JP2023513496A - Heterocyclic compounds as inhibitors of dihydroorotate dehydrogenase - Google Patents

Abstract

Compounds, compositions, and methods for treating diseases, disorders, or conditions affected by modulation of DHODH are disclosed. Embodiments of such compounds are represented by formulas (I) and (II) below. TIFF2023513496000221.tif37128 wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, X3, X4, Y and Z are as defined herein.

Description

(Cross reference to related applications)
This application is entitled pursuant to 35 U.S.C. incorporated into.

(Field of Invention)
The present invention relates to novel compounds that are dihydroorotate dehydrogenase (DHODH) inhibitors. These compounds may be useful in treating diseases, disorders, or conditions where inhibition of DHODH would be beneficial. The invention also provides pharmaceutical compositions comprising one or more of such compounds, processes for preparing such compounds and compositions, cancer, and autoimmune and inflammatory diseases, syndromes, and disorders. and the use of such compounds or pharmaceutical compositions for methods of treatment.

Acute myelogenous leukemia (AML) is a clonal disease of the blood and bone marrow caused by 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 accumulation of clonal abnormal bone marrow progenitor cells known as myeloblasts. . These cells exhibit disruption of normal myeloid differentiation and excessive proliferation, resulting in decreased hematopoietic cell formation. Although disease remission can be achieved with standard induction chemotherapy, refractory and recurrent disease remains a challenge due to residual leukemic stem cells. Therefore, AML represents an unmet medical need with over 20,000 new cases per year in the United States, with a 5-year overall survival rate of less than 30% (Stein ET et al., Health Qual Life Outcomes 16 : 193, 2018).

Differentiation therapy appears to be an attractive approach to treating AML based on the finding that loss of differentiation and stem cell self-renewal in normal cells is associated. Treatment of acute promyelocytic leukemia, which accounts for 10-15% of total AML, with all-trans retinoic acid is a paradigm for differentiation therapy. Retinoic acid is a promyelocytic leukemia protein (PML)-retinoic acid receptor-α (RAR-α) fusion encoded by a t(15,17) chromosomal translocation. Target proteins. Targeting the PML-RAR specifically relieved the block of transcriptionally mediated differentiation induced by the fusion protein, and early clinical trials with single-agent ATRA demonstrated complete blood transfusion in all treated patients. clinical remission (McCulloch D et al. Onco Targets Ther 2017; 10:1585-1601; Nowak D et al. Blood 113:3655, 2009).

Differentiation therapy has been successful, but is only applicable to a small subset of AML patients. Studies aimed at identifying additional differentiation-inducing agents have met with limited success. Recently, dihydroorotate was identified as a potentially more broadly applicable differentiation target in phenotypic screens aimed at identifying small molecules that overcome the block in maturation of primary mouse myeloid cells expressing the homeobox protein HoxA9. Dehydrogenase (DHODH) has emerged. This protein, a key transcription factor involved in balancing stem cell maintenance/differentiation, is normally expressed in hematopoietic progenitor cells, downregulated upon induction of differentiation, and found to be widely overexpressed in AML. (Sykes et al., Cell 167:171, 2016).

DHODH is a flavin mononucleotide (FMN) flavoprotein located in the inner mitochondrial membrane that catalyzes the oxidation of dihydroorotic acid to orotic acid, the fourth step in the de novopyrimidine biosynthetic pathway. Inhibition of DHODH reduces not only pyrimidine synthesis, a key precursor for nucleotide synthesis, but also glycoprotein and phospholipid biosynthesis (Reis RAG et al., Archives Biochem Biophysics 632:175, 2017; Vyas VK et al., Mini Rev Med Chem 11:1039, 2011). DHODH is a target that has been validated 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, resulting in a dose-dependent anti-leukemia effect, decreased leukemic stem cells, and increased survival time in vivo. Since the initial observation by Sykes et al. showing that the small molecule DHODH inhibitors mediate anti-proliferative activity against AML cells with concomitant cell cycle arrest, upregulation of CD11b and CD14, and induction of apoptosis There is additional evidence showing that (Wu D et al. Haematologica 103:1472, 2018; Sainas S et al., J Med Chem 61:6034, 2018; 23rd Epub ahead of print). Furthermore, preclinical solid tumors in in vitro and in vivo models demonstrated efficacy of DHODH inhibition, and DHODH was identified as a synthetic lethality in PTEN and KRAS mutant solid tumors (Pharmacology and Therapeutics, Epub October 19th, 2018; Mathur D et al., Cancer Discovery 7:1, 2017; Cell Chemical Biology 25:1, 2018).

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

Embodiments of the present invention are directed to compounds, pharmaceutical compositions containing such compounds, methods of making and purifying such compounds, methods of using such compounds as inhibitors of DHODH enzymatic activity, and methods of treating autoimmune or inflammatory disorders such as autoimmune or inflammatory disorders. It relates to methods of using the compounds in the treatment of a disease, disorder, or condition, or a subject suffering from or diagnosed with a disease, such as cancer.

An embodiment of the present invention is a compound of formula (I),

［式中、
Ｘ^１及びＸ^２は、それぞれ独立してＣＨ又はＮであり、
ＹはＯ、ＮＨ又はＳであり、
Ｒ^１は、Ｃ_１～６アルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６アルキル；Ｃ_２～６アルケニル；Ｃ_１～６ハロアルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６ハロアルキル；Ｃ_３～６シクロアルキル；Ｃ_３～６ヘテロシクロアルキル；及びフェニルからなる群から選択され、
Ｒ^２は、

[In the 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;
^R2 is

（式中、
Ｒ^ｂは、ＯＨ、ハロ、ＣＮ、ＯＣ_１～６アルキル、ＯＣ_１～６ハロアルキル、及びＯＣ_３～６シクロアルキルからなる群から選択されるメンバーで置換されたＣ_１～６アルキルであり、
Ｒ^ｃは、Ｃ_１～６アルキル、Ｃ_１～６ハロアルキル、及びＣ_３～６シクロアルキルからなる群から選択される）であり、
Ｒ^３はＨ、Ｃｌ又はＦであり、
Ｒ^４は、
（ａ）Ｃ_１～６アルキル；ＯＨ及びＯＣＨ_３からなる群からそれぞれ独立して選択される１つ又は２つの置換基で置換されたＣ_１～６アルキル；テトラヒドロ－２Ｈ－ピラン－４－イル；ＯＣＨ_３で置換されたテトラヒドロ－２Ｈ－ピラン－４－イル；ＣＨ_３で置換されたシクロヘキシル；及びテトラヒドロ－２Ｈ－チオピラン１，１－ジオキシド；並びに、
（ｂ）

(In the formula,
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;
^R4 is
(a) C _1-6 alkyl; C _1-6 alkyl substituted with one or two 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;
(b)

（式中、
Ｒ^ｄは、Ｈ；ハロ；Ｃ_１～６アルキル；ＯＨ、ＯＣＨ_３、ＳＣＨ_３、及びＯＣＦ_３からなる群から選択されるメンバーで置換されたＣ_１～６アルキル；Ｃ_１～６ハロアルキル；ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＣ_１～６ハロアルキル；ＣＮ；ＯＨ；ＣＯ_２Ｈ；Ｎ（ＣＨ_３）_２；（Ｃ＝Ｏ）ＮＨ－ＣＨ_２ＣＨ_２ＯＨ；ＮＨＳＯ_２ＣＨ_３；ＯＣ_１～６アルキル；並びに、ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＯＣ_１～６アルキル、からなる群から独立して選択され、
Ｒ^ｅは、ハロ；Ｃ_１～６アルキル；ＯＨ、ＯＣＨ_３、ＳＣＨ_３、及びＯＣＦ_３からなる群から選択されるメンバーで置換されたＣ_１～６アルキル；ＯＣ_１～６アルキル；Ｃ_１～６ハロアルキル；ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＣ_１～６ハロアルキル、からなる群から選択され、
ｎは１又は２である）からなる群から選択される］の化合物、
又はその医薬的に許容される塩、溶媒和物、立体異性体、同位体変種、若しくはＮ－オキシドである。

(In the formula,
R ^d is 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 and OCH ₃ ; _CN ; OH; CO ₂ H; N(CH ₃ ) ₂ ; _{2 CH} ; 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 _{; 6} haloalkyl; C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;
n is 1 or 2);
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

An embodiment of the present invention is a compound of formula (II),

［式中、
Ｘ^３及びＸ^４は、それぞれ独立してＣＨ又はＮであり、Ｘ^３がＮである場合、Ｘ^４はＣＨであり、Ｘ^３がＣＨである場合、Ｘ^４はＮであり、
Ｚは、Ｏ、Ｓ、又はＮＨであり、
Ｒ^５は、Ｃ_１～６アルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６アルキル；Ｃ_１～６ハロアルキル；ＯＨ又はＯＣＨ_３で置換されたＣ_１～６ハロアルキル；及びＣ_３～６シクロアルキルからなる群から選択され、
Ｒ^６は、

[In the formula,
X ³ and X ⁴ are each independently CH or N, when X ³ is N, X ⁴ is CH, 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 ;} is selected from the group consisting of alkyl,
^R6 is

であり、
Ｒ^７は、Ｈ又はＦであり、
Ｒ^８は、

and
R ⁷ is H or F;
^R8 is

（式中、
Ｒ^ｆは、Ｈ；ハロ；Ｃ_１～６アルキル；ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＣ_１～６アルキル；ＣＮ；ＯＨ；ＣＯ_２Ｈ；Ｎ（ＣＨ_３）_２；（Ｃ＝Ｏ）ＮＨ－ＣＨ_２ＣＨ_２ＯＨ；ＮＨＳＯ_２ＣＨ_３；並びにＯＣ_１～６アルキルからなる群から独立して選択され、
Ｒ^ｇは、ハロ、Ｃ_１～６アルキル及びＯＣ_１～６アルキルからなる群から選択され、
ｍは、１又は２である）である］の化合物、
又はその医薬的に許容される塩、溶媒和物、立体異性体、同位体変種、若しくはＮ－オキシドである。

(In the formula,
R ^f is H; halo; C _1-6 alkyl _; C _1-6 alkyl substituted with _a member selected from the group consisting of OH and OCH _{3 ;} (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)],
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

The present invention further uses compounds of formula (I) (and compounds of formula (II)), or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof. to treat diseases, syndromes, conditions or disorders in subjects, including mammals and/or humans, that are affected by inhibition of DHODH enzymatic activity, including but not limited to cancer and/or inflammatory or immune disorders. Or provide a way to improve.

Further embodiments, features, and advantages of the invention will become apparent from the following Detailed Description and by practice of the invention.

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

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

The term "independently" when used in connection with substituents, when more than one substituent is contemplated, refers to the circumstance in which the substituents may be the same or different from each other.

The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, the substitution is meant to occur at any position in the system where valences are allowed.

Unless specifically limited in a particular instance of use, the term "alkyl" refers to straight or branched chain alkyl groups having 1 to 8 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that would be considered equivalent to any one of the above examples in light of the ordinary skill in the art and the teachings presented herein. "C _1-6 alkyl" refers to a straight or branched chain alkyl group having from 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 analogous in length and possible substitution to the alkyls described above, except that they contain 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 which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (eg, C2-6 for straight chain, C3-6 for branched chain).

The term "cycloalkyl" refers to a saturated or partially saturated monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle. “C _3-6 cycloalkyl” refers to carbocycles having from 3 to 6 ring atoms per carbocycle. Specific examples of cycloalkyl groups include the following entities, in the form of suitably linked moieties:

The term "halogen" or "halo" denotes 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 substituted with halogen for hydrogen. point to The term “C _1-4 haloalkyl,” as used herein, refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms in the chain, optionally substituted with halogen for hydrogen. point to Examples of "haloalkyl" groups include trifluoromethyl ( _CF3 ), difluoromethyl ( _CF2H ), monofluoromethyl ( _CH2F ) _, pentafluoroethyl ( _CF2CF3 ), tetrafluoroethyl ( _CHFCF3 ), monofluoroethyl (CH ₂ CH ₂ F), trifluoroethyl (CH ₂ CF ₃ ), tetrafluorotrifluoromethylethyl (CF(CF ₃ ) ₂ ), as well as those of ordinary skill in the art and herein. Examples include groups that would be considered equivalent to any one of the foregoing examples in light of the teaching provided in .

The term "aryl" refers to monocyclic aromatic carbocycles (cyclic structures in which the ring atoms are all carbon) having 6 atoms per ring. (The carbon atoms in the aryl group are sp2 hybridized.)

The term "phenyl" refers to the moieties:

The terms "4- to 7-membered heterocycloalkyl" and "4- to 6-membered heterocycloalkyl" refer to the term "4- to 6-membered heterocycloalkyl", wherein the heterocycloalkyl group may be fused through any one of the carbon atoms or, if present and not specifically excluded, through the nitrogen atom. containing 1 or 2 identical or different ring heteroatoms from series N, O, and S, respectively, which are capable of being attached to the rest of the molecule, in total of 4, 5, 6, or 7 , or a monocyclic saturated heterocycle having 4, 5, or 6 ring atoms. Illustrative examples of heterocycloalkyl groups include the following entities, in the form of suitably linked moieties:

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

を表す。

represents

The term "tetrahydrofuranyl" denotes the moiety:

The term "tetrahydropyranyl" denotes the moiety:

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

A person of ordinary skill in the art may select additional species within these defined terms, as the species of heterocycloalkyl, cycloalkyl, heteroaryl, and aryl groups listed or exemplified above are not exhaustive. you will understand.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible through a low energy barrier. For example, proton tautomers (also known as proton tautomers) include interconversions through proton transfer, such as keto-enol and imine-enamine isomerizations. Valence tautomers involve interconversions by rearranging some of the bonding electrons.

For example, hydroxypyridine or tautomeric pyridone is represented below.

The term "variable points of attachment" means that the group is attached at two or more alternative positions within the structure. This bond always replaces a hydrogen atom with one of the ring atoms. In other words, all permutations of bonds are represented by a single figure, as shown in the figure below.

Those skilled in the art will recognize that when more than one such substituent is present for a given ring, the attachment of each substituent is independent of all others. The groups listed or exemplified above are not exhaustive.

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

As used herein, the terms “comprise,” “contain,” and “comprise” are used in their broad, non-limiting sense.

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

As used herein, the terms “treat,” “treating,” or “treatment” of any disease, condition, syndrome, or disorder refer to In refers to ameliorating the disease, condition, syndrome or disorder (ie, slowing or preventing or reducing the onset of at least one of the disease or its clinical symptoms). In another embodiment, "treat," "treating," or "treatment" refers to at least Refers to alleviating or improving one physiological or biochemical parameter. In further embodiments, "treating," "treating," or "treatment" refers to physical (e.g., stabilization of recognizable symptoms), physiological (e.g., stabilization of physical parameters), or in both, to modulate a disease, condition, syndrome, or disorder. In yet another embodiment, "treating," "treating," or "treatment" refers to preventing or delaying the onset or development or progression of a disease, condition, syndrome, or disorder.

The terms "subject" and "patient" are used interchangeably herein and can refer to animals, preferably mammals, and most preferably humans.

As used herein, the terms active compound, drug, and active ingredient are used interchangeably to refer to a pharmaceutically active compound. Other components 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) comprises an active ingredient in combination with one or more carriers and/or one or more excipients and/or one or more diluents. You can stay.

The term "therapeutically effective amount" (used interchangeably herein with "effective amount") refers to reducing or inhibiting the activity of an enzyme or protein, or ameliorating symptoms, alleviating pathology, slowing or delaying disease progression. or to elicit a biological or pharmaceutical response in a tissue system, animal, or human that is sought by researchers, veterinarians, physicians, or other clinicians, including prevention of disease (e.g., compounds of the invention It refers to the amount of active compound or drug such as Stated another way, the term therapeutically effective amount means by inhibiting, alleviating or curing a disease, condition, syndrome or disorder in a particular subject when administered to a particular subject; It can refer to an amount that achieves a therapeutic effect by prophylactically inhibiting, preventing, or delaying the onset of a syndrome or disorder, or symptoms thereof. A therapeutically effective amount alleviates to some extent one or more symptoms of a disease, condition, syndrome or disorder in a subject; and/or one or more physiological or partially or completely return a biochemical parameter to normal; and/or reduce the likelihood of developing a disease, condition, syndrome, or disorder, or symptoms thereof.

"Pharmaceutically acceptable" means useful in the preparation of pharmaceutical compositions that are generally safe, non-toxic, and devoid of biological or other undesirable aspects. , including those that are acceptable for veterinary and human pharmaceutical use.

A "pharmaceutically acceptable salt" is represented by Formula (I) that is non-toxic, biologically acceptable, or otherwise biologically suitable for administration to a subject. (and compounds of formulas (IA), (IB), and (II))). Generally, S. M. Berge, et al. , "Pharmaceutical Salts", J. Am. 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 to contact the patient's tissue without causing undue toxicity, irritation, or allergic reactions.

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-dioic acid Salt, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate, Hydroxybenzoate, Methoxybenzoate, Phthalate, Sulfonate, Xylenesulfonate, Phenylacetate, Phenylpropionate salt, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methane-sulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfone acid salts, and mandelate salts.

The compounds of formula (I) (and the compounds of formula (II)) have sufficiently acidic groups, sufficiently basic groups or both types of functional groups and are therefore compatible with many inorganic or organic bases and It can be reacted with inorganic and organic acids to form pharmaceutically acceptable salts.

Since compounds of formula (I) (and compounds of formula (II)) may contain at least one nitrogen with basic character, the desired pharmaceutically acceptable salts are available in the art by any suitable method, e.g. stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidyl acid (e.g. glucuronic acid or galacturonic acid), α-hydroxy acid (e.g. mandelic acid, citric acid, or tartaric acid), amino acid (e.g. aspartic acid or glutamic acid), aromatic acid (e.g. benzoic acid, 2- acetoxybenzoic acid, naphthoic acid, or cinnamic acid); It can be prepared by treating the free base with any compatible mixture, as well as any other acids and mixtures thereof that are considered equivalents.

Compounds of formula (I) (and compounds of formula (II)) may contain a carboxylic acid moiety and the desired pharmaceutically acceptable salt may be prepared in any suitable manner, e.g. or organic bases such as amines (primary, secondary, tertiary), alkali metal hydroxides, alkaline earth metal hydroxides, any of the bases as exemplified herein. It can be prepared by treatment with compatible mixtures and other bases and mixtures thereof that are considered equivalents or acceptable alternatives in the light of the ordinary level of skill in the art. Illustrative examples of suitable salts include amino acids such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, as well as benzylamine, pyrrolidine, piperidine, Organic salts derived from cyclic amines such as morpholine, piperazine, N-methyl-glucamine, and tromethamine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. be done.

Each compound used herein can be discussed interchangeably with respect to its chemical formula, chemical name, abbreviations, and the like.

Any formula given herein is intended to represent compounds having structures depicted by that structural formula, as well as specific variants or forms. Specifically, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of compounds of the general formula and mixtures thereof are considered within the scope of such formula. Compounds of the present invention may possess one or more asymmetric centers, and such compounds can be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. . Thus, any formula given herein is intended to represent the racemate, one or more of its enantiomeric forms, one or more of its diastereomeric forms, and mixtures thereof. Further, any formula given herein may refer to hydrates, solvates, and polymorphs of such compounds, and mixtures thereof, even if such forms are not explicitly recited. intended to refer to any one of

The term "R" at a stereocenter indicates that the stereocenter is in the R-configuration only, as defined in the art. Similarly, the term "S" means that the stereocenter is of the S-configuration only. As used herein, the term "RS" refers to stereocenters that exist as a mixture of R- and S-configurations.

Compounds containing one stereocenter, shown without a stereochemical bond designation, are mixtures of the two enantiomers. A compound containing two stereocenters, shown without a stereochemical bond designation, is a mixture of four diastereomers. Compounds containing two stereocenters labeled "RS" and illustrated with stereochemical bond designations are binary mixtures with the relative stereochemistry as illustrated. . Unlabeled stereocenters shown without a stereobond designation are a mixture of R- and S-configurations. For unlabeled stereocenters shown with stereochemical bond designations, the absolute stereochemistry is as shown.

Unless otherwise indicated, the description or naming of a particular compound in this specification and claims is intended to include both its individual enantiomers and mixtures of racemates or others. Methods for determination of stereochemistry and separation of stereoisomers are well known in the art.

References to compounds described herein are either (a) the recited form of such compound and (b) the form of such compound in the medium in which the compound is believed to exist at the time of naming; represents a reference to any one of For example, reference herein to a compound such as R-COOH includes reference to any one of, eg, R-COOH(s), R-COOH(sol), and R-COO-(sol). In this example, R-COOH(s) refers to the solid compound as it may be present, for example, in a tablet or some other solid pharmaceutical composition or preparation, and R-COOH(sol) is the solvent R-COO-(sol) refers to the undissociated form of a compound in a solvent, e.g., whether such dissociated form is derived from R-COOH, from a salt thereof, or in a medium Refers to the dissociated form, such as the dissociated form of a compound in an aqueous environment, whether derived from any other entity that yields R-COO- when thought to undergo dissociation in water. In another example, a phrase such as "exposing an entity to a compound of formula R-COOH" refers to exposing such entity to the form of the compound R-COOH present in the medium in which such exposure occurs. In yet another example, a phrase such as "reacting an entity with a compound of formula R-COOH" means that (a) a chemically related form of such entity present in the medium in which such reaction occurs is , (b) chemically related forms of the compound R—COOH present in the medium in which such reaction occurs. In this context, when such entities are present in, for example, an aqueous environment, the entities are R—COOH(aq) and/or R -COO-(aq) (the subscript "(aq)" means "aqueous solution" according to its customary meaning in chemistry and biochemistry). In these nomenclature examples, the carboxylic acid functionality was chosen, but this choice is not meant to be limiting, but merely illustrative. Similar examples include, but are not limited to, hydroxyls, basic nitrogen members such as those in amines, and any other group that interacts or transforms in a known manner in a medium containing the compound. , can also be provided for other functional groups. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerism, solvolysis (including hydrolysis), solvation (including hydration), protonation, and deprotonation. not. No further examples are provided in this connection here because these interactions and transformations that occur in a given medium are known to those skilled in the art.

Also, any formula given herein is intended to represent unlabeled as well as isotopically labeled forms of the compounds. Isotopically-labeled compounds have the structures depicted in the formulas given herein, except that one or more atoms, in enriched form, have been replaced with atoms having selected atomic masses or mass numbers. have. Examples of isotopes that can be incorporated into compounds of the invention in their supranatural abundance forms are ² H (or chemical symbol D), ³ H (or chemical symbol T), ¹¹ C, ¹³ C, respectively. , ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, and ¹²⁵ I, such as hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine isotopes of Such isotopically labeled compounds are useful in metabolic studies (preferably using ¹⁴ C), reaction kinetic studies (e.g. using ² H or ³ H), detection or imaging techniques [positron emission tomography (PET) or single photon single-photon emission computed tomography (SPECT), etc.] (including drug or substrate tissue distribution assays), or in patient radiotherapy. In particular, ¹⁸ F- or ¹¹ C-labeled compounds may be particularly preferred for PET or SPECT studies. Furthermore, substitution with heavier isotopes, such as deuterium (i.e., ² H, or D), may result in greater metabolic stability, e.g., increased in vivo half-life or lower required dosages. Certain therapeutic benefits may be obtained as a result, such as less. Isotopically-labeled compounds of the invention can generally be prepared by substituting readily available isotopically-labeled reagents for non-isotopically-labeled reagents by carrying out the schemes illustrated below or the procedures disclosed in the Examples and Preparations. It can be prepared by

The term C _n-m alkyl refers to an aliphatic chain, whether linear or branched, where the total number of carbon members in the chain, N, satisfies n≦N≦m, where m>n.

When multiple identical substituents are assigned to various groups, the specific individual substituent assignments to each such group are made independently of the specific individual substituent assignments to the remaining groups. means that By way of illustration and not by way of limitation, when each of the Q and R groups can be H or F, the selection of H or F for the Q group is made independently of the selection of H or F for the R group, The choice of assignment to the Q group does not determine or condition the choice of assignment to the R group, and vice versa, unless expressly indicated otherwise. In this regard, exemplary claim recitations include "each of the Q and R groups is independently H or F" or "each of the Q and R groups independently from the group consisting of H and F selected as ”.

In another example, a zwitterionic compound is defined herein by reference to a compound known to form a zwitterion, even if not explicitly named in its zwitterionic form. included in the specification. Terms such as zwitterions and their synonyms zwitterionic compounds are standard names recognized by the IUPAC that are part of the standard set of well-known and defined scientific names. be. In this context, the name dipolar ion has been assigned the identification name CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities. As is generally known, zwitterions or zwitterionic compounds are neutral compounds having formal unit charges of opposite signs. These compounds are sometimes referred to by the term "inner salts". Others refer to these compounds as "dipolar ions", but this latter term is misnamed in still others. As a specific example, aminoethanoic acid (the amino acid glycine) has the formula H ₂ NCH ₂ COOH and in some media (in this case neutral media) the dipolar ion form ⁺ H ₃ NCH ₂ COO ^- exist. Zwitterions, zwitterionic compounds, inner salts, and zwitterions in the known and well-established meanings of these terms are, in all cases, recognized as such by those skilled in the art. Within range. Structures of zwitterionic compounds related to the compounds of the present invention are not explicitly shown herein, as there is no need to name every embodiment that would be recognized by one of ordinary skill in the art. However, these are also part of the embodiments of the present invention. Since the interactions and transformations in a given medium leading to the various forms of a given compound are known to those skilled in the art, no further examples relating to this are provided here.

When referring to any formula given herein, the selection of a particular moiety from a list of possible species for a given variable defines such same selection for variables appearing elsewhere. is not intended to In other words, if a variable appears more than once, the selection of species from a designated list is independent of the selection of species for the same variable elsewhere in the formula, unless otherwise indicated.

As a first example in terms of substituents, if _{an instance} of substituent S ¹ is one of S ₁ and S ² and _{an instance} of S ₂ is one of S ₃ and S ₄ , These assignments are the _following alternatives; S ¹ _instance is S ₁ and S ² instance is S ₃ ; S ¹ _instance is S ₁ and S ² _instance is S ₄ ; S ¹ _instance is S ₁ and S ² _examples are S ₄ ; S ¹ _examples are S ₂ and S ² _examples are S ₃ ; S ¹ _examples are S ₂ and S ² _examples are S ₃ ; S ¹ _instance is S ₂ and S ² _instance is S ₄ ; and embodiments of the invention given according to the equivalents of each of such alternatives. S ¹ _instance is S ₂ and S ² _instance is S ₄ ; and the equivalents of each of such alternatives. Therefore, the shorter term " _example S ¹ is one of S ₁ and S ₂ and _example S ² is one of S ₃ and S ₄ " is used herein for simplification. Used for purposes, but not as a limitation. Therefore, the shorter term " _example S ¹ is one of S ₁ and S ₂ and _example S ² is one of S ₃ and S ₄ " is used herein for simplification. Used for purposes, but not as a limitation. The above first example of substituent terms stated in generic terms is meant to illustrate the various substituent assignments described herein.

