. The reaction was then warmed to room temperature over 2 hours. The reaction solution was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification (silica gel column on an Agilent purification system using 20-60% ethyl acetate in heptanes) afforded the title product (92 mg, 75.8%) as a white solid. MS (ESI): mass calcd. for C₁₀H₇CIF₃N₃O₂, 293.0; m/z found, 294.4 [M+H]⁺.

Step B, 7-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1 ,2.4-triazol- 1 -yl )-5 (( 1.1.1 -trifluoropropan-2-yl)oxy)p\Tidol 3.4-d|pyridazin-4(3H)-one. A solution of 7- chloro-5-((l, 1, l-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-4(3H)-one, 5- ((benzyloxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (159 mg, 0.68 mmol) and Cs₂CO₃ (221 mg, 0.68 mmol) in DMF (2 mL) was heated at 80 °C overnight. The reaction solution was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification (silica gel column on an Agilent purification system using 20-80% ethyl acetate in heptanes) afforded the title product (105 mg, 63%) as an off white solid. MS (ESI): mass calcd. for C₂₂H₂₁F₃N₆O₄, 490.2; m/z found, 491.5 [M+H]⁺.

Step C: 3-((Benzyloxy)methyl)-1-(4-chloro-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3.4-d]pyridazin-7-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Intermediate 20, Step E. MS (ESI): mass calcd. for C₂₂H₂₀CIF₃N₆O₃, 508.9; m/z found, 509.6 [M+H]⁺.

Intermediate 25 : ( S)-6-Bromo- 1 -chloro-8-(( 1,1.1 -trifluoropropan-2-yl)oxy)phthalazine .

Step A. Methyl (S)-4-bromo-2-((1,1,1-trifluoropropan-2-yDoxy Ibenzoate. To a solution of (S)-1,1,1-trifluoro-2 -propanol (54 μL, 1.28 g/mL, 0.6 mmol) in DMF (1.5 mL) at 0 °C was added NaH (60% dispersion in mineral oil) (26 mg, 0.66 mmol). The mixture was stirred for 10 min then methyl 4-bromo-2-fluorobenzoate (128 mg, 0.55 mmol) was added. The mixture was slowly warmed to room temperature, stirred for 15 minutes then quenched with water. The organics were extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was adsorbed onto silica and purified by column chromatography (0-5% EtO Ac/heptane) to provide the title compound as a colorless oil (85 mg, 47%). MS (ESI): mass calcd. for

C₁₁H₁₀BrF₃O₃, 327.1; m/z found, 327.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.71 (d, J= 8.3 Hz, 1H), 7.23-7.28 (m, 1H), 7.18 (s, 1H), 4.60-4.74 (m, 1H), 3.89 (s, 3H), 1.56 (d, J= 6.4 Hz, 3H).

Step B, (S)-4-Bromo-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoic acid. Methyl (S)-4- bromo-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoate (84 mg, 0.23 mmol) in dioxane (1.0 mL) and 1M NaOH (1.5 mL) was stirred at room temperature for 2 h. The mixture was diluted with water and EtOAc and acidified with IN HCl. The organics were extracted, washed with brine, dried over sodium sulfate, filtered and concentrated to provide the title compound as a white solid which was used without further purification. MS (ESI): mass calcd. for C₁₀H₈BrF₃O₃ 313.1; m/z found, 313.0 [M+H]⁺.

Step C. (S)-5-Bromo-7-((1,1,1-trifluoropropan-2-yl)oxylisobenzofuran-1(3H)-one. (S)- 4-Bromo-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoic acid (31 mg, 0.1 mmol), palladium acetate (2.2 mg, 0.01 mmol), potassium bicarbonate (25 mg, 0.25 mmol), and dibromomethane (0.4 mL, 6.0 mmol) were mixed together and heated to 140 °C for 60 h. The reaction mixture was cooled and then diluted with DCM and adsorbed onto silica. Purification by column chromatography (0-15% EtO Ac/heptane) provided the title compound as a colorless oil (19.3 mg, 59%). MS (ESI): mass calcd. for C₁₁H₈BrF₃O₃, 325.1; m/z found, 325.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.33 (s, 1H), 7.19-7.24 (m, 1H), 5.25 (s, 2H), 4.92-5.04 (m, 1H), 1.64 (d, J= 6.4 Hz, 3H).

Step D. (S)-3.5-Dibromo-7-((1,1,1-trifluoropropan-2-yl)oxy)isobenzofuran-1(3H)-one. A vial was charged with (S)-5-bromo-7-((1,1,1-trifluoropropan-2-yl)oxy)isobenzofuran- l(3H)-one (540 mg, 1.661 mmol), N-bromosuccinimide (NBS) (325 mg, 1.8 mmol), 2,2'-azobis(2-methylpropionitrile) (14 mg, 0.08 mmol) and 1,2-dichloroethane (DCE) (10.8 mL). The reaction was heated to 80 °C and stirred for 1.5 h. It was cooled down and then concentrated under reduced pressure to give the crude product, which was not purified further.

Step E, (S)-6-Bromo-8-(( 1, 1, 1 -trifluoropropan-2-yl)oxy)phthalazin- 1 (2H)-one. (Sl-3.5- Dibromo-7-((1,1,1-trifluoropropan-2-yl)oxy)isobenzofuran-1(3H)-one (670 mg, 1.6 mmol) was dissolved in EtOH (6.5 mL) and hydrazine hydrate (0.41 mL, 1.027 g/mL, 8.3 mmol) was added then heated to 80 °C for 5 h. The mixture was concentrated then taken up in EtO Ac and water. The organics were extracted with EtO Ac (2 x). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was adsorbed onto silica and purified by column chromatography (20-50% EtOAc/heptane) to provide the title compound (2 steps, 377 mg, 67%). MS (ESI): mass calcd. for C₁₁H₈Br N₂O₂, 337.1; m/z found, 337.0 [M+H]⁺. ¹H NMR 5 (400 MHz, CD₃OD) δ ppm: 8.15 (s, 1H), 7.77 (d, J= 1.5 Hz, 1H), 7.66 (s, 1H), 5.09-5.31 (m, 1H), 1.58 (d, J= 6.4 Hz, 3H).

Step F, (S)-6-Bromo- 1 -chloro-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)phthalazinc. (S)-6- Bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)phthalazin-1(2H)-one (73 mg, 0.22 mmol) was stirred in POCl₃ (1.46 mL, 1.65 g/mL, 15.7 mmol) at 100 °C for 2 h. The reaction was cooled down and then concentrated under reduced pressure and placed under vacuum overnight (~80 mg). The crude product was not purified further. MS (ESI): mass calcd. for C₁₁H₇BrClF₃N₂O, 353.5; m/z found, 354.7 [M+H]⁺.

Intermediate 26: 5-((Benzyloxy)methyl)-2-(4-chloro-5-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)-1.6-naphthyridin-7-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one.

The title compound was prepared in a manner analogous to Intermediate 24, Steps A-C, using 5,7-dichloro-1,6-naphthyridin-4(1H)-one instead of 5,7-dichloropyrido[3,4- d]pyridazin-4(3H)-one in Step A. MS (ESI): mass calcd. for C₂₃H₂₁CIF₃N₅O₃, 507.9; m/z found, 508.8 [M+H]⁺.

Intermediate 27 : 5-(((tert-Butyldiphenylsilyl)oxy)methyl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol-3-one.

Step A, 4-Ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1.2.4-triazol-3-one .

To a solution of 5-[(benzyloxy)methyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (intermediate 1) (4.0 g, 17.1 mmol) in methanol (200 mL) was added 10% Pd/C (3.65 g, 3.43 mmol). The resulting mixture was vigorously shaken in the atmosphere of hydrogen (45 psi) at rt for 20 h. Then the resulting mixture was filtered through a short pad of Celite and the filtrate was concentrated to afford the crude product 4-ethyl-5- (hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one as a white solid (2.4 g, 98%). MS (ESI): mass calcd. for C₅H₉N₃O₂, 143.2; m/z found, 144.4 [M+H]⁺.

Step B, 5-(((tert-Butyldiphenylsilyl)oxy)methyl)-4-ethyl-2.4-dihydro-3H- 1 ,2.4-triazol- 3 -one. To a solution of 4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2.4 g, 16.8 mmol) in DCM (50 mL) was added tert-butylchlorodiphenylsilane (6.9 g,

25.1 mmol) and imidazole (2.28 g, 33.5 mmol). The resulting mixture was stirred at rt for overnight. The reaction mixture was quenched with water (100 mL). The resulting mixture was extracted with DCM (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was then purified by a Agilent purification system using silica gel chromatography (50-100 % ethyl acetate / heptane) to afford the 5-(((tert- butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one as a white solid (4.9 g, 76 %). MS (ESI): mass calcd. for C₂₁H₂₇N₃O₂Si, 381.6; m/z found, 382.4 [M+H]⁺.

Intermediate 28: 3-Chloro-5-fluoro-2-methoxypyridin-4-ol.

A mixture of 5-fluoro-2-methoxypyridin-4-ol (650 mg, 4.54 mmol) and NCS (910 mg, 6.81 mmol) in MeCN (20 mL) was heated to 70 °C for 16 hours. The mixture was cooled down, concentrated and dissolved into the ethyl acetate (30 mL) and water (15 mL). The mixture was separated and the organic layer was washed by brine (15 mL), dried by Na₂SO₄, filtered and evaporated. The residue was purified by column chromatography (SiO₂, gradient elution: 0 - 100% ethyl acetate in petroleum ether) to give the title compound (280 mg, 34.4% yield) as yellow oil. MS (ESI): mass calcd. for C₆H₅CIFNO₂, 177.0; m/z found, 177.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 7.80 (d, J= 1.3 Hz,

1H), 6.10 (br s, 1H), 3.92 (s, 3H).

Intermediate 29 : 5-1 (Benzyloxy)methyl)-2-(4-chloro-8-fluoro-5 -isopropoxypyrido 13,4- dlpyridazin-7-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one.

Step A. 7-Chloro-8-fluoro-5-isopropoxYPYridol3.4-d|pyridazin-4(3H)-one. To a solution of iso-propanol (0.4 mL, 6.92 mmol) in DMF (2 mL) was added sodium hydride (60%, 56 mg, 1.4 mmol) in several portions at 0 °C in 10 min. After the addition of NaH was complete, the mixture was stirred for another 30 min. To the reaction mixture was added 5,7-dichloropyrido[3,4-d]pyridazin-4(3H)-one (300 mg, 1.4 mmol) in DMF (1 mL) at 0 °C. The reaction was then warmed to room temperature over 2 hours. The reaction solution was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification (silica gel column on an Agilent purification system using 20-60% ethyl acetate in heptanes) afforded the title product (288 mg, 81%) as a white solid. MS (ESI): mass calcd. for C₁₀H₉CIFN₃O₂, 257.7; m/z found, 258.6 [M+H]⁺.

Step B, 7-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1-yl)-8- fluoro-5 -isopropoxypyrido[3.4-d]pyridazin-4(3H)-one . 7-chloro-8-fluoro-5- isopropoxypyrido[3,4-d]pyridazin-4(3H)-one (200 mg, 0.78 mmol) and Cs₂CO₃ (253 mg, 0.78 mmol) in DMF (2 mL) was heated at 80 °C overnight. The reaction solution was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification (silica gel column on an Agilent purification system using 20-80% ethyl acetate in heptanes) afforded the title product (213 mg, 60%) as an off white solid. MS (ESI): mass calcd. for C₂₂H₂₃FN₆O₄, 454.5; m/z found, 455.5 [M+H]⁺. Step C: 5-((Benzyloxy)methyl)-2-(4-chloro-8-fluoro-5-isopropoxypyridol3.4- dlpyridazin-7-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one. The title compound was prepared in a manner analogous to Intermediate 20, Step E. MS (ESI): mass calcd. for C₂₂H₂₂CIFN₆O₃, 472.9; m/z found, 473.6 [M+H]⁺. Example 1: 2-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one.

Step A. 5-((Benzyloxy)methyl)-2-(1-(2-chloro-6-fluorophenoxy)-8-(( 1 , 1, 1- trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one. 5 -((Benzyloxy)methyl)-2-( 1 -chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6- yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20, 60 mg, 0.118 mmol), 2-chloro-6-fluorophenol (173 mg, 1.18 mmol) and KOH (26.6 mg, 0.47 mmol) in a seal tube were heated to 110 °C for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturate ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solution was then concentrated and purified by silica gel cartridge on an Agilent purification system using 0-60% ethyl acetate/heptanes to give the title compound (48 mg, 66%) as an off white solid. MS (ESI): mass calcd. for C₃₀H₂₅CIF₄N₄O₄, 616.2; m/z found, 617.2 [M+H]⁺. Step B, 2-(1-(2-Chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)iso quinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2 4-dihydro-3H- 1 ,2.4-triazol-3-one. 5-((Benzyloxy)methyl)-2-( 1 -(2-chloro-6-fluorophenoxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (48 mg, 0.08 mmol) in trifluoroacetic acid (TFA) (0.5 mL) was refluxed for 4 hour. The solvent was concentrated under reduced pressure and the residue was treated with acetonitrile (ACN) (1 mL) and IN NaOH (1 mL) solution for 10 min at room temperature. The solution was purified by prep-HPLC using 20-80% ACN/water 0.1% TFA (Method B) to give the title compound as a white solid after lyophilization. MS (ESI): mass calcd. for C₂₃H₁₉CIF₄N₄O₄, 526.1; m/z found, 527.5 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ = 8.12 (d, J= 1.9 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J= 5.8 Hz, 1H), 7.31 (d, J= 5.8 Hz, 2H), 7.22 - 7.12 (m, 2H), 5.08 - 4.94 (m, 1H), 4.73 (d, J = 6.4 Hz, 2H), 3.94 (q, J= 7.3 Hz, 2H), 2.09 - 2.00 (m, 1H), 1.65 (dd, J= 6.5, 10.5 Hz, 3H), 1.45 (t, J= 7.2 Hz, 3H). Example 2: (S)-2-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 ,2.4-triazol-3- one. Step A. (S)-5 -( (Benzyloxy)methyl)-2-( 1 -(2-chloro-6-fluorophenoxy)-8-( (1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H-L2.4-triazol-3-one. To a solution of (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan- 2- yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21, 100 mg, 197.28 μmol) and 2-chloro-6-fluorophenol (255.56 mg, 1.98 mmol) in N-methyl-2- pyrrolidone (NMP) (2.5 mL) was added KOH (44.28 mg, 789.1 μmol). The reaction mixture was sealed and heated in microwave at 150 °C for 3 hours. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give a residue. Purification (prep-TLC, petroleum ether/ethyl acetate=2/l) to give the title compound (41 mg, 33.3% yield) as yellow oil. MS (ESI): mass calcd. for C₂₉H₂₅CIF₃N₅O₄, 599.1; m/z found, 600.1 [M+H]⁺.

Step B, (S)-2-( l-(2-Chloro-6-fluorophenoxy)-8-((1.1.1 -trifluoropropan-2-yl)oxyl isoqiiinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 ,2.4-triazol-3-one. To a solution of (S)-5-((benzyloxy)methyl)-2-( 1 -(2-chloro-6-fluorophenoxy)-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (40 mg, 67.00 μmol) in DCM (3 mL) was added BCl₃ (1 M, 200 μL). The mixture was stirred at -78 °C for 1 hr. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL ×3). The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by RP HPLC (condition A) to give title compound (22 mg, 62.0% yield) as a white solid. MS (ESI): mass calcd. for C₂₃H₁₉CIF₄N₄O₄; m/z found, 526.1; m/z found, 527.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.12 (d, J= 1.9 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J= 5.8 Hz, 1H), 7.31 (d, J = 5.8 Hz, 2H), 7.22 - 7.12 (m, 2H), 5.08 - 4.94 (m, 1H), 4.73 (d, J= 6.4 Hz, 2H), 3.94 (q, J= 7.3 Hz, 2H), 2.09 - 2.00 (m, 1H), 1.65 (dd, J= 6.5, 10.5 Hz, 3H), 1.45 (t, J= 7.2 Hz, 3H). Example 3: 2-( 1 -((2-Chloro-6-fluorophenyl)amino)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1.2.4-triazol-3- one.

Step A. 7-(3-( (Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H- 1 ,2.4-triazol- 1 -yl)-3 - (2-chloro-6-fluorophenyl)-6-fluoro- l-isopropyl-2.2-dimethyl-2.3-dihydroquinazolin- 4(1H)- one. 5 -((Benzyloxy)methyl)-2-( 1 -chloro-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20, 5 mg, 0.01 mmol), 2-chloro-6-fluoroaniline (14 mg, 0.1 mmol) and Cs₂CO₃ (6.4 mg, 0.02 mmol) in dioxane (1 mL) in a seal tube were heated to 130 °C overnight. The reaction mixture was partitioned between ethyl acetate and saturate ammonium chloride solution. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The resulting solution was then concentrated and purified by silica gel cartridge on an Agilent purification system using 0-60% ethyl acetate/heptanes to give the title compound (5 mg, 83%) as an off white solid. MS (ESI): mass calcd. for C₃₀H₂₆CIF₄N₅O₃, 615.2; m/z found, 616.4 [M+H]⁺.

Step B. 3-(2-Chloro-6-fluorophenyl)-7-(4-ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro- 1H- 1 ,2,4-triazol- 1 -yl)-6-fluoro- 1 -isopropyl -2.2-dimethyl -2.3 -dihydroquinazolin-4( 1H)- one. The title compound was prepared according to the procedure of Example 1, Step B. MS (ESI): mass calcd. for C₂₃H₂₀CIF₄N₅O₃, 525.1; m/z found, 526.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm, 9.40 (br s, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.76 (br d, J = 6.85 Hz, 1H), 7.28 - 7.56 (m, 2H), 7.13 - 7.25 (m, 2H), 7.02 (d, J= 6.36 Hz, 1H), 5.23 (m, 1H), 4.68 (s, 2H), 3.94 (d, J=7.34 Hz, 2H), 1.76 (d, J= 6.36 Hz, 3H), 1.42 (t, J= 7.09 Hz, 3H). Example 4: 2-(1-((2-Chloro-6-fluorot)henyl)thio)-8-(( 1,1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one.

Step A, 5-((Benzyloxy)methyl)-2-(1-((2-chloro-6-fluorophenyl)thio)-8-((1,1,1- ixv)isoquinolin-6-vl)-4-ethvl-2.4-dihvdro-3H-1.2.4-triazol-3-one.

5 -((Benzyloxy)methyl)-2-( 1 -chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6- yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20, 10 mg, 0.02 mmol), 2- chloro-6-fluorobenzenethiol (16 mg, 0.1 mmol) and Cs₂CO₃ (32 mg, 0.1 mmol) in DMF (0.5 mL) were stirred at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate and saturate ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solution was then concentrated and purified by silica gel cartridge on an Agilent purification system using 0-60% ethyl acetate/heptanes to give the title compound (12 mg, 96%) as an off white solid. MS (ESI): mass calcd. for C₃₀H₂₅CIF₄N₄O₃S, 632.1; m/z found, 633.2 [M+H]⁺.

Step B, 2-(1-((2-Chloro-6-fluorophenyl)thio)-8-((1.1.1-trifluoropropan-2-yl) oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one. The title compound was prepared according to the procedure of Example 1, Step B.

MS (ESI): mass calcd. for C₂₃H₁₉CIF₂N₄O₃S, 542.1; m/z found, 543.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm, 8.16 (d, J= 5.38 Hz, 1H), 8.03 (d, J= 1.96 Hz, 1H), 7.99 (d, J= 1.47 Hz, 1H), 7.52 (d, J= 5.87 Hz, 2H), 7.31 - 7.43 (m, 2H), 4.97 - 5.20 (m, 1H), 4.58 (m, 2H), 3.87 (q, J= 7.34 Hz, 2H), 1.57 - 1.77 (m, 3H), 1.31 - 1.45 (m, 3H).

Example 5: 4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro-1H- 1,2.4-triazol- 1 - yl)-8-(( 1, 1, 1 -trifluoropropan-2-yl)oxy)isoauinolin- 1 -yl)oxy)-3.5-difluorobenzonitrile.

Step A. 4-((6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1- yl)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3.5-difluorobenzonitrile. The title compound was prepared a manner analogous to Example 1, Step A by coupling 3,5-difluoro-4-hydroxybenzonitrile with 5-((benzyloxy)methyl)-2-(1-chloro-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20). MS (ESI): mass calcd. for C₃₁H₂₄F₅N₅O₄, 625.2; m/z found, 626.3 [M+H]⁺. Step B, 4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro-1H- 1.2.4-triazol- l-yl)-8- ((1,1.1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 -yl)oxy)-3.5 -difluorobenzonitrile . The title compound was prepared in a manner analogous to Example 1, Step B. MS (ESI): mass calcd. for C₂₄H₁₈F₅N₅O₄, 535.1; m/z found, 536.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm, 8.11 (s, 1H), 7.98 (s, 1H), 7.83 (d, J= 5.87 Hz, 1H), 7.29 - 7.52 (m, 3H), 4.85 - 5.04 (m, 1 H), 4.73 (s, 2H), 3.93 (q, J= 6.85 Hz, 2H), 1.87 (m, 3H), 1.44 (t, J=

7.09 Hz, 3H).

Example 6: 2-( 1 -(2.6-Difluoro-4-(bydroxymethyl)phenoxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoauinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 , 2.4-triazol -3- one.

Step A, 4-((6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1.2.4-triazol- 1 - yl)-8-(( 1.1.1 -tnfluoropropan-2-yl)oxy)isoquinolin- 1 -yl)oxy)-3.5-difluorobenzaldchydc. The title compound was prepared in a manner analogous to Example 1, Step A, by coupling 3,5-difluoro-4-hydroxybenzaldehyde with 5-((benzyloxy)methyl)-2-(1-chloro- 8-(( 1 , 1 , 1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H- 1,2,4- triazol-3-one (Intermediate 20). MS (ESI): mass calcd. for C₃₁H₂₅F₅N₄O₅, 628.2; m/z found, 629.5 [M+H]⁺. Step B. 5-((Benzyloxy)methyl)-2-( 1 -(2.6-dif1uoro-4-(hydroxymethyl)phenoxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol- 3 -one. (4-((6-(3 -((Benzyloxy)methyl)-4-ethyl-5 -oxo-4,5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl)- 8-(( 1, 1 , 1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 -yl)oxy)-3,5-difluorobenzaldehyde (10 mg, 0.02 mmol) in MeOH (1 mL) at 0 °C was treated with sodium borohydride (3 mg, 0.08 mmol) for 10 min. The solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, filtered and concentrated to give the crude product. The crude product was then purified by silica gel cartridge on an Agilent purification system using 10-60% ethyl acetate/heptanes to give the title compound (8.0 mg, 80%) as an off white solid. MS (ESI): mass calcd. for C₃₁H₂₇F₅N₄O₅, 630.2; m/z found, 631.4 [M+H]⁺.

Step C. 2-(1-(2.6-Difluoro-4-(hydroxymethyl)phenoxy)-8-(( 1.1.1 -trifluoropropan-2- yl )oxy) isoq uinolin-6-yl )-4-ethyl-5 -(hydroxymethyl)-2.4-dih ydro-3H- 1 ,2.4-triazol-3- one. The title compound was prepared in a manner analogous to Example 1, Step B. (ESI): mass calcd. for C₂₄H₂₁F₅N₄O₅, 540.1; m/z found, 541.3 [M+H]⁺. ¹H NMR (400 MHz, CD3OD) δ ppm, 8.13 (d, J= 1.47 Hz, 1H), 7.96 (d, J= 1.96 Hz, 1H), 7.81 (d, J = 5.87 Hz, 1H), 7.34 - 7.49 (m, 2H), 7.07 (d, J= 8.80 Hz, 1H), 5.02 (m, 1H), 4.65 (s, 2H), 4.10 (s, 2H), 3.95 (q, .7= 7.01 Hz, 2H), 2.05 (br, s, 1H), 1.99 (br, s, 1H), 1.54 - 1.82 (m, 3H), 1.31 - 1.53 (m, 3H).

Example 7: 4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro- 1H- 1.2.4-triazol- 1 - yl)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 -yl)oxy)-3.5-dif1uorobenzoic acid. Step A. 4-((6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1.2.4-triazol- 1 - yl)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 -yl)oxy)-3.5-dif1uorobenzoic acid. 4-((6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4, 5-dihydro- 1H-1, 2, 4-triazol-1-yl)-8- ((1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 -yl)oxy)-3 ,5 -difluorobenzonitrile (Example 5, Product from Step A, 25 mg, 0.04 mmol) in a mixture of MeOH (1 mL), THF (1 mL) and water (1 mL) was treated with 50% NaOH (0.02 mL) and heated at 80 °C overnight. The solution was acidified with IN HCl to pH=4 and extracted with ethyl acetate (3 X). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification (silica gel column on Agilent purification system using 20-100% ethyl acetate in heptanes) afforded the title compound as a white solid (21 mg, 82.4%). MS (ESI): mass calcd. for C₃₁H₂₅F₅N₄O₆, 644.2; m/z found, 644.5 [M+H]⁺.

Step B, 4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro- 1H- 1.2.4-triazol- 1-yl)-8- ((1,1.1 -trifluoropropan-2-yl)oxylisoauinolin- 1 -yl)oxy)-3.5-difluorobenzoic acid. The title compound was prepared according to Example 1, Step B to yield a white solid. MS (ESI): mass calcd. for C₂₄H₁₉F₅N₄O₆, 554.2; m/z found, 555.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm, 8.12 (d, J= 1.96 Hz, 1H), 7.98 (d, J= 1.96 Hz, 1H), 7.86 (d, J = 5.87 Hz, 1H), 7.67 - 7.81 (m, 2H), 7.27 - 7.52 (m, 1H), 4.98 (d, J= 5.87 Hz, 1H), 4.73 (s, 2 H), 3.94 (q, J= 7.01 Hz, 2H), 1.65 (d, J= 6.85 Hz, 3H), 1.44 (t, J= 7.09 Hz, 3H).

