KR20220137709A - Heterocyclic Compounds as Dihydroorotate Dehydrogenase Inhibitors - Google Patents

Abstract

및

(상기 식에서, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X¹, X², X³, X⁴, Y 및 Z는 본 명세서에 정의됨).Disclosed are compounds, compositions and methods for treating a disease, disorder, or medical condition affected by modulation of DHODH. Embodiments of such compounds are represented by formulas (I) and (II) as follows:

and

(Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X ¹ , X ² , X ³ , X ⁴ , Y and Z are defined herein).

Description

Heterocyclic Compounds as Dihydroorotate Dehydrogenase Inhibitors

Cross-reference to related applications

This application is filed on February 4, 2020, with respect to 35 U.S.C. You are entitled to claim priority under § 119(e), the disclosure of which is incorporated herein by reference in its entirety.

technical field

The present invention relates to novel compounds that are dihydroorotate dehydrogenase (DHODH) inhibitors. Such compounds may be useful in the treatment of a disease, disorder or medical condition that would benefit from inhibiting DHODH. The present invention also relates to pharmaceutical compositions comprising one or more such compounds, methods for preparing such compounds and compositions, and the use of such compounds or pharmaceutical compositions for the treatment of cancer, and autoimmune and inflammatory diseases, syndromes and disorders. it's about

Acute myeloid leukemia (AML) is a clonal disease of the blood and bone marrow due to mutations occurring in normal hematopoietic stem cells. AML is a heterogeneous disease in that it exhibits diverse cytogenetic, morphological and immunophenotypic features, and is characterized by an accumulation of clonal abnormal myeloid progenitor cells known as myeloblasts. These cells show disruption of normal myeloid differentiation and excessive proliferation, reducing the formation of hematopoietic cells. Although disease remission can be achieved with standard induction chemotherapy, refractory and recurrent disease remains a challenge due to the persistence of leukemia stem cells. Thus, with over 20,000 new cases per year in the United States and a 5-year overall survival rate of less than 30%, AML represents an unmet medical need (Stein ET et al., Health Qual Life Outcomes 16: 193, 2018).

Based on the knowledge that loss of stem cell self-renewal and differentiation are combined in normal cells, differentiation therapy is considered an attractive approach for the treatment of AML. Treatment with all-trans retinoic acid for acute promyelocytic leukemia, which accounts for 10-15% of all AMLs, is a classic example of differentiation therapy. Retinoic acid targets a promyelocytic leukemia protein (PML)-retinoic acid receptor-α (RAR-α) fusion protein encoded by a t(15,17) chromosomal translocation. Targeting PML-RAR specifically elevates the transcriptionally mediated differentiation block induced by the fusion protein, and initial clinical trials with single agent ATRA showed 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).

Differentiation therapy, although successful, is only applicable to a small population of AML patients. Research activities aimed at finding additional differentiation inducers have had limited success. Recently, dihydroorotate dehydrogenase (dihydroorotate dehydrogenase) as a potentially more broadly applicable differentiation target in phenotypic screening aimed at finding small molecules that overcome the blockade of maturation of primary murine bone marrow cells expressing the homeobox protein HoxA9 ( DHODH) was highlighted. These proteins are key transcription factors involved in the balancing of stem cell maintenance/differentiation, are commonly expressed in hematopoietic progenitor cells, are downregulated upon induction of differentiation, and have been shown 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 novel pyrimidine biosynthetic pathway. Inhibition of DHODH causes a decrease in glycoprotein and phospholipid biosynthesis, as well as pyrimidine synthesis, an important precursor in nucleotide synthesis (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 small molecule DHODH inhibitors leflunomide and teriflunomide, which are FDA-approved for rheumatoid arthritis and multiple sclerosis, respectively (Lolli ML et al., Recent patents on Anti-Cancer Drug Discovery 13: 86, 2018]).

DHODH inhibition drives AML differentiation in vitro , as evidenced by upregulation of the differentiation markers CD11b and CD14, and in vivo dose-dependent anti-leukemia effects, reduced leukemia stem cells, and Since the initial observation by Sykes et al., which showed that it induces long-term viability, it has been shown that small molecule DHODH inhibitors mediate antiproliferative activity against AML cells by concomitant cell cycle arrest, upregulation of CD11b and CD14, and induction of apoptosis. Additional evidence has emerged (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]). In addition, preclinical solid tumor in vitro and in vivo models have demonstrated the effectiveness of DHODH inhibition, and DHODH has been identified as 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 therapeutic benefit to patients suffering from cancer and/or inflammatory and immunological diseases.

Embodiments of the present invention relate to compounds, pharmaceutical compositions containing them, methods for their preparation and purification, methods for using them as inhibitors of DHODH enzyme activity, and diseases, disorders or medical conditions such as autoimmune disorders or inflammatory disorders or cancer. To a method of using them in the treatment of a subject suffering from or diagnosed with a disease such as

An embodiment of the present invention is a compound of formula (I); or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof:

[Formula (I)]

(In the above formula,

X ¹ and X ² are each independently CH or N;

Y is O, NH or S;

R ¹ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _2-6 alkenyl; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; C _3-6 cycloalkyl; C _3-6 heterocycloalkyl; and phenyl;

또는

이며;R ² is

or

is;

here,

R ^b is C _1-6 alkyl substituted with a member selected from the group consisting of OH, halo, CN, OC _1-6 alkyl, OC _1-6 haloalkyl and OC _3-6 cycloalkyl;

R ^c is selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;

R ³ is H, Cl or F;

R ⁴ is selected from the group consisting of:

(a) C _1-6 alkyl; C _1-6 alkyl substituted with 1 or 2 substituents each independently selected from the group consisting of OH and OCH ₃ ; tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH ₃ ; cyclohexyl substituted with CH ₃ ; and tetrahydro-2H-thiopyran 1,1-dioxide; and

(b)

및

;

and

;

here,

R ^d is independently H; halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH, OCH ₃ , SCH ₃ , and OCF ₃ ; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; OC _1-6 alkyl; and OC _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;

R ^e is halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH, OCH ₃ , SCH ₃ , and OCF ₃ ; OC _1-6 alkyl; C _1-6 haloalkyl; selected from the group consisting of C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;

n is 1 or 2).

An embodiment of the present invention provides a compound of formula (II); or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof:

[Formula (II)]

(In the above formula,

X ³ and X ⁴ are each independently CH or N; wherein when X ³ is N, X ⁴ is CH, and when X ³ is CH, X ⁴ is N;

Z is O, S, or NH;

R ⁵ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; and C _3-6 cycloalkyl;

이고;R ⁶ is

ego;

R ⁷ is H or F;

이고;R ⁸ is

ego;

here,

R ^f is independently H; halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; and OC _1-6 alkyl;

R ^g is selected from the group consisting of halo, C _1-6 alkyl and OC _1-6 alkyl;

m is 1 or 2).

The present invention relates to a disease in a subject, including a mammal and/or a human, in which a disease, syndrome, disorder or disorder, including but not limited to, cancer and/or inflammatory disease or immunological disease, is affected by inhibition of DHODH enzyme activity; A syndrome, disease or disorder is treated or ameliorated using a compound of formula (I) (and a compound of formula (II)), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof provides additional ways to do so.

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

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

The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

With respect to substituents, the term “independently” refers to a situation in which more than one substituent is possible, in which case the substituents may be the same or different from each other.

The term “substituted” means that a particular group or moiety has one or more substituents. The term “unsubstituted” means that a particular group has no substituents. The term “optionally substituted” means that a particular group is unsubstituted or substituted with one or more substituents. When the term “substituted” is used to describe a structural system, it is meant that the substitution occurs at any valence permissive position on the system.

Unless specifically limited in a particular use case, 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, iso Included are hexyl, and groups considered equivalent to any of the foregoing examples, given the teachings given herein and those of ordinary skill in the art. “C _1-6 alkyl” refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms in the chain. “C _1-4 alkyl” refers to a straight or branched chain alkyl group having from 1 to 4 carbon atoms in the chain.

The term “alkenyl” includes unsaturated aliphatic groups similar in length and possible substitutions to the alkyls described above, but containing at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (eg, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.). . The term alkenyl further includes alkenyl groups comprising oxygen, nitrogen, sulfur or phosphorus 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 (eg, C ₂ -C ₆ for straight chain, C ₃ -C ₆ for branched chain).

The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic, fused polycyclic or spiro polycyclic carbon ring having from 3 to 12 ring atoms per carbon ring. “C _3-6 cycloalkyl” refers to a carbon ring having 3 to 6 ring atoms per carbon ring. Illustrative examples of cycloalkyl groups include the following entities in the form of appropriately bound moieties:

또는

.

or

.

The term “halogen” or “halo” refers to 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 replacing hydrogen with halogen. The term “C _1-6 haloalkyl” as used herein refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms in the chain, optionally replacing hydrogen with halogen. The term “C _1-4 haloalkyl” as used herein refers to a straight or branched chain alkyl group having from 1 to 4 carbon atoms in the chain, optionally replacing hydrogen with halogen. Examples of “haloalkyl” groups include trifluoromethyl (CF ₃ ), difluoromethyl (CF ₂ H), monofluoromethyl (CH ₂ F), pentafluoroethyl (CF ₂ CF ₃ ), tetrafluoro roethyl (CHFCF ₃ ), monofluoroethyl (CH ₂ CH ₂ F), trifluoroethyl (CH ₂ CF ₃ ), tetrafluorotrifluoromethylethyl (CF(CF ₃ ) ₂ ) and the art In view of the ordinary skill in the art and the teachings given herein, groups that are considered equivalent to any of the above examples are included.

The term “aryl” refers to a monocyclic, aromatic carbon ring (a ring structure in which all of the ring atoms are carbon) having 6 atoms per ring. (The carbon atom of the aryl group is sp2 hybridized.)

The term “phenyl” refers to the following moieties:

.

.

The terms "4- to 7-membered heterocycloalkyl" and "4- to 6-membered heterocycloalkyl" mean a total of 4, each containing one or two identical or different ring heteroatoms of the N, O and S series; means a monocyclic saturated heterocycle having 5, 6 or 7 ring atoms, or 4, 5 or 6 ring atoms, wherein the heterocycloalkyl group is not excluded from the presence of any one of the carbon atoms , it can be attached to the rest of the molecule via a nitrogen atom. Illustrative examples of heterocycloalkyl groups include the following entities in the form of appropriately bound moieties:

및

.

and

.

The term “tetrahydro-2H-thiopyran 1,1-dioxide” refers to the following moieties:

.

.

The term "tetrahydrofuranyl" refers to the following moieties:

.

.

The term "tetrahydropyranyl" refers to the following moieties:

.

.

The term "heteroaryl" refers to a monocyclic or fused bicyclic heterocycle (a carbon atom and up to 4 heteroatoms selected from nitrogen, oxygen and sulfur), having 3 to 9 ring atoms per heterocycle. ring structures having ring atoms). Illustrative examples of heteroaryl groups include the following entities in the form of suitably bound moieties:

및

.

and

.

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

The term “tautomeric” or “tautomeric form” refers to structural isomers having different energies that are interconvertible through a low energy barrier. For example, proton tautomers (also known as proton tautomers) include interconversions through migration of protons, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by restructuring of some bonding electrons.

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

The term “variable point of attachment” means that any group may be attached at more than one alternative position within the structure. The attachment will always replace a hydrogen atom at one of the ring atoms. In other words, all substitutions of bonds are represented in a single diagram, as shown in the examples below.

One of ordinary skill in the art will recognize that when more than one such substituent is present for a given ring, the bond of each substituent is independent of all other substituents. The groups listed or exemplified above are not exhaustive.

As used herein, unless stated otherwise, the term “or” means “and/or”.

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

As used herein, the term “composition” is intended to include products comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.

The term "treat", "treating" or "treatment" of any disease, condition, syndrome or disorder, as used herein, in one embodiment, is intended to ameliorate the disease, condition, syndrome or disorder (i.e., disease delay, arrest or reduce the occurrence of or at least one clinical symptom thereof). In other embodiments, “treat”, “treating” or “treatment” refers to one or more physiology associated with or contributing to a disease, disorder, syndrome or disorder, including those that may not be discernible by the patient. Refers to alleviating or improving a chemical or biochemical parameter. In another embodiment, “treat”, “treating” or “treatment” refers to treating a disease, disorder, syndrome or disorder physically (eg, stabilization of perceptible symptoms), physiologically (eg, physically stabilization of parameters), or both. In another embodiment, “treat”, “treating” or “treatment” refers to preventing or delaying the onset or occurrence or progression of a disease, disorder, 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 the 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 with "effective amount" herein) refers to reducing or inhibiting enzyme or protein activity, ameliorating symptoms, alleviating disease, slowing or delaying disease progression, or eliciting a biological or medicinal response in a tissue system, animal or human being sought by a researcher, veterinarian, physician or other clinician (e.g., an active compound or pharmaceutical agent , such as a compound of the present invention). In other words, the term therapeutically effective amount, when administered to a particular subject, inhibits, ameliorates, or treats a disease, disorder, syndrome or disorder in the subject, or the disease, condition, syndrome or disorder, or symptom(s) thereof. ) can refer to an amount that achieves a therapeutic effect by prophylactically inhibiting, preventing, or delaying the onset of them. A therapeutically effective amount relieves to some extent one or more symptoms of a disease, disorder, syndrome or disorder in a subject; return to normal or completely one or more physiological or biochemical parameters associated with or contributing to a disease, disorder, syndrome or disorder; an amount that reduces the likelihood of developing a disease, disorder, syndrome or disorder, or symptom(s) thereof.

"Pharmaceutically acceptable" means useful in the manufacture of a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes those that are acceptable for veterinary as well as human pharmaceutical use.

"Pharmaceutically acceptable salts" are compounds represented by formula (I) (and formulas (IA), (IB) and (II) that are nontoxic, biologically acceptable, or otherwise biologically suitable for administration to a subject. ) is intended to mean salts of acids or bases of compounds of ). As generally described in SM 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 tissue of a patient without undue toxicity, irritation or allergic reaction.

Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogen-phosphate, metaphosphate, pyrophosphate, chloride, bromide, Iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, Sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxy Benzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methane-sulfonate, propanesulfonate , naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

Compounds of formula (I) (and compounds of formula (II)) may possess sufficiently acidic groups, sufficiently basic groups, or both functional groups, and thus react with a number of inorganic or organic bases with inorganic and organic acids. to form a pharmaceutically acceptable salt.

The compounds of formula (I) (and compounds of formula (II)) may contain at least one nitrogen of basic character, so that the desired pharmaceutically acceptable salts can be obtained by any suitable method available in the art. , for example, the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, etc., or with an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid 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, pyranosidyl acid such as glucuronic acid or Galacturonic acid, alpha-hydroxy acids such as mandelic acid, citric acid, or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, sulfonic acid such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given by way of example herein, and any other acids and mixtures thereof considered equivalents It can be prepared by processing.

The compounds of formula (I) (and compounds of formula (II)) may contain a carboxylic acid moiety, and the desired pharmaceutically acceptable salts can be prepared by any suitable method, for example, the free acid is converted to an inorganic or organic bases such as amines (primary, secondary, or tertiary), alkali metal hydroxides, alkaline earth metal hydroxides, any compatible mixture of bases such as those given as examples herein, and the level of ordinary skill in the art In view of the above, it may be prepared by treatment with any other bases and mixtures thereof considered equivalents or acceptable substitutes. Illustrative examples of suitable salts include amino acids such as glycine and arginine, ammonia, carbonate, bicarbonate, primary, secondary, and tertiary amines, and cyclic amines such as benzylamine, pyrrolidine, piperidine, morpholine, organic salts derived from 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 formula, chemical name, abbreviation, and the like.

Any formula given herein is intended to represent a compound having the structure shown in the structural formula as well as in any variation or form. In particular, compounds of any formula given herein may have asymmetric centers and thus exist as various enantiomers. All optical isomers and stereoisomers of the compounds of the general formulas and mixtures thereof are considered to be within the scope of these formulas. The compounds of the present invention may have one or more asymmetric centers; Accordingly, such compounds may occur as individual ( R )- or ( S )-stereoisomers or mixtures thereof. Accordingly, any formula given herein is intended to represent a racemate, one or more enantiomeric forms thereof, one or more diastereomeric forms thereof, and mixtures thereof. Moreover, any formula given herein is also intended to represent any of the hydrates, solvates, and polymorphs of such compounds, and mixtures thereof (even if such forms are not explicitly recited).

In stereocenters, the term “R” means that the stereocenter is purely in the R -configuration as defined in the art; Likewise, the term “S” means that the stereocenter is purely in the S -configuration. As used herein, the term “RS” refers to a stereocenter that exists as a mixture of R- and S -configurations.

A compound containing one stereocenter drawn without a steric bond mark is a mixture of the two enantiomers. A compound containing two stereocenters, both drawn without steric bond marks, is a mixture of the four diastereomers. A compound having two stereocenters, both denoted "RS" and plotted using the steric bond notation, is a two-component mixture with the relative stereochemistry as plotted. Unmarked stereocenters drawn without steric bond marks are a mixture of R- and S -configurations. For unmarked stereocenters drawn using stereobonding representations, the absolute stereochemistry is as shown.

Unless otherwise indicated, the description or nomenclature of a particular compound in the specification and claims of the present invention is intended to include the individual enantiomers and mixtures thereof, racemic mixtures thereof or others. Methods for stereochemical determination and separation of stereoisomers are well known in the art.

Reference to a compound herein means reference to either (a) the recited form of such compound and (b) any form of such compound in the medium contemplated when the compound is named. For example, reference herein to a compound such as R-COOH includes, for example, reference to any one of R-COOH _(s) , R-COOH _(sol) and R-COO- _(sol) do. In this example, R-COOH _(s) refers to a solid compound, as it may be, for example, into a tablet or some other solid pharmaceutical composition or formulation; R-COOH _(sol) refers to the undissociated form of the compound in solvent; R-COO ⁻ _(sol) represents the dissociation of a compound in a solvent, whether the dissociated form is derived from R-COOH, a salt thereof, or any other entity that upon dissociation in the medium under consideration yields R-COO ⁻ refers to a dissociated form of a compound, such as in an aqueous environment. In another example, expressions such as "exposing an entity to a compound of formula R-COOH" refer to exposure of that entity to a form or forms of compound R-COOH that is present in the medium in which such exposure occurs. In another example, expressions such as "reacting an entity with a compound of formula R-COOH" refer to (a) a chemically related form or forms of that entity present in the medium in which the reaction takes place; Refers to reacting a chemically related form or forms of the compound R-COOH present in the medium in which such a reaction occurs. In this regard, if such an entity is, for example, in an aqueous environment, then the compound R-COOH is in that same medium, and thus the entity is R-COOH _(aq) and/or R-COO- _(aq) (wherein The subscript "(aq)" is understood to mean "aqueous" according to its ordinary meaning in chemistry and biochemistry). Carboxylic acid functionality was chosen as an example of these nomenclatures; These selections are illustrative only and not intended to be limiting. It is understood that similar examples may be provided with respect to other functional groups including, but not limited to, hydroxyl, basic nitrogen members such as those of amines, and any other groups that interact or convert according to known methods in the medium containing the compound. do. Such interactions and transformations include, but are not limited to, dissociation, bonding, tautomerism, solvolysis including hydrolysis, solvation including hydration, protonation and deprotonation. No further examples are provided herein in this regard, as the interactions and transformations in a given medium are known to those skilled in the art.

Any formula given herein is also intended to represent unlabeled as well as isotopically labeled forms of the compound. Isotopically labeled compounds have structures represented 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 may be incorporated into the compounds of the present invention in forms beyond their natural abundance include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as ² H (or chemical symbol D), respectively, , ³ H (or chemical symbol T), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²⁵ I. Such isotopically labeled compounds can be used in detection or imaging techniques, including metabolic studies (preferably using ¹⁴ C), kinetics studies (eg using ² H or ³ H), and tissue distribution analysis of drugs or substrates. It is useful [eg, positron emission tomography (PET) or single photon emission computed tomography (SPECT)], or radioactive treatment of patients. In particular, ¹⁸ F or ¹¹ C labeled compounds may be particularly desirable for PET or SPECT studies. In addition, substitution with heavier isotopes such as deuterium (i.e., ² H or D) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased local in vivo half-life or reduced dosage requirements. can provide The isotopically labeled compounds of the present invention can generally be prepared by carrying out the procedures disclosed in the Schemes or in the Examples and Preparations described below, using readily available isotopically labeled reagents instead of isotopically labeled reagents. can

The term C _nm alkyl, whether straight or branched, refers to an aliphatic chain, wherein the total number of carbon atoms N in the chain is n ≤ N ≤ m, where m > n.

When the same plurality of substituents are assigned to various groups, it is meant that the specific individual substituent designation for each of these groups is independent of the specific individual substituent designation for the remaining groups. By way of example and not limitation, if the groups Q and R can each be H or F, then the choice of H or F for Q is irrespective of the choice of H or F for R, and therefore the choice of designation for Q does not determine or condition the choice of assignment to R, and vice versa, unless expressly indicated otherwise. Recitation of exemplary claims in this regard will be interpreted as "Q and R are each independently H or F" or "Q and R are each independently selected from the group consisting of H and F".

In other instances, zwitterionic compounds are included herein by referring to compounds known to form zwitterions, although not explicitly named zwitterionic forms. Terms such as zwitterions, zwitterions, and their synonym zwitterionic compound(s) are well known and standard IUPAC approved names that are part of the standard set of defined scientific names. In this regard, the name "zwitterion" is assigned by the Chemical Entities of Biological Inerest (ChEBI) Dictionary of Molecular Entities under the identification name CHEBI:27369. As is generally well known, a zwitterion or zwitterionic compound is a neutral compound with a formal unit charge of opposite sign. Such compounds are also referred to by the term "flame resistant". Other publications refer to these compounds as "zwitterions", but the latter term is considered a misnomer in other publications. As a specific example, aminoethanoic acid (the amino acid glycine) has the formula H ₂ NCH ₂ COOH, which exists in some media (in this case neutral media) in the form of zwitterionic ⁺ H ₃ NCH ₂ COO ⁻ . Zwitterions, zwitterionic compounds, internal salts and zwitterions, in the known and well-established sense of these terms, are in any case within the scope of the present invention, as are so recognized by those skilled in the art. No structures of zwitterionic compounds to which the compounds of the present invention relate are explicitly given herein, as there is no need to name each and every embodiment that will be recognized by one of ordinary skill in the art. However, they are part of the embodiment of the present invention. Since the interactions and transformations in a given medium that lead to the various forms of a given compound are known to those skilled in the art, no further examples are provided herein in this regard.

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 limit the selection of the same species for a variable appearing elsewhere. In other words, if a variable occurs more than once, the selection of the species from the specified list is independent of the selection of the species for the same variable elsewhere in the formula, unless otherwise specified.

As a first example for a substituent term, when a substituent S ¹ _example is one of S ₁ and S ₂ and a substituent S ² _example is one of S ₃ and S ₄ , these designations are that S ¹ _example is S ₁ , S ² Select _{for example} S ₃ ; selection in which S ¹ _example is S ₁ and S ² _example is S ₄ ; selection in which S ¹ _example is S ₂ and S ² _example is S ₃ ; selection in which S ¹ _example is S ₂ and S ² _example is S ₄ ; and embodiments of the invention given in accordance with the equivalent of each one of these choices. Accordingly, the shorter term “S ¹ _example is one of S ₁ and S ₂ , and S ² _example is one of S ₃ and S ₄ ” is used herein for simplicity, but not limitation. The first example given above of substituent terms referred to in general terms is intended to illustrate the various substituent designations described herein.

Also, where more than one designation is given for any member or substituent, embodiments of the invention include various groups that may be formed from the listed designations taken independently and equivalents thereof. As a second example of a substituent term, if a substituent S _example is described herein as being one of S ₁ , S ₂ , and S ₃ , this list includes that S _example is S ₁ ; S _example is S ₂ ; S _example is S ₃ ; S _example is one of S ₁ and S ₂ ; S _example is one of S ₁ and S ₃ ; S _example is one of S ₂ and S ₃ ; S _example is one of S ₁ , S ₂ and S ₃ ; Examples of S represent embodiments of the invention in which _examples are any equivalent of each of these choices. Accordingly, the shorter term “S _example is one of S ₁ , S ₂ and S ₃ ” is used herein for brevity, but not limitation. The second example set forth above for substituent terms referred to in general terms is intended to illustrate the various substituent designations described herein.

When the nomenclature "C _i -C _j " (where j > i) is applied herein to a class of substituents, every single number of carbon members from i to j, including i and j, is independently realized. It is intended to show an embodiment of the present invention. By way of example, the term “C ₁ -C ₃ ” independently refers to embodiments having one carbon member (C ₁ ), embodiments having two carbon members (C ₂ ) and embodiments having three carbon members (C ₃ ). An embodiment with

An embodiment of the present invention is a compound of formula (I); or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof:

[Formula (I)]

(In the above formula,

X ¹ and X ² are each independently CH or N;

Y is O, NH or S;

R ¹ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _2-6 alkenyl; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; C _3-6 cycloalkyl; C _3-6 heterocycloalkyl; and phenyl;

또는

이며; 여기서,R ² is

or

is; here,

R ^b is C _1-6 alkyl substituted with a member selected from the group consisting of OH, halo, CN, OC _1-6 alkyl, OC _1-6 haloalkyl and OC _3-6 cycloalkyl;

R ^c is selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;

R ³ is H, Cl or F;

R ⁴ is selected from the group consisting of:

(a) C _1-6 alkyl; C _1-6 alkyl substituted with 1 or 2 substituents each independently selected from the group consisting of OH and OCH ₃ ; tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH ₃ ; cyclohexyl substituted with CH ₃ ; and tetrahydro-2H-thiopyran 1,1-dioxide; and

(b)

및

;

and

;

here,

R ^d is independently H; halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH, OCH ₃ , SCH ₃ , and OCF ₃ ; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; OC _1-6 alkyl; and OC _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;

R ^e is halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH, OCH ₃ , SCH ₃ , and OCF ₃ ; OC _1-6 alkyl; C _1-6 haloalkyl; selected from the group consisting of C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;

n is 1 or 2).

A further embodiment of the invention are compounds of formula (I), wherein X ¹ is CH.

A further embodiment of the invention are compounds of formula (I), wherein X ¹ is N.

A further embodiment of the invention are compounds of formula (I), wherein X ² is CH.

A further embodiment of the invention are compounds of formula (I), wherein X ² is N.

A further embodiment of the invention are compounds of formula (I), wherein Y is O.

A further embodiment of the invention are compounds of formula (I), wherein Y is NH.

A further embodiment of the invention are compounds of formula (I), wherein Y is S.

A further embodiment of the present invention provides that R ¹ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _2-6 alkenyl; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; C _3-6 cycloalkyl; tetrahydropyran-4-yl; and phenyl.