Furthermore, when more than one assignment is given for any member or substituent, embodiments of the invention are subject to the various assignments that can be made from the listed assignments and their equivalents by independent interpretation. including groupings. As a second example in terms of substituents, when a substituent S _instance is described herein as being one of S ₁ , S ₂ , and S ₃ , the list is such that the S _instance is S is ₁ ; as a second example in terms of substituents, when a substituent S _instance is described herein as being one of S ₁ , S ₂ , and S ₃ , the list is: 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 S ₁ and S ₃ the S _instance is one of _S2 and _S3 ; the S _instance is one of _S1 , _S2 , and _S3 ; and any of each of these alternatives refers to an embodiment of the present invention that is equivalent to Refers to embodiments of the invention in which the S _instance is one of S ₁ , S ₂ , and S ₃ ; and any equivalents of each of these alternatives. Accordingly, the shorter term “S _instance is one of S ₁ , S ₂ , and S ₃ ” is used herein for brevity and not as a limitation. Accordingly, the shorter term “S _instance is one of S ₁ , S ₂ , and S ₃ ” is used herein for brevity and not as a limitation. The above second example of substituent terminology stated in generic terms is intended to illustrate the various substituent assignments described herein.

When the nomenclature “C _i -C _j ” (j>i) is applied herein to a class of substituents, it refers to each of the i to j (inclusive) carbon members and It is meant to refer to embodiments of the invention that are all independently implemented. By way of example, the terms C ₁ -C ₃ independently refer to embodiments having one carbon member (C ₁ ), embodiments having two carbon members (C ₂ ), and three carbon members ( C ₃ ).

An embodiment of the present invention is a compound of formula (I),

［式中、
Ｘ^１及びＸ^２は、それぞれ独立してＣＨ又はＮであり、
ＹはＯ、ＮＨ又はＳであり、
Ｒ^１は、Ｃ_１～６アルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６アルキル；Ｃ_２～６アルケニル；Ｃ_１～６ハロアルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６ハロアルキル；Ｃ_３～６シクロアルキル；Ｃ_３～６ヘテロシクロアルキル；及びフェニルからなる群から選択され、
Ｒ^２は、

[In the 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;
^R2 is

（式中、
Ｒ^ｂは、ＯＨ、ハロ、ＣＮ、ＯＣ_１～６アルキル、ＯＣ_１～６ハロアルキル、及びＯＣ_３～６シクロアルキルからなる群から選択されるメンバーで置換されたＣ_１～６アルキルであり、
Ｒ^ｃは、Ｃ_１～６アルキル、Ｃ_１～６ハロアルキル、及びＣ_３～６シクロアルキルからなる群から選択される）であり、
Ｒ^３はＨ、Ｃｌ又はＦであり、
Ｒ^４は、
（ａ）Ｃ_１～６アルキル；ＯＨ及びＯＣＨ_３からなる群からそれぞれ独立して選択される１つ又は２つの置換基で置換されたＣ_１～６アルキル；テトラヒドロ－２Ｈ－ピラン－４－イル；ＯＣＨ_３で置換されたテトラヒドロ－２Ｈ－ピラン－４－イル；ＣＨ_３で置換されたシクロヘキシル；及びテトラヒドロ－２Ｈ－チオピラン１，１－ジオキシド；並びに、
（ｂ）

(In the formula,
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;
^R4 is
(a) C _1-6 alkyl; C _1-6 alkyl substituted with one or two 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;
(b)

（式中、
Ｒ^ｄは、Ｈ；ハロ；Ｃ_１～６アルキル；ＯＨ、ＯＣＨ_３、ＳＣＨ_３、及びＯＣＦ_３からなる群から選択されるメンバーで置換されたＣ_１～６アルキル；Ｃ_１～６ハロアルキル；ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＣ_１～６ハロアルキル；ＣＮ；ＯＨ；ＣＯ_２Ｈ；Ｎ（ＣＨ_３）_２；（Ｃ＝Ｏ）ＮＨ－ＣＨ_２ＣＨ_２ＯＨ；ＮＨＳＯ_２ＣＨ_３；ＯＣ_１～６アルキル；並びに、ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＯＣ_１～６アルキル、からなる群から独立して選択され、
Ｒ^ｅは、ハロ；Ｃ_１～６アルキル；ＯＨ、ＯＣＨ_３、ＳＣＨ_３、及びＯＣＦ_３からなる群から選択されるメンバーで置換されたＣ_１～６アルキル；ＯＣ_１～６アルキル；Ｃ_１～６ハロアルキル；ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＣ_１～６ハロアルキル、からなる群から選択され、
ｎは１又は２である）からなる群から選択される］の化合物、
又はその医薬的に許容される塩、同位体、Ｎ－オキシド、溶媒和物、若しくは立体異性体と、又はこれらの同位体、Ｎ－オキシド、溶媒和物、若しくは立体異性体の医薬的に許容される塩を含む。

(In the formula,
R ^d is 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 and OCH ₃ ; _CN ; OH; CO ₂ H; N(CH ₃ ) ₂ ; _{2 CH} ; 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 _{; 6} haloalkyl; C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;
n is 1 or 2);
or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, or a pharmaceutically acceptable isotope, N-oxide, solvate, or stereoisomer thereof contains salt that is

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 ^X2 is CH.

A further embodiment of the invention are the compounds of formula (I), wherein ^X2 is N.

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

A further embodiment of this invention is _wherein R ¹ is _{C 1-6 alkyl} ; C _1-6 alkyl substituted with OH or OCH ₃ ; C _2-6 alkenyl; A compound of formula (I) selected from the group consisting of substituted C _1-6 haloalkyl; C _3-6 cycloalkyl; tetrahydropyran-4-yl; and phenyl.

A further embodiment of the present invention is 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} substituted with OH or OCH ₃ A compound of formula (I) which is ₄ haloalkyl; tetrahydropyran-4-yl; or C _3-6 cycloalkyl.

_A further embodiment _of the present _{invention is} ^a ) is a compound of

A further embodiment of the invention are the compounds of formula (I), wherein Y is O and ^R1 is CH( _CH3 ) ₂ or CH( _CH3 )( _CF3 ).

A further embodiment of the invention is characterized in that R ¹ is

である、式（Ｉ）の化合物である。

is a compound of formula (I).

A further embodiment of the present invention is wherein R ² is

である、式（Ｉ）の化合物である。

is a compound of formula (I).

A further embodiment of the present invention is wherein R ² is

であり、
Ｒ^ｂが、ＯＨ、ハロ、ＣＮ、ＯＣ_１～４アルキル、ＯＣ_１～４ハロアルキル、若しくはＯＣ_３～６シクロアルキルで置換されたＣ_１～４アルキルであり、
Ｒ^ｃが、Ｃ_１～４アルキル、Ｃ_１～４ハロアルキル、又はＣ_３～６シクロアルキルである、式（Ｉ）の化合物である。

and
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;
Compounds of formula (I) wherein R ^c is C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl.

A further embodiment of the present invention is wherein R ² is

である、式（Ｉ）の化合物である。

is a compound of formula (I).

A further embodiment of the invention are the compounds of formula (I), wherein ^R3 is H.

A further embodiment of the invention are compounds of formula (I), wherein ^R3 is Cl.

A further embodiment of the invention are the compounds of formula (I), wherein ^R3 is F.

A further embodiment of the present invention is wherein R ⁴ is

である、式（Ｉ）の化合物である。

is a compound of formula (I).

A further embodiment of the present invention is wherein R ⁴ is

であり、
Ｒ^ｄが、Ｈ；ハロ；ＣＨ_３；ＣＨ_２ＯＨ；ＣＮ；ＯＨ；ＣＯ_２Ｈ；Ｎ（ＣＨ_３）_２；（Ｃ＝Ｏ）ＮＨ－ＣＨ_２ＣＨ_２ＯＨ；ＮＨＳＯ_２ＣＨ_３；ＯＣＨ_３、ＯＣＨ_２ＣＨ_２ＯＨ、及びＯＣＨ_２ＣＨ_２ＯＣＨ_３からなる群から独立して選択され、
Ｒ^ｅが、Ｃｌ、Ｆ、ＣＨ_３、及びＯＣＨ_３からなる群から選択され、
ｎが、１又は２である、式（Ｉ）の化合物である。

and
^CH2OH ; _CN ; _OH ; _CO2H ; _N ( _CH3 ) ₂ ; (C=O)NH- _CH2CH2OH ; _{NHSO2CH3 ; OCH3 , OCH2CH2OH , and OCH2CH2OCH3} ;
R ^e is selected from the group consisting of Cl, F, _CH3 , and _OCH3 ;
A compound of formula (I), wherein n is 1 or 2.

A further embodiment of the present invention is wherein R ⁴ is

である、式（Ｉ）の化合物である。

is a compound of formula (I).

A further embodiment of the present invention is wherein R ⁴ is

である、式（Ｉ）の化合物である。

is a compound of formula (I).

A further embodiment of the present invention is wherein R ⁴ is

であり、
式中、
Ｒ^ｄが、Ｈ、Ｃｌ、ＣＨ_３、ＯＨ及びＯＣＨ_３からなる群から独立して選択され、
Ｒ^ｅが、Ｆ、Ｃｌ、又はＣＨ_３であり、
ｎが、１又は２である、式（Ｉ）の化合物である。

and
During the ceremony,
R ^d is independently selected from the group consisting of H, Cl, _CH3 , OH and _OCH3 ;
R ^e is F, Cl, or _CH3 ;
A compound of formula (I), wherein n is 1 or 2.

A further embodiment of the present invention is wherein R ⁴ is

である、式（Ｉ）の化合物である。

is a compound of formula (I).

A further embodiment of the present invention is wherein R ⁴ is

である、式（Ｉ）の化合物である。

is a compound of formula (I).

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

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

A further embodiment of this invention is where Y is NH and R ⁴ is

である、式（Ｉ）の化合物である。

is a compound of formula (I).

A further embodiment of this invention is where Y is S and R ⁴ is

である、式（Ｉ）の化合物である。

is a compound of formula (I).

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

A further embodiment of the invention is a compound of formula (IA),

［式中、
ＹはＯ、ＮＨ又はＳであり、
Ｒ^１は、Ｃ_１～６アルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６アルキル；Ｃ_２～６アルケニル；Ｃ_１～６ハロアルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６ハロアルキル；Ｃ_３～６シクロアルキル；Ｃ_３～６ヘテロシクロアルキル；及びフェニルからなる群から選択され、
Ｒ^ｂは、ＯＨ、ハロ、ＣＮ、ＯＣ_１～６アルキル、ＯＣ_１～６ハロアルキル、及びＯＣ_３～６シクロアルキルからなる群から選択されるメンバーで置換されたＣ_１～６アルキルであり、
Ｒ^ｃは、Ｃ_１～６アルキル、Ｃ_１～６ハロアルキル、及びＣ_３～６シクロアルキルからなる群から選択され、
Ｒ^３は、Ｈ又はＦであり、
Ｒ^４は、
（ａ）Ｃ_１～６アルキル；ＯＨ及びＯＣＨ_３からなる群からそれぞれ独立して選択される１つ又は２つの置換基で置換されたＣ_１～６アルキル；テトラヒドロ－２Ｈ－ピラン－４－イル；ＯＣＨ_３で置換されたテトラヒドロ－２Ｈ－ピラン－４－イル；ＣＨ_３で置換されたシクロヘキシル；及びテトラヒドロ－２Ｈ－チオピラン１，１－ジオキシド；並びに、
（ｂ）

[In the 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;
^R4 is
(a) C _1-6 alkyl; C _1-6 alkyl substituted with one or two 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;
(b)

（式中、Ｒ^ｄは、Ｈ；ハロ；Ｃ_１～６アルキル；ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＣ_１～６アルキル；ＣＮ；ＯＨ；ＣＯ_２Ｈ；Ｎ（ＣＨ_３）_２；（Ｃ＝Ｏ）ＮＨ－ＣＨ_２ＣＨ_２ＯＨ；ＮＨＳＯ_２ＣＨ_３；ＯＣ_１～６アルキル；並びに、ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＯＣ_１～６アルキル、からなる群から独立して選択され、
Ｒ^ｅは、ハロ、Ｃ_１～６アルキル及びＯＣ_１～６アルキルからなる群から選択され、
ｎは、１又は２である）からなる群から選択される］を有する式（Ｉ）の化合物、並びにその医薬的に許容される塩、同位体、Ｎ－オキシド、溶媒和物、及び立体異性体を含む。

(wherein R ^d is 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 ( (C=O)NH—CH ₂ CH ₂ OH; _{NHSO 2 CH 3} ; OC _1-6 alkyl; and OC _1-6 substituted with a member selected from the group consisting of OH and OCH _{3 6} alkyl, independently selected from the group consisting of
R ^e is selected from the group consisting of halo, C _1-6 alkyl and OC _1-6 alkyl;
and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof. Including body.

A further embodiment of the invention is a compound of formula (IB)

［式中、
Ｘ^１は、ＣＨ又はＮであり、
Ｙは、Ｏ又はＮＨであり、
Ｒ^１は、Ｃ_１～６アルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６アルキル；Ｃ_２～６アルケニル；Ｃ_１～６ハロアルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６ハロアルキル；Ｃ_３～６シクロアルキル；Ｃ_３～６ヘテロシクロアルキル；及びフェニルからなる群から選択され、
Ｒ^２は、

[In the 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;
^R2 is

（式中、
Ｒ^ｂは、ＯＨ、ハロ、ＣＮ、ＯＣ_１～６アルキル、ＯＣ_１～６ハロアルキル、及びＯＣ_３～６シクロアルキルからなる群から選択されるメンバーで置換されたＣ_１～６アルキルであり、
Ｒ^ｃは、Ｃ_１～６アルキル、Ｃ_１～６ハロアルキル、及びＣ_３～６シクロアルキルからなる群から選択される）であり、
Ｒ^３は、Ｈ又はＦであり、
Ｒ^４は、

(In the formula,
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;
^R4 is

（式中、Ｒ^ｄは、Ｈ、Ｃｌ、及びＦからなる群から独立して選択され、
Ｒ^ｅは、Ｆ、ＣＨ_３、及びＯＣＨ_３からなる群から選択され、
ｎは、１又は２である）からなる群から選択される］を有する式（Ｉ）の化合物、並びにその医薬的に許容される塩、同位体、Ｎ－オキシド、溶媒和物、及び立体異性体を含む。

(wherein R ^d is independently selected from the group consisting of H, Cl, and F;
R ^e is selected from the group consisting of F, _CH3 , and _OCH3 ;
and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof. Including body.

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 formula (IB), wherein Y is N.

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

Embodiments of the present invention also include formula (II)

［式中、
Ｘ^３及びＸ^４は、それぞれ独立してＣＨ又はＮであり、Ｘ^３がＮである場合、Ｘ^４はＣＨであり、Ｘ^３がＣＨである場合、Ｘ^４はＮであり、
Ｚは、Ｏ、Ｓ、又はＮＨであり、
Ｒ^５は、Ｃ_１～６アルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６アルキル；Ｃ_１～６ハロアルキル；ＯＨ又はＯＣＨ_３で置換されたＣ_１～６ハロアルキル；及びＣ_３～６シクロアルキルからなる群から選択され、
Ｒ^６は、

[In the formula,
X ³ and X ⁴ are each independently CH or N, when X ³ is N, X ⁴ is CH, 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 ;} is selected from the group consisting of alkyl,
^R6 is

であり、
Ｒ^７は、Ｈ又はＦであり、
Ｒ^８は、

and
R ⁷ is H or F;
^R8 is

（式中、
Ｒ^ｆは、Ｈ；ハロ；Ｃ_１～６アルキル；ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＣ_１～６アルキル；ＣＮ；ＯＨ；ＣＯ_２Ｈ；Ｎ（ＣＨ_３）_２；（Ｃ＝Ｏ）ＮＨ－ＣＨ_２ＣＨ_２ＯＨ；ＮＨＳＯ_２ＣＨ_３；並びにＯＣ_１～６アルキルからなる群から独立して選択され、
Ｒ^ｇは、ハロ、Ｃ_１～６アルキル及びＯＣ_１～６アルキルからなる群から選択され、
また、
ｍは、１又は２である）である］の化合物、並びにそれらの医薬的に許容される塩、同位体、Ｎ－オキシド、溶媒和物、及び立体異性体を含む。

(In the formula,
R ^f is H; halo; C _1-6 alkyl _; C _1-6 alkyl substituted with _a member selected from the group consisting of OH and OCH _{3 ;} (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;
again,
m is 1 or 2), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

A further embodiment of the invention are compounds of formula (II), wherein ^X3 is N and ^X4 is CH.

A further embodiment of the invention are compounds of formula (II), wherein ^X3 is CH and ^X4 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 ^R7 is H.

A further embodiment of the present invention is wherein R ⁸ is

である、式（Ｉ）の化合物である。

is a compound of formula (I).

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

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

In general, even when the compounds of the present embodiments, including pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, can be administered alone, pharmaceutically acceptable carriers, pharmaceutically acceptable excipients and/or pharmaceutically acceptable excipients selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice Administered as a mixture with a diluent.

Thus, certain embodiments of the present invention provide a compound of formula (I) (and a compound of formula (II)) together with at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and Pharmaceutical and veterinary compositions, including/or a pharmaceutically acceptable diluent. By way of example, in the pharmaceutical compositions of embodiments of this invention, the compound of formula (I) (and the compound of formula (II)) may be combined with any suitable binder, lubricant, suspending agent, coating agent, It may be mixed with solubilizers and combinations thereof.

Embodiments of the present invention are compounds of formula (I) (and compounds of formula (II)), and pharmaceutically acceptable salts, isotopes, N-oxides, according to any of the embodiments described herein. , solvates, and stereoisomers thereof, and at least one pharmaceutically acceptable excipient.

A further embodiment of the invention comprises:
(A) Formula (I)

［式中、
Ｘ^１及びＸ^２は、それぞれ独立してＣＨ又はＮであり、
ＹはＯ、ＮＨ又はＳであり、
Ｒ^１は、Ｃ_１～６アルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６アルキル；Ｃ_２～６アルケニル；Ｃ_１～６ハロアルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６ハロアルキル；Ｃ_３～６シクロアルキル；Ｃ_３～６ヘテロシクロアルキル；及びフェニルからなる群から選択され、
Ｒ^２は、

[In the 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;
^R2 is

（式中、
Ｒ^ｂは、ＯＨ、ハロ、ＣＮ、ＯＣ_１～６アルキル、ＯＣ_１～６ハロアルキル、及びＯＣ_３～６シクロアルキルからなる群から選択されるメンバーで置換されたＣ_１～６アルキルであり、
Ｒ^ｃは、Ｃ_１～６アルキル、Ｃ_１～６ハロアルキル、及びＣ_３～６シクロアルキルからなる群から選択される）であり、
Ｒ^３はＨ、Ｃｌ又はＦであり、
Ｒ^４は、
（ａ）Ｃ_１～６アルキル；ＯＨ及びＯＣＨ_３からなる群からそれぞれ独立して選択される１つ又は２つの置換基で置換されたＣ_１～６アルキル；テトラヒドロ－２Ｈ－ピラン－４－イル；ＯＣＨ_３で置換されたテトラヒドロ－２Ｈ－ピラン－４－イル；ＣＨ_３で置換されたシクロヘキシル；及びテトラヒドロ－２Ｈ－チオピラン１，１－ジオキシド；並びに、
（ｂ）

(In the formula,
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;
^R4 is
(a) C _1-6 alkyl; C _1-6 alkyl substituted with one or two 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;
(b)

（式中、
Ｒ^ｄは、Ｈ；ハロ；Ｃ_１～６アルキル；ＯＨ、ＯＣＨ_３、ＳＣＨ_３、及びＯＣＦ_３からなる群から選択されるメンバーで置換されたＣ_１～６アルキル；Ｃ_１～６ハロアルキル；ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＣ_１～６ハロアルキル；ＣＮ；ＯＨ；ＣＯ_２Ｈ；Ｎ（ＣＨ_３）_２；（Ｃ＝Ｏ）ＮＨ－ＣＨ_２ＣＨ_２ＯＨ；ＮＨＳＯ_２ＣＨ_３；ＯＣ_１～６アルキル；並びに、ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＯＣ_１～６アルキル、からなる群から独立して選択され、
Ｒ^ｅは、ハロ；Ｃ_１～６アルキル；ＯＨ、ＯＣＨ_３、ＳＣＨ_３、及びＯＣＦ_３からなる群から選択されるメンバーで置換されたＣ_１～６アルキル；ＯＣ_１～６アルキル；Ｃ_１～６ハロアルキル；ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＣ_１～６ハロアルキル、からなる群から選択され、
ｎは１又は２である）からなる群から選択される］の化合物、
又は式（Ｉ）の化合物の医薬的に許容される塩、同位体、Ｎ－オキシド、溶媒和物、若しくは立体異性体から選択される少なくとも１つの有効量の化合物と、
（Ｂ）少なくとも１つの医薬的に許容される賦形剤とを含む、医薬組成物である。

(In the formula,
R ^d is 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 and OCH ₃ ; _CN ; OH; CO ₂ H; N(CH ₃ ) ₂ ; _{2 CH} ; 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 _{; 6} haloalkyl; C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;
n is 1 or 2);
or an effective amount of at least one compound selected from pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers of the compound of formula (I);
(B) at least one pharmaceutically acceptable excipient.

A further embodiment of the invention comprises:
(A) Formula (II)

［式中、
Ｘ^３及びＸ^４は、それぞれ独立してＣＨ又はＮであり、Ｘ^３がＮである場合、Ｘ^４はＣＨであり、Ｘ^３がＣＨである場合、Ｘ^４はＮであり、
Ｚは、Ｏ、Ｓ、又はＮＨであり、
Ｒ^５は、Ｃ_１～６アルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６アルキル；Ｃ_１～６ハロアルキル；ＯＨ又はＯＣＨ_３で置換されたＣ_１～６ハロアルキル；及びＣ_３～６シクロアルキルからなる群から選択され、
Ｒ^６は、

[In the formula,
X ³ and X ⁴ are each independently CH or N, when X ³ is N, X ⁴ is CH, 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 ;} is selected from the group consisting of alkyl,
^R6 is

であり、
Ｒ^７は、Ｈ又はＦであり、
Ｒ^８は、

and
R ⁷ is H or F;
^R8 is

（式中、
Ｒ^ｆは、Ｈ；ハロ；Ｃ_１～６アルキル；ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＣ_１～６アルキル；ＣＮ；ＯＨ；ＣＯ_２Ｈ；Ｎ（ＣＨ_３）_２；（Ｃ＝Ｏ）ＮＨ－ＣＨ_２ＣＨ_２ＯＨ；ＮＨＳＯ_２ＣＨ_３；並びにＯＣ_１～６アルキルからなる群から独立して選択され、
Ｒ^ｇは、ハロ、Ｃ_１～６アルキル及びＯＣ_１～６アルキルからなる群から選択され、
ｍは、１又は２である）である］の化合物、
又は式（ＩＩ）の化合物の医薬的に許容される塩、同位体、Ｎ－オキシド、溶媒和物、若しくは立体異性体から選択される少なくとも１つの有効量の化合物と、
（Ｂ）少なくとも１つの医薬的に許容される賦形剤とを含む、医薬組成物である。

(In the formula,
R ^f is H; halo; C _1-6 alkyl _; C _1-6 alkyl substituted with _a member selected from the group consisting of OH and OCH _{3 ;} (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)],
or an effective amount of at least one compound selected from pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers of the compound of formula (II);
(B) at least one pharmaceutically acceptable excipient.

A further embodiment of the present invention provides an effective amount of a compound shown in Table 1 (eg, a compound selected from Examples 1-78), or a pharmaceutically acceptable salt, isotope, N - an oxide, 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 at least one pharmaceutically acceptable and an excipient.

Solid oral dosage forms such as tablets or capsules containing one or more compounds of the invention may optionally be administered in at least 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 this invention can be administered include elixirs, solutions, syrups, and suspensions, each optionally containing flavorings and colorings.

Alternatively, one or more compounds of formula (I) (and compounds of formula (II)) may be administered by inhalation (intratracheally or intranasally) or in the form of suppositories or pessaries, or lotions. , in the form of a solution, cream, ointment, or dusting powder. For example, the compounds may be added to a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycols or liquid paraffin. The compound comprises, consists of, and/or consists essentially of a wax or soft paraffin base, optionally with stabilizers and preservatives, at a concentration of from about 1% to about 10% by weight of the cream. It can also be added to other ointments. Alternative means of administration include transdermal administration, through the use of skin or transdermal patches.

The pharmaceutical compositions of the invention (as well as the compounds of the invention alone) can be injected parenterally, eg, intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally, or intrathecally. In this case the composition also comprises at least one of a suitable carrier, a suitable excipient and a suitable diluent.

For parenteral administration, the pharmaceutical compositions of this invention are most often used in the form of sterile aqueous solutions which may contain other substances such as, for example, sufficient salts and simple sugars to make the solution isotonic with blood. .

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

As a further example, a pharmaceutical composition comprising at least one compound of formula (I) (and a compound of formula (II)) as an active ingredient can be prepared according to conventional pharmaceutical compounding techniques to ensure that the compounds are pharmaceutically acceptable. can be prepared by mixing with a carrier, pharmaceutically acceptable diluent and/or pharmaceutically acceptable excipient. Carriers, excipients and diluents can take a wide variety of forms depending on the desired route of administration (eg, oral, parenteral, etc.). Thus, for liquid oral formulations such as suspensions, syrups, elixirs, and solutions, suitable carriers, excipients, and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives. agents, stabilizers, colorants, and the like. For solid oral formulations such as powders, capsules and tablets, suitable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like. is mentioned. Solid oral dosage forms can optionally be coated with substances such as sugars or be enteric-coated so as to modulate major sites of absorption and disintegration. For parenteral administration, the carriers, excipients and diluents usually comprise sterile water and other ingredients may be added to enhance the solubility and storage stability of the composition. Injectable suspensions or solutions can also be prepared using aqueous carriers along with suitable additives such as solubilizers and preservatives.

According to certain embodiments, a therapeutically effective amount of a compound of formula (I) (and a compound of formula (II)) or pharmaceutical composition thereof is about 1 to about (4 times) regimen, from about 0.1 mg to about 3000 mg or any particular amount or range therein, specifically from about 1 mg to about 1000 mg or any particular amount or range therein; or More specifically, the treatment of compounds of formula (I) (and compounds of formula (II)) may comprise a dosage range of active ingredient from about 10 mg to about 500 mg, or any specific amount or range therein. It is clear to those skilled in the art that effective amounts will vary with the disease, syndrome, condition and disorder being treated.