Example 8: 4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1- yl)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3.5-difluoro-N-(2- hydroxyethyl)benzamide .

Step A, 4-((6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1 ,2.4-triazol- 1 - yl)-8-(( 1, 1, 1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 -yl)oxy)-3.5-difluoro-N-(2- hydroxyethyl ) benzamide . A mixture of 4-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo- 4,5-dihydro- 1H- 1 ,2,4-triazol- 1 -yl)-8-(( 1, 1 , 1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 - yl)oxy)-3,5-difluorobenzoic acid (Example 7, Product from Step A, 14 mg, 0.022 mmol), 2-aminoethan-1-ol (6.6 mg, 0.11 mmol), N-(3-dimethylaminopropyl)-N- ethylcarbodiimide hydrochloride (EDCI) (12.5 mg, 0.065 mmol), hydroxy- benzotriazole (HOBt) (8.8 mg, 0.065 mmol), diisopropylethylamine (DIPEA) (0.019 mL, 0.11 mmol) in DCM (2 mL) was stirred at room temperature overnight. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification (silica gel column, on Agilent purification system using 20-80% ethyl acetate in heptanes) afforded the title compound as a colorless oil (11.2 mg, 73.7%). MS (ESI): mass calcd. for C₃₃H₃₀F₅N₅O₆, 687.2; m/z found, 688.5 [M+H]⁺.

Step B, 4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1-yl)-8- ((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3.5-difluoro-N-(2-hydroxyethyl) benzamide. The title compound was prepared according to Example 1, Step B. MS (ESI): mass calcd. for C₂₆H₂₄F₅N₅O₆, 597.2; m/z found, 598.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm, 8.12 (d, J= 1.96 Hz, 1H), 7.97 (d, J= 1.96 Hz, 1H), 7.84 (d, J= 5.87 Hz, 1H), 7.41 - 7.67 (m, 2H), 7.28 - 7.40 (m, 1H), 4.85 - 5.02 (m, 1H), 4.73 (s,

2H), 3.99 (m, 2H), 3.77 (m, 2H), 3.60 - 3.74 (m, 2H), 1.44 (t, J= 7.09 Hz, 3H), 1.25 (m, 3H). Example 9: 2-( 1 -(2-Chloro-4,6-difluorophenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyD-2.4-dihydro-3H-1.2.4-triazol-3-one. Step A, 5-((Benzyloxy)methyl)-2-( 1 -(2-chloro-4.6-difluorophenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxylisoauinolin-6-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one. The title compound was prepared according to the procedure of Example 1, Step A by coupling 2-chloro-4,6-difluorophenol with 5-((benzyloxy)methyl)-2-(1-chloro-8- ((1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H- 1 ,2,4-triazol- 3-one (Intermediate 20). MS (ESI): mass calcd. for C₃₀H₂₄CIF₅N₄O₄, 634.1; m/z found, 634.5 [M+H]⁺.

Step B, 2-(1-(2-Chloro-4,6-difluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.

The title compound was prepared in a manner analogous to Example 1, Step B. MS (ESI): mass calcd. for C₂₃H₁₈CIF₅N₄O₄, 544.1; m/z found, 545.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm, 8.09 (d, J= 1.47 Hz, 1H), 7.96 (s, 1H), 7.84 (d, J= 5.87 Hz, 1H), 7.28 - 7.52 (m, 1H), 7.02 - 7.25 (m, 1H), 6.92 (t, J= 9.05 Hz, 1H), 4.86 - 5.10 (m, 1H), 4.72 (br, s, 2H), 3.92 (q, J= 7.34 Hz, 2H), 1.60 - 1.67 (m, 3H), 1.43 (t, J = 7.34 Hz, 3H).

Example 10: 2-(1-(2-Chloro-6-fluorophenoxy)-8-isopropoxyisoquinolin-6-yl)-4-ethyl-

5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.

The title compound was prepared according to the procedure of Example 1, Steps A-B using 3-((benzyloxy)methyl)- 1 -(1-chloro-8-isopropoxyisoquinolin-6-yl)-4-ethyl- 1H- 1,2,4-triazol-5(4H)-one (Intermediate 22) instead of 5-((benzyloxy)methyl)-2 -(1-chloro- 8-(( 1 , 1 , 1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H- 1,2,4- triazol-3-one (Intermediate 20) in Step A. MS (ESI): mass calcd. for C₂₃H₂₂CIFN₄O₄, 472.1; m/z found, 473.3 [M+H]⁺. 'HNMR (400 MHz, CDCl₃) δ ppm 7.92 (d, J= 14.7 Hz, 1H), 7.80 (s, 1H), 7.28 - 7.34 (m, 3H) 6.97 - 7.24 (m, 2H), 4.77 - 4.89 (m, 1H), 4.71 (br, s, 2 H), 3.92 (m, J= 6.85 Hz, 2 H) 1.61 (d, J= 8.5 Hz, 6H), 1.38 (t, J= 7.5 Hz, 3H).

Example 11: (S)-2-( 1 -((4-Chloropyridin-3-yl)oxy)-8-(( 1 , 1, 1 -trifluoropropan-2-yl) oxy)isoauinolin-6-ylt-4-ethyl-5-(bydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.

Step A, (S)-5-((Benzyloxy)methyD-2-(T-((4-chloropyridin-3-yl)oxy)-8-((1- 1, 1- trifluoropropan-2-yl)oxylisoauinolin-6-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one. To a solution of (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan- 2- yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21, 80 mg, 157.82 μmol) and 4-chloropyridin-3-ol (204.45 mg, 1.58 mmol) in N-methyl pyrrolidone (NMP) (1.5 mL) was added KOH (35.42 mg, 631.28 μmol). The reaction mixture was sealed and heated employing microwave irradiation at 150 °C for 3h.

The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue.

Purification (prep-TLC (petroleum ether/ethyl acetate=2/l) afforded the title compound (30 mg, 29.15% yield) as yellow oil. MS (ESI): mass calcd. for C₂₉H₂₅CIF₃N₅O₄, 599.1; m/z found, 600.1 [M+H]⁺.

Step B, (S)-2-(1-((4-Chloropyridin-3-yl)oxy)-8-(( 1.1 , 1-trifluorporopan-2-yl) oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.

To a solution of (S)-3-((benzyloxy)methyl)-1-(1-((4-chloropyridin-3-yl)oxy)-8- ((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (60 mg, 100.00 μmol) in DCM (3 mL) was added BCl₃ (1 M, 300.01 μL). The mixture was stirred at -78 °C for 1 hr. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL ×3). The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by Reverse Phase HPLC (condition A) to give title compound (17 mg, 31.0% yield) as a white solid. MS (ESI): mass calcd. for C₂₂H₁₉CIF₃N₅O₄, 509.1; m/z found, 510.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.30 (br d, J= 3.9 Hz, 1H), 9.15 - 9.07 (m, 1H), 8.14 (d, J= 1.8 Hz, 1H), 8.04 (d, J= 1.6 Hz, 1H), 7.90 (d, J= 6.5 Hz, 1H), 7.84 (d, J= 5.8 Hz, 1H), 7.43 (d, J= 5.8 Hz, 1H), 5.09 - 4.97 (m, 1H), 4.75 (s, 2H), 3.95 (q, J= 7.2 Hz, 2H), 1.69 (d, J= 6.4 Hz, 3H), 1.45 (t, J= 7.2 Hz, 3H).

Example 12: (S)-2-( 1 -((2-Chloropyridin-3-yl)oxy)-8-(( 1, 1, 1-trifluoropropan-2-yl) isoaiimolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 ,2.4-triazol-3-one.

Step A, (S)-5-((Benzyloxy)methyD-2-(1-((2-chloropyridin-3-yl)oxy)-8-((1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol-3-one. The title compound was prepared in a manner analogous to Example 2, Step A by coupling 2-chloropyridin-3-ol with (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₂₉H₂₅CIF₃N₅O₄, 599.2; m/z found, 600.4 [M+H]⁺.

Step B, (S)-2-(1-((2-Chloropyridin-3-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl) oxy)isoq u inol in -6-yl)-4-ethyl -5 -(hydroxymethyl )-2.4-dihydro-3H- 1 ,2.4-triazol-3-one.

The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₂H₁₉CIF₃N₅O₄; m/z found, 509.1; m/z found, 510.1 [M+H]⁺. 1H NMR (400 MHz, CDCl₃) δ = 8.31 (dd, J= 1.7, 4.7 Hz, 1H), 8.11 (d, J= 1.8 Hz, 1H), 7.98 (d, J= 1.8 Hz, 1H), 7.86 (d, J= 5.8 Hz, 1H), 7.62 (dd, J= 1.7, 8.0 Hz, 1H), 7.37 - 7.32 (m, 2H), 5.09 - 4.95 (m, 1H), 4.74 (br d, J= 1.1 Hz, 2H), 3.94 (d, J= 7.3

Hz, 2H), 2.10 (br s, 1H), 1.66 (d, J = 6.4 Hz, 3H), 1.45 (t, J= 7.2 Hz, 3H).

Example 13: (S)-2-( 1 -((2-Chloro-4-methylpyridin-3-yl)oxy)-8-(( 1.1.1 -trifluoropropan-

2-yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one.

Step A, (S)-5-((Benzyloxy)methyl)-2-(1-((2-chloro-4-methylpyridin-3-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol- 3 -one. The title compound was prepared in a manner analogous to Example 2, Step A by coupling 2-chloro-4-methylpyridin-3-ol with (S)-3-((benzyloxy)methyl)-1-(1-chloro- 8-(( 1 , 1 , 1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol-5 (4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₀H₂₇CIF₃N₅O₄; m/z found, 613.2; m/z found, 614.6 [M+H]⁺.

Step B, (S)-2-(1-((2-Chloro-4-methylpyridin-3-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one. The title compound was prepared in a manner analogous to Example 2, Step B.

MS (ESI): mass calcd. for C₂₃H₂₁CIF₃N₅O₄; m/z found, 523.1; m/z found, 524.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.18 (d, J= 4.9 Hz, 1H), 8.09 (d, J= 1.6 Hz, 1H), 7.99 - 7.95 (m, 1H), 7.86 - 7.81 (m, 1H), 7.30 (d, J= 5.8 Hz, 1H), 7.22 - 7.19 (m, 1H), 5.05 (m, , J= 6.0, 12.4 Hz, 1H), 4.74 (s, 2H), 3.94 (q, J= 7.2 Hz, 2H), 2.27 (s,

3H), 2.10 (br s, 1H), 1.70 - 1.62 (m, 3H), 1.45 (t, J= 7.3 Hz, 3H).

Example 14: (S)-2-( 1 -((2.4-Dimethylpyridin-3-yl)oxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 ,2.4-triazol-3- one.

Step A. (S)-5-((Benzyloxy)methyl)-2-( 1 -((2.4-dimethylpyridin-3-yl)oxy)-8-(( 1, 1, 1- trifluoropropan-2-yl) isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol-3-one. The title compound was prepared in a manner analogous to Example 2, Step A by coupling 2,4-dimethylpyridin-3-ol with (S)-3-((benzyloxy)methyl)-1-(1-chloro-8- ((1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol-5 (4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₁H₃₀F₃N₅O₄; m/z found, 593.2; m/z found, 594.6 [M+H]⁺.

Step B, (S)-2-(1-((2.4-Dimethylpyridin-3-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3- one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₄H₂₄F₃N₅O₄; m/z found, 503.2; m/z found, 504.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.28 (dd, J= 1.1, 5.0 Hz, 1H), 8.05 (d, J= 1.6 Hz, 1H), 7.96 (d, J= 1.6 Hz, 1H), 7.83 (d, J= 5.8 Hz, 1H), 7.25 (d, J= 5.8 Hz, 1H), 7.12 - 7.08 (m, 1H), 5.10 - 4.95 (m, 1H), 4.74 (s, 2H), 3.99 - 3.90 (m, 2H), 2.36 (s, 3H), 2.17

(s, 3H), 1.67 - 1.64 (m, 3H), 1.45 (s, 3H).

Example 15: (S)-4-Ethyl-5-(hydroxymethyl)-2-(1-((4-methylpyridin-3-yl)oxy)-8- ((1,1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H- 1 ,2.4-triazol-3 -one .

Step A. (S)-5-((Benzyloxy)methyl)-4-ethyl-2-(1-((4-methylpyridin-3-yl)oxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H-1.2.4-triazol-3-one. The title compound was prepared in a manner analogous to Example 2, Step A by coupling 4- methylpyridin-3-ol with (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₀H₂₈F₃N₅O₄; m/z found, 579.2; m/z found, 580.5 [M+H]⁺.

Step B, (S)-4-Ethyl-5-(hydroxymethyl)-2-(1-((4-methylpyridin-3-yl)oxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H-1.2.4-triazol-3-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₃H₂₂F₃N₅O₄, 489.1; m/z found, 490.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.57 (s, 1H), 8.49 (d, J= 5.5 Hz, 1H), 8.08 (d, J= 1.8 Hz, 1H), 8.00 (d, J= 1.6 Hz, 1H), 7.83 (d, J= 5.8 Hz, 1H), 7.57 (d, J= 5.5 Hz, 1H), 7.34 (d, J= 5.8 Hz, 1H), 5.01 (td, J= 6.2, 12.4 Hz, 1H), 4.74 (s, 2H), 3.94 (q, J= 7.3 Hz, 2H), 2.42 (s, 3H), 1.66

(d, J= 6.4 Hz, 3H), 1.45 (t, J = 7.2 Hz, 3H).

Example 16: (S)-2-(1-(2-Chloro-5-methylphenoxy)-8-((l.1. l-trifluoropropan-2-yl) oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.

Step A. (S)-5-((Benzyloxy)methyl)-2-( 1 -(2-chloro-5-methylphenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol-3-one.

The title compound was prepared in a manner analogous to Example 2, Step A by coupling 2-chloro-5-methylphenol with (S)-3-((benzyloxy)methyl)-1-(1-chloro-8- ((1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol-5 (4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₁H₂₈CIF₃N₄O₄; m/z found, 612.2; m/z found, 613.5 [M+H]⁺.

Step B, (S)-2-(1-(2-Chloro-5-methylphenoxy)-8-(( 1, 1, 1 -trifluoropropan-2-yl) oxylisoauinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.

The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₄H₂₂CIF₃N₄O₄; m/z found, 522.1; m/z found, 523.1 [M+H]⁺. 1H NMR (400MHz, CDCl₃) δ = 8.11 (d, .7=1.9 Hz, 1H), 7.96 (d, 7=1.9 Hz, 1H), 7.90 (d, .7=5.8 Hz, 1H), 7.37 (d, 7=8.2 Hz, 1H), 7.29 (s, 1H), 7.09 (d, J=1.4 Hz, 1H), 7.04 - 7.00 (m, 1H), 5.01 (q, J= 6.2 Hz, 1H), 4.73 (s, 2H), 3.93 (q, 7=7.2 Hz, 2H), 2.38 (s, 3H), 2.13

- 2.00 (m, 1H), 1.63 (d, 7=6.4 Hz, 3H), 1.44 (t, 7=7.2 Hz, 3H).

Example 17: (S)-1-(l -((4-Chloro-2-methylpyridin-3 -yl)oxy)-8-(( 1.1.1 -trifluoropropan-

2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3 -(hydroxymethyl)- 1H- 1 ,2.4-triazol-5 (4H)-one .

Step A. (S)-5-((Benzyloxy)methyl)-2-( 1 -((4-chloro-2-methylpyridin-3-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol- 3 -one. The title compound was prepared in a manner analogous to Example 2, Step A by coupling 4-chloro-2-methylpyridin-3-ol with (S)-3-((benzyloxy)methyl)-1-(1-chloro- 8-(( 1 , 1 , 1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol-5 (4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₀H₂₇CIF₃N₅O₄; m/z found, 613.2; m/z found, 614.7 [M+H]⁺.

Step B, (S)- 1 -( 1 -((4-Chloro-2-methyl_Dyridin-3-yl)oxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₃H₂₁CIF₄N₅O₄; m/z found, 523.1; m/z found, 524.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.32 - 8.30 (m, 1H), 8.09 (s, 1H), 7.99 - 7.93 (m, 1H), 7.83 (d, J= 5.8 Hz, 1H), 7.33 - 7.28 (m, 2H), 5.10 - 4.96 (m, 1H), 4.74 (s, 2H), 3.94 (q, J= 7.3 Hz, 2H), 2.46 (s, 3H), 2.27 (br s, 1H), 1.66 (d, J= 6.4 Hz, 3H), 1.45 (t, J= 7.2 Hz, 3H).

Example 18: (S)- 1 -( 1 -((3-Chloropyridin-2-yl)oxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy) isoqiiinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2.4-triazol-5(4H)-one. . (S)-3-((Benzyloxy)methyl)- ,1,1- trifluoro propan-2 -yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1.2.4-triazol-5(4H)-one. To a mixture of (S)-3 -((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1 -trifluoropropan- 2-yl)oxy)isoquinolin- 6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21, 50 mg, 98.64 μmol) and 3- chloropyridin-2-ol (25.56 mg, 197.28 μmol) in dioxane (1.5 mL) was added Cs₂CO₃ (96.41 mg, 295.91 μmol) followed by copper(II) acetylacetonate [Cu(acac)₂] (5.16 mg, 19.73 μmol) in one portion under N₂. The mixture was heated at 120 °C for 24 h.

The reaction mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Purification (prep-TLC, Petroleum ether: Ethyl acetate=l/l) afforded the title compound (35 mg, 53.82% ) as yellow solid. MS (ESI): mass calcd. for C₂₉H₂₅CIF₃N₅O₄, 599.1; m/z found, 600.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.15 - 8.06 (m, 3H), 7.94 (d, J= 1.5 Hz, 1H), 7.82 (dd, J= 1.6, 7.8 Hz, 1H), 7.49 (d, J = 5.6 Hz, 1H), 7.43 - 7.34 (m, 5H), 7.04 (dd, J= 4.8, 7.7 Hz, 1H), 4.97 (td, J= 6.2, 12.2 Hz, 1H), 4.64 (s, 2H), 4.57 (s, 2H), 3.88 (q, J= 7.2 Hz, 2H), 1.48 (d, J = 6.3 Hz, 3H), 1.38 (t, J= 7.2 Hz, 3H).

Step B, (S)-1-(1-((3-Chloropyridin-2-yl)oxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy) iso quinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)-one. To a solution of (S)-3 -((benzyloxy)methyl)- 1 -( 1 -((3 -chloropyridin-2-yl)oxy)-8-(( 1,1,1- trifluoro propan- 2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (75 mg, 125 μmol) in DCM (5 mL) was added BCl₃ (1 M, 250 μL). The mixture was stirred at -78 °C for 1 hr. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL ×3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by RP HPLC (condition A) to give title compound (35 mg, 55.6% yield) as a white solid. MS (ESI): mass calcd. for C₂₂H₁₉CIF₃N₅O₄, 509.1; m/z found, 510.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.13 - 8.06 (m, 3H), 7.92 (d, J= 1.7 Hz, 1H), 7.82 (dd, J= 1.7, 7.7 Hz, 1H), 7.47 (d, J= 5.7 Hz, 1H), 7.05 (dd, J= 4.8, 7.8 Hz, 1H), 4.95 (td, J= 6.2, 12.5 Hz, 1H), 4.72 (br d, J= 4.5 Hz, 2H), 3.93 (q, J= 7.2 Hz, 2H), 2.31 (br s, 1H), 1.51 - 1.39 (m, 6H).

Example 19: (S)- 1 -( 1 -((3.5-Dimethylisoxazol-4-yl)oxy)-8-(( 1, 1, 1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.

Step A, (S)-5-((Benzyloxy)methyl)-2-(T-((3.5-dimethylisoxazol-4-yl)oxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared according to the procedure of Example 2, Step A by coupling 3,5-dimethylisoxazol-4-ol with (S)-3-((benzyloxy)methyl)-1-(1-chloro-8- ((1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol-5 (4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₂₉H₂₈F₃N₅O₄; m/z found, 583.2; m/z found, 584.4 [M+H]⁺. Step B. (S)- 1 -( 1 -((3.5-Dimethylisoxazol-4-yl)oxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoauinolin-6-yl)-4-ethyl-3-(liydroxymethyl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₂H₂₂F₃N₅O₅; m/z found, 493.2; m/z found, 494.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8. 07 (d, J= L8 Hz, 1H), 7.95 (d, J= 1.8 Hz, 1H), 7.90 (d, J = 5.7 Hz, 1H), 7.30 (d, J= 5.9 Hz, 1H), 4.99 (td, J= 6.2, 12.4 Hz, 1H), 4.74 (d, J= 6.2

Hz, 2H), 3.94 (q, J= 7.2 Hz, 2H), 2.34 (s, 3H), 2.20 - 2.10 (m, 4H), 1.67 (d, J= 6.4 Hz, 3H), 1.45 (t, J= 7.2 Hz, 3H). Example 20: 2-(8-(2-Chloro-6-fluorophenoxy)- 1 -(( 1. 1.1 -trifluoropropan-2-yl)oxy)-2.7- naphthyridin-3-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.

The title compound was prepared according to the procedure of Example 1, Steps A-B using 3-((benzyloxy)methyl)-1-(8-chloro-1-((1, 1, 1-trifluoropropan-2-yl)oxy)-2,7- naphthyridin-3-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 23) instead of 3- ((benzyloxy)methyl)- 1 -(1 -chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 4-ethyl-1H-1,2,4-triazol-5(4H)-one in Step A. MS (ESI): mass calcd. for C₂₂H₁₈CIF₄N₅O₄, 527.1; m/z found, 528.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) d ppm, 8.01 (d, J= 5.87 Hz, 1H), 7.95 (s, 1H), 7.27 - 7.52 (m, 2H), 7.10 - 7.25 (m, 2H), 6.13

(br, d , J= 3.91 Hz, 1H), 4.73 (s, 2H), 3.94 (q, J= 7.17 Hz, 2H), 1.66 (d, J= 6.36 Hz, 3H), 1.43 (t, J= 7.09 Hz, 3H).

Example 21: 2-(4-(2-Chloro-6-fluorophenoxy)-5-(( 1.1.1 -trifluoropropan-2-yl)oxy ) pyridol3.4-dlpyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-

3 -one. The title compound was prepared according to the procedure of Example 1, Steps A-B; except using 3 -((benzyloxy)methyl)- 1 -(4-chloro-5 -(( 1,1,1 -trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 24) instead of 5-((benzyloxy)methyl)-2-(1-chloro-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20) in Step A. MS (ESI): mass calcd. for C₂₁H₁₇CIF₄N₆O₄, 528.1; m/z found, 529.6 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm, 8.15 (s, 1H), 7.31 (d, J =7 .49 Hz, 1H), 7.26 (m, 1H), 7.20 (m, 1H), 7.14 (m, 1H), 5.01 (m, 1H), 4.73 (br, s, 2 H), 3.96 (d, J = 7.34 Hz, 2 H), 2.89 - 3.17 (m, 3H), 1.44 (t, J= 7.34 Hz, 3 H).

Example 22: 2-(4-(2-Chloro-6-fluorophenoxY)-5-(( 1.1.1 -trifluoropropan-2-yl)oxy)- 1.6- naphthyridin-7-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1.2.4-triazol-3-one.

The title compound was prepared according to the procedure of Example 1, Steps A-B; using 5-((benzyloxy)methyl)-2-(4-chloro-5-((l, 1, l-trifluoropropan-2-yl)oxy)-1,6- naphthyridin-7-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 26) instead of 5-((benzyloxy)methyl)-2-( 1 -chloro-8-(( 1, 1 , 1 -trifluoropropan-2-yl)oxy)isoquinolin-6- yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20) in Step A. MS (ESI): mass calcd. for C₂₂H₁₈CIF₄N₅O₄, 527.1; m/z found, 528.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm, 7.78 (d, J= 6.85 Hz, 1H), 7.72 (s, 1H), 7.25 - 7.48 (m, 2H), 7.05 - 7.20 (m, 2H), 6.20 (m, 1H), 4.85 (s, 2H), 3.97 (q, J= 7.5 Hz, 2H), 1.72 (d, J= 7.25 Hz, 3H), 1.48 (t, J= 7.24 Hz, 3H). Example 23: (S)-3-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy) isoquinolin-6-yl)- 1 -ethyl- 1 -methylurea.

Step A. (S)-6-Bromo-1-chloro-8-((1.1,1-trifluoropropan-2-yl)oxyfisoauinoline. A solution of (S)-6-bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one (Intermediate 21, product from Step B, 200 mg, 595.05 μmol) in POCl₃ (4 mL) was heated to 110 °C for 2 hours. The mixture was cooled and then concentrated under reduced pressure. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL X2). The combined organic phase was washed with brine (20 mL X 2), dried with anhydrous Na₂SO₃, filtered and concentrated under vacuum to give the title compound (205 mg, crude) as yellow solid. MS (ESI): mass calcd. for C₁₂H₈BrClF₃NO, 352.9; m/z found, 354.0, 356.0 [M+H]⁺. Step B. (S)-6-Bromo- 1-(2-chloro-6-fluorophenoxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy) isoauinoline. A mixture of (S)-6-bromo-1-chloro-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinoline (150 mg, 423.07 μmol) and 2-chloro-6-fluoro-phenol (620.00 mg, 4.23 mmol) and KOH (94.95 mg, 1.69 mmol) in NMP (0.5 mL) was heated to 110 °C for 2 hours in a sealed tube. The residue was cooled and then poured into sat. Na₂SO₃ (30 mL). The aqueous phase was extracted with ethyl acetate (20 mL X 2). The combined organic phase was washed with brine (10 mL X 2), dried with anhydrous Na₂SO₄, filtered and concentrated under vacuum. Purification (prep-TLC, Petroleum ether/Ethyl acetate=10/l) afforded the title compound (105 mg, 51.5%) as yellow solid. MS (ESI): mass calcd. for C₁₈H₁₁BrClF₃ NO₂, 462.9; m/z found, 464.0, 466.0 [M+H]⁺. Step C. (S)-1-(2-Chloro-6-fluorophenoxy)-N-(diphenylmethylene)-8-((1,1,1-trifluoro propan-2 -ylfoxyfisoquinolin-6-amine. To a mixture of (S)-6-bromo-1-(2-chloro-6- fluorophenoxy)-8-((1,1,1-trifluoropropan- 2-yl)oxy)isoquinoline (100 mg, 215.22 μmol) and diphenylmethanimine (78.01 mg, 430.44 μmol. 72.23 μL) in dioxane (2 mL) was added CS₂CO₃ (84.15 mg, 258.27 μmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos) (12.45 mg, 21.52 μmol) and tris(dibenzylideneacetone) dipalladium(O) (Pd₂(dba)₃) (9.85 mg, 10.76 μmol) in one portion under N₂. The mixture was stirred at 110 °C for 12 hours. The mixture was cooled and then poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL X 2). The combined organic phase was washed with brine (10 mL X 2), dried with anhydrous Na₂SO₄, filtered and concentrated under vacuum to give the title compound (130 mg, crude) as yellow oil. MS (ESI): mass calcd. for C₃₁H₂₁CIF₄N₂O₂, 564.1; m/z found, 565.1 [M+H]⁺.