A further embodiment of the present invention provides that R ¹ is C _1-4 alkyl; C _1-4 alkyl substituted with OH or OCH ₃ ; C _1-4 haloalkyl; C _1-4 haloalkyl substituted with OH or OCH ₃ ; tetrahydropyran-4-yl; or C _3-6 cycloalkyl.

A further embodiment of the invention is a formula (I) wherein Y is O and R ¹ is CH(CH ₃ ) ₂ , CH(CH ₃ )(CF ₃ ), cyclopropyl, cyclobutyl, or tetrahydropyranyl. is a compound.

A further embodiment of the invention are compounds of formula (I), wherein Y is O and R ¹ is CH(CH ₃ ) ₂ or CH(CH ₃ )(CF ₃ ).

인 화학식 (I)의 화합물이다.A further embodiment of the invention is that R ¹ is

is a compound of formula (I).

인 화학식 (I)의 화합물이다.A further embodiment of the invention is that R ² is

is a compound of formula (I).

이며; 여기서,A further embodiment of the invention is that R ² is

is; here,

R ^b is C _1-4 alkyl substituted with OH, halo, CN, OC _1-4 alkyl, OC _1-4 haloalkyl or OC _3-6 cycloalkyl;

is a compound of Formula (I) wherein R ^c is C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl.

인 화학식 (I)의 화합물이다.A further embodiment of the invention is that R ² is

is a compound of formula (I).

A further embodiment of the invention are compounds of formula (I), wherein R ³ is H.

A further embodiment of the invention are compounds of formula (I), wherein R ³ is Cl.

A further embodiment of the invention are compounds of formula (I), wherein R ³ is F.

또는

인 화학식 (I)의 화합물이다.A further embodiment of the invention is that R ⁴ is

or

is a compound of formula (I).

이며, 여기서A further embodiment of the invention is that R ⁴ is

and where

R ^d is independently H; halo; CH ₃ ; CH ₂ OH; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; OCH ₃ , OCH ₂ CH ₂ OH and OCH ₂ CH ₂ OCH ₃ ;

R ^e is selected from the group consisting of Cl, F, CH ₃ , and OCH ₃ ;

and n is 1 or 2.

A further embodiment of the invention is that R ⁴ is

또는

인 화학식 (I)의 화합물이다.

or

is a compound of formula (I).

인 화학식 (I)의 화합물이다.A further embodiment of the invention is that R ⁴ is

is a compound of formula (I).

또는

이며,A further embodiment of the invention is that R ⁴ is

or

is,

here

R ^d is independently selected from the group consisting of H, Cl, CH ₃ , OH and OCH ₃ ;

R ^e is F, Cl, or CH ₃ ;

and n is 1 or 2.

A further embodiment of the invention is that R ⁴ is

또는

인 화학식 (I)의 화합물이다.

or

is a compound of formula (I).

A further embodiment of the invention is that R ⁴ is

또는

인 화학식 (I)의 화합물이다.

or

is a compound of formula (I).

A further embodiment of the invention are compounds of formula (I), wherein n is 1.

A further embodiment of the invention are compounds of formula (I), wherein n is 2.

인 화학식 (I)의 화합물이다.A further embodiment of the invention is that Y is NH and R ⁴ is

is a compound of formula (I).

인 화학식 (I)의 화합물이다.A further embodiment of the invention is that Y is S and R ⁴ is

is a compound of formula (I).

Further embodiments of the present invention include compounds as shown in Table 1 below, and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof.

[Table 1]

Further embodiments of the present invention include compounds of formula (I) having formula (IA), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof:

[Formula (IA)]

(In the above formula,

Y is O, NH or S;

R ¹ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _2-6 alkenyl; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; C _3-6 cycloalkyl; C _3-6 heterocycloalkyl; and phenyl;

R ^b is C _1-6 alkyl substituted with a member selected from the group consisting of OH, halo, CN, OC _1-6 alkyl, OC _1-6 haloalkyl and OC _3-6 cycloalkyl;

R ^c is selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;

R ³ is H or F;

R ⁴ is selected from the group consisting of:

(a) C _1-6 alkyl; C _1-6 alkyl substituted with 1 or 2 substituents each independently selected from the group consisting of OH and OCH ₃ ; tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH ₃ ; cyclohexyl substituted with CH ₃ ; and tetrahydro-2H-thiopyran 1,1-dioxide; and

(b)

및

;

and

;

R ^d is independently H; halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; OC _1-6 alkyl; and OC _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;

R ^e is selected from the group consisting of halo, C _1-6 alkyl, and OC _1-6 alkyl;

n is 1 or 2).

Further embodiments of the present invention include compounds of formula (I) having formula (IB), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof:

[Formula (IB)]

(In the above formula,

X ¹ is CH or N;

Y is O or NH;

R ¹ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _2-6 alkenyl; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; C _3-6 cycloalkyl; C _3-6 heterocycloalkyl; and phenyl;

이며; 여기서,R ² is

is; here,

R ^b is C _1-6 alkyl substituted with a member selected from the group consisting of OH, halo, CN, OC _1-6 alkyl, OC _1-6 haloalkyl and OC _3-6 cycloalkyl;

R ^c is selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;

R ³ is H or F;

R ⁴ is selected from the group consisting of:

및

;

and

;

R ^d is independently selected from the group consisting of H, Cl, and F;

R ^e is selected from the group consisting of F, CH ₃ , and OCH ₃ ;

n is 1 or 2).

A further embodiment of the invention are compounds of formula (I) having formula (IA) wherein Y is O.

A further embodiment of the invention are compounds of formula (I) having formula (IA) wherein R ¹ is C _1-6 alkyl or C _1-6 haloalkyl.

A further embodiment of the invention are compounds of formula (I) having the formula (IB) wherein Y is N.

A further embodiment of the invention are compounds of formula (I) having the formula (IB) wherein Y is O.

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

[Formula (II)]

(In the above formula,

X ³ and X ⁴ are each independently CH or N; wherein when X ³ is N, X ⁴ is CH, and when X ³ is CH, X ⁴ is N;

Z is O, S, or NH;

R ⁵ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; and C _3-6 cycloalkyl;

이고;R ⁶ is

ego;

R ⁷ is H or F;

이고;R ⁸ is

ego;

here,

R ^f is independently H; halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; and OC _1-6 alkyl;

R ^g is selected from the group consisting of halo, C _1-6 alkyl and OC _1-6 alkyl;

m is 1 or 2).

A further embodiment of the invention are compounds of formula (II), wherein X ³ is N and X ⁴ is CH.

A further embodiment of the invention are compounds of formula (II), wherein X ³ is CH and X ⁴ is N.

A further embodiment of the invention are compounds of formula (II), wherein Z is O.

A further embodiment of the invention are compounds of formula (II) wherein R ⁵ is C _1-6 alkyl or C _1-6 haloalkyl.

A further embodiment of the invention are compounds of formula (II), wherein R ⁷ is H.

인 화학식 (I)의 화합물이다.A further embodiment of the invention is that R ⁸ is

is a compound of formula (I).

Enantiomers and diastereomers of the compounds of Formula (I) (and Formula (IA), Formula (IB), and Formula (II)) are also within the scope of the present invention. Also within the scope of the present invention are pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (I) (and Formula (IA), Formula (IB), and Formula (II)). Pharmaceutically acceptable prodrugs of compounds of Formula (I) (and Formula (IA), Formula (IB), and Formula (II)) and Formula (I) (and Formula (IA), Formula (IB), and Pharmaceutically active metabolites of the compounds of formula (II)) are also within the scope of the present invention.

Isotopic variants of compounds of formula (I) (and formulas (IA), (IB), and (II)), such as deuterated compounds of formula (I), are also within the scope of the present invention. Pharmaceutically acceptable salts, N-oxides or solvates of isotopic variants of compounds of Formula (I) (and Formulas (IA), (IB), and (II)) are also within the scope of the present invention. Pharmaceutically acceptable prodrugs of isotopic variants of compounds of Formula (I) (and Formula (IA), Formula (IB), and Formula (II)) and Formula (I) (and Formula (IA), Formula ( IB), and pharmaceutically active metabolites of isotopic variants of compounds of formula (II)) are also within the scope of the present invention.

Although the compounds of the embodiments of the present invention (including pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof) may be administered alone, they are usually administered by the intended route of administration and standard pharmaceutical or water administration. It will be administered in the form of a mixture with a pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluent of choice in connection with medical practice.

Accordingly, certain embodiments of the present invention provide a compound of formula (I) (and a compound of formula (II)) with at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and/or pharmaceutically acceptable Pharmaceutical and veterinary compositions comprising diluents. By way of example, in the pharmaceutical composition of an embodiment of the invention, the compound of formula (I) (and the compound of formula (II)) can be any suitable binder(s), lubricant(s), suspending agent(s), coating agent (s), solubilizer(s), and combinations thereof.

An embodiment of the present invention comprises at least one compound selected from compounds of formula (I) (and compounds of formula (II)), and pharmaceutically acceptable salts thereof, according to any embodiment described herein; effective amounts of isotopes, N-oxides, solvates and stereoisomers; and one or more pharmaceutically acceptable excipients.

A further embodiment of the present invention is a pharmaceutical composition, said pharmaceutical composition comprising:

(A) an effective amount of at least one compound selected from compounds of formula (I), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer of a compound of formula (I):

[Formula (I)]

(In the above formula,

X ¹ and X ² are each independently CH or N;

Y is O, NH or S;

R ¹ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _2-6 alkenyl; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; C _3-6 cycloalkyl; C _3-6 heterocycloalkyl; and phenyl;

또는

이며; 여기서,R ² is

or

is; here,

R ^b is C _1-6 alkyl substituted with a member selected from the group consisting of OH, halo, CN, OC _1-6 alkyl, OC _1-6 haloalkyl and OC _3-6 cycloalkyl;

R ^c is selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;

R ³ is H, Cl or F;

R ⁴ is selected from the group consisting of:

(a) C _1-6 alkyl; C _1-6 alkyl substituted with 1 or 2 substituents each independently selected from the group consisting of OH and OCH ₃ ; tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH ₃ ; cyclohexyl substituted with CH ₃ ; and tetrahydro-2H-thiopyran 1,1-dioxide; and

(b)

및

and

here,

R ^d is independently H; halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH, OCH ₃ , SCH ₃ , and OCF ₃ ; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; OC _1-6 alkyl; and OC _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;

R ^e is halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH, OCH ₃ , SCH ₃ , and OCF ₃ ; OC _1-6 alkyl; C _1-6 haloalkyl; selected from the group consisting of C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;

n is 1 or 2);

and (B) at least one pharmaceutically acceptable excipient.

A further embodiment of the present invention is a pharmaceutical composition, said pharmaceutical composition comprising:

(A) an effective amount of at least one compound selected from compounds of formula (II), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer of a compound of formula (II):

[Formula (II)]

(In the above formula,

X ³ and X ⁴ are each independently CH or N; wherein when X ³ is N, X ⁴ is CH, and when X ³ is CH, X ⁴ is N;

Z is O, S, or NH;

R ⁵ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; and C _3-6 cycloalkyl;

이고;R ⁶ is

ego;

R ⁷ is H or F;

이고;R ⁸ is

ego;

here,

R ^f is independently H; halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; and OC _1-6 alkyl;

R ^g is selected from the group consisting of halo, C _1-6 alkyl and OC _1-6 alkyl;

m is 1 or 2);

and (B) at least one pharmaceutically acceptable excipient.

A further embodiment of the present invention relates to a compound shown in Table 1 (eg, a compound selected from Examples 1-78), or a pharmaceutically acceptable salt, isotope, N-oxide of a compound of Table 1 , an effective amount of a solvate or stereoisomer, a pharmaceutically acceptable prodrug of a compound of Table 1, or a pharmaceutically active metabolite of a compound of Table 1; and one or more pharmaceutically acceptable excipients.

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

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

Alternatively, one or more compounds of a compound of formula (I) (and a compound of formula (II)) may be administered by inhalation (intratracheal or intranasal) or in the form of a suppository or pessary, or they may It can be applied topically in the form of lotions, solutions, creams, ointments, or dusting powders. For example, they may be incorporated into a cream comprising, consisting of, or consisting essentially of, an aqueous emulsion of liquid paraffin or polyethylene glycol. They also contain a cream in an ointment comprising, consisting of, or consisting essentially of, a wax or soft paraffin base in a concentration of from about 1% to about 10% by weight, optionally stabilizers and It can be introduced with preservatives. Alternative means of administration include transdermal administration using dermal or transdermal patches.

The pharmaceutical compositions of the present invention (and the compounds of the present invention alone) may also be injected parenterally, for example, intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally or intrathecally. In such cases, the composition will also include at least one of a suitable carrier, a suitable excipient and a suitable diluent.

For parenteral administration, the pharmaceutical composition of the present invention is best used in the form of a sterile aqueous solution which may contain other substances, for example, salts and monosaccharides sufficient to render the solution isotonic with blood.

For buccal or sublingual administration, the pharmaceutical composition of the present invention may be administered in the form of a tablet or lozenge that may be formulated in a conventional manner.

As a further example, a pharmaceutical composition containing at least one compound of formula (I) (and a compound of formula (II)) as an active ingredient may contain the compound(s) as pharmaceutically acceptable according to conventional pharmaceutical compounding techniques. It may be prepared by mixing with a carrier, a pharmaceutically acceptable diluent and/or a pharmaceutically acceptable excipient. Carriers, excipients, and diluents can take a wide variety of forms depending upon the route of administration desired (eg, 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, stabilizing agents, 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 formulations may also be optionally coated with substances such as sugars or enteric coated to control the major sites 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. Suspensions or solutions for injection may also be prepared using the aqueous carrier with appropriate additives, such as stabilizers and preservatives.

According to certain embodiments, a therapeutically effective amount of a compound of Formula (I) (and a compound of Formula (II)) or a pharmaceutical composition thereof is administered on an average (70 kg) human on a regimen of from about 1 to about 4 times per day. ) from about 0.1 mg to about 3000 mg, or any specific amount or range therein, in particular from about 1 mg to about 1000 mg, or any specific amount or range therein, or more particularly from about 10 mg to about 500 mg, or any specific amount or range of active ingredient therein; It will be apparent to those skilled in the art that a therapeutically effective amount of a compound of formula (I) (and a compound of formula (II)) will vary depending on the disease, syndrome, condition, and disorder being treated.

For oral administration, the pharmaceutical composition is 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). can be provided.

One embodiment of the present invention relates to a pharmaceutical composition for oral administration comprising a compound of formula (I) (and a compound of formula (II)) in an amount from about 1 mg to about 500 mg.

Advantageously, the compound of formula (I) (and the compound of formula (II)) may be administered in a single daily dose, or the total daily dose may be administered in divided doses of 2, 3, and 4 times daily. can

The optimal dose of a compound of formula (I) (and a compound of formula (II)) to be administered can be readily determined, and the specific compound used, the mode of administration, the strength of the agent, and the disease, syndrome, condition or It will depend on the progression of the disorder. Moreover, depending on factors related to the particular subject being treated, including subject sex, age, weight, diet and time of administration, the dosage will have to be adjusted to achieve the appropriate level of treatment and the desired therapeutic effect. Accordingly, the above dosage is an example of an average case. Of course, there may be individual instances in which a higher or lower dosage range would be beneficial, and such cases are within the scope of the present invention.

Whenever the use of a compound of formula (I) (and a compound of formula (II)) is administered to a subject in need thereof, the compound of formula (I) (and compound of formula (II)) comprises the aforementioned compositions and It can be administered in any of the dosage regimens, or by compositions and dosage regimens established in the art.

According to certain embodiments, one or more compounds of Formula (I) (and compounds of Formula (II)) treat, ameliorate, and / or useful for prevention.

A further embodiment of the present invention provides a compound of formula (I), for example by inhibiting dihydroorotate oxygenase enzyme activity, in the treatment of a disorder such as an inflammatory disorder, an autoimmune disorder or cancer, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[Formula (I)]

(In the above formula,

X ¹ and X ² are each independently CH or N;

Y is O, NH or S;

R ¹ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _2-6 alkenyl; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; C _3-6 cycloalkyl; C _3-6 heterocycloalkyl; and phenyl;

또는

이며; 여기서,R ² is

or

is; here,

R ^b is C _1-6 alkyl substituted with a member selected from the group consisting of OH, halo, CN, OC _1-6 alkyl, OC _1-6 haloalkyl and OC _3-6 cycloalkyl;

R ^c is selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;

R ³ is H, Cl or F;

R ⁴ is selected from the group consisting of:

(a) C _1-6 alkyl; C _1-6 alkyl substituted with 1 or 2 substituents each independently selected from the group consisting of OH and OCH ₃ ; tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH ₃ ; cyclohexyl substituted with CH ₃ ; and tetrahydro-2H-thiopyran 1,1-dioxide; and

(b)

및

;

and

;

here,

R ^d is independently H; halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH, OCH ₃ , SCH ₃ , and OCF ₃ ; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; OC _1-6 alkyl; and OC _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;

R ^e is halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH, OCH ₃ , SCH ₃ , and OCF ₃ ; OC _1-6 alkyl; C _1-6 haloalkyl; selected from the group consisting of C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;

n is 1 or 2).

A further embodiment of the present invention provides a compound of formula (II), for example by inhibiting dihydroorotate oxygenase enzyme activity, in the treatment of a disorder such as an inflammatory disorder, an autoimmune disorder or cancer, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[Formula (II)]

(In the above formula,

X ³ and X ⁴ are each independently CH or N; wherein when X ³ is N, X ⁴ is CH, and when X ³ is CH, X ⁴ is N;

Z is O, S, or NH;

R ⁵ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; and C _3-6 cycloalkyl;

이고;R ⁶ is

ego;

R ⁷ is H or F;

이고;R ⁸ is

ego;

here,

R ^f is independently H; halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; and OC _1-6 alkyl;

R ^g is selected from the group consisting of halo, C _1-6 alkyl and OC _1-6 alkyl;

m is 1 or 2).

In a further aspect the invention provides a method comprising contacting dihydroorotate dehydrogenase (DHODH) with a compound of Formula (I) (and a compound of Formula (II)), an aspect, or any compound of an embodiment disclosed herein; A method of inhibiting or altering DHODH enzyme activity is provided, comprising the step of inhibiting or otherwise altering the DHODH enzyme activity.

A further embodiment of the present invention relates to a dihydroorotate dehydrogenase (DHODH) enzyme activity comprising administering a compound of formula (I) (and a compound of formula (II)) to a subject in need thereof. A method of treating a disease, disorder, or medical condition mediated by or otherwise affected by

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

A further embodiment of the present invention provides a compound of formula (I) (and formula (IA), formula ( IB), and compounds of formula (II), such as those in Table 1), compounds of formula (I) (and compounds of formulas (IA), (IB), and (II), such as compounds of Table 1) at least one compound selected from enantiomers and diastereomers of and a method of treating a subject suffering from or diagnosed with a disease, disorder or medical condition mediated by or otherwise affected by DHODH enzyme activity, comprising administering an effective amount of a pharmaceutically acceptable salt of any of the foregoing. to be. In other words, according to one embodiment, the method of treating a subject suffering from or diagnosed with a disease, disorder or medical condition, such as cancer, comprises a compound of Formula (I) (and Formula (IA), Formula (IB), and Formula administering to the subject an effective amount of at least one compound selected from a compound of (II), such as a compound of Table 1), and a pharmaceutically acceptable salt thereof (e.g., dihydroorotate oxygena in the subject); by inhibiting or otherwise altering the activity of the second enzyme).

In another embodiment, the inhibitor of DHODH of the present invention is an autoimmune disorder and inflammatory disorder such as arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic erythematosus Lupus lupus, lupus nephritis, rheumatic fever, gout, organ transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic dermatitis, dermatomyositis, psoriasis, Behcet's disease, uveitis, Myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjogren's syndrome, bullous disease, antibody-mediated vasculitis syndrome, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, edema, embolism , fibrosis, sarcoidosis, hypertension, and pulmonary diseases including emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, beryllium poisoning, and immunological diseases including but not limited to polymyositis. have.

As used herein, unless otherwise indicated, the terms "affecting" or "affected" (when referring to a disease, disorder or medical condition affected by inhibition or alteration of DHODH enzyme activity) ) comprises a reduction in the frequency and/or severity of one or more symptoms or signs of said disease, syndrome, condition or disorder; It includes the occurrence of one or more symptoms or signs of the disease, syndrome, condition or disorder, or the prevention of the occurrence of the disease, disorder, syndrome or disorder.

A further embodiment of the present invention provides a compound of formula (I) (and a compound of formula (II)), or a pharmaceutically acceptable salt, isotope, N-oxide, A method of treating cancer comprising administering a therapeutically effective amount of a solvate or stereoisomer is provided.

According to one embodiment, the cancer is selected from, but not limited to, lymphoma, leukemia, carcinoma and sarcoma.

A further embodiment of the present invention provides a compound of formula (I) (and a compound of formula (II)), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate thereof, for the treatment of one or more types of cancer. or stereoisomers.

According to certain embodiments, the uses and methods of treatment described herein relate to the treatment of cancer, wherein the cancer comprises:

Acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), biphenotype B myelomonocytic leukemia, chronic myelogenous leukemia ( CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS), which can also develop into acute myeloid leukemia (MDS);

AIDS-related lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin's lymphoma (T-NHL), subtypes of NHL such as diffuse large cell lymphoma (DLBCL), activated B-cell DLBCL, germinal center B -lymphomas including but not limited to cell DLBCL, double-hit lymphoma and double-expressor lymphoma; Anaplastic giant cell lymphoma, marginal zone B-cell lymphoma, and primary mediastinal B-cell lymphoma, immunoblastic giant cell lymphoma, Burkitt's lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoma plasmacytic 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, enteropathic T-cell lymphoma, subcutaneous steatomatitis-like T-cell lymphoma, anaplastic giant cell lymphoma;

sarcomas including but not limited to sarcoma of soft tissue, neuroblastoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma;

and

solid tumors including, but not limited to, breast cancer, colorectal carcinoma, gastric cancer, glioma, head and neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, and sarcoma; selected from, but not limited to, other cancers such as

In one embodiment, cancers that would benefit from treatment with an inhibitor of DHODH of the invention are lymphomas, leukemias, carcinomas, and sarcomas such as non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma, T-cell lymphoma, Hodgkin lymphoma, Burkitt's lymphoma, multiple myeloma, brain (glioma), glioblastoma, breast cancer, colorectal/colon cancer, prostate cancer, Non-small cell lung cancer, stomach cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, male blastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary adenocarcinoma, nasopharyngeal cancer, oral cancer, cancer of the oral cavity and GIST (gastrointestinal stromal tumor).

In another embodiment of the invention, the compounds of the invention are administered in combination with one or more other medicaments, more particularly one or more anticancer agents, such as chemotherapeutic agents, antiproliferative agents, or immunomodulatory agents, or as an adjuvant in cancer therapy; For example, it may be used in combination with an immunosuppressant or anti-inflammatory agent. Additional non-limiting examples of anticancer agents that may be administered in combination with a compound of the present invention include biological compounds, such as monoclonal antibodies (eg, which mediate effector function upon binding to cancer cell-associated antigens, or on cancer cells). blocking the interaction of soluble or cell-bound ligands with receptors expressed in ), and bispecific antibodies that mediate immune cell redirection. According to one embodiment, the method of treating cancer comprises a compound of the invention (eg, a compound of Formula (I) (and a compound of Formula (II)), such as a compound shown in Table 1, a pharmaceutically acceptable a salt, isotope, N-oxide, solvate and stereoisomer) and an effective amount of one or more additional anti-cancer agents, wherein the method comprises a compound of the invention and an additional anti-cancer agent(s). concurrently (eg, as part of the same pharmaceutical composition) or sequentially. According to one embodiment, the pharmaceutical composition comprises a compound of the invention (e.g., a compound of Formula (I) (and a compound of Formula (II), such as the compounds shown in Table 1), a pharmaceutically acceptable salt thereof, an effective amount selected from isotopes, N-oxides, solvates and stereoisomers), an effective amount of one or more additional anticancer agents, and optionally one or more excipients.

A further embodiment of the present invention provides a compound of formula (I) (and compound of formula (II)), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

General Synthesis Methods

Hereinafter, exemplary compounds useful in the methods of the present invention will be described with reference to the following exemplary synthetic schemes for their general preparation and the specific examples set forth below. One of ordinary skill in the art will recognize that starting materials can be appropriately selected to obtain the various compounds of the present disclosure, with or without adequate protection, finally moving the desired substituents through the scheme to obtain the desired product. will be. Alternatively, in place of the finally desired substituent, it may be necessary or desirable to use an appropriate group that may have throughout the scheme and may be substituted with a desired substituent as necessary. Unless otherwise specified, variables are as defined above with respect to formula (I) (and compounds of formula (II)). The reaction may be carried out between the melting point of the solvent and the reflux temperature, preferably at 0° C. to the reflux temperature of the solvent. The reaction may be heated using conventional heating or microwave heating. The reaction may also be conducted in a closed pressure vessel above the normal reflux temperature of the solvent.

Abbreviations used herein, particularly in the schemes and examples, are as follows:

ACN acetonitrile

AcOH glacial acetic acid

aq. Mercury

Bn or Bzl benzyl

Boc tert-butoxycarbonyl

conc. thick

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

EZ 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 hour

HPLC High Performance Liquid Chromatography

KHMDS Potassium bis(trimethylsilyl)amide

LiHMDS Lithium bis(trimethylsilyl)amide

MeOH methanol

MHz megahertz

min minute

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 residence time

sec candle

TBDPS tert -Butyldiphenylchlorosilane

TBS tert-Butyldimethylsilyl

TES triethylsilane

TIPS triisopropylsilane

TEA or Et ₃ N triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

Preliminary Example

Hereinafter, exemplary compounds useful in the methods of the present invention will be described with reference to the following exemplary synthetic schemes for their general preparation and the specific examples set forth below.

[Scheme 1]

According to Scheme 1, a 1,2,4-triazol-5(4H)-one compound of formula (V), wherein PG is Bn, was prepared in three steps from ethyl 2-(benzyloxy)acetate do. In the first step, 2-(benzyloxy)acetohydrazide is prepared by reacting ethyl 2-(benzyloxy)acetate with hydrazine hydrate in a suitable solvent such as EtOH and the like at a temperature ranging from 70 to 85°C. Reaction of a hydrazide with an isocyanate of the formula R ^c -NCO (wherein R ^c is C _1-6 alkyl) in a suitable solvent such as water and the like gives the corresponding semicarbazide. Subsequent cyclization of the semicarbazide with a suitable base such as NaOH in a suitable solvent such as water gives the compound of formula (V), wherein PG is Bn.