For oral administration, the pharmaceutical composition contains about 1.0 mg, about 10 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 500 mg (milligrams) of the compound of formula (I). It may be provided in the form of one or more tablets.

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

Advantageously, compounds of formula (I) (and compounds of formula (II)) may be administered in a single daily dose, or the total daily dose is divided into two, three, or three times daily doses. , and (four) divided doses.

Optimal doses of compounds of formula (I) (and compounds of formula (II)) to be administered can be readily determined, depending on the particular compound employed, method of administration, strength of formulation, and disease, It will vary with the progression of the syndrome, condition or disorder. In addition, factors associated with the particular subject being treated, such as the subject's sex, age, weight, diet, and time of administration, will necessitate adjusting the dose to achieve the appropriate therapeutic level and desired therapeutic effect. occurs. The above dosages are therefore exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.

Compounds of formula (I) (and compounds of formula (II)) are used when the compounds of formula (I) (and compounds of formula (II)) are administered to a subject in need of treatment, Any of the compositions and dosage regimens described above or those compositions and dosage regimens established in the art can be administered.

According to certain embodiments, one or more compounds of formula (I) (and compounds of formula (II)) treat, ameliorate diseases, syndromes, conditions, or disorders affected by inhibition of DHODH enzymatic activity. , and/or in a method of prophylaxis.

A further embodiment of the present invention provides a compound of formula (I) in the treatment of disorders such as inflammatory disorders, autoimmune diseases or cancer, for example by inhibiting dihydroorotate oxygenase enzymatic activity;

［式中、
Ｘ^１及びＸ^２は、それぞれ独立してＣＨ又はＮであり、
ＹはＯ、ＮＨ又はＳであり、
Ｒ^１は、Ｃ_１～６アルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６アルキル；Ｃ_２～６アルケニル；Ｃ_１～６ハロアルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６ハロアルキル；Ｃ_３～６シクロアルキル；Ｃ_３～６ヘテロシクロアルキル；及びフェニルからなる群から選択され、
Ｒ^２は、

[In the 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;
^R2 is

（式中、
Ｒ^ｂは、ＯＨ、ハロ、ＣＮ、ＯＣ_１～６アルキル、ＯＣ_１～６ハロアルキル、及びＯＣ_３～６シクロアルキルからなる群から選択されるメンバーで置換されたＣ_１～６アルキルであり、
Ｒ^ｃは、Ｃ_１～６アルキル、Ｃ_１～６ハロアルキル、及びＣ_３～６シクロアルキルからなる群から選択される）であり、
Ｒ^３はＨ、Ｃｌ又はＦであり、
Ｒ^４は、
（ａ）Ｃ_１～６アルキル；ＯＨ及びＯＣＨ_３からなる群からそれぞれ独立して選択される１つ又は２つの置換基で置換されたＣ_１～６アルキル；テトラヒドロ－２Ｈ－ピラン－４－イル；ＯＣＨ_３で置換されたテトラヒドロ－２Ｈ－ピラン－４－イル；ＣＨ_３で置換されたシクロヘキシル；及びテトラヒドロ－２Ｈ－チオピラン１，１－ジオキシド；並びに、
（ｂ）

(In the formula,
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;
^R4 is
(a) C _1-6 alkyl; C _1-6 alkyl substituted with one or two 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;
(b)

（式中、
Ｒ^ｄは、Ｈ；ハロ；Ｃ_１～６アルキル；ＯＨ、ＯＣＨ_３、ＳＣＨ_３、及びＯＣＦ_３からなる群から選択されるメンバーで置換されたＣ_１～６アルキル；Ｃ_１～６ハロアルキル；ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＣ_１～６ハロアルキル；ＣＮ；ＯＨ；ＣＯ_２Ｈ；Ｎ（ＣＨ_３）_２；（Ｃ＝Ｏ）ＮＨ－ＣＨ_２ＣＨ_２ＯＨ；ＮＨＳＯ_２ＣＨ_３；ＯＣ_１～６アルキル；並びに、ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＯＣ_１～６アルキル、からなる群から独立して選択され、
Ｒ^ｅは、ハロ；Ｃ_１～６アルキル；ＯＨ、ＯＣＨ_３、ＳＣＨ_３、及びＯＣＦ_３からなる群から選択されるメンバーで置換されたＣ_１～６アルキル；ＯＣ_１～６アルキル；Ｃ_１～６ハロアルキル；ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＣ_１～６ハロアルキル、からなる群から選択され、
ｎは１又は２である）からなる群から選択される］の化合物、
又はその医薬的に許容される塩、同位体、Ｎ－オキシド、溶媒和物、若しくは立体異性体の使用に関する。

(In the formula,
R ^d is 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 and OCH ₃ ; _CN ; OH; CO ₂ H; N(CH ₃ ) ₂ ; _{2 CH} ; 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 _{; 6} haloalkyl; C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;
n is 1 or 2);
or the use of pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof.

A further embodiment of the present invention provides a compound of formula (II) in the treatment of disorders such as inflammatory disorders, autoimmune diseases or cancer, for example by inhibiting dihydroorotate oxygenase enzymatic activity;

［式中、
Ｘ^３及びＸ^４は、それぞれ独立してＣＨ又はＮであり、Ｘ^３がＮである場合、Ｘ^４はＣＨであり、Ｘ^３がＣＨである場合、Ｘ^４はＮであり、
Ｚは、Ｏ、Ｓ、又はＮＨであり、
Ｒ^５は、Ｃ_１～６アルキル；ＯＨ若しくはＯＣＨ_３で置換されたＣ_１～６アルキル；Ｃ_１～６ハロアルキル；ＯＨ又はＯＣＨ_３で置換されたＣ_１～６ハロアルキル；及びＣ_３～６シクロアルキルからなる群から選択され、
Ｒ^６は、

[In the formula,
X ³ and X ⁴ are each independently CH or N, when X ³ is N, X ⁴ is CH, 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 ;} is selected from the group consisting of alkyl,
^R6 is

であり、
Ｒ^７は、Ｈ又はＦであり、
Ｒ^８は、

and
R ⁷ is H or F;
^R8 is

（式中、
Ｒ^ｆは、Ｈ；ハロ；Ｃ_１～６アルキル；ＯＨ及びＯＣＨ_３からなる群から選択されるメンバーで置換されたＣ_１～６アルキル；ＣＮ；ＯＨ；ＣＯ_２Ｈ；Ｎ（ＣＨ_３）_２；（Ｃ＝Ｏ）ＮＨ－ＣＨ_２ＣＨ_２ＯＨ；ＮＨＳＯ_２ＣＨ_３；並びにＯＣ_１～６アルキルからなる群から独立して選択され、
Ｒ^ｇは、ハロ、Ｃ_１～６アルキル及びＯＣ_１～６アルキルからなる群から選択され、
ｍは、１又は２である）である］の化合物、
又はその医薬的に許容される塩、同位体、Ｎ－オキシド、溶媒和物、若しくは立体異性体の使用に関する。

(In the formula,
R ^f is H; halo; C _1-6 alkyl _; C _1-6 alkyl substituted with _a member selected from the group consisting of OH and OCH _{3 ;} (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)],
or the use of pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof.

In a further aspect, the invention provides a method of inhibiting or altering dihydroorotate dehydrogenase (DHODH) enzymatic activity, wherein DHODH is any compound of formula (I) (and compound of formula (II)) herein. Methods are provided comprising contacting the aspects or embodiments disclosed therein, thereby inhibiting or otherwise altering DHODH enzymatic activity.

A further embodiment of the invention is mediated by dihydroorotate dehydrogenase (DHODH) enzymatic 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 condition that is or is otherwise affected is provided.

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

In one embodiment, the term "therapeutically effective amount" (or "effective amount") is defined as (1) (i) mediated by or (ii) DHODH enzymatic activity when administered to a subject. (iii) at least partially alleviate, inhibit, prevent, and/or ameliorate a condition or disorder or disease characterized by activity (normal or abnormal) of the DHODH enzyme; or (2) DHODH It refers to the amount of a compound of the invention effective to reduce or inhibit the activity of an enzyme; or (3) reduce or inhibit the expression of DHODH; or (4) alter the protein level of DHODH. Without wishing to be bound by theory, DHODH inhibitors inhibit nucleic acid synthesis, arrest the cell cycle, or alter post-translational glycosylation of proteins involved in the control of myeloid differentiation in progenitor tumor cells. It is thought that it works by letting

A further embodiment of the present invention is suffering from or diagnosed with a disease, disorder or condition mediated or otherwise affected by DHODH enzymatic activity. wherein the subject in need of such treatment is treated with a compound of Formula (I) (and Formulas (IA), (IB), and (II), e.g. compounds of Table 1), Formula ( I) (and formulas (IA), (IB), and (II), e.g. compounds of Table 1), formula (I) (and formulas (IA), (IB), and ( II), e.g., compounds of Table 1), isotopic variants of the compounds, and pharmaceutically acceptable salts of all of the above, comprising administering an effective amount of at least one compound. . Stated another way, according to one embodiment, a method of treating a subject suffering from or diagnosed with a disease, disorder, or condition, such as cancer, comprises the formula ( at least one selected from the group consisting of compounds of I) (and compounds of formulas (IA), (IB) and (II), e.g., Table 1), and pharmaceutically acceptable salts of all of the above including administering to the subject an effective amount of the compound (eg, by inhibiting or otherwise altering dihydroorotate oxygenase enzymatic activity in the subject).

In another embodiment, the inhibitors of DHODH of the present invention are useful in autoimmune and inflammatory disorders such as arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease. , multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or graft rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis, including atopic dermatitis, skin Myositis, psoriasis, Behcet's disease, uveitis, myasthenia gravis, Graves' disease, Hashimoto thyroiditis, Sjögren's syndrome, blister formation disorder, antibody-mediated vasculitis syndrome, immune complex vasculitis, allergic disorders, asthma, bronchial pulmonary diseases including inflammation, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary edema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, It can be used to treat immune disorders including, but not limited to, acute respiratory distress syndrome, BENTA disease, beryllium disease, and polymyositis.

As used herein, unless otherwise noted, the term "affected" or "affected" (when referring to a disease, disorder, or condition affected by inhibition or alteration of DHODH enzymatic activity) includes including reducing the frequency and/or severity of one or more symptoms or signs of a disease, syndrome, condition or disorder and/or one or more symptoms or signs of the disease, syndrome, condition or disorder or preventing the development of any of the above diseases, conditions, syndromes, or disorders.

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

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

A further embodiment of the present invention provides compounds of formula (I) (and compounds of formula (II)), or pharmaceutically acceptable salts, isotopes thereof, for the treatment of one or more cancer types. , N-oxides, solvates, or stereoisomers.

According to certain embodiments, the uses and treatment methods described herein are directed to the treatment of cancer, wherein the cancer is selected from, but not limited to:
Acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), biphenotypic B myeloma mono Includes leukemia, chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS) which can progress to acute myelogenous leukemia Leukemia including but not limited to;
AIDS-related lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin's lymphoma (T-NHL), diffuse large cell lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double match NHL subtypes such as lymphoma and double expression lymphoma; anaplastic large cell lymphoma, peripheral B-cell lymphoma, and primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt's lymphoma, follicular lymphoma, Hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma, precursor B lymphoblastic lymphoma, central nervous system lymphoma, small lymphocytic lymphoma (SLL), and chronic lymphocytic leukemia (CLL) ); precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy Lymphomas including, but not limited to, T-cell NHL such as T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma;
sarcoma including, but not limited to, sarcoma of soft tissue, neurosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma;
again,
Breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head and neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, and sarcoma, but Other cancers, including but not limited to solid tumors.

In one embodiment, cancers that may benefit from treatment with an inhibitor of DHODH of the present invention include lymphomas, leukemias, carcinomas, and sarcomas, including non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL). , mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, brain (glioma), glioblastoma, breast cancer, colorectal / Colon cancer, prostate cancer, lung cancer including non-small cell lung cancer, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, renal cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, These include, but are not limited to, oral cancer, mouth cancer, and GIST (gastrointestinal stromal tumor).

In another embodiment of the invention, the compounds of the invention are used in combination with one or more other pharmaceutical agents, more particularly one or more anticancer agents, such as chemotherapeutic agents, antiproliferative agents, or immunological agents. It may be used in combination with modulatory agents, or in combination with adjuvant agents in cancer therapy, such as immunosuppressants or anti-inflammatory agents. Further non-limiting examples of anti-cancer agents that may be administered in combination with the compounds of the present invention include biological compounds such as monoclonal antibodies (e.g., antibodies that mediate effector functions upon binding to cancer cell-associated antigens or cancer cells). blocking the interaction of expressed receptors with soluble or cell-bound ligands), bispecific antibodies that mediate immune cell redirection, and the like. According to an embodiment, a method of treating cancer comprises administering an effective amount of a compound of the invention (e.g., a compound of formula (I) (and a compound of formula (II)), such as those shown in Table 1, pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers) and an effective amount of one or more additional anticancer agents, the method comprising: Administration of the compound of the invention and the additional anti-cancer agent simultaneously (eg, as part of the same pharmaceutical composition) or sequentially. According to embodiments, the pharmaceutical composition comprises an effective amount of a compound of the invention (e.g., a compound of formula (I) (and a compound of formula (II)) such as those shown in Table 1, a pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof), an effective amount of one or more additional anticancer agents, and optionally one or more excipients. .

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

General Synthetic Methods Exemplary compounds useful in the methods of the present invention are now described by reference to the following illustrative synthetic schemes for their general preparation and the specific examples that follow. To obtain the various compounds herein, ultimately desired substituents are retained throughout the reaction schemes, with or without protection as appropriate, to afford the desired products. can be suitably selected as will be understood by those skilled in the art. Alternatively, it may be necessary or desirable to use a suitable group that is retained throughout the reaction scheme and optionally substituted with the desired substituent in place of the ultimate desired substituent. Unless otherwise indicated, each variable is as defined above for formula (I) (and compounds of formula (II)). The reaction can be carried out between the melting point and the reflux temperature of the solvent, preferably between 0° C. and the reflux temperature of the solvent. The reaction may be carried out under heat using conventional heating or microwave heating. The reaction may also be carried out in a closed pressure vessel at a temperature above the normal reflux temperature of the solvent. Abbreviations used herein, particularly in the schemes and examples, are as follows.

PREPARATIVE EXAMPLES Exemplary compounds useful in the methods of the present invention are now illustrated by reference to the following illustrative synthetic schemes for their general preparation and the following specific examples.

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

T. W. Greene andP. G. M. Wuts, "Protective Groups in Organic Synthesis," 3 ed. , John Wiley & Sons, 1999, to convert a compound of formula (V) (where PG is Bn) in two steps. Protecting group exchange to the compound (where PG is TBDPS) is accomplished. In the first step, deprotection of the benzyl group is accomplished under hydrogenolysis conditions well known to those skilled in the art to provide the alcohol. For example, using a palladium catalyst such as Pd/C, under H ₂ in a suitable solvent such as EtOH, MeOH, EtOAc, or mixtures thereof, preferably EtOH, in the presence or absence of HCl, 4 Deprotection is accomplished over ~72 hours. In a second step, using a suitable base such as tert-butyldimethylsilyl chloride, imidazole, dimethylaminopyridine, pyridine, etc., in a solvent such as DMF, DCM, at a temperature ranging from 0° C. to room temperature, the corresponding Protection of the alcohol as a silyl ether affords compounds of formula (V) where PG is TBDPS.

According to Scheme 2, commercially available or synthetically obtainable 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one is treated with sodium azide, methylsulfonic acid (MSA), etc. in the presence of a suitable acid of 6-bromo-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one in a suitable solvent such as THF at a temperature range of 0°C to 50°C. get 6-bromo-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one is commercially available or synthetically obtainable according to the formula R ¹ OH, where R ¹ is C _1-6 alkyl; or C _1-6 alkyl substituted with OCH ₃ ; C _2-6 alkenyl; C _1-6 haloalkyl; OH _or C _1-6 haloalkyl substituted with OCH _{3 ;} heterocycloalkyl; and is phenyl] in the presence of a suitable base such as NaH in an aprotic solvent such as DMF at a temperature range of 0° C. to 100° C., preferably 30° C.; A compound of formula (VI) is obtained.

A compound of formula (VI) is oxidized with a suitable oxidizing agent such as MnO ₂ , DDQ, etc. in a suitable solvent such as dioxane, toluene at a temperature in the range of 60° C. to 120° C., preferably 100° C. to give the compound of formula ( VII) compound is obtained. Compounds of formula (VII) are commercially available or synthetically obtainable according to formula (VIII) [wherein R ^b is C _1-6 alkyl substituted with O-PG, PG is Bn, allyl, p - is a suitable alcohol protecting group such as methoxy Bn (PMB), TBDMS, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM)] and Ullmann N - picolinic acid, trans-N, using a suitable catalyst such as CuI, Cu(acac) ₂ , CuO and a suitable base such as K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuOK under arylation conditions; coupling with or without a suitable ligand such as N-dimethylcyclohexane-1,2-diamine, dimethylglycine, etc. in a suitable solvent such as dioxane, DMF, DMSO at a temperature range of 80° C. to about 120° C., A compound of formula (IX) is obtained. A compound of formula (IX) is reacted with a chlorinating agent such as POCl ₃ , SOCl ₂ at a temperature ranging from 60° C. to about 100° C. to give a compound of formula (X).

According to Scheme 3, commercially available or synthetically obtainable 2,6-dichloro-4-methylnicotinonitrile is prepared according to the formula (VIII) [wherein R ^b is O-PG substituted C _{1- 6} alkyl and PG is a suitable alcohol protecting group] and a suitable base such as NaH, Cs ₂ CO ₃ in an aprotic solvent such as DMF, DMSO from 60° C. to about 120° C. C., preferably 80.degree. C., to give compounds of formula (XI). Compounds of formula (XI) are treated with alcohols of formula R ¹ OH, which may be commercially available or synthetically obtainable, using the conditions previously described to provide compounds of formula (XII).

Compounds of formula (XIII) are prepared in two steps from compounds of formula (XII). In the first step a compound of formula (XII) is treated with a suitable oxidizing agent such _{as H2O2} , _NaClO with a suitable base such as _K2CO3 , _{Cs2CO3 ,} DMSO, dioxane, It is hydrolyzed in a solvent such as THF at a temperature range of 0-60°C. Subsequent coupling with commercially available 1,1-dimethoxy-N,N-dimethylmethanamine at a temperature range of 80° C. to about 120° C. provides compounds of formula (XIII).

Compounds of formula (XIII) are treated with a suitable base such as NaH, t-BuOK, LiHMDS in an aprotic solvent such as THF, dioxane at temperatures ranging from 0° C. to about 80° C. to give formula (XIV). to obtain a compound of A compound of formula (XIV) is reacted with a chlorinating agent such as POCl ₃ , SOCl ₂ at a temperature ranging from 60° C. to about 100° C. to give a compound of formula (XV).

According to Scheme 4, 5,7-dichloropyrido[3,4-d]pyridazin-4(3H)-one (a commercially available compound (or Vasudevan, A. et al, Bicyclic heterocycles as ALK inhibitors and their preparation and use for )) is combined with a commercially available or synthetically obtainable alcohol of formula R ¹ OH according to the methods described above. Coupling provides compounds of formula (XVI). Compounds of formula (XVI) are reacted with compounds of formula (VIII), which are commercially available or synthetically obtainable, using methods previously described to give compounds of formula (XVII). Compounds of formula (XVII) are reacted with a chlorinating agent using methods previously described to provide compounds of formula (XVIII).

According to Scheme 4, 5,7-dichloro-1,6-naphthyridin-4(1H)-one (a commercially available compound (or Long, Y. et al, Pyrido-azaheterocyclic compound and preparation method and use thereof, US Patent Application Publication No. 2018/0244667 (A1))) is coupled with a commercially available or synthetically obtainable alcohol of formula R ¹ OH according to the methods previously described to give compounds of formula (XIX). get Compounds of formula (XIX) can be prepared from commercially available or synthetically obtainable compounds of formula (VIII) with a catalyst such as CuI, Cu(acac) ₂ , CuO, K ₃ PO ₄ under Ullmann N-arylation conditions. , Cs ₂ CO ₃ , t-BuOK, with or without a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane-1,2-diamine, dimethylglycine. , DMF, DMSO, etc. to give compounds of formula (XX). Compounds of formula (XX) are reacted with a chlorinating agent using methods previously described to provide compounds of formula (XXI).

According to Scheme 6, compounds of formula (VII) are reacted with a chlorinating agent using the conditions previously described to provide compounds of formula (XXII). Compounds of formula (XXII) are commercially available or synthetically obtainable according to the 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 ] and a suitable base such as KOH, Cs ₂ CO ₃ , t-BuOK under nucleophilic substitution conditions in a suitable solvent such as NMP, DMF, DMSO. or react without solvent to give compounds of formula (XXIII). A compound of formula (XXIII) is treated with diphenylmethanimine under Buchwald-Hartwig amination conditions with a suitable catalyst such as Pd( _Ph3P ) ₄ , _Pd2 (dba) ₃ , _PdCl2 ( _Ph3P ) ₂ . Xantphos ( _4,5 -bis( _{diphenylphosphino} )-9,9 _- dimethylxanthene), _CPhos (2 -dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)biphenyl), with a suitable ligand such as BINAP, in a suitable solvent such as dioxane, DMF, DMSO, etc., from 60° C. to about 120° C. C. to obtain a compound of formula (XXIV). A compound of formula (XXIV) is deprotected with an acidic agent such as TFA, HCl, H ₂ SO ₄ in a suitable solvent such as dioxane, THF, DCM at a temperature range of 0° C. to about 80° C. to give a compound of formula A compound of (XXV) is obtained.

A compound of formula (XXV) is treated with phenylcarbonochloridate and a suitable base such as TEA, DIPEA, pyridine, etc. in a suitable solvent such as dioxane, THF, DCM at a temperature ranging from 0°C to about 60°C. to obtain a compound of formula (XXVI).

According to Scheme 7, commercially available 2-amino-4-bromo-6-fluorobenzonitrile is synthesized under a base such as K ₂ CO ₃ in a protic solvent such as water at temperatures ranging from 80° C. to about 160° C. , hydrolysis using conventional heating or microwave irradiation to give 2-amino-4-bromo-6-fluorobenzamide. 2-Amino-4-bromo-6-fluorobenzamide is treated with a formylating agent such as DMF in the presence of an acid such as pTSA, MSA at a temperature ranging from 60° C. to about 140° C. to form 7-bromo- 5-Fluoroquinazolin-4(3H)-one is obtained. 7-Bromo-5-fluoroquinazolin-4(3H)-one is coupled with a commercially available or synthetically obtainable alcohol of formula R ¹ OH using the conditions previously described to give compounds of formula (XXVII) get Compounds of formula (XXVII) are synthesized with compounds of formula (VIII), which are commercially available or synthetically obtainable, under Ullmann N-arylation conditions under suitable catalysts such as CuI, Cu(acac) ₂ , CuO. , K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuOK, etc., with a suitable base such as picolinic acid, trans-N,N-dimethylcyclohexane-1,2-diamine, dimethylglycine. With or without reaction in a suitable solvent such as dioxane, DMF, DMSO to give compounds of formula (XXVIII). Compounds of formula (XXVIII) are reacted with chlorinating agents such as POCl ₃ , SOCl ₂ using the conditions previously described to give compounds of formula (XXIX).

According to Scheme 8, commercially available methyl 4-bromo-2-fluorobenzoate is coupled with a commercially available or synthetically obtainable alcohol of formula R ¹ OH using the conditions previously described to give formula (XXX) to obtain a compound of Compounds of formula (XXX) are hydrolyzed in the presence of a suitable base such as NaOH, LiOH and the like in a suitable solvent such as THF, MeOH, water at a temperature ranging from 20° C. to about 80° C. to give compounds of formula (XXXI ) is obtained. A compound of formula (XXXI) can be treated with _a suitable base such _{as K3PO4} , _Cs2CO3 , _K2CO3 using a suitable catalyst such as Pd ₍ OAc) ₂ , _Pd2 (dba) ₃ . cyclization with a suitable electrophile such as 1,2- using conventional heating or under microwave irradiation at temperatures ranging from 100° C. to about 160° C. to give formula (XXXII) to obtain a compound of A compound of formula (XXXII) is treated with a bromine source such as NBS, _Br2 and a suitable radical initiator such as BPO, AIBN in a suitable solvent such as DCE, _CCl4 at a temperature between 70°C and about 120°C. Halogenation reaction at a range of temperatures gives compounds of formula (XXXIII). Compounds of formula (XXXIII) are reacted with hydrazine in a suitable solvent such as EtOH, dioxane, etc. at a temperature of 80° C. to about 120° C. to give compounds of formula (XXXIV). Compounds of formula (XXXIV) are reacted with a chlorinating agent according to the methods previously described to provide compounds of formula (XXXV).

According to Scheme 9, commercially available 2,6-dichloro-5-fluoronicotinic acid is treated with a suitable base such as LDA, LiHMDS, etc. in a solvent such as THF, ether, etc. from −78° C. to about 0° C., for example about − Treatment at temperatures in the range of 40° C. followed by reaction with a formyl source such as DMF yields 4,6-dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridine-3(1H)- get on. 4,6-dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridin-3(1H)-one with hydrazine in a suitable solvent such as THF, MeOH, EtOH at 20° C. to about The reaction is carried out in the temperature range of 80° C. to obtain 5,7-dichloro-8-fluoropyrido[3,4-d]pyridazin-4(3H)-one. 5,7-Dichloro-8-fluoropyrido[3,4-d]pyridazin-4(3H)-one is coupled with a commercially available or synthetically obtainable alcohol of formula R ¹ OH according to the previously described methods. , to obtain a compound of formula (XXXVI). Compounds of formula (XXXVI) are reacted with compounds of formula (VIII), which are commercially available or synthetically obtainable, according to the methods previously described under Ullmann N-arylation conditions to give compounds of formula (XXXVII). Compounds of formula (XXXVII) are reacted with chlorinating agents such as POCl ₃ , SOCl ₂ using methods previously described to provide compounds of formula (XXXVIII).