Step D. (S)- 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy) iso quinolin-6-amine . To a mixture of (S)-1-(2-chloro-6-fluorophenoxy)-N- (diphenylmethylene)-8- ((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-amine (130 mg) in THF (2 mL) was added HCl (2 M, 345 μL). The mixture was stirred at 15 °C for 2 hours. The mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL X 2). The combined organic phase was washed with brine (10 mL X 2), dried with anhydrousNa₂SO₄, filtered and concentrated under vacuum. Purification (prep-TLC, Petroleum ether/Ethyl acetate=2/1) afforded the title compound (80 mg, 75.6%) as yellow solid. MS (ESI): mass calcd. for C₁₈H₁₃CIF₄N₂O₂, 400.0; m/z found, 401.1 [M+H]⁺.

Step E, (S)-Phenyl (1-(2-chloro-6-fluorophenoxy)-8-((1.1.1 -trifluoropropan-2-yl)oxy) isoquinolin-6-yl)carbamate. To a mixture of (S)-1-(2-chloro-6-fluorophenoxy)-8- ((1,1,1-trifluoropropan-2-yl)oxy) isoquinolin-6-amine (80 mg, 199.62 μmol) in DCM (2 mL) was added pyridine (47.37 mg, 598.87 μmol) and phenyl carbonochloridate (40.63 mg, 259.51 μmol) at 0 °C under N₂. The reaction mixture was stirred at 15 °C for 1 hour. The mixture was poured into water (10 mL). The aqueous phase was extracted with DCM (10 mL X 2). The combined organic phase was washed with brine (5 mL X 2), dried with anhydrousNa₂SO₄, filtered and concentrated under vacuum to give the title compound (110 mg, crude) as yellow oil. MS (ESI): mass calcd. for C₂₅H₁₇CIF₄N₂O₄, 520.0; m/z found, 521.2 [M+H]⁺.

Step F, (S)-3-(1-(2-Chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy) iso quinolin-6-yl)- 1 -ethyl- 1 -methylurea. To a mixture of (S)-phenyl (1-(2-chloro-6- fluorophenoxy)-8-(( 1,1,1 -trifluoropropan- 2-yl)oxy)isoquinolin-6-yl)carbamate (104 mg, crude) and N-methylethanamine (23.60 mg, 399.34 μmol) in dichloromethane (DCM) (2 mL) was added triethethylamine (TEA)(40.41 mg, 399.34 μmol) at 15°C under N₂. The mixture was stirred at 30 °C for 3 hours. The mixture was poured into water (30 mL). The aqueous phase was extracted with DCM (20 mL X2). The combined organic phase was washed with brine (10 mL X2), dried with anhydrous Na₂SO₄, filtered and concentrated under vacuum. Purification (Reverse Phase HPLC (condition A) afforded the title compound (55 mg) as white solid. MS (ESI): mass calcd. for C₂₂H₂₀CIF₄N₃O₃, 485.1; m/z found, 486.1 [M+H]+. ¹H NMR (400 MHz, CDCl₃) δ = 7.79 (d, J= 5.7 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.29 (br d, J= 7.5 Hz, 1H), 7.21 - 7.10 (m, 3H), 6.55 (s, 1H), 5.02 - 4.91 (m, 1H), 3.49 (q, J= 7.1 Hz, 2H), 3.09 (s, 3H), 1.60 (dd, J= 6.4, 11.4 Hz, 3H), 1.26 (t, J= 7.2 Hz, 3H).

Example 24: (S)-2-(4-(2-Chloro-6-fluorophenoxy)-5-(( 1.1.1 -trifluoropropan-2-yl) qiiinazolin-7-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 ,2.4-triazol-3-one.

Step A: 2-Amino-4-bromo-6-fluorobenzamide. A solution of 2-amino-4-bromo-6- fluorobenzonitrile (536 mg, 2.5 mmol), K₂CO₃ (137.8 mg, 1.0 mmol) and water (10 mL) was heated at 150 °C for 45 minutes employing microwave irradiation. The reaction mixture was extracted with EtOAc. The combined organics layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a tan solid. The crude product was used without further purification in the subsequent step. MS (ESI): mass calcd. for C₇H₆BrFN₂O, 233.0; m/z found, 233.1 [M+H]⁺.

Step B: 7-Bromo-5-fluoroqiiinazolin-4(3H)-one. To a solution of 2-amino-4-bromo-6- fluorobenzamide (415 mg, 1.8 mmol) in DMF (10 mL) was added p-toluenesulfonic acid monohydrate (677 mg, 3.6 mmol). The mixture was stirred at 120°C overnight after which additional p-toluenesulfonic acid monohydrate (677 mg, 3.6 mmol) was added and the reaction was continued at 120 °C for another 2 h. An additional amount of p-toluenesulfonic acid monohydrate was added (677 mg, 3.6 mmol) and the mixture stirred at 120 °C for a further 2 h. The mixture was cooled and then diluted with EtOAc and water. The organics were extracted with EtOAc, washed with brine and dried over sodium sulfate and filtered. The crude mixture was concentrated under reduced pressure to a solid. The solid was washed with EtOAc and filtered. The orange solid (100 mg, yield 23%) proved to be pure title compound which was used without further purification. The filtrate was adsorbed onto silica and purified by column chromatography using a gradient of 50-70% EtO Ac/heptane to provide another crop of the title compound (156 mg, yield 36%). MS (ESI): mass calcd. for C₈H₄BrFN₂O.

243.0; m/z found, 243.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.02 (s, 1H), 7.75 (t , J = 1.7 Hz, 1H), 7.36 (dd, J= 9.8, 2.0 Hz, 1H).

Step C. (S)-7-Bromo-5-((1,1,1-trifluoropropan-2-yl)oxy)quinazolin-4(3H)-one. To a solution of (S)-1,1,1-trifluoro-2 -propanol (145 mg, 1.3 mmol) in DMF (2.1 mL) at 0 °C was added NaH (60% dispersion in mineral oil) (51 mg, 1.3 mmol). The mixture was stirred 10 minutes then 7-bromo-5-fluoroquinazolin-4(3H)-one (155 mg, 0.64 mmol) in DMF (1.0 mL) was added. The mixture was warmed to room temperature and stirred for 4 h then diluted with EtOAc and quenched with water. The organics were extracted, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was adsorbed onto silica and purified by column chromatography (50-70% EtO Ac/heptane) to provide the title compound as an off- white solid (216 mg). MS (ESI): mass calcd. for C₁₁H₈BrF₃N₂O₂, 337.1; m/z found, 337.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm : 7.95 (d, J= 3.4 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.16 (d, J= 2.0 Hz, 1H), 4.69-4.85 (m, 1H), 1.64 (d, J= 6.4 Hz, 3H). Step D. (S)-7-(3-(((tert-Butyldiphenylsilyl)oxy)methyD-4-ethyl-5-oxo-4.5-dihydro-1H- 1.2.4-triazol- 1 -yl)-5-(( 1.1.1 -trifluoropropan-2-yl)oxy)quinazolin-4(3H)-one. To a solution of dioxane (1.5 mL) was added 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4- ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 27) (68 mg, 0.178 mmol), (S)-7- bromo-5-((1,1,1-trifluoropropan-2-yl)oxy)quinazolin-4(3H)-one (50 mg, 0.148 mmol), Cul (11 mg, 0.06 mmol), potassium phosphate tribasic (63 mg, 0.297 mmol), trans-

N,N’-dimethylcyclohexane- 1,2-diamine (14 μL, 0.902 g/mL, 0.089 mmol). The mixture was sparged with argon then heated to 120 °C for 4 h. The mixture was cooled and then filtered over Celite®, and washed with EtOAc. Purification by column chromatography (40-100% EtO Ac/heptane) afforded the title compound (77 mg, yield 82%) as a pale yellow oil. MS (ESI): mass calcd. for C₃₂H₃₄F₃N₅O₄S1, 637.7; m/z found, 638.3 [M+H]⁺.

Step E, (S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-(4-(2-chloro-6-fluorophenoxy)- 5-111,1.1-trifluoropropan-2-yl)oxylauinazolin-7-yl)-4-ethyl-2.4-dihydro-3H- 1,2.4- triazol-3-one. To a solution of (S)-7-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-5- oxo-4, 5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl)-5 -((1,1,1 -trifluoropropan-2-yl)oxy)quinazolin- 4(3H)-one (69 mg, 0.11 mmol) in acetonitrile (MeCN or ACN) (3.5 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (62 mg, 0.14 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (24 μL, 1.019 g/mL,

0.16 mmol). The solution was stirred for 2 h at room temperature then 2-chloro-6- fluorophenol (24 mg, 0.16 mmol) was added. After stirring overnight, the mixture was diluted with EtOAc and water. The organics were extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-40% EtO Ac/heptane) afforded the title compound as a colorless oil (27 mg, 33%). MS (ESI): mass calcd. for C₃₈H₃₆ClF₄N₅O₄Si, 766.3; m/z found, 766.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.64 (s, 1H), 8.20 (t, J= 2.0 Hz, 1H), 8.07 (t, J= 2.0 Hz, 1H), 7.67-7.74 (m, 4H), 7.37-7.55 (m, 6H), 7.30-7.35 (m, 1H), 7.13-7.25 (m, 2H), 4.90-5.07 (m, 1H), 4.69 (s, 2H), 3.94 (q, J= 7.0 Hz, 2H), 1.65 (t, J= 5.9 Hz, 3H), 1.41 (t, J= 7.3 Hz, 3H), 1.11 (s, 9H).

Step F, (S)-2-(4-(2-Chloro-6-fluorophenoxy)-5-(( 1.1.1 -trifluoropropan-2-yl)oxy) quinazolin-7-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one. To a solution of (S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(4-(2-chloro-6- fluorophenoxy)-5 -(( 1,1,1 -trifluoropropan-2-yl)oxy)quinazolin-7-yl)-4-ethyl-2,4- dihydro-3H-1,2,4-triazol-3-one (27 mg, 0.035 mmol) in THF (0.5 mL) was added tetrabutylammonium fluoride (TBAF) (1M in THF) (0.106 mL, 1 M, 0.106 mmol). The mixture was stirred for 0.5 h at room temperature then diluted with diethyl ether. The organics were washed with saturated aqueous NH4CI, dried over sodium sulfate, filtered and concentrated. The crude mixture was purified by column chromatography (70- 100% EtOAc/heptane) followed by Reverse Phase HPFC (Isco ACCQPrep, 30x100 mm, 20-100% ACN/10 mM NH4OH in water) to provide the title compound as a white solid (10 mg, 54%). MS (ESI): mass calcd. for C₂₂H₁₈CIF₄N₅O₄, 527.9; m/z found, 528.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.63 (s, 1H), 7.94-8.09 (m, 2H), 7.30-7.36 (m, 1H), 7.13-7.25 (m, 2H), 4.91-5.02 (m, 1H), 4.65-4.72 (m, 2H), 3.89-4.00 (m, 2H), 1.64 (t, J= 6.6 Hz, 3H), 1.44 (t, J= 7.3 Hz, 3H).

Example 25: (S)-2-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1, 1, 1 -trifluoropropan-2- ylIoxyk)hthalazin-6-ylI-4-ethyl-5-(hydroxymethylI-2.4-dihydro-3H-1.2.4-triazol-3-one.

Step A. (S)-6-Bromo-1-(2-chloro-6-fluorophenoxy)-8-((1.1.1-trifluoropropan-2- yl)oxy )phthalazinc . 2-Chloro-6-fluoronhenol (159 mg, 1.1 mmol) was added to (S)-6- bromo-1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)phthalazine (Intermediate 25, 80 mg, 0.225 mmol) followed by dioxane (1.0 mL). l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (0.0647 mL, 1.019 g/mL, 0.43 mmol) was added and the reaction stirred at 100 °C for 2 h. The mixture was diluted with EtOAc and water. The organics were extracted with EtOAc twice. The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and adsorbed onto silica. Purification by column chromatography (0-30% EtOAc/heptane) provided the title compound as a yellow semi- solid with minor impurities (80 mg, 82%). MS (ESI): mass calcd. for C₁₇H₁₀BrCIFrN₂O₂, 465.6; m/z found, 465.0 [M+H]⁺.

Step B, (S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-( 1 -(2-chloro-6-fluorophenoxy)- 8-1(1. l-1-trifluoropropan-2-yr)oxy)phthalazin-6-yl)-4-ethyl-2.4-dihydro-3H- 1,2.4- triazol-3-one. A mixture of 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4- dihydro-3H-1,2,4-triazol-3-one (67 mg, 0.18 mmol), (S)-6-bromo-1-(2-chloro-6- fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)phthalazine (68 mg, 0.15 mmol),

Cul (5.6 mg, 0.03 mmol), potassium phosphate tribasic (62 mg, 0.3 mmol), and trans- N,N’-dimethylcyclohexane- 1,2-diamine (9.2 μL, 0.902 g/mL, 0.06 mmol) in dioxane (1.5 mL) was sparged with argon. The mixture was then heated to 120 °C for 2 h. It was cooled down and then filtered over a pad of Celite®, washing with EtOAc and concentrated. Purification by column chromatography (40-80% EtOAc/heptane) afforded the title compound with minor impurities as a colorless oil (94 mg, 84%). MS (ESI): mass calcd. forC₃₈H₃₆ClF₄N₅O₄Si. 766.3; m/z found, 766.2 [M+H]⁺. Step C. (S)-2-(1-(2-Chloro-6-fluorophenoxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy) Dhthalazin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1.2.4-triazol-3-one. To a solution of (S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-( 1 -(2-chloro-6- fluorophenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)phthalazin-6-yl)-4-ethyl-2,4- dihydro-3H-1,2,4-triazol-3-one (90 mg, 0.12 mmol) in THF (1.0 mL) was added tetra- butyl ammonium fluoride (TBAF) (1M in THF) (0.14 mL, 1 M, 0.14 mmol). The mixture was stirred at room temperature for 1 h. Diethyl ether and saturated aqueous NH4CI were added to the reaction mixture. The organics were extracted, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (40-100% EtO Ac/heptane) then RP HPLC (Isco ACCQ Prep, 30x100 mm, 20-100% ACN/ 10 mM NH4OH in water) to provide the title compound as a white solid (39 mg, 62%). MS (ESI): mass calcd. for C₂₂H₁₈CIF₄N₅O₄, 527.9; m/z found, 528.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm: 9.16 (d, J= 5.4 Hz, 1H), 8.14-8.30 (m, 2H), 7.27-7.36 (m, 1H), 7.12-7.24 (m, 2H), 4.90-5.08 (m, 1H), 4.66-4.70 (m, 2H), 3.94 (q, J= 7.0 Hz, 2H), 3.08-3.20 (m, 1H), 1.66 (t, J= 6.1 Hz, 3H),

1.44 (t, J= 7.1 Hz, 3H).

Example 26: (S)-1-(1-((2.5-Dichloropyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxylisoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4Hl-one. Step A. (S)-3-((Benzyloxy)methyD-1-(1-((2.5-dichloropyridin-4-yl)oxy)-8-((l· 1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one . The title compound was prepared in a manner analogous to Example 2, Step A by coupling 2,5- dichloropyridin-4-ol with (S)-3 -((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one

(Intermediate 21). MS (ESI): mass calcd. for C₂₉H₂₄CI₂F₃N₅O₄, 633.1; m/z found, 634.1 [M+H]⁺.

Step B, (S)- 1 -(1-((2.5-Dichloropyridin-4-yl)oxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₂H₁₈CI₂F₃N₅O₄, 543.1; m/z found, 544.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.44 (s, 1H), 8.13 (d, J= 1.8 Hz, 1H), 8.02 - 7.93 (m, 2H), 7.45 (d, J = 5.7 Hz, 1H), 7.11 (s, 1H), 5.04 - 4.94 (m, 1H), 4.74 (d, J= 6.2 Hz, 2H), 3.94 (q, J= 7.2 Hz, 2H), 2.20 - 2.08 (m, 1H), 1.62 (d, J= 6.5 Hz, 3H), 1.45 (t, J= 7.3 Hz, 3H).

Example 27: (S)-2-( 1 -((5-chloro-2-methylpyridin-4-yl)oxy)-8-(( 1.1. 1-trifluoropropan-2- yl)oxy)isoauinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 ,2.4-triazol-3- one. Step A. (S)-3-((Benzyloxy)methyl)- 1 -( 1 -((5-chloro-2-methylpyridin-4-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy )isoauinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one . To a solution of (S)-3-((benzyloxy)methyl)-1-(1-((2,5-dichloropyridin-4-yl)oxy)-8- ((1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol-5(4H)-one (product from Example 26, Step A, 20 mg, 31.52 μmol), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (11.87 mg, 47.29 μmol. 13.22 μL) and (2-dicyclohexylphosphino- 2' ,6' -dimethoxybiphenyl) [2-(2 ' -amino- 1,1 ' -biphenyl)]palladium(II) methanesulfonate (SPhos Pd G3) (2.46 mg, 3.15 μmol) in DMF (0.3 mL) was added Cs₂CO₃ (30.81 mg, 94.57 μmol) at 20 °C under N₂. The mixture was stirred at 95 °C for 16 h. The reaction mixture was cooled down to room temperature and quenched by addition IN HCl (10 mL), and then extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (15 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. Purification (prep-TLC, SiO₂, petroleum ether / ethyl acetate=3/l) afforded the title compound (3 mg, 9%) as colorless oil. MS (ESI): mass calcd. for C₃₀H₂₇CIF₃N₅O₄, 613.2; m/z found, 614.1 [M+H]⁺.

Step B, (S)-1-(5-Chloro-1-((5-chloro-2-methylpyridin-4-yl)oxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol- 5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₃H₂₀CIF₃N₅O₄, 523.1; m/z found, 524.1 [M+H]⁺.

Example 28: (S)-1-(1-((5-Chloro-2-methoxypyridin-4-yl)oxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-

5(4H)-one.

Step A. (S)-5-((Benzyloxy (methyl )-2-( 1 -((5-chloro-2-methoxypyridin-4-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol- 3 -one. The title compound was prepared in a manner analogous to Example 2, Step A by coupling 5-chloro-2-methoxypyridin-4-ol with (S)-3-((benzyloxy)methyl)- 1 -( 1 - chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol- 5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₀H₂₇CIF₃N₅O₅, 630.1; m/z found, 631.3 [M+H]⁺.

Step B, (S)-1-(1-((5-Chloro-2-methoxypyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxylisoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4II)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₃H₂₁CIF₃N₅O₅, 539.1; m/z found, 540.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.22 (s, 1H), 8.13 (d, J= 1.8 Hz, 1H), 8.00 - 7.96 (m, 2H), 7.41 (d, J= 5.8 Hz, 1H), 6.54 (s, 1H), 5.03 - 4.96 (m, 1H), 4.75 (d, J= 5.9 Hz, 2H), 3.99 - 3.92 (m, 5H), 2.13 (brt, J= 6.1 Hz, 1H), 1.62 (br d, J= 6.4 Hz, 5H), 1.46 (t, J= 7.2 Hz, 3H).

Example 29: (S)-1-(5-Chloro- l-((5-chloro-2-methoxypyridin-4-yl)oxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1 ,2.4-triazol-

5(4H)-one.

Step A. (S)-3-((Benzyloxy)methyl)- 1 -(5-chloro- 1 -((5-chloro-2-methoxYpyridin-4- yl)oxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2.4-triazol- 5(4H)-one. To a solution of (S)-3-((benzyloxy)methyl)-1-(1-((5-chloro-2- methoxypyridin-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H-1,2,4-triazol-5(4H)-one (product from Example 28, Step A, 16 mg, 25.40 μmol) in MeCN (1 mL) was added NCS (5.09 mg, 38.09 μmol). The mixture was stirred at 20 °C for 12 h and then heated to 60 °C for another 12 h. The solvent was removed under reduced pressure. Purification (prep-TLC, SiO₂, petroleum ether / ethyl acetate = 2/1) afforded the title compound (10 mg, 46%) as yellow oil. MS (ESI): mass calcd. for C₃₀H₂₆Cl₂F₃N₅O₅, 663.1; m/z found, 664.3 [M+H]⁺.

Step B, (S)- 1 -(5-Chloro- 1 -((5-chloro-2-methoxyDyridin-4-yl)oxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol- 5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₃H₂₁CIF₃N₅O₅, 539.1; m/z found, 540.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.22 (s, 1H), 8.12 (d, J= 6.0 Hz, 1H), 7.90 (d, J= 6.0 Hz, 1H), 7.16 (s, 1H), 6.60 (s, 1H), 4.92-4.86 (m, 1H), 4.73 (d, J= 6.0 Hz, 2H), 4.00 - 3.90 (m, 5H), 2.12 - 2.01 (m, 1H), 1.60 (d, J= 6.6 Hz, 3H), 1.47 (t, J= 7.2 Hz, 3H). Example 30: (S)- 1 -( 1 -((5-Chloro-2-hydroxypyridin-4-yl)oxy)-8-(( 1.1.1 -trifluoropropan- 2-yl)oxy)isoqiiinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)-one.

Step A. (S)-3-((Benzyloxy)methyl)- 1 -( 1 -((5-chloro-2-hydroxypyridin-4-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one . To a solution of (S)-3-((benzyloxy)methyl)-1-(1-((5-chloro-2-methoxypyridin-4- yl)oxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol-

5(4H)-one (product from Example 28, Step A, 110 mg, 155.39 μmol) in MeCN (4 mL) was added trimethylsilyl chloride (TMSCl) (33.76 mg, 310.79 μmol, 39.44 μL) and Nal (46.58 mg, 310.79 μmol) at 15 °C. The mixture was then stirred at 40 °C for 16 h.

The reaction mixture was quenched by addition 1 N HCl at room temperature (20 mL), extracted with ethyl acetate (15 mL × 2). The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. Purification prep-TLC (SiO₂, petroleum ether / ethyl acetate=0/l) afforded the title compound (63 mg, 59%) as white solid. MS (ESI): mass calcd. for C₂₉H₂₄Cl₂F₃N₅O₅, 649.1; m/z found, 650.3 [M+H]⁺. Step B, (S)-1-( l-((5-Chloro-2-hydroxypyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoauinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₂H₁₉CIF₃N₅O₅, 525.1; m/z found, 526.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.12 (d, J= 1.8 Hz, 1H), 8.06 (d, J= 5.7 Hz, 1H), 7.97 (d, J= 1.6 Hz, 1H), 7.47 (d, J= 5.9 Hz, 1H), 7.45 (s, 1H), 6.03 (s, 1H), 5.01- 4.95 (m, 1H), 4.73 (s, 2H),

3.93 (q, J= 7.2 Hz, 2H), 1.59 (d, J= 6.5 Hz, 3H), 1.44 (t, J= 7.2 Hz, 3H). Example 31 : (S)- 1 -( 1 -(( 1.3-Dimethyl-1H-pyrazol-4-yl)oxy)-8-(( 1. l.l-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.

Step A. (S)-3-((Benzyloxy)methyD-1-(1-((1.3-dimethyl-1H-pyrazol-4-yl)oxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one . The title compound was prepared in a manner analogous to Example 2, Step A by coupling 1 ,3 -dimethyl- 1H-pyrazol-4-ol with (S)-3 -((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd for C₂₉H₂₉F₃N₆O₄, 582.2; m/z found, 583.3 [M+H]⁺.

Step B, (S)-1-(1-((1.3-Dimethyl-1H-pyrazol-4-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd for C₂₂H₂₃F₃N₆O₄, 492.2; m/z found, 493.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.05 (d, J= 1.8 Hz, 1H), 7.95 - 7.92 (m, 2H), 7.53 (s, 1H), 7.26 (d, J= 5.9 Hz, 1H), 5.01 - 4.94 (m, 1H), 4.72 (d, J= 3.7 Hz, 2H), 3.96 - 3.91 (m, 2H), 3.87 (s, 3H), 2.38 (s, 1H), 2.21 (s, 3H), 1.66 (d, J= 6.5 Hz, 3H), 1.44 (t, J= 7.3 Hz, 3H).

Example 32: (S)-4-Ethyl-1-(1-(2-fluoro-5-methylphenoxy)-8-((1.1.1-trifluoropropan- 2-yl)oxy)isoauinolin-6-yl)-3 -(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)-one ,

Step A. (S)-3-((Benzyloxy)methyl)-4-ethyl- 1 -(1-(2-fluoro-5-methylphenoxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 1H- 1.2.4-triazol-5(4H)-one . The title compound was prepared in a manner analogous to Example 2, Step A by coupling 2-fluoro-5-methylphenol with (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. For C₃₁H₂₈F₄N₄O₄, 596.2; m/z found, 597.3 [M+H]⁺.