Protecting group exchange of a compound of formula (V) wherein PG is Bn with a compound of formula (V) wherein PG is TBDPS is described in TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis," 3 ed., John Wiley & Sons , 1999] using established methods such as those described in two steps. In the first step, deprotection of the benzyl group is achieved under hydrocracking conditions known to those skilled in the art to obtain an alcohol. For example, using a palladium catalyst such as Pd/C etc. under H ₂ in a suitable solvent such as EtOH, MeOH, EtOAc, or mixtures thereof, preferably EtOH in the presence or absence of HCl for 4 to 72 hours achieve deprotection. In a second step, protection of the corresponding alcohol as a silyl ether is carried out with tert -butyldimethylsilyl chloride, a suitable base such as imidazole, dimethylaminopyridine, This is achieved using pyridine and the like to give the compound of formula (V), wherein 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 prepared in a suitable solvent at a temperature ranging from 0° C. to 50° C. 6-bromo-8-fluoro-3,4-dihydroisoquinoline-1(2H)- by reaction with sodium azide in the presence of a suitable acid such as methylsulfonic acid (MSA) and the like in THF and the like. get on 6-Bromo-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one at a temperature ranging from 0° C. to 100° C., preferably at 30° C. in an aprotic solvent such as DMF, etc. Alcohols of the formula R ¹ OH, commercially available or synthetically accessible, in the presence of a suitable base such as NaH and the like, wherein R ¹ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _2-6 alkenyl; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; C _3-6 cycloalkyl; C _3-6 heterocycloalkyl; and phenyl) The compound of (VI) is obtained.

Oxidation of the compound of formula (VI) with a suitable oxidizing agent such as MnO ₂ , DDQ, etc. in a suitable solvent such as dioxane, toluene and the like at a temperature in the range of 60 °C to 120 °C, preferably at 100 °C, gives the compound of formula (VII) get Compounds of formula (VII) are prepared in a suitable solvent such as dioxane, DMF, DMSO and the like at a temperature ranging from 80° C. to about 120° C. with a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane-1,2 - a suitable catalyst, such as CuI, Cu(acac) ₂ , CuO, etc., in the presence or absence of diamine, dimethylglycine, etc. in the presence or absence of a suitable base such as K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuOK etc. A _compound of formula (VIII) that is ^commercially available or synthetically accessible under Ullman N-arylation conditions using alcohol protecting groups such as Bn, allyl, p -methoxy-Bn (PMB), TBDMS, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM) ) to give a compound of formula (IX). The compound of formula (IX) is reacted with a chlorinating agent such as POCl ₃ , SOCl ₂ and the like at a temperature in the range of 60° C. to 100° C. to obtain the compound of formula (X).

[Scheme 3]

According to Scheme 3, commercially available or synthetically accessible 2,6-dichloro-4-methylnicotinonitrile is mixed with an aprotic solvent such as at a temperature ranging from 60° C. to about 120° C., preferably 80° C. Compounds of formula (VIII) commercially available or synthetically accessible in the presence of a suitable base such as NaH, Cs ₂ CO ₃ and the like in DMF, DMSO and the like, wherein R ^b is C _1-6 substituted with O-PG alkyl, wherein PG is a suitable alcohol protecting group) to give compounds of formula (XI). Treatment of a compound of formula (XI) with an alcohol of formula R ¹ OH, either commercially available or synthetically accessible, using the conditions described above, gives a compound of formula (XII).

A compound of formula (XIII) is prepared from a compound of formula (XII) in two steps. In the first step, the compound of formula (XII) is dissolved in a solvent such as DMSO, dioxane, THF and the like at a temperature in the range of 0 to 60° C. with a suitable base such as K ₂ CO ₃ , Cs ₂ CO ₃ , etc. with a suitable oxidizing agent, For example, it is hydrolyzed using H ₂ O ₂ , NaClO or the like. Subsequent coupling with commercially available 1,1-dimethoxy-N,N-dimethylmethanamine at a temperature ranging from 80° C. to about 120° C. affords the compound of formula (XIII).

Treatment of a compound of formula (XIII) with a suitable base such as NaH, t-BuOK, LiHMDS, etc. in an aprotic solvent such as THF, dioxane and the like at a temperature in the range of 0 °C to 80 °C gives the compound of formula (XIV) . The compound of formula (XIV) is reacted with a chlorinating agent such as POCl ₃ , SOCl ₂ and the like at a temperature ranging from 60° C. to 100° C. to obtain a compound of formula (XV).

[Scheme 4]

According to Scheme 4, 5,7-dichloropyrido[3,4-d]pyridazin-4(3H)-one (either a commercially available compound or as described in Vasudevan, A. et al, Bicyclic heterocycles as ALK) inhibitors and their preparation and use for the treatment of cancer. synthesized according to the method described in US Patent Application Publication No. 2014/0155389 A1), commercially available or synthetically accessible according to the method described above, of formula R ¹ OH The compound of formula (XVI) is obtained by coupling with an alcohol of A compound of formula (XVI) is reacted with a compound of formula (VIII) that is commercially available or synthetically accessible, using methods previously described, to give a compound of formula (XVII). The compound of formula (XVII) is reacted with a chlorinating agent using the method previously described to give the compound of formula (XVIII).

[Scheme 5]

According to Scheme 4, 5,7-dichloro-1,6-naphthyridin-4(1H)-one (either a commercially available compound or as described in Long, Y. et al, Pyrido-azaheterocyclic compound and preparation method and use thereof, synthesized according to the method described in U.S. Patent Application Publication No. 2018/0244667 A1], according to the method described above, is coupled with an alcohol of the formula R ¹ OH that is commercially available or synthetically accessible to obtain the formula (XIX ) to obtain a compound of Compounds of formula (XIX) in a suitable solvent such as dioxane, DMF, DMSO and the like in the presence of a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane-1,2-diamine, dimethylglycine, etc. under Ulman N-arylation conditions using a suitable catalyst such as CuI, Cu(acac) ₂ , CuO, etc. with or without a suitable base such as K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuOK and the like, Reaction with a compound of formula (VIII), either commercially available or synthetically accessible, gives a compound of formula (XX). The compound of formula (XX) is reacted with a chlorinating agent using the method previously described to give the compound of formula (XXI).

[Scheme 6]

According to Scheme 6, a compound of formula (VII) is reacted with a chlorinating agent using the conditions previously described to give a compound of formula (XXII). Compounds of formula (XXII) are commercially available or under nucleophilic substitution conditions using a suitable base such as KOH, Cs ₂ CO _{3 ,} t-BuOK and the like in the absence of a suitable solvent such as NMP, DMF, DMSO and the like. Synthetically accessible compounds of formula R ⁴ -Y ¹ wherein R ⁴ is a suitably substituted aryl or 5 or 6 membered heteroaryl ring and Y ¹ is OH, SH, or NH ₂ A compound of formula (XXIII) is obtained. The compound of formula (XXIII) is prepared in a suitable solvent such as dioxane, DMF, DMSO and the like at a temperature ranging from 60°C to 120°C in a suitable ligand such as Xantphos(4,5-bis(diphenylphosphino)-9,9-di methylxanthene), CPhos (2-dicyclohexylphosphino-2′,6′-bis( N,N -dimethylamino)biphenyl), a suitable base such as K ₃ PO ₄ , Cs ₂ in the presence of BINAP and the like. Buchwald-Hartwig in the presence of a suitable catalyst, such as Pd(Ph ₃ P) ₄ , Pd ₂ (dba) ₃ , PdCl ₂ (Ph ₃ P) ₂ , etc. under the use of CO ₃ , t-BuOK, etc. ) was reacted with diphenylmethanimine under amination conditions to obtain a compound of formula (XXIV). Deprotection of the compound of formula (XXIV) with an acidic agent such as TFA, HCl and H ₂ SO ₄ and the like in a suitable solvent such as dioxane, THF, DCM and the like at a temperature ranging from 0° C. to 80° C. to deprotect the compound of formula (XXV) get

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

[Scheme 7]

According to Scheme 7, commercially available 2-amino-4-bromo-6-fluorobenzonitrile is prepared using conventional heating or microwave irradiation at a temperature ranging from 80° C. to about 160° C. in a protic solvent such as water, etc. Hydrolysis in a base such as K ₂ CO ₃ and the like gives 2-amino-4-bromo-6-fluorobenzamide. 2-amino-4-bromo-6-fluorobenzamide is treated with a formylating agent such as DMF or the like in the presence of an acid such as pTSA, MSA and the like at a temperature ranging from 60° C. to 140° C. to 7-bromo- 5-fluoroquinazolin-4(3H)-one. A compound of formula (XXVII) by coupling 7-bromo-5-fluoroquinazolin-4(3H)-one with an alcohol of formula R ¹ OH that is commercially available or synthetically accessible, using the conditions described above get Compounds of formula (XXVII) in a suitable solvent such as dioxane, DMF, DMSO and the like in the presence of a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane-1,2-diamine, dimethylglycine, etc. commercially available under Ulman N-arylation conditions under suitable catalysts such as CuI, Cu(acac) ₂ , CuO, etc. with or without a suitable base such as K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuOK and the like or reacted with a synthetically accessible compound of formula (VIII) to obtain a compound of formula (XXVIII). The compound of formula (XXVIII) is reacted with a chlorinating agent such as POCl ₃ , SOCl ₂ and the like using the conditions described above to give the compound of formula (XXIX).

[Scheme 8]

According to Scheme 8, commercially available methyl 4-bromo-2-fluorobenzoate is coupled with an alcohol of formula R ¹ OH that is commercially available or synthetically accessible using the conditions described above to obtain Formula (XXX) to obtain a compound of Hydrolysis of the compound of formula (XXX) 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 a temperature ranging from 20° C. to 80° C. affords the compound of formula (XXXI). Compounds of formula (XXXI) can be reacted with a suitable base such as K ₃ PO ₄ , Cs ₂ using conventional heating at a temperature ranging from 100° C. to about 160° C. or under microwave irradiation with a suitable electrophile such as 1,2-. Cyclization using a suitable catalyst such as Pd(OAc) ₂ , Pd ₂ (dba) ₃ and the like under the use of CO ₃ , K ₂ CO ₃ , etc. gives the compound of formula (XXXII). The compound of formula (XXXII) is reacted with a bromine source such as NBS, Br ₂ and the like using a suitable radical initiator such as BPO, AIBN and the like in a suitable solvent such as DCE, CCl ₄ and the like at a temperature ranging from 70° C. to about 120° C. Halogenation affords the compound of formula (XXXIII). The compound of formula (XXXIII) is reacted with hydrazine in a suitable solvent such as EtOH, dioxane and the like at a temperature in the range of 80°C to about 120°C to give the compound of formula (XXXIV). The compound of formula (XXXIV) is reacted with a chlorinating agent according to the method previously described to give the compound of formula (XXXV).

[Scheme 9]

According to Scheme 9, commercially available 2,6-dichloro-5-fluoronicotinic acid at a temperature ranging from -78°C to about 0°C, for example at about -40°C, in a solvent such as THF, ether, etc. 4,6-dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridine-3(1H) after treatment with a base such as LDA, LiHMDS, etc. followed by reaction with a formyl source such as DMF, etc. )-on is obtained. 4,6-dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridin-3(1H)-one at a temperature ranging from 20°C to 80°C in a suitable solvent such as THF, MeOH, Reaction with hydrazine in EtOH or the like gives 5,7-dichloro-8-fluoropyrido[3,4-d]pyridazin-4(3H)-one. 5,7-dichloro-8-fluoropyrido[3,4-d]pyridazin-4(3H)-one, according to the methods previously described, is commercially available or synthetically accessible alcohols of formula R ¹ OH to give a compound of formula (XXXVI). A compound of formula (XXXVI) is reacted with a commercially available or synthetically accessible compound of formula (VIII) under Ulman N-arylation conditions according to the method described above to obtain a compound of formula (XXXVII). The compound of formula (XXXVII) is reacted with a chlorinating agent such as POCl ₃ , SOCl ₂ and the like using the method described above to give the compound of formula (XXXVIII).

[Scheme 10]

According to Scheme 10, commercially available 2,6-dichloro-5-fluoronicotinic acid at a temperature ranging from -78°C to about 0°C, for example at about -40°C, in a solvent such as THF, ether, etc. 4-bromo-2,6-dichloroethane by treatment with a base such as LDA, LiHMDS, etc., followed by reaction with a bromine source such as NBS, 1,2-dibromo-1,1,2,2-tetrachloroethane, etc. - 5-fluoronicotinic acid is obtained. 4-Bromo-2,6-dichloro-5-fluoronicotinic acid is dissolved in a suitable solvent such as DCM, THF, ether and the like at a temperature ranging from 0° C. to about 80° C. in a chloro source such as oxalyl chloride, thionyl chloride and the like. After reaction, reaction with t-butyl amine in a suitable base such as TEA, DIPEA, etc. gives 4-bromo-N-(tert-butyl)-2,6-dichloro-5-fluoronicotinamide. 4-Bromo-N-(tert-butyl)-2,6-dichloro-5-fluoronicotinamide is dissolved in a suitable ligand in a suitable solvent such as dioxane, DMF, DMSO, etc. at a temperature ranging from 80°C to about 120°C. , such as in the presence or absence of triphenylphosphine, tricyclohexylphosphine and the like, with a suitable base such as K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuOK and the like in the presence of a suitable catalyst such as Pd(OAc) ₂ , (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1 commercially available or synthetically accessible under Suzuki coupling conditions under Pd ₂ (dba) ₃ etc. Coupling with ,3,2-dioxaborolane gives (E)-N-(tert-butyl)-2,6-dichloro-4-(2-ethoxyvinyl)-5-fluoronicotinamide. (E)-N-(tert-butyl)-2,6-dichloro-4-(2-ethoxyvinyl)-5-fluoronicotinamide at a temperature ranging from 20°C to 80°C in a suitable solvent such as DCM Intramolecular cyclization in a suitable acid such as TFA, formic acid and the like in THF, ether and the like gives 6,8-dichloro-5-fluoro-2,7-naphthyridin-1(2H)-one. Coupling 6,8-dichloro-5-fluoro-2,7-naphthyridin-1(2H)-one with an alcohol of formula R ¹ OH that is commercially available or synthetically accessible, using the conditions previously described to obtain a compound of formula (XXXIX). A compound of formula (XXXIX) is reacted with a commercially available or synthetically accessible compound of formula (VIII) under Ulman N-arylation conditions using the conditions described above to give a compound of formula (XL). The compound of formula (XXXXVIII) is reacted with a chlorinating agent such as POCl ₃ , SOCl ₂ and the like using the conditions described above to give the compound of formula (XLI).

[Scheme 11]

According to Scheme 11, compounds of Formula (XLII), including compounds of Formula (X), Formula (XV), Formula (XVII), Formula (XXXVIII), and Formula (XLI), were prepared using conventional heating or microwave heating. at a temperature ranging from 0° C. to 150° C. in the absence of or in a suitable solvent such as NMP, DMF, DMSO, dioxane, etc. using a suitable base such as NaH, KOH, Cs ₂ CO ₃ , t-BuOK, DBU, etc. A compound of formula R ⁴ -Y ¹ that is commercially available or synthetically accessible under nucleophilic substitution conditions, wherein R ⁴ is optionally with 1 or 2 substituents each independently selected from the group consisting of OH and OCH ₃ substituted C _1-6 alkyl, C _3-6 cycloalkyl substituted with C _1-3 alkyl, suitably substituted aryl, 5 or 6 membered heteroaryl ring, or optionally substituted 6 membered heterocycloalkyl; Y ¹ is OH, SH, or NH ₂ ).

When a compound of Formula R ⁴ -Y ¹ , 3,5-difluoro-4-hydroxybenzaldehyde, is coupled with a compound of Formula (X) using the methods previously described, the resulting aldehyde functionality is at about 0° C. Reduction to the CH ₂ OH functional group using a reducing agent such as sodium borohydride in a suitable solvent such as MeOH at a temperature of

When the compound of formula R ⁴ -Y ¹ , 3,5-difluoro-4-hydroxybenzonitrile, is coupled with the compound of formula (X) using the methods described above, the nitrile functional group at a temperature of about 80° C. in a suitable solvent, such as an aqueous NaOH solution in MeOH/THF, to CO ₂ H. Additionally, the CO ₂ H functional group may be further coupled with an amine, such as 2-aminoethan-1-ol, under conventional amide bond formation techniques known to those skilled in the art; For example, in this case, the acid may optionally be hydroxybenzotriazole (HOBt) and/or a catalyst such as 4-dimethylaminopyridine (DMAP); Halotrisaminophosphonium salts such as (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), or bromotripyrrolidinophosphonium hexafluorophosphate ( ^PyBroP® ) ); suitable pyridinium salts such as 2-chloro-1-methyl pyridinium chloride; or other suitable coupling agents such as N,N,N′,N′ -tetramethyl- O- (1 H -benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), 1-[bis(di methylamino)methylene]-1H- 1,2,3 -triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate (HATU), 2,4,6-tripropyl-1,3 In the presence of ,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P ^® ) and the like, 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). a suitable solvent, 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 room temperature; For example, the coupling reaction is performed in DCM, THF, DMF, or the like.

When the compound of formula R ⁴ -Y ¹ , 2,5-dichloropyridin-4-ol, is coupled with the compound of formula (X) using the method described above, the aryl chloro group at a temperature of about 20-100° C. _A suitable catalyst such as ( _{2 -} dicyclohexylphosphino _{- 2} ′,6′ _- di Methoxybiphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (SPhos Pd G3), [1,1′-bis(diphenylphosphino)ferrocene ] is further reacted with a methylating agent such as 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivorinane using dichloropalladium(II) or the like.

When a compound of formula R ⁴ -Y ¹ , 5-chloro-2-methoxypyridin-4-ol, is coupled with a compound of formula (X), wherein R ³ is H, using the method previously described, Further chlorination is carried out with a chlorinating agent such as N-chloro-succinimide (NCS) or Palau'Chlor ^® (2-chloro-1,3-bis(2-chloro-1,3-bis( Methoxycarbonyl) guanidine) and the like are reacted to obtain a compound in which R ³ is Cl.

When a compound of formula R ⁴ -Y ¹ , 5-chloro-2-methoxypyridin-4-ol, is coupled with a compound of formula (X), wherein R ³ is H, using the method previously described, Demethylation of 5-chloro-2-methoxypyridine (prepared by mixing trimethylsilyl chloride (TMSC1) with sodium iodide in a suitable solvent such as ACN, THF at a temperature of about 10-50° C.) It is achieved by reacting with odide (TMSI).

When coupling the compound of formula R ⁴ -Y ¹ , 2-chloro-6-fluoro-3-(2-methoxyethoxy)phenol with the compound of the formula, a suitable solvent at a temperature of about 0 to 35° C.; This is achieved, for example, using boron tribromide (BBr ₃ ) in DCM, THF.

When a compound of Formula R ⁴ -Y ¹ , methyl 2-chloro-4-fluoro-3-hydroxybenzoate, is coupled to a compound of Formula (X) using the methods previously described, the carboxylate functional group is about Hydrolysis to CO ₂ H using an aqueous LiOH solution in a suitable solvent such as MeOH/THF at a temperature of 50 to 80° C. Additionally, the CO ₂ H functional group was further converted to an NH ₂ group by treatment with diphenylphosphoryl azide (DPPA) and an organic base such as TEA or DIPEA in a suitable alcoholic solvent such as t-BuOH at a temperature of 60-100° C. then hydrolyzed in an acidic solvent such as HCl/dioxane solution at a temperature of 20 to 30°C; Alkylation of the amino group with formaldehyde, an acid such as acetic acid and a reducing agent such as NaBH ₃ CN in a suitable solvent such as MeOH or THF at a temperature of about 0-50° C. gives the dimethylamino group (NMe ₂ ). In an alternative method, the amino group is also reacted with methanesulfonyl chloride to obtain a compound in which the amine is replaced with SO ₂ CH ₃ .

Alternatively, the compound of formula (XLII) is reacted with a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane in a suitable solvent such as dioxane, DMF, DMSO and the like at a temperature ranging from 80° C. to about 120° C. A suitable catalyst such as CuI, Cu(acac) ₂ in the presence or absence of -1,2-diamine, dimethylglycine and the like with a suitable base such as K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuOK and the like Compounds of formula R ⁴ -Y ¹ that are commercially available or synthetically accessible under Ulman arylation conditions using CuO, etc., wherein R ⁴ is a suitably substituted aryl or 5 or 6 membered heteroaryl ring, Y ¹ is OH, SH, or NH ₂ ).

Deprotection of PGs according to procedures known to those skilled in the art and using established methods such as those described in TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis," 3 ed., John Wiley & Sons, 1999 achieve For example, when PG is benzyl, H in a suitable solvent such as EtOH, MeOH, EtOAc, or mixtures thereof, preferably EtOH in the presence or absence of HCl (preferably 0.75 equiv) for 4 to 72 hours. Deprotection is achieved using Pd/C under ₂ to give compounds of formula (I). Additionally, when PG is benzyl, by treatment with BCl ₃ in a suitable solvent such as DCM, toluene, etc., at reduced temperatures ranging from -78° C. to room temperature for a period of about 1 to 4 hours, or trifluoroacetic acid as a solvent. can be used to perform deprotection. Additionally, when PG is TBDPS, deprotection using conditions known to those skilled in the art, preferably using TBAF in a suitable solvent such as THF, etc., gives the compound of formula (I).

[Scheme 12]

According to Scheme 12, compounds of formula (XLIII), including compounds of formulas (XXI) and (XXIX), wherein R ⁵ is C _1-6 alkyl or C _1-6 haloalkyl, R ⁷ is H or F, X ³ is CH or N, and X ⁴ is CH or N) in the absence or in a suitable solvent such as NMP, DMF, DMSO and the like, a suitable base such as KOH, Cs ₂ CO ₃ , t-BuOK, etc., commercially available or synthetically accessible under nucleophilic substitution conditions, wherein R ⁸ is a suitably substituted aryl or 5- or ⁶ -membered heteroaryl ring, Z is OH, SH, or NH ₂ ).

Alternatively, the compound of formula (XLIII) is reacted with a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane in a suitable solvent such as dioxane, DMF, DMSO and the like at a temperature ranging from 80° C. to about 120° C. A suitable catalyst such as CuI, Cu(acac) ₂ in the presence or absence of -1,2-diamine, dimethylglycine and the like with a suitable base such as K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuOK and the like Compounds of formula R ⁸ -Z that are commercially available or synthetically accessible under Ulman arylation conditions using CuO, etc., wherein R ⁸ is a suitably substituted aryl or 5 or 6 membered heteroaryl ring, Z is OH, SH, or NH ₂ ).

Deprotection of PGs according to procedures known to those skilled in the art and using established methods such as those described in TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis," 3 ed., John Wiley & Sons, 1999 achieve For example, when PG is benzyl, H in a suitable solvent such as EtOH, MeOH, EtOAc, or mixtures thereof, preferably EtOH in the presence or absence of HCl (preferably 0.75 equiv) for 4 to 72 hours. Deprotection is achieved using Pd/C under ₂ to give the compound of formula (II). Additionally, when PG is benzyl, deprotection can be carried out using trifluoroacetic acid as a solvent. Additionally, when PG is TBDPS, deprotection using conditions known to those skilled in the art, preferably with TBAF in a suitable solvent such as THF, etc., gives the compound of formula (II).

[Scheme 13]

이고, R³은 H임)을 얻는다.According to Scheme 13, a compound of formula (XXVI), wherein R ¹ is C _1-6 alkyl or C _1-6 haloalkyl, and Y is O, is commercially available under nucleophilic substitution conditions or accessed synthetically possible primary or secondary amines, wherein the amines are substituted with one or two C _1-6 alkyl or C _1-6 haloalkyl members. For example, N-methylethanamine is reacted with a compound of formula (XXVI) using a suitable base such as TEA or DIPEA and the like in a suitable solvent such as DCM, THF and the like at a temperature ranging from 0 to 30° to react with a compound of formula (XXVI) ) of a compound (wherein R ² is

, and R ³ is H).

[Scheme 14]

According to Scheme 14, a compound of formula (XXXV) is prepared at a temperature ranging from 0° C. to 150° C. using conventional heating or microwave heating in the absence or in the absence of a suitable solvent such as NMP, DMF, DMSO, dioxane, etc. Compounds of the formula R ⁴ -Y ¹ , commercially available or synthetically accessible, under nucleophilic substitution conditions using a base such as NaH, KOH, Cs ₂ CO ₃ , t-BuOK, DBU and the like, wherein R ⁴ is OH and C _1-6 alkyl optionally substituted with 1 or 2 substituents each independently selected from the group consisting of OCH ₃ , C _3-6 cycloalkyl substituted with C _1-3 alkyl, suitably substituted aryl, 5 or 6 membered heteroaryl ring, or optionally substituted 6 membered heterocycloalkyl; Y ¹ is OH, SH, or NH ₂ . Compounds of formula (XLIV) can be reacted with a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane-1,2 in a suitable solvent such as dioxane, DMF, DMSO and the like at a temperature ranging from 80° C. to about 120° C. - a suitable catalyst such as CuI, Cu(acac)2, CuO, etc. in the presence or absence of diamine, dimethylglycine, etc. in the presence or absence of a suitable base such as K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuOK etc. A _compound of formula (VIII) that is commercially available or synthetically accessible under ^Ulman N-arylation conditions using a suitable alcohol protecting group) to give a compound of formula (XLV).

Deprotection of PGs according to procedures known to those skilled in the art and using established methods such as those described in TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis," 3 ed., John Wiley & Sons, 1999 achieve For example, when PG is benzyl, H in a suitable solvent such as EtOH, MeOH, EtOAc, or mixtures thereof, preferably EtOH in the presence or absence of HCl (preferably 0.75 equiv) for 4 to 72 hours. Deprotection is achieved using Pd/C under ₂ to give the compound of formula (II). Additionally, when PG is benzyl, deprotection can be carried out using trifluoroacetic acid as a solvent. Additionally, when PG is TBDPS, deprotection using conditions known to those skilled in the art, preferably using TBAF in a suitable solvent such as THF, etc., gives the compound of formula (I).

Compounds of formula (I) (and compounds of formula (II)) can be converted to their corresponding salts using methods known to those skilled in the art. For example, treatment of an amine of formula (I) with trifluoroacetic acid, HCl or citric acid in a solvent such as Et ₂ O, CH ₂ Cl ₂ , THF, MeOH, chloroform or isopropanol gives the corresponding salt form . Alternatively, the trifluoroacetic acid or formic acid salt is obtained as a result of reverse phase HPLC purification conditions. The crystalline form of the pharmaceutically acceptable salt of the compound of formula (I) is obtained by recrystallization from a polar solvent (including mixtures of polar solvents and aqueous mixtures of polar solvents) or non-polar solvents (including mixtures of non-polar solvents) to obtain crystalline can be obtained in the form

If the compounds according to the invention have at least one chiral center, they may accordingly exist as enantiomers. When a compound has two or more chiral centers, it may further exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are included within the scope of the present invention.