According to Scheme 10, commercially available 2,6-dichloro-5-fluoronicotinic acid is treated with a suitable base such as LDA, LiHMDS, etc. in a solvent such as THF, ether, etc. from −78° C. to about 0° C., for example about − Treatment at 40° C. followed by reaction with a bromine source such as NBS, 1,2-dibromo-1,1,2,2-tetrachloroethane to give 4-bromo-2,6-dichloro-5-fluoronicotine get acid. 4-bromo-2,6-dichloro-5-fluoronicotinic acid is reacted with a chloro source such as oxalyl chloride, thionyl chloride, etc. in a suitable solvent such as DCM, THF, ether at a temperature from 0°C to about 80°C. followed by reaction with t-butylamine and a suitable base such as TEA, DIPEA to give 4-bromo-N-(tert-butyl)-2,6-dichloro-5-fluoronicotinamide. 4-bromo-N-(tert-butyl)-2,6-dichloro-5-fluoronicotinamide, commercially available or synthetically obtainable (E)-2-(2-ethoxyvinyl)-4,4 ,5,5-tetramethyl-1,3,2-dioxaborolane with K ₃ PO ₄ , Cs ₂ CO under suitable catalysts such as Pd(OAc) ₂ , Pd ₂ (dba) ₃ under Suzuki coupling conditions. ₃ , under a suitable base such as t-BuOK, with or without a suitable ligand such as triphenylphosphine, tricyclohexylphosphine, etc., in a suitable solvent such as dioxane, DMF, DMSO at a temperature of 80° C. to about 120° C. to give (E)-N-(tert-butyl)-2,6-dichloro-4-(2-ethoxyvinyl)-5-fluoronicotinamide. (E)-N-(tert-butyl)-2,6-dichloro-4-(2-ethoxyvinyl)-5-fluoronicotinamide with a suitable acid such as TFA, formic acid, DCM, THF, ether, etc. in a suitable solvent at a temperature range of 20° C. to about 80° C. to give 6,8-dichloro-5-fluoro-2,7-naphthyridin-1(2H)-one. 6,8-dichloro-5-fluoro-2,7-naphthyridin-1(2H)-one is coupled with a commercially available or synthetically obtainable alcohol of formula R ¹ OH 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 obtainable compound of formula (VIII) under Ullmann N-arylation conditions using the conditions previously described to give a compound of formula (XL). . A compound of formula (XXXXVIII) is reacted with a chlorinating agent such as POCl ₃ , SOCl ₂ using the conditions previously described to give a compound of formula (XLI).

According to Scheme 11, compounds of formula (XLII), including compounds of formulas (X), (XV), (XVII), (XXXVIII), and (XLI), are commercially available or synthetically obtainable according to formula R ⁴ -Y ¹ [wherein R ⁴ is C _1-6 alkyl optionally substituted with 1 or 2 substituents each independently selected from the group consisting of OH and OCH ₃ , C _1-3 C _3-6 cycloalkyl substituted with alkyl, appropriately substituted aryl, 5- or 6-membered heteroaryl ring, or optionally substituted 6-membered heterocycloalkyl, and Y ¹ is OH, SH , or NH ₂ ] and a suitable base such as NaH, KOH, Cs ₂ CO ₃ , t-BuOK, DBU under nucleophilic substitution conditions with a suitable The reaction is carried out in a solvent or without solvent at a temperature range of 0° C. to 150° C. using conventional heating or microwave heating.

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

When a compound of formula R ⁴ -Y ¹ , which is 3,5-difluoro-4-hydroxybenzonitrile, is coupled with a compound of formula (X) using the methods previously described, the nitrile functionality is converted to CO ₂ H, Hydrolyze using aqueous NaOH in a suitable solvent such as MeOH/THF at a temperature of about 80°C. Additionally, the CO ₂ H functionality can be further coupled with amines such as 2-aminoethan-1-ol under conventional amide bond forming techniques known to those skilled in the art. For example, an acid may be added to a suitable activating reagent, for example a carbodiimide such as N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI). (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphite, optionally in the presence of a catalyst such as hydroxybenzotriazole (HOBt) and/or dimethylaminopyridine (DMAP). halotrisaminophosphonium salts, such as phate ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, BOP), or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP®), 2-chloro-1 - a suitable pyridinium salt such as methylpyridinium chloride or N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (N,N, N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, HBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b] pyridinium 3-oxide hexafluorophosphate (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, HATU), 2, The presence of other suitable coupling agents such as 4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P®) activated below. The coupling reaction is carried out in a suitable solvent such as DCM, THF, DMF, optionally in the presence of a tertiary amine such as N-methylmorpholine, N-ethyldiisopropylamine (DIEA, DIPEA), or triethylamine (TEA). , at temperatures ranging from about 0° C. to rt.

When a compound of formula R ⁴ -Y ¹ that is 2,5-dichloropyridin-4-ol is coupled with a compound of formula (X) using the methods previously described, the arylchloro group is replaced by 2,4,6 a methylating agent such as -trimethyl-1,3,5,2,4,6-trioxatriborinane, and (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino -1,1′-biphenyl)]palladium(II) methanesulfonate (SPhos Pd G3), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), etc. ₂ CO ₃ , K ₂ CO ₃ , K ₃ PO ₄ , an inorganic base such as DMF, dioxane and the like in a suitable solvent at a temperature of about 20-100°C.

A compound of formula R ⁴ -Y ¹ , which is 5-chloro-2-methoxypyridin-4-ol, is coupled with a compound of formula (X), wherein R ³ is H, using the method previously described. For ringing, a chlorinating agent such as N-chloro-succinimide (NCS), Palau'Chlor® (2-chloro-1,3-bis(methoxycarbonyl)guanidine) is combined with a suitable Further chlorination is achieved by reaction in a solvent at a temperature of about 20-60° C. to give compounds in which R ³ is Cl.

A compound of formula R ⁴ -Y ¹ , which is 5-chloro-2-methoxypyridin-4-ol, is coupled with a compound of formula (X), wherein R ³ is H, using the method previously described. When ringing, the demethylation of 5-chloro-2-methoxypyridine is carried out by trimethylsilyl iodide (TMSI) (trimethylsilyl chloride (TMSCl) and sodium iodide in a suitable solvent such as ACN, THF, etc., about 10-50 (Prepared by mixing at a temperature of ° C.).

When coupling a compound of formula R ⁴ -Y ¹ which is 2-chloro-6-fluoro-3-(2-methoxyethoxy)phenol with a compound of formula, boron tribromide (BBr ₃ ) is used to Accomplished in a suitable solvent such as DCM, THF, etc. at a temperature of about 0-35°C.

When the compound of formula R ⁴ -Y ¹ , which is methyl 2-chloro-4-fluoro-3-hydroxybenzoate, is coupled with a compound of formula (X) using the methods previously described, the carboxylate functionality is replaced by CO ₂ H is hydrolyzed with aqueous LiOH in a suitable solvent such as MeOH/THF at a temperature of about 50-80°C. Furthermore, the CO ₂ H functional group is treated with NH ₂ group 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. and then , HCl/dioxane solution at a temperature of 20-30° C. for further conversion by hydrolysis. Amino groups are alkylated to give dimethylamino groups (NMe ₂ ) using formaldehyde, an acid such as acetic acid, a reducing agent such as NaBH ₃ CN, in a suitable solvent such as MeOH or THF at about 0-50°C. Alternatively, the amino group is reacted with methanesulfonyl chloride to give a compound _in which the amine is replaced with _SO2CH3 .

Alternatively, compounds of formula (XLII) are commercially available or synthetically obtainable of formula R ⁴ -Y ¹ , wherein R ⁴ is a suitably substituted aryl or 5- or 6-membered heteroaryl ring; , Y ¹ is OH, SH or NH ₂ ] with a catalyst such as CuI, Cu(acac) ₂ , CuO, K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuOK, etc. under Ullmann arylation conditions. with or without a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane-1,2-diamine, dimethylglycine, etc., in a suitable solvent such as dioxane, DMF, DMSO, etc. , 80°C to about 120°C.

Deprotection of PG is performed according to procedures known to those skilled in the art, according to T.W. W. Greene andP. G. M. Wuts, "Protective Groups in Organic Synthesis", 3 ed. , John Wiley & Sons, 1999. For example, when PG is benzyl, using Pd/C under _H2 in a suitable solvent such as EtOH, MeOH, EtOAc, or mixtures thereof, preferably EtOH, in the presence or absence of HCl. with preferably 0.75 equivalents for 4-72 hours to give compounds of formula (I). Further, when PG is benzyl, deprotection can be carried out using trifluoroacetic acid as solvent or by treatment with BCl ₃ in a suitable solvent such as DCM, toluene at low temperature ranging from −78° C. to rt to about It can be done over 1 to 4 hours. Further, when PG is TBDPS, it is deprotected using conditions known to those skilled in the art, preferably with TBAF in a suitable solvent such as THF, to give compounds of formula (I).

According to Scheme 12, formula (XLIII) [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 is commercially available or synthetically obtainable, including compounds of formulas (XXI) and (XXIX), of formula R ⁸ -Z, wherein R ⁸ is an appropriately substituted aryl or 5 is a 6-membered or 6-membered heteroaryl ring and Z is OH, SH or _NH2 ] with _a suitable base such as KOH, _Cs2CO3 , t-BuOK under nucleophilic substitution conditions, React in a suitable solvent such as NMP, DMF, DMSO or without solvent.

Alternatively, compounds of formula (XLIII) are commercially available or synthetically obtainable of formula R ⁸ -Z, wherein R ⁸ is a suitably substituted aryl or 5- or 6-membered heteroaryl ring; Z is OH, SH, or NH ₂ ] with catalysts such as CuI, Cu(acac) ₂ , CuO, K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuOK, etc. under Ullmann arylation conditions. using a suitable base, with or without a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane-1,2-diamine, dimethylglycine, in a suitable solvent such as dioxane, DMF, DMSO; The reaction is carried out at a temperature range of 80°C to about 120°C.

Deprotection of PG is performed according to procedures known to those skilled in the art, according to T.W. W. Greene andP. G. M. Wuts, "Protective Groups in Organic Synthesis", 3 ed. , John Wiley & Sons, 1999. For example, when PG is benzyl, using Pd/C under _H2 in a suitable solvent such as EtOH, MeOH, EtOAc, or mixtures thereof, preferably EtOH, in the presence or absence of HCl. with preferably 0.75 equivalents for 4-72 hours to give compounds of formula (II). Additionally, when PG is benzyl, deprotection can be used using trifluoroacetic acid as solvent. Further, when PG is TBDPS, it is deprotected using conditions known to those skilled in the art, preferably with TBAF, in a suitable solvent such as THF to give compounds of formula (II).

According to Scheme 13, compounds of formula (XXVI), where R ¹ is C _1-6 alkyl or C _1-6 haloalkyl and Y is O, are combined with one or two C _1-6 Commercially available or synthetically obtainable primary or secondary amines substituted with alkyl or C _1-6 haloalkyl members are reacted, for example, under nucleophilic substitution conditions. For example, N-methylethanamine is reacted with a compound of formula (XXVI) with a suitable base such as TEA or DIPEA in a suitable solvent such as DCM, THF at a temperature of 0-30° to give a compound of formula (I) [wherein R ² is

であり、Ｒ^３はＨである］の化合物を得る。

and R ³ is H].

According to Scheme 14, compounds of formula (XXXV) are commercially available or synthetically obtainable of formula R ⁴ —Y ¹ , wherein R ⁴ is each independently selected from the group consisting of OH and OCH ₃ C _1-6 alkyl optionally substituted with 1 or 2 substituents; C _3-6 cycloalkyl substituted with C _1-3 alkyl; optionally substituted aryl; heteroaryl ring; or optionally substituted 6-membered heterocycloalkyl, Y ¹ is OH, SH, or NH ₂ ] and NaH, KOH, Cs ₂ CO ₃ , t-BuOK, DBU, etc. Conventional or microwave heating in a temperature range from 0° C. to 150° C. in a suitable solvent such as NMP, DMF, DMSO, dioxane or without a solvent under nucleophilic substitution conditions using a suitable base of react with Compounds of formula (XLIV) can be obtained commercially or synthetically from formula (VIII) [wherein Rb is C _1-6 alkyl substituted with O-PG and PG is a suitable is an alcohol protecting group] with a suitable catalyst such as CuI, Cu(acac) ₂ , CuO, a suitable catalyst such as K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuOK under Ullmann N-arylation conditions. using a base, with or without a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane-1,2-diamine, dimethylglycine, etc., in a suitable solvent such as dioxane, DMF, DMSO at 80°C. Coupling at a temperature range of to about 120° C. provides compounds of formula (XLV).

Deprotection of PG is performed according to procedures known to those skilled in the art, according to T.W. W. Greene andP. G. M. Wuts, "Protective Groups in Organic Synthesis", 3 ed. , John Wiley & Sons, 1999. For example, when PG is benzyl, using Pd/C under _H2 in a suitable solvent such as EtOH, MeOH, EtOAc, or mixtures thereof, preferably EtOH, in the presence or absence of HCl. with preferably 0.75 equivalents for 4-72 hours to give compounds of formula (II). Additionally, when PG is benzyl, deprotection can be used using trifluoroacetic acid as solvent. Further, when PG is TBDPS, it is deprotected using conditions known to those skilled in the art, preferably with TBAF, in a suitable solvent such as THF to give compounds 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, amines of formula (I) are treated with trifluoroacetic acid, HCl, or citric acid in solvents such as Et ₂ O, CH ₂ Cl ₂ , THF, MeOH, chloroform, or isopropanol to give the corresponding salt forms. get Alternatively, reverse-phase HPLC purification conditions result in trifluoroacetate or formate salts. The crystalline form of the pharmaceutically acceptable salt of the compound of formula (I) can be obtained from polar solvents (including mixtures of polar solvents and aqueous mixtures of polar solvents) or non-polar solvents (including mixtures of non-polar solvents). It can be obtained in crystalline form by recrystallization.

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

Compounds prepared according to the above schemes may be obtained as a single form, such as a single enantiomer, by form-specific synthesis or by resolution. Alternatively, the compounds prepared according to the above schemes can be obtained as mixtures of various forms, such as racemic (1:1) mixtures or non-racemic (not 1:1) mixtures. Where racemic and non-racemic mixtures of enantiomers are obtained, conventional isolation methods known to those skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization to diastereomeric adducts , biotransformation, or enzymatic transformation can be used to isolate single enantiomers. Where regioisomeric or diastereomeric mixtures are obtained, single isomers may be separated using conventional methods such as chromatography or crystallization, if appropriate.

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

In obtaining the compounds and corresponding analytical data described in the examples below, the following experimental and analytical protocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Where solutions were "dried", they were typically dried with _a drying agent such as _Na2SO4 or _MgSO4 . When "concentrating" mixtures, solutions, and extracts, they were typically concentrated on a rotary evaporator under reduced pressure.

Normal-phase silica gel chromatography (FCC) was performed on silica gel ( _SiO2 ) using prepacked cartridges.

Preparative reverse-phase high performance liquid chromatography (RP HPLC) was performed by either of the following methods.
Method A. 25 mL/min with PhenomeneX Synergi C18 (10 μm, 150×25 mm) or Boston Green ODS C18 (5 μm, 150×30 mm) and mobile phase of 5-99% ACN in water (with 0.225% FA) Gilson GX-281 semi-preparative HPLC with a flow rate of 10 minutes for 10 minutes and then a 2 minute hold at 100% ACN.
or Method B. Gilson GX-281 semi-preparative HPLC (PhenomeneX Synergi C18 (10 μm, 150×25 mm) or Boston Green ODS C18 (5 μm, 150×30 mm) and mobile phase of 5-99% ACN in water (0.1% TFA) is held for 10 minutes, then held at 100% ACN for 2 minutes at a flow rate of 25 mL/min.
or Method C. Gilson GX-281 semi-preparative HPLC (PhenomeneX Synergi C18 (10 μm, 150×25 mm), or Boston Green ODS C18 (5 μm, 150×30 mm), and a mobile phase of 5-99% ACN in water (0.05% HCl) is held for 10 minutes, then held at 100% ACN for 2 minutes at a flow rate of 25 mL/min.
or Method D. Phenomenex Gemini C18 (10 μm, 150×25 mm), AD (10 μm, 250 mm×30 mm), or Waters XBridge C18 column (5 μm, 150×30 mm), 0 in water (containing 0.05% ammonium hydroxide v/v) Gilson GX-281 semi-preparative HPLC with a mobile phase of ˜99% ACN at a flow rate of 25 mL/min for 10 min followed by a 2 min hold at 100% ACN.
or Method E. Gilson GX-281 semi-preparative HPLC equipped with PhenomeneX Gemini C18 (10 μm, 150×25 mm) or Waters XBridge C18 column (5 μm, 150×30 mm), 5-99% ACN transfer in water over 10 min at 25 mL/min flow rate phase (10 mM NH ₄ HCO ₃ ), then hold at 100% ACN for 2 minutes.

Preparative supercritical fluid high performance liquid chromatography (SFC) was performed on either a Thar 80 Prep-SFC system or a Waters 80Q Prep-SFC system from Waters. The ABPR is set to 100 bar to maintain CO2 in SF conditions and the flow rate can be verified according to compound properties with flow rates ranging from 50 g/min to 70 g/min. Column temperature was ambient temperature.

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

Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker AVIII 400 spectrometer. The definition of multiplicity is as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. For compounds containing exchangeable protons, the protons may or may not be visible in the NMR spectrum, depending on the choice of solvent used to conduct the NMR spectrum and the concentration of the compound in solution. It will be understood.

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

Compounds designated R ^* or S ^* are enantiomerically pure compounds whose absolute configuration has not been determined.

Intermediate 1: 4-chloro-2-methylpyridin-3-ol.

BBr ₃ (1.43 g, 5.71 mmol, 550.26 μL) was added to a solution of 4-chloro-3-methoxy-2-methylpyridine (300 mg, 1.90 mmol) in dichloromethane (DCM) (2 mL) at −78 °C under _N2 . The mixture was stirred at 15° C. for 12 hours. The reaction mixture was quenched by adding MeOH (2 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. Purification (FCC, _SiO2 , 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, 1 H), 7.93 (d, J = 6.3 Hz, 1 H), 2.69 (s, 3 H) .

Intermediate 2: 3,5-dimethylisoxazol-4-ol.

To a solution of (3,5-dimethylisoxazol-4-yl)boronic acid (300 mg, 2.13 mmol) in tetrahydrofuran (THF) (5 mL) and H ₂ O (5 mL) was added sodium perborate tetrahydrate. (1.31 g, 8.51 mmol, 1.64 mL) was added. The reaction mixture was stirred at 15° C. for 12 hours. The reaction mixture was quenched by adding 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 _Na2SO4 , 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, _CDCl3 ) [delta] = 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) was added meta-chloroperbenzoic acid (m-CPBA) (1. 47 g, 7.25 mmol, 85% pure) was added and the resulting mixture was stirred at 16° C. for 15 hours. The reaction mixture was poured into saturated Na ₂ SO ₃ (40 mL) and extracted with DCM (40 mL×2). The combined organic phase was 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-ylformate. . 1,3-Dimethyl-1H-pyrazol-4-ylformate 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-ylformate 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 impurity, which was repurified by preparative HPLC (Method A) to give the title compound (55 mg, 20.3%). was obtained as a white solid. MS (ESI): mass calculated _{for C5H8N2O ,} 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.

Process A. 2-chloro-4-fluoro-1-(2-methoxyethoxy)benzene. To a solution of 2-chloro-4-fluoro-phenol (5 g, 34.12 mmol) and 1-bromo-2-methoxy-ethane (5.69 g, 40.94 mmol, 3.85 mL) in MeCN (100 mL), K ₂ CO ₃ (9.43 g, 68.24 mmol) was added. The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was cooled, diluted with H ₂ O (50 mL) and diluted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous _Na2SO4 , 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 = 4.8Hz, 2H ), 3.78 (t, J=4.8 Hz, 2H), 3.18 (s, 3H).

Process B. 2-chloro-6-fluoro-3-(2-methoxyethoxy)benzaldehyde. To a solution of 2-chloro-4-fluoro-1-(2-methoxyethoxy)benzene (2 g, 9.70 mmol) in THF (20 mL) was added n-BuLi (2.5 M in hexane, 4.5 M in hexanes) at -78°C. 65 mL) was added slowly. After the reaction mixture was stirred at −78° C. for 1 hour, 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 hour, then warmed to 10° C. for 2 hours, then stirred at 15° C. for 12 hours. The reaction mixture was poured into HCl (0.5N, 50 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous _Na2SO4 , 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).

Process C. 2-chloro-6-fluoro-3-(2-methoxyethoxy)phenylformate.
To a solution of 2-chloro-6-fluoro-3-(2-methoxyethoxy)benzaldehyde (1.9 g, 8.08 mmol) in DCM (30 mL) was added m-CPBA (3.28 g, 16.17 mmol) at 0 °C. , 85% purity) was added. The reaction mixture was stirred at 40° C. for 16 hours. The reaction mixture was then quenched with saturated aqueous NaHCO ₃ (40 mL) at room temperature and then extracted with EtOAc (50 mL×6). The combined organic layers were washed with saturated _{aqueous Na2SO3} (50 mL x 2) and brine (50 mL x 2), dried over anhydrous _Na2SO4 , filtered, concentrated under reduced pressure, and purified without further purification _. The title compound (2.1 g) was obtained.

Process D. 2-chloro-6-fluoro-3-(2-methoxyethoxy)phenol. 2-Chloro-6-fluoro-3-(2-methoxyethoxy)phenylformate (2.1 g) was dissolved in MeOH (30 mL). Then aqueous NaOH (0.5 M, 40.42 mL) was added. The mixture was stirred at 15° C. for 16 hours. The reaction mixture was adjusted to pH 1 with HCl (1N), diluted with H ₂ O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous _Na2SO4 , 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)) gave the title compound (1.05 g, 57% yield). ) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ=6.96 (t, J=9.6 Hz, 1 H), 6.48-6.45 (m, 1 H), 5.57 (m, 1 H), 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.

Process A. 3-chloro-1-methyl-1H-pyrazole-4-carbaldehyde. POCl ₃ (21.88 g, 142.71 mmol, 13.26 mL) was added dropwise to stirred dry DMF (4.47 g, 61.16 mmol, 4.71 mL) at -15°C. 1-Methylpyrazol-3-ol (2.0 g, 20.39 mmol) was then added and the solution was stirred at 90° C. for 12 hours. After cooling to room temperature, the reaction was quenched with H ₂ O (80 ml) and the mixture was basified to pH 8 with 1N NaOH solution. The phases were separated and _the aqueous layer was further extracted with _CH2Cl2 (8 x 60 mL). The organic layers were combined, dried over _NaSO4 , filtered and the solvent 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, _CDCl3 ) [delta] = 9.83 (s, 1H), 7.87 (s, 1H), 3.92 (s, 3H).

Process 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) was added m-CPBA (1.40 g, 6.92 mmol, 85% purity) at 0 °C. was added. The reaction mixture was then warmed to 25° C. and stirred for 12 hours. The reaction mixture was quenched with saturated aqueous Na ₂ SO ₃ (3 mL), filtered, the solvent was removed under reduced pressure and the crude was used in the next step. MeOH (10 mL) and TEA (2.18 g, 21.55 mmol, 3 mL) were then added to the reaction mixture, the reaction mixture was stirred at 25° C. for 2 hours, and 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, _CDCl3 ) [delta] = 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 hour. The reaction was cooled, adjusted to pH=7 by adding HCl (1N) 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): Mass calc'd, _{C5H3Cl2NO ,} 163.0; m/z found, 164.0 [M+H]< ₊ ^> . ^<1> H NMR (400 MHz, _CDCl3 ) [delta] = 7.62 (d, J = 8.0 Hz, 1 H), 6.58 (d, J = 8.0 Hz, 1 H).

Intermediate 7: 3-chloro-2-methoxy-5-methylpyridin-4-ol.

Process A. 2-chloro-4-methoxy-5-methylpyridine. To a solution of 2,4-dichloro-5-methyl-pyridine (13 g, 80.24 mmol) in MeOH (195 mL) was added NaOH (3.59 g, 89.87 mmol) under _N2 . The mixture was stirred at 70° C. for 24 hours. The mixture was cooled 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): mass calculated for _C7H8ClNO , 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).

Process B. 2-chloro-5-methylpyridin-4-ol. To a mixture of 2-chloro-4-methoxy-5-methylpyridine (3 g, 19.04 mmol) in 1,2-dichloroethane (DCE) (30 mL) was added BBr ₃ (28.61 g, 114.22 mmol, 11.01 mL). ) was added in one portion at 0 °C under _N2 . The mixture was stirred at 80° C. for 12 hours. The mixture was cooled, quenched with MeOH (250 mL) and basified with _K2CO3 to pH=8 before being filtered and concentrated in _vacuo . Purification (silica gel chromatography (1000 mesh silica gel, dichloromethane:methanol=50/1 to 10/1)) gave the title compound (2.4 g, 86%) as a white solid. MS (ESI): mass calculated for _C6H6ClNO , 143.0; m/z found, 144.2 [M+H] ^<+> _.

Process C. 2,3-dichloro-5-methylpyridin-4-ol. To a mixture of 2-chloro-5-methylpyridin-4-ol (1 g, 6.97 mmol) in MeCN (12 mL) was added N-chlorosuccinimide (NCS) (930.09 mg, 6.97 mmol) under _N2 . added at once. The mixture was stirred at 75° C. for 1 hour. 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): mass calculated _{for C6H5Cl2NO} , 176.9; m _/ z found, 178.0 [M+H] ^<+> .

Process D. 3-chloro-2-methoxy-5-methylpyridin-4-ol. To a mixture of 2,3-dichloro-5-methylpyridin-4-ol (300 mg, 1.69 mmol) in N-methyl-2-pyrrolidone (NMP) (10 mL) was added CH ₃ ONa (1.82 g, 33. 70 mmol) was added in one portion under _N2 . The reaction mixture was heated to 180° C. and stirred for 12 hours. The reaction mixture was cooled and poured into water (40 mL). AcOH was added to the resulting mixture to adjust the pH=7. The aqueous phase was extracted with ethyl acetate (20 mL x 4). The combined organic phase was washed with brine (15 mL x 2), dried over anhydrous _Na2SO4 , 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 ): mass calculated for _C7H8ClNO2 , 173.0; m/z found _, 174.0 [M+H] ^<+> .

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

Process A. 4-(benzyloxy)-2,3-dichloropyridine. To a solution of NaH (876.94 mg, 21.93 mmol, 60% pure) in DMF (20 mL) was added benzyl alcohol (BnOH) (1.19 g, 10.96 mmol) dropwise at 0°C. The reaction mixture was stirred at 0° C. for 0.5 hours. 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 phase was washed with brine (200 mL x 4), dried over _Na2SO4 , 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): mass calculated for _{C12H9Cl2NO ,} 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, 1 H), 7.45-7.27 (m=13.6 Hz, 5 H), 6.86 −6.84 (d, J=1.5 Hz, 1 H), 5.27 (s, 1 H).