Step B, (S)-4-Ethyl-1-(1-(2-fluoro-5-methylphenoxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. For C₂₄H₂₂F₄N₄O₄, 506.2; m/z found, 507.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.09 (d, J= 1.8 Hz, 1H), 7.95 (d, J= 2.0 Hz, 1H), 7.89 (d, J= 5.8 Hz, 1H), 7.28 (s, 1H), 7.11 - 7.05 (m, 2H), 7.02 - 6.97 (m, 1H), 4.95 (td, J= 6.2, 12.4 Hz, 1H), 4.71 (s, 2H), 3.92 (q, J= 7.2 Hz, 2H), 2.36 (s, 3H), 2.12 (br s, 1H), 1.62 (d, J= 6.4 Hz,

3H), 1.43 (t, J= 7.2 Hz, 3H).

Example 33: (S)- 1 -( 1 -(2-Chloro-6-fluoro-3-(2-methoxycthoxy)phenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2.4-triazol- 5(4H)-one.

Step A. (S)-3-((Benzyloxy)methyl)- 1 -( 1 -(2-chloro-6-fluoro-3-(2- methoxycthoxy)phenoxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step A by coupling 2-chloro-6-fluoro-3-(2-methoxyethoxy)phenol with (S)-3 -((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin- 6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd.

For C₃₃H₃₁CIF₄N₄O₆, 690.2; m/z found, 691.1 [M+ H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.13 (s, 1H), 7.97 (s, 1H), 7.87 - 7.86 (m, 1H), 7.42 - 7.34 (m, 5H), 7.32 - 7.30 (m, 1H), 7.11 - 7.07 (m, 1H), 6.86 - 6.82 (m, 1H), 5.02 (m, 1H), 4.765 (s, 2H), 4.57 (s, 2H),

4.23 - 4.29 (m, 2H), 3.91 - 3.81 (m, 4H), 3.49 (s, 3H), 1.66 - 1.58 (m, 3H), 1.40 - 1.37 (m, 3H).

Step B.(S)-1-(1-(2-Chloro-6-fluoro-3-(2-methoxyethoxy)phenoxy)-8-((1,1,1- trifluoroDroDan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2,4-triazol- 5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step

B. MS (ESI): mass calcd. For C₂₆H₂₅CIF₄N₄O₆, 600.1; m/z found, 601.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.11 (d, J= 1.6 Hz, 1H), 7.97 (t, J= 1.6 Hz, 1H), 7.85 (d, .7= 1.6 Hz, 1H), 7.30 (d, J= 1.6 Hz, 1H), 7.11 - 7.06 (m, 1H), 6.85 - 6.82 (m, 1H), 5.02 (s, 1H), 4.73 d, J = 5.2 Hz, 2H), 4.23 - 4.18 (m, 2H), 3.96 - 3.90 (m, 2H), 3.83 - 3.80 (m, 2H), 3.49 (s, 3H), 2.13 (s, 1H), 1.65 - 1.60 (m, 3H), 1.44 (t, J= 7.2 Hz, 3H). Example 34: (S)- 1 -( 1 -(2-Chloro-6-fluoro-3-(2-hydroxycthoxy)phenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2.4-triazol-

5(4H)-one. To a solution of (S)-3-((benzyloxy)methyl)-1-(1-(2-chloro-6-fluoro-3-(2- methoxyethoxy)phenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H-1,2,4-triazol-5(4H)-one (product from Example 33, Step A, 140 mg, 202.59 μmol) in DCM (4 mL) was slowly added BBr₃ (162.41 mg, 648.27 μmol, 62.46 μL) at 0°C. The mixture was stirred at 20°C for 4.5 hrs. The reaction mixture was poured into iced water (20 mL) and adjusted the pH to 7 with sat. NaHCCh. The mixture was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. Purification (prep-HPLC, METHOD A) afforded 90 mg of a mixture of compounds which was subsequently re-purified by prep-HPLC (METHOD D) to give two title compounds:

(S)- 1 -( 1 -(2-Chloro-6-fluoro-3 -(2-hydroxyethoxy)phenoxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one MS (ESI): mass calcd. for C₂₅H₂₃CIF₄N₄O₆, 586.1; m/z found, 587.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.11 (s, 1H), 7.97 (s, 1H), 7.85 (d, J= 5.6 Hz, 1H), 7.31 (d, J= 6.0 Hz, 1H), 7.10 - 7.08 (m, 1H), 6.85 - 6.81 (m, 1H), 5.03 - 5.01 (m, 1H), 4.73 (d, J =

6.0 Hz„ 2H), 4.19 - 4.17 (m, 2H), 4.03 - 4.01 (m, 2H), 3.96 - 3.91 (m, 2H), 2.23 - 2.16 (m, 2H), 1.66 - 1.62 (m, 3H), 1.46(t, J= 7.2 Hz, 3H) and (S)-1-(1-(2-chloro-6-fluoro-3- hydroxyphenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3 - (hydroxymethyl)- 1H- 1 ,2,4-triazol-5 (4H)-one .

Example 34b: (S)- 1 -( 1 -(2-Chloro-6-fluoro-3-hydroxyphenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2.4-triazol-

5(4H)-one.

The title compound was isolated from Example 34. MS (ESI): mass calcd. for C₂₃H₁₉CIF₄N₄O₅, 542.1; m/z found, 543.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.11 (s, 1H), 7.97 (d, J= 1.6 Hz, 1H), 7.86 (d, J= 6.0 Hz, 1H), 7.32 (d, J= 6.0 Hz,

1H)„ 7.09 - 7.07 (m, 1H), 6.91 - 6.88 (m, 1H), 5.04 - 4.98 (m, 1H), 4.73 (s, 2H), 3.96 - 3.91 (m, 2H), 1.66 - 1.63 (m, 3H), 1.44(t, J= 7.6 Hz, 3H).

Example 35: (S)-1-(1-(2.5-Dimethylphenoxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3 -(hydroxymethyl)- 1H-1.2.4-triazol-5(4H)-one. Step A. (S)-3-((Benzyloxylmethyl)- 1 -( 1 -(2.5-dimethylphenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-one , The title compound was prepared in a manner analogous to Example 2, Step A by coupling 2,5- dimethylphenol with (S)-3 -((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1 -trifluoropropan- 2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₂H₃₁F₃N₄O₄, 592.2; m/z found, 593.3 [M+H]⁺.

Step B, (S)- 1 -(1-(2.5-Dimeth\lphenoxy)-8-(( 1 , 1, 1 -trifluoropropan-2- yl)oxylisoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4Hl-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₅H₂₅F₃N₄O₄, 502.1; m/z found, 503.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.05 (d, J = 1.9 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.89 (d, J = 5.8 Hz, 1H), 7.22 (d, J = 5.8 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.93 (s, 1H), 5.04 - 4.95 (m, 1H), 4.72 (br s, 2H), 3.93 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 2.19 (br s, 1H), 2.14 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H), 1.44 (t, J = 7.2 Hz, 3H).

Example 36: (S)-1-(1-((3-Chloro-1-methyl-1H-pyrazol-4-yl)oxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-

5(4H)-one. Step A. (S)-3-((Benzyloxy)methyl)- 1 -( 1 -((3-chloro- 1 -methyl- 1H-Dyrazol-4-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one . The title compound was prepared in a manner analogous to Example 2, Step A by coupling 3-chloro-1 -methyl -pyrazol-4-ol with (S)-3-((benzyloxy)methyl)-1-(1-chloro-8- ((1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol-5 (4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₂₈H₂₆CIF₃N₆O₄, 602.1; m/z found, 603.2 [M+H]⁺.

Step B, (S)-1-(1-((3-Chloro-1-methyl-1H-pyrazol-4-yl)oxy)-8-((1,1,1-trifluoropropan- 2-yl)oxy)isoqiiinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₁H₂₀CIF₃N₆O₄, 512.1, m/z found, 513.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.09 (d, J= 1.6 Hz, 1H), 7.97 - 7.92 (m, 2H), 7.62 (s, 1H), 7.31 (d, J= 6.0 Hz, 1H), 5.04 - 4.95 (m, 1H), 4.77 - 4.69 ( s, 2H), 3.97 - 3.91 (m, 2H), 3.90 (s, 3H), 2.13 (br s, 1H), 1.67 (d, J= 6.4 Hz, 3H), 1.44 (t, J= 7.2 Hz, 3H).

Example 37: (S)-N-(2-Chloro-3-((6-(4-ethyl-3-(liydroxymethyl)-5-oxo-4.5-dihydro-1H-

1.2,4-triazol- 1 -yl)-8-(( 1.1.1 -trifluoropropan-2-yl)oxylisoauinolin- 1 -yl)oxy)-4- fl uo ro ph c n yl ) m c th an c s ul fo n am i dc .

Step A, (S)-Methyl 3-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4- triazol- 1 -yl)-8-( (1.1.1 -trifluoropropan-2-yl)oxylisoquinolin- 1 -yl)oxy)-2-chloro-4- fluorobenzoate. The title compound was prepared in a manner analogous to Example 2, Step A by coupling methyl 2-chloro-4-fluoro-3-hydroxybenzoate with (S)-3- ((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₂H₂₇CIF₄N₄O₆, 674.1; m/z found, 675.3 [M+H]⁺.

Step B, (S)-3-((6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1.2.4-triazol-

1 -yl)-8-(( 1.1.1 -trifluoropropan-2-yl)oxylisoquinolin- 1 -yl)oxy)-2-chloro-4- fluorobenzoic acid. A mixture of (S)-methyl 3-((6-(3-((benzyloxy)methyl)-4-ethyl-5- oxo-4, 5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin- l-yl)oxy)-2-chloro-4-fluorobenzoate (1 g, 1.48 mmol), L1OH.H₂O (186.50 mg, 4.44 mmol) in THF (2 mL) and H₂O (0.5 mL) was stirred at 60 °C for 3 hrs under N₂ atmosphere. The reaction mixture was cooled down and diluted with H₂O (10 mL) and extracted with ethyl acetate (15 mL × 2). The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. Purification (reversed-phase HPLC (0.1% FA) afforded the title compound (150 mg, 15%) as a yellow solid. MS (ESI): mass calcd. for C₃₁H₂₅CIF₄N₄O₆, 660.1; m/z found, 661.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.13 (d, J= 1.7 Hz, 1H),

8.02 - 7.96 (m, 2H), 7.84 (d, J= 5.7 Hz, 1H), 7.44 - 7.35 (m, 5H), 7.35 - 7.33 (m, 1H), 7.26 - 7.20 (m, 1H), 5.11 - 4.95 (m, 1H), 4.65 (s, 2H), 4.58 (s, 2H), 3.89 (q, J= 7.2 Hz, 2H), 1.65 (dd, J= 6.4, 11.8 Hz, 3H), 1.39 (t, J= 7.2 Hz, 3H).

Step C. (S)-1-(1-(3-Amino-2-chloro-6-fluorophenoxy)-8-((1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-3-((benzyloxy)methyl)-4-ethyl-1H-1.2.4-triazol-5(4H)-one. To a solution of (S)-3-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4- triazol- 1 -yl)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 -yl)oxy)-2-chloro-4- fluorobenzoic acid (70 mg, 105.90 μmol) in t-BuOH (2 mL) was added DPPA (43.72 mg, 158.85 μmol) and TEA (21.43 mg, 211.80 μmol) at 25 °C stirred for 3 h. Then the mixture was heated to 100 °C stirred for 12 h. The reaction mixture was cooled down and diluted with H₂O (10 mL) and extracted with ethyl acetate (15 mL × 2). The combined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. To the residue was charged with HCl/dioxane (2 mL), and then stirred at 20 °C for 1 h. The reaction mixture was quenched by addition NaHCO₃ (1M) 10 mL at 0 °C and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. Then Purification (prep- TLC (SiO₂, petroleum ether: ethyl acetate =1: 1) afforded the title compound (20 mg, 30% yield) as a yellow solid. MS (ESI): mass calcd. for C₃₀H₂₆CIF₄N₅O₄, 631.1; m/z found, 632.1 [M+H]⁺.

Step D. (S)-N-(3-((6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4- triazol- 1 -yl)-8-( (1.1.1 -trifluoropropan-2-yl)oxylisoquinolin- 1 -yl)oxyl-2-chloro-4- fluorophenyl)methanesulfonamide . To a solution of (S)-1-(1-(3-amino-2-chloro-6- fluorophenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-3- ((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (8 mg, 12.66 μmol), pyridine (2.00 mg, 25.32 μmol) and 4-dimethylaminopyridine (DMAP) (154.64 pg, 1.27 μmol) in DCM (2 mL) was added methanesulfonyl chloride (MsCl) (1.31 mg, 11.39 μmol) at 20°C, The mixture was stirred at 40 °C for 16 h. The reaction mixture was cooled down and diluted with H₂O (10 mL) and extracted with DCM (10 mL × 2). The combined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. Purification (prep-TLC, SiO₂, petroleum ether: ethyl acetate =0: 1) afforded the title compound (3 mg, 29%) as a yellow solid.

MS (ESI): mass calcd. for C₃₁H₂₈CIF₄N₅O₆S, 709.1; m/z found, 710.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.12 (d, J= 1.5 Hz, 1H), 7.99 (d, J= 1.7 Hz, 1H), 7.83 (d, J= 5.7 Hz, 1H), 7.56 (dd, J= 4.8, 9.3 Hz, 1H), 7.43 - 7.36 (m, 5H), 7.35 - 7.33 (m, 1H), 7.20 (t, J= 9.1 Hz, 1H), 6.71 (s, 1H), 5.07 - 4.96 (m, 1H), 4.65 (s, 2H), 4.57 (s, 2H), 3.92 - 3.85 (m, 2H), 3.05 (d, J= 3.2 Hz, 3H), 1.67 - 1.64 (m, 3H), 1.40 - 1.37 (m, 3H). Step E, (S)-N-(2-Chloro-3-((6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro-1H- 1.2.4-triazol- 1 -yl)-8-(( 1.1.1 -trifluoropropan-2-yl)oxylisoquinolin- 1-yl)oxyl-4- fl uo ro ph e n yl ) m e th an c s ul fo n am i dc . The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₄H₂₂CIF₄N₅O₆S, 619.1; m/z found, 620.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.11 (d, J= 1.3 Hz, 1H), 7.98 (d, J= 1.7 Hz, 1H), 7.83 (d, J= 5.7 Hz, 1H), 7.57 (dd, J= 5.1, 9.0 Hz, 1H), 7.33 (d, J= 5.7 Hz, 1H), 7.20 (t , J= 9.1 Hz, 1H), 5.07 - 4.94 (m, 1H), 4.74 (s, 2H), 3.99 - 3.89 (m, 2H), 3.06 (d, J= 3.1 Hz, 3H), 1.67 - 1.64 (m, 3H), 1.48 - 1.41 (m, 4H).

Example 38: (S)- 1 -( 1 -(2-Chloro-3-(dimethYlamino)-6-fluorophenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyD- 1H- 1.2.4-triazol-

5(4H)-one.

Step A. (S)-3-((Benzyloxy)methyl)- 1 -( 1 -(2-chloro-3-(dimethylamino)-6- fluorophenoxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoauinolin-6-\l)-4-ethyl- 1H- 1,2,4- triazol-5(4H)-one. Amixture of (S)-1-(1-(3-amino-2-chloro-6-fluorophenoxy)-8- ((1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-3 -((benzyloxy)methyl)-4-ethyl- 1H- 1,2,4-triazol-5(4H)-one (product from Example 37, step C, 105 mg, 166.14 μmol). HCHO (163.50 mg, 5.45 mmol) and CH₃COOH (19.95 mg, 332.28 μmol) in MeOH (3 mL) was added NaBH₃CN (104.40 mg, 1.66 mmol) was stirred at 25 °C for 24 hr under N₂ atmosphere. The reaction mixture was diluted with H₂O (15 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. Then Purification (prep-TLC, SiO₂, petroleum etherethyl acetate =2: 1) afforded the title compound (90 mg, 81%) as a yellow solid. MS (ESI): mass calcd. for C32H₃₀CIP4N₅O₄, 659.2; m/z found, 600.1 [M+H]⁺.

Step B, (S)-1-(1-(2-Chloro-3-(dimethylamino)-6-fluorophenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2.4-triazol- 5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₅H₂₄CIF₄N₅O₄, 569.1; m/z found, 570.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.11 (d, J = 1.5 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J= 5.7 Hz, 1H), 7.30 (d, J= 5.9 Hz, 1H), 7.13 - 7.06 (m, 1H), 6.99 - 6.93 (m, 1H), 5.11 - 4.94 (m, 1H), 4.73 (br d, J= 5.5 Hz, 2H), 3.97 - 3.88 (m, 2H), 2.83 (s, 6H), 2.16 - 2.04 (m, 1H), 1.64 (dd, J= 6.4, 13.1 Hz, 3H), 1.44 (t, J= 7.2 Hz, 3H).

Example 39: (S)-1-(1-((3.6-Dichloropyridin-2-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydro\ymethyl)- 1H- 1 ,2.4-triazol-5(4H)-one.

Step A, (S)-3-((Benzyloxy)methyl)- 1 -( l-((3.6-dichloropyridin-2-yl)oxy)-8-(( 1, 1.1 - trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one . The title compound was prepared in a manner analogous to Example 2, Step A by coupling 3,6- dichloropyridin-2( 1H)-one with (S)-3 -((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. For C₂₉H₂₄Cl₂F₃N₅O₄, 633.1; m/z found, 634.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.12 (d, J= 1.6 Hz, 1H), 8.07 (d, J =

5.8 Hz, 1H), 7.93 (d, .7= 1.6 Hz, 1H), 7.74 (d, J= 8.2 Hz, 1H), 7.48 (d, J= 5.8 Hz, 1H), 7.42 - 7.32 (m, 5H), 7.07 (d, J= 8.2 Hz, 1H), 4.96 (td, J= 6.2, 12.4 Hz, 1H), 4.63 (s, 2H), 4.56 (s, 2H), 3.87 (q, J= 7.2 Hz, 2H), 1.50 (d, J= 6.4 Hz, 3H), 1.37 (t, J= 7.2 Hz, 3H). Step B, (S)- 1 -(1-((3.6-Dichloropyridin-2-yl)oxy)-8-(( 1. 1. 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.

The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. For C₂₂H₁₈Cl₂F₃N₅O₄, 543.1; m/z found, 544.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.09 - 8.05 (m, 2H), 7.92 (d, J= 1.6 Hz, 1H), 7.75 (d, J= 8.2 Hz, 1H), 7.46 (d, J= 5.8 Hz, 1H), 7.07 (d, J= 8.2 Hz, 1H), 4.95 (td, J= 6.4, 12.4 Hz, 1H), 4.71 (s, 2H), 3.92 (q, J= 7.2 Hz, 2H), 2.23 (br s, 1H), 1.50 (d, J = 6.4 Hz, 3H),

1.42 (t, J= 7.2 Hz, 3H). Example 40: (S)-1-(1-(2-Chloro-6-fluoro-3-methoxyphenoxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-

5(4H)-one.

Step A, (S)-3-((Benzyloxy)methyl)-1-(1-(2-chloro-6-fluoro-3-methoxyphenoxy)-8- ((1.1.1 -trifluoropropan-2-yl) isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-one ,

The title compound was prepared in a manner analogous to Example 2, Step A by coupling 2-chloro-6-fluoro-3-m ethoxy-phenol with (S)-3-((benzyloxy)methyl)-1-(1- chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol- 5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₁H₂₇CIF₄N₄O₅, 646.1; m/z found, 647.2 [M+H]⁺.

Step B, (S)- 1 -( l-(2-Chloro-6-fluoro-3-methoxyphenoxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoauinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₄H₂₁CIF₄N₄O₅; m/z found, 556.1; m/z found, 557.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.11 (d, J = 1.7 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J= 5.7 Hz, 1H),

7.31 (d, J= 5.7 Hz, 1H), 7.11 (dt, J= 2.7, 9.2 Hz, 1H), 6.80 (dd, J= 4.2, 9.2 Hz, 1H), 5.10 - 4.93 (m, 1H), 4.73 (d, J= 5.5 Hz, 2H), 3.97 - 3.90 (m, 5H), 2.19 - 2.09 (m, 1H), 1.64 (dd, J= 6.4, 11.6 Hz, 3H), 1.44 (t, J= 7.2 Hz, 3H). Example 41: (S)-1-(1-((3-Chloro-2-methoxy-5-methylpyridin-4-yl)oxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(bydroxymethyl)- 1H- 1.2.4-triazol- 5(4H)-one.

Step A. (S)-3-((Benzyloxy)methyl)- 1 -( 1 -((3-chloro-2-methoxY-5-methylpYridin-4- yl)oxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2.4-triazol- 5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step A by coupling 3-chloro-2-methoxy-5-methylpyridin-4-ol with (S)-3- ((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-

4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₁H₂₉CIF₃N₅O₅, 643.1; m/z found, 644.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.13 (br d, J= 1.8 Hz, 1H), 8.01 - 7.95 (m, 2H), 7.86 - 7.83 (m, 1H), 7.43 - 7.34 (m,

5H), 7.32 - 7.30 (m, 1H), 5.10 - 4.97 (m, 1H), 4.65 (s, 2H), 4.58 (s, 2H), 4.05 (s, 3H), 3.89 (d, J= 7.2 Hz, 2H), 1.64 (dd, J= 4.0, 6.4 Hz, 3H), 1.44 - 1.33 (m, 3H).

Step B, (S)- 1 -( 1 -((3-Chloro-2-methoxy-5-methyl_Dyridin-4-yl)oxy)-8-(( 1, 1, 1- trifluoroDroDan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-3-(bydroxymethyl)- 1H- 1.2,4-triazol- 5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. ¹H NMR (400 MHz, CDCl₃) δ = 8.09 (d, J= 1.6 Hz, 1H), 8.00 - 7.94 (m, 2H), 7.87 - 7.82 (m, 1H), 7.33 - 7.29 (m, 1H), 5.09 - 4.97 (m, 1H), 4.77 - 4.70 (m, 2H), 4.09 - 4.02

(s, 3H), 4.00 - 3.87 (m, 2H), 2.15 - 2.05 (m, 4H), 1.68 - 1.61 (m, 3H), 1.45 (t, J= 7.2 Hz, 3H). Example 42: (S)-1-(1-((3-Chloro-2-methoxypyridin-4-yl)oxyl-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-

5(4H)-one. Step A. (S)-3-((Benzyloxy)methyl)- 1 -( 1 -((3-chloiO-2-methoxypyridin-4-yl)oxy)-8-

((1.1.1 -trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one .

The title compound was prepared in a manner analogous to Example 2, Step A by coupling 3-chloro-2-methoxypyridin-4-ol with (S)-3-((benzyloxy)methyl)-1-(1-chloro- 8-(( 1 , 1 , 1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol-5 (4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₀H₂₇CIF₃N₅O₅, 629.1; m/z found, 630.1 [M+H]⁺.

Step B, (S)- 1 -( 1 -((3-Chloro-2-methoxy_Dyridin-4-yl)oxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₃H₂₁F₃N₅O₅, 539.1; m/z found, 540.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.11 (d, J= 1.5 Hz, 1H), 8.06 (d, J= 5.6 Hz, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.93 (d, J= 5.7 Hz, 1H), 7.40 - 7.35 (m, 1H), 6.77 (d, J = 5.5 Hz, 1H), 5.05 - 4.94 (m, 1H), 4.73 (d, J= 5.5 Hz, 2H), 4.08 (s, 3H), 3.93 (q, J= 7.2 Hz, 2H), 2.18 - 2.11 (m,

1H), 1.62 (br d, J= 6.4 Hz, 3H), 1.44 (t, J= 7.2 Hz, 3H).

Example 43: (S)-1-(1-((5-Chloro-3-methyl-1H-pyrazol-4-yl)oxyl-8-((1,1,1- trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-

5(4H)-one.

Step A. (S)-3-((Benzyloxy)methyl)- 1 -( 1 -((5-chloro-3-methyl- 1 -(42- (trimethylsilyl)ethoxylmethyl)- 1H-pyrazol-4-yl)oxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoauinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step A by coupling 5 -chloro-3 -methyl- 1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol (Intermediate 9) with (S)-3- ((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₄H₄₀ClF₃N₆O₅Si, 732.2, m/z found, 733.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.10 (d, J= 1.9 Hz, 1H), 8.03 - 7.85 (m, 2H), 7.44 - 7.32 (m, 5H), 7.30 (d, J= 5.9 Hz,

1H), 5.39 (d, J= 2.5 Hz, 1H), 5.40 - 5.34 (m, 1H), 5.08 - 4.90 (m, 1H), 4.65 (s, 2H), 4.57 (s, 2H), 3.88 (q, .7= 7.1 Hz, 2H), 3.69 - 3.64 (m, 2H), 2.28 (br s, 1H), 2.26 (s, 2H), 1.66 (d, J= 6.5 Hz, 3H), 1.38 (t, J= 7.2 Hz, 3H), 0.93 - 0.90 (m, 2H), 0.02 (s, 7H).

Step B, (S)- 1 -( 1 -((5-Chloro-3-methyl- 1H-pyrazol-4-ylk>xy)-8-(( 1, 1, 1-trifluoropropan- 2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3 -(hydroxymethyl)- 1H- 1 ,2.4-triazol-5 (4H)-one . A solution of (S)-3-((benzyloxy)methyl)- 1 -( 1 -((5 -chloro-3 -methyl- 1 -((2- (trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (70 mg, 95.47 μmol) in TFA (2 mL) was heated to 80 °C for 15 h. The reaction was cooled down and TFA was removed in vacuo. The residue was re-dissolved in MeOH (3 mL) and added 140 mg K₂CO₃. The mixture was stirred for 0.5 h. The mixture was purified by prep-HPLC (METHOD A) to give the title compound (20.7 mg, 41% yield) as white solid. MS (ESI): mass calcd. for C₂₁H₂₀CIF₃N₆O₄, 512.1; m/z found, 513.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ = 8.08 (d, J= 1.9 Hz, 1H), 7.95 (d, J= 1.8 Hz, 1H), 7.91 (d, J = 5.6 Hz, 1H), 7.29 (d, J = 5.8 Hz, 1H), 5.05 - 4.93 (m, 1H), 4.73 (s, 2H), 3.94 (q, J= 7.3 Hz, 2H), 2.24 (s, 3H), 1.66 (d, J = 6.4 Hz, 3H), 1.44 (t, J= 7.2 Hz, 3H).