Compounds prepared according to the schemes described above can be obtained as a single form, such as a single enantiomer, by conformation-specific synthesis or resolution. The compounds prepared according to the above schemes can alternatively be obtained as mixtures in various forms, such as racemic (1:1) or non-racemic (not 1:1) mixtures. When racemic and non-racemic mixtures of enantiomers are obtained, the single enantiomer can be resolved by conventional separation methods known to the person skilled in the art, for example chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, It can be isolated using biotransformation or enzymatic transformation. Where a regioisomeric or diastereomeric mixture is obtained, the single isomers may be separated, where applicable, using conventional methods, such as chromatography or crystallization.

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

Example

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, the reaction mixture was magnetically stirred at room temperature (rt) under a nitrogen atmosphere. When the solution is "dried", it is generally dried with a desiccant such as Na ₂ SO ₄ or MgSO ₄ . When mixtures, solutions and extracts are "concentrated", they are typically concentrated on a rotary evaporator under reduced pressure.

Normal phase silica gel chromatography (FCC) was performed on silica gel (SiO ₂ ) using a pre-filled cartridge.

Preparative reverse phase high performance liquid chromatography (RP HPLC) was performed in one of the following:

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

or

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

or

Method C. Phenomenex Synergi C18 (10 μm, 150 x 25 mm) or Boston Green ODS C18 (5 μm, 150 x 30 mm) and 5-99% ACN (0.05) in water over 10 min at a flow rate of 25 mL/min. % HCl) followed by Gilson GX-281 semi-prep-HPLC with mobile phase holding in 100% ACN for 2 min.

or

Method D. Phenomenex Gemini C18 (10 μm, 150 x 25 mm), AD (10 μm, 250 mm x 30 mm) or Waters XBridge C18 column (5 μm, 150 x 30 mm), 10 at a flow rate of 25 mL/min. Gilson GX-281 semi-prep-HPLC with mobile phase holding 0-99% ACN (with 0.05% (v/v) ammonia hydroxide) in water over minutes followed by 100% ACN for 2 minutes.

or

Method E. Phenomenex Gemini C18 (10 μm, 150 x 25 mm) or Waters XBridge C18 column (5 μm, 150 x 30 mm), 5 to 99% ACN in water over 10 minutes at a flow rate of 25 mL/min (10 mM NH ₄ HCO ₃ ) and then Gilson GX-281 semi-prep-HPLC with mobile phase held in 100% ACN for 2 min.

Preparative supercritical fluid high performance liquid chromatography (SFC) was performed on a Thar 80 prep-SFC system, or a Waters 80Q prep-SFC system from Waters. CO ₂ ABPR was set to 100 bar to maintain the SF condition, and the flow rate can be confirmed according to the compound characteristics at a flow rate in the range of 50 g/min to 70 g/min. The column temperature was ambient.

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

Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker model AVIII 400 spectrometer. The definition of multiplicity is as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. It will be appreciated that for compounds comprising an exchangeable proton, the proton may be visible or invisible on the NMR spectrum, depending on the concentration of the compound in solution and the choice of solvent used to run the NMR spectrum.

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

Compounds designated as R* or S* are pure enantiomers of no absolute configuration.

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) under N ₂ at -78 °C BBr ₃ (1.43 g, 5.71 mmol, 550.26 μL) was added. 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, SiO ₂ , DCM/MeOH; 100/1 to 10/1) gave the title compound (270 mg, 1.88 mmol, 99% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) 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-dimethylisooxazol-4-ol.

Sodium perborate 4 in a solution of (3,5-dimethylisooxazol-4-yl)boronic acid (300 mg, 2.13 mmol) in tetrahydrofuran (THF) (5 mL) and H ₂ O (5 mL) Hydrate (1.31 g, 8.51 mmol, 1.64 mL) was added. The reaction mixture was stirred at 15° C. for 12 h. The reaction mixture was quenched by addition of Na ₂ SO ₃ (20 mL), 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , petroleum ether/ethyl acetate: 1/0 to 1/1) gave the title compound (70 mg, 29.1% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 2.31 (s, 3H), 2.21 (s, 3H).

Intermediate 3: 1,3-dimethyl-1H-pyrazol-4-ol.

To a stirred solution of 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (0.3 g, 2.42 mmol) in CHCl ₃ (8 mL) at 16° C. with meta-chloroperoxybenzoic acid (m-CPBA) (1.47 g, 7.25 mmol, 85% purity) was added and the resulting mixture was stirred at 16° C. for 15 h. The reaction mixture was poured into saturated Na ₂ SO ₃ (40 mL) and extracted with DCM (40 mL×2). The combined organic phases were washed with brine (50 mL×2), dried over anhydrous Na ₂ SO ₄ , 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 aqueous NaOH: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 hour. The reaction mixture was concentrated under reduced pressure. Purification (preparative TLC SiO ₂ , dichloromethane:methanol = 10:1) gave 130 mg of impure product, which was repurified by preparative HPLC (Method A) to obtain the title compound (55) as a white solid. mg, 20.3%) was obtained. MS (ESI): calculated mass for C ₅ H ₈ N ₂ O, 112.1; m/z found, 113.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 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. K ₂ in 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) CO ₃ (9.43 g, 68.24 mmol) was added. The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled, diluted with H ₂ O (50 mL), then with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 20/1) gave the title compound (6.9 g, 98%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) 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) at -78 °C n-BuLi (2.5 M in hexanes, 4.65) mL) was added slowly. The reaction mixture was stirred at -78 °C for 1 h, 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 h, then warmed to 10° C. for 2 h, then stirred at 15° C. for 12 h. The reaction mixture was poured into HCl (0.5 N, 50 mL), then extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , petroleum ether/ethyl acetate = 80/1 to 10/1) gave the title compound (1.9 g, 83%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) 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) at 0 °C was m -CPBA (3.28 g, 16.17 mmol, 85% purity) was added. The reaction mixture was stirred at 40° C. for 16 h. The reaction mixture was then quenched with saturated aqueous NaHCO ₃ aqueous solution (40 mL) at room temperature, then extracted with EtOAc (50 mL×6). The combined organic layers were washed with saturated aqueous Na ₂ SO ₃ aqueous solution (50 mL×2) and brine (50 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to the title The compound (2.1 g) was obtained.

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 aqueous NaOH solution (0.5 M, 40.42 mL) was added. The mixture was stirred at 15° C. for 16 h. The reaction mixture was adjusted to pH 1 with HCl (1 N), then diluted with H ₂ O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 10/1) followed by reverse phase HPLC (0.1% FA conditions)) was carried out to obtain the title compound (1.05 g, 57% yield) as a white solid. ) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) 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 dry DMF (4.47 g, 61.16 mmol, 4.71 mL) stirred at -15°C was added dropwise POCl ₃ (21.88 g, 142.71 mmol, 13.26 mL). Then 1-methylpyrazol-3-ol (2.0 g, 20.39 mmol) was added and the solution was stirred at 90° C. for 12 h. After cooling to room temperature, the reaction was quenched with H ₂ O (80 ml) and the mixture was basified to pH 8 with 1 N NaOH solution. The phases were separated and the aqueous layer was further extracted with CH ₂ Cl ₂ (8×60 mL). The organic layers were combined, dried over NaSO ₄ , filtered and the solvent was removed under reduced pressure. Purification (column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 2/1)) gave the title compound (740 mg, 25%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.83 (s, 1H), 7.87 (s, 1H), 3.92 (s, 3H).

Step B. 3-Chloro-1-methyl-1H-pyrazol-4-ol. To a solution of 3-chloro-1-methyl-pyrazole-4-carbaldehyde (500 mg, 3.46 mmol) in DCM (5 mL) at 0 °C was added m -CPBA (1.40 g, 6.92 mmol, 85% purity) added. The reaction mixture was then warmed to 25° C. and stirred for 12 h. The reaction mixture was quenched with saturated aqueous Na ₂ SO ₃ aqueous solution (3 mL), filtered, the solvent removed under reduced pressure and used crude in the next step. MeOH (10 mL) and TEA (2.18 g, 21.55 mmol, 3 mL) were then 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, SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 1/1) gave the title compound (330 mg, 72%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) 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 H ₂ O (4 mL). The mixture was stirred at 110° C. for 1 h. The reaction was cooled, adjusted to pH = 7 by addition of HCl (1 N) and filtered. The filter cake was purified by preparative HPLC (Method A) to give the title compound (300 mg, 34% yield) as a white solid. MS (ESI): calculated mass for C ₅ H ₃ Cl ₂ NO, 163.0; m/z found, 164.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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) under N ₂ was added NaOH (3.59 g, 89.87 mmol). The mixture was stirred at 70° C. for 24 h. The mixture was cooled and concentrated in vacuo. Purification (silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate = 100/1 to 50/1)) gave the title compound (11 g, 87%) as a white solid. MS (ESI): calculated mass for C ₇ H ₈ ClNO, 157.0; m/z found, 158.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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) under N ₂ at 0° C. BBr ₃ (28.61 g, 114.22 mmol, 11.01 mL) were added in one portion. The mixture was stirred at 80° C. for 12 h. The mixture was cooled, quenched with MeOH (250 mL), basified to pH=8 with K ₂ CO ₃ , then filtered and concentrated in vacuo. Purification (silica gel chromatography (1000 mesh silica gel, dichloromethane: methanol = 50/1 to 10/1)) was carried out to obtain the title compound (2.4 g, 86%) as a white solid. MS (ESI): calculated mass for C ₆ H ₆ ClNO, 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) under N ₂ was added N-chlorosuccinimide (NCS) (930.09 mg, 6.97 mmol) in one portion did. The mixture was stirred at 75° C. for 1 h. The mixture was cooled, filtered and concentrated in vacuo. Purification (reverse phase flash (0.1% TFA)) gave the title compound (400 mg, 32%) as a white solid. MS (ESI): calculated mass for C ₆ H ₅ Cl ₂ NO, 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) under N ₂ CH ₃ ONa (1.82) g, 33.70 mmol) were added in one portion. The reaction mixture was heated to 180° C. and stirred for 12 h. The reaction mixture was cooled and poured into water (40 mL). AcOH was added to the resulting mixture to adjust pH = 7. The aqueous phase was extracted with ethyl acetate (20 mL×4). The combined organic phases were washed with brine (15 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting product was purified by preparative TLC (petroleum ether/ethyl acetate = 3/1) to give the title compound (240 mg, 80%) as a white solid. MS (ESI): calculated mass for C ₇ H ₈ ClNO ₂ , 173.0; m/z found, 174.0 [M+H] ⁺ .

Intermediate 8: 3-chloro-2-methoxypyridin-4-ol.

Step A. 4-(Benzyloxy)-2,3-dichloropyridine. To a solution of NaH (876.94 mg, 21.93 mmol, 60% purity) in DMF (20 mL) at 0° C. was added benzyl alcohol (BnOH) (1.19 g, 10.96 mmol) dropwise. 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 hour. The reaction mixture was poured into water (100 mL), then the mixture was filtered and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with brine (200 mL×4), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , petroleum ether: ethyl acetate = 100:1 to 10:1) gave the title compound (1.5 g, 53%) as a white solid. MS (ESI): calculated mass for C ₁₂ H ₉ Cl ₂ NO, 253.0; m/z found, 254.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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) CuI (209.85 mg, 1.10 mmol), N,N,N',N'-tetra Methylmethanediamine (506.64 mg, 4.96 mmol) and sodium methoxide (NaOMe) (595.27 mg, 11.02 mmol) were added. The reaction mixture was purged with nitrogen for 3 times and then heated at 100° C. for 12 hours. The reaction mixture was cooled, 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 anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (preparative HPLC (0.1% FA conditions)) gave the title compound (800 mg, 58%) as a brown solid. MS (ESI): calculated mass for C ₁₃ H ₁₂ ClNO ₂ , 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 BCl ₃ (1 M in DCM, 4.81 mL). The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was warmed to room temperature and quenched by addition of H ₂ O (5 mL), then the mixture was partitioned between DCM and water. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (preparative TLC (SiO ₂ , DCM:MeOH = 11:1)) gave the title compound (105 mg, 41% yield) as a yellow solid. MS (ESI): calculated mass for C ₆ H ₆ ClNO ₂ , 159.0; m/z found, 160.0 [M+H] ⁺ .

Intermediate 9: 5-Chloro-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol.

Step A: 5-Chloro-3-methyl-1H-pyrazole-4-carbaldehyde. POCl ₃ (62.52 g, 407.73 mmol, 37.89 mL) was added dropwise to DMF (14.90 g, 203.87 mmol, 15.69 mL) 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 h. The reaction mixture was cooled to 25° C. and poured into ice water (300 ml). The mixture was then adjusted to pH=8 with 2N NaOH solution. The aqueous layer was extracted with ethyl acetate (80 ml x 6). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , petroleum ether/ethyl acetate = 3/1) gave the title compound (1.5 g, 20%) as a yellow solid. MS (ESI): calculated mass for C ₅ H ₅ ClN ₂ O, 144.01; m/z found, 145.1 [M+H] ⁺ . ¹ H 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-pyrazole-4-carbaldehyde. To a suspension of NaH (719.36 mg, 17.99 mmol, 60% purity) in THF (13 mL) at 0 °C 5-chloro-3-methyl-1H-pyrazole-4-carbaldehyde (1.3 in THF (13 mL)) g, 8.99 mmol) was added. 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 the reaction mixture at 0° C. The reaction mixture was warmed to 25° C. and stirred for 2 h. The mixture was poured into H ₂ O (200 mL) and the aqueous layer was extracted with ethyl acetate (50 ml×4). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , petroleum ether/ethyl acetate = 10/1) gave the title compound (2.0 g, 78%) as a pale yellow oil. MS (ESI): calculated mass for C ₁₁ H ₁₉ ClN ₂ O ₂ Si, 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) at 0 °C m-CPBA (2.95 g, 14.56 mmol, 85% purity) was added. The reaction mixture was warmed to 25° C. and stirred for 12 h. The reaction mixture was diluted with DCM (20 ml) and washed with Na ₂ SO ₃ (10 mL×2, saturated aqueous solution). The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure and used crude in the next step. The resulting residue was redissolved 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 hours. The solvent was removed under reduced pressure. Purification (FCC, SiO ₂ , petroleum ether/ethyl acetate = 10/1) gave the title compound (710 mg, 36%) as a pale yellow oil. MS (ESI): mass calculated for C ₁₀ H ₁₉ ClN ₂ O ₂ Si, 262.0; m/z found, 262.8 [M+H] ⁺ .

Intermediate 10: 3-chloro-2,5-dimethylpyridin-4-ol.

Step A. 2,5-Dimethylpyridin-4-ol. 2-Chloro-5-methylpyridin-4-ol (1 g, 6.97 mmol), 2,4,6-trimethyl-1,3,5,2 in dioxane (20 mL) and H ₂ O (2 mL) ,4,6-trioxatrivorinane (2.27 g, 9.05 mmol), K ₂ CO ₃ (2.89 g, 20.90 mmol), 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride ( A mixture of Pd(dppf)Cl ₂ ) (509.65 mg, 696.52 μmol) was degassed and purged with N ₂ for 3 times. The mixture was stirred at 120° C. under N ₂ atmosphere for 12 hours. The reaction mixture was cooled, filtered and washed with ethyl acetate (100 mL) and MeOH (20 mL). The filtrate was concentrated under reduced pressure. Purification (FCC, SiO ₂ , DCM/MeOH = 50/1 to 5/1) gave crude product (0.9 g). The crude product (0.9 g) was purified by preparative HPLC (Method A) to give the title compound (0.6 g, 67% yield) as a white solid. MS (ESI): calculated mass for C ₇ H ₉ NO, 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 h. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO ₂ , DCM/MeOH = 30/1 to 20/1) gave the title compound (0.38 g, 52%) as a yellow solid. MS (ESI): calculated mass for C ₇ H ₈ ClNO, 157.0; m/z found, 157.9 [M+H] ⁺ .

Intermediate 11: 3-chloro-6-methoxypyridin-2(1H)-one.

Step A. 5-Chloro-2-methoxypyridine 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 h. The mixture was concentrated under reduced pressure and purified (FCC, SiO ₂ , DCM:MeOH = 0/1 to 10/1) to give the title compound (1.4 g, 58%) as a white solid. MS (ESI): calculated mass for C ₆ H ₆ ClNO ₂ , 159.01; m/z found, 160.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-methoxypyridin-2(1H)-one. To a solution of 5-chloro-2-methoxy-1-oxido-pyridin-1-ium (1.3 g, 7.50 mmol) in THF (30 mL) at 0-10 °C triethylamine (TEA) (3.79 g, 37.48 mmol, 5.22 mL) and trifluoroacetic anhydride (TFAA) (2.05 g, 9.74 mmol, 1.36 mL) were added. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 0/1) followed by trituration with a mixture of petroleum ether/ethyl acetate (5 mL/1 mL), The title compound (380 mg, 31%) was obtained as a yellow solid. MS (ESI): calculated mass for C ₆ H ₆ ClNO ₂ , 159.01; m/z found, 160.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.55 (d, J = 8.0 Hz, 1H), 5.65 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H).

Intermediate 12: 1-(benzyloxy)-3-methoxypropan-2-ol.

To a solution of 2-((benzyloxy)methyl)oxirane (10 g, 60.90 mmol) in MeOH (10 mL) was added a solution of NaOMe (2.4 g, 44.42 mmol) in MeOH (10 mL). The reaction mixture was stirred at 50° C. for 1.5 h. The reaction mixture was cooled, quenched by addition of NaHCO ₃ at 0° C., the pH adjusted to 7-9, then diluted with H ₂ O (10 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (FCC, petroleum ether/ethyl acetate = 20:1 to 2:1) gave the title compound (9.32 g, 45.12 mmol) as a yellow oil. MS (ESI): calculated mass for C ₁₁ H ₁₆ O ₃ , 196.1; m/z found, 197.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-dimethylpyridin-4-ol.

NaNO ₂ (759 mg, 11.00 mmol), 2-methoxy-3 in H ₂ SO ₄ /H ₂ O (v/v, 3/1, 15 mL) in an ice-water bath to keep the temperature below 5° C., To a solution of 5-dimethylpyridin-4-amine (1.4 g, 9.17 mmol) was added slowly. After the addition was complete, the reaction mixture was stirred at 0° C. for 1 h. The mixture was diluted with ethyl acetate (20 mL) and saturated aqueous Na ₂ CO ₃ aqueous solution (15 mL). The mixture was separated and the organic layer was washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and evaporated. Purification (FCC, SiO ₂ , gradient elution: 0-100% ethyl acetate in petroleum ether) gave the title compound (1.2 g, 7.83 mmol, 85.45% yield) as a pale yellow solid. MS (ESI): calculated mass for C ₈ H ₁₁ NO ₂ , 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(2H)-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 added dropwise to the reaction and stirring was maintained for an additional 30 min. 1,2-Dibromo-1,1,2,2-tetrachloroethane (3.1 g, 9.52 mmol) in THF (5 mL) was added dropwise to the reaction at -78 °C and stirring was maintained for an additional 2 hours. The reaction was then warmed to room temperature and quenched with 1N HCl. The reaction mixture was then partitioned between a solution of citric acid and a solution of DCM/MeOH (10:1). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the crude product. It was then purified by flash system using silica gel with 5: 1 DCM: MeOH to give the title product (650 mg, 47.2%) as a turbid off-yellow solid. MS (ESI): calculated mass for C ₆ HBrCl ₂ FNO ₂ , 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 h. The solvent was cooled and removed in vacuo. The residue was redissolved in DCM (5 mL) and 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 Na ₂ SO ₄ and concentrated to give the crude product. It was then purified by flash system using silica gel with 10-60% ethyl acetate in heptane to give the title product (310 mg, 87%) as an off-white foam. MS (ESI): calculated mass for C ₁₀ H ₁₀ BrCl ₂ FN ₂ O, m/z found, 344.0; m/z found, 345.2 [M+H] ⁺ .

Step C. (E)—N-( tert -Butyl)-2,6-dichloro-4-(2-ethoxyvinyl)-5-fluoronicotinamide. 4-bromo-N-(tert-butyl)-2,6-dichloro-5-fluoronicotinamide (200 mg, 0.58 mmol), Pd ₂ (dba) in dioxane (10 mL) and water (1 mL) ) 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) and sodium carbonate (184 mg, 1.74 mmol) were heated at 100° C. for 2 h. The solution was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the crude product. Purification (flash system using silica gel with 0-50% ethyl acetate in heptane) gave the title product (160 mg, 84%) as a cloudy yellow oil. MS (ESI): calculated mass for C ₁₄ H ₁₇ Cl ₂ FN ₂ O ₂ , 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) in DCM (2.5 mL) and TFA (2.5 mL) , 0.30 mmol) was heated at 60° C. overnight in a sealed tube. The reaction was cooled 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 anhydrous Na ₂ SO ₄ and concentrated to give the crude product. Purification (flash system using silica gel with 20-80% ethyl acetate in heptane) gave the title product (50 mg, 72%) as an off-white solid. MS (ESI): calculated mass for C ₈ H ₃ Cl ₂ FN ₂ O, 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) in portions at 0 °C in 10 min. were added each. After addition, the mixture was stirred for an additional 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) as a white solid. , 75.8%) was obtained. MS (ESI): calculated mass for C ₁₁ H ₇ ClF ₄ N ₂ O ₂ , 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)pyrido[3,4-d]pyridazin-4-ol .

Step A. 4,6-Dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridin-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) under N ₂ at -78°C. The mixture was stirred at -78 °C for 1 h. Then, to the mixture was added dropwise a mixture of 2,6-dichloro-5-fluoronicotinic acid (10 g, 47.62 mmol) in THF (25 mL) at -78°C, and the mixture was stirred at -78°C for 1 h. did. DMF (19.00 g, 259.94 mmol) was added dropwise at -78°C. The mixture was stirred at -78 °C for 3 h. The mixture was warmed to room temperature, poured into water (200 mL) and adjusted to pH 4-5 with 1 N HCl. The mixture was then extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with brine (150 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (11.64 g, 41.57 mmol, 87.30% yield) as a yellow solid. . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.82 (s, 1H), 6.85(s, 1H).

Step B. 5,7-Dichloro-8-fluoropyrido[3,4-d]pyridazin-4-ol. 4,6-dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridin-3(1H)-one (11.5 g, 41.07 mmol) and hydrazine sulfuric acid in H ₂ O (100 mL) To a solution of (13.36 g, 102.68 mmol) was added sodium acetate (10.11 g, 123.21 mmol). The mixture was stirred at 105° C. for 1 h. The mixture was cooled, poured into water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with NaHCO ₃ (500 mL, saturated) and brine (500 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (recrystallization from a mixed solvent of petroleum ether/ethyl acetate (2/1, 100 mL)) was carried out at 20° C. to give the title compound (9.26 g, 95.50%) as a yellow solid. MS (ESI): calculated mass for C ₇ H ₂ Cl ₂ FN ₃ O, m/z found, 232.9; m/z found, 233.9 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-ol. To a mixture of 1,1,1-trifluoropropan-2-ol (1.5 g, 13.13 mmol) in DMF (10 mL) at 0° C. was added NaH (500 mg, 12.5 mmol, 60% purity) in one portion. The mixture was stirred at 0° C. for 0.5 h. The mixture was added dropwise 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) at 0 °C. The resulting mixture was stirred at 0° C. for 1 h. The mixture was warmed to room temperature, poured into 1N HCl (100 mL) and extracted with ethyl acetate (100 mL×2). The combined organic phases were washed with brine (200 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (2.07 g, 56%) as a yellow solid. MS (ESI): calculated mass for C ₁₀ H ₆ ClF ₄ N ₃ O ₂ , 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)pyrido[3,4-d]pyridazine-4 -all.

(S)-1,1,1-trifluoropropan-2-ol and 5,7-dichloro-8-fluoropyrido[3,4-d]pyridazin-4-ol (intermediate 15, step The title compound was prepared in an analogous manner to Intermediate 15, Step C using the product from B). MS (ESI): calculated mass for C ₁₀ H ₆ ClF ₄ N ₃ O ₂ , m/z found, 311.0; m/z found, 312.4 [M+H] ⁺ .

Intermediate 17: 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.

Step A. 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 . 7-Chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazine-4- in dioxane (30 mL) N ₂ in a mixture of 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) Cs ₂ CO ₃ (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) under , followed by CuI (1.08 g, 5.68 mmol). The mixture was stirred at 110° C. for 16 h. Then, the reaction was cooled and 3-(benzyloxymethyl)-4-ethyl-1H-1,2,4-triazol- ₅ -one (1.99 g, 8.52 mmol), Cs ₂ CO ₃ ( 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 CuI (1.08 g) , 5.68 mmol) was added. The reaction mixture was stirred at 110° C. for an additional 16 h. The mixture was cooled and poured into water (150 mL). The aqueous phase was extracted with ethyl acetate (150 mL×2). The combined organic phases were washed with brine (30 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (silica gel chromatography, 1000 mesh silica gel, petroleum ether/ethyl acetate = 10/1 to 1/1) gave the title compound (400 mg, 26%) as a yellow solid. MS (ESI): calculated mass for C ₂₂ H ₂₀ F ₄ N ₆ O ₄ , m/z found, 508.1; m/z found, 509.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)oxy)pyrido[3 ,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one . 3-((benzyloxy)methyl)-4-ethyl-1-(8-fluoro-4-hydroxy-5-((1,1,1-trifluoropropane-2) in POCl ₃ (1 mL) -yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-1H-1,2,4-triazol-5(4H)-one (50 mg, 98.34 μmol) in a solution of 90 It was stirred at ℃ for 1 hour. The reaction mixture was cooled, filtered and concentrated under reduced pressure. Toluene (20 mL) was added, the mixture was concentrated under reduced pressure, then another batch of toluene (20 mL) was added, and the mixture was concentrated once more under reduced pressure. The title compound was obtained as a yellow oil (52 mg), which was used directly in the next step. MS (ESI): calculated mass for C ₂₂ H ₁₉ ClF ₄ N ₆ O ₃ , 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) Pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one.

Step A. (S)-3-((benzyloxy)methyl)-4-ethyl-1-(8-fluoro-4-hydroxy-5-((1,1,1-trifluoropropane-2) -yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-1H-1,2,4-triazol-5(4H)-one. (S)-7-chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-4-ol ( Using Intermediate 16), the title compound was prepared in an analogous manner to Intermediate 17, Step A. MS (ESI): calculated mass for C ₂₂ H ₂₀ F ₄ N ₆ O ₄ , m/z found, 508.1; m/z found, 509.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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) Pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in an analogous manner to Intermediate 17, Step B. MS (ESI): calculated mass for C ₂₂ H ₁₉ ClF ₄ N ₆ O ₃ , m/z found, 526.1; m/z found, 527.1 [M+H] ⁺ .