Process B. 4-(benzyloxy)-3-chloro-2-methoxypyridine. To a mixture of 4-(benzyloxy)-2,3-dichloropyridine (1.4 g, 5.51 mmol) in toluene (20 mL) was added CuI (209.85 mg, 1.10 mmol), N,N,N', N′-tetramethylmethanediamine (506.64 mg, 4.96 mmol) and sodium methoxide (NaOMe) (595.27 mg, 11.02 mmol) were added. After purging the reaction mixture with nitrogen three times, it was heated at 100° C. for 12 hours. The reaction mixture was cooled, diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous _Na2SO4 , 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): mass calculated for _C13H12ClNO2 , _249.0 ; m/z found, 249.8 [M+H] ^<+> _.

Process 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 hour. The reaction mixture was allowed to warm to room temperature and quenched by the addition of H ₂ O (5 mL), after which the mixture was partitioned between DCM and water. The organic layer was dried over _{anhydrous Na2SO4} , 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): mass calculated for _C6H6ClNO2 , 159.0; m/z found _, 160.0 _[ M+H] ^<+> .

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

Process 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 hours. The reaction mixture was cooled to 25° C. and poured into ice-H ₂ O (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 Na2SO4} , filtered and concentrated under reduced pressure. Purification (FCC, _SiO2 , petroleum ether/ethyl acetate = 3/1) gave the title compound (1.5 g, 20%) as a yellow solid. MS ( _ESI ): mass calculated _{for C5H5ClN2O} , 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).

Process 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) was added 5-chloro-3-methyl-1H-pyrazole-4-carbaldehyde (1 .3 g, 8.99 mmol) was added at 0°C. The resulting suspension was stirred at 25° C. for 1 hour. 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 hours. The mixture was poured into H ₂ O (200 mL) and the aqueous layer was extracted with ethyl acetate (50 ml x 4). The combined organic phases were dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. Purification (FCC, _SiO2 , petroleum ether/ethyl acetate = 10/1) gave the title compound (2.0 g, 78%) as a light yellow oil. MS (ESI) _: mass calculated _{for C11H19ClN2O2Si} , 274.0, m/z found, 275.1 [M+H] ^<+> _.

Process C. 5-chloro-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol.
m-CPBA (2 .95 g, 14.56 mmol, 85% purity) was added. The reaction mixture was warmed to 25° C. and stirred for 12 hours. 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 _Na2SO4 , concentrated under reduced pressure and used crude in the next step _. The residue obtained was redissolved in 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. Solvent was removed under reduced pressure. Purification (FCC, _SiO2 , petroleum ether/ethyl acetate = 10/1) gave the title compound (710 mg, 36%) as a light yellow oil. MS (ESI): _mass calculated _{for C10H19ClN2O2Si} , 262.0, m/z found, 262.8 [M+H] ^<+> _.

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

Process A. 2,5-dimethylpyridin-4-ol. 2-chloro-5-methylpyridin-4-ol (1 g, 6.97 mmol), 2,4,6-trimethyl-1,3,5,2,4 in dioxane (20 mL) and H ₂ O (2 mL) ,6-trioxatriborinane (2.27 g, 9.05 mmol), K ₂ CO ₃ (2.89 g, 20.90 mmol), 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (Pd A mixture of (dppf)Cl ₂ ) (509.65 mg, 696.52 μmol) was degassed and purged with N ₂ three times. The mixture was stirred at 120° C. for 12 hours under N ₂ atmosphere. 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%) as a white solid. MS (ESI): mass calculated _{for C7H9NO} , 123.0; m/z found, 124.1 [M+H] ^<+> .

Process 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 hours. 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): mass calculated for _C7H8ClNO , 157.0; m/z found, 157.9 [M+H] ^<+> _.

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

Process 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 hours. The mixture was concentrated and purified under reduced pressure (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): mass calculated _{for C6H6ClNO2} , 159.01; m/z found, 160.0 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.36 (d, J = 2.4 Hz, 1 H), 7.31 (dd, J = 4.8 Hz, 2.4 Hz, 1 H), 6.85 (d , J=4.8 Hz, 1H), 4.08(s, 3H).

Process B. 3-chloro-6-methoxypyridin-2(1H)-one. 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 at 0-10°C. The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. After purification (FCC, SiO ₂ , petroleum ether/ethyl acetate=10/1 to 0/1), trituration with a mixture of petroleum ether/ethyl acetate (5 mL/1 mL) gave the title compound (380 mg, 31%) as a yellow solid. Obtained as a solid. MS (ESI): mass calculated _{for C6H6ClNO2} , 159.01; m/z found, 160.1 [M+H] ^<+> _. ^<1> H NMR (400 MHz, _CDCl3 ) [delta] = 7.55 (d, J = 8.0 Hz, 1 H), 5.65 (d, J = 8.4 Hz, 1 H), 3.87 (s, 3 H).

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 hours. The reaction mixture was cooled and quenched by adding NaHCO ₃ at 0° C. to adjust pH 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 x 2), dried over _Na2SO4 , 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): mass calculated for _C11H16O3 , _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=4.3Hz, 1H).

Intermediate 13.2-Methoxy-3,5-dimethylpyridin-4-ol.

NaNO ₂ (759 mg, 11.00 mmol) was dissolved in 2-methoxy-3,5-dimethylpyridin-4-amine (1.4 g) in H ₂ SO ₄ /H ₂ O (v/v, 3/1, 15 mL). , 9.17 mmol) with an ice-water bath, keeping the temperature below 5°C. After the addition was complete, the reaction mixture was stirred at 0° C. for 1 hour. The mixture was diluted with ethyl acetate (20 mL) and saturated aqueous Na ₂ CO ₃ (15 mL). The mixture was separated and the organic layer was washed with brine (10 mL), dried over _Na2SO4 , filtered and evaporated _. Purification (FCC, SiO ₂ , gradient elution: 0-100% ethyl acetate/petroleum ether) gave the title compound (1.2 g, 7.83 mmol, 85.45% yield) as a light yellow solid. MS (ESI): mass calculated for _{C8H11NO2 ,} 153.1; m/z found, 153.8 [M+H] ^<+> _.

Intermediate 14: 6-chloro-5-fluoro-8-((1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthyridin-1(2H)-one.

Process 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) in THF (5 mL) at −78° C. for 10 minutes. Then 2,6-dichloro-5-fluoronicotinic acid (1.0 g, 4.76 mmol) was added dropwise to the reaction and stirring continued for an additional 30 minutes. 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 continued 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 citric acid solution and DCM/MeOH (10:1) solution. The organic layer was _washed with brine, dried over anhydrous _Na2SO4 and concentrated to give crude product. It was then purified on a silica gel flash system with 5:1 DCM:MeOH to give the title product as an off-white solid (650 mg, 47.2%). MS (ESI): mass calculated _{for C6HBrCl2FNO2} ; m/z found _, 288.9; m/z found, 289.8 [M+H] ^<+> .

Process B. 4-bromo-N-(tert-butyl)-2,6-dichloro-5-fluoronicotinamide. 4-bromo-2,6-dichloro-5-fluoronicotinic acid (300 mg, 1.04 mmol) was treated with thionyl chloride (2 mL) at 70° C. for 2 hours. Solvent was cooled and removed in vacuo. The residue was redissolved in DCM (5 mL) and treated at 0° C. with triethylamine (0.3 mL, 2.08 mmol) followed by t-butylamine (0.13 mL, 1.25 mmol). The reaction was slowly warmed to room temperature over 2 hours. The solution was partitioned between DCM and water. The organic layer was _washed with brine, dried over anhydrous _Na2SO4 and concentrated to give crude product. It was then purified on a silica gel flash system of 10-60% ethyl acetate in heptane to give the title product as an off-white foam (310 mg, 87%). MS (ESI): Mass calc'd, _{C10H10BrCl2FN2O} ; m/z found, _344.0 ; m/z found _, 345.2 [M+H]< ₊ ^> .

Process 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) ₃ (53 mg) in dioxane (10 mL) and water (1 mL) , 0.058 mmol), tricyclohexylphosphine (16 mg, 0.058 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (172 mg , 0.87 mmol), sodium carbonate (184 mg, 1.74 mmol) were heated at 100° C. for 2 hours. The solution was cooled and partitioned between ethyl acetate and water. The organic layer was _washed with brine, dried over anhydrous _Na2SO4 and concentrated to give crude product. Purification (flash system with silica gel 0-50% ethyl acetate in heptane) gave the title product as an off-white oil (160 mg, 84%). MS (ESI): mass calculated for _{C14H17Cl2FN2O2} ; m/z _found , _335.2 ; m/z _found , 336.2 [M+H]< ₊ ^> .

Process D. 6,8-dichloro-5-fluoro-2,7-naphthyridin-1(2H)-one. (E)-N-(tert-butyl)-2,6-dichloro-4-(2-ethoxyvinyl)-5-fluoronicotinamide (100 mg, 0.30 mmol) was heated at 60° C. overnight in a sealed tube. The reaction was cooled and the solvent removed. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was _washed with brine, dried over anhydrous _Na2SO4 and concentrated to give crude product. Purification (flash system with silica gel 20-80% ethyl acetate in heptane) gave the title product as an off-white solid (50 mg, 72%). MS (ESI): mass calculated for _C8H3Cl2FN2O ; m/z found, 232.9; m/z found, 233.7 [M+H ^]< _{+ > .}

Process 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) at 0° C. for 10 minutes. It was added in portions over a period of minutes. After the addition, the mixture was stirred for an additional 30 minutes. 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 allowed to warm 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 heptane to give the title product as a white solid (1. 05 g, 75.8%). MS (ESI): mass calculated _{for C11H7ClF4N2O2} ; m/z _found , 310.6; m/z found, 311.5 [M+H] ^<+ _{> .}

Intermediate 15: 7-chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-4-ol.

Process 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) dropwise at −78° C. under N ₂ . The mixture was stirred at -78°C for 1 hour. To the mixture was then 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 hour. DMF (19.00 g, 259.94 mmol) was added dropwise at -78°C. The mixture was stirred at -78°C for 3 hours. The mixture was warmed to room temperature, poured into water (200 mL) and adjusted to pH 4-5 with 1N 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 _Na2SO4 , filtered and concentrated under reduced pressure to give the title compound (11.64 _g , 41.57 mmol, 87.30% yield). ) was obtained as a yellow solid. ^<1> H NMR (400 MHz, _CDCl3 ) [delta] = 8.82 (s, 1H), 6.85 (s, 1H).

Process 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 sulfate (100 mL) in H ₂ O (100 mL) 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 hour. The mixture was cooled, poured into water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phase was 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) at 20° C. gave the title compound (9.26 g, 95.50%) as a yellow solid. MS (ESI) m _/ z found _, 232.9; m/z found, 233.9 [M+H] ₊ ^{. 1H} _NMR (400 MHz, _CDCl3 ) δ= 13.31 (s, 1H), 8.50 (s, 1H).

Process 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) was added NaH (500 mg, 12.5 mmol, 60% pure) in one portion at 0 °C. added. The mixture was stirred at 0° C. for 0.5 hours. The mixture was added dropwise at 0° C. 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). The resulting mixture was stirred at 0° C. for 1 hour. The mixture was warmed to room temperature, poured into 1N HCl (100 mL) and extracted with ethyl acetate (100 mL×2). The combined organic phase was washed with brine (200 mL x 2), dried over anhydrous _Na2SO4 , filtered and concentrated _under reduced pressure to give the title compound (2.07 g, 56%) as a yellow solid. MS (ESI): mass calculated _{for C10H6ClF4N3O2} ; 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]pyridazin-4-ol.

The title compound was prepared in a manner analogous to that of Intermediate 15, Step C, to (S)-1,1,1-trifluoropropan-2-ol and 5,7-dichloro-8-fluoropyrido[3,4-d]. Prepared with pyridazin-4-ol (Intermediate 15, product from Step B). MS (ESI): mass calculated _{for C10H6ClF4N3O2} ; 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.

Process 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]pyridazin-4-ol (intermediate 15, 1.7 g, 2.84 mmol) and 3-(benzyloxymethyl)-4-ethyl-1H-1,2,4-triazol-5-one (1.99 g, 8.52 mmol) was added with 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) under _N2 . The mixture was stirred at 110° C. for 16 hours. The reaction was then cooled and treated with 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 under _N2 . The reaction mixture was stirred at 110° C. for an additional 16 hours. The mixture was cooled and poured into water (150 mL). The aqueous phase was extracted with ethyl acetate (150 mL x 2). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous _Na2SO4 , 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): mass calculated _{for C22H20F4N6O4} ; 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, 4H), 3.78-3.75 (m, 2H), 1.53 (d, J = 6.8Hz, 3H), 1.53 ( t, J=7.2 Hz, 3H).

Process B. 3-((benzyloxy)methyl)-1-(4-chloro-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. 3-((benzyloxy)methyl)-4-ethyl-1-(8-fluoro-4-hydroxy-5-((1,1,1-trifluoropropan-2-yl) in POCl ₃ (1 mL) A solution of oxy)pyrido[3,4-d]pyridazin-7-yl)-1H-1,2,4-triazol-5(4H)-one (50 mg, 98.34 μmol) was stirred at 90° C. for 1 hour. bottom. The reaction mixture was cooled, filtered and concentrated under reduced pressure. Toluene (20 mL) was added and the mixture was concentrated under reduced pressure, then another batch of toluene (20 mL) was added and the mixture was concentrated under reduced pressure once more. The title compound was obtained as a yellow oil (52mg) and used directly in the next step. MS ( _ESI ): mass calculated _{for C22H19ClF4N6O3} ; 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.

Process A. (S)-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. (S)-7-chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-4-ol ( Prepared in a similar manner to intermediate 17, step A, using intermediate 16). MS (ESI): mass calculated _{for C22H20F4N6O4} ; 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, 4H), 3.78-3.75 (m, 2H), 1.53 (d, J = 6.8Hz, 3H), 1.53 ( t, J=7.2 Hz, 3H).

Process 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 a similar manner to Intermediate 17, Step B. MS ( _ESI ): mass calculated _{for C22H19ClF4N6O3} ; 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.

Process A. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-8-(( 1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthyridin-1(2H)-one. The title compound was converted to 6-chloro-5-fluoro-8-((1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthyridin-1(2H)-one (Intermediate 14) Prepared in a similar manner to intermediate 17, step A, using MS (ESI): mass calculated _{for C23H21F4N5O4} ; m/z found, _507.5 ; m/z found, 508.5 [M+H] ^<+ _{> .}

Process B. 5-((benzyloxy)methyl)-2-(8-chloro-4-fluoro-1-((1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthyridine-3- yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared in a similar manner to Intermediate 17, Step B. MS ( _ESI ): mass calculated _{for C23H20ClF4N5O3} ; 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.

Process A. 6-bromo-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one. Methylsulfonic 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 in 3 portions to the reaction and the reaction temperature was maintained at 0° C. for an additional 2 hours. 20% NaOH (40 mL) was slowly added to the reaction, after which the reaction was allowed to warm to room temperature and stirred for an additional 15 minutes. The reaction mixture was extracted with DCM (3 times). The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate to give the product as an off-white solid (1.95g, 86.3%). MS (ESI): mass calcd for _C9H7BrFNO , 242.9; m/z found, _244.0 , 246.0 [M+H] ^<+> .

Process 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) at 0° C. for 10 minutes. It was added in portions over a period of minutes. After the addition, 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 (1.0 g, 4.1 mmol) in N,N-dimethylmethanamide (DMF) (5 mL). Add at 0°C. The reaction was then allowed to warm 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 heptane to give the title product (1.05 g, 75 .8%) was obtained as a white solid. MS (ESI): mass calcd for _{C12H11BrF3NO2} , _336.9 ; m _/ z found, _338.0 , 340.0 [M+H] ^<+> .

Process 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 mg, 0.89 mmol) in dioxane (5 mL) ) 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 was heated at 120° C. for an additional 4 hours. The reaction was cooled and the solvent 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 on 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): mass calcd, _C12H9BrF3NO2 , 334.9; m/z _found , 336.0, 338.0 _[ M+H]< ₊ ^> . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.08 (s, 1 H), 7.44 (d, J = 1.8 Hz, 1 H), 7.17 (d, J = 1.6 Hz, 1 H), 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 = 6.4Hz, 3H).

Process 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-(( benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (58 mg, 0.25 mmol), K _PO ( ₇₉ mg, 0.37 mmol), KI (24 mg, 0.15 mmol), trans-N,N-dimethyl-cyclohexane-1,2-diamine (0.02 mL, 0.12 mmol) and CuI (20 mg, 0.10 mmol) was degassed and purged with argon ( three times). The mixture was stirred overnight at 100°C. The reaction mixture was filtered and concentrated under reduced pressure. The residue was partitioned with ethyl acetate and an aqueous solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The solution was then concentrated and purified on 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): mass calculated _{for C24H23F3N4O4} , _488.5 ; m _/ z found, 489.2.1 _[ M+H] ^<+> .

Process 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)-8 in POCl ₃ (2 mL) -((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one (75 mg, 0.154 mmol) was refluxed for 2 hours. The solvent was removed under reduced pressure and the residue 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 as a clear oil (55 mg, 71%) without further purification. MS (ESI) _: mass calculated for _{C24H22ClF3N4O3} , _506.9 ; m/z _found , _507.2 [M+H] ^<+> .

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

Process A. (S)-6-bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydroisoquinolin-1(2H)-one. NaH (183.54 mg, 4.59 mmol, 60 % purity) was added. The reaction mixture was stirred at 0° C. for 0.5 hours. 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) ) was added to the mixture and stirred at 0° C. for 2 hours. The reaction mixture was stirred at 15° C. for 6 hours and the mixture was poured into water (25 mL). The aqueous phase was extracted with ethyl acetate (25 mL x 2). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous _Na2SO4 , 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 ): mass calcd for _{C12H11BrF3NO2} , 336.9; m _/ z found, _338.0 , 340.0 [M+H] ^<+> .

Process 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-dihydroisoquinolin-1(2H)-one (5 g in dioxane (160 mL) , 14.79 mmol) under _N2 was added DDQ (10.07 g, 44.36 mmol) in one portion. The mixture was stirred at 130° C. for 24 hours. Further DDQ (10.07 g, 44.36 mmol) was then added and the mixture was stirred at 130° C. for a further 24 hours. The mixture was poured into 1N NaOH (300 mL). The aqueous phase was extracted with ethyl acetate (300 mL x 2). The combined organic phase was washed with brine (100 mL x 2), dried over anhydrous _Na2SO4 , 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): mass calcd, _C12H9BrF3NO2 , 334.9; m/z _found , 336.0, 338.0 _[ M+H]< ₊ ^> . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.08 (s, 1 H), 7.44 (d, J = 1.8 Hz, 1 H), 7.17 (d, J = 1.6 Hz, 1 H), 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 = 6.4Hz, 3H).

Process 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 mmol) in dioxane (150 mL) and 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) was added in one portion under _N2 . The mixture was heated to 110° C. and stirred for 36 hours. The mixture was poured into water (60 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous _Na2SO4 , 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 ₎ : mass calculated _{for C24H23F3N4O4} , _488.1 ; m _/ z found, 489.2 [M+H] ^<+> .

Process D. (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4- Ethyl-1H-1,2,4-triazol-5(4H)-one. (S)-6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1- in POCl ₃ (8 mL) A solution of yl)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one (300 mg, 411.50 μmol) was heated at 110° C. for 2 hours. 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 x 2). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous _Na2SO4 , 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) _: mass calculated _{for C24H22ClF3N4O3} , _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.

Process A. 6-bromo-8-isopropoxy-3,4-dihydroisoquinolin-1(2H)-one. To a solution of isopropanol (0.174 mL, 2.27 mmol) in DMF (5 mL) was added sodium hydride (60%, 90 mg, 2.27 mmol) in portions over 10 minutes at 0°C. 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.degree. The reaction mixture was then allowed to warm 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 with 20-60% ethyl acetate in heptane) gave the title product (150 mg, 70%) as a white solid. MS (ESI): mass calculated _{for C12H14BrNO2} , _283.0 ; m/z found, 284.3 [M+H] ^<+> .

Process B. 3-((benzyloxy)methyl)-1-(1-chloro-8-isopropoxyisoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in an analogous manner to Intermediate 20, Steps C to E, to give bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydroisoquinoline of Step E. Prepared using 6-bromo-8-isopropoxy-3,4-dihydroisoquinolin-1(2H)-one in place of -1(2H)-one. MS (ESI): mass calculated _{for C24H25ClN4O3} , _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.

Process A. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-chloro-4-methylnicotin Nonitrile. To a solution of 5-((benzyloxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (500 mg, 2.14 mmol) in THF (5 mL) was 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 for an additional hour at -78°C. . 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 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 an Agilent purification system using 0-60% ethyl acetate in heptane) gave the title compound and its regioisomers as a mixture (225 mg, 27%). MS (ESI): mass calculated _{for C19H18ClN5O2} , 383.1; m/z found, _384.5 [M+H]< ₊ ^> .

Process 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) at 0° C. for 10 minutes. It was added in several portions over a period of minutes. After the NaH addition was complete, the mixture was stirred for an additional 30 minutes. To the reaction mixture was added 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)- in 2 mL of THF. 2-Chloro-4-methylnicotinonitrile (250mg, 0.65mmol) was added at 0°C. The reaction was then allowed to warm 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 ₎ : mass calculated for _C22H22F3N5O3 , _461.2 ; m _/ z found, 462.5 [M+H] ^<+> _.

Process 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)-4- in ACN (5 mL) to a solution of 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) at room temperature. Hydrogen peroxide (30%, 0.1 mL, 0.87 mmol) was added over 2 hours. The solvent was removed under reduced pressure and the residue 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 as an off-white solid (55 mg, 66%). MS (ESI): mass calculated _{for C22H24F3N5O4} , _479.2 ; m _/ z found, 480.4 [ _M +H] ^<+> .

Process D. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-((dimethylamino)methylene )-4-methyl-2-((1,1,1-trifluoropropan-2-yl)oxy)nicotinamide.
6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4- in dioxane (5 mL) Methyl-2-((1,1,1-trifluoropropan-2-yl)oxy)nicotinamide (100 mg, 0.21 mmol) was treated with 1,1-dimethoxy-N,N-dimethylmethanamine (0.12 mL). , 1.04 mmol) at 80° C. for 2 hours. The solvent was removed under reduced pressure and the residue was dried in vacuo without further purification (85mg, 76%). MS (ESI) _: mass calculated _{for C25H29F3N6O4} , _534.2 ; m _/ z found, 535.5 [M+H] ^<+> .

Process 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)-N- in THF (3 mL) To a solution of ((dimethylamino)methylene)-4-methyl-2-((1,1,1-trifluoropropan-2-yl)oxy)nicotinamide (100 mg, 0.187 mmol) was added t-BuOK at room temperature. (1.0 N, 0.35 mL, 0.347 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification (silica gel column on an Agilent purification system using 20-100% ethyl acetate in heptane) gave the title product as an off-white solid (25 mg, 27%). MS (ESI) _: mass calculated _{for C23H22F3N5O4} , _489.2 ; m _/ z found, 490.5 [M+H] ^<+> .

Process F. 3-((benzyloxy)methyl)-1-(8-chloro-1-((1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthyridin-3-yl)-4 -ethyl-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a similar manner to Intermediate 20, Step C. MS (ESI): mass calculated for _{C23H21ClF3N5O3} , _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]pyridazine -7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one.

Process 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) at 0°C. It was added in several portions over 10 minutes. After the NaH addition was complete, the mixture was stirred for an additional 30 minutes. 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 allowed to warm 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): mass calculated _{for C10H7ClF3N3O2} , _293.0 ; m _/ z found _, 294.4 [M+H] ^<+> .

Process 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, 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). The solution was heated at 80° C. overnight. The reaction solution was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification (silica gel column on an Agilent purification system using 20-80% ethyl acetate in heptane) gave the title product (105 mg, 63%) as an off-white solid. MS (ESI) _: mass calculated _{for C22H21F3N6O4} , _490.2 ; m _/ z found, 491.5 [M+H] ^<+> .

Process C. 3-((benzyloxy)methyl)-1-(4-chloro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl )-4-ethyl-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a similar manner to Intermediate 20, Step E. MS (ESI): mass calculated for _{C22H20ClF3N6O3} , _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.

Process A. Methyl (S)-4-bromo-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoate. NaH (60% dispersion) (26 mg, 0.66 mmol) was added. After stirring the mixture for 10 minutes, methyl 4-bromo-2-fluorobenzoate (128 mg, 0.55 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 15 minutes before being quenched with water. 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 as a colorless oil (85mg, 47%). MS (ESI): mass calculated _{for C11H10BrF3O3} , _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, 1 H), 7.23-7.28 (m, 1 H), 7.18 (s, 1 H), 4. 60-4.74 (m, 1H), 3.89 (s, 3H), 1.56 (d, J=6.4Hz, 3H).

Process 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) and 1 M NaOH ( 1.5 mL) was stirred at room temperature for 2 hours. 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): mass calculated _{for C10H8BrF3O3} , _313.1 ; m/z found, 313.0 [M+H]< ₊ ^> .

Process 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), Potassium bicarbonate (25 mg, 0.25 mmol) and dibromomethane (0.4 mL, 6.0 mmol) were mixed together and heated to 140° C. for 60 hours. The reaction mixture was cooled, diluted with DCM and adsorbed onto silica. Purification by column chromatography (0-15% EtOAc/heptane) gave the title compound as a colorless oil (19.3 mg, 59%). MS (ESI): mass calculated _{for C11H8BrF3O3} , _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, 1 H), 1.64 (d, J=6.4 Hz, 3 H).

Process D. (S)-3,5-dibromo-7-((1,1,1-trifluoropropan-2-yl)oxy)isobenzofuran-1(3H)-one. In a vial, (S)-5-bromo-7-((1,1,1-trifluoropropan-2-yl)oxy)isobenzofuran-1(3H)-one (540 mg, 1.661 mmol), N- Bromosuccinimide (NBS) (325 mg, 1.8 mmol), 2,2′-azobis(2-methylpropionitrile) (14 mg, 0.08 mmol) and 1,2-dichloroethane (DCE) (10.8 mL) were added. rice field. The reaction was heated to 80° C. and stirred for 1.5 hours, then cooled and concentrated under reduced pressure to give crude product without further purification.

Process 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) in EtOH (6 .5 mL), hydrazine hydrate (0.41 mL, 1.027 g/mL, 8.3 mmol) was added and after heating to 80° C. for 5 h, the mixture was concentrated and dissolved in EtOAc and water. . The organics were extracted with EtOAc (2x). The combined organic phases 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%). MS (ESI): mass calculated _{for C11H8BrF3N2O2 ,} 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=1.5Hz, 1H), 7.66 (s, 1H), 5.09-5 .31 (m, 1 H), 1.58 (d, J=6.4 Hz, 3 H).