Example 44: (S)-1-(1-((3-Chloro-2.5-dimethylpyridin-4-yl)oxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol- 5(4H)-one.

Step A . (S)-3-((Benzyloxy)methyl)- 1 -( 1 -((3-chloro-2.5-dimethylpyridin-4-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one . The title compound was prepared in a manner analogous to Example 2, Step A by coupling 3-chloro-2,5-dimethylpyridin-4-ol with (S)-3-((benzyloxy)methyl)-1-(1- chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol- 5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₁H₂₉CIF₃N₅O₄, 627.2; m/z found, 628.2 [M+H]⁺. Step B, (S)-3-((Benzyloxy)methyl)-1-(1-((3-chloro-2.5-dimethylpyridin-4-yl)oxy)-8- ((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1.2.4-triazol-5(4H)-one The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calcd. for C₂₄H₂₃CIF₃N₅O₄, 537.1; m/z found, 538.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ = 8.31 (d, J= 2.8 Hz, 1H), 8.09 (d, J= 1.6 Hz, 1H), 7.96 (dd, J = 1.7, 4.5 Hz, 1H), 7.83 (d, J= 5.8 Hz, 1H), 7.30 (d, J= 5.8 Hz, 1H), 5.10 - 4.95 (m, 1H),

4.74 (s, 2H), 3.94 (q, J= 7.2 Hz, 2H), 2.65 (s, 3H), 2.44 (br s, 1H), 2.16 (s, 3H), 1.66 (br s, 3H), 1.45 (t, J= 7.2 Hz, 3H).

Example 45: (S)-2-(4-((3-Chloro-5-fluoro-2-methoxypyridin-4-yl)oxyl-8-fluoro-5- (( 1.1.1 -trifluoropropan-2-yl)oxy)pyridol 3.4-dlpyridazin-7-yl)-4-ethyl-5- (hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.

Step A. (,S)-3-((Benzyloxy)methyl)- 1 -(4-((3-chloro-5-fluoro-2-methoxypyridin-4- yl)oxy)-8-fluoro-5-(( 1.1.1 -trifluoropropan-2-yl)oxy)pyrido|3.4-c/|pyridazin-7-yl)-4- ethyl- 1H- 1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 63, Step A by coupling 3-chloro-5-fluoro-2-methoxypyridin-4-ol Intermediate 28) with (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1- trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)- one (Intermediate 18). MS (ESI): mass calcd. for C₂₈H₂₃CIF₅N₇O₅, 667.1; m/z found, 668.1 [M+H]⁺.

Step B, (, S') -4-Ethyl- 1 -(8-fluoro-4-(4-fluoro-2-methylphenoxy)-5-(( 1.1.1- trifluoropropan-2-yl)oxy)pyridol 3.4-d]lpyridazin-7-yl)-3-(hydroxymethyl)- 1H- 1.2.4- triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 63, Step B as an off-white solid. MS (ESI): mass calcd. for C₂₁H₁₇CIF₅N₇O₅, 577.1; m/z found, 578.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.54 (s, 1H), 8.01 (s, 1H), 5.94 - 5.75 (m, 1H), 4.65 (d, J= 5.7 Hz, 2H), 3.98 (s, 3H), 3.91 - 3.76 (m, 2H), 2.18 (br, t, J= 5.9 Hz, 1H), 1.59 (d, J= 6.4 Hz, 3H), 1.38 (t, J= 7.2 Hz, 3H). Example 46: (S)-4-Ethyl-3-(hydroxymethyl)-1-(1-((l-methyl-1H-pyrazol-5-yl)oxy)-8- ((1,1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 1H- 1 ,2.4-triazol-5 (4H)-one .

Step A. (S)-3-((Benzyloxy)methyl)-4-ethyl- 1-( 1 -(( 1 -methyl- 1H-pyrazol-5-yl )oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoauinolin-6-yl)- 1H- 1.2.4-triazol-5(4H)-one . The title compound was prepared in a manner analogous to Example 18, Step A by coupling 1- methyl-1H-pyrazol-5-ol with (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. For C₂₈H₂7F₃N₆O₄, 568.2; m/z found, 569.2 [M+H]⁺.

Step B_, (S)-4-Ethyl-3-(hydroxymethyl)-1-(1-((1-methyl-1H-pyrazol-5-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 1H- 1.2.4-triazol-5(4H)-one . The title compound was prepared in a manner analogous to Example 18, Step B. MS (ESI): mass calcd. For C₂₁H₂₁F₃N₆O₄, 478.2; m/z found, 479.2 [M+H]⁺. ¹H NMR (400 MHz,

CDCl₃) δ = 8.09 (d, J= 2.0 Hz, 1H), 7.98 (d, J= 1.8 Hz, 1H), 7.96 (d, J= 5.8 Hz, 1H), 7.50 (d, J= 2.0 Hz, 1H), 7.36 (d, J= 5.8 Hz, 1H), 6.02 (d, J= 2.0 Hz, 1H), 5.03 - 4.97 (m, 1H), 4.73 (d, J= 6.0 Hz, 2H), 3.93 (q, J= 7.2 Hz, 2H), 3.76 (s, 3H), 2.17 (t, J= 6.2

Hz, 1H), 1.65 (d, J= 6.4 Hz, 3H), 1.44 (t, J= 7.2 Hz, 3H).

Example 47: (S)-1-(1-((3-Chloro-6-methoxypyridin-2-yl)oxyl-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2.4-triazol- 5(4H)-one.

Step A. (S)-3-((Benzyloxy)methyD-1-(1-((3-chloro-6-methoxypyridin-2-yl)oxy)-8 - ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one . The title compound was prepared in a manner analogous to Example 18, Step A by coupling 3-chloro-6-methoxypyridin-2(1H)-one with (S)-3-((benzyloxy)methyl)-1-(1- chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol- 5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₀H₂₇CIF₃N₅O₅, 629.17; m/z found, 630.3 [M+H]⁺. Tl NMR (400 MHz, CDCl₃) δ = 8.13 (d, J= 1.6 Hz, 1 H), 8.08 (d, J= 5.6 Hz, 1 H), 7.92 (d, J= 1.6 Hz, 1 H) 7.64 (d, J= 8.4 Hz, 1 H) 7.46 (d, J= 5.6 Hz, 1 H) 7.31-7.44 (m, 5 H), 6.47 (d, J= 8.4 Hz, 1 H), 5.02-4.934.97 (m, 1 H), 4.63 (s,

2 H), 4.56 (s, 2 H), 3.90-3.84 (m, 2 H) 3.50 (s, 3 H) 1.50 (d, J= 6.4 Hz, 3 H) 1.37 (t, J = 7.2 Hz, 3 H).

Step B, (S)-1-(1-((3-Chloro-6-methoxypyridin-2-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 18, Step B. MS (ESI): mass calcd. for C₂₃H₂₁CIF₃N₅O₅, 539.12; m/z found, 540.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.11 (d, J= 1.6 Hz, 1H), 8.08 (d, J= 6.0 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.45 (d, J= 5.6 Hz, 1H), 6.48 (d, J= 8.4 Hz, 1H), 4.99-4.93 (m, 1H), 4.72 (d, J= 5.6 Hz, 2H), 3.92 (q, J= 7.2 Hz, 2H), 3.50 (s, 3H), 2.11 (s, 1H), 1.50 (d, .7= 6.4 Hz, 3H), 1.43 (t, J= 7.2 Hz, 3H).

Example 48: (S)- 1 -( 1 -(( 1.3 -Dimethyl- 1H-pyrazol-5 -yl)oxy)-8-( (1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.

Step A. (S)-3 -( (benzyloxylmethyl)- 1-11-1(1 ,3 -dimethyl- 1H-pyrazol-5 -yl)oxyl-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-one , The title compound was prepared in a manner analogous to Example 18, Step A by coupling 1,3- dimethyl- 1H-pyrazol-5-ol with (S)-3-((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆O₄, 582.2; m/z found, 583.4

[M+H]⁺.

Step B, (S)- 1 -( 1 -(( 1.3-Dimethyl- 1H-_Dyrazol-5-yl)oxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydro\ymethyl)- 1H- 1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 18, Step B. MS (ESI): mass calcd. for C₂₂H₂₃F₃N₆O₄, 492.1; m/z found, 493.3 [M+H]⁺. ¹H NMR (400

MHz, CDCl₃) δ = 8.08 (d, J= 1.8 Hz, 1H), 7.98 -7.95 (m, 2H), 5.83 (s, 1H), 4.99 (td, J = 6.3, 12.5 Hz, 1H), 4.72 (s, 2H), 3.93 (q, J= 7.2 Hz, 2H), 3.68 (s, 3H), 2.54 - 2.35 (m, 1H), 2.29 (s, 3H), 1.64 (d, J= 6.5 Hz, 3H), 1.43 (t, J= 7.2 Hz, 3H).

Example 49: (S)-1-(1-((2-Chloro-5-fluoropyridin-4-yl)oxy)-8-((l.1. l-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2.4-triazol-5(4H)-one. Step A. (S)-3-((Benzyloxylmethyl)- 1 -( 1 -((2-chloro-5-fluoropyridin-4-yl)oxyl-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one , The title compound was prepared in a manner analogous to Example 18, Step A by coupling 2- chloro-5 -fluoropyridin-4-ol with (S)-3 -((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one

(Intermediate 21). MS (ESI): mass calcd. for C₂₉H₂₄CIF₄N₅O₄, 617.1; m/z found, 618.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.32 (d, J= 2.1 Hz, 1H), 8.14 (d, J= 1.8 Hz, 1H), 7.99 (d, J= 1.7 Hz, 1H), 7.95 (d, J= 5.6 Hz, 1H), 7.45 - 7.42 (m, 1H), 7.42 - 7.34 (m, 5H), 7.27 - 7.24 (m, 1H), 5.03 - 4.93 (m, 1H), 4.67 - 4.63 (m, 2H), 4.60 - 4.55 (m, 2H), 3.92 - 3.85 (m, 2H), 1.64 (d, J= 6.5 Hz, 3H), 1.38 (t, J= 7.2 Hz, 3H).

Step B, (S)-1-(1-((2-Chloro-5-fluoropyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 18, Step B. MS (ESI): mass calcd. for C₂₂H₁₈CIF₄N₅O₄, 527.1; m/z found, 528.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.32 (d, J= 2.1 Hz, 1H), 8.13 (d, J= 1.8 Hz, 1H), 7.98 (d, J =

1.6 Hz, 1H), 7.95 (d, J= 5.8 Hz, 1H), 7.43 (d, J= 5.9 Hz, 1H), 7.26 - 7.24 (m, 1H), 5.01 - 4.92 (m, 1H), 4.74 (d, J= 6.3 Hz, 2H), 3.98 - 3.89 (m, 2H), 2.18 (s, 1H), 1.64 (d, J= 6.5 Hz, 3H), 1.44 (t, J= 7.2 Hz, 3H). Example 50: (S)-4-Ethyl-3-(hydroxymethyl)-1-(1-((tetrahydro-2H-pyran-4-yl)oxy)-8-

((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 1H- 1.2.4-triazol-5(4H)-one .

Step A. (S)-3-((Benzyloxy)methyl)-4-ethyl- 1 -( l-((tetrahydro-2H-pyran-4-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxylisoquinolin-6-yl)- 1H- 1 ,2.4-triazol-5(4H)-one , NaH (27.62 mg, 690.47 μmol , 60% purity) was added to tetrahydropyran-4-ol (2.04 g, 19.97 mmol, 2 mL) at 0 °C under N₂. The mixture was stirred at 0 °C for 30 min, then added (S)-3 -((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin- 6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21, 70 mg, 138 μmol) at 0 °C and heated to 120 °C for 6 hours. The mixture was cooled down and poured into IN HCl (5 mL). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Purification (silica gel chromatography, Petroleum ether/Ethyl acetate = 15/1 to 3/1) to give the title compound (150 mg, crude) as yellow oil. MS (ESI): mass calcd. for C₂₉H₃₁F₃N₄O₅, 572.2; m/z found, 573.1 [M+H]⁺.

Step B , (S)-4-Ethyl-3 -(hydroxymethyl!- 1 -( 1 -( (tetrahydro-2H-pyran-4-yl)oxy)-8-(( 1,1.1- trif1uoropropan-2-yl)oxy)isoauinolin-6-yl)- 1H- 1 ,2.4-triazol-5(4H)-one. To a solution of (S)-3-((benzyloxy)methyl)-4-ethyl- 1 -( 1 -((tetrahydro-2H-pyran-4-yl)oxy)-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one (100 mg, 179 μmol) in DCM (5 mL) was added BCl₃ (1 M, 358 μL). The mixture was stirred at - 78 °C for 1 hr. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL ×3). The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by RP HPLC (condition A) to give title compound (41 mg, 47.6% yield) as a white solid. MS (ESI): mass calcd. for C₂₂H₂₅F₃N₄O₅; m/z found, 482.1; m/z found, 483.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 7.95 (d, J= 1.8 Hz, 1H), 7.91 (d, J= 5.7 Hz, 1H), 7.83 (d, J= 1.8 Hz, 1H), 7.14 (d, J= 5.9 Hz, 1H), 5.53 - 5.41 (m, 1H), 5.02 - 4.91 (m, 1H), 4.72 (br s, 2H), 4.06 (br dd, J= 4.4, 11.6 Hz, 2H), 3.92 (q, J= 7.2 Hz, 2H), 3.71 - 3.59 (m, 2H), 2.23 - 2.12 (m, 2H), 2.12 - 2.05 (m, 1H), 2.00 - 1.86 (m, 2H), 1.64 (d, J= 6.5 Hz, 3H), 1.43 (t, J= 7.2 Hz, 3H). Example 51: (S)-4-Ethyl-3-(hydroxymethyl)- 1 -( 1 -(pentan-3-yloxy)-8-(( 1.1.1- trifluoropropan-2-yl) isoquinolin-6-yl)- 1H- 1.2.4-triazol-5(4H)-one.

Step A: (S)-5-((benzyloxy)methyl)-4-ethyl-2-(T-(pentan-3-yloxy)-8-((l.l.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H-1.2.4-triazol-3-one.

The title compound was prepared in a manner analogous to Example 50, Step A by coupling pentan-3-ol with (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₂₉H₃₃F₃N₄O₄; m/z found, 558.6; m/z found, 559.5 [M+H]⁺.

Step B: (S)-4-Ethyl-3-(hydroxymethyl)-1-(1-(pentan-3-yloxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 50, Step B as a white solid. MS (ESI): mass calcd. for C₂₂H₂₇F₃N₄O₄; m/z found, 468.2; m/z found, 469.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 7.83 (d, J= 5.6 Hz, 2H), 7.70 (d, .J=1.6 Hz, 1H), 7.01

(d, J= 1.6 Hz, 1H), 5.26 - 5.23 (m, 1H), 4.90 - 4.86 (m, 1H), 4.62 (s, 2H), 4.51 - 4.25 (m,1H), 3.86 - 3.80 (m, 2H), 1.74 - 1.67 (m, 4H), 1.54 - 1.52 (m, 3H), 1.42 - 1.34 (m, 3H), 0.91 - 0.86 (m, 6H). Example 52: (S)- 1 -( 1 -(( 1.3-Dimethoxypropan-2-yl)oxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.

Step A: (S)-5-((benzyloxy)methyl)-2-( 1 -(( 1.3-dimethoxypropan-2-yl)oxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2,4-triazol-3-one. The title compound was prepared in a manner analogous to Example 50, Step A by coupling 1,3-dimethoxypropan-2-ol with (S)-3-((benzyloxy)methyl)-1-(1-chloro-8- ((1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol-5 (4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₂₉H₃₃F₃N₄O₆; m/z found, 590.6; m/z found, 591.5 [M+H]⁺.

Step B: (S)- 1-( 1 -(( 1.3-Dimethoxypropan-2-yl)oxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.

The title compound was prepared in a manner analogous to Example 50, Step B as a white solid. MS (ESI): mass calcd. for C₂₂H₂₇F₃N₄O₆; m/z found, 500.2; m/z found, 501.3 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ = 7.96 (d, J= 1.9 Hz, 1H), 7.92 (d, J = 5.8 Hz, 1H), 7.81 (d, J= 1.8 Hz, 1H), 7.14 (d, J= 5.9 Hz, 1H), 5.86 - 5.78 (m, 1H), 5.03 - 4.92 (m, 1H), 4.70 (s, 2H), 3.95 - 3.86 (m, 2H), 3.83 - 3.67 (m, 4H), 3.41 (d, J= 2.9

Hz, 6H), 2.31 - 1.89 (m, 1H), 1.62 - 1.60 (m, 3H), 1.42 (t, J= 7.2 Hz, 3H).

Example 53: 4-Ethyl-3 -(hydroxymethyl)- l-(T-trans-2-methylcyclohexyl)oxy) -8-(((S)-

1.1.1 -trifluoropropan-2-yl)oxy)isoauinolin-6-yl)- 1H- 1.2.4-triazol-5(4H)-one . Step A: 5-((benzyloxy)methyl)-4-ethyl-2-( !-((( 1 R.2R)-2-methylcyclohc\yl)oxy)-8- (((S)-1.l.l -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H- 1 ,2.4-triazol-3 - one. The title compound was prepared in a manner analogous to Example 50, Steps A by coupling irons -2-methyl cyclohexanol with (S)-3-((benzyloxy)methyl)-1-(1-chloro-8- ((1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol-5 (4H)-one

(Intermediate 21). MS (ESI): mass calcd. for C₃₁H₃₅F₃N₄O₄; m/z found, 584.6; m/z found, 585.7 [M+H]⁺.

Step B: 4-Ethyl-3-(hydroxymethyD-1-(1-trans-2-methylcyclohexyl)oxy) -8-(((S)- 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 50, Step B as a white solid. MS (ESI): mass calcd. for C₂₄H₂₉F₃N₄O₄; m/z found, 494.2; m/z found, 495.2 [M+H]⁺. 1H NMR (400 MHz, CDCl₃) δ = 7.91 (d, J= 5.7 Hz, 2H), 7.80 (s, 1H), 7.11 - 7.07 (m, 1H), 5.04 - 4.89 (m, 2H), 4.71 (s, 2H), 3.96 - 3.87 (m, 2H), 2.34 - 2.24 (m, 1H), 1.89 - 1.65 (m, 5H), 1.64 - 1.61 (m, 3H), 1.45 - 1.41 (m, 3H), 1.40 - 1.11 (m, 4H), 1.03 - 0.98 (m, 3H).

Example 54: (S)- 1 -( 1 -(( 1.3-Dihydroxypropan-2-yl)oxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one. Step A: (S)-5-((benzyloxy)methyl)-2-( 1 -(( 1.3-bis(benzyloxy)propan-2-yl)oxy)-8-

((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol- 3 -one. The title compound was prepared in a manner analogous to Example 50, Steps A by coupling l,3-bis(benzyloxy)propan-2-ol for tetrahydropyran-4-ol with (S)-3- ((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 4-ethyl- 1H-1, 2, 4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₄₁H₄₁F₃N₄O₆; m/z found, 742.8; m/z found, 743.5 [M+H]⁺.

Step B: (S)- 1 -( 1 -(( 1.3-Dihydroxypropan-2-yl)oxy)-8-(( 1 , 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3 -(hydroxymethyl)- 1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 50, Step B as a white solid. MS (ESI): mass calcd. for C₂₀H₂₃F₃N₄O₆; m/z found, 472.1; m/z found, 473.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ = 8.03 (d, J= 1.8 Hz, 1H), 7.94 - 7.85 (m, 2H), 7.24 (d, J= 5.9 Hz, 1H), 5.26 - 5.15 (m, 1H), 4.65 - 4.61 (m, 2H), 4.53 - 4.41 (m, 2H), 4.17 - 4.07 (m, 1H), 3.96 - 3.88 (m, 2H), 3.86 - 3.65 (m, 2H), 1.66 - 1.58 (m, 3H), 1.39 (t, J= 7.2 Hz, 3H).

Example 55: (S)-4-Ethyl-3-(hydro\ymethyl)- 1-( 1 -isobutoxy-8-(( 1.1.1 -trifluoropropan- 2.4-triazol-5(4H)-one. Step A: (S)-5-((benzyloxy)methyl)-4-ethyl-2-(1-isobutoxy-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H-1.2.4-triazol-3-one. The title compound was prepared in a manner analogous to Example 50, Step A by coupling 2-methylpropan-1- ol with (S)-3-((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1, 1 , 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₂₈H₃₁F₃N₄O₄, 544.6; m/z found, 545.4 [M+H]⁺. Step B: (S)-4-Ethyl-3-(hydroxymethyl)- 1 -( 1 -isobutoxy-8-(( 1 , 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 50, Step B as a white solid. MS (ESI): mass calcd. for C₂₁H₂₅F₃N₄O₄, 454.2; m/z found, 455.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 7.95 - 7.92 (m, 2H), 7.85 - 7.83 (m, 1H), 7.13 (d, J= 5.9 Hz, 1H), 5.04 - 4.95 (m, 1H),

4.71 (d, J= 5.9 Hz, 2H), 4.26 - 4.15 (m, 2H), 3.92 (q, J= 7.2 Hz, 2H), 2.27 - 2.17 (m, 2H), 1.63 (d, J= 6.4 Hz, 3H), 1.43 (t, J= 7.2 Hz, 3H), 1.08 (dd, J= 2.3, 6.7 Hz, 6H).

Example 56: (S)-4-Ethyl-3-(hydro\ymethyl)- 1-( 1 -(2-methoxyethoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoauinolin-6-yl)- 1H- 1.2.4-triazol-5(4H)-one.

Step A:

The title compound was prepared in a manner analogous to Example 50, Steps A by coupling 2-methoxyethanol with (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol-5 (4H)-one

(Intermediate 21). MS (ESI): mass calcd. for C₂₇H₂₉F₃N₄O₅; m/z found, 546.6; m/z found, 547.5 [M+H]⁺.

Step B: (S)-4-Ethyl-3-(liydroxymethyl)-1-(T-(2-methoxyethoxy)-8-(( 1-1-1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 50, Step B as a white solid. MS (ESI): mass calcd. for C₂₀H₂₃F₃N₄O₅; m/z found, 456.1; m/z found, 457.1 [M+H]⁺. 1H NMR (400 MHz, CDCl₃) δ = 7.96 (d, J= 1.8 Hz, 1H), 7.83 (d, J= 1.7 Hz, 1H), 7.16

(d, J= 5.9 Hz, 1H), 5.05 - 4.91 (m, 1H), 4.70 (d, J= 6.1 Hz, 2H), 4.60 (t, J= 4.8 Hz, 2H), 3.97 - 3.80 (m, 4H), 2.34 - 2.21 (m, 1H), 1.63 (d, J= 6.4 Hz, 3H), 1.42 (t, J= 7.2 Hz, 3H). Example 57: 4-Ethyl-3-(hydroxymethyl)-1-(1-((3-methoxytetrahydro-2H-pyran-4- yl)oxy)-8-(((S)- 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 1H- 1.2.4-triazol-

5(4H)-one.

Step A: 5-((Benzyloxy)methyl)-4-ethyl-2-( 1 -((3-methoxytctrahydro-2H-_Dyran-4- yl)oxy)-8-(((S)- 1.1 , 1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H- 1.2.4- triazol-3-one. The title compound was prepared in a manner analogous to Example 50, Steps A by coupling 3-methoxytetrahydro-2H-pyran-4-ol with (S)-3- ((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₀H₃₃F₃N₄O₆; m/z found, 602.6; m/z found, 603.3 [M+H]⁺.

Step B: 4-Ethyl-3-(hydroxymethyl)-1-(1-((3-methoxytetrahydro-2H-pyran-4-yl)oxy)-8- (((S)-1.l.l -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 1H- 1 ,2.4-triazol-5 (4H)-one . The title compound was prepared in a manner analogous to Example 50, Step B as a white solid. MS (ESI): mass calcd. for C₂₃H₂₇F₃N₄O₆; m/z found, 512.1; m/z found, 513.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.02 - 7.88 (m, 2H), 7.88 - 7.82 (m, 1H), 7.19 - 7.13 (m, 1H), 5.79 - 5.45 (m, 1H), 5.12 - 4.94 (m, 1H), 4.72 (s, 2H), 3.96 (br s, 2H), 3.95 - 3.86 (m, 2H), 3.84 - 3.77 (m, 1H), 3.76 - 3.55 (m, 2H), 3.53 - 3.37 (m, 3H), 2.50 - 2.26 (m, 1H), 2.22 - 2.05 (m, 1H), 1.92 - 1.73 (m, 1H), 1.70 - 1.61 (m, 3H), 1.43 (t, J = 7.2 Hz, 3H).

Example 58: 4-Ethyl- 1 -(1-(( 1 -hydroxy-3-methoxypropan-2-yl)oxy)-8-(((S)- 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-3-(hydroxymethyl)- 1H- 1.2.4-triazol-5(4H)- one.

Step A: 2-(1-(( 1 -(benzyloxy)-3-methoxypropan-2-yl)oxy)-8-(((S)- 1.1. 1-trifluoropropan-

2-yl)oxy)isoauinolin-6-yl)-5-((benzyloxy)methyl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol-

3 -one. The title compound was prepared in a manner analogous to Example 50, Step A by coupling l-(benzyloxy)-3-methoxypropan-2-ol with (S)-3-((benzyloxy)methyl)-1- (1 -chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2,4-triazol-

5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₃₅H₃₇F₃N₄O₆; m/z found, 666.7; m/z found, 667.8 [M+H]⁺.