Intermediate 19: 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-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-yl)-5-fluoro Rho-8-((1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthyridin-1(2H)-one. Using 6-chloro-5-fluoro-8-((1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthyridin-1(2H)-one (intermediate 14) Thus, the title compound was prepared in a similar manner to Intermediate 17, Step A. MS (ESI): calculated mass for C ₂₃ H ₂₁ F ₄ N ₅ O ₄ , 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)oxy)-2,7 -naphthyridin-3-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared in an analogous manner to Intermediate 17, Step B. MS (ESI): calculated mass for C ₂₃ H ₂₀ ClF ₄ N ₅ O ₃ , 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)isoquinolin-6-yl)-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) at 0° C. Fonic acid (MSA) (11 mL, 170 mmol, 27.5 mL) was added slowly. After 5 minutes, sodium azide (1.20 g, 18.5 mmol) was added to the reaction in 3 portions and the reaction temperature was maintained at 0° C. for an additional 2 hours. 20% NaOH (40 mL) was added slowly to the reaction, then the reaction was allowed to warm to room temperature and stirred for an additional 15 minutes. 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 (1.95 g, 86.3%) as an off-white solid. MS (ESI): calculated mass for C ₉ H ₇ BrFNO, 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) in portions at 0 °C in 10 min. were added each. After addition, the mixture was stirred for an additional 30 min. To the reaction mixture was added 6-bromo-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one (1.0 g) in N,N-dimethylmethanamide (DMF) (5 mL) at 0 °C. , 4.1 mmol) was added. 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) as a white solid. , 75.8%) was obtained. MS (ESI): calculated mass for C ₁₂ H ₁₁ BrF ₃ NO ₂ , 336.9; m/z found, 338.0, 340.0 [M+H] ⁺ .

Step C. 6-Bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one . 6-Bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydroisoquinolin-1(2H)-one (300) in dioxane (5 mL) mg, 0.89 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (241 mg, 1.07 mmol) were heated at 120° C. overnight. Additional DDQ (200 mg) was added and the reaction heated at 120° C. for an additional 4 h. The reaction was cooled and the solvent was removed under vacuum. The residue was partitioned between ethyl acetate and 1N NaOH solution. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was then concentrated and purified with a silica gel cartridge on an Agilent purification system using 0-60% ethyl acetate/heptane to give the title compound (135 mg, 45.3%) as a white solid. MS (ESI): calculated mass for C ₁₂ H ₉ BrF ₃ NO ₂ , 334.9; m/z found, 336.0, 338.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-( (1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one . 6-Bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one (70 mg, 0.21 mmol), 3 in dioxane (5 mL) -((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (58 mg, 0.25 mmol), K ₃ PO ₄ (79 mg, 0.37 mmol), A mixture of KI (24 mg, 0.15 mmol), trans-N,N-dimethyl-cyclohexane-1,2-diamine (0.02 mL, 0.12 mmol) and CuI (20 mg, 0.10 mmol) was degassed, argon was purged for 3 times. 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 with a silica gel cartridge on an Agilent purification system using 0-100% ethyl acetate/heptane to give the title compound (55 mg, 54%) as an off-white solid. MS (ESI): calculated mass for C ₂₄ H ₂₃ F ₃ N ₄ O ₄ , 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) isoquinolin-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) in POCl ₃ (2 mL) -8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one (75 mg, 0.154 mmol) was refluxed for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated 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 (55 mg, 71%) as a clear oil without further purification. MS (ESI): calculated mass for C ₂₄ H ₂₂ ClF ₃ N ₄ O ₃ , 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)isoquinoline-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 of (2S)-1,1,1-trifluoropropan-2-ol (490.74 mg, 4.30 mmol) in DMF (15 mL) at 0 °C was added NaH (183.54 mg, 4.59 mmol, 60% purity) added. The reaction mixture was stirred at 0° C. for 0.5 h. Then 6-bromo-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one (intermediate 20, product from step A) (0.7 g, 2.87 mmol) in DMF (8 mL) (0.7 g, 2.87 mmol) was added to the mixture and stirred at 0° C. for 2 hours. The reaction mixture was stirred at 15° C. for 6 hours. The mixture was poured into water (25 mL). The aqueous phase was extracted with ethyl acetate (25 mL×2). The combined organic phases were washed with brine (10 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification (silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate = 10/1, 2/1)) gave the title compound (850 mg, 87.7%) as a white solid. MS (ESI): calculated mass for C ₁₂ H ₁₁ BrF ₃ NO ₂ , 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. (S)-6-bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydroisoquinoline-1(2H) in dioxane (160 mL) To a solution of -one (5 g, 14.79 mmol) was added DDQ (10.07 g, 44.36 mmol) in one portion under N ₂ . The mixture was stirred at 130° C. for 24 h. Then more DDQ (10.07 g, 44.36 mmol) was added and the mixture was stirred at 130° C. for an additional 24 h. The mixture was poured into 1N NaOH (300 mL). The aqueous phase was extracted with ethyl acetate (300 mL×2). The combined organic phases were washed with brine (100 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification (silica gel chromatography, 1000 mesh silica gel, petroleum ether/ethyl acetate = 10/1, 1/1) gave the title compound (2 g, 28.97% yield) as a yellow solid. MS (ESI): calculated mass for C ₁₂ H ₉ BrF ₃ NO ₂ , 334.9; m/z found, 336.0, 338.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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 . (S)-6-bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one (2 g, 5.95) in dioxane (150 mL) mmol) and 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (2.08 g, 8.93 mmol) under N ₂ Cs ₂ CO ₃ (3.49 g, 10.71 mmol), CuI (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) were added in one portion. The mixture was heated to 110° C. and stirred for 36 h. The mixture was poured into water (60 mL). The aqueous phase was extracted with ethyl acetate (30 mL×2). The combined organic phases were washed with brine (30 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification (silica gel chromatography, 1000 mesh silica gel, petroleum ether/ethyl acetate = 10/1, 1/1) gave the title compound (1.2 g, 38.6% yield) as a yellow solid. MS (ESI): calculated mass for C ₂₄ H ₂₃ F ₃ N ₄ O ₄ , 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)isoquinoline-6- yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one . (S)-6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole- in POCl ₃ (8 mL) A solution of 1-yl)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one (300 mg, 411.50 μmol) was stirred at 110° C. for 2 hours. heated with The mixture was concentrated under reduced pressure. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with brine (10 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification (silica gel chromatography, 1000 mesh silica gel, petroleum ether/ethyl acetate = 10/1, 1/1) gave the title compound (190 mg, 86.5% yield) as a yellow solid. MS (ESI): calculated mass for C ₂₄ H ₂₂ ClF ₃ N ₄ O ₃ , 506.1; m/z found, 507.2 [M+H] ⁺ .

Intermediate 22: 3-((benzyloxy)methyl)-1-(1-chloro-8-isopropoxyisoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazole-5 ( 4H)-on.

Step A. 6-Bromo-8-isopropoxy-3,4-dihydroisoquinolin-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) in portions at 0° C. in 10 min. After the addition was complete, the mixture was stirred for an additional 30 minutes. 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 of DMF at 0°C. The reaction mixture was then warmed to room temperature over 2 h. 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 Agilent purification system using 20-60% ethyl acetate in heptane) gave the title product (150 mg, 70%) as a white solid. MS (ESI): calculated mass for C ₁₂ H ₁₄ BrNO ₂ , 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-triazole-5 ( 4H)-on . 6- instead of bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydroisoquinolin-1(2H)-one in Intermediate 20, Step E The title compound was prepared in an analogous manner to Intermediate 20, Step C-E, using bromo-8-isopropoxy-3,4-dihydroisoquinolin-1(2H)-one. MS (ESI): calculated mass for C ₂₄ H ₂₅ ClN ₄ O ₃ , 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-naphthyridine-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. 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) Potassium hexamethyldisilane (KHMDS) (1.0 N, 2.4 mL, 2.36 mmol) was added dropwise at -78°C, and the reaction was stirred for 30 minutes. 2,6-Dichloro-4-methylnicotinonitrile (400 mg, 2.14 mmol) in tetrahydrofuran (THF) (1.5 mL) was added dropwise to the reaction and the reaction was stirred at -78 °C for an additional 1 h. 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 between 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 heptane) gave the title compound as a mixture (225 mg, 27%) with its regioisomers. MS (ESI): calculated mass for C ₁₉ H ₁₈ ClN ₅ O ₂ , 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-trifluoropropan-2-yl)oxy)nicotinonitrile. 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 portions at 0 °C for 10 min. Each was added in several portions. After the addition of NaH was complete, the mixture was stirred for an additional 30 min. To the reaction mixture 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole- in 2 mL of THF at 0°C 1-yl)-2-chloro-4-methylnicotinonitrile (250 mg, 0.65 mmol) was added. 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 Agilent purification system using 20-80% ethyl acetate in heptane) gave the title product (150 mg, 49.9%) as a yellow solid. MS (ESI): calculated mass for C ₂₂ H ₂₂ F ₃ N ₅ O ₃ , 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. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)- in ACN (5 mL)- In a solution of 4-methyl-2-((1,1,1-trifluoropropan-2-yl)oxy)nicotinonitrile (80 mg, 0.173 mmol) and K ₂ CO ₃ (24 mg, 0.173 mmol) Hydrogen peroxide (30%, 0.1 mL, 0.87 mmol) was added at room temperature for 2 h. 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 heptane) gave the title product (55 mg, 66%) as a cloudy yellow solid. MS (ESI): calculated mass for C ₂₂ H ₂₄ F ₃ N ₅ O ₄ , 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)- in dioxane (5 mL)- 4-Methyl-2-((1,1,1-trifluoropropan-2-yl)oxy)nicotinamide (100 mg, 0.21 mmol) was mixed with 1,1-dimethoxy-N at 80° C. for 2 hours. ,N-dimethylmethanamine (0.12 mL, 1.04 mmol). The solvent was removed under reduced pressure and the residue was dried in vacuo without further purification (85 mg, 76%). MS (ESI): calculated mass for C ₂₅ H ₂₉ F ₃ N ₆ O ₄ , 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-1-yl)-8-( (1,1,1-Trifluoropropan-2-yl)oxy)-2,7-naphthyridin-1(2H)-one. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl in THF (3 mL) at room temperature In a solution of )-N-((dimethylamino)methylene)-4-methyl-2-((1,1,1-trifluoropropan-2-yl)oxy)nicotinamide (100 mg, 0.187 mmol) t-BuOK (1.0 N, 0.35 mL, 0.347 mmol) was added 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 Agilent purification system using 20-100% ethyl acetate in heptane) gave the title product (25 mg, 27%) as a cloudy yellow solid. MS (ESI): calculated mass for C ₂₃ H ₂₂ F ₃ N ₅ O ₄ , 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-naphthyridine-3 -yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one . The title compound was prepared in an analogous manner to Intermediate 20, Step C. MS (ESI): calculated mass for C ₂₃ H ₂₁ ClF ₃ N ₅ O ₃ , 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 .

Step A. 7-Chloro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-4(3H)-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 portions at 0 °C for 10 min. Each was added in several portions. After the addition of NaH was complete, the mixture was stirred for an additional 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 Agilent purification system using 20-60% ethyl acetate in heptane) gave the title product (92 mg, 75.8%) as a white solid. MS (ESI): calculated mass for C ₁₀ H ₇ ClF ₃ N ₃ O ₂ , 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)pyrido[3,4-d]pyridazin-4(3H)-one . 7-chloro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-4(3H)-one in DMF (2 mL), 5-((benzyloxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (159 mg, 0.68 mmol) and Cs ₂ CO ₃ (221 mg , 0.68 mmol) 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 Agilent purification system using 20-80% ethyl acetate in heptane) gave the title product (105 mg, 63%) as an off-white solid. MS (ESI): calculated mass for C ₂₂ H ₂₁ F ₃ N ₆ O ₄ , 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 an analogous manner to Intermediate 20, Step E. MS (ESI): calculated mass for C ₂₂ H ₂₀ ClF ₃ N ₆ O ₃ , 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-yl)oxy)benzoate . NaH (60% dispersion in mineral oil) in 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 (26 mg, 0.66 mmol) was added. 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 min, 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% EtOAc/heptane) to give the title compound (85 mg, 47% yield) as a colorless oil. MS (ESI): calculated mass for C ₁₁ H ₁₀ BrF ₃ O ₃ , 327.1; m/z found, 327.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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) was stirred at room temperature for 2 h. The mixture was diluted with water and EtOAc and acidified with 1N HCl. The organics were extracted, washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound as a white solid, which was used without further purification. MS (ESI): calculated mass for C ₁₀ H ₈ BrF ₃ O ₃ , 313.1; m/z found, 313.0 [M+H] ⁺ .

Step C. (S)-5-Bromo-7-((1,1,1-trifluoropropan-2-yl)oxy)isobenzofuran-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), bicarbonate Potassium (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, then diluted with DCM and adsorbed onto silica. Purification by column chromatography (0-15% EtOAc/heptane) gave the title compound (19.3 mg, 59%) as a colorless oil. MS (ESI): calculated mass for C ₁₁ H ₈ BrF ₃ O ₃ , 325.1; m/z found, 325.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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. (S)-5-bromo-7-((1,1,1-trifluoropropan-2-yl)oxy)isobenzofuran-1(3H)-one (540 mg, 1.661 mmol) in a vial; 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) was charged. The reaction was heated to 80° C. and stirred for 1.5 h. It was cooled 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. (S)-3,5-dibromo-7-((1,1,1-trifluoropropan-2-yl)oxy)isobenzofuran-1(3H)-one (670 mg, 1.6 mmol) It was dissolved in EtOH (6.5 mL), hydrazine hydrate (0.41 mL, 1.027 g/mL, 8.3 mmol) was added and then heated to 80° C. for 5 h. The mixture was concentrated and then taken up in EtOAc and water. The organics were extracted with EtOAc (2x). 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 give the title compound (2 steps, 377 mg, 67% yield). MS (ESI): mass calculated for C ₁₁ H ₈ BrF ₃ N ₂ O ₂ , 337.1; m/z found, 337.0 [M+H] ⁺ . ¹ H NMR δ (400 MHz, CD ₃ OD) 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)phthalazine. (S)-6-bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)phthalazin-1(2H)-one (73 mg, 0.22 mmol) at 100° C. was stirred in POCl ₃ (1.46 mL, 1.65 g/mL, 15.7 mmol) for 2 h. The reaction was cooled, then concentrated under reduced pressure and placed under vacuum overnight (ca. 80 mg). The crude product was not purified further. MS (ESI): calculated mass for C ₁₁ H ₇ BrClF ₃ N ₂ O, 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-naphthyridine-7 -yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one .

5,7-dichloro-1,6-naphthyridin-4 (1H) instead of 5,7-dichloropyrido[3,4-d]pyridazin-4(3H)-one in Intermediate 24, Step A The title compound was prepared in an analogous manner to Intermediate 24, Step A-C, using -on. MS (ESI): calculated mass for C ₂₃ H ₂₁ ClF ₃ N ₅ O ₃ , 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. 5-[(benzyloxy)methyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (intermediate 1) (4.0 g, 17.1) in methanol (200 mL) mmol) was added 10% Pd/C (3.65 g, 3.43 mmol). The resulting mixture was vigorously shaken in a hydrogen atmosphere (45 psi) at room temperature for 20 hours. The resulting mixture was then filtered through a short pad of celite and the filtrate was concentrated to give the crude product 4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1 as a white solid, 2,4-triazol-3-one (2.4 g, 98%) was obtained. MS (ESI): calculated mass for C ₅ H ₉ N ₃ O ₂ , 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) with tert -Butylchlorodiphenylsilane (6.9 g, 25.1 mmol) and imidazole (2.28 g, 33.5 mmol) were added. The resulting mixture was stirred at room temperature 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 Agilent purification system using silica gel chromatography (50-100% ethyl acetate/heptane) as a white solid As 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (4.9 g, 76%) got MS (ESI): calculated mass for C ₂₁ H ₂₇ N ₃ O ₂ Si, 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 h. The mixture was cooled, concentrated and dissolved in ethyl acetate (30 mL) and water (15 mL). The mixture was separated and the organic layer was washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography (SiO ₂ , gradient elution: 0-100% ethyl acetate in petroleum ether) to give the title compound (280 mg, 34.4% yield) as a yellow oil. MS (ESI): calculated mass for C ₆ H ₅ ClFNO ₂ , 177.0; m/z found, 177.8 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.80 (d, J = 1.3 Hz, 1H), 6.10 (br s, 1H), 3.92 (s, 3H).

Intermediate 29: 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.

Step A. 7-Chloro-8-fluoro-5-isopropoxypyrido[3,4-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 portions at 0° C. in 10 minutes. After the addition of NaH was complete, the mixture was stirred for an additional 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 Agilent purification system using 20-60% ethyl acetate in heptane) gave the title product (288 mg, 81%) as a white solid. MS (ESI): calculated mass for C ₁₀ H ₉ ClFN ₃ O ₂ , 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 rho-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 Cs ₂ CO ₃ in DMF (2 mL) (253 mg, 0.78 mmol) 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 Agilent purification system using 20-80% ethyl acetate in heptane) gave the title product (213 mg, 60%) as an off-white solid. MS (ESI): calculated mass for C ₂₂ H ₂₃ FN ₆ O ₄ , 454.5; m/z found, 455.5 [M+H] ⁺ .

Step C: 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. The title compound was prepared in an analogous manner to Intermediate 20, Step E. MS (ESI): calculated mass for C ₂₂ H ₂₂ ClFN ₆ O ₃ , 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)isoquinolin-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 in sealed tube -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) were heated to 110° C. for 2 h. The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The solution was then concentrated and purified with a silica gel cartridge on an Agilent purification system using 0-60% ethyl acetate/heptane to give the title compound (48 mg, 66%) as an off-white solid. MS (ESI): calculated mass for C ₃₀ H ₂₅ ClF ₄ N ₄ O ₄ , 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)isoquinolin-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-) in trifluoroacetic acid (TFA) (0.5 mL) trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (48 mg, 0.08 mmol ) was refluxed for 4 hours. The solvent was concentrated under reduced pressure and the residue was treated with a solution of acetonitrile (ACN) (1 mL) and 1N NaOH (1 mL) at room temperature for 10 min. The solution was purified by preparative HPLC (Method B) using 20-80% ACN/water (0.1% TFA) to afford the title compound as a white solid after lyophilization. MS (ESI): mass calculated for C ₂₃ H ₁₉ ClF ₄ N ₄ O ₄ , 526.1; m/z found, 527.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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), 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)isoquinoline- 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-trifluoropropane- 2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoro) in N-methyl-2-pyrrolidone (NMP) (2.5 mL) Ropropan-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 To a solution of -chloro-6-fluorophenol (255.56 mg, 1.98 mmol) was added KOH (44.28 mg, 789.1 μmol). The reaction mixture was sealed and heated in a microwave at 150° C. for 3 hours. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. Purification (preparative TLC, petroleum ether/ethyl acetate = 2/1) gave the title compound (41 mg, 33.3% yield) as a yellow oil. MS (ESI): mass calculated for C ₂₉ H ₂₅ ClF ₃ N ₅ O ₄ , 599.1; m/z found, 600.1 [M+H] ⁺ .

Step B. (S)-2-(1-(2-Chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy) isoquinoline-6 -yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. (S)-5-((benzyloxy)methyl)-2-(1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoro) in DCM (3 mL) of lopropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (40 mg, 67.00 μmol) To the solution was added BCl ₃ (1 M, 200 μL). The mixture was stirred at -78 °C for 1 h. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by RP HPLC (condition A) to give the title compound (22 mg, 62.0% yield) as a white solid. MS (ESI): calculated mass for C ₂₃ H ₁₉ ClF ₄ N ₄ O ₄ , m/z found, 526.1; m/z found, 527.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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), 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)isoquinoline-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-1-isopropyl-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-one . 5-((benzyloxy)methyl)-2-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline- in dioxane (1 mL) in sealed tube 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 Cs ₂ CO ₃ (6.4 mg, 0.02 mmol) were heated to 130° C. overnight. The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with brine, dried over sodium sulfate and filtered. The resulting solution was then concentrated and purified with a silica gel cartridge on an Agilent purification system using 0-60% ethyl acetate/heptane to give the title compound (5 mg, 83%) as an off-white solid. MS (ESI): calculated mass for C ₃₀ H ₂₆ ClF ₄ N ₅ O ₃ , 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 . Following the procedure of Example 1, Step B, the title compound was prepared. MS (ESI): calculated mass for C ₂₃ H ₂₀ ClF ₄ N ₅ O ₃ , 525.1; m/z found, 526.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-fluorophenyl)thio)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-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-trifluoropropane-2- yl)oxy)isoquinolin-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 in DMF (0.5 mL) ) -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 Cs ₂ CO ₃ (32 mg, 0.1 mmol) were stirred at room temperature for 1 h. The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The solution was then concentrated and purified with a silica gel cartridge on an Agilent purification system using 0-60% ethyl acetate/heptane to give the title compound (12 mg, 96%) as an off-white solid. MS (ESI): mass calculated for C ₃₀ H ₂₅ ClF ₄ N ₄ O ₃ S, 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. Following the procedure of Example 1, Step B, the title compound was prepared. MS (ESI): mass calculated for C ₂₃ H ₁₉ ClF ₂ N ₄ O ₃ S, 542.1; m/z found, 543.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)isoquinolin-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 . 3,5-difluoro-4-hydroxybenzonitrile to 5-((benzyloxy)methyl)-2-(1-chloro-8-((1,1,1-trifluoropropan-2-yl) Example 1, Step A by coupling with )oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20) The title compound was prepared in a similar manner to MS (ESI): calculated mass for C ₃₁ H ₂₄ F ₅ N ₅ O ₄ , 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-1-yl)-8 -((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3,5-difluorobenzonitrile . The title compound was prepared in a similar manner to Example 1, Step B. MS (ESI): calculated mass for C ₂₄ H ₁₈ F ₅ N ₅ O ₄ , 535.1; m/z found, 536.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-(hydroxymethyl)phenoxy)-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. 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. 3,5-difluoro-4-hydroxybenzaldehyde to 5-((benzyloxy)methyl)-2-(1-chloro-8-((1,1,1-trifluoropropan-2-yl) Example 1, Step A by coupling with )oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20) The title compound was prepared in a similar manner to MS (ESI): calculated mass for C ₃₁ H ₂₅ F ₅ N ₄ O ₅ , 628.2; m/z found, 629.5 [M+H] ⁺ .

Step B. 5-((benzyloxy)methyl)-2-(1-(2,6-difluoro-4-(hydroxymethyl)phenoxy)-8-((1,1,1-trifluoro) lopropan-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) is treated with sodium borohydride (3 mg, 0.08 mmol) for 10 minutes.The solution is partitioned between ethyl acetate and water.The organic layer is washed with brine, dried, filtered and concentrated. Obtain crude product.Then crude product was purified by silica gel cartridge on Agilent purification system using 10-60% ethyl acetate/heptane to obtain title compound (8.0 mg, 80%) as off-white solid.MS (ESI) ): calculated mass for C ₃₁ H ₂₇ F ₅ N ₄ O ₅ , 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)iso Quinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared in a similar manner to Example 1, Step B. (ESI): calculated mass for C ₂₄ H ₂₁ F ₅ N ₄ O ₅ , 540.1; m/z found, 541.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) 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, J = 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-difluorobenzoic 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-difluorobenzoic acid. 4-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-di in a mixture of MeOH (1 mL), THF (1 mL) and water (1 mL) Hydro-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) was treated with 50% NaOH (0.02 mL) and heated at 80° C. overnight. The solution was acidified to pH = 4 with 1N HCl and extracted with ethyl acetate (3x). 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 heptane) gave the title compound (21 mg, 82.4%) as a white solid. MS (ESI): calculated mass for C ₃₁ H ₂₅ F ₅ N ₄ O ₆ , 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)oxy)isoquinolin-1-yl)oxy)-3,5-difluorobenzoic acid. The title compound was prepared according to Example 1, Step B to give a white solid. MS (ESI): calculated mass for C ₂₄ H ₁₉ F ₅ N ₄ O ₆ , 554.2; m/z found, 555.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)benz amide . 4-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 in DCM (2 mL) -yl)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3,5-difluorobenzoic acid (Example 7, Step A product from, 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) 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 heptane) gave the title compound (11.2 mg, 73.7%) as a colorless oil. MS (ESI): calculated mass for C ₃₃ H ₃₀ F ₅ N ₅ O ₆ , 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): calculated mass for C ₂₆ H ₂₄ F ₅ N ₅ O ₆ , 597.2; m/z found, 598.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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) isoquinoline-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-4,6-difluorophenoxy)-8-((1,1,1-trifluoropropane-2) -yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. 2-Chloro-4,6-difluorophenol to 5-((benzyloxy)methyl)-2-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy ) by coupling with isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20), The title compound was prepared according to the procedure. MS (ESI): calculated mass for C ₃₀ H ₂₄ ClF ₅ N ₄ O ₄ , 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) isoquinoline -6- yl)-4-ethyl-5-( hydroxymethyl )-2,4 - dihydro-3H-1,2,4-triazol-3-one . The title compound was prepared in a similar manner to Example 1, Step B. MS (ESI): mass calculated for C ₂₃ H ₁₈ ClF ₅ N ₄ O ₄ , 544.1; m/z found, 545.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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.

5-((benzyloxy)methyl)-2-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-6- in Example 1, Step A 3-((benzyloxy)methyl)-1-(1-chloro instead of yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (intermediate 20) Example 1, step A and using -8-isopropoxyisoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 22) The title compound was prepared following the procedure in Step B. MS (ESI): calculated mass for C ₂₃ H ₂₂ ClFN ₄ O ₄ , 472.1; m/z found, 473.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)isoquinoline -6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Step A. (S)-5-((benzyloxy)methyl)-2-(1-((4-chloropyridin-3-yl)oxy)-8-((1,1,1-trifluoropropane) -2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane-) in N-methyl pyrrolidone (NMP) (1.5 mL) 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-chloropyridine To a solution of -3-ol (204.45 mg, 1.58 mmol) was added KOH (35.42 mg, 631.28 μmol). The reaction mixture was sealed and heated using microwave irradiation at 150° C. for 3 hours. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. Purification (preparative TLC (petroleum ether/ethyl acetate = 2/1)) gave the title compound (30 mg, 29.15% yield) as a yellow oil. MS (ESI): mass calculated for C ₂₉ H ₂₅ ClF ₃ N ₅ O ₄ , 599.1; m/z found, 600.1 [M+H] ⁺ .