Process 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) was added to POCl ₃ (1. 46 mL, 1.65 g/mL, 15.7 mmol) at 100° C. for 2 h, then the reaction was cooled, concentrated under reduced pressure and placed under vacuum overnight (˜80 mg). The crude product was not purified further. MS (ESI) _: mass calculated _{for C11H7BrClF3N2O} , 353.5; m _/ z found, 354.7 [M+H] ^<+> .

Intermediate 26.5-((benzyloxy)methyl)-2-(4-chloro-5-((1,1,1-trifluoropropan-2-yl)oxy)-1,6-naphthyridine-7- yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one.

The title compound was synthesized in an analogous manner to Intermediate 24, Steps A-C by replacing 5,7-dichloropyrido[3,4-d]pyridazin-4(3H)-one in Step A with 5,7-dichloro- Prepared with 1,6-naphthyridin-4(1H)-one. MS (ESI): mass calculated for _{C23H21ClF3N5O3} , _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.

Process 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 mmol) was added with 10% Pd/C (3.65 g, 3.43 mmol). After vigorously shaking the resulting mixture under a hydrogen atmosphere (45 psi) at room temperature for 20 hours, the resulting mixture was filtered through a short pad of celite and the filtrate was concentrated to yield crude 4-ethyl-5-( Hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one was obtained as a white solid (2.4 g, 98%). MS (ESI): mass calculated for _C5H9N3O2 , _143.2 ; m/ _z found, 144.4 [M+H] ^<+> _.

Process B. 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. To a solution of 4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2.4 g, 16.8 mmol) in DCM (50 mL) was added tert -Butylchlorodiphenylsilane (6.9 g, 25.1 mmol) and imidazole (2.28 g, 33.5 mmol) were added. The resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (100 mL). The resulting mixture was extracted with DCM (3x100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was then purified on an Agilent purification system using silica gel chromatography (50-100% ethyl acetate/heptane). 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one was obtained as a white solid (4.9 g, 76 %). MS (ESI) _: mass calculated for _C21H27N3O2Si , _381.6 ; m/z found, 382.4 [M+H]< ₊ ^> .

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

A mixture of 5-fluoro-2-methoxypyridin-4-ol (650 mg, 4.54 mmol) and NCS (910 mg, 6.81 mmol) in MeCN (20 mL) was heated to 70° C. for 16 hours. The mixture was cooled, 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 _Na2SO4 , 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 ): mass calculated for _C6H5ClFNO2 , 177.0; m/z found, 177.8 [M+H] ^<+> _. ^<1> H NMR (400 MHz, _CDCl3 ) [delta] = 7.80 (d, J = 1.3 Hz, 1 H), 6.10 (br s, 1 H), 3.92 (s, 3 H).

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.

Process A. 7-chloro-8-fluoro-5-isopropoxypyrido[3,4-d]pyridazin-4(3H)-one. To a solution of isopropanol (0.4 mL, 6.92 mmol) in DMF (2 mL) was added sodium hydride (60%, 56 mg, 1.4 mmol) portionwise at 0° C. for 10 minutes. After the NaH addition was complete, the mixture was stirred for an additional 30 minutes. 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 allowed to warm 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): mass calculated _{for C10H9ClFN3O2} , _257.7 ; m/z found, 258.6 [M+H]< ₊ ^> .

Process B. 7-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-8-fluoro-5-isopropoxy pyrido[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 (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): mass calculated _{for C22H23FN6O4} , _454.5 ; m/z found, 455.5 [M+H]< ₊ ^> .

Process 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 a similar manner to Intermediate 20, Step E. MS (ESI): mass calculated _{for C22H22ClFN6O3} , _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.

Process A. 5-((benzyloxy)methyl)-2-(1-(2-chloro-6-fluorophenoxy)-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-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2, 4-dihydro-3H-1,2,4-triazol-3-one (intermediate 20, 60 mg, 0.118 mmol), 2-chloro-6-fluorophenol (173 mg, 1.18 mmol) and KOH (26.6 mg , 0.47 mmol) was heated to 110° C. for 2 h in a sealed tube. 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 on 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 )} : mass calculated _{for C30H25ClF4N4O4 ,} 616.2; m/z found, 617.2 [M+H]< ₊ ^> .

Process 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-trifluoroacetic acid) (0.5 mL) in trifluoroacetic acid (TFA) Fluoropropan-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. bottom. The solvent was concentrated under reduced pressure and the residue was treated with acetonitrile (ACN) (1 mL) and 1N NaOH (1 mL) solution at room temperature for 10 minutes. The solution was purified by preparative HPLC using 20-80% ACN/water 0.1% TFA (Method B) to give the title compound as a white solid after lyophilization. MS ( _{ESI )} : mass calculated for _{C23H19ClF4N4O4} , 526.1; m/z found, 527.5 [M+H] ^<+ _{> .} ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.12 (d, J = 1.9 Hz, 1 H), 7.97 (s, 1 H), 7.86 (d, J = 5.8 Hz, 1 H), 7.31 (d, J = 5.8Hz, 2H), 7.22-7.12 (m, 2H), 5.08-4.94 (m, 1H), 4.73 (d, J = 6 .4Hz, 2H), 3.94 (q, J = 7.3Hz, 2H), 2.09-2.00 (m, 1H), 1.65 (dd, J = 6.5, 10.5Hz, 3H), 1.45 (t, J=7.2 Hz, 3H).

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

Process A. (S)-5-((benzyloxy)methyl)-2-(1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-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) Propan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21, 100 mg, 197.28 μmol) and 2-chloro To a solution of -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 the microwave at 150° C. for 3 hours. The reaction mixture was diluted with _H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , filtered and concentrated _under reduced pressure to give a residue. Purification (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 _{C29H25ClF3N5O4} , _599.1 ; m _/ z found, _600.1 [M+H] ^<+> .

Process B. (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. (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 (40 mg, 67.00 μmol) was dissolved in BCl ₃ (1 M). , 200 μL) was added. The mixture was stirred at -78°C for 1 hour. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , filtered and concentrated _under reduced pressure to give a residue. The crude product was purified by RP HPLC (conditions A) to give the title compound (22 mg, 62.0% yield) as a white solid. MS (ESI) _: mass _calculated for _{C23H19ClF4N4O4} ; 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, 1 H), 7.97 (s, 1 H), 7.86 (d, J = 5.8 Hz, 1 H), 7.31 (d, J = 5.8Hz, 2H), 7.22-7.12 (m, 2H), 5.08-4.94 (m, 1H), 4.73 (d, J = 6 .4Hz, 2H), 3.94 (q, J = 7.3Hz, 2H), 2.09-2.00 (m, 1H), 1.65 (dd, J = 6.5, 10.5Hz, 3H), 1.45 (t, J=7.2 Hz, 3H).

Example 3: 2-(1-((2-chloro-6-fluorophenyl)amino)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Process 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)isoquinolin-6-yl)- in dioxane (1 mL) 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 in a sealed tube. 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 on 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) _: mass _calculated for _{C30H26ClF4N5O3} , _615.2 ; m/z found, 616.4 [M+H]< ₊ ^> .

Process B. 3-(2-chloro-6-fluorophenyl)-7-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl )-6-fluoro-1-isopropyl-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-one. The title compound was prepared according to the procedure of Example 1, Step B. MS (ESI) _: mass calculated for _{C23H20ClF4N5O3} , _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. 85Hz, 1H), 7.28-7.56 (m, 2H), 7.13-7.25 (m, 2H), 7.02 (d, J = 6.36Hz, 1H), 5.23 ( m, 1H), 4.68 (s, 2H), 3.94 (d, J = 7.34Hz, 2H), 1.76 (d, J = 6.36Hz, 3H), 1.42 (t, J=7.09Hz, 3H).

Example 4: 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.

Process A. 5-((benzyloxy)methyl)-2-(1-((2-chloro-6-fluorophenyl)thio)-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-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 hour. 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 on 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 C30H25ClF4N4O3S} , _632.1 ; m/z _found , 633.2 [M+H]< ₊ ^> .

Process B. 2-(1-((2-chloro-6-fluorophenyl)thio)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 5-(Hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.
The title compound was prepared according to the procedure of Example 1, Step B. MS (ESI) _: mass calculated _{for C23H19ClF2N4O3S} , _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, 1 H), 8.03 (d, J=1.96 Hz, 1 H), 7.99 (d, J=1 .47Hz, 1H), 7.52 (d, J = 5.87Hz, 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.

Process A. 4-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-8-(( 1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3,5-difluorobenzonitrile. The title compound was treated in a manner analogous to Example 1, Step A, with 3,5-difluoro-4-hydroxybenzonitrile and 5-((benzyloxy)methyl)-2-(1-chloro-8-((1 ,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20) was prepared by coupling MS (ESI): mass calculated _{for C31H24F5N5O4} , _625.2 ; m _/ z found, 626.3 [ _M +H] ^<+> .

Process 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 manner similar to Example 1, Step B. MS (ESI ₎ : mass calculated for _C24H18F5N5O4 , _535.1 ; m _/ z found, 536.3 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm, 8.11 (s, 1 H), 7.98 (s, 1 H), 7.83 (d, J=5.87 Hz, 1 H), 7.29-7. 52 (m, 3H), 4.85-5.04 (m, 1H), 4.73 (s, 2H), 3.93 (q, J = 6.85Hz, 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.

Process 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.
The title compound was converted to 3,5-difluoro-4-hydroxybenzaldehyde and 5-((benzyloxy)methyl)-2-(1-chloro-8-((1, 1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20) prepared by coupling. MS (ESI ₎ : mass calculated for _C31H25F5N4O5 , _628.2 ; m _/ z found, 629.5 [M+H] ^<+> _.

Process B. 5-((benzyloxy)methyl)-2-(1-(2,6-difluoro-4-(hydroxymethyl)phenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy ) isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. (4-(6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl in MeOH (1 mL) )-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3,5-difluorobenzaldehyde (10 mg, 0.02 mmol) was added to hydrogen Treated with sodium borohydride (3 mg, 0.08 mmol) for 10 minutes. The solution was partitioned with ethyl acetate and water. The organic layer was washed with brine, dried, filtered and concentrated to give crude product. The crude product was then purified by silica gel cartridge on an Agilent purification system using 10-60% ethyl acetate/heptane to give the title compound (8.0 mg, 80%) as an off-white solid. MS (ESI): mass calculated for _C31H27F5N4O5 , _630.2 ; m _/ z _found , 631.4 [M+H] ^<+> _.

Process C. 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. The title compound was prepared in a manner similar to Example 1, Step B. (ESI): mass calculated for _C24H21F5N4O5 , _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, 1 H), 7.96 (d, J=1.96 Hz, 1 H), 7.81 (d, J= 5.87Hz, 1H), 7.34-7.49 (m, 2H), 7.07 (d, J = 8.80Hz, 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.

Process 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-dihydro-1H in a mixture of MeOH (1 mL), THF (1 mL) and water (1 mL) -1,2,4-triazol-1-yl)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3,5-difluorobenzonitrile (product from Example 5, 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 with 1N HCl to pH=4 and extracted with ethyl acetate (3 times). 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 as a white solid (21 mg, 82.4%). MS (ESI) _: mass calculated _{for C31H25F5N4O6 , 644.2} ; m _/ z found, 644.5 [M+H] ^<+> .

Process 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): mass calculated for _C24H19F5N4O6 , _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, 1 H), 7.98 (d, J=1.96 Hz, 1 H), 7.86 (d, J=5 .87Hz, 1H), 7.67-7.81 (m, 2H), 7.27-7.52 (m, 1H), 4.98 (d, J = 5.87Hz, 1H), 4.73 (s, 2H), 3.94 (q, J = 7.01Hz, 2H), 1.65 (d, J = 6.85Hz, 3H), 1.44 (t, J = 7.09Hz, 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.

Process A. 4-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-8-(( 1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3,5-difluoro-N-(2-hydroxyethyl)benzamide. 4-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl in DCM (2 mL) )-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3,5-difluorobenzoic acid (Example 7, product from step A, 14 mg, 0.022 mmol), 2-aminoethan-1-ol (6.6 mg, 0.11 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDCI) (12.5 mg, 0.11 mmol). 065 mmol), hydroxybenzotriazole (HOBt) (8.8 mg, 0.065 mmol), diisopropylethylamine (DIPEA) (0.019 mL, 0.11 mmol) was stirred overnight at room temperature. 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, Agilent purification system using 20-80% ethyl acetate in heptane) gave the title compound as a colorless oil (11.2 mg, 73.7%). MS (ESI): mass calculated _{for C33H30F5N5O6} , _687.2 ; m _/ z found, 688.5 [M+H] ^<+> _.

Process B. 4-((6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-8-((1,1 ,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3,5-difluoro-N-(2-hydroxyethyl)benzamide. The title compound was prepared according to Example 1, Step B. MS (ESI): mass calculated _{for C26H24F5N5O6} , _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, 1 H), 7.97 (d, J=1.96 Hz, 1 H), 7.84 (d, J=5 .87 Hz, 1H), 7.41-7.67 (m, 2H), 7.28-7.40 (m, 1H), 4.85-5.02 (m, 1H), 4.73 (s , 2H), 3.99 (m, 2H), 3.77 (m, 2H), 3.60-3.74 (m, 2H), 1.44 (t, J = 7.09 Hz, 3H), 1.25 (m, 3H).

Example 9: 2-(1-(2-chloro-4,6-difluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4 -ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Process A. 5-((benzyloxy)methyl)-2-(1-(2-chloro-4,6-difluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline- 6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was synthesized with 2-chloro-4,6-difluorophenol and 5-((benzyloxy)methyl)-2-(1-chloro-8-((1,1,1,1,1) according to the procedure of Example 1, Step A. Coupling 1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20) It was prepared by MS (ESI ₎ : mass calculated _{for C30H24ClF5N4O4} , _634.1 ; m/z found, 634.5 [M+H]< ₊ ^> .

Process B. 2-(1-(2-chloro-4,6-difluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-5 -(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.
The title compound was prepared in a manner similar to Example 1, Step B. MS (ESI): mass calculated _{for C23H18ClF5N4O4} , _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, 1 H), 7.96 (s, 1 H), 7.84 (d, J=5.87 Hz, 1 H), 7.28-7.52 (m, 1H), 7.02-7.25 (m, 1H), 6.92 (t, J=9.05Hz, 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 = 7.34Hz, 3H).

Example 10: 2-(1-(2-chloro-6-fluorophenoxy)-8-isopropoxyisoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H- 1,2,4-triazol-3-one.

The title compound was prepared with 5-((benzyloxy)methyl)-2-(1-chloro-8-((1,1,1-trifluoropropane-) in Step A according to the procedure of Example 1, Steps AB. 3-((benzyl oxy)methyl)-1-(1-chloro-8-isopropoxyisoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 22) was prepared. MS (ESI): mass calculated for _{C23H22ClFN4O4} , _472.1 ; m/z found _, 473.3 [M+H]< ₊ ^> . ¹ H NMR (400 MHz, CDCl ₃ ) δppm 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, 2H), 3.92 (m, J=6.85Hz, 2H) 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.

Process A. (S)-5-((benzyloxy)methyl)-2-(1-((4-chloropyridin-3-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl ) oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one.
(S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane-2) in N-methylpyrrolidone (NMP) (1.5 mL) -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-3 - To a solution of 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 _H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , filtered and concentrated _under reduced pressure to give a residue. Purification (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 _{C29H25ClF3N5O4} , _599.1 ; m _/ z found, _600.1 [M+H] ^<+> .

Process B. (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)-3-((benzyloxy)methyl)-1-(1-((4-chloropyridin-3-yl)oxy)-8-((1,1,1-tri BCl ₃ (1M , 300.01 μL) was added. The mixture was stirred at -78°C for 1 hour. The reaction mixture was diluted with _H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , filtered and concentrated _under reduced pressure to give a residue. 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): mass calculated for _{C22H19ClF3N5O4} , _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, 1 H), 8.04 (d, J = 1.6 Hz, 1 H), 7.90 (d, J = 6.5 Hz, 1 H), 7.84 (d, J = 5.8 Hz, 1 H), 7.43 (d, J = 5.8Hz, 1H), 5.09-4.97 (m, 1H), 4.75 (s, 2H), 3.95 (q, J = 7.2Hz, 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.

Process A. (S)-5-((benzyloxy)methyl)-2-(1-((2-chloropyridin-3-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl ) oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one.
The title compound was treated with 2-chloropyridin-3-ol and (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) Prepared by ringing. MS (ESI): _mass calculated for _{C29H25ClF3N5O4} , _599.2 ; m _/ z found, _600.4 [M+H] ^<+> .

Process B. (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.
The title compound was prepared in a manner similar to Example 2, Step B. MS (ESI): mass calculated _{for C22H19ClF3N5O4} ; 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, 1 H), 8.11 (d, J = 1.8 Hz, 1 H), 7.98 (d , J=1.8 Hz, 1 H), 7.86 (d, J=5.8 Hz, 1 H), 7.62 (dd, J=1.7, 8.0 Hz, 1 H), 7.37-7. 32 (m, 2H), 5.09-4.95 (m, 1H), 4.74 (br d, J=1.1Hz, 2H), 3.94 (d, J=7.3Hz, 2H) , 2.10 (br s, 1 H), 1.66 (d, J=6.4 Hz, 3 H), 1.45 (t, J=7.2 Hz, 3 H).

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.

Process A. (S)-5-((benzyloxy)methyl)-2-(1-((2-chloro-4-methylpyridin-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. The title compound was treated with 2-chloro-4-methylpyridin-3-ol and (S)-3-((benzyloxy)methyl)-1-(1-chloro- 8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21). MS (ESI): mass calculated _{for C30H27ClF3N5O4} ; m/z found, _613.2 ; m/z found, 614.6 [M+H] ^<+ _{> .}

Process B. (S)-2-(1-((2-chloro-4-methylpyridin-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): mass calculated _{for C23H21ClF3N5O4} ; 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, 1 H), 8.09 (d, J = 1.6 Hz, 1 H), 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, 1 H), 4.74 (s, 2 H), 3.94 (q, J=7.2 Hz, 2 H), 2.27 (s, 3 H), 2. 10 (br s, 1H), 1.70-1.62 (m, 3H), 1.45 (t, J=7.3Hz, 3H).

Example 14: (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.

Process A. (S)-5-((benzyloxy)methyl)-2-(1-((2,4-dimethylpyridin-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.
The title compound was treated in a manner analogous to Example 2, Step A, with 2,4-dimethylpyridin-3-ol and (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) was prepared by coupling MS (ESI): mass calculated for _C31H30F3N5O4 ; m/z _found , _593.2 ; m/ _z found, 594.6 [M+H]< ₊ ^> .

Process B. (S)-2-(1-((2,4-dimethylpyridin-3-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl )-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): _mass calculated for _C24H24F3N5O4 ; 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, 1 H), 8.05 (d, J = 1.6 Hz, 1 H), 7.96 (d , J = 1.6 Hz, 1 H), 7.83 (d, J = 5.8 Hz, 1 H), 7.25 (d, J = 5.8 Hz, 1 H), 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-trifluoro Propan-2-yl)oxy)isoquinolin-6-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Process A. (S)-5-((benzyloxy)methyl)-4-ethyl-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. The title compound was treated with 4-methylpyridin-3-ol and (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) Prepared by ringing. MS (ESI): mass calculated for _C30H28F3N5O4 ; m/z found, _579.2 ; m/ _z found _, 580.5 [M+H]< ₊ ^> .

Process B. (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. The title compound was prepared in a manner similar to Example 2, Step B. MS (ESI): mass calculated _{for C23H22F3N5O4} , _489.1 ; m _{/ z} found, 490.2 [M+H] ^<+> . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.57 (s, 1 H), 8.49 (d, J = 5.5 Hz, 1 H), 8.08 (d, J = 1.8 Hz, 1 H), 8.00 (d, J = 1.6Hz, 1H), 7.83 (d, J = 5.8Hz, 1H), 7.57 (d, J = 5.5Hz, 1H), 7.34 (d , J=5.8 Hz, 1 H), 5.01 (td, J=6.2, 12.4 Hz, 1 H), 4.74 (s, 2 H), 3.94 (q, J=7.3 Hz, 2H), 2.42 (s, 3H), 1.66 (d, J=6.4Hz, 3H), 1.45 (t, J=7.2Hz, 3H).

Example 16: (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.

Process A. (S)-5-((benzyloxy)methyl)-2-(1-(2-chloro-5-methylphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was treated with 2-chloro-5-methylphenol and (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) Prepared by ringing. MS (ESI): _mass calculated _{for C31H28ClF3N4O4} ; m/z found, _612.2 ; m/z found, 613.5 [M+H]< ₊ ^> .

Process B. (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.
The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI _{) :} mass calcd, _{C24H22ClF3N4O4} ; 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, 1 H), 7.96 (d, J = 1.9 Hz, 1 H), 7.90 (d, J = 5 .8Hz, 1H), 7.37 (d, J = 8.2Hz, 1H), 7.29 (s, 1H), 7.09 (d, J = 1.4Hz, 1H), 7.04-7 .00 (m, 1H), 5.01 (q, J=6.2Hz, 1H), 4.73 (s, 2H), 3.93 (q, J=7.2Hz, 2H), 2.38 (s, 3H), 2.13-2.00 (m, 1H), 1.63 (d, J=6.4Hz, 3H), 1.44 (t, J=7.2Hz, 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.

Process A. (S)-5-((benzyloxy)methyl)-2-(1-((4-chloro-2-methylpyridin-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. The title compound was treated with 4-chloro-2-methylpyridin-3-ol and (S)-3-((benzyloxy)methyl)-1-(1-chloro- 8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21). MS (ESI): mass calculated _{for C30H27ClF3N5O4} ; m/z _found , _613.2 ; m/z found, 614.7 [M+H]< ₊ ^> .

Process B. (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. The title compound was prepared in a manner similar to Example 2, Step B. MS (ESI): mass calculated for _{C23H21ClF4N5O4} ; 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 = 6.4Hz, 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.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-((3-chloropyridin-2-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-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), Cs ₂ CO ₃ (96.41 mg, 295.91 μmol) followed by copper(II) acetylacetonate [Cu(acac) ₂ ] (5.16 mg, 19.73 μmol) in N ₂ at a time. The mixture was heated at 120° C. for 24 hours. The reaction mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous _Na2SO4 , 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 C29H25ClF3N5O4 , 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, 1 H), 7.49 (d, J = 5.6 Hz, 1 H), 7.43-7.34 (m, 5 H), 7.04 (dd, J = 4.8, 7. 7Hz, 1H), 4.97 (td, J = 6.2, 12.2Hz, 1H), 4.64 (s, 2H), 4.57 (s, 2H), 3.88 (q, J = 7.2 Hz, 2 H), 1.48 (d, J=6.3 Hz, 3 H), 1.38 (t, J=7.2 Hz, 3 H).

Process B. (S)-1-(1-((3-chloropyridin-2-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. (S)-3-((benzyloxy)methyl)-1-(1-((3-chloropyridin-2-yl)oxy)-8-((1,1,1-tri BCl ₃ (1 M, 250 μL) was added. The mixture was stirred at -78°C for 1 hour. The reaction mixture was diluted with _H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , filtered and concentrated _under reduced pressure to give a residue. The crude product was purified by RP HPLC (conditions A) to give the title compound (35 mg, 55.6% yield) as a white solid. MS (ESI): mass calculated for _{C22H19ClF3N5O4} , _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, 1 H), 7.47 (d, J = 5.7 Hz, 1 H), 7.05 (dd, J = 4.8, 7.8 Hz, 1 H), 4.95 (td, J = 6.2, 12.5 Hz, 1 H), 4.72 (br d, J = 4.5 Hz, 2 H), 3.93 (q, J = 7.2 Hz, 2 H), 2.31 (br s, 1 H ), 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.

Process A. (S)-5-((benzyloxy)methyl)-2-(1-((3,5-dimethylisoxazol-4-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. The title compound was prepared according to the procedure of Example 2, Step A with 3,5-dimethylisoxazol-4-ol and (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) prepared by coupling. MS (ESI) _: mass calculated _{for C29H28F3N5O4} ; m/z found, _583.2 ; m/z found, 584.4 [M+H]< ₊ ^> .

Process B. (S)-1-(1-((3,5-dimethylisoxazol-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. The title compound was prepared in a manner analogous to Example 2, Step B. MS ( _ESI ): mass calculated for _C22H22F3N5O5 ; 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, 1 H), 7.95 (d, J = 1.8 Hz, 1 H), 7.90 (d, J = 5 .7 Hz, 1 H), 7.30 (d, J=5.9 Hz, 1 H), 4.99 (td, J=6.2, 12.4 Hz, 1 H), 4.74 (d, J=6. 2Hz, 2H), 3.94 (q, J = 7.2Hz, 2H), 2.34 (s, 3H), 2.20-2.10 (m, 4H), 1.67 (d, J = 6.4 Hz, 3H), 1.45 (t, J = 7.2 Hz, 3H).

Example 20: 2-(8-(2-chloro-6-fluorophenoxy)-1-((1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthyridin-3-yl )-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

The title compound was prepared with 3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropane-) in Step A according to the procedure of Example 1, Steps AB. 3-((benzyloxy)methyl )-1-(8-chloro-1-((1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthyridin-3-yl)-4-ethyl-1H-1,2 , 4-triazol-5(4H)-one. MS (ESI ₎ : mass calculated for _{C22H18ClF4N5O4} , _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, 1 H), 7.95 (s, 1 H), 7.27-7.52 (m, 2 H), 7. 10-7.25 (m, 2H), 6.13 (br, d, J = 3.91Hz, 1H), 4.73 (s, 2H), 3.94 (q, J = 7.17Hz, 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]pyridazine- 7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

The title compound was prepared according to the procedure of Example 1, Steps AB, with the exception of 5-((benzyloxy)methyl)-2-(1-chloro-8-((1,1, instead of 1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20) , 3-((benzyloxy)methyl)-1-(4-chloro-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 (Intermediate 24) was used. MS (ESI): mass calculated _{for C21H17ClF4N6O4} , _528.1 ; m/z found, 529.6 [M+H] ^<+ _{> .} ¹ H NMR (400 MHz, CDCl ₃ ) δppm, 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, 2H), 3.96 (d, J = 7.34Hz, 2H), 2.89 −3.17 (m, 3H), 1.44 (t, J=7.34 Hz, 3H).

Example 22: 2-(4-(2-chloro-6-fluorophenoxy)-5-((1,1,1-trifluoropropan-2-yl)oxy)-1,6-naphthyridin-7-yl )-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

The title compound was prepared in Step A according to the procedure of Example 1, Steps AB, with 5-((benzyloxy)methyl)-2-(1-chloro-8-((1,1,1-trifluoropropane- 5-((benzyl oxy)methyl)-2-(4-chloro-5-((1,1,1-trifluoropropan-2-yl)oxy)-1,6-naphthyridin-7-yl)-4-ethyl-2, Prepared with 4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 26). MS (ESI ₎ : mass calculated for _{C22H18ClF4N5O4} , _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, 1 H), 7.72 (s, 1 H), 7.25-7.48 (m, 2 H), 7. 05-7.20 (m, 2H), 6.20 (m, 1H), 4.85 (s, 2H), 3.97 (q, J = 7.5Hz, 2H), 1.72 (d, J=7.25 Hz, 3H), 1.48 (t, J=7.24 Hz, 3H).