Step B: 4-Ethyl- 1 -( 1 -(( 1 -hydroxy-3-methoxypropan-2-yl)oxy)-8-(((S)- 1. 1.1- trifluoropropan-2-yl)oxy)isoauinohn-6-yl)-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)- one. The title compound was prepared in a manner analogous to Example 50, Step B as a white solid. MS (ESI): mass calcd. for C₂₁H₂₅F₃N₄O₆; m/z found, 486.1; m/z found, 487.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 7.99 - 7.92 (m, 1H), 7.92 - 7.81 (m, 2H), 7.20 - 7.15 (m, 1H), 5.04 - 4.91 (m, 1H), 4.71 (br s, 2H), 4.64 - 4.46 (m, 2H), 4.30 - 4.21 (m, 1H), 4.07 - 3.79 (m, 3H), 3.78 - 3.54 (m, 2H), 3.46 - 3.40 (m, 3H), 2.36 (br d, J= 2.1 Hz, 1H), 1.68 - 1.65 (m, 3H), 1.43 (t, J= 7.2 Hz, 3H).

Example 59: (SM-(1-((Tetrahydro-2H-thiopyran 1.1 -dioxide)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1 ,2.4-triazol- 5(4H)-one.

Step A: ( S)-5-((Benzyloxy)methyl)-2-( 1 -(( 1.1 -dioxidotetrahydro-2H-thiopyran-4- yl)oxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1 ,2.4-triazol-3 -one . The title compound was prepared in a manner analogous to Example 50 Step A by coupling 4-hydroxytetrahydro-2H-thiopyran 1,1 -dioxide with (S)-3 -((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin- 6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calcd. for C₂₉H₃₁F₃N₄O₆S; m/z found, 620.6; m/z found, 621.5 [M+H]⁺.

Step B: (S)-l-(1-((Tetrahydro-2H-thiopyran l.l-dioxide)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 50, Step B as a white solid. MS (ESI): mass calcd. for C₂₂H₂₅F₃N₄O₆S; m/z found, 530.1; m/z found, 531.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.00 (d, J= 1.8 Hz, 1H), 7.95 - 7.87 (m, 2H), 7.20 (d, J= 5.7 Hz, 1H), 5.73 - 5.60 (m, 1H), 5.12 - 4.97 (m, 1H), 4.73 (s, 2H), 4.01 - 3.85 (m, 2H), 3.59 - 3.24 (m, 2H), 3.12 - 2.93 (m, 2H), 2.77 - 2.38 (m, 4H), 2.17 - 2.02

(m, 1H), 1.69 (d, J= 6.4 Hz, 3H), 1.43 (t, J= 7.2 Hz, 3H). Example 60: 2-( 1 -(6-Chloro-2-fluoro-3-methoxyphenoxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy) isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one. Step A: 5-((Benzyloxy)methyl)-2-( 1 -(6-chloro-2-fluoro-3-methoxyphenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol-3-one. The title compound was prepared in a manner analogous to Example 1, Step A by coupling 6-chloro-2-fluoro-3-methoxyphenol with 5-((benzyloxy) methyl)-2-(1-chloro- 8-(( 1 , 1 , 1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H- 1,2,4- triazol-3-one (Intermediate 20). MS (ESI): mass calcd. for C₃₁H₂₇CIF₄N₄O₅; m/z found, 647.0; m/z found, 648.2 [M+H]⁺.

Step B: 2-< 1 -(6-Chloro-2-fluoro-3-methoxyphenoxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy) isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one. The title compound was prepared in a manner analogous to Example 1, Step B as a white solid. MS (ESI): mass calcd. for C₂₄H₂₁CIF₄N₄O₅; m/z found, 556.1; m/z found, 557.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.15 (s, 1H), 7.96 (s, 1H), 7.88 (d, J = 6.5 Hz, 1H), 7.32 (d, J= 6.8 Hz, 1H), 7.22 (dd, J= 7.0, 5.5 Hz, 1H), 6.81 (m, 1H), 5.01 (m, 1H), 4.73 (s, 2H), 3.96 (s, 3H), 3.94 (t, J= 8.2 Hz, 2H), 1.65 (t, J= 8.5 Hz, 3H), 1.42 (t, J= 8.0 Hz, 3H).

Example 61: 2-( 1 -(2-Chloro-6-fluorophenoxy)-4-fluoro-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoauinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1.2.4-triazol-3- one.

Step A. 6-(3-((BenzyloxyfmethyD-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1-ylf-4- fluoro-3 -methoxy-8-( (1.1.1 -trifluoropropan-2-yl)oxyl-3.4-dihydroisoauinolin- 1 (2H)- one. 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-8- ((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one (product from Intermediate 20, Step D, 15 mg, 0.031 mmol) was treated with l-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2. 2]octane bis(tetrafluoroborate) (Selectfluor^®) (16.3 mg, 0.046 mmol) in mixed solvent of ACN (1 mL) and MeOH (1 mL) at 50 °C for 1 h. The reaction was cooled down and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and concentrated to give crude product as diastereomeric mixture without further purification. MS (ESI): mass calcd. for C₂₅H₂₆F₄N₄O₅; m/z found, 538.2; m/z found, 539.4 [M+H]⁺.

Step B, 5-((Benzyloxy)methyl)-2-( 1 -chloro-4-fluoro-3-methoxy-8-(( 1.1.1- trifluoropropan-2-yl)oxyf-3.4-dihydroisoauinolin-6-ylV4-ethyl-2 4-dihydro-3H-1.2.4- triazol-3 -one . 6-(3 -( (Benzvloxv)methvl)-4-ethvl-5 -oxo-4.5 -dihvdro- 1H- 1.2.4-triazol- 1 - yl)-4-fluoro-3-methoxy-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)-3,4-dihydroisoquinolin- l(2H)-one (20 mg, 0.037 mmol) in POCl₃ (0.5 mL) was heated at 80 °C for 1 h. The solvent was removed in vacuum and dried to give crude product without further purification. MS (ESI): mass calcd. for C₂₅H₂₅CIF₄N₄O₄; m/z found, 556.2; m/z found, 557.4 [M+H]⁺.

Step C. 5-((Benzyloxy)methyl)-2-( 1 -chloro-4-fluoro-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one. 5- ((Benzyloxy)methyl)-2-( 1 -chloro-4-fluoro-3 -methoxy-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)-3,4-dihydroisoquinolin-6-yl)-4-ethyl-2,4-diliydro-3H-1,2,4-triazol-3-one (20 mg, 0.036 mmol) in mixed solvent of DCM (1 mL) and TFA (0.5 mL) was stirred at room temperature for 1 h. The solvent was removed in vacuum and Purification (silica gel flash column system using 20-80% ethyl acetate in heptanes) afforded the title compound as a white solid (12 mg, 63%). MS (ESI): mass calcd. for C₂₄H₂₁CIF₄N₄O₃; m/z found, 524.1; m/z found, 525.4 [M+H]⁺.

Step D: 5-((Benzyloxy)methyl)-2-(1-(2-chloro-6-fluorot)henoxy)-4-fluoro-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one. The title compound was prepared in a manner analogous to Example 1, Step A by coupling 2-chloro-6-fluorophenol with 5-((benzyloxy)methyl)-2-(1-chloro-4-fluoro-8- ((1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H- 1 ,2,4-triazol-

3-one. MS (ESI): mass calcd. for C₃₀H₂₄CIF₅N₄O₄, 634.1; m/z found, 635.4 [M+H]⁺. Step E, 2-(T-(2-Chloro-6-fluorophenoxyf-4-fluoro-8-((1,1,1-trifluoropropan-2- yl) isoauinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 ,2.4-triazol-3- one. The title compound was prepared in a manner analogous to Example 1, Step B. MS (ESI): mass calcd. for C₂₃H₁₈CIF₅N₄O₄; m/z found, 544.1; m/z found, 545.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.21 (s, 1H), 8.01 (s, 1H), 7.82 (s, 1H), 7.45 (m, 1H), 7.10 (m, 2H), 5.32 (s, 2H), 5.01 (m, 1H), 3.92 (m, 2H), 1.65 (m, 3H), 1.32 (m, 3H).

Example 62: 2-(4-(2-Chloro-6-fluorophenoxyf-8-fluoro-5-((1,1,1-trifluoropropan-2- yl!oxy!pyrido 13.4-d]pyrida zin -7 -yl!-4-ethyl-5 -(hydroxymethyl) -2.4-dihydro-3H- 1,2.4- triazol-3-one.

Step A, 3-((Benzyloxy)methyl)-1-(4-(2-chloro-6-fluorophenoxy)-8-fluoro-5-((1,1,1- trifluoropropan-2-yl) pyrido[3.4-d]pyridazin-7-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)- one. The title compound was prepared in a manner analogous to Example 1, Step A by coupling 6-chloro-2-fluoro-phenol with 3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5- ((1,1,1 -trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl- 1H- 1 ,2,4-triazol- 5(4H)-one (Intermediate 17). MS (ESI): mass calcd. for C₂₈H₂₂CIF₅N₆O₄; m/z found, 636.1; m/z found, 637.1 [M+H]⁺.

Step B, 1-(4-(2-Chloro-6-fluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2- yl)oxylpyrido 13.4-dlpyridazin-7 -yl)-4-ethyl-3 -(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)- one. The title compound was prepared in a manner analogous to Example 1, Step B. MS (ESI): mass calcd. for C₂₁H₁₆CIF₅N₆O₄; m/z found, 546.1; m/z found, 547.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.59 (s, 1H), 7.34 - 7.30 (m, 1H), 7.26 - 7.21 (m, 1H),

7.21 - 7.15 (m, 1H), 5.97-5.90 (m, 1H), 4.73 (d, J= 6.2 Hz, 2H), 3.95 (q, J= 7.2 Hz, 2H), 2.29 - 2.12 (m, 1H), 1.67 (d, J= 6.5 Hz, 3H), 1.46 (t, J= 7.2 Hz, 3H).

Example 63: (S)- 1 -(4-(2-Chloro-6-fluorophenoxy)-8-fluoro-5-(( 1, 1, 1 -trifluoropropan-2- yl)oxylpyrido 13.4-dlpyridazin-7 -yl)-4-ethyl-3 -(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)- one.

Step A, (S)-3-((Benzyloxy)methyl)- 1 -(4-(2-chloro-6-fluorophenoxy)-8-fluoro-5-(( 1.1.1- trifluoropropan-2-yl)oxy)pyridol3.4-dlpyridazin-7-yl)-4-ethyl-1H-1.2.4-triazol-5(4H)- one. NaH (60% purity, 418 mg, 10.44 mmol) was slowly added into the mixture of 2- chloro-6-fluorophenol (6.12 g, 41.76 mmol) in DMF (5 mL) at room temperature. After addition, the mixture was heated to 70 °C for 0.5 hour. Then (S)-3-((benzyloxy)methyl)- 1 -(4-chloro-8-fluoro-5-(( 1.1.1 -trifluoropropan-2-yl)oxy)pyrido| 3.4-d]|pyridazin-7-yl)-4- ethyl- 1H- 1 ,2.4-triazol-5(4H)-one (Intermediate 18, 1.1 g crude, 2.09 mmol) was slowly added into the mixture solution at 70 °C and the reaction mixture was further stirred at

70 °C for 2 hours. The mixture was cooled down and diluted by ethyl acetate (20 mL), slowly added 1 M aq. HCl to adjust the pH to 6 at ice-water bath. The mixture was separated and the organic layer was washed by brine (15 mL), dried byNa₂SO₄, filtered and evaporated. Purification (column chromatography, gradient elution: 0 - 100% ethyl acetate in petroleum ether) afforded the title compound (900 mg, 52%) as yellow oil.

MS (ESI): mass calcd. C₂₈H₂₂CIF₅N₆O₄; m/z found, 636.1; m/z found, 637.1 [M+H]^{+ 1}H NMR (400 MHz, CDCl₃) δ = 9.51 (s, 1H), 7.35 - 7.32 (m, 1H), 7.31 - 7.22 (m, 4H), 7.20 - 7.05 (m, 3H), 5.95 - 5.76 (m, 1H), 4.58 (s, 2H), 4.49 (s, 2H), 3.89 - 3.75 (m, 2H), 1.59 (d, J= 6.6 Hz, 3H), 1.36 - 1.29 (m, 3H).

Step B, (S)-1-(4-(2-Chloro-6-fluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2- yl!oxy!pyrido 13.4-dlpyridazin-7 -yl)-4-ethyl-3 -(hydroxymethyl )- 1H- 1 ,2.4-triazol-5(4H)- one. To a solution of (iS)-3-((benzyloxy)methyl)-1-(4-(2-chloro-6-fluorophenoxy)-8- fluoro-5- (( 1.1.1 -trifluoropropan-2-yl)oxy)pyrido| 3.4-z/| py ridazin-7-\ l )-4-cthy l- 1 H- 1 ,2.4-triazol-5(4H)-onc (900 mg, 1.08 mmol) in DCM (10 mL) was added BCl₃ (1 M solution in toluene, 6.52 mL, 6.52 mmol) at -78 °C for 1 hour under N₂. The reaction mixture was quenched by addition of sat. aq. NaHCO₃ (20 mL) at 0 °C, and then warmed to room temperature and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. Purification (column chromatography, gradient elution: 0 - 100% ethyl acetate in petroleum ether), and it was further purified by prep- HPLC (Stationary phase: Boston Prime C18, 5 μm, 150 x 30 mm; Mobile phase: water (0.04% NH₃/H₂O + 10 mM NH4HCO₃) (A) - MeCN (B), gradient elution: 40 - 70% B in A over 7 min (flow rate: 25 mL/min) afforded the title compound (420 mg, 69%) as white solid. MS (ESI): mass calcd. for C₂₁H₁₆CIF₅N₆O₄; m/z found, 546.1; m/z found, 547.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ = 9.72 (s, 1H), 7.59 - 7.33 (m, 3H), 5.92 (br d, J = 4.6 Hz, 1H), 5.82 (br t, J= 5.7 Hz, 1H), 4.49 (d, J= 5.5 Hz, 2H), 3.79 (q, J= 7.3 Hz, 2H), 1.58 (d, J= 6.4 Hz, 3H), 1.27 (t, J= 7.2 Hz, 3H). Example 64: 4-Ethyl-1-(8-fluoro-4-((3-methoxytetrahydro-2H-pyran-4-yl)oxy)-5-(((Sl- 1.1.1 -trifluoropropan-2-yl)oxy)pyrido G 3.4-dlpyridazin-7 -yl)-3 -(hydroxymethyl )- 1H- 1 ,2.4-triazol-5(4H)-one.

Step A, 3-((Benzyloxy)methyl)-4-cth\ 1- 1-(8-fluoro-4-((3-methoxytctrahydro-2H-p\Tan- 4-yl)oxy)-5-(((S)- 1.1.1 -trifluoropropan-2-yl)oxy)pyridol 3.4-d|pyridazin-7-yl)- 1H- 1.2.4- triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 50, Step A by coupling 3-methoxytetrahydro-2H-pyran-4-ol with (S)-3- ((benzyloxy)methyl)- 1 -(4-chloro-8-fluoro-5 -((1,1,1 -trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 18). MS (ESI): mass calcd. for C₂₈H₃₀F₄N₆O₆; m/z found, 622.2; m/z found, 623.1 [M+H]⁺.

Step B , 4-Ethyl- 1 -(8-fluoro-4-((3 -methoxytetrahydro-2H-pyran-4-yl)oxy)-5 -(((SI- 1.1.1- trifluoropropan-2-yl)oxy)pyrido 13.4-dlpyridazin-7 -yl)-3 -(hydroxymethyl)- 1H- 1.2.4- triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 50, Step B. MS (ESI): mass calcd. for C₂₁H₂₄F₄N₆O₆; m/z found, 532.2; m/z found, 533.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ = 9.53 - 9.40 (m, 1H), 6.37 - 5.70 (m,

2H), 4.77 - 4.65 (m, 2H), 4.17 - 3.89 (m, 4H), 3.54 (s, 1H), 3.49 (s, 1H), 3.45 - 3.33 (m, 1H), 2.52 - 2.30 (m, 1H), 2.05 - 1.80 (m, 1H), 1.72 - 1.64 (m, 3H), 1.49 - 1.40 (m, 3H).

Example 65: 2-(8-(2-Chloro-6-fluorophenoxy)-4-fluoro-1-((1,1,1-trifluoropropan-2- yl)oxy)-2.7-naphthyridin-3-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4- triazol-3-one.

Step A. 5-((Benzyloxy)methyl)-2-(8-(2-chloro-6-fluorophenoxy)-4-fluoro- 1 -(( 1.1.1 - trifluoropropan-2-yl)oxy)-2.7-naphthyridin-3-yl)-4-ethyl-2.4-dihydro-3H- 1 .2.4-triazol-

3 -one. The title compound was prepared in a manner analogous to Example 1, Step A by coupling 6-chloro-2-fluoro-phenol with 5-((benzyloxy)methyl)-2-(8-chloro-4-fluoro- 1 -(( 1 , 1 , 1 -trifluoropropan-2-yl)oxy)-2,7-naphthyridin-3 -yl)-4-ethyl-2,4-dihydro-3H- l,2,4-triazol-3-one (Intermediate 19). MS (ESI): mass calcd. for C₂₉H₂₃CIF₅N₅O₄; m/z found, 635.2; m/z found, 636.5 [M+H]⁺.

Step B , 2-( 8-(2-Chloro-6-fluorophenoxy)-4-fluoro- 1 -(( 1.1.1 -trifluoropropan-2-yl)oxy)- 2.7-naphthyridin-3-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.

The title compound was prepared in a manner analogous to Example 1, Step B. MS (ESI): mass calcd. for C₂₂H₁₇CIF₅N₅O₄; m/z found, 545.1; m/z found, 546.4 [M+H]⁺. 1H NMR (400 MHz, CDCl₃) δ = 8.25 (d, J= 6.5 Hz, 1H), 7.55 (d, J= 7.1 Hz, 1H), 7.32 (m, 1H), 7.25 (m, 2H), 5.98 (m, 1H), 4.75 (s, 2H), 3.98 (m, J= 8.5 Hz, 2H), 1.78 (t, J = 9.0 Hz, 3H), 1.52 (t, J= 9.5 Hz, 3H).

Example 66: (S)-4-ethyl-2-(8-fluoro-4-(o-tolyloxy)-5-((1,1,1-trifluoropropan-2- yl)oxy)pyridol3.4-dlpyridazin-7-yl)-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one. Step A. (,S')-3-((Benzyloxy)methyl)-4-ethyl- 1 -(8-fluoro-4-(o-tolyloxy)-5-(( 1.1.1 - trifluoropropan-2-yl)oxy)pyridol 3.4-c/|pyridazin-7-yl)- 1H- 1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 63, Step A by coupling o-cresol with (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-trifluoropropan- 2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 18). MS (ESI): mass calcd. for C₂₉H₂₆F₄N₆O₄; m/z found, 598.2; m/z found, 599.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.55 (s, 1H), 7.46 - 7.35 (m, 5H), 7.34 - 7.29 (m, 2H), 7.27 - 7.20 (m, 2H), 6.01 - 5.92 (m, 1H), 4.67 (s, 2H), 4.58 (s, 2H), 3.91 (q, J = 7.2 Hz, 2H), 2.23 (s, 3H), 1.67 (d, J= 6.6 Hz, 3H), 1.42 (t, J= 7.2 Hz, 3H). Step B, (,S')-4-Ethyl- 1 -(8-fluoro-4-(o-tolyloxy)-5-(( 1.1.1 -trifluoropropan-2- yl)oxy)pyrido|3.4-_<Apyridazin-7-yl)-3-(hydroxymethyl)- 1H- 1.2.4-triazol-5(4H)-one.

The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): mass calcd. for C₂₂H₂₀F₄N₆O₄; m/z found, 508.1; m/z found, 509.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.55 (s, 1H), 7.37 - 7.29 (m, 2H), 7.26 - 7.19 (m, 2H), 5.96 (m, J = 6.3 Hz, 1H), 4.72 (s, 2H), 3.96 (q, J= 7.2 Hz, 2H), 2.65 (br s, 1H), 2.23 (s,

3H), 1.67 (s, 3H), 1.47 (t, J= 7.2 Hz, 3H).

Example 67: (S)-4-Ethyl-2-(8-fluoro-4-(4-fluoro-2-methylphenoxy)-5-((1,1,1- trifluoropropan-2-yl) pyrido[3.4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2.4-dihydro- 3H-1.2.4-triazol-3-one. 5-((1,1,1-trifluoropropan-2-yl)oxy)pyridol3.4-anpyridazin-7-yl)-1i7-1.2.4-triazol-5(4H)- one. The title compound was prepared in a manner analogous to Example 63, Step A by coupling 4-fluoro-2-methylphenol with (S)-3-((benzyloxy)methyl)-1-(4-chloro-8- fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H- l,2,4-triazol-5(4H)-one (Intermediate 18). MS (ESI): mass calcd. C₂₉H₂₅F₅N₆O₄; m/z found, 616.2; m/z found, 617.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.70 - 9.39 (m, 1H), 7.36 (br s, 5H), 7.14 (br dd, J= 5.2, 8.3 Hz, 1H), 7.04 - 6.89 (m, 2H), 5.98 -

5.85 (m, 1H), 4.63 (s, 2H), 4.58 - 4.51 (m, 2H), 3.94 - 3.80 (m, 2H), 2.22 - 2.14 (m,

3H), 1.63 (br d, J= 6.4 Hz, 3H), 1.37 (br t, J= 7.1 Hz, 3H).

Step B, (,V)-4-Ethyl- 1 -(8-fluoro-4-(4-fluoro-2-methylphenoxy)-5-(( 1.1.1- trifluoropropan-2-yl)oxy)pyridol 3.4-J|p\Tidazin-7-yl)-3-(h\droxymethyl)- 1H- 1.2.4- triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): mass calcd. for C₂₂H₁₉F₅N₆O₄; m/z found, 526.1; m/z found, 527.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.47 (s, 1H), 7.10 (dd, J= 5.0, 8.7 Hz, 1H), 7.02 - 6.86 (m, 2H), 5.85 (td, J=6.3, 12.7 Hz, 1H), 4.65 (s, 2H), 3.87 (q, .7=7.1 Hz, 2H), 2.21 (br s, 1H), 2.12 (s, 3H), 1.58 (d, J=6.6 Hz, 3H), 1.39 (t, J=7.2 Hz, 3H).

Example 68: (S)-4-Ethyl-2-(8-fluoro-4-(5-fluoro-2-methylphenoxy)-5-((1,1,1- trifluoropropan-2-yl)oxy)pyridol3.4-dlpyridazin-7-yl)-5-(hydroxymethyl)-2.4-dihydro-

3H-1.2.4-triazol-3-one. Step A, (,S')-3-((benzyloxy)methyl)-4-ethyl- 1 -(8-fluoro-4-(5-fluoro-2-methylphenoxy)- 5-111.1. l-trifluoropropan-2-yl)oxy)pyridol3.4-anpyridazin-7-yl)-1i7-1.2.4-triazol-5(4Ef)- one. The title compound was prepared in a manner analogous to Example 63, St ep A by coupling 5-fluoro-2-methylphenol with (S)-3-((benzyloxy)methyl)-1-(4-chl oro-8-fluoro-5-(( 1,1,1 -trifluoropropan-2-yl)oxy)pyrido[3 ,4-d]pyridazin-7 -yl)-4-ethyl- 1 H-1,2,4-triazol-5(4H)-one (Intermediate 18) as yellow oil. MS (ESI): mass calcd. for C₂₉H₂₅F₅N₆O₄, 616.2; m/z found, 617.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) d = 9.48 (s, 1H), 7.40 - 7.25 (m, 5H), 7.21 (s, 1H), 6.96 - 6.80 (m, 2H), 5.85 (quin, J = 6.4 Hz, 1H), 4.58 (s, 2H), 4.49 (s, 2H), 3.89 - 3.75 (m, 2H), 2.09 (s, 3H), 1.58 (d, J = 6.6 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H).

Step B , (,S')-4-ethyl- 1 -(8-fluoro-4-(5 -fluoro-2-methylphenoxy)-5-(( 1.1.1 -trifluoropropa n-2-yl)oxy)pyridor3.4-<71pyridazin-7-yl)-3-(hydroxymethyl)- 177-1, 2.4-triazol-5(47/)-one

The title compound was prepared in a manner analogous to Example 63, Step B as off- white powder. MS (ESI): mass calcd. for C₂₂H₁₉F₅N₆O₄, 526.1; m/z found, 527.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ = 9.71 (s, 1H), 7.53 - 7.36 (m, 1H), 7.20 (dd, J = 2.7, 9.6 Hz, 1H), 7.11 (dt, J= 2.6, 8.5 Hz, 1H), 6.03 - 5.81 (m, 2H), 4.53 (d, J= 5.5 Hz, 2H), 3.83 (q, J= 7.1 Hz, 2H), 2.13 (s, 3H), 1.60 (d, J= 6.4 Hz, 3H), 1.31 (t, J= 7.2 Hz, 3H). Example 69: (S)-2-(4-(2-Chloro-4.6-difluorophenoxy)-8-fluoro-5-((1,1,1- trifluoropropan-2-yl)oxylpyrido 13.4-dlpyridazin-7 -yl)-4-ethyl-5 -(hydroxymethyl)-2.4- dihydro-3H- 1.2.4-triazol-3 -one .

Step A. (,S')-3-((Benzyloxy)methyl)- 1 -(4-(2-chloro-4.6-difluorophenoxy)-8-fluoro-5- ((1.1.1 -trifluoropropan-2-yl)oxy)pyrido G 3.4-_<7|pyridazin-7 -yl)-4-ethyl- 1 H- 1.2.4-triazol-

5(4H)-one. The title compound was prepared in a manner analogous to Example 63, Step A by coupling 2-chloro-4,6-difluorophenol with (S)-3-((benzyloxy)methyl)-1-(4- chloro-8-fluoro-5 -((1,1,1 -trifluoropropan-2-yl)oxy)pyrido [3 ,4-d]pyridazin-7 -yl)-4- ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 18). MS (ESI): mass calcd. CisHiiClFeNeOr; m/z found, 654.1; m/z found, 655.1 [M+H]⁺.