Step B. (S)-2-(1-((4-chloropyridin-3-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline- 6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one . (S)-3-((benzyloxy)methyl)-1-(1-((4-chloropyridin-3-yl)oxy)-8-((1,1,1-tri) in DCM (3 mL) BCl in a solution of fluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (60 mg, 100.00 μmol) ₃ (1 M, 300.01 μL) was added. The mixture was stirred at -78 °C for 1 h. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (condition A) to give the title compound (17 mg, 31.0% yield) as a white solid. MS (ESI): calculated mass for C ₂₂ H ₁₉ ClF ₃ N ₅ O ₄ , 509.1; m/z found, 510.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)oxy)isoquinoline -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-chloropyridin-3-yl)oxy)-8-((1,1,1-trifluoropropane) -2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one . 2-chloropyridin-3-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy The title compound in an analogous manner to Example 2, Step A by coupling with )isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) was prepared. MS (ESI): calculated mass for C ₂₉ H ₂₅ ClF ₃ N ₅ O ₄ , 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)isoquinoline- 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): calculated mass for C ₂₂ H ₁₉ ClF ₃ N ₅ O ₄ , m/z found, 509.1; m/z found, 510.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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. 2-Chloro-4-methylpyridin-3-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane-2) Similar to Example 2, Step A by coupling with -yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21) The title compound was prepared in this manner. MS (ESI): calculated mass for C ₃₀ H ₂₇ ClF ₃ N ₅ O ₄ , 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): calculated mass for C ₂₃ H ₂₁ ClF ₃ N ₅ O ₄ , m/z found, 523.1; m/z found, 524.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-tri Fluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. 2,4-dimethylpyridin-3-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane-2- In analogous manner to Example 2, Step A by coupling with yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21) to prepare the title compound. MS (ESI): calculated mass for C ₃₁ H ₃₀ F ₃ N ₅ O ₄ , 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): calculated mass for C ₂₄ H ₂₄ F ₃ N5O ₄ , m/z found, 503.2; m/z found, 504.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ )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-tri Fluoropropan-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. 4-methylpyridin-3-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy The title compound in an analogous manner to Example 2, Step A by coupling with )isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) was prepared. MS (ESI): calculated mass for C ₃₀ H ₂₈ F ₃ N ₅ O ₄ , 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-trifluoro Ropropan-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): calculated mass for C ₂₃ H ₂₂ F ₃ N ₅ O ₄ , 489.1; m/z found, 490.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ )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-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-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-trifluoropropane-2) -yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. 2-Chloro-5-methylphenol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy The title compound in an analogous manner to Example 2, Step A by coupling with )isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) was prepared. MS (ESI): calculated mass for C ₃₁ H ₂₈ ClF ₃ N ₄ O ₄ , 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)oxy)isoquinoline-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): calculated mass for C ₂₄ H ₂₂ ClF ₃ N ₄ O ₄ , m/z found, 522.1; m/z found, 523.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.11 (d, J =1.9 Hz, 1H), 7.96 (d, J =1.9 Hz, 1H), 7.90 (d, J =5.8 Hz, 1H), 7.37 ( d, J =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, J =7.2 Hz, 2H), 2.38 (s, 3H), 2.13 - 2.00 (m, 1H), 1.63 (d, J =6.4 Hz, 3H), 1.44 (t) , J =7.2 Hz, 3H).

Example 17: (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.

Step A. (S)-5-((benzyloxy)methyl)-2-(1-((4-chloro-2-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. 4-Chloro-2-methylpyridin-3-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane-2) Similar to Example 2, Step A by coupling with -yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21) The title compound was prepared in this manner. MS (ESI): calculated mass for C ₃₀ H ₂₇ ClF ₃ N ₅ O ₄ , m/z found, 613.2; m/z found, 614.7 [M+H] ⁺ .

Step B. (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. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): calculated mass for C ₂₃ H ₂₁ ClF ₄ N ₅ O ₄ , m/z found, 523.1; m/z found, 524.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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) isoquinoline -6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

Step A. (S)-3-((benzyloxy)methyl)-1-(1-((3-chloropyridin-2-yl)oxy)-8-((1,1,1-trifluoropropane) -2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one . (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline in dioxane (1.5 mL) -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) was added Cs ₂ CO ₃ (96.41 mg, 295.91 μmol) under N ₂ , followed by copper(II) acetylacetonate [Cu(acac) ₂ ] (5.16 mg, 19.73 μmol) in one portion. 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×2). The combined organic phases were washed with brine (20 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (preparative TLC, petroleum ether:ethyl acetate = 1/1) gave the title compound (35 mg, 53.82%) as a yellow solid. MS (ESI): mass calculated for C ₂₉ H ₂₅ ClF ₃ N ₅ O ₄ , 599.1; m/z found, 600.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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) isoquinoline- 6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one . (S)-3-((benzyloxy)methyl)-1-(1-((3-chloropyridin-2-yl)oxy)-8-((1,1,1-tri) in DCM (5 mL) BCl in a solution of fluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (75 mg, 125 μmol) ₃ (1 M, 250 μL) was added. The mixture was stirred at -78 °C for 1 h. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by RP HPLC (condition A) to give the title compound (35 mg, 55.6% yield) as a white solid. MS (ESI): calculated mass for C ₂₂ H ₁₉ ClF ₃ N ₅ O ₄ , 509.1; m/z found, 510.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-(1-((3,5-dimethylisooxazol-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. 3,5-dimethylisoxazol-4-ol (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane- Example 2, Step A, by coupling with 2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) The title compound was prepared according to the procedure of MS (ESI): calculated mass for C ₂₉ H ₂₈ F ₃ N ₅ O ₄ , m/z found, 583.2; m/z found, 584.4 [M+H] ⁺ .

Step B. (S)-1-(1-((3,5-dimethylisooxazol-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): calculated mass for C ₂₂ H ₂₂ F ₃ N ₅ O ₅ , m/z found, 493.2; m/z found, 494.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8. 07 (d, J = 1.8 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-naphthyridine -3-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-6- in Example 1, Step A 3-((benzyloxy)methyl)-1-(8-chloro-1-((1,1) instead of yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one ,1-trifluoropropan-2-yl)oxy)-2,7-naphthyridin-3-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 23) to prepare the title compound according to the procedure of Example 1, Step A and Step B. MS (ESI): mass calculated for C ₂₂ H ₁₈ ClF ₄ N ₅ O ₄ , 527.1; m/z found, 528.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 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)pyrido[3,4- d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

5-((benzyloxy)methyl)-2-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-6- in Example 1, Step A 3-((benzyloxy)methyl)-1-(4-chloro in place of yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (intermediate 20) -5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4 The title compound was prepared according to the procedure of Example 1, Step A and Step B, except that -triazol-5(4H)-one (Intermediate 24) was used. MS (ESI): mass calculated for C ₂₁ H ₁₇ ClF ₄ N ₆ O ₄ , 528.1; m/z found, 529.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-naphthyridine -7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

5-((benzyloxy)methyl)-2-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-6- in Example 1, Step A 5-((benzyloxy)methyl)-2-(4-chloro instead of yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (intermediate 20) -5-((1,1,1-trifluoropropan-2-yl)oxy)-1,6-naphthyridin-7-yl)-4-ethyl-2,4-dihydro-3H-1, The title compound was prepared according to the procedure of Example 1, Step A and Step B, using 2,4-triazol-3-one (Intermediate 26). MS (ESI): mass calculated for C ₂₂ H ₁₈ ClF ₄ N ₅ O ₄ , 527.1; m/z found, 528.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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) isoquinoline- 6-yl)-1-ethyl-1-methylurea .

Step A. (S)-6-Bromo-1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline . (S)-6-bromo-8-((1,1,1 _- trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one (intermediate 21, A solution of the product from step B, 200 mg, 595.05 μmol) was heated to 110° C. for 2 h. 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×2). The combined organic phases were washed with brine (20 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (205 mg, crude) as a yellow solid. MS (ESI): calculated mass for C ₁₂ H ₈ BrClF ₃ NO, 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) isoquinoline . (S)-6-bromo-1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline (150 mg, 423.07 μmol) in NMP (0.5 mL) and A mixture of 2-chloro-6-fluoro-phenol (620.00 mg, 4.23 mmol) and KOH (94.95 mg, 1.69 mmol) was heated to 110° C. in a sealed tube for 2 h. The residue was cooled and then poured into saturated Na ₂ CO ₃ (30 mL). The aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with brine (10 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification (preparative TLC, petroleum ether/ethyl acetate = 10/1) gave the title compound (105 mg, 51.5%) as a yellow solid. MS (ESI): calculated mass for C ₁₈ H ₁₁ BrClF ₄ NO ₂ , 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-trifluoropropan-2-yl)oxy ) isoquinolin-6-amine . (S)-6-bromo-1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy in dioxane (2 mL) ) Cs ₂ CO ₃ (84.15 mg, 258.27 μmol), 4,5-bis(di) in a mixture of isoquinoline (100 mg, 215.22 μmol) and diphenylmethanimine (78.01 mg, 430.44 μmol, 72.23 μL) under N ₂ Phenylphosphino)-9,9-dimethylxanthene (Xantphos) (12.45 mg, 21.52 μmol) and tris(dibenzylideneacetone) dipalladium(0)(Pd ₂ (dba) ₃ ) (9.85 mg, 10.76 μmol) ) were added all at once. The mixture was stirred at 110° C. for 12 h. The mixture was cooled and then poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with brine (10 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (130 mg, crude) as a yellow oil. MS (ESI): calculated mass for C ₃₁ H ₂₁ ClF ₄ N ₂ O ₂ , 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)isoquinolin-6-amine . (S)-1-(2-chloro-6-fluorophenoxy)-N-(diphenylmethylene)-8-((1,1,1-trifluoropropane-2- in THF (2 mL)) To a mixture of yl)oxy)isoquinolin-6-amine (130 mg) was added HCl (2 M, 345 μL). The mixture was stirred at 15° C. for 2 h. The mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with brine (10 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification (preparative TLC, petroleum ether/ethyl acetate = 2/1) gave the title compound (80 mg, 75.6%) as a yellow solid. MS (ESI): calculated mass for C ₁₈ H ₁₃ ClF ₄ N ₂ O ₂ , 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) isoquinoline-6- 1) Carbamate . (S)-1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy) isoquinoline-6 in DCM (2 mL) -Pyridine (47.37 mg, 598.87 μmol) and phenyl carbonochloridate (40.63 mg, 259.51 μmol) were added to a mixture of -amines (80 mg, 199.62 μmol) at 0° C. under N ₂ . The reaction mixture was stirred at 15° C. for 1 h. The mixture was poured into water (10 mL). The aqueous phase was extracted with DCM (10 mL×2). The combined organic phases were washed with brine (5 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (110 mg, crude) as a yellow oil. MS (ESI): calculated mass for C ₂₅ H ₁₇ ClF ₄ N ₂ O ₄ , 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) isoquinoline-6 -yl)-1-ethyl-1-methylurea . (S)-phenyl (1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl) in dichloromethane (DCM) (2 mL) Triethylamine (TEA) (40.41) in a mixture of )oxy)isoquinolin-6-yl)carbamate (104 mg, crude) and N-methylethanamine (23.60 mg, 399.34 μmol) under N ₂ at 15° C. mg, 399.34 μmol) was added. 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×2). The combined organic phases were washed with brine (10 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification (reverse phase HPLC (condition A)) gave the title compound (55 mg) as a white solid. MS (ESI): calculated mass for C ₂₂ H ₂₀ ClF ₄ N ₃ O ₃ , 485.1; m/z found, 486.1 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) 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)oxy) quinazoline- 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), K ₂ CO ₃ (137.8 mg, 1.0 mmol) and water (10 mL) was prepared using microwave irradiation at 150° C. heated for 45 min. The reaction mixture was extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a tan solid. The crude product was used in the next step without further purification. MS (ESI): calculated mass for C ₇ H ₆ BrFN ₂ O, 233.0; m/z found, 233.1 [M+H] ⁺ .

Step B: 7-Bromo-5-fluoroquinazolin-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 more p-toluenesulfonic acid monohydrate (677 mg, 3.6 mmol) was added and the reaction was continued at 120° C. for an additional 2 hours. An additional amount of p-toluenesulfonic acid monohydrate (677 mg, 3.6 mmol) was added and the mixture was 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, 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. An orange solid (100 mg, yield 23%) proved to be the 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% EtOAc/heptane to give an additional crop (crop) of the title compound (156 mg, yield 36%). MS (ESI): calculated mass for C ₈ H ₄ BrFN ₂ O, 243.0; m/z found, 243.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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. NaH (60% dispersion in mineral oil) (51 mg, 1.3) in a solution of (S)-1,1,1-trifluoro-2-propanol (145 mg, 1.3 mmol) in DMF (2.1 mL) at 0 °C mmol) was added. The mixture was stirred for 10 min, 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% EtOAc/heptane) to give the title compound (216 mg) as an off-white solid. MS (ESI): mass calculated for C ₁₁ H ₈ BrF ₃ N ₂ O ₂ , 337.1; m/z found, 337.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)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 . 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), CuI (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) was added. The mixture was sparged with argon and then heated to 120° C. for 4 hours. The mixture was cooled, then filtered over Celite® and washed with EtOAc. Purification by column chromatography (40-100% EtOAc/heptane) gave the title compound (77 mg, yield 82%) as a pale yellow oil. MS (ESI): calculated mass for C ₃₂ H ₃₄ F ₃ N ₅ O ₄ , 637.7; m/z found, 638.3 [M+H] ⁺ .

Step E. (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 . (S)-7-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-5-oxo-4,5-dihydro in acetonitrile (MeCN or ACN) (3.5 mL) -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 a solution of 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) was added. The solution was stirred at room temperature for 2 h, 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% EtOAc/heptane) gave the title compound (27 mg, 33%) as a colorless oil. MS (ESI): mass calculated for C ₃₈ H ₃₆ ClF ₄ N ₅ O ₄ Si, 766.3; m/z found, 766.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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) quinazoline-7 -yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. (S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(4-(2-chloro-6-fluorophenoxy)-5-((1) in THF (0.5 mL) ,1,1-trifluoropropan-2-yl)oxy)quinazolin-7-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one ( To a solution of 27 mg, 0.035 mmol) was added tetrabutylammonium fluoride (TBAF) (1M in THEE) (0.106 mL, 1 M, 0.106 mmol). The mixture was stirred at room temperature for 0.5 h, then diluted with diethyl ether. The organics were washed with saturated aqueous NH ₄ Cl solution, dried over sodium sulfate, filtered and concentrated. The crude mixture was purified by column chromatography (70-100% EtOAc/heptane) followed by reverse-phase HPLC (Isco ACCQPrep, 30×100 mm, 20-100% ACN/10 mM NH ₄ OH in water), titled as a white solid. The compound (10 mg, 54%) was obtained. MS (ESI): calculated mass for C ₂₂ H ₁₈ ClF ₄ N ₅ O ₄ , 527.9; m/z found, 528.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-yl)oxy)phthalazine -6-yl)-4-ethyl-5-(hydroxymethyl)-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)phthala jin. 2-Chloro-6-fluorophenol (159 mg, 1.1 mmol) was mixed with (S)-6-bromo-1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy ) was added to phthalazine (intermediate 25, 80 mg, 0.225 mmol), followed by dioxane (1.0 mL). 1,8-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 twice with EtOAc. 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) gave the title compound (80 mg, 82%) as a yellow semi-solid with a small amount of impurities. MS (ESI): calculated mass for C ₁₇ H ₁₀ BrClF ₄ N ₂ O ₂ , 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, 1-Trifluoropropan-2-yl)oxy)phthalazin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (67) in dioxane (1.5 mL) 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), CuI (5.6 mg, 0.03 mmol), potassium phosphate tribasic (62 mg, 0.3 mmol), and trans-N,N'-dimethylcyclohexane-1,2- A mixture of diamine (9.2 μL, 0.902 g/mL, 0.06 mmol) was sparged with argon. The mixture was then heated to 120° C. for 2 h. It was cooled, then filtered through a pad of Celite®, washed with EtOAc and concentrated. Purification by column chromatography (40-80% EtOAc/heptane) gave the title compound (94 mg, 84%) as a colorless oil with small amounts of impurities. MS (ESI): mass calculated for C ₃₈ H ₃₆ ClF ₄ N ₅ O ₄ Si, 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)phthalazine- 6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one . (S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(1-(2-chloro-6-fluorophenoxy)-8-((1) in THF (1.0 mL) ,1,1-Trifluoropropan-2-yl)oxy)phthalazin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one To a solution of (90 mg, 0.12 mmol) 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 NH ₄ Cl solution 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% EtOAc/heptane) followed by RP HPLC (Isco ACCQ Prep, 30×100 mm, 20-100% ACN/10 mM NH ₄ OH in water) as a white solid The title compound (39 mg, 62%) was obtained as MS (ESI): calculated mass for C ₂₂ H ₁₈ ClF ₄ N ₅ O ₄ , 527.9; m/z found, 528.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)oxy )Isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

Step A. (S)-3-((benzyloxy)methyl)-1-(1-((2,5-dichloropyridin-4-yl)oxy)-8-((1,1,1-tri Fluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. 2,5-Dichloropyridin-4-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane-2- In analogous manner to Example 2, Step A by coupling with yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21) to prepare the title compound. MS (ESI): mass calculated for C ₂₉ H ₂₄ Cl ₂ F ₃ N ₅ O ₄ , 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 calculated for C ₂₂ H ₁₈ Cl ₂ F ₃ N ₅ O ₄ , 543.1; m/z found, 544.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)isoquinolin-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)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. (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 (from Example 26, Step A) product of, 20 mg, 31.52 μmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivorinane (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 G ₃ ) ( To a solution of 2.46 mg, 3.15 μmol) was added Cs ₂ CO ₃ (30.81 mg, 94.57 μmol) at 20° C. under N ₂ . The mixture was stirred at 95° C. for 16 h. The reaction mixture was cooled to room temperature, quenched by addition of 1N HCl (10 mL), and then extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (preparative TLC, SiO ₂ , petroleum ether/ethyl acetate = 3/1) gave the title compound (3 mg, 9%) as a colorless oil. MS (ESI): calculated mass for C ₃₀ H ₂₇ ClF ₃ N ₅ O ₄ , 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-trifluoropropane-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 calculated for C ₂₃ H ₂₀ ClF ₃ N ₅ O ₄ , 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. 5-chloro-2-methoxypyridin-4-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane- Example 2, Step A by coupling with 2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) The title compound was prepared in a similar manner. MS (ESI): calculated mass for C ₃₀ H ₂₇ ClF ₃ N ₅ O ₅ , 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) 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): calculated mass for C ₂₃ H ₂₁ ClF ₃ N ₅ O ₅ , 539.1; m/z found, 540.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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 (br t, 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-1-((5-chloro-2-methoxypyridin-4-yl)oxy)-8-((1,1,1-trifluoropropane -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 . (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 (Example 28, step To a solution of product from A, 16 mg, 25.40 μmol) was added NCS (5.09 mg, 38.09 μmol). The mixture was stirred at 20° C. for 12 h, then heated to 60° C. for a further 12 h. The solvent was removed under reduced pressure. Purification (preparative TLC, SiO ₂ , petroleum ether/ethyl acetate = 2/1) gave the title compound (10 mg, 46%) as a yellow oil. MS (ESI): calculated mass for C ₃₀ H ₂₆ Cl ₂ F ₃ N ₅ O ₅ , 663.1; m/z found, 664.3 [M+H] ⁺ .

Step B. (S)-1-(5-Chloro-1-((5-chloro-2-methoxypyridin-4-yl)oxy)-8-((1,1,1-trifluoropropane- 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): calculated mass for C ₂₃ H ₂₁ ClF ₃ N ₅ O ₅ , 539.1; m/z found, 540.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)isoquinolin-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. (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 (Example 28, step To a solution of the product from A, 110 mg, 155.39 μmol) at 15° C. was added trimethylsilyl chloride (TMSC1) (33.76 mg, 310.79 μmol, 39.44 μL) and NaI (46.58 mg, 310.79 μmol). The mixture was then stirred at 40° C. for 16 h. The reaction mixture was quenched by addition of 1 N HCl (20 mL) at room temperature and extracted with ethyl acetate (15 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 0/1)) gave the title compound (63 mg, 59%) as a white solid. MS (ESI): mass calculated for C ₂₉ H ₂₄ Cl ₂ F ₃ N ₅ O ₅ , 649.1; m/z found, 650.3 [M+H] ⁺ .

Step B. (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. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): calculated mass for C ₂₂ H ₁₉ ClF ₃ N ₅ O ₅ , 525.1; m/z found, 526.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-((1,1,1-trifluoropropane-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-((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. 1,3-dimethyl-1H-pyrazol-4-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoro Example 2, step by coupling with propan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21) The title compound was prepared in a similar manner to A. MS (ESI): calculated mass for C ₂₉ H ₂₉ F ₃ N ₆ O ₄ , 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-trifluoropropane-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): calculated mass for C ₂₂ H ₂₃ F ₃ N ₆ O ₄ , 492.2; m/z found, 493.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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 )Isoquinolin-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-tri) Fluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one . 2-fluoro-5-methylphenol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl) Titled in a manner analogous to Example 2, Step A by coupling with oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21) The compound was prepared. MS (ESI): calculated mass for C ₃₁ H ₂₈ F ₄ N ₄ O ₄ , 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): calculated mass for C ₂₄ H ₂₂ F ₄ N ₄ O ₄ , 506.2; m/z found, 507.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-methoxyethoxy)phenoxy)-8-((1,1,1-trifluoro Propan-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-methoxyethoxy)phenoxy)-8-(( 1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one . 2-chloro-6-fluoro-3-(2-methoxyethoxy)phenol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1, by coupling with 1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) The title compound was prepared in a manner analogous to Example 2, Step A. MS (ESI): calculated mass for C ₃₃ H ₃₁ ClF ₄ N ₄ O ₆ , 690.2; m/z found, 691.1 [M+ H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-trifluoropropane) -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): calculated mass for C ₂₆ H ₂₅ ClF ₄ N ₄ O ₆ , 600.1; m/z found, 601.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.11 (d, J = 1.6 Hz, 1H), 7.97 (t, J = 1.6 Hz, 1H), 7.85 (d, J = 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-hydroxyethoxy)phenoxy)-8-((1,1,1-trifluoro Propan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

(S)-3-((benzyloxy)methyl)-1-(1-(2-chloro-6-fluoro-3-(2-methoxyethoxy)phenoxy)-8 in DCM (4 mL) -((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one ( To a solution of Example 33, product from step A, 140 mg, 202.59 μmol) at 0° C. was slowly added BBr ₃ (162.41 mg, 648.27 μmol, 62.46 μL). The mixture was stirred at 20° C. for 4.5 h. The reaction mixture was poured into ice water (20 mL) and the pH was adjusted to 7 with saturated NaHCO ₃ . The mixture was extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (preparative HPLC, method A) gave 90 mg of a mixture of compounds, which was subsequently repurified by preparative HPLC (method D) to give two title compounds:

(S)-1-(1-(2-chloro-6-fluoro-3-(2-hydroxyethoxy)phenoxy)-8-((1,1,1-trifluoropropane-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one MS (ESI): C ₂₅ H ₂₃ mass calculated for ClF ₄ N ₄ O ₆ , 586.1; m/z found, 587.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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 calculated for C ₂₃ H ₁₉ ClF ₄ N ₄ O ₅ , 542.1; m/z found, 543.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)isoquinoline-6- yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

Step A. (S)-3-((benzyloxy)methyl)-1-(1-(2,5-dimethylphenoxy)-8-((1,1,1-trifluoropropane-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. 2,5-dimethylphenol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy) The title compound was prepared in a manner analogous to Example 2, Step A by coupling with isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) prepared. MS (ESI): calculated mass for C ₃₂ H ₃₁ F ₃ N ₄ O ₄ , 592.2; m/z found, 593.3 [M+H] ⁺ .

Step B. (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. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calculated for C ₂₅ H ₂₅ F ₃ N ₄ O ₄ , 502.1; m/z found, 503.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-trifluoropropane- 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-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. 3-Chloro-1-methyl-pyrazol-4-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane) Example 2, Step A by coupling with -2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) The title compound was prepared in a similar manner to MS (ESI): calculated mass for C ₂₈ H ₂₆ ClF ₃ N ₆ O ₄ , 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-trifluoropropane-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 calculated for C ₂₁ H ₂₀ ClF ₃ N ₆ O ₄ , 512.1; m/z found, 513.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-(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)methanesulfone amides.

Step A. (S)-Methyl 3-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-2-chloro-4-fluorobenzoate . Methyl 2-chloro-4-fluoro-3-hydroxybenzoate to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoro Example 2 by coupling with ropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21), The title compound was prepared in a manner analogous to Step A. MS (ESI): calculated mass for C ₃₂ H ₂₇ ClF ₄ N ₄ O ₆ , 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-triazole- 1-yl)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-2-chloro-4-fluorobenzoic acid . (S)-methyl 3-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro in THF (2 mL) and H ₂ O (0.5 mL) -1H-1,2,4-triazol-1-yl)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-2- A mixture of chloro-4-fluorobenzoate (1 g, 1.48 mmol) and LiOH.H ₂ O (186.50 mg, 4.44 mmol) was stirred under N ₂ atmosphere at 60° C. for 3 hours. The reaction mixture was cooled, diluted with H ₂ O (10 mL) and extracted with ethyl acetate (15 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (reverse phase HPLC (0.1% FA)) gave the title compound (150 mg, 15%) as a yellow solid. MS (ESI): calculated mass for C ₃₁ H ₂₅ ClF ₄ N ₄ O ₆ , 660.1; m/z found, 661.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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 . t (S)-3-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2, in -BuOH (2 mL) 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) was added DPPA (43.72 mg, 158.85 μmol) and TEA (21.43 mg, 211.80 μmol) at 25° C., and stirred for 3 hours. The mixture was then heated to 100° C. and stirred for 12 h. The reaction mixture was cooled, diluted with H ₂ O (10 mL) and extracted with ethyl acetate (15 mL×2). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was charged with HCl/dioxane (2 mL) and then stirred at 20° C. for 1 hour. The reaction mixture was quenched by adding 10 mL of NaHCO ₃ (1M) at 0° C. and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification was then performed (preparative TLC (SiO ₂ , petroleum ether:ethyl acetate = 1:1)) to give the title compound (20 mg, 30% yield) as a yellow solid. MS (ESI): calculated mass for C ₃₀ H ₂₆ ClF ₄ N ₅ O ₄ , 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)oxy)isoquinolin-1-yl)oxy)-2-chloro-4-fluorophenyl)methane sulfonamides . (S)-1-(1-(3-amino-2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl) in DCM (2 mL) )oxy)isoquinolin-6-yl)-3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (8 mg, 12.66 μmol), To a solution of pyridine (2.00 mg, 25.32 μmol) and 4-dimethylaminopyridine (DMAP) (154.64 μg, 1.27 μmol) at 20° C. was added methanesulfonyl chloride (MsCl) (1.31 mg, 11.39 μmol). The mixture was stirred at 40° C. for 16 h. The reaction mixture was cooled, diluted with H ₂ O (10 mL) and extracted with DCM (10 mL×2). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (preparative TLC, SiO ₂ , petroleum ether:ethyl acetate = 0:1) gave the title compound (3 mg, 29%) as a yellow solid. MS (ESI): mass calculated for C ₃₁ H ₂₈ ClF ₄ N ₅ O ₆ S, 709.1; m/z found, 710.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)oxy)isoquinolin-1-yl)oxy)-4-fluorophenyl)methanesulfonamide . The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calculated for C ₂₄ H ₂₂ ClF ₄ N ₅ O ₆ S, 619.1; m/z found, 620.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-trifluoropropane-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-3-(dimethylamino)-6-fluorophenoxy)-8-((1,1) ,1-Trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. (S)-1-(1-(3-amino-2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl) in MeOH (3 mL) )oxy)isoquinolin-6-yl)-3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (from Example 37, Step C) To a mixture of the product of, 105 mg, 166.14 μmol), HCHO (163.50 mg, 5.45 mmol) and CH ₃ COOH (19.95 mg, 332.28 μmol) was added NaBH ₃ CN (104.40 mg, 1.66 mmol) and under N ₂ atmosphere. Stirred at 25° C. for 24 hours. The reaction mixture was diluted with H ₂ O (15 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification was then carried out (preparative TLC, SiO ₂ , petroleum ether:ethyl acetate = 2:1) to give the title compound (90 mg, 81%) as a yellow solid. MS (ESI): calculated mass for C ₃₂ H ₃₀ ClF ₄ N ₅ O ₄ , 659.2; m/z found, 600.1 [M+H] ⁺ .