Example 23: (S)-3-(1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl) -1-ethyl-1-methylurea.

Process 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, Step B) in POCl ₃ (4 mL) product, 200 mg, 595.05 μmol) was heated to 110° C. for 2 hours. The mixture was cooled and then concentrated under reduced pressure. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL X 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous _Na2SO4 , filtered and concentrated under _vacuum to give the title compound (205 mg, crude) as a yellow solid. MS (ESI): mass calcd, _{C12H8BrClF3NO} , 352.9; m _/ z found, _354.0 , 356.0 [M+H] ^<+> .

Process 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), 2 in NMP (0.5 mL) A mixture of -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 hours. After cooling the residue was poured into saturated aqueous Na ₂ CO ₃ (30 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous _Na2SO4 , filtered and concentrated under _vacuum . Purification (preparative TLC, petroleum ether/ethyl acetate = 10/1) gave the title compound (105 mg, 51.5%) as a yellow solid. MS (ESI): mass calcd for _{C18H11BrClF4NO2} , 462.9; m _/ z _found , 464.0 _, 466.0 [M+H] ^<+> .

Process 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)isoquinoline (100 mg) in dioxane (2 mL) , 215.22 μmol) and diphenylmethanimine (78.01 mg, 430.44 μmol, 72.23 μL), Cs ₂ CO ₃ (84.15 mg, 258.27 μmol), 4,5-bis(diphenylphosphino)- 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 treated with N ₂ at a time. The mixture was stirred at 110° C. for 12 hours. After cooling the mixture, it was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous _Na2SO4 , filtered and concentrated under vacuum to give _the title compound (130 mg, crude) as a yellow oil. MS (ESI): mass calculated _{for C31H21ClF4N2O2} , 564.1; m _/ z found, 565.1 _[ M+H]< ₊ ^> .

Process 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-trifluoropropan-2-yl)oxy) in THF (2 mL) HCl (2M, 345 μL) was added to the mixture of isoquinolin-6-amine (130 mg). The mixture was stirred at 15° C. for 2 hours. The mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous _Na2SO4 , filtered and concentrated under _vacuum . Purification (preparative TLC, petroleum ether/ethyl acetate = 2/1) gave the title compound (80 mg, 75.6%) as a yellow solid. MS (ESI): mass _{calculated for C18H13ClF4N2O2} , 400.0; m _/ z found _, 401.1 [M+H] ^<+> .

Process E. (S)-phenyl (1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)carbamate. (S)-1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-amine (80 mg in DCM (2 mL) , 199.62 μmol) was added pyridine (47.37 mg, 598.87 μmol) and phenylcarbonochloridate (40.63 mg, 259.51 μmol) at 0 °C under _N2 . The reaction mixture was stirred at 15° C. for 1 hour. This mixture was poured into water (10 mL). The aqueous phase was extracted with DCM (10 mL x 2). The combined organic phase was washed with brine (5 mL x 2), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to give the title compound (110 mg, crude) as a yellow oil. MS (ESI) _: mass calculated _{for C25H17ClF4N2O4} , _520.0 ; m/z found, 521.2 [M+H]< ₊ ^> .

Process F. (S)-3-(1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1-ethyl -1-methylurea. (S)-Phenyl(1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline- in dichloromethane (DCM) (2 mL) 6-yl)carbamate (104 mg, crude) and N-methylethanamine (23.60 mg, 399.34 μmol) was treated with triethylamine (TEA) (40.41 mg, 399.34 μmol) at 15° C. under N ₂ . Added in The mixture was stirred at 30° C. for 3 hours. This mixture was poured into water (30 mL). The aqueous phase was extracted with DCM (20 mL X 2). The combined organic phase was washed with brine (10 mL X 2), dried over anhydrous _Na2SO4 , filtered and concentrated under _vacuum . Purification (reverse phase HPLC (conditions A)) gave the title compound (55 mg) as a white solid. MS (ESI): mass calculated for _{C22H20ClF4N3O3} , _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)quinazolin-7-yl) -4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Process 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 heated to 150 using microwave irradiation. ℃ for 45 minutes. The reaction mixture was extracted with EtOAc. The combined organic layers 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): mass _{calculated for C7H6BrFN2O} , 233.0; m/z found, 233.1 [M+H] ^<+> .

Process 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). After stirring the mixture at 120° C. overnight, additional p-toluenesulfonic acid monohydrate (677 mg, 3.6 mmol) was added and the reaction continued at 120° C. for an additional 2 hours. An additional amount of p-toluenesulfonic acid monohydrate was added (677 mg, 3.6 mmol) and the mixture was stirred at 120° C. for a further 2 hours. The mixture was cooled and then diluted with EtOAc and water. 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, 23% yield) was found to be pure title compound and 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 further afford the title compound (156 mg, 36% yield). MS (ESI): mass _{calculated for C8H4BrFN2O} , 243.0; m/z found, 243.0 [M+H] ^<+> . ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 8.02 (s, 1H), 7.75 (t, J=1.7Hz, 1H), 7.36 (dd, J=9.8, 2.0Hz , 1H).

Process 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 mmol) was added. After stirring the mixture for 10 minutes, 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 hours before being 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 as an off-white solid (216mg). MS (ESI): mass calculated _{for C11H8BrF3N2O2 ,} 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, 1 H), 7.63 (d, J = 1.5 Hz, 1 H), 7.16 (d, J = 2 .0 Hz, 1 H), 4.69-4.85 (m, 1 H), 1.64 (d, J = 6.4 Hz, 3 H).

Process 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), tribasic potassium phosphate (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 heated to 120° C. for 4 hours. The mixture was cooled, then filtered through Celite® and washed with EtOAc. Purification by column chromatography (40-100% EtOAc/heptane) gave the title compound (77 mg, 82% yield) as a pale yellow oil. MS (ESI): mass _{calculated for C32H34F3N5O4Si} , 637.7; m _{/ z} found, 638.3 [M+H] ^<+> .

Process E. (S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(4-(2-chloro-6-fluorophenoxy)-5-((1,1,1-trifluoropropane- 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-1H-1,2 in acetonitrile (MeCN or ACN) ,4-triazol-1-yl)-5-((1,1,1-trifluoropropan-2-yl)oxy)quinazolin-4(3H)-one (69 mg, 0.11 mmol) in solution (3. 5 mL) 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. After the solution was stirred at room temperature for 2 hours, 2-chloro-6-fluorophenol (24 mg, 0.16 mmol) was added. After stirring overnight, the mixture was diluted with EtOAc and water. 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 as a colorless oil (27 mg, 33%). MS (ESI _{) :} mass calculated for _{C38H36ClF4N5O4Si} , _766.3 ; m/z found, 766.3 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 8.64 (s, 1 H), 8.20 (t, J = 2.0 Hz, 1 H), 8.07 (t, J = 2.0 Hz, 1 H), 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 = 7.0Hz, 2H), 1.65 (t, J = 5.9Hz , 3H), 1.41 (t, J=7.3 Hz, 3H), 1.11 (s, 9H).

Process F. (S)-2-(4-(2-chloro-6-fluorophenoxy)-5-((1,1,1-trifluoropropan-2-yl)oxy)quinazolin-7-yl)-4-ethyl -5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. (S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(4-(2-chloro-6-fluorophenoxy)-5-((1, 1,1-trifluoropropan-2-yl)oxy)quinazolin-7-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (27 mg, 0.035 mmol ) was added tetrabutylammonium fluoride (TBAF) (1 M in THF) (0.106 mL, 1 M, 0.106 mmol). The mixture was stirred at room temperature for 0.5 hours and then diluted with diethyl ether. The organics were washed with saturated aqueous _NH4Cl , 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 x 100 mm, 20-100% ACN/10 mM NH ₄ OH in water) to give the title compound as a white solid. obtained (10 mg, 54%). MS (ESI): mass calculated for _{C22H18ClF4N5O4} , _527.9 ; m/z _found , 528.2 [M+H] ^<+ _{> .} ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 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)phthalazin-6-yl) -4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Process A. (S)-6-bromo-1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)phthalazine. 2-Chloro-6-fluorophenol (159 mg, 1.1 mmol) was treated with (S)-6-bromo-1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)phthalazine ( Intermediate 25, 80 mg, 0.225 mmol) was added 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 was stirred at 100° C. for 2 hours to give the mixture was diluted with EtOAc and water. 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 as a yellow semi-solid (80 mg, 82%) with minor impurities. MS (ESI): mass calculated _{for C17H10BrClF4N2O2} , _465.6 ; m/z _found , 465.0 [M+H]< ₊ ^> .

Process B. (S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropane- 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 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), tribasic potassium phosphate (62 mg, 0.3 mmol), and trans-N,N′-dimethylcyclohexane-1,2-diamine (9.2 μL). , 0.902 g/mL, 0.06 mmol) was sparged with argon. The mixture was then heated at 120° C. for 2 hours, cooled, filtered over a pad of Celite®, washed with EtOAc and concentrated. Purification by column chromatography (40-80% EtOAc/heptane) gave the title compound as a colorless oil (94 mg, 84%) with minor impurities. MS (ESI) _: mass calculated _{for C38H36ClF4N5O4Si} , _766.3 ; m/z found, 766.2 [M+H]< ₊ ^> .

Process C. (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)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(1-(2-chloro-6-fluorophenoxy)-8-((1, 1,1-trifluoropropan-2-yl)oxy)phthalazin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (90 mg, 0.12 mmol ) was added tetrabutylammonium fluoride (TBAF) (1 M in THF) (0.14 mL, 1 M, 0.14 mmol). The mixture was stirred at room temperature for 1 hour. Diethyl ether and saturated aqueous NH ₄ Cl were added to the reaction mixture. 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) to give the title compound as a white solid ( 39 mg, 62%). MS ( _ESI ): mass calculated for _{C22H18ClF4N5O4} , _527.9 ; m/ _z found, 528.2 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 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, 2 H), 3.08-3.20 (m, 1 H), 1.66 (t, J=6.1 Hz, 3 H), 1.44 (t, J=7.1 Hz, 3 H).

Example 26: (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.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-((2,5-dichloropyridin-4-yl)oxy)-8-((1,1,1-trifluoropropane-2 -yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. The title compound was treated in a manner analogous to Example 2, Step A, with 2,5-dichloropyridin-4-ol and (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) was prepared by coupling _MS ( _ESI ): mass calculated _{for C29H24Cl2F3N5O4} , _633.1 ; m/z found, 634.1 [M+H]< ₊ ^> .

Process 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 similar to Example 2, Step B. MS ( _{ESI )} : mass calculated _{for C22H18Cl2F3N5O4} , _543.1 ; m/z found, 544.1 [M+H]< ₊ ^> . ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.44 (s, 1 H), 8.13 (d, J=1.8 Hz, 1 H), 8.02-7.93 (m, 2 H), 7. 45 (d, J = 5.7Hz, 1H), 7.11 (s, 1H), 5.04-4.94 (m, 1H), 4.74 (d, J = 6.2Hz, 2H), 3.94 (q, J = 7.2Hz, 2H), 2.20-2.08 (m, 1H), 1.62 (d, J = 6.5Hz, 3H), 1.45 (t, J = 7.3Hz, 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.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-((5-chloro-2-methylpyridin-4-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-((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 (Example 26, production from step A product, 20 mg, 31.52 μmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (11.87 mg, 47.29 μmol, 13.22 μL), (2- Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (SPhos Pd G ₃ ) (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 hours. The reaction mixture was cooled to room temperature and quenched by adding 1N HCl (10 mL), then extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (15 mL), dried over _Na2SO4 , 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) _: mass calculated for _{C30H27ClF3N5O4} , _613.2 ; m _/ z found, 614.1 [M+H]< ₊ ^> .

Process B. (S)-1-(5-chloro-1-((5-chloro-2-methylpyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy ) isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner similar to Example 2, Step B. MS (ESI) _: mass calculated for _{C23H20ClF3N5O4} , _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.

Process A. (S)-5-((benzyloxy)methyl)-2-(1-((5-chloro-2-methoxypyridin-4-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. The title compound was treated with 5-chloro-2-methoxypyridin-4-ol and (S)-3-((benzyloxy)methyl)-1-(1-chloro- 8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21). MS (ESI): mass calculated for _{C30H27ClF3N5O5} , _630.1 ; m _/ z _found , 631.3 [M+H]< ₊ ^> .

Process B. (S)-1-(1-((5-chloro-2-methoxypyridin-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. The title compound was prepared in a manner similar to Example 2, Step B. MS (ESI): mass _calculated for _{C23H21ClF3N5O5} , _539.1 ; m _{/ z} found, 540.1 [M+H] ^<+> . ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.22 (s, 1 H), 8.13 (d, J=1.8 Hz, 1 H), 8.00-7.96 (m, 2 H), 7. 41 (d, J = 5.8Hz, 1H), 6.54 (s, 1H), 5.03-4.96 (m, 1H), 4.75 (d, J = 5.9Hz, 2H), 3.99-3.92 (m, 5H), 2.13 (br t, J = 6.1Hz, 1H), 1.62 (br d, J = 6.4Hz, 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.

Process 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, production from step A NCS (5.09 mg, 38.09 μmol) was added to a solution of the compound (16 mg, 25.40 μmol). The mixture was stirred at 20° C. for 12 hours and then heated to 60° C. for an additional 12 hours. 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 ): mass calculated _{for C30H26Cl2F3N5O5} , _663.1 ; m/z found, _664.3 [M+H]< ₊ ^> .

Process B. (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. The title compound was prepared in a manner similar to Example 2, Step B. MS (ESI): mass _calculated for _{C23H21ClF3N5O5} , _539.1 ; m _{/ z} found, 540.1 [M+H] ^<+> . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.22 (s, 1 H), 8.12 (d, J = 6.0 Hz, 1 H), 7.90 (d, J = 6.0 Hz, 1 H), 7.16 (s, 1H), 6.60 (s, 1H), 4.92-4.86 (m, 1H), 4.73 (d, J = 6.0Hz, 2H), 4.00- 3.90 (m, 5H), 2.12-2.01 (m, 1H), 1.60 (d, J = 6.6Hz, 3H), 1.47 (t, J = 7.2Hz, 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.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-((5-chloro-2-hydroxypyridin-4-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-((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 (from Example 28, Step A) 110 mg, 155.39 μmol) at 15° C. was added trimethylsilyl chloride (TMSCl) (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 hours. The reaction mixture was quenched by adding 1N HCl at room temperature (20 mL) and extracted with ethyl acetate (15 mL×2). The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , 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 C29H24Cl2F3N5O5} , _649.1 ; m/z found, _650.3 [M+H]< ₊ ^> .

Process B. (S)-1-(1-((5-chloro-2-hydroxypyridin-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. The title compound was prepared in a manner similar to Example 2, Step B. MS (ESI): mass calculated for _{C22H19ClF3N5O5} , _525.1 ; m/ _z found, _526.1 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.12 (d, J = 1.8 Hz, 1 H), 8.06 (d, J = 5.7 Hz, 1 H), 7.97 (d, J = 1 .6Hz, 1H), 7.47 (d, J = 5.9Hz, 1H), 7.45 (s, 1H), 6.03 (s, 1H), 5.01-4.95 (m, 1H) ), 4.73 (s, 2H), 3.93 (q, J = 7.2Hz, 2H), 1.59 (d, J = 6.5Hz, 3H), 1.44 (t, J = 7 .2Hz, 3H).

Example 31: (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.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-((1,3-dimethyl-1H-pyrazol-4-yl)oxy)-8-((1,1,1-trifluoro Propan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. The title compound was treated with 1,3-dimethyl-1H-pyrazol-4-ol and (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 prepared by coupling body 21). MS (ESI) _: mass calculated _{for C29H29F3N6O4} , _582.2 ; m _/ z found, 583.3 [M+H] ^<+> .

Process B. (S)-1-(1-((1,3-dimethyl-1H-pyrazol-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. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI ₎ : mass calculated _{for C22H23F3N6O4} , _492.2 ; m _/ z found, 493.1 [M+H] ^<+> . ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.05 (d, J=1.8 Hz, 1 H), 7.95-7.92 (m, 2 H), 7.53 (s, 1 H), 7. 26 (d, J = 5.9Hz, 1H), 5.01-4.94 (m, 1H), 4.72 (d, J = 3.7Hz, 2H), 3.96-3.91 (m , 2H), 3.87 (s, 3H), 2.38 (s, 1H), 2.21 (s, 3H), 1.66 (d, J = 6.5Hz, 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)isoquinoline- 6-yl)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

Process A. (S)-3-((benzyloxy)methyl)-4-ethyl-1-(1-(2-fluoro-5-methylphenoxy)-8-((1,1,1-trifluoropropane-2- yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one. The title compound was treated with 2-fluoro-5-methylphenol and (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) Prepared by ringing. MS (ESI ₎ : mass calculated for _C31H28F4N4O4 , _596.2 ; m _/ z found, 597.3 [M+H]< ₊ ^> .

Process B. (S)-4-ethyl-1-(1-(2-fluoro-5-methylphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl) -3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI): mass calculated _{for C24H22F4N4O4} , _506.2 ; m/z found, 507.2 [M+H] _{< +} ^> . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.09 (d, J = 1.8 Hz, 1 H), 7.95 (d, J = 2.0 Hz, 1 H), 7.89 (d, J = 5 .8Hz, 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, 1 H), 1.62 (d, J=6.4 Hz, 3 H), 1.43 (t, J=7.2 Hz, 3 H).

Example 33: (S)-1-(1-(2-chloro-6-fluoro-3-(2-methoxyethoxy)phenoxy)-8-((1,1,1-trifluoropropan-2-yl ) oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-(2-chloro-6-fluoro-3-(2-methoxyethoxy)phenoxy)-8-((1,1,1-tri Fluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. The title compound was converted to 2-chloro-6-fluoro-3-(2-methoxyethoxy)phenol and (S)-3-((benzyloxy)methyl)-1- (1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazole-5(4H) -one (Intermediate 21). MS (ESI): mass calculated for _{C33H31ClF4N4O6} , _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).

Process B. (S)-1-(1-(2-chloro-6-fluoro-3-(2-methoxyethoxy)phenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline -6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner similar to Example 2, Step B. MS (ESI): mass _calculated for _{C26H25ClF4N4O6} , _600.1 ; m/z found _, 601.2 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.11 (d, J = 1.6 Hz, 1 H), 7.97 (t, J = 1.6 Hz, 1 H), 7.85 (d, J = 1 .6Hz, 1H), 7.30 (d, J = 1.6Hz, 1H), 7.11-7.06 (m, 1H), 6.85-6.82 (m, 1H), 5.02 (s, 1H), 4.73 d, J=5.2Hz, 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. 2Hz, 3H).

Example 34: (S)-1-(1-(2-chloro-6-fluoro-3-(2-hydroxyethoxy)phenoxy)-8-((1,1,1-trifluoropropan-2-yl ) oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

(S)-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 (from Example 33, Step A product, 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 hours. 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 x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure _. Purification (preparative HPLC, method A) gave 90 mg of a mixture of compounds, which was then repurified by preparative HPLC (method D) to give the two title compounds.
(S)-1-(1-(2-chloro-6-fluoro-3-(2-hydroxyethoxy)phenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline -6-yl)-4-ethyl-3-(hydroxymethyl)-1H _- 1,2,4 _- triazol-5(4H)-one MS (ESI): calculated mass, _{C25H23ClF4N4 . O6} , 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 = 5.6Hz, 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=7.2Hz, 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)isoquinoline- 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 C23H19ClF4N4O5} , _542.1 ; _m /z found, 543.1 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.11 (s, 1 H), 7.97 (d, J = 1.6 Hz, 1 H), 7.86 (d, J = 6.0 Hz, 1 H), 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. 6Hz, 3H).

Example 35: (S)-1-(1-(2,5-dimethylphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4 -ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-(2,5-dimethylphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline- 6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. The title compound was treated with 2,5-dimethylphenol and (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1, Coupling 1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21) It was prepared by MS (ESI ₎ : mass calculated _{for C32H31F3N4O4} , _592.2 ; m _/ z found, 593.3 [M+H] ^<+> .

Process 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 C25H25F3N4O4} , _502.1 ; m _/ z found, 503.2 [M+H] ^<+> . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.05 (d, J = 1.9 Hz, 1 H), 7.92 (d, J = 1.8 Hz, 1 H), 7.89 (d, J = 5 .8Hz, 1H), 7.22 (d, J = 5.8Hz, 1H), 7.18 (d, J = 7.7Hz, 1H), 6.98 (d, J = 7.8Hz, 1H) , 6.93 (s, 1H), 5.04-4.95 (m, 1H), 4.72 (br s, 2H), 3.93 (q, J=7.2Hz, 2H), 2. 35 (s, 3H), 2.19 (br s, 1H), 2.14 (s, 3H), 1.63 (d, J=6.4Hz, 3H), 1.44 (t, J=7 .2Hz, 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.

Process 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.
The title compound was treated with 3-chloro-1-methyl-pyrazol-4-ol and (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 prepared by coupling body 21). MS (ESI) _: mass calculated _{for C28H26ClF3N6O4} , _602.1 ; m/z found, 603.2 [M+H]< ₊ ^> .

Process B. (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. The title compound was prepared in a manner similar to Example 2, Step B. MS (ESI): mass calculated for _{C21H20ClF3N6O4} , _512.1 , m/z found, 513.1 _[ M+H] ^<+ _{> .} ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.09 (d, J=1.6 Hz, 1 H), 7.97-7.92 (m, 2 H), 7.62 (s, 1 H), 7. 31 (d, J = 6.0Hz, 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 = 6.4Hz, 3H), 1.44 (t, J = 7.2Hz, 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)methanesulfonamide.

Process A. (S)-methyl 3-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-2-chloro-4-fluorobenzoate. The title compound was converted to methyl 2-chloro-4-fluoro-3-hydroxybenzoate and (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 prepared by coupling body 21). MS (ESI): mass calculated for _{C32H27ClF4N4O6} , _674.1 ; m _/ z found, _675.3 [M+H]< ₊ ^> .

Process B. (S)-3-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)- 8-((1,1,1-trifluoropropan-2-yl)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-chloro-4 - fluorobenzoate (1 g, 1.48 mmol), LiOH. A mixture of H ₂ O (186.50 mg, 4.44 mmol) was stirred at 60° C. for 3 hours under N ₂ atmosphere. 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 _Na2SO4 , 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): mass calculated _{for C31H25ClF4N4O6} , _660.1 ; m/z found _, 661.5 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.13 (d, J=1.7 Hz, 1 H), 8.02-7.96 (m, 2 H), 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).

Process 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. (S)-3-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4 in t-BuOH (2 mL) -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), DPPA (43.72 mg, 158.85 μmol) and TEA (21.43 mg, 211.80 μmol) were added at 25° C. and stirred for 3 hours, after which the mixture was heated to 100° C. and stirred for 12 hours. After stirring, 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 _Na2SO4 , filtered and concentrated under reduced pressure _. HCl/dioxane (2 mL) was added to the residue and then stirred at 20° C. for 1 hour. The reaction mixture was quenched by adding 10 mL of NaHCO ₃ (1 M) at 0° C. and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure _. Subsequent purification (preparative TLC (SiO ₂ , petroleum ether:ethyl acetate=1:1)) gave the title compound (20 mg, 30% yield) as a yellow solid. MS (ESI ₎ : mass calculated for _{C30H26ClF4N5O4} , _631.1 ; m/z _found , 632.1 [M+H]< ₊ ^> .

Process D. (S)-N-(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-fluorophenyl)methanesulfonamide. (S)-1-(1-(3-amino-2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy) in DCM (2 mL) isoquinolin-6-yl)-3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (8 mg, 12.66 μmol), pyridine (2.00 mg , 25.32 μmol) and 4-dimethylaminopyridine (DMAP) (154.64 μg, 1.27 μmol) was added methanesulfonyl chloride (MsCl) (1.31 mg, 11.39 μmol) at 20° C. and 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 _Na2SO4 , 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 _{C31H28ClF4N5O6S} , _709.1 ; m/z found, 710.2 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.12 (d, J = 1.5 Hz, 1 H), 7.99 (d, J = 1.7 Hz, 1 H), 7.83 (d, J = 5 .7Hz, 1H), 7.56 (dd, J = 4.8, 9.3Hz, 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=3.2Hz, 3H), 1.67-1.64 (m, 3H), 1.40 -1.37 (m, 3H).

Process E. (S)-N-(2-chloro-3-((6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-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 similar to Example 2, Step B. MS (ESI) _: mass _calculated for _{C24H22ClF4N5O6S} , _619.1 ; m/z found, 620.1 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.11 (d, J = 1.3 Hz, 1 H), 7.98 (d, J = 1.7 Hz, 1 H), 7.83 (d, J = 5 .7 Hz, 1 H), 7.57 (dd, J=5.1, 9.0 Hz, 1 H), 7.33 (d, J=5.7 Hz, 1 H), 7.20 (t, J=9. 1Hz, 1H), 5.07-4.94 (m, 1H), 4.74 (s, 2H), 3.99-3.89 (m, 2H), 3.06 (d, J=3. 1 Hz, 3H), 1.67-1.64 (m, 3H), 1.48-1.41 (m, 4H).

Example 38: (S)-1-(1-(2-chloro-3-(dimethylamino)-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy ) isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-(2-chloro-3-(dimethylamino)-6-fluorophenoxy)-8-((1,1,1-trifluoropropane -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)oxy) in MeOH (3 mL) isoquinolin-6-yl)-3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (product from Example 37, Step C, 105 mg , 166.14 μmol) To a mixture of HCHO (163.50 mg, 5.45 mmol) and _CH3COOH (19.95 mg, 332.28 μmol) was added _NaBH3CN (104.40 mg, 1.66 mmol) under _N2 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 x 3). The combined organic layers were washed with brine (30 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure _. Purification (preparative TLC, SiO ₂ , petroleum ether:ethyl acetate=2:1) then gave the title compound (90 mg, 81%) as a yellow solid. MS (ESI) _: mass calculated for _{C32H30ClF4N5O4} , _659.2 ; m/ _z found, 600.1 [M+H]< ₊ ^> .