Step B, (S)- 1 -(4-(2-chloro-4.6-difluorophenoxy)-8-fluoro-5-(( 1.1.1 -trifluoropropan-2- yl)oxy)pyrido|3.4-r/|pyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)- one. The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): mass calcd. for C₂₁H₁₅CIF₆N₆O₄; m/z found, 564.1; m/z found, 565.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.57 (s, 1H), 7.13 - 7.01 (m, 1H), 6.98 - 6.87 (m, 1H), 5.89 (br d, J= 6.4 Hz, 1H), 4.71 (d, J= 6.2 Hz, 2H), 3.92 (q, J= 7.3 Hz, 2H), 2.16 (br s, 1H), 1.64 (d, J= 6.4 Hz, 3H), 1.43 (t, J= 7.2 Hz, 3H).

Example 70: (S)-4-Ethyl-2-(8-fluoro-4-(2-methoxyt)henoxy)-5-((1,1,1-trifluorot)rot)an-

2-yl)oxy)pyridol 3.4-dlpyridazin-7-yl)-5-(hydroxymethyl)-2.4-dihydro-3H- 1.2.4-triazol-

3 -one. Step A, (S)-3-((Benzyloxy)methyl)-4-etfayl-1-(8-fluoro-4-(2-methoxyphenoxy)-5-

(( 1.1.1 -trifluoropropan-2-yl)oxy)pyrido|3.4-r/|pyridazin-7-yl)- 1H- 1.2.4-triazol-5(4H)- one. The title compound was prepared in a manner analogous to Example 63, Step A by coupling 2-methoxyphenol with (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5- ((1,1,1 -trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl- 1H- 1 ,2,4-triazol- 5(4H)-one (Intermediate 18). MS (ESI): mass calcd. C₂₉H₂₆F₄N₆O₅; m/z found, 614.2; m/z found, 615.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.50 (s, 1H), 7.42 - 7.31 (m, 5H), 7.26 (d, J= 1.5 Hz, 1H), 7.23 (br s, 1H), 7.05 - 6.99 (m, 2H), 5.88 (quin, J= 6.4 Hz, 1H), 4.66 - 4.60 (m, 2H), 4.56 - 4.49 (m, 2H), 3.88 - 3.81 (m, 2H), 3.70 (s, 3H),

1.63 (br d, J= 6.4 Hz, 3H), 1.37 (t, J= 7.3 Hz, 3H). Step B. (,V) -4-Ethyl- 1 -(8-fluoro-4-(2-methoxyphenoxy)-5-(( 1.1.1 -trifluoropropan-2- yl)oxy)pyrido|3.4-c/|pyridazin-7-yl)-3-(hydroxymethyl)- 1H- 1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): mass calcd. for C₂₂H₂₀F₄N₆O₅; m/z found, 524.1; m/z found, 525.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ = 9.65 (s, 1H), 7.35 - 7.28 (m, 1H), 7.27 - 7.18 (m, 2H), 7.06 (dt, J= 1.3, 7.7 Hz, 1H), 5.93 (quin, J= 6.5 Hz, 1H), 5.87 (t, J= 5.8 Hz, 1H), 4.53 (d, J= 5.7 Hz, 2H), 3.83 (q, J= 7.0 Hz, 2H), 3.69 (s, 3H), 1.60 (d, J= 6.4 Hz, 3H), 1.31 (t, .7= 7.1 Hz, 3H). Example 71 : (S)-4-Ethyl-2-(8-fluoro-4-((2-methoxy-3.5-dimethylpyridin-4-yl)oxy)-5-

((1,1,1-trifluoropropan-2-yl)oxy)pyridol3.4-dlpyridazin-7-yl)-5-(hydroxymethyl)-2.4- dihydro-3H- 1.2.4-triazol-3 -one .

Step A, (iS)-3-((Benzyloxy)methyl)-4-ethyl-1-(8-fluoro-4-((2-methoxy-3.5- dimethylpyridin-4-yl)oxy)-5 -(( 1.1.1 -trifluoropropan-2-yl)oxy)pyrido 13.4-c/|pyridazin-7 - yl)- 1 H- 1.2.4-triazol-5(4H)-one , The title compound was prepared in a manner analogous to Example 63, Step A by coupling 2-methoxy-3,5-dimethylpyridin-4-ol with (S)-3 -((benzyloxy)methyl)- 1 -(4-chloro-8-fluoro-5 -(( 1,1,1 -trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 18). MS (ESI): mass calcd. for C₃₀H₂₉F₄N₇O₅, 643.2; m/z found, 644.1 [M+H]⁺.

Step B, (, S') -4-Ethyl- 1 -( 8-fluoro-4-((2-methoxy-3.5-dimethylpyridin-4-yBoxy)-5-(( 1.1.1- trifluoropropan-2-yl)oxy)pyridol3.4-anpyridazin-7-yl)-3-(hydroxymethyl)-1i7-1.2.4- triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): mass calcd. for C₂₃H₂₃F₄N₇O₅, 553.2; m/z found, 554.5 [M+H]⁺. 1H NMR (400 MHz, CDCl₃) δ = 9.57 (s, 1H), 7.96 (s, 1H), 5.95 (dq, 7 = 4.5, 6.4 Hz, 1H), 4.75 (d, 7 = 6.2 Hz, 2H), 4.06 - 3.85 (m, 5H), 2.30 (brt, 7 = 6.1 Hz, 1H), 2.12 - 1.97 (m, 6H), 1.67 (d, 7= 6.6 Hz, 3H), 1.48 (t, 7 = 7.2 Hz, 3H).

Example 72: (S)-2-(4-((2-Chloro-4-methylpyridin-3-yl)oxy)-8-fluoro-5-((1,1,1- trifluoropropan-2-yl)oxy)pyrido 13.4-dlpyridazin-7 -yl)-4-ethyl-5 -(hydroxymethyl)-2.4- dihydro-3H- 1.2.4-triazol-3 -one . Step A, (iS)-3-((Benzyloxy)methyl)-1-(4-((2-chloro-4-methylpyridin-3-yl)oxy)-8-fluoro- 5 -(( 1.1.1 -trifluoropropan-2-yl)oxy)pyrido 13.4-7|pyridazin-7 -yl)-4-ethyl- 177- 1.2.4- triazol-5(477)-one. The title compound was prepared in a manner analogous to Example 63, Step A by coupling 2-chloro-4-methylpyridin-3-ol with (S)-3-((benzyloxy)methyl)- l-(4-chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4- ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 18). MS (ESI): mass calcd. C₂₈H₂₄CIF₄N₇O₄; m/z found, 633.2; m/z found, 634.1 [M+H]⁺.

Step B, (iS)-1-(4-((2-Chloro-4-methylpyridin-3-yl)oxy)-8-fluoro-5-((1,1,1- trifluoropropan-2-yl)oxy)pyridol3.4-71pyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)-1H- 1.2.4-triazol-5(4/7)-one. The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): mass calcd. for C₂₁H₁₈CIF₄N₇O₄; m/z found, 543.1; m/z found, 544.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ = 9.56 (s, 1H), 8.21 (d, 7=4.9 Hz, 1H), 7.22 - 7.20 (m, 1H), 5.91 (td, 7=6.3, 12.6 Hz, 1H), 4.71 (d, 7=6.2 Hz, 2H), 3.93 (q, .7=7.1 Hz, 2H), 2.33 - 2.23 (m, 3H), 2.17 (s, 1H), 1.65 (dd, .7=3.1, 6.4 Hz, 3H), 1.44 (t, 7=7.2 Hz, 3H). Example 73: (S)-2-(4-((5-Chloro-3-methyl-1H-pyrazol-4-yl)oxy)-8-fluoro-5-((1,1,1- trifluoropropan-2-yl)oxy)pyrido G 3.4-dlpyridazin-7 -yl)-4-ethyl-5 -(hydroxymethyl 1-2.4- dihydro-3H- 1 ,2,4-triazol-3 -one .

Step A. (S)-3-((Benzyloxy )methyl)- 1 -(4-((5-chloro-3-methyl- 1 -((2- (trimethylsih'l)cthoxy)methyl)- lH-pyrazol-4-yl)oxy)-8-fluoro-5-(( 1.1.1- trifluoropropan-2-yl)oxy)pyridol 3.4-c/lpyridazin-7-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4Hl- one. The title compound was prepared in a manner analogous to Example 63, Step A by coupling 5-chloro-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol (Intermediate 9) with (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1- trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)- one (Intermediate 18). MS (ESI): mass calcd. for C₃₂H₃₇ClF₄N₈O₅Si, 752.2; m/z found, 753.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.56 (s, 1H), 7.42 - 7.31 (m, 5H), 5.89 (quin, J= 6.4 Hz, 1H), 5.37 (s, 2H), 4.63 (s, 2H), 4.54 (s, 2H), 3.87 (q, J= 7.2 Hz, 2H), 3.72 - 3.61 (m, 2H), 2.29 (s, 3H), 1.68 - 1.62 (m, 3H), 1.37 (t, J= 7.2 Hz, 3H), 0.96 - 0.87 (m, 2H), 0.00 (s, 9H).

Step B, (S)- 1 -(4-((5-Chloro-3-methyl- lH-pyrazol-4-yl)oxy)-8-fluoro-5-(( 1.1.1- trifluoropropan-2-yl)oxy)pyridol3.4-anpyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)-1i7- 1.2.4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to

Example 63, Step B. MS (ESI): mass calcd. for C₁₉H₁₇CIF₄N₈O₄, 532.1; m/z found, 533.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.51 (s, 1H), 5.84 (td, J= 6.3, 12.7 Hz, 1H), 4.65 (s, 2H), 3.88 (q, J= 7.2 Hz, 2H), 2.72 (br s, 1H), 2.20 (s, 3H), 1.60 (br s, 3H), 1.38 (t, J= 7.2 Hz, 3H). Example 74: (S)-2-(4-(( 1.3-Dimethoxypropan-2-ylk>xy)-8-fluoro-5-(( 1.1.1- trifluoropropan-2-yl)oxy)pyrido [ 3.4-dlpyridazin-7 -yl)-4-ethyl-5 -(hydroxymethyl 1-2.4- dihydro-3H- 1 ,2,4-triazol-3 -one .

Step A. (,S')-3-((Benzyloxy)methyl)- 1 1.3-dimethoxypropan-2-yl)oxy)-8-fluoro-5-

((1.1.1 -trifluoropropan-2-yl)oxy)pyrido [ 3.4-d]|pyridazin-7 -yl)-4-ethyl- 1 H- 1.2.4-triazol- 5(4H)-one. The title compound was prepared in a manner analogous to Example 63,

Step A by coupling l,3-dimethoxypropan-2-ol with (S)-3-((benzyloxy)methyl)-1-(4- chloro-8-fluoro-5 -((1,1,1 -trifluoropropan-2-yl)oxy)pyrido [3 ,4-d]pyridazin-7 -yl)-4- ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 18). MS (ESI): mass calcd. C₂₇H₃₀F₄N₆O₆; m/z found, 610.2; m/z found, 611.1 [M+H]⁺.

Step B, (S)- 1 -(4-(( 1.3-Dimethoxypropan-2-yl)oxy)-8-fluoro-5-(( 1, 1, 1 -trifluoropropan- 2-yl)oxylpyrido 13.4-c/|pyridazin-7 -yl)-4-ethyl-3-(hydroxymethyl)- 1 H- 1.2.4-triazol- 5(4H)-one. The title compound was prepared in a manner analogous to Example 63,

Step B. MS (ESI): mass calcd. for C₂₀H₂₄F₄N₆O₆; m/z found, 520.2; m/z found, 521.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.37 (s, 1H), 5.88 (quin, J= 5.0 Hz, 1H), 5.78 - 5.61 (m, 1H), 4.64 (d, J= 6.3 Hz, 2H), 3.86 (q, J= 7.3 Hz, 2H), 3.78 - 3.69 (m, 4H), 3.33 (d, J= 9.9 Hz, 6H), 2.15 (t, J= 6.3 Hz, 1H), 1.56 (d, J= 6.4 Hz, 3H), 1.37 (t, J = 7.2 Hz, 3H).

Example 75: 2-(4-(2-Chloro-6-fluorophenoxy)-8-fluoro-5-isopropoxypyridol3.4- dlpyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.

Step A: 5-((Benzyloxy)methyl)-2-(4-(2-chloro-6-fluorophenoxy)-8-fluoro-5- isopropoxypyridor3.4-dlpyridazin-7-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one

The title compound was prepared in a manner analogous to Example 63, Step A by coupling 2-chloro-6-fluorophenol with 5-((benzyloxy)methyl)-2-(4-chloro-8-fluoro-5- isopropoxypyrido[3,4-d]pyridazin-7-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 29). MS (ESI): mass calcd. C₂₈H₂₅CIF₂N₆O₄; m/z found, 582.9; m/z found, 583.9 [M+H]⁺.

Step B: 2-(4-(2-Chloro-6-fluorophenoxy)-8-fluoro-5-isopropoxy p\Tidol3.4-d|p\Tidazin- 7-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one. The title compound was prepared in a manner analogous to Example 63, Step B as an off white solid. MS (ESI): mass calcd. for C₂₁H₁₉CIF₂N₆O₄; m/z found, 492.8; m/z found, 493.6 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 8.24 (s, 1H), 7.02 (d, J= 7.5 Hz, 1H), 6.91 (d, J= 7.0 Hz, 1H), 6.82 ( m, J= 6.2 Hz, 1H), 4.90 (br, s, 1H), 4.72 (m, J= 5.6 Hz, 1H), 4.52 (t , J= 7.5 Hz, 2H), 3.92 (q, J= 9.5 Hz, 2H), 1.34 (d, J= 9.5 Hz, 6H), 1.21 (t , J =

8.5 Hz, 3H).

Example 76: (S)-4-Ethyl-2-(8-fluoro-4-(o-tolylaminol-5-(( 1.1.1 -trifluoropropan-2- yl)oxy)pyridol3.4-dlpyridazin-7-yl)-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one. Step A. (S)-5-((Benzyloxy)methyl)-4-ethyl-2-(8-fluorc)-4-(o-tolylamino)-5-(( 1.1.1- trif1uoropropan-2-yl)oxy)pyrido|3.4-d|pyridazin-7-yl)-2.4-dihydro-3H- 1.2.4-triazol-3- one. NaH (60% purity, 200 mg, 4.27 mmol) was slowly added into the mixture of o- toluidine (1.76 g, 16.4 mmol) in DMF (10 mL) at room temperature. After addition, the mixture reaction was heated to 60 °C for 0.5 hour. Then (S)-3-((bcnzyloxy)methyl)- 1 - (4-chloro-8-fluoro-5-(( 1.1. 1-trifluoropropan-2-yl)oxy)pyrido|3.4-£/|pyridazin-7-yl)-4- cthyl- 1H- 1 ,2.4-triazol-5(4H)-onc (900 mg, 1.09 mmol) was slowly added into the mixture solution at 60 °C and the reaction mixture was further stirred at 60 °C for 1 hour. The mixture was cooled down and diluted by ethyl acetate (20 mL), slowly added 1 M aq. HCl to adjust the pH to 6 at ice-water bath. The mixture was separated and the organic layer was washed by brine (45 mL), dried byNa₂SO₄, filtered and evaporated. The residue was purified by column chromatography (SiO₂, gradient elution: 0 - 100% ethyl acetate in petroleum ether) to give the title compound (163 mg, 25% yield) as yellow oil. MS (ESI): mass ealed. for C₂₉H₂₇F₄N₇O₃, 597.6; m/z found, 598.5 [M+H]⁺. Step B. (S)-4-Ethyl-2-(8-fluoro-4-(o-tolylamino)-5-(( 1.1. 1-trifluoropropan-2- yl)oxy)pyridor3.4-dlpyridazin-7-yl)-5-(hydroxymethyl)-2.4-dihydro-3H-L2.4-triazol-3- one. The title compound was prepared in a manner analogous to Example 63, Step B as as a white powder. MS (ESI): mass ealed. for C₂₂H₂₁F₄N₇O₃, 507.5; m/z found, 508.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.25 (s, 1H), 8.36 (s, 1H), 7.25 - 7.20 (m,

1H), 7.19 - 7.15 (m, 1H), 6.91 (m, 1H), 5.90 (quin, J= 6.4 Hz, 1H), 4.52 (d, J= 6.2 Hz, 2H), 3.92 (q, J= 7.3 Hz, 2H), 2.12 (s, 3H), 1.45 (d, J= 6.6 Hz, 3H), 1.28 (t, J= 7.2 Hz, 3H).

Example 77: (S)-2-(4-((2-Chloro-6-fluorophenyl)amino)-8-fluoro-5-(( 1.1.1- trifluoropropan-2-ylf oxyfpyrido 13.4-dlpyridazin-7 -ylf -4-ethyl-5 -(hydroxymethyl! -2,4- dihydro-3H- 1.2.4-triazol-3 -one .

Step A. (,S')-3-((Benzyloxy)methyl)- 1 -(4-((2-chloro-6-fluorophenyl)amino)-8-fluoro-5- ((1.1.1 -trifluoropropan-2-yl)oxy)p\Tido G 3.4-c/|pyridazin-7 -nP-4-ethyl- 1 H- 1.2.4-triazol- 5(4H)-one. NaH (60% purity, 57 mg, 1.43 mmol) was slowly added into the mixture of 2-chloro-6-fluoroaniline (797 mg, 5.48 mmol) in DMF (3 mL) at room temperature. After addition, the mixture reaction was heated to 60 °C for 0.5 hour. Then (S)-3- ((benzyloxy)methyl)- 1 -(4-chloro-8-fluoro-5 -((1,1,1 -trifluoropropan-2- yl)oxy)pyrido|3.4-£/|pyridazin-7-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-onc (300 mg, 364.42 pimol ) was slowly added into the mixture solution at 60 °C and the reaction mixture was further stirred at 60 °C for 1 hour. The mixture was cooled down and diluted by ethyl acetate (20 mL), slowly added 1 M aq. HCl to adjust the pH to 6 at ice- water bath. The mixture was separated and the organic layer was washed by brine (15 mL), dried byNa₂SO₄, filtered and evaporated. The residue was purified by column chromatography (SiO₂, gradient elution: 0 - 100% ethyl acetate in petroleum ether) to give the title compound (80 mg, 20.5% yield) as yellow oil. MS (ESI): mass calcd. for C28H₂₃CIF₅N₇O₃, 635.1; m/z found, 636.1 [M+H]⁺.

Step B, (S)- 1 -(4-((2-chloro-6-fluorophenyl)amino)-8-fluoro-5-(( 1.1. 1-trifluoropropan-2- yl)oxylpyridoI3.4-anpyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)-1i7-L2.4-triazol-5(4Ff)- one. The title compound was prepared in a manner analogous to Example 63, Step B as white powder. MS (ESI): mass calcd. for C₂₁H₁₇CIF₅N₇O₃, 545.1; m/z found, 546.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.27 (s, 1H), 8.23 (s, 1H), 7.28 - 7.23 (m,

1H), 7.19 - 7.14 (m, 1H), 7.13 - 7.02 (m, 1H), 5.95 (quin, J= 6.4 Hz, 1H), 4.64 (d, J = 6.2 Hz, 2H), 3.87 (q, J= 7.3 Hz, 2H), 2.47 - 2.26 (m, 1H), 1.65 (d, J= 6.6 Hz, 3H), 1.38 (t, J= 7.2 Hz, 3H). Example 78: (S)-2-(4-(4.5-Difluoro-2-methylphenoxy)-8-fluoro-5-(( 1,1.1- trifluoropropan-2-yl)oxy)pyrido 13.4-dlpyridazin-7 -yl)-4-ethyl-5 -(hydroxymethyl 1-2.4- dihydro-3H-1.2.4-triazol-3-one.

Step A. (,V)-3-((Benzyloxy (methyl )- 1 -(4-(4.5-difluoro-2-methylphenoxy)-8-fluoro-5- ((1.1.1 -trifluoropropan-2-yl)oxy)pyrido 13.4-c/|pyridazin-7 -yl)-4-ethyl- 1 H- 1.2.4-triazol- 5(4H)-one. The title compound was prepared in a manner analogous to Example 63,

Step A by coupling 4,5-difluoro-2-methylphenol with (S)-3-((benzyloxy)methyl)-1-(4- chloro-8-fluoro-5 -((1,1,1 -trifluoropropan-2-yl)oxy)pyrido [3 ,4-d]pyridazin-7 -yl)-4- ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 18). MS (ESI): mass calcd. for C₂₉H₂₄F₆N₆O₄, 634.2; m/z found, 635.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.63 - 9.52 (m, 1H), 7.50 - 7.37 (m, 5H), 7.19 - 7.09 (m, 2H), 6.00 - 5.88 (m, 1H), 4.67 (s, 2H), 4.58 (s, 2H), 3.91 (q, J= 7.3 Hz, 2H), 2.17 (s, 3H), 1.68 (d, J= 6.5 Hz, 3H), 1.42 (t, J= 7.3 Hz, 3H).

Step B, (S)- 1 -(4-(4.5-Difluoro-2-methylphenoxy)-8-fluoro-5-(( 1.1.1 -trifluoropropan-2- yl)oxylpyridoI3.4-rinpyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)-1i7-1.2.4-triazol-5(4Ef)- one. The title compound was prepared in a manner analogous to Example 63, Step B as an off-white solid. MS (ESI): mass calcd. for C₂₂H₁₈F₆N₆O₄, 544.1; m/z found, 545.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ = 9.49 (s, 1H), 7.10 - 6.97 (m, 2H), 5.84 (m, J = 6.4 Hz, 1H), 4.65 (d, J= 6.3 Hz, 2H), 3.87 (q, J=7.2 Hz, 2H), 2.22 (t, J= 6.3 Hz, 1H), 2.08 (s, 3H), 1.58 (d, J= 6.4 Hz, 3H), 1.38 (t, J= 7.2 Hz, 3H). Biological Data

DHODH inhibitory activities of the compounds of Examples 1-78 were assessed using the following assays. The half maximal inhibitory concentration values (IC₅₀) are summarized in Table 2.

BIOLOGICAL ASSAYS In vitro Assay: DHODH enzymatic assay

To detect DHODH enzyme activities, dichloroindophenol (DCIP) is added as the final electron acceptor in the assay. DCIP can accept electrons from the reduced coenzyme Q generated in the assay, or from dihydroorotate (DHO) via LMN by binding presumably to the ubiquinone pocket. DCIP solutions are blue, with an intense absorbance around 600 nm, but becomes colorless upon reduction ( J Biol. Chem. (1986) 261, 11386). The assay buffer contained 50 nM HEPES, pH 7.5, 150 mM NaCl, 0.5 mM EDTA, and 0.1% Triton X-100 in MilliQ water. Substrate consisting of 20 mM DHO, 5mM CoQ₆, and ImM DCIP in assay buffer, initiates the reaction. The assay is run in end-point mode by quenching the reaction with the potent DHODH inhibitor brequinar. Absorbance measurements were obtained using the BMG Phera Star plate-reading spectrophotomer. Purified human DHODH was purchased from Proteros (cat. No. PR- 0044). Chemicals were purchased from Sigma- Aldrich, Teknova, and Avanti Polar Lipids. Liquid handling was performed using Labcyte Echo and Lormulatrix Tempest.

In vitro Assay: MOLM-13 Cellular Assay

MOLM-13 cells were obtained from DSMZ and were maintained in RPMI 1640 + Glutamax + 25mM HEPES (Invitrogen, catalog number 72400) supplemented with 10% heat inactivated fetal bovine serum (FBS; Invitrogen, catalog number 16140). The day prior to assay set-up, cells were pelleted, resuspended in fresh media, counted, and cells were plated at 0.4 x 10⁶ cell/mL in a T150 flask. On the day of the assay, cells were pelleted, resuspend in fresh media, counted and seeded at 5,000 cells/well in white opaque 96-well tissue culture treated microplates (Perkin Elmer, catalog number 6005680). Cells were exposed to different concentrations of test compounds at 37 °C, 5% CO₂ for 72 hours immediately after seeding. Cell viability was acquired on a Perkin Elmer Envision 2104 multilabel reader using the CellTiter-Glo assay (Promega) according to the manufacturer’s instructions.

Table 2.

NT or nt means not tested.

Claims

CLAIMS What is claimed is:

1. A compound having the structure of Formula (I): wherein

X¹ and X² are each independently CH or N;

Y is O, NH or S;

OH, halo, CN, OC_1-6alkyl, OC_1-6haloalkyl and OC_3-6cycloalkyl;

R³ is H, Cl orF;

R⁴ is selected from the group consisting of:

(a) C_1-6alkyl; C_1-6alkyl substituted with one or two substituents each independently selected from the group consisting of OH and OCH₃; tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH₃; cyclohexyl substituted with CH₃; and tetrahydro-2H-thiopyran 1,1 -dioxide; and

(b)

wherein

OCH₃, SCH₃, and OCF₃; C_1-6haloalkyl; C_1-6haloalkyl substituted with a member selected from the group consisting of: OH, and OCH₃; CN; OH; CO₂H; N(CH₃)₂; (C=O)NH-CH₂CH₂OH; NHSO₂CH₃; OC_1-6alkyl; and OC_1-6alkyl substituted with a member selected from the group consisting of: OH, and OCH₃; is selected from the group consisting of: halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of: OH, OCH₃, SCH₃, and OCF₃; OC_1-6alkyl; C_1-6haloalkyl; C_1-6haloalkyl substituted with a member selected from the group consisting of: OH, and OCH₃; and n is 1 or 2; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- oxide thereof.

2. The compound according to claim 1, wherein X¹ is CH; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

3. The compound according to claim 1, wherein X¹ is N; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

4. The compound according to any of claims 1-3, wherein X² is CH; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

5. The compound according to any of claims 1-3, wherein X² is N; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

6. The compound according to any of claims 1-5, wherein Y is O; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

7. The compound according to any of claims 1-5, wherein Y is NH; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

8. The compound according to any of claims 1-5, wherein Y is S; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

9. The compound according to any of claims 1-8, wherein R¹ is selected from the group consisting of: C_1-6alkyl; C_1-6alkyl substituted with OH, or OCH₃; C_2-6alkenyl; C_1-6haloalkyl; C_1-6haloalkyl substituted with OH, or OCH₃; C_3-6cycloalkyl; tetrahydropyran-4-yl; and phenyl; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

10. The compound according to any of claims 1-8, wherein R¹ is C_1-4alkyl; C_1-4alkyl substituted with OH, or OCH₃; C_1-4haloalkyl; C_1-4haloalkyl substituted with OH, or OCH₃; tetrahydropyran-4-yl; or C_3-6cycloalkyl; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

11. The compound according to any of claims 1-5, wherein Y is O and R¹ is CH(CH₃)₂, CH(CH₃)(CF₃), cyclopropyl, cyclobutyl, or tetrahydropyranyl; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- oxide thereof.