Step B. (S)-1-(1-(2-Chloro-3-(dimethylamino)-6-fluorophenoxy)-8-((1,1,1-trifluoropropane-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 calculated for C ₂₅ H ₂₄ ClF ₄ N ₅ O ₄ , 569.1; m/z found, 570.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

Step A. (S)-3-((benzyloxy)methyl)-1-(1-((3,6-dichloropyridin-2-yl)oxy)-8-((1,1,1-tri Fluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one . 3,6-Dichloropyridin-2(1H)-one to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane) Example 2, Step A by coupling with -2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) The title compound was prepared in a similar manner to MS (ESI): mass calculated for C ₂₉ H ₂₄ Cl ₂ F ₃ N ₅ O ₄ , 633.1; m/z found, 634.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.12 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 5.8 Hz, 1H), 7.93 (d, J = 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 calculated for C ₂₂ H ₁₈ Cl ₂ F ₃ N ₅ O ₄ , 543.1; m/z found, 544.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. 2-Chloro-6-fluoro-3-methoxy-phenol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoro Example 2, step by coupling with propan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21) The title compound was prepared in a manner analogous to A. MS (ESI): calculated mass for C ₃₁ H ₂₇ ClF ₄ N ₄ O ₅ , 646.1; m/z found, 647.2 [M+H] ⁺ .

Step B. (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 . The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): calculated mass for C ₂₄ H ₂₁ ClF ₄ N ₄ O ₅ , m/z found, 556.1; m/z found, 557.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-trifluoropropane -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-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 . 3-Chloro-2-methoxy-5-methylpyridin-4-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-tri Example 2 by coupling with fluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) , Prepared the title compound in a similar manner to Step A. MS (ESI): mass calculated for C ₃₁ H ₂₉ ClF ₃ N ₅ O ₅ , 643.1; m/z found, 644.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-methylpyridin-4-yl)oxy)-8-((1,1,1-trifluoropropane- 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. ¹ H NMR (400 MHz, CDCl ₃ ) 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)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-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. 3-chloro-2-methoxypyridin-4-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane- Example 2, Step A by coupling with 2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) The title compound was prepared in a similar manner. MS (ESI): calculated mass for C ₃₀ H ₂₇ ClF ₃ N ₅ O ₅ , 629.1; m/z found, 630.1 [M+H] ⁺ .

Step B. (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. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): calculated mass for C ₂₃ H ₂₁ F ₃ N ₅ O ₅ , 539.1; m/z found, 540.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)oxy)-8-((1,1,1-trifluoropropane- 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-((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. 5-Chloro-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol (intermediate 9) was replaced 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- The title compound was prepared in an analogous manner to Example 2, Step A by coupling with triazol-5(4H)-one (Intermediate 21). MS (ESI): mass calculated for C ₃₄ H ₄₀ ClF ₃ N ₆ O ₅ Si, 732.2; m/z found, 733.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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, J = 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-yl)oxy)-8-((1,1,1-trifluoropropane-2 -yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. (S)-3-((benzyloxy)methyl)-1-(1-((5-chloro-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl in TFA (2 mL)) )-1H-pyrazol-4-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1 A solution of ,2,4-triazol-5(4H)-one (70 mg, 95.47 μmol) was heated to 80° C. for 15 h. The reaction was cooled and the TFA was removed in vacuo. The residue was redissolved in MeOH (3 mL) and 140 mg of K ₂ CO ₃ were added. The mixture was stirred for 0.5 h. The mixture was purified by preparative HPLC (Method A) to give the title compound (20.7 mg, 41% yield) as a white solid. MS (ESI): mass calculated for C ₂₁ H ₂₀ ClF ₃ N ₆ O ₄ , 512.1; m/z found, 513.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-trifluoropropane-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)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. 3-Chloro-2,5-dimethylpyridin-4-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoro Example 2, step by coupling with propan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21) The title compound was prepared in a similar manner to A. MS (ESI): calculated mass for C ₃₁ H ₂₉ ClF ₃ N ₅ O ₄ , 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 calculated for C ₂₄ H ₂₃ ClF ₃ N ₅ O ₄ , 537.1; m/z found, 538.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)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.

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- d ]pyridazin-7-yl)-4-ethyl- 1H - 1,2, 4-Triazol-5( 4H )-one . 3-Chloro-5-fluoro-2-methoxypyridin-4-ol Intermediate 28) was synthesized from (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-triazole The title compound was prepared in an analogous manner to Example 63, Step A by coupling with -5(4H)-one (Intermediate 18). MS (ESI): calculated mass for C ₂₈ H ₂₃ ClF ₅ N ₇ O ₅ , 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-trifluoropropane-2) -yl )oxy)pyrido[3,4- d ]pyridazin-7-yl)-3-(hydroxymethyl)-1H - 1,2,4 -triazol-5( 4H )-one. In a manner analogous to Example 63, Step B, the title compound was prepared as an off-white solid. MS (ESI): calculated mass for C ₂₁ H ₁₇ ClF ₅ N ₇ O ₅ , 577.1; m/z found, 578.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-((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.

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)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one. 1-Methyl-1H-pyrazol-5-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane-2) Similar to Example 18, Step A by coupling with -yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) The title compound was prepared in this manner. MS (ESI): calculated mass for C ₂₈ H ₂₇ F ₃ N ₆ O ₄ , 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): calculated mass for C ₂₁ H ₂₁ F ₃ N ₆ O ₄ , 478.2; m/z found, 479.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)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-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. 3-Chloro-6-methoxypyridin-2(1H)-one to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoro Example 18 by coupling with ropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21), The title compound was prepared in a manner analogous to Step A. MS (ESI): calculated mass for C ₃₀ H ₂₇ ClF ₃ N ₅ O ₅ , 629.17; m/z found, 630.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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 calculated for C ₂₃ H ₂₁ ClF ₃ N ₅ O ₅ , 539.12; m/z found, 540.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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, J = 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-trifluoropropane-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-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)-8-((1,1) ,1-Trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. 1,3-dimethyl-1H-pyrazol-5-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoro Example 18, step by coupling with propan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21) The title compound was prepared in a similar manner to A. MS (ESI): calculated mass for C ₂₉ H ₂₉ F ₃ N ₆ O ₄ , 582.2; m/z found, 583.4 [M+H] ⁺ .

Step B. (S)-1-(1-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)-8-((1,1,1-trifluoropropane-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): calculated mass for C ₂₂ H ₂₃ F ₃ N ₆ O ₄ , 492.1; m/z found, 493.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-((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-5-fluoropyridin-4-yl)oxy)-8-((1,1,1) -Trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. 2-Chloro-5-fluoropyridin-4-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane- Example 18, Step A by coupling with 2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) The title compound was prepared in a similar manner. MS (ESI): calculated mass for C ₂₉ H ₂₄ ClF ₄ N ₅ O ₄ , 617.1; m/z found, 618.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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 calculated for C ₂₂ H ₁₈ ClF ₄ N ₅ O ₄ , 527.1; m/z found, 528.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-(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. NaH (27.62 mg, 690.47 μmol, 60% pure) was added to tetrahydropyran-4-ol (2.04 g, 19.97 mmol, 2 mL) under N ₂ at 0° C. The mixture was stirred at 0° C. for 30 min, then at 0° C. (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane) -2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21, 70 mg, 138 μmol) was added, Heated to 120° C. for 6 hours. The mixture was cooled and poured into 1N HCl (5 mL). The aqueous phase was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with brine (20 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification (silica gel chromatography, petroleum ether/ethyl acetate = 15/1 to 3/1) gave the title compound (150 mg, crude) as a yellow oil. MS (ESI): calculated mass for C ₂₉ H ₃₁ F ₃ N ₄ O ₅ , 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- Trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one. (S)-3-((benzyloxy)methyl)-4-ethyl-1-(1-((tetrahydro-2H-pyran-4-yl)oxy)-8-((1) in DCM (5 mL) A solution of ,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one (100 mg, 179 μmol) to BCl ₃ (1 M, 358 μL) was added. The mixture was stirred at -78 °C for 1 h. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by RP HPLC (condition A) to give the title compound (41 mg, 47.6% yield) as a white solid. MS (ESI): calculated mass for C ₂₂ H ₂₅ F ₃ N ₄ O ₅ , m/z found, 482.1; m/z found, 483.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-trifluoropropane-2) -yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one.

Step A: (S)-5-((benzyloxy)methyl)-4-ethyl-2-(1-(pentan-3-yloxy)-8-((1,1,1-trifluoropropane- 2-yl)oxy)isoquinolin-6-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Pentan-3-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline The title compound was prepared in an analogous manner to Example 50, Step A by coupling with -6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) . MS (ESI): calculated mass for C ₂₉ H ₃₃ F ₃ N ₄ O ₄ , 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. In a manner analogous to Example 50, Step B, the title compound was prepared as a white solid.

MS (ESI): calculated mass for C ₂₂ H ₂₇ F ₃ N ₄ O ₄ , m/z found, 468.2; m/z found, 469.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. 1,3-dimethoxypropan-2-ol was replaced with (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane-2) Similar to Example 50, Step A by coupling with -yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21) The title compound was prepared in this manner. MS (ESI): calculated mass for C ₂₉ H ₃₃ F ₃ N ₄ O ₆ , 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. In a manner analogous to Example 50, Step B, the title compound was prepared as a white solid. MS (ESI): calculated mass for C ₂₂ H ₂₇ F ₃ N ₄ O ₆ , m/z found, 500.2; m/z found, 501.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)-1-(1-trans-2-methylcyclohexyl)oxy)-8-(((S)-1,1,1-trifluoropropane -2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one.

Step A: 5-((benzyloxy)methyl)-4-ethyl-2-(1-(((1R,2R)-2-methylcyclohexyl)oxy)-8-(((S)-1,1 ,1-Trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one. Trans-2-methylcyclohexanol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy ) The title compound in a manner analogous to Example 50, Step A by coupling with isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21) was prepared. MS (ESI): calculated mass for C ₃₁ H ₃₅ F ₃ N ₄ O ₄ , m/z found, 584.6; m/z found, 585.7 [M+H] ⁺ .

Step B: 4-Ethyl-3-(hydroxymethyl)-1-(1-trans-2-methylcyclohexyl)oxy)-8-(((S)-1,1,1-trifluoropropane- 2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one. In a manner analogous to Example 50, Step B, the title compound was prepared as a white solid. MS (ESI): calculated mass for C ₂₄ H ₂₉ F ₃ N ₄ O ₄ , m/z found, 494.2; m/z found, 495.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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. Replace 1,3-bis(benzyloxy)propan-2-ol with 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) and The title compound was prepared in a manner analogous to Example 50, Step A by coupling. MS (ESI): calculated mass for C ₄₁ H ₄₁ F ₃ N ₄ O ₆ , 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. In a manner analogous to Example 50, Step B, the title compound was prepared as a white solid. MS (ESI): calculated mass for C ₂₀ H ₂₃ F ₃ N ₄ O ₆ , m/z found, 472.1; m/z found, 473.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-(hydroxymethyl)-1-(1-isobutoxy-8-((1,1,1-trifluoropropan-2-yl)oxy) Isoquinolin-6-yl)-1H-1,2,4-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. 2-methylpropan-1-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy ) The title compound in a manner analogous to Example 50, Step A by coupling with isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21) was prepared. MS (ESI): calculated mass for C ₂₈ H ₃₁ F ₃ N ₄ O ₄ , 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)iso Quinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one. In a manner analogous to Example 50, Step B, the title compound was prepared as a white solid. MS (ESI): calculated mass for C ₂₁ H ₂₅ F ₃ N ₄ O ₄ , 454.2; m/z found, 455.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-(hydroxymethyl)-1-(1-(2-methoxyethoxy)-8-((1,1,1-trifluoropropane-2) -yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one.

Step A:

2-Methoxyethanol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline The title compound was prepared in an analogous manner to Example 50, Step A by coupling with -6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) . MS (ESI): calculated mass for C ₂₇ H ₂₉ F ₃ N ₄ O ₅ , m/z found, 546.6; m/z found, 547.5 [M+H] ⁺ .

Step B: (S)-4-ethyl-3-(hydroxymethyl)-1-(1-(2-methoxyethoxy)-8-((1,1,1-trifluoropropane-2- yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one . In a manner analogous to Example 50, Step B, the title compound was prepared as a white solid. MS (ESI): calculated mass for C ₂₀ H ₂₃ F ₃ N ₄ O ₅ , m/z found, 456.1; m/z found, 457.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-methoxytetrahydro-2H-pyran-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. 3-Methoxytetrahydro-2H-pyran-4-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane) Example 50, Step A by coupling with -2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) The title compound was prepared in a similar manner to MS (ESI): calculated mass for C ₃₀ H ₃₃ F ₃ N ₄ O ₆ , 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, 1,1-Trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one. In a manner analogous to Example 50, Step B, the title compound was prepared as a white solid. MS (ESI): calculated mass for C ₂₃ H ₂₇ F ₃ N ₄ O ₆ , m/z found, 512.1; m/z found, 513.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-trifluoro Propan-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-trifluoropropane-2 -yl)oxy)isoquinolin-6-yl)-5-((benzyloxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. 1-(benzyloxy)-3-methoxypropan-2-ol to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoro Example 50 by coupling with ropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21), The title compound was prepared in a manner analogous to Step A. MS (ESI): calculated mass for C ₃₅ H ₃₇ F ₃ N ₄ O ₆ , 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-trifluoropropane -2-yl)oxy)isoquinolin-6-yl)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. In a manner analogous to Example 50, Step B, the title compound was prepared as a white solid. MS (ESI): calculated mass for C ₂₁ H ₂₅ F ₃ N ₄ O ₆ , m/z found, 486.1; m/z found, 487.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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 ( 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: (S)-1-(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. 4-Hydroxytetrahydro-2H-thiopyran 1,1-dioxide to (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoro) Example 50 by coupling with ropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21), The title compound was prepared in a manner analogous to Step A. MS (ESI): calculated mass for C ₂₉ H ₃₁ F ₃ N ₄ O ₆ S, found m/z, 620.6; m/z found, 621.5 [M+H] ⁺ .

Step B: (S)-1-(1-((tetrahydro-2H-thiopyran 1,1-dioxide)-8-((1,1,1-trifluoropropan-2-yl)oxy)iso Quinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one In a manner analogous to Example 50, step B, white solid The title compound was prepared as MS (ESI): mass calculated for C ₂₂ H ₂₅ F ₃ N ₄ O ₆ S, m/z found, 530.1; m/z found, 531.2 [M+H] ^{+ .1} H NMR (400 MHz, CDCl ₃ ) 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) isoquinoline -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-trifluoropropane) -2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. 6-Chloro-2-fluoro-3-methoxyphenol to 5-((benzyloxy) methyl)-2-(1-chloro-8-((1,1,1-trifluoropropan-2-yl) Example 1, Step A by coupling with )oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20) The title compound was prepared in a similar manner to MS (ESI): calculated mass for C ₃₁ H ₂₇ ClF ₄ N ₄ O ₅ , 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) isoquinoline- 6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. In a manner analogous to Example 1, Step B, the title compound was prepared as a white solid. MS (ESI): calculated mass for C ₂₄ H ₂₁ ClF ₄ N ₄ O ₅ , m/z found, 556.1; m/z found, 557.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)isoquinoline -6-yl)-4-ethyl-5-(hydroxymethyl)-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-yl)-4-fluoro Rho-3-methoxy-8-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydroisoquinolin-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 mixed with ACN (1 mL) and MeOH (1 mL) in a mixed solvent of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2. 2]octane bis(tetrafluoroborate) (Selectfluor ^® ) (16.3 mg, 0.046 mmol). The reaction was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and concentrated to give the crude product as a mixture of diastereomers without further purification. MS (ESI): calculated mass for C ₂₅ H ₂₆ F ₄ N ₄ O ₅ , 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)oxy )-3,4-dihydroisoquinolin-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) in POCl ₃ (0.5 mL) -4-fluoro-3-methoxy-8-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydroisoquinolin-1(2H)-one (20 mg, 0.037 mmol) was heated at 80° C. for 1 h. The solvent was removed in vacuo and dried to give the crude product without further purification. MS (ESI): calculated mass for C ₂₅ H ₂₅ ClF ₄ N ₄ O ₄ , 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)isoquinoline-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-dihydro-3H-1,2,4-triazole- 3-one (20 mg, 0.036 mmol) was stirred at room temperature for 1 h. The solvent was removed in vacuo and purification (silica gel flash column system using 20-80% ethyl acetate in heptane) gave the title compound (12 mg, 63%) as a white solid. MS (ESI): calculated mass for C ₂₄ H ₂₁ ClF ₄ N ₄ O ₃ , m/z found, 524.1; m/z found, 525.4 [M+H] ⁺ .

Step D: 5-((benzyloxy)methyl)-2-(1-(2-chloro-6-fluorophenoxy)-4-fluoro-8-((1,1,1-trifluoropropane) -2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. 2-Chloro-6-fluorophenol to 5-((benzyloxy)methyl)-2-(1-chloro-4-fluoro-8-((1,1,1-trifluoropropan-2-yl In a manner analogous to Example 1, Step A by coupling with )oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one The title compound was prepared. MS (ESI): calculated mass for C ₃₀ H ₂₄ ClF ₅ N ₄ O ₄ , 634.1; m/z found, 635.4 [M+H] ⁺ .

Step E. 2-(1-(2-Chloro-6-fluorophenoxy)-4-fluoro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline- 6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared in a similar manner to Example 1, Step B. MS (ESI): calculated mass for C ₂₃ H ₁₈ ClF ₅ N ₄ O ₄ , m/z found, 544.1; m/z found, 545.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-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.

Step A. 3-((benzyloxy)methyl)-1-(4-(2-chloro-6-fluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropane) -2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one . 6-Chloro-2-fluoro-phenol to 3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-trifluoropropane-2- by coupling with yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 17) The title compound was prepared in an analogous manner to Example 1, Step A. MS (ESI): calculated mass for C ₂₈ H ₂₂ ClF ₅ N ₆ O ₄ , 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)oxy)pyrido[ 3,4-d]pyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one . The title compound was prepared in a similar manner to Example 1, Step B. MS (ESI): calculated mass for C ₂₁ H ₁₆ ClF ₅ N ₆ O ₄ , m/z found, 546.1; m/z found, 547.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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) Oxy)pyrido[3,4-d]pyridazin-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)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. NaH (60% purity, 418 mg, 10.44 mmol) was added slowly to a 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 h. Then ( S )-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyri do[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 to the mixture solution at 70°C, and the reaction mixture was further stirred at 70°C for 2 hours. The mixture was cooled in an ice-water bath, diluted with ethyl acetate (20 mL), and the pH was adjusted to 6 by the slow addition of 1 M aqueous HCl solution. The mixture was separated and the organic layer was washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and evaporated. Purification (column chromatography, gradient elution: 0-100% ethyl acetate in petroleum ether) gave the title compound (900 mg, 52%) as a yellow oil. MS (ESI): calculated mass for C ₂₈ H ₂₂ ClF ₅ N ₆ O ₄ , m/z found, 636.1; m/z found, 637.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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[3,4-d]pyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. ( S )-3-((benzyloxy)methyl)-1-(4-(2-chloro-6-fluorophenoxy)-8-fluoro-5- ((1,1) in DCM (10 mL) ,1-trifluoropropan-2-yl)oxy)pyrido[3,4- d ]pyridazin-7-yl)-4-ethyl- 1H -1,2,4-triazole-5(4 To a solution of H )-one (900 mg, 1.08 mmol) was added BCl ₃ (1 M solution in toluene, 6.52 mL, 6.52 mmol) under N ₂ at -78°C for 1 h. The reaction mixture was quenched by addition of saturated aqueous NaHCO ₃ aqueous solution (20 mL) at 0° C., then warmed to room temperature and extracted with DCM (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (column chromatography, gradient elution: 0-100% ethyl acetate in petroleum ether) was carried out and it was subjected to preparative HPLC (stationary phase: Boston Prime C18, 5 μm, 150 x 30 mm; mobile phase: water (0.04% NH ₃ ) Further purification with /H ₂ O + 10 mM NH ₄ HCO ₃ ) (A) - MeCN (B), gradient elution: 40-70% B in A over 7 min (flow: 25 mL/min)) The title compound (420 mg, 69%) was obtained as a white solid. MS (ESI): calculated mass for C ₂₁ H ₁₆ ClF ₅ N ₆ O ₄ , m/z found, 546.1; m/z found, 547.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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-(((S)-1,1, 1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-3-(hydroxymethyl)-1H-1,2,4-triazole-5 (4H)-on.

Step A. 3-((benzyloxy)methyl)-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)-1H-1,2,4-triazole- 5(4H)-on . 3-Methoxytetrahydro-2H-pyran-4-ol to (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 The title compound was prepared in an analogous manner to Example 50, Step A by coupling with (Intermediate 18). MS (ESI): calculated mass for C ₂₈ H ₃₀ F ₄ N ₆ O ₆ , 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-(((S)-1,1,1 -trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-3-(hydroxymethyl)-1H-1,2,4-triazole-5 ( 4H)-on. The title compound was prepared in a manner analogous to Example 50, Step B. MS (ESI): calculated mass for C ₂₁ H ₂₄ F ₄ N ₆ O ₆ , m/z found, 532.2; m/z found, 533.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-trifluoropropane) -2-yl)oxy)-2,7-naphthyridin-3-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one . 6-Chloro-2-fluoro-phenol to 5-((benzyloxy)methyl)-2-(8-chloro-4-fluoro-1-((1,1,1-trifluoropropane-2- by coupling with yl)oxy)-2,7-naphthyridin-3-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 19) The title compound was prepared in an analogous manner to Example 1, Step A. MS (ESI): calculated mass for C ₂₉ H ₂₃ ClF ₅ N ₅ O ₄ , 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 similar manner to Example 1, Step B. MS (ESI): calculated mass for C ₂₂ H ₁₇ ClF ₅ N ₅ O ₄ , m/z found, 545.1; m/z found, 546.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) 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) Pyrido[3,4-d]pyridazin-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-trifluoro) Ropropan -2-yl)oxy)pyrido[3,4- d ]pyridazin-7-yl)-1H -1,2,4-triazol-5( 4H )-one . o -cresol to (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy Example 63 by coupling with )pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 18) , Prepared the title compound in a similar manner to Step A. MS (ESI): calculated mass for C ₂₉ H ₂₆ F ₄ N ₆ O ₄ , m/z found, 598.2; m/z found, 599.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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)pyri do[3,4 - d ]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): calculated mass for C ₂₂ H ₂₀ F ₄ N ₆ O ₄ , m/z found, 508.1; m/z found, 509.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-trifluoropropane- 2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazole-3 -On.

Step A. ( S )-3-((benzyloxy)methyl)-4-ethyl-1-(8-fluoro-4-(4-fluoro-2-methylphenoxy)-5-((1, 1,1-trifluoropropan-2-yl)oxy)pyrido[3,4- d ]pyridazin-7-yl)-1H - 1,2,4 -triazole-5( 4H )- came . 4-Fluoro-2-methylphenol to (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-trifluoropropane) -2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 18) and The title compound was prepared in a manner analogous to Example 63, Step A by coupling. MS (ESI): calculated mass for C ₂₉ H ₂₅ F ₅ N ₆ O ₄ , m/z found, 616.2; m/z found, 617.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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. ( S )-4-ethyl-1-(8-fluoro-4-(4-fluoro-2-methylphenoxy)-5-((1,1,1-trifluoropropane-2) -yl )oxy)pyrido[3,4- d ]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): calculated mass for C ₂₂ H ₁₉ F ₅ N ₆ O ₄ , m/z found, 526.1; m/z found, 527.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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, J =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-trifluoropropane- 2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazole-3 - On .

Step A. ( S )-3-((benzyloxy)methyl)-4-ethyl-1-(8-fluoro-4-(5-fluoro-2-methylphenoxy)-5-((1, 1,1-trifluoropropan-2-yl)oxy)pyrido[3,4- d ]pyridazin-7-yl)-1H - 1,2,4 -triazole-5( 4H )- On. 5-Fluoro-2-methylphenol to (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-trifluoropropane) -2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 18) and By coupling, in a similar manner to Example 63, Step A, the title compound was prepared as a yellow oil. MS (ESI): calculated mass for C ₂₉ H ₂₅ F ₅ N ₆ O ₄ , 616.2; m/z found, 617.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 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-trifluoropropane-2) -yl )oxy)pyrido[3,4- d ]pyridazin-7-yl)-3-(hydroxymethyl)-1H - 1,2,4 -triazol-5( 4H )-one. In a manner analogous to Example 63, Step B, the title compound was prepared as an off-white powder. MS (ESI): calculated mass for C ₂₂ H ₁₉ F ₅ N ₆ O ₄ , 526.1; m/z found, 527.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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-trifluoropropane-2) -yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-tri azole-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[3,4- d ]pyridazin-7-yl)-4-ethyl- 1H -1,2,4-triazole-5(4 H )-on . 2-Chloro-4,6-difluorophenol to (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-tri Fluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 18) to prepare the title compound in a similar manner to Example 63, Step A. MS (ESI): calculated mass for C ₂₈ H ₂₁ ClF ₆ N ₆ O ₄ , 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-trifluoropropane-2- yl)oxy)pyrido[3,4- d ]pyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)-1H - 1,2,4 -triazole-5( 4H ) - On . The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): calculated mass for C ₂₁ H ₁₅ ClF ₆ N ₆ O ₄ , m/z found, 564.1; m/z found, 565.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-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.

Step A. ( S )-3-((benzyloxy)methyl)-4-ethyl-1-(8-fluoro-4-(2-methoxyphenoxy)-5-((1,1,1-(1,1,1-) trifluoropropan-2-yl)oxy)pyrido[3,4- d ]pyridazin-7-yl)-1H - 1,2,4 -triazol-5( 4H )-one . 2-Methoxyphenol to (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl) carried out by coupling with )oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 18) The title compound was prepared in a manner analogous to Example 63, Step A. MS (ESI): calculated mass for C ₂₉ H ₂₆ F ₄ N ₆ O ₅ , m/z found, 614.2; m/z found, 615.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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. ( S )-4-ethyl-1-(8-fluoro-4-(2-methoxyphenoxy)-5-((1,1,1-trifluoropropan-2-yl)oxy )pyrido[3,4 - d ]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): calculated mass for C ₂₂ H ₂₀ F ₄ N ₆ O ₅ , m/z found, 524.1; m/z found, 525.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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, J = 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)pyrido[3,4-d]pyridazin-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-((2-methoxy-3,5-dimethylpyridin-4-yl) oxy)-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4- d ]pyridazin-7-yl)-1H - 1,2,4- Triazol-5( 4H )-one. 2-Methoxy-3,5-dimethylpyridin-4-ol to (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-triazole-5(4H) The title compound was prepared in an analogous manner to Example 63, Step A by coupling with -one (intermediate 18). MS (ESI): calculated mass for C ₃₀ H ₂₉ F ₄ N ₇ O ₅ , 643.2; m/z found, 644.1 [M+H] ⁺ .

Step B. ( S )-4-ethyl-1-(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)-3-(hydroxymethyl)-1H - 1,2,4 -triazole -5(4 H )-on. The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): calculated mass for C ₂₃ H ₂₃ F ₄ N ₇ O ₅ , 553.2; m/z found, 554.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.57 (s, 1H), 7.96 (s, 1H), 5.95 (dq, J = 4.5, 6.4 Hz, 1H), 4.75 (d, J = 6.2 Hz, 2H) ), 4.06 - 3.85 (m, 5H), 2.30 (br t, J = 6.1 Hz, 1H), 2.12 - 1.97 (m, 6H), 1.67 (d, J = 6.6 Hz, 3H), 1.48 (t, J ) = 7.2 Hz, 3H).

Example 72: (S)-2-(4-((2-chloro-4-methylpyridin-3-yl)oxy)-8-fluoro-5-((1,1,1-trifluoropropane -2-yl)oxy)pyrido[3,4-d]pyridazin-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-methylpyridin-3-yl)oxy)-8-fluoro-5-((1) ,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4- d ]pyridazin-7-yl)-4-ethyl- 1H -1,2,4-triazole-5 (4 H )-on. 2-Chloro-4-methylpyridin-3-ol to (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-tri Fluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 18) to prepare the title compound in a similar manner to Example 63, Step A. MS (ESI): calculated mass for C ₂₈ H ₂₄ ClF ₄ N ₇ O ₄ , m/z found, 633.2; m/z found, 634.1 [M+H] ⁺ .

Step B. ( S )-1-(4-((2-chloro-4-methylpyridin-3-yl)oxy)-8-fluoro-5-((1,1,1-trifluoropropane- 2-yl)oxy)pyrido[3,4- d ]pyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazole-5( 4H )-On. The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): calculated mass for C ₂₁ H ₁₈ ClF ₄ N ₇ O ₄ , m/z found, 543.1; m/z found, 544.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.56 (s, 1H), 8.21 (d, J =4.9 Hz, 1H), 7.22 - 7.20 (m, 1H), 5.91 (td, J =6.3, 12.6 Hz) , 1H), 4.71 (d, J =6.2 Hz, 2H), 3.93 (q, J =7.1 Hz, 2H), 2.33 - 2.23 (m, 3H), 2.17 (s, 1H), 1.65 (dd, J = 3.1, 6.4 Hz, 3H), 1.44 (t, J =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[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one.

Step A. ( S )-3-((benzyloxy)methyl)-1-(4-((5-chloro-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazol-4-yl)oxy)-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4- d ]pyridazine- 7-yl)-4-ethyl- 1H -1,2,4-triazol-5( 4H )-one. 5-Chloro-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol (intermediate 9) was replaced 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 The title compound was prepared in an analogous manner to Example 63, Step A by coupling with )-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 18). MS (ESI): mass calculated for C ₃₂ H ₃₇ ClF ₄ N ₈ O ₅ Si, 752.2; m/z found, 753.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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- 1H -pyrazol-4-yl)oxy)-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 -tri Azole-5( 4H )-one. The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): mass calculated for C ₁₉ H ₁₇ ClF ₄ N ₈ O ₄ , 532.1; m/z found, 533.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-yl)oxy)-8-fluoro-5-((1,1,1-trifluoropropane) -2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4 -Triazol-3-one.

Step A. ( S )-3-((benzyloxy)methyl)-1-(4-((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- 1H -1,2,4-triazole-5 (4 H )-on. 1,3-dimethoxypropan-2-ol to (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-tri Fluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 18) to prepare the title compound in a similar manner to Example 63, Step A. MS (ESI): calculated mass for C ₂₇ H ₃₀ F ₄ N ₆ O ₆ , 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-trifluoropropane- 2-yl)oxy)pyrido[3,4- d ]pyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)-1H - 1,2,4 -triazole-5(4 H )-on. The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): calculated mass for C ₂₀ H ₂₄ F ₄ N ₆ O ₆ , m/z found, 520.2; m/z found, 521.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-isopropoxypyrido[3,4-d]pyridazin-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-isopropoxypyrido[3,4-d] Pyridazin-7-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. 2-Chloro-6-fluorophenol to 5-((benzyloxy)methyl)-2-(4-chloro-8-fluoro-5-isopropoxypyrido[3,4-d]pyridazine-7 The title compound was prepared in an analogous manner to Example 63, Step A by coupling with -yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 29) prepared. MS (ESI): calculated mass for C ₂₈ H ₂₅ ClF ₂ N ₆ O ₄ , m/z found, 582.9; m/z found, 583.9 [M+H] ⁺ .

Step B: 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. In a manner analogous to Example 63, Step B, the title compound was prepared as an off-white solid. MS (ESI): calculated mass for C ₂₁ H ₁₉ ClF ₂ N ₆ O ₄ , m/z found, 492.8; m/z found, 493.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-tolylamino)-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.

Step A. (S)-5-((benzyloxy)methyl)-4-ethyl-2-(8-fluoro-4-(o-tolylamino)-5-((1,1,1-trifluoro) Ropropan-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 added slowly to a mixture of o-toluidine (1.76 g, 16.4 mmol) in DMF (10 mL) at room temperature. After addition, the mixture was heated to 60° C. for 0.5 h. Then ( S )-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyri do[3,4- d ]pyridazin-7-yl)-4-ethyl- 1H -1,2,4-triazol-5( 4H )-one (900 mg, 1.09 mmol) at 60°C It was added slowly to the mixture solution, and the reaction mixture was further stirred at 60° C. for 1 hour. The mixture was cooled in an ice-water bath, diluted with ethyl acetate (20 mL), and the pH was adjusted to 6 by the slow addition of 1 M aqueous HCl solution. The mixture was separated and the organic layer was washed with brine (45 mL), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography (SiO ₂ , gradient elution: 0-100% ethyl acetate in petroleum ether) to give the title compound (163 mg, 25% yield) as a yellow oil. MS (ESI): calculated mass for C ₂₉ H ₂₇ F ₄ N ₇ O ₃ , 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)pyri do[3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. In a manner analogous to Example 63, Step B, the title compound was prepared as a white powder. MS (ESI): calculated mass for C ₂₂ H ₂₁ F ₄ N ₇ O ₃ , 507.5; m/z found, 508.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-trifluoropropane-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazole -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)pyrido[3,4- d ]pyridazin-7-yl)-4-ethyl- 1H -1,2,4-triazole-5( 4H ) - on . NaH (60% purity, 57 mg, 1.43 mmol) was added slowly to a mixture of 2-chloro-6-fluoroaniline (797 mg, 5.48 mmol) in DMF (3 mL) at room temperature. After addition, the mixture was heated to 60° C. for 0.5 h. Then ( S )-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyri do[3,4- d ]pyridazin-7-yl)-4-ethyl- 1H -1,2,4-triazol-5( 4H )-one (300 mg, 364.42 μmol) at 60°C It was added slowly to the mixture solution, and the reaction mixture was further stirred at 60° C. for 1 hour. The mixture was cooled in an ice-water bath, diluted with ethyl acetate (20 mL), and the pH was adjusted to 6 by the slow addition of 1 M aqueous HCl solution. The mixture was separated and the organic layer was washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography (SiO ₂ , gradient elution: 0-100% ethyl acetate in petroleum ether) to give the title compound (80 mg, 20.5% yield) as a yellow oil. MS (ESI): calculated mass for C ₂₈ H ₂₃ ClF ₅ N ₇ O ₃ , 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 )oxy)pyrido[3,4- d ]pyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)-1H - 1,2,4 -triazole-5( 4H )- came . In a manner analogous to Example 63, Step B, the title compound was prepared as a white powder. MS (ESI): calculated mass for C ₂₁ H ₁₇ ClF ₅ N ₇ O ₃ , 545.1; m/z found, 546.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-trifluoropropane-2) -yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-tri azole-3-one .

Step A. ( S )-3-((benzyloxy)methyl)-1-(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- 1H -1,2,4-triazole-5(4 H )-on . 4,5-difluoro-2-methylphenol to (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-tri Fluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 18) to prepare the title compound in a similar manner to Example 63, Step A. MS (ESI): calculated mass for C ₂₉ H ₂₄ F ₆ N ₆ O ₄ , 634.2; m/z found, 635.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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-trifluoropropane-2- yl)oxy)pyrido[3,4- d ]pyridazin-7-yl)-4-ethyl-3-(hydroxymethyl)-1H - 1,2,4 -triazole-5( 4H ) - On . In a manner analogous to Example 63, Step B, the title compound was prepared as an off-white solid. MS (ESI): calculated mass for C ₂₂ H ₁₈ F ₆ N ₆ O ₄ , 544.1; m/z found, 545.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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

The DHODH inhibitory activity of the compounds of Examples 1-78 was evaluated using the following assay. The half maximal inhibitory concentration values (IC ₅₀ ) are summarized in Table 2.

bioassay

In vitro assay: DHODH enzymatic assay

To detect DHODH enzyme activity, dichloroindophenol (DCIP) is added as the final electron acceptor in this assay. DCIP can accept electrons from reduced coenzyme Q generated in this assay or derived from dihydroorotate (DHO) via FMN, presumably by binding to the uniquinone pocket. The DCIP solution is blue with strong absorbance at about 600 nm, but becomes colorless upon reduction ( J. Biol. Chem. (1986) 261, 11386). This 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. A substrate consisting of 20 mM DHO, 5 mM CoQ ₆ , and 1 mM DCIP in assay buffer initiates the reaction. This assay is run in endpoint mode by quenching the reaction with the potent DHODH inhibitor Brequinar. Absorbance measurements were obtained using a BMG Phera Star plate-reading spectrophotometer. 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 Formulatrix Tempest.

In Vitro Assay: MOLM-13 Cell Assay

MOLM-13 cells were obtained from DSMZ and maintained in 25 mM HEPES (Invitrogen, catalog number 72400) supplemented with RPMI 1640 + Glutamax + 10% heat inactivated fetal bovine serum (FBS; Invitrogen, catalog number 16140). The day before assay set-up, cells were pelleted, resuspended in fresh medium, counted, and plated at 0.4 x 10 ⁶ cells/mL in T150 flasks. On the day of assay, cells were pelleted, resuspended in fresh medium, counted and seeded at 5,000 cells/well in white opaque 96-well tissue culture treated microplates (Perkin Elmer, Cat. No. 6005680). Cells were exposed to different concentrations of test compounds immediately after seeding at 37° C., 5% CO ₂ for 72 hours. 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]

Claims (60)

a compound having the structure of formula (I); or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof:
[Formula (I)]

(In the above formula,
X ¹ and X ² are each independently CH or N;
Y is O, NH or S;
R ¹ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _2-6 alkenyl; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; C _3-6 cycloalkyl; C _3-6 heterocycloalkyl; and phenyl;
R ² is

or

is; here,
R ^b is C _1-6 alkyl substituted with a member selected from the group consisting of OH, halo, CN, OC _1-6 alkyl, OC _1-6 haloalkyl and OC _3-6 cycloalkyl;
R ^c is selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;
R ³ is H, Cl or F;
R ⁴ is selected from the group consisting of:
(a) C _1-6 alkyl; C _1-6 alkyl substituted with 1 or 2 substituents each independently selected from the group consisting of OH and OCH ₃ ; tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH ₃ ; cyclohexyl substituted with CH ₃ ; and tetrahydro-2H-thiopyran 1,1-dioxide; and
(b)

and

;
here,
R ^d is independently H; halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH, OCH ₃ , SCH ₃ , and OCF ₃ ; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; OC _1-6 alkyl; and OC _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;
R ^e is halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH, OCH ₃ , SCH ₃ , and OCF ₃ ; OC _1-6 alkyl; C _1-6 haloalkyl; selected from the group consisting of C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;
n is 1 or 2). The compound of claim 1 , wherein X ¹ is CH; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. The compound of claim 1 , wherein X ¹ is N; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 4. A compound according to any one of claims 1 to 3, wherein X ² is CH; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 4. The compound of any one of claims 1 to 3, wherein X ² is N; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 6. The compound according to any one of claims 1 to 5, wherein Y is O; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 6. The compound according to any one of claims 1 to 5, wherein Y is NH; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 6. The compound according to any one of claims 1 to 5, wherein Y is S; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 9. The method of any one of claims 1 to 8, wherein R ¹ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _2-6 alkenyl; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; C _3-6 cycloalkyl; tetrahydropyran-4-yl; and a compound selected from the group consisting of phenyl; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 9. The method of any one of claims 1 to 8, wherein R ¹ is C _1-4 alkyl; C _1-4 alkyl substituted with OH or OCH ₃ ; C _1-4 haloalkyl; C _1-4 haloalkyl substituted with OH or OCH ₃ ; tetrahydropyran-4-yl; or C _3-6 cycloalkyl; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 6. The method of any one of claims 1-5, wherein Y is O and R ¹ is CH(CH ₃ ) ₂ , CH(CH ₃ )(CF ₃ ), cyclopropyl, cyclobutyl, or tetrahydropyranyl. phosphorus, compounds; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 6. The compound of any one of claims 1-5, wherein Y is O and R ¹ is CH(CH ₃ ) ₂ or CH(CH ₃ )(CF ₃ ); or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 9. The method of any one of claims 1 to 8, wherein R ¹ is

phosphorus, compounds; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 14. The method of any one of claims 1 to 13, wherein R ² is

phosphorus, compounds; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 14. The method of any one of claims 1 to 13, wherein R ² is

and where
R ^b is C _1-4 alkyl substituted with OH, halo, CN, OC _1-4 alkyl, OC _1-4 haloalkyl or OC _3-6 cycloalkyl;
R ^c is C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 14. The method of any one of claims 1 to 13, wherein R ² is

phosphorus, compounds; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 17. The compound of any one of claims 1 to 16, wherein R ³ is H; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 17. The compound of any one of claims 1 to 16, wherein R ³ is Cl; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 17. The compound of any one of claims 1 to 16, wherein R ³ is F; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 20. The method of any one of claims 1 to 19, wherein R ⁴ is

, or

phosphorus, compounds; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 20. The method of any one of claims 1 to 19, wherein R ⁴ is

and where
R ^d is independently H; halo; CH ₃ ; CH ₂ OH; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; OCH ₃ , OCH ₂ CH ₂ OH and OCH ₂ CH ₂ OCH ₃ ;
R ^e is selected from the group consisting of Cl, F, CH ₃ , and OCH ₃ ;
n is 1 or 2;
compound; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 20. The method of any one of claims 1 to 19, wherein R ⁴ is

or

phosphorus, compounds; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 20. The method of any one of claims 1 to 19, wherein R ⁴ is

phosphorus, compounds; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 20. The method of any one of claims 1 to 19, wherein R ⁴ is

, or

is;
here,
R ^d is independently selected from the group consisting of H, Cl, CH ₃ , OH and OCH ₃ ;
R ^e is F, Cl, or CH ₃ ;
n is 1 or 2;
compound; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 20. The method of any one of claims 1 to 19, wherein R ⁴ is

, or

phosphorus, compounds; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 20. The method of any one of claims 1 to 19, wherein R ⁴ is

, or

phosphorus, compounds; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 25. The compound of any one of claims 1-19, 21 and 24, wherein n is 1; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 25. The compound of any one of claims 1-19, 21 and 24, wherein n is 2; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 6. The method of any one of claims 1-5, wherein Y is NH and R ⁴ is

phosphorus, compounds; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 6. The method of any one of claims 1-5, wherein Y is S and R ⁴ is

phosphorus, compounds; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. The compound of claim 1 , comprising a compound having the structure of Formula (IA); or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof:
[Formula (IA)]

(In the above formula,
Y is O, NH or S;
R ¹ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _2-6 alkenyl; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; C _3-6 cycloalkyl; C _3-6 heterocycloalkyl; and phenyl;
R ^b is C _1-6 alkyl substituted with a member selected from the group consisting of OH, halo, CN, OC _1-6 alkyl, OC _1-6 haloalkyl and OC _3-6 cycloalkyl;
R ^c is selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;
R ³ is H or F;
R ⁴ is selected from the group consisting of:
(a) C _1-6 alkyl; C _1-6 alkyl substituted with 1 or 2 substituents each independently selected from the group consisting of OH and OCH ₃ ; tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH ₃ ; cyclohexyl substituted with CH ₃ ; and tetrahydro-2H-thiopyran 1,1-dioxide; and
(b)

, and

;
R ^d is independently H; halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; OC _1-6 alkyl; and OC _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;
R ^e is selected from the group consisting of halo, C _1-6 alkyl, and OC _1-6 alkyl;
n is 1 or 2). The compound of claim 1 , comprising a compound having the structure of Formula (IB); or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof:
[Formula (IB)]

(In the above formula,
X ¹ is CH or N;
Y is O or NH;
R ¹ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _2-6 alkenyl; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; C _3-6 cycloalkyl; C _3-6 heterocycloalkyl; and phenyl;
R ² is

is; here,
R ^b is C _1-6 alkyl substituted with a member selected from the group consisting of OH, halo, CN, OC _1-6 alkyl, OC _1-6 haloalkyl and OC _3-6 cycloalkyl;
R ^c is selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;
R ³ is H or F;
R ⁴ is selected from the group consisting of:

. and

;
R ^d is independently selected from the group consisting of H, Cl, and F;
R ^e is selected from the group consisting of F, CH ₃ , and OCH ₃ ;
n is 1 or 2). 32. The compound of claim 31, wherein Y is O. 34. The compound of claim 31 or 33, wherein R ¹ is C _1-6 alkyl or C _1-6 haloalkyl. 33. The compound of claim 32, wherein Y is N. 33. The compound of claim 32, wherein Y is O. a compound having the structure of formula (II); or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof:
[Formula (II)]

(In the above formula,
X ³ and X ⁴ are each independently CH or N; wherein when X ³ is N, X ⁴ is CH, and when X ³ is CH, X ⁴ is N;
Z is O, S, or NH;
R ⁵ is C _1-6 alkyl; C _1-6 alkyl substituted with OH or OCH ₃ ; C _1-6 haloalkyl; C _1-6 haloalkyl substituted with OH or OCH ₃ ; and C _3-6 cycloalkyl;
R ⁶ is

ego;
R ⁷ is H or F;
R ⁸ is

ego;
here,
R ^f is independently H; halo; C _1-6 alkyl; C _1-6 alkyl substituted with a member selected from the group consisting of OH and OCH ₃ ; CN; OH; CO ₂ H; N(CH ₃ ) ₂ ; (C=O)NH-CH ₂ CH ₂ OH; NHSO ₂ CH ₃ ; and OC _1-6 alkyl;
R ^g is selected from the group consisting of halo, C _1-6 alkyl and OC _1-6 alkyl;
m is 1 or 2). 38. The compound of claim 37, wherein X ³ is N and X ⁴ is CH; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 38. The compound of claim 37, wherein X ³ is CH and X ⁴ is N; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 40. The compound of any one of claims 37-39, wherein Z is O; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 41. The compound of any one of claims 37-40, wherein R ⁵ is C _1-6 alkyl or C _1-6 haloalkyl; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 42. The compound of any one of claims 37-41, wherein R ⁷ is H; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 43. The method of any one of claims 37-42, wherein R ⁸ is

phosphorus, compounds; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 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)isoquinolin-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)isoquinolin-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) isoquinolin-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)isoquinolin-1-yl)oxy)-3,5-difluorobenzonitrile;
2-(1-(2,6-difluoro-4-(hydroxymethyl)phenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-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)isoquinolin-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-hydroxyethyl) benzamide;
2-(1-(2-Chloro-4,6-difluorophenoxy)-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;
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) isoquinolin-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)isoquinolin-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) isoquinoline -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)isoquinoline- 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-trifluoropropane- 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)isoquinolin-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)isoquinoline -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) iso quinolin-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]pyridazine -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)isoquinoline- 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)isoquinoline -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)iso quinolin-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)iso quinolin-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)isoquinoline- 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-trifluoropropane-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-trifluoropropane-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)isoquinoline -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)-N-(2-chloro-3-((6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-tri azol-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)isoquinoline- 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)isoquinoline -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)iso quinolin-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-trifluoro Ropropan-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-tri fluoropropan-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)iso quinolin-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)iso quinolin-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-trifluoro propan-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-((1,3-dimethoxypropan-2-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline -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)isoquinoline -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)isoquinoline-6 -yl)-1H-1,2,4-triazol-5(4H)-one;
(S)-4-ethyl-3-(hydroxymethyl)-1-(1-(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)-1,1,1 -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-trifluoropropane-2- yl)oxy)isoquinolin-6-yl)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((tetrahydro-2H-thiopyran 1,1-dioxide)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-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-trifluoro Ropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-3-(hydroxymethyl)-1H-1,2,4-triazole-5(4H)- On;
2-(8-(2-chloro-6-fluorophenoxy)-4-fluoro-1-((1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthy Ridin-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-triazole-3- On;
(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-triazole- 3-one;
(S)-2-(4-((5-chloro-3-methyl-1H-pyrazol-4-yl)oxy)-8-fluoro-5-((1,1,1-trifluoropropane) -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-((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-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazole- 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-3H-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-triazole-3- On;
and pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants, and N-oxides thereof. (A) a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof; and (B) at least one pharmaceutically acceptable excipient. (A) a compound according to any one of claims 37 to 43, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof; and (B) at least one pharmaceutically acceptable excipient. an effective amount of the compound of claim 44; and at least one pharmaceutically acceptable excipient. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition, comprising:
37. By administering to the subject an effective amount of at least one compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. A method comprising inhibiting or altering dihydroorotate oxygenase enzyme activity in a subject. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition, comprising:
44. By administering to the subject an effective amount of at least one compound according to any one of claims 37 to 43, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. A method comprising inhibiting or altering dihydroorotate oxygenase enzyme activity in a subject. 49. The method of claim 48, wherein the disorder, disease or medical condition is selected from the group consisting of an inflammatory disorder and an autoimmune disorder. 49. The method of claim 48, wherein the disorder, disease or medical condition is cancer. 49. The method of claim 48, wherein the disorder, disease or medical condition is selected from the group consisting of lymphoma, leukemia, carcinoma, and sarcoma. 49. The method of claim 48, wherein the disorder, disease or medical condition is acute lymphoblastic leukemia, acute myeloid leukemia, (acute) T-cell leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute proostosis. Myelomonocytic leukemia, biphenotype B myelomonocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, large granular lymphocytic leukemia, plasma cell leukemia, and also to develop into acute myeloid leukemia A method selected from the group consisting of possible myelodysplastic syndromes. 49. The method of claim 48, wherein the disorder, disease or medical condition is acute myeloid leukemia. 50. The method of claim 49, wherein the disorder, disease or medical condition is selected from the group consisting of an inflammatory disorder and an autoimmune disorder. 50. The method of claim 49, wherein the disorder, disease or medical condition is cancer. 50. The method of claim 49, wherein the disorder, disease or medical condition is selected from the group consisting of lymphoma, leukemia, carcinoma, and sarcoma. 50. The method of claim 49, wherein said disorder, disease or medical condition is acute lymphoblastic leukemia, acute myeloid leukemia, (acute) T-cell leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute proostosis. Myelomonocytic leukemia, biphenotype B myelomonocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, large granular lymphocytic leukemia, plasma cell leukemia, and also to develop into acute myeloid leukemia wherein the method is selected from the group consisting of possible myelodysplastic syndromes. 50. The method of claim 49, wherein the disorder, disease or medical condition is acute myeloid leukemia. 60. The method of any one of claims 48-59, wherein the at least one compound is 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)isoquinolin-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)isoquinolin-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) isoquinolin-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)isoquinolin-1-yl)oxy)-3,5-difluorobenzonitrile;
2-(1-(2,6-difluoro-4-(hydroxymethyl)phenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-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)isoquinolin-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-hydroxyethyl) benzamide;
2-(1-(2-Chloro-4,6-difluorophenoxy)-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;
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) isoquinolin-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)isoquinolin-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) isoquinoline -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)isoquinoline- 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-trifluoropropane- 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)isoquinolin-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)isoquinoline -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) iso quinolin-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]pyridazine -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)isoquinoline- 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)isoquinoline -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)iso quinolin-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)iso quinolin-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)isoquinoline- 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-trifluoropropane-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-trifluoropropane-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)isoquinoline -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)-N-(2-chloro-3-((6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-tri azol-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)isoquinoline- 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)isoquinoline -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)iso quinolin-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-trifluoro Ropropan-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-tri fluoropropan-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)iso quinolin-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)iso quinolin-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-trifluoro propan-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-((1,3-dimethoxypropan-2-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline -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)isoquinoline -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)isoquinoline-6 -yl)-1H-1,2,4-triazol-5(4H)-one;
(S)-4-ethyl-3-(hydroxymethyl)-1-(1-(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)-1,1,1 -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-trifluoropropane-2- yl)oxy)isoquinolin-6-yl)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((tetrahydro-2H-thiopyran 1,1-dioxide)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-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-trifluoro Ropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-3-(hydroxymethyl)-1H-1,2,4-triazole-5(4H)- On;
2-(8-(2-chloro-6-fluorophenoxy)-4-fluoro-1-((1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthy Ridin-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-triazole-3- On;
(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-triazole- 3-one;
(S)-2-(4-((5-chloro-3-methyl-1H-pyrazol-4-yl)oxy)-8-fluoro-5-((1,1,1-trifluoropropane) -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-((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-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazole- 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-3H-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-triazole-3- On;
and pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants, and N-oxides thereof.