Process B. (S)-1-(1-(2-chloro-3-(dimethylamino)-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-6 -yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner similar to Example 2, Step B. MS (ESI): mass calculated _{for C25H24ClF4N5O4} , _569.1 ; m/ _z found, 570.1 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.11 (d, J = 1.5 Hz, 1 H), 7.97 (s, 1 H), 7.86 (d, J = 5.7 Hz, 1 H), 7.30 (d, J=5.9Hz, 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, 1 H), 1.64 (dd, J=6.4, 13.1 Hz, 3 H), 1.44 (t, J=7.2 Hz, 3 H).

Example 39: (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.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-((3,6-dichloropyridin-2-yl)oxy)-8-((1,1,1-trifluoropropane-2 -yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. The title compound was treated in a manner analogous to Example 2, Step A, with 3,6-dichloropyridin-2(1H)-one and (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 prepared by coupling body 21). MS ( _ESI ): mass calculated _{for C29H24Cl2F3N5O4} , _633.1 ; m/z _found , 634.1 [M+H]< ₊ ^> . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.12 (d, J = 1.6 Hz, 1 H), 8.07 (d, J = 5.8 Hz, 1 H), 7.93 (d, J = 1 .6Hz, 1H), 7.74 (d, J = 8.2Hz, 1H), 7.48 (d, J = 5.8Hz, 1H), 7.42-7.32 (m, 5H), 7 .07 (d, J = 8.2 Hz, 1 H), 4.96 (td, J = 6.2, 12.4 Hz, 1 H), 4.63 (s, 2 H), 4.56 (s, 2 H) , 3.87 (q, J=7.2 Hz, 2H), 1.50 (d, J=6.4 Hz, 3H), 1.37 (t, J=7.2 Hz, 3H).

Process 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 similar to Example 2, Step B. MS ( _{ESI )} : mass calculated _{for C22H18Cl2F3N5O4} , _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 = 5.8Hz, 1H), 7.07 (d, J = 8.2Hz, 1H), 4.95 (td, J = 6.4, 12.4Hz, 1H), 4.71 (s, 2H), 3.92 (q, J = 7.2Hz, 2H), 2.23 (br s, 1H), 1.50 (d, J = 6.4Hz, 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)isoquinoline- 6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-(2-chloro-6-fluoro-3-methoxyphenoxy)-8-((1,1,1-trifluoropropane-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one.
The title compound was treated with 2-chloro-6-fluoro-3-methoxy-phenol and (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 prepared by coupling body 21). MS (ESI): mass calculated _{for C31H27ClF4N4O5} , _646.1 ; m _/ z found, 647.2 [M+H]< ₊ ^> .

Process 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) _: mass calculated for _{C24H21ClF4N4O5} ; 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, 1 H), 7.97 (s, 1 H), 7.86 (d, J = 5.7 Hz, 1 H), 7.31 (d, J=5.7Hz, 1H), 7.11 (dt, J=2.7, 9.2Hz, 1H), 6.80 (dd, J=4.2, 9.2Hz, 1H), 5.10-4.93 (m, 1H), 4.73 (d, J=5.5Hz, 2H), 3.97-3.90 (m, 5H), 2.19-2. 09 (m, 1H), 1.64 (dd, J=6.4, 11.6Hz, 3H), 1.44 (t, J=7.2Hz, 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.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-((3-chloro-2-methoxy-5-methylpyridin-4-yl)oxy)-8-((1,1,1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. The title compound was treated in a manner analogous to Example 2, Step A, with 3-chloro-2-methoxy-5-methylpyridin-4-ol and (S)-3-((benzyloxy)methyl)-1-( 1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazole-5(4H)- Prepared by coupling on (intermediate 21). MS (ESI _{): mass calculated for C31H29ClF3N5O5 , 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).

Process B. (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. The title compound was prepared in a manner similar 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 = 7.2Hz, 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.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-((3-chloro-2-methoxypyridin-4-yl)oxy)-8-((1,1,1-trifluoropropane -2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one.
The title compound was treated with 3-chloro-2-methoxypyridin-4-ol and (S)-3-((benzyloxy)methyl)-1-(1-chloro- 8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21). MS (ESI): mass calculated for _{C30H27ClF3N5O5} , _629.1 ; m/z _found , _630.1 [M+H]< ₊ ^> .

Process B. (S)-1-(1-((3-chloro-2-methoxypyridin-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. The title compound was prepared in a manner similar to Example 2, Step B. MS (ESI): mass calculated _{for C23H21F3N5O5 , 539.1} ; m _/ z found, _540.1 [M+H] ^<+> . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.11 (d, J = 1.5 Hz, 1 H), 8.06 (d, J = 5.6 Hz, 1 H), 7.96 (d, J = 1 .5Hz, 1H), 7.93 (d, J = 5.7Hz, 1H), 7.40-7.35 (m, 1H), 6.77 (d, J = 5.5Hz, 1H), 5 .05-4.94 (m, 1H), 4.73 (d, J = 5.5Hz, 2H), 4.08 (s, 3H), 3.93 (q, J = 7.2Hz, 2H) , 2.18-2.11 (m, 1H), 1.62 (br d, J=6.4Hz, 3H), 1.44 (t, J=7.2Hz, 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.

Process 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-triazole-5(4H)- on. The title compound was prepared in a manner analogous to Example 2, Step A, to give 5-chloro-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol (Intermediate 9). and (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4 -ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21). MS (ESI) _: mass calculated for _{C34H40ClF3N6O5Si} , 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 = 5.9Hz, 1H), 5.39 (d, J = 2.5Hz, 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=7.1Hz, 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).

Process B. (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)-3-((benzyloxy)methyl)-1-(1-((5-chloro-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H in TFA (2 mL) -pyrazol-4-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazole A solution of -5(4H)-one (70 mg, 95.47 μmol) was heated to 80° C. for 15 hours, the reaction was cooled and the TFA was removed in vacuo. The residue was redissolved in MeOH (3 mL) and 140 mg _{of K2CO3} was added. The mixture was stirred for 0.5 h and 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 _{C21H20ClF3N6O4} , _512.1 ; m/ _z found, _513.1 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.08 (d, J = 1.9 Hz, 1 H), 7.95 (d, J = 1.8 Hz, 1 H), 7.91 (d, J = 5 .6Hz, 1H), 7.29 (d, J = 5.8Hz, 1H), 5.05-4.93 (m, 1H), 4.73 (s, 2H), 3.94 (q, J = 7.3 Hz, 2H), 2.24 (s, 3H), 1.66 (d, J = 6.4 Hz, 3H), 1.44 (t, J = 7.2 Hz, 3H).

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

Process A. (S)-3-((benzyloxy)methyl)-1-(1-((3-chloro-2,5-dimethylpyridin-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.
The title compound was treated with 3-chloro-2,5-dimethylpyridin-4-ol and (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 ( Prepared by coupling intermediate 21). MS (ESI) _: mass calculated for _{C31H29ClF3N5O4} , _627.2 ; m _/ z found, _628.2 [M+H] ^<+> .

Process B. (S)-3-((benzyloxy)methyl)-1-(1-((3-chloro-2,5-dimethylpyridin-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.
The title compound was prepared in a manner analogous to Example 2, Step B. MS (ESI) _: mass calculated for _{C24H23ClF3N5O4} , _537.1 ; m/z found _, 538.2 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.31 (d, J = 2.8 Hz, 1 H), 8.09 (d, J = 1.6 Hz, 1 H), 7.96 (dd, J = 1 .7, 4.5Hz, 1H), 7.83 (d, J = 5.8Hz, 1H), 7.30 (d, J = 5.8Hz, 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-tri Fluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazole -3-on.

Process 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 . The title compound was prepared in a manner analogous to Example 63, Step A, with 3-chloro-5-fluoro-2-methoxypyridin-4-ol (Intermediate 28) and (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- Prepared by coupling ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 18). MS (ESI): mass calculated for _{C28H23ClF5N7O5} , _667.1 ; m/ _z found, 668.1 _[ M+H]< ₊ ^> .

Process B. (S)-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)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner similar to Example 63, Step B, as an off-white solid. MS (ESI): mass calculated _{for C21H17ClF5N7O5} , _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 = 5.7Hz, 2H), 3.98 (s, 3H), 3.91-3.76 (m, 2H), 2.18 (br, t, J = 5.9Hz, 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.

Process 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. The title compound was treated with 1-methyl-1H-pyrazol-5-ol and (S)-3-((benzyloxy)methyl)-1-(1-chloro-8) in a manner analogous to Example 18, Step A. -((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21 ) was prepared by coupling MS (ESI): mass calculated _{for C28H27F3N6O4} , _568.2 ; m _/ z _found , 569.2 [M+H] ^<+> .

Process B. (S)-4-ethyl-3-(hydroxymethyl)-1-(1-((1-methyl-1H-pyrazol-5-yl)oxy)-8-((1,1,1-trifluoropropane -2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 18, Step B. MS (ESI) _: mass calculated for _C21H21F3N6O4 , _478.2 ; m _/ z _found , 479.2 [M+H] ^<+> . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.09 (d, J = 2.0 Hz, 1 H), 7.98 (d, J = 1.8 Hz, 1 H), 7.96 (d, J = 5 .8Hz, 1H), 7.50 (d, J = 2.0Hz, 1H), 7.36 (d, J = 5.8Hz, 1H), 6.02 (d, J = 2.0Hz, 1H) , 5.03-4.97 (m, 1H), 4.73 (d, J = 6.0Hz, 2H), 3.93 (q, J = 7.2Hz, 2H), 3.76 (s, 3H), 2.17 (t, J=6.2 Hz, 1 H), 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.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-((3-chloro-6-methoxypyridin-2-yl)oxy)-8-((1,1,1-trifluoropropane -2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one.
The title compound was treated with 3-chloro-6-methoxypyridin-2(1H)-one and (S)-3-((benzyloxy)methyl)-1-(1) in a manner analogous to Example 18, Step A. -chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one Prepared by coupling (Intermediate 21). MS (ESI _{): mass calculated for C30H27ClF3N5O5 , 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. 6Hz, 1H) 7.64 (d, J = 8.4Hz, 1H) 7.46 (d, J = 5.6Hz, 1H) 7.31-7.44 (m, 5H), 6.47 (d , J = 8.4 Hz, 1H), 5.02-4.934.97 (m, 1H), 4.63 (s, 2H), 4.56 (s, 2H), 3.90-3.84 (m, 2H) 3.50 (s, 3H) 1.50 (d, J = 6.4 Hz, 3H) 1.37 (t, J = 7.2 Hz, 3H).

Process B. (S)-1-(1-((3-chloro-6-methoxypyridin-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. The title compound was prepared in a manner analogous to Example 18, Step B. MS (ESI) _: mass _calculated for _{C23H21ClF3N5O5} , _539.12 ; m/z found, 540.2 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.11 (d, J = 1.6 Hz, 1 H), 8.08 (d, J = 6.0 Hz, 1 H), 7.90 (d, J = 2 0 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 1 H), 7.45 (d, J = 5.6 Hz, 1 H), 6.48 (d, J = 8.4 Hz, 1 H) , 4.99-4.93 (m, 1H), 4.72 (d, J = 5.6Hz, 2H), 3.92 (q, J = 7.2Hz, 2H), 3.50 (s, 3H), 2.11 (s, 1H), 1.50 (d, J=6.4Hz, 3H), 1.43 (t, J=7.2Hz, 3H).

Example 48: (S)-1-(1-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl) Oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)-8-((1,1,1-trifluoro Propan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. The title compound was treated with 1,3-dimethyl-1H-pyrazol-5-ol and (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 prepared by coupling body 21). MS (ESI): mass calculated _{for C29H29F3N6O4} , _582.2 ; m _/ z found, _583.4 [M+H] ^<+> .

Process B. (S)-1-(1-((1,3-dimethyl-1H-pyrazol-5-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. The title compound was prepared in a manner analogous to Example 18, Step B. MS (ESI): mass calculated _{for C22H23F3N6O4} , _492.1 ; m _/ z found, 493.3 [ _M +H] ^<+> . ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.08 (d, J=1.8 Hz, 1 H), 7.98-7.95 (m, 2 H), 5.83 (s, 1 H), 4. 99 (td, J = 6.3, 12.5Hz, 1H), 4.72 (s, 2H), 3.93 (q, J = 7.2Hz, 2H), 3.68 (s, 3H), 2.54-2.35 (m, 1H), 2.29 (s, 3H), 1.64 (d, J = 6.5Hz, 3H), 1.43 (t, J = 7.2Hz, 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.

Process A. (S)-3-((benzyloxy)methyl)-1-(1-((2-chloro-5-fluoropyridin-4-yl)oxy)-8-((1,1,1-trifluoropropane -2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. The title compound was treated with 2-chloro-5-fluoropyridin-4-ol and (S)-3-((benzyloxy)methyl)-1-(1-chloro- 8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21). MS (ESI): mass calculated for _{C29H24ClF4N5O4} , _617.1 ; _m / _z found, 618.2 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.32 (d, J = 2.1 Hz, 1 H), 8.14 (d, J = 1.8 Hz, 1 H), 7.99 (d, J = 1 .7Hz, 1H), 7.95 (d, J = 5.6Hz, 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=6.5Hz, 3H), 1.38 (t, J=7.2Hz, 3H).

Process B. (S)-1-(1-((2-chloro-5-fluoropyridin-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. The title compound was prepared in a manner analogous to Example 18, Step B. MS ( _{ESI )} : mass calculated for _{C22H18ClF4N5O4} , _527.1 ; m/z found, 528.1 [M+H] ^<+> _. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.32 (d, J = 2.1 Hz, 1 H), 8.13 (d, J = 1.8 Hz, 1 H), 7.98 (d, J = 1 .6Hz, 1H), 7.95 (d, J = 5.8Hz, 1H), 7.43 (d, J = 5.9Hz, 1H), 7.26-7.24 (m, 1H), 5 .01-4.92 (m, 1H), 4.74 (d, J=6.3Hz, 2H), 3.98-3.89 (m, 2H), 2.18 (s, 1H), 1 .64 (d, J=6.5 Hz, 3 H), 1.44 (t, J=7.2 Hz, 3 H).

Example 50: (S)-4-ethyl-3-(hydroxymethyl)-1-(1-((tetrahydro-2H-pyran-4-yl)oxy)-8-((1,1,1-tri Fluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one.

Process A. (S)-3-((benzyloxy)methyl)-4-ethyl-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. NaH (27.62 mg, 690.47 μmol, 60% purity) was added to tetrahydropyran-4-ol (2.04 g, 19.97 mmol, 2 mL) at 0° C. under N ₂ . The mixture was stirred at 0°C for 30 minutes and then (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 and heated to 120° C. for 6 h. bottom. The mixture was cooled and poured into 1N HCl (5 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous _Na2SO4 , 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) _: mass calculated _{for C29H31F3N4O5} , _572.2 ; m _/ z found, 573.1 [M+H] ^<+> .

Process B. (S)-4-ethyl-3-(hydroxymethyl)-1-(1-((tetrahydro-2H-pyran-4-yl)oxy)-8-((1,1,1-trifluoropropane-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, To a solution of 1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one (100 mg, 179 μmol) was added BCl ₃ (1M , 358 μL) was added. The mixture was stirred at -78°C for 1 hour. The reaction mixture was diluted with _H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , filtered and concentrated _under reduced pressure to give a residue. The crude product was purified by RP HPLC (conditions A) to give the title compound (41 mg, 47.6% yield) as a white solid. MS (ESI): mass calculated for _C22H25F3N4O5 ; 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, 1 H), 7.91 (d, J = 5.7 Hz, 1 H), 7.83 (d, J = 1 .8Hz, 1H), 7.14 (d, J = 5.9Hz, 1H), 5.53-5.41 (m, 1H), 5.02-4.91 (m, 1H), 4.72 (br s, 2H), 4.06 (br dd, J = 4.4, 11.6 Hz, 2H), 3.92 (q, J = 7.2 Hz, 2H), 3.71-3.59 ( m, 2H), 2.23-2.12 (m, 2H), 2.12-2.05 (m, 1H), 2.00-1.86 (m, 2H), 1.64 (d, J=6.5 Hz, 3H), 1.43 (t, J=7.2 Hz, 3H).

Example 51: (S)-4-ethyl-3-(hydroxymethyl)-1-(1-(pentan-3-yloxy)-8-((1,1,1-trifluoropropan-2-yl) Oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one.

Process A. (S)-5-((benzyloxy)methyl)-4-ethyl-2-(1-(pentan-3-yloxy)-8-((1,1,1-trifluoropropan-2-yl)oxy ) isoquinolin-6-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one.
The title compound was treated with pentan-3-ol and (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) Prepared by MS (ESI): _{mass calculated} for _C29H33F3N4O4 ; m/z found, _558.6 ; m/ _z found, 559.5 [M+H] ^<+> .

Process B. (S)-4-ethyl-3-(hydroxymethyl)-1-(1-(pentan-3-yloxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline- 6-yl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner similar to Example 50, Step B, as a white solid. MS (ESI): _{mass calculated} for _C22H27F3N4O4 ; 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 .6Hz, 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)isoquinoline -6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

Process A. (S)-5-((benzyloxy)methyl)-2-(1-((1,3-dimethoxypropan-2-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.
The title compound was purified with 1,3-dimethoxypropan-2-ol and (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) was prepared by coupling MS (ESI) _: mass calculated for _C29H33F3N4O6 ; m/z found, _590.6 ; m/z found, 591.5 [M+H] ^<+ _{> .}

Process B. (S)-1-(1-((1,3-dimethoxypropan-2-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl )-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.
The title compound was prepared in a manner similar to Example 50, Step B, as a white solid. MS (ESI) _: mass _calculated for _C22H27F3N4O6 ; 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, 1 H), 7.92 (d, J = 5.8 Hz, 1 H), 7.81 (d, J = 1 .8Hz, 1H), 7.14 (d, J = 5.9Hz, 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=2.9Hz, 6H), 2.31 −1.89 (m, 1H), 1.62-1.60 (m, 3H), 1.42 (t, J=7.2Hz, 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.

Process A. 5-((benzyloxy)methyl)-4-ethyl-2-(1-(((1R,2R)-2-methylcyclohexyl)oxy)-8-(((S)-1,1,1-tri Fluoropropan-2-yl)oxy)isoquinolin-6-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was treated with trans-2-methylcyclohexanol and (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). It was prepared by MS (ESI): _mass calculated for _C31H35F3N4O4 ; m/z found, _584.6 ; m/ _z found, 585.7 [M+H]< ₊ ^> .

Process B. 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. The title compound was prepared in a manner similar to Example 50, Step B, as a white solid. _MS (ESI): mass calculated for _C24H29F3N4O4 ; 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)isoquinoline -6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

Process A. (S)-5-((benzyloxy)methyl)-2-(1-((1,3-bis(benzyloxy)propan-2-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. The title compound was treated in a manner analogous to Example 50, Step A, with 1,3-bis(benzyloxy)propan-2-ol of tetrahydropyran-4-ol and (S)-3-((benzyloxy)methyl )-1-(1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazole- Prepared by coupling 5(4H)-one (Intermediate 21). MS ( _ESI ) _: mass calculated for _C41H41F3N4O6 ; m/z found, _742.8 ; m/z found, 743.5 [M+H]< ₊ ^> .

Process B. (S)-1-(1-((1,3-dihydroxypropan-2-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl )-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner similar to Example 50, Step B, as a white solid. MS (ESI) _: mass calculated for _C20H23F3N4O6 ; 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, 1 H), 7.94-7.85 (m, 2 H), 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)isoquinoline-6- yl)-1H-1,2,4-triazol-5(4H)-one.

Process A. (S)-5-((benzyloxy)methyl)-4-ethyl-2-(1-isobutoxy-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl )-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was treated with 2-methylpropan-1-ol and (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) Prepared by ringing. MS (ESI): mass calculated _{for C28H31F3N4O4} , _544.6 ; m _/ z found, _545.4 [M+H] ^<+> .

Process B. (S)-4-ethyl-3-(hydroxymethyl)-1-(1-isobutoxy-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H -1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner similar to Example 50, Step B, as a white solid. MS (ESI ₎ : mass calculated _{for C21H25F3N4O4} , _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 = 5.9Hz, 1H ), 5.04-4.95 (m, 1H), 4.71 (d, J = 5.9Hz, 2H), 4.26-4.15 (m, 2H), 3.92 (q, J = 7.2Hz, 2H), 2.27-2.17 (m, 2H), 1.63 (d, J = 6.4Hz, 3H), 1.43 (t, J = 7.2Hz, 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-trifluoropropan-2-yl)oxy ) isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one.

Step A:
The title compound was treated with 2-methoxyethanol and (S)-3-((benzyloxy)methyl)-1-(1-chloro-8-((1,1, by coupling 1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21) prepared. MS ( _ESI ) _: mass calculated for _C27H29F3N4O5 ; m/z found, _546.6 ; m/z found, 547.5 [M+H]< ₊ ^> .

Process B. (S)-4-ethyl-3-(hydroxymethyl)-1-(1-(2-methoxyethoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-6 -yl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner similar to Example 50, Step B, as a white solid. MS ( _ESI ): mass calculated for _C20H23F3N4O5 ; 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, 1 H), 7.83 (d, J = 1.7 Hz, 1 H), 7.16 (d, J = 5 .9Hz, 1H), 5.05-4.91 (m, 1H), 4.70 (d, J = 6.1Hz, 2H), 4.60 (t, J = 4.8Hz, 2H), 3 .97-3.80 (m, 4H), 2.34-2.21 (m, 1H), 1.63 (d, J=6.4Hz, 3H), 1.42 (t, J=7. 2Hz, 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.

Process 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. The title compound was treated with 3-methoxytetrahydro-2H-pyran-4-ol and (S)-3-((benzyloxy)methyl)-1-(1-chloro- 8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21). MS (ESI) _: mass calculated for _C30H33F3N4O6 ; m/z found, _602.6 ; m/z found, 603.3 _[ M+H]< ₊ ^> .

Process B. 4-ethyl-3-(hydroxymethyl)-1-(1-((3-methoxytetrahydro-2H-pyran-4-yl)oxy)-8-(((S)-1,1,1-trifluoro Propan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner similar to Example 50, Step B, as a white solid. MS (ESI): mass calcd, _C23H27F3N4O6 ; 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, 3 H).

Example 58: 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.

Process A. 2-(1-((1-(benzyloxy)-3-methoxypropan-2-yl)oxy)-8-(((S)-1,1,1-trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-5-((benzyloxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was treated with 1-(benzyloxy)-3-methoxypropan-2-ol and (S)-3-((benzyloxy)methyl)-1-(1) in a manner analogous to Example 50, Step A. -chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one Prepared by coupling (Intermediate 21). MS (ESI) _: mass _calculated for _C35H37F3N4O6 ; m/z _found , _666.7 ; m/z found, 667.8 [M+H] ^<+> .

Process B. 4-ethyl-1-(1-((1-hydroxy-3-methoxypropan-2-yl)oxy)-8-(((S)-1,1,1-trifluoropropan-2-yl)oxy ) isoquinolin-6-yl)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner similar to Example 50, Step B, as a white solid. MS (ESI): mass calculated for _C2IH25F3N4O6 ; 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 (br s, 2H), 4.64-4.46 (m, 2H), 4.30-4.21 (m, 1H), 4 .07-3.79 (m, 3H), 3.78-3.54 (m, 2H), 3.46-3.40 (m, 3H), 2.36 (br d, J=2.1Hz , 1H), 1.68-1.65 (m, 3H), 1.43 (t, J=7.2Hz, 3H).

Example 59: (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.

Process A. (S)-5-((benzyloxy)methyl)-2-(1-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-8-((1,1,1- Trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was treated in a manner analogous to Example 50, Step A, with 4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide and (S)-3-((benzyloxy)methyl)-1-(1-chloro- 8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (intermediate 21). MS (ESI) _: mass calculated for _{C29H31F3N4O6S} ; m/z _found , _620.6 ; m _/ z found, 621.5 [M+H] ^<+> .

Process B. (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 The title compound was prepared as a white solid in a manner analogous to Example 50, Step B. MS (ESI): calculated mass, _{C22H25F3N4O6S} ; m _/ z found, _530.1 ; m/ _{z found} , 531.2 [M+H] ^{+ .1H} NMR (400 MHz, CDCl ₃ ) δ=8.00 (d, J=1.8 Hz, 1 H), 7.95-7.87 (m, 2 H), 7.20 (d, J=5.7 Hz, 1 H), 5. 73-5.60 (m, 1H), 5.12-4.97 (m, 1H), 4.73 (s, 2H), 4.01-3.85 (m, 2H), 3.59- 3.24 (m, 2H), 3.12-2.93 (m, 2H), 2.77-2.38 (m, 4H), 2.17-2.02 (m, 1H), 1. 69 (d, J=6.4 Hz, 3H), 1.43 (t, J=7.2 Hz, 3H).

Example 60: 2-(1-(6-chloro-2-fluoro-3-methoxyphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl) -4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Process A. 5-((benzyloxy)methyl)-2-(1-(6-chloro-2-fluoro-3-methoxyphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was converted to 6-chloro-2-fluoro-3-methoxyphenol and 5-((benzyloxy)methyl)-2-(1-chloro-8-(( 1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 20 ) was prepared by coupling MS (ESI): mass calculated for _{C31H27ClF4N4O5} ; m/z found, _647.0 ; m/z found, _648.2 [M+H] ^<+ _{> .}

Process B. 2-(1-(6-chloro-2-fluoro-3-methoxyphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl -5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared in a manner similar to Example 1, Step B, as a white solid. MS ( _ESI ): mass calculated for _{C24H21ClF4N4O5} ; 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 = 6.5Hz, 1H), 7.32 (d, J = 6.8Hz, 1H), 7.22 (dd, J = 7.0, 5.5Hz, 1H), 6.81 (m, 1H), 5.01 (m, 1H), 4.73 ( s, 2H), 3.96 (s, 3H), 3.94 (t, J = 8.2Hz, 2H), 1.65 (t, J = 8.5Hz, 3H), 1.42 (t, J=8.0Hz, 3H).

Example 61: 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.

Process A. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-fluoro-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 (Intermediate 20, product D from step, 15 mg, 0.031 mmol) was treated with 1-chloromethyl-4-fluoro-1 ,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (Selectfluor®) (16.3 mg, 0.046 mmol) in a mixed solvent of ACN (1 mL) and MeOH (1 mL). , 50° C. for 1 hour. 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): mass calculated for _C25H26F4N4O5 ; m/z found, _538.2 ; m/ _z found, _539.4 [M+H]< ₊ ^> .

Process 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 hour. Solvent was removed in vacuo and dried to give crude product without further purification. MS (ESI): mass calculated _{for C25H25ClF4N4O4} ; m/z found, _556.2 ; m/z found, 557.4 [M+H] ^<+ _{> .}

Process C. 5-((benzyloxy)methyl)-2-(1-chloro-4-fluoro-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4- Ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. 5-((benzyloxy)methyl)-2-(1-chloro