12. The compound according to any of claims 1-5, wherein Y is O and R¹ is CH(CH₃)₂ or CH(CH₃)(CF₃); or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

13. The compound according to any of claims 1-8, wherein R¹ is ; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- oxide thereof.

14. The compound according any of claims 1-13, wherein R² . is or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

15. The compound according to any of claims 1-13, wherein R² is wherein

R^b is C_1-4alkyl substituted with OH, halo, CN, OC_1-4alkyl, OC_1-4haloalkyl or OC_3-6cycloalkyl; and

R^c is C_1-4alkyl, C_1-4haloalkyl, or C_3-6cycloalkyl; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

16. The compound according to any of claims 1-13, wherein R² is ; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

17. The compound according to any of claims 1-16, wherein R³ is H; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

18. The compound according to any of claims 1-16, wherein R³ is Cl; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

19. The compound according to any of claims 1-16, wherein R³ is F; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

20. The compound according to any of claims 1-19, wherein R⁴ is or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- oxide thereof.

21. The compound according to any of claims 1-19, wherein R⁴ is where

R^d is independently selected from the group consisting of: H; halo; CH₃; CH₂OH; CN; OH; CO₂H; N(CH₃)₂; (C=O)NH-CH₂CH₂OH; NHSO₂CH₃; OCH₃, OCH₂CH₂OH and OCH₂CH₂OCH₃;

R^e is selected from the group consisting of: Cl, F, CH₃, and OCH₃; and n is 1 or 2; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- oxide thereof.

22. The compound according to any of claims 1-19, wherein R⁴ is or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- oxide thereof.

23. The compound according to any of claims 1-19, wherein pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant ;, orN-oxide thereof.

24. The compound according to any of claims 1-19, wherein R⁴ is wherein

R^d is independently selected from the group consisting of: H, Cl, CH₃, OH and OCH₃; R^e is F, Cl, or CH₃; and n is 1 or 2; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- oxide thereof.

25. The compound according to any of claims 1-19, wherein R⁴ is or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- oxide thereof.

26. The compound according to any of claims 1-19, wherein R⁴ is or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- oxide thereof.

27. The compound according to any of claims 1-19, 21 and 24, wherein n is 1; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

28. The compound according to any of claims 1-19, 21 and 24, wherein n is 2; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

29. The compound according to any of claims 1-5, wherein Y is NH and R⁴ is or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

30. The compound according to any of claims 1-5, wherein or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- oxide thereof.

31. The compound according to claim 1, having the structure of Formula (IA): wherein

Y is O, NH or S;

OH, halo, CN, OC_1-6alkyl, OC_1-6haloalkyl and OC_3-6Cycloalkyl;

R^c is selected from the group consisting of: C_1-6alkyl, C_1-6haloalkyl, and C_3-6Cycloalkyl; R³ is H or F;

R⁴ is selected from the group consisting of:

(a) C_1-6alkyl; C_1-6alkyl substituted with one or two substituents each independently selected from the group consisting of OH and OCH₃; tetrahydro- 2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH₃; cyclohexyl substituted with CH₃; and tetrahydro-2H-thiopyran 1,1-dioxide; and

(b)

R^d is independently selected from the group consisting of: H; halo; C_1-6alkyl; C_1-6alkyl substituted with a member selected from the group consisting of:

OH, and OCH₃; CN; OH; CO₂H; N(CH₃)₂; (C=O)NH-CH₂CH₂OH; NHSO₂CH₃; OC_1-6alkyl; and OC_1-6alkyl substituted with a member selected from the group consisting of: OH, and OCH₃;

R^e is selected from the group consisting of: halo, C_1-6alkyl, and OC_1-6alkyl; and n is 1 or 2; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

32. The compound according to claim 1, having the structure of Formula (IB): wherein X¹ is CH orN;

Y is O or NH;

R¹ is selected from the group consisting of: C_1-6alkyl; C_1-6alkyl substituted with OH, or OCH₃; C_2-6alkenyl; C_1-6haloalkyl; C_1-6haloalkyl substituted with OH, or OCH₃; C_3-6Cyeloalkyl; C_3-6heterocycloalkyl; and phenyl;

R² is ; wherein

OH, halo, CN, OC_1-6alkyl, OC_1-6haloalkyl and OC_3-6Cyeloalkyl;

R³ is H or F;

R⁴ is selected from the group consisting of:

R^d is independently selected from the group consisting of: H, Cl, and F; R^e is selected from the group consisting of: F, CH₃, and OCH₃; and n is 1 or 2; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

33. The compound according to claim 31, wherein Y is O.

34. The compound according to claim 31 or 33, wherein R¹ is C_1-6alkyl or C_1-6haloalkyl.

35. The compound according to claim 32, wherein Y is N.

36. The compound according to claim 32, wherein Y is O.

37. A compound having the structure of Formula (II): wherein

Z is O, S, or NH;

R⁵ is selected from the group consisting of: C_1-6alkyl; C_1-6alkyl substituted with OH, or OCH₃; C_1-6haloalkyl; C_1-6haloalkyl substituted with OH, or OCH₃; and C_3-6Cycloalkyl; wherein

R^g is selected from the group consisting of: halo, C_1-6alkyl and OC_1-6alkyl; and m is 1 or 2; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- oxide thereof.

38. The compound according to claim 37, wherein X³ is N and X⁴ is CH; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

39. The compound according to claim 37, wherein X³ is CH and X⁴ is N; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

40. The compound according to any of claims 37-39, wherein Z is O; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

41. The compound according to any of claims 37-40, wherein R⁵ is C_1-6alkyl or C₁- 6haloalkyl; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

42. The compound according to any of claims 37-41, wherein R⁷ is H; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

43. The compound according to any of claims 37-42, wherein R⁸ is or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

44. A compound selected from the group consisting of:

2-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6- yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-2-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)iso quinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

2-( 1 -((2-Chloro-6-fluorophenyl)amino)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)iso quinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 2-( 1 -((2-Chloro-6-fluorophenyl)thio)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy) iso quinolin-6-yl)-4-ethyl-5-(hydroxymetliyl) -2,4-dihydro-3H-1,2,4-triazol-3-one;

4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-8- ((1,1,1 -trifluoropropan-2-yl)oxy)iso quinolin- 1 -yl)oxy)-3 ,5 -difluorobenzonitrile;

2-( 1 -(2,6-Difluoro-4-(hydroxymethyl) phenoxy)-8-(( 1, 1 , 1 -trifluoropropan-2- yl)oxy)isoquinohn-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H -1,2,4- triazol-3-one;

4-((6-(4-Ethyl-3 -(hydroxymethyl)-5 -oxo-4,5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl)-8- ((1,1,1 -trifluoropropan-2-yl)oxy)iso quinolin- 1 -yl)oxy)-3 ,5 -difluorobenzoic acid;

4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-8- ((1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin - 1 -yl)oxy)-3 ,5 -difluoro-N-(2- hydroxy ethyl) benzamide;

2-( 1 -(2-Chloro-4,6-difluorophenoxy)-8-(( 1 , 1 , l-trifluoropropan-2-yl)oxy)iso quinolin-6-yl)-4-ethyl-5-(hydroxy methyl) -2,4-dihydro-3H-1,2,4-triazol-3-one;

2-(1-(2-Chloro-6-fluorophenoxy)-8-isopropoxyisoquinolin-6-yl)-4-ethyl-5-

(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-2-( 1 -((4-Chloropyridin-3-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2-yl) oxy) iso quinolin-6-yl)-4-ethyl-5-(hydroxymethyl) -2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-2-( 1 -((2-Chloropyridin-3-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2-yl) oxy)iso quinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-2-( 1 -((2-Chloro-4-methylpyridin-3-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-5-(hydroxy methyl)-2,4-dihydro-3H-1,2,4-triazol-3- one;

(S)-2-( 1 -((2,4-Dimethylpyridin-3 -yl)oxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)iso quinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-4-Ethyl-5-(hydroxymethyl)-2-( 1 -((4-methylpyridin-3-yl)oxy)-8-(( 1,1,1 -trifluoro propan-2-yl)oxy)isoquinolin-6-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one. (S)-2-( 1 -(2-Chloro-5-methylphenoxy)-8-(( 1, 1 , 1 -trifluoropropan-2-yl) oxy)iso quinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-1-(1 -((3-Chloropyridin-2-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-3-(hydroxy methyl) -1H-1,2,4-triazol-5(4H)-one;

(S)-1-(1 -((4-Chloro-2-methylpyridin-3-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2-yl) oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;

(S)-1-(1 -((3,5 -Dimethylisoxazol-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-3-(hydroxy methyl)-1H-1,2,4-triazol-5(4H)-one;

2-(8-(2-Chloro-6-fluorophenoxy)- 1 -((1,1,1 -trifluoropropan-2-yl)oxy)-2,7- naphthyridin-3-yl)-4-ethyl-5 -(hydroxy methyl)-2,4-dihydro-3H-1,2,4-triazol-3- one;

2-(4-(2-Chloro-6-fluorophenoxy)-5-((1,1,1-trifluoropropan-2-yl)oxy) pyrido[3,4- d]pyridazin-7-yl)-4-ethyl-5 -(hydroxy methyl)-2,4-dihydro-3H-1,2,4-triazol-3- one;

2-(4-(2-Chloro-6-fluorophenoxy)-5-(( 1,1,1 -trifluoropropan-2-yl)oxy)- 1,6- naphthyridin-7-yl)-4-ethyl-5-(hydroxymethyl)-2, 4-dihydro -3H-1,2,4-triazol-3- one;

(S)-3-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy) isoquinolin-6-yl)- 1 -ethyl- 1 -methylurea;

(S)-2-(4-(2-Chloro-6-fluorophenoxy)-5-(( 1,1,1 -trifluoropropan-2-yl)oxy) quinazolin-7-yl)-4-ethyl-5-(hydroxy methyl)-2,4-dihydro-3H-1,2,4-triazol-3- one;

(S)-2-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)phthalazin- 6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-1-(1 -((2,5 -Dichloropyridin-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinohn-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one; (S)-2-( 1 -((5 -Chloro-2-methylpyridin-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4- triazol-3-one;

(S)-1-(1-((5-Chloro-2-methoxypyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1 -(5 -Chloro- 1 -((5 -chloro-2-methoxypyridin-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan- 2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1 -( 1 -((5-Chloro-2-hydroxypyridin-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1 -( 1 -(( 1 ,3-Dimethyl- 1H-pyrazol-4-yl)oxy)-8-(( 1, 1 , 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)-4-Ethyl- 1 -( 1 -(2-fluoro-5-methylphenoxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;

(S)-1-(1-(2-Chloro-6-fluoro-3-(2-methoxyethoxy)phenoxy)-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymetliyl)-1H-1,2,4- triazol-5 (4H)-one ;

(S)- 1 -( 1 -(2-Chloro-6-fluoro-3-(2-hydroxyethoxy)phenoxy)-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4- triazol-5 (4H)-one ;

(S)- 1 -( 1 -(2-Chloro-6-fluoro-3 -hydroxyphenoxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymetliyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1-( 1 -(2,5-Dimethylphenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6- yl)-4-ethyl-3 -(hydroxymethyl)- 1H- 1 ,2, 4-triazol-5 (4H)-one ; (S)-1-(1 -((3 -Chloro- 1 -methyl- 1H-pyrazol-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)-N-(2-Chloro-3-((6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4- triazol- 1 -yl)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 -yl)oxy)-4- fluorophenyl)methanesulfonamide;

(S)- 1-( 1 -(2-Chloro-3-(dimethylamino)-6-fluorophenoxy)-8-(( 1,1,1 -trifluoropropan- 2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1 -( 1 -((3 ,6-Dichloropyridin-2-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1 -( 1 -(2-Chloro-6-fluoro-3 -methoxyphenoxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1 -( 1 -((3 -Chloro-2-methoxy-5 -methylpyridin-4-yl)oxy)-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4- triazol-5 (4H)-one ;

(S)- 1 -( 1 -((3 -Chloro-2-methoxypyridin-4-yl)oxy)-8-(( 1 , 1 , 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1 -( 1 -((5 -Chloro-3 -methyl- 1H-pyrazol-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1 -( 1 -((3-Chloro-2,5 -dimethylpyridin-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one; (S)-2-(4-((3-Chloro-5-fluoro-2-methoxypyridin-4-yl)oxy)-8-fluoro-5-((1,1,1- trifluoropropan-2-yl)oxy)pyrido [3 ,4-d]pyridazin-7 -yl)-4-ethyl-5 - (hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-4-Ethyl-3 -(hydroxymethyl)- 1 -( 1 -(( 1 -methyl- 1H-pyrazol-5 -yl)oxy)-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-1-(1-((3-Chloro-6-methoxypyridin-2-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1 -( 1 -(( 1 ,3-Dimethyl- 1H-pyrazol-5-yl)oxy)-8-(( 1, 1 , 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1 -( 1 -((2-Chloro-5 -fluoropyridin-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)-4-Ethyl-3-(hydroxymethyl)- 1 -( 1 -((tetrahydro-2H-pyran-4-yl)oxy)-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-4-Ethyl-3-(hydroxymethyl)-1-(1-(pentan-3-yloxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)- 1 -( 1 -(( l,3-Dimethoxypropan-2-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

4-Ethyl-3 -(hydroxymethyl)- 1 -( 1 -trans-2-methylcyclohexyl)oxy) -8-(((S)- 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)- 1-( 1 -(( 1 ,3-Dihydroxypropan-2-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)-4-Ethyl-3 -(hydroxymethyl)- 1 -( 1 -isobutoxy-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one; (S)-4-Ethyl-3-(hydroxymethyl)- 1 -( l-(2-methoxyethoxy)-8-(( 1,1,1 -trifluoropropan- 2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one;

4-Ethyl-3 -(hydroxymethyl)- 1 -( 1 -((3 -methoxytetrahydro-2H-pyran-4-yl)oxy)-8- (((S)-1,l, 1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 1H- 1 ,2,4-triazol-5 (4H)- one;

4-Ethyl- 1 — ( 1 — (( 1 -hydroxy-3 -methoxypropan-2-yl)oxy)-8-(((S)- 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-3-(hydroxymethyl)-1H-1,2,4-triazol-

5(4H)-one;

(S)-1-(1-((tetrahydro-2H-thiopyran l,l-dioxide)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

2-( 1 -(6-Chloro-2-fluoro-3 -methoxyphenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3- one;

2-( 1 -(2-Chloro-6-fluorophenoxy)-4-fluoro-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4- triazol-3-one;

2-(4-(2-Chloro-6-fluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro- 3H- 1 ,2,4-triazol-3 -one;

(S)-1-(4-(2-Chloro-6-fluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4- triazol-5(4H)-one;

4-Ethyl- 1 -(8-fluoro-4-((3 -methoxytetrahydro-2H-pyran-4-yl)oxy)-5 -(((S)- 1 , 1 , 1 - trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-3-(hydroxymethyl)-1H- 1 ,2,4-triazol-5 (4H)-one; 2-(8-(2-Chloro-6-fluorophenoxy)-4-fluoro- 1 -(( 1 , 1 , 1 -trifluoropropan-2-yl)oxy)-2,7- naphthyridin-3 -yl)-4-ethyl-5 -(hydroxymethyl)-2,4-dihydro-3H- 1 ,2,4-triazol-3 - one;

(S)-4-Ethyl-2-(8-fluoro-4-(o-tolyloxy)-5-(( 1,1,1 -trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4- triazol-3-one;

(S)-4-Ethyl-2-(8-fluoro-4-(4-fluoro-2-methylphenoxy)-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4- triazol-3-one;

(S)-4-Ethyl-2-(8-fluoro-4-(5-fluoro-2-methylphenoxy)-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4- triazol-3-one;

(S)-2-(4-(2-Chloro-4,6-difluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro- 3H- 1 ,2,4-triazol-3 -one;

(S)-4-Ethyl-2-(8-fluoro-4-(2-methoxyphenoxy)-5-(( 1,1,1 -trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4- triazol-3-one;

(S)-4-Ethyl-2-(8-fluoro-4-((2-methoxy-3,5-dimethylpyridin-4-yl)oxy)-5-((1,1,1- trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4- dihydro-3H-1,2,4-triazol-3-one;

(S)-2-(4-((2-Chloro-4-methylpyridin-3-yl)oxy)-8-fluoro-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro- 3H- 1 ,2,4-triazol-3 -one ;

(S)-2-(4-((5-Chloro-3-methyl-1H-pyrazol-4-yl)oxy)-8-fluoro-5-((1,1,1- trifluoropropan-2-yl)oxy)pyrido [3 ,4-d]pyridazin-7 -yl)-4-ethyl-5 - (hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (S)-2-(4-((l,3-Dimethoxypropan-2-yl)oxy)-8-fluoro-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro- 3H- 1 ,2,4-triazol-3 -one ;

2-(4-(2-Chloro-6-fluorophenoxy)-8-fluoro-5-isopropoxypyrido[3,4-d]pyridazin-7- yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-4-Ethyl-2-(8-fluoro-4-(o-tolylamino)-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3El-1,2,4- triazol-3-one;

(S)-2-(4-((2-Chloro-6-fluorophenyl)amino)-8-fluoro-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro- 3H-1,2,4-triazol-3-one; and

(S)-2-(4-(4,5-Difluoro-2-methylphenoxy)-8-fluoro-5-(( 1 , 1 , 1 -trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro- 3H- 1 ,2,4-triazol-3 -one ; and pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants, and N-oxides thereof.

45. A pharmaceutical composition comprising: (A) a compound according to any of claims 1-36, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof; and (B) at least one pharmaceutically acceptable excipient.

46. A pharmaceutical composition comprising: (A) a compound according to any of claims 37-43, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof; and (B) at least one pharmaceutically acceptable excipient.

47. A pharmaceutical composition comprising an effective amount of a compound of claim 44; and at least one pharmaceutically acceptable excipient.

48. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition comprising inhibiting or altering dihydroorotate oxygenase enzyme activity in the subject by administering to the subject an effective amount of at least one compound according to any of claims 1-36, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

49. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition comprising inhibiting or altering dihydroorotate oxygenase enzyme activity in the subject by administering to the subject an effective amount of at least one compound according to any of claims 37-43, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, orN-oxide thereof.

50. The method according to claim 48, wherein the disorder, disease or medical condition is selected from the group consisting of: inflammatory disorders and autoimmune disorders.

51. The method according to claim 48, wherein the disorder, disease or medical condition is cancer.

52. The method according to claim 48, wherein the disorder, disease or medical condition is selected from the group consisting of: lymphomas, leukemias, carcinomas, and sarcomas.

53. The method according to claim 48, wherein the disorder, disease or medical condition is selected from the group consisting of: acute lymphoblastic leukemia, acute myeloid leukemia, (acute) T-cell leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, bisphenotypic B myelomonocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, large granular lymphocytic leukemia, plasma cell leukemia, and also myelodysplastic syndrome, which can develop into an acute myeloid leukemia.

54. The method according to claim 48, wherein the disorder, disease or medical condition is acute myeloid leukemia.

55. The method according to claim 49, wherein the disorder, disease or medical condition is selected from the group consisting of: inflammatory disorders and autoimmune disorders.

56. The method according to claim 49, wherein the disorder, disease or medical condition is cancer.

57. The method according to claim 49, wherein the disorder, disease or medical condition is selected from the group consisting of: lymphomas, leukemias, carcinomas, and sarcomas.

58. The method according to claim 49, wherein the disorder, disease or medical condition is selected from the group consisting of: acute lymphoblastic leukemia, acute myeloid leukemia, (acute) T-cell leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, bisphenotypic B myelomonocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, large granular lymphocytic leukemia, plasma cell leukemia, and also myelodysplastic syndrome, which can develop into an acute myeloid leukemia.

59. The method according to claim 49, wherein the disorder, disease or medical condition is acute myeloid leukemia.

60. The method according to any of claims 48-59, wherein the at least one compound is selected from the group consisting of:

(S)-2-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)iso quinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 2-( 1 -((2-Chloro-6-fluorophenyl)amino)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)iso quinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

2-( 1 -((2-Chloro-6-fluorophenyl)thio)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy) iso quinolin-6-yl)-4-ethyl-5-(hydroxymetliyl) -2,4-dihydro-3H-1,2,4-triazol-3-one;

2-( 1 -(2,6-Difluoro-4-(hydroxymethyl) phenoxy)-8-(( 1, 1 , 1 -trifluoropropan-2- yl)oxy)isoquinohn-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3E[-1,2,4- triazol-3-one;

2-(1-(2-Chloro-6-fluorophenoxy)-8-isopropoxyisoquinolin-6-yl)-4-ethyl-5-

(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-2-( 1 -((2-Chloro-4-methylpyridin-3-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-5 -(hydroxy methyl)-2,4-dihydro-3H-1,2,4-triazol-3- one;

(S)-2-( 1 -((2,4-Dimethylpyridin-3 -yl)oxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)iso quinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (S)-4-Ethyl-5-(hydroxymethyl)-2-( 1 -((4-methylpyridin-3-yl)oxy)-8-(( 1,1,1 -trifluoro propan-2-yl)oxy)isoquinolin-6-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

(S)-2-( 1 -(2-Chloro-5-methylphenoxy)-8-(( 1, 1 , 1 -trifluoropropan-2-yl) oxy)iso quinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-2-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)phthalazin- 6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (S)- 1 -( 1 -((2,5-Dichloropyridin-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymetliyl)-1H-1,2,4-triazol-5(4H)- one;

(S)-2-( 1 -((5 -Chloro-2-methylpyridin-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymetliyl)-2,4-diliydro-3H-1,2,4- triazol-3-one;

(S)-1-(1-((5-Chloro-2-methoxypyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymetliyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1 -(5 -Chloro- 1 -((5 -chloro-2-methoxypyridin-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan- 2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymetliyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1 -( 1 -((5-Chloro-2-hydroxypyridin-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymetliyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1 -( 1 -(( 1 ,3 -Dimethyl- 1H-pyrazol-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)-1-(1-(2-Chloro-6-fluoro-3-(2-methoxyethoxy)phenoxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4- triazol-5 (4H)-one ;

(S)- 1 -( 1 -(2-Chloro-6-fluoro-3-(2-hydroxyethoxy)phenoxy)-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4- triazol-5 (4H)-one ; (S)-1-(1 -(2-Chloro-6-fluoro-3 -hydroxyphenoxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)- 1-( 1 -(2,5-Dimethylphenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6- yl)-4-ethyl-3 -(hydroxymethyl)- 1H- 1 ,2, 4-triazol-5 (4H)-one ;

(S)- 1 -( 1 -((3-Chloro- 1 -methyl- 1H-pyrazol-4-yl)oxy)-8-(( 1, 1 , 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)-1-(1-((3-Chloro-2-methoxypyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one; (S)-1-(1 -((5 -Chloro-3 -methyl- 1H-pyrazol-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)-1-(1 -((3-Chloro-2,5 -dimethylpyridin-4-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)-2-(4-((3-Chloro-5-fluoro-2-methoxypyridin-4-yl)oxy)-8-fluoro-5-((1,1,1- trifluoropropan-2-yl)oxy)pyrido [3 ,4-d]pyridazin-7 -yl)-4-ethyl-5 - (hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)- 1 -( 1 -(( l,3-Dimethoxypropan-2-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one; 4-Ethyl-3 -(hydroxymethyl)- 1 -( 1 -trans-2-methylcyclohexyl)oxy) -8-(((S)- 1 , 1 , 1 - trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)- 1 -( 1 -(( 1 ,3 -Dihydroxypropan-2-yl)oxy)-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)- one;

(S)-4-Ethyl-3 -(hydroxymethyl)- 1 -( 1 -isobutoxy-8-(( 1,1,1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-4-Ethyl-3-(hydroxymethyl)- 1 -( l-(2-methoxyethoxy)-8-(( 1,1,1 -trifluoropropan- 2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one;

5(4H)-one;

2-(4-(2-Chloro-6-fluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro- 3H- 1 ,2,4-triazol-3 -one; (S)-1-(4-(2-Chloro-6-fluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4- triazol-5 (4H)-one ;

4-Ethyl- 1 -(8-fluoro-4-((3 -methoxytetrahydro-2H-pyran-4-yl)oxy)-5 -(((S)- 1 , 1 , 1 - trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-3-(hydroxymethyl)-1H- 1 ,2,4-triazol-5 (4H)-one ;

2-(8-(2-Chloro-6-fluorophenoxy)-4-fluoro- 1 -(( 1 , 1 , 1 -trifluoropropan-2-yl)oxy)-2,7- naphthyridin-3-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3- one;

(S)-4-Ethyl-2-(8-fluoro-4-((2-methoxy-3,5-dimethylpyridin-4-yl)oxy)-5-((1,1,1- trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4- dihydro-3H-1,2,4-triazol-3-one; (S)-2-(4-((2-Chloro-4-methylpyridin-3-yl)oxy)-8-fluoro-5-(( 1 , 1 , 1 -trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro- 3H- 1 ,2,4-triazol-3 -one ;

(S)-2-(4-((5-Chloro-3-methyl-1H-pyrazol-4-yl)oxy)-8-fluoro-5-(( 1,1,1- trifluoropropan-2-yl)oxy)pyrido [3 ,4-d]pyridazin-7 -yl)-4-ethyl-5 - (hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-2-(4-((l,3-Dimethoxypropan-2-yl)oxy)-8-fluoro-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro- 3H- 1 ,2,4-triazol-3 -one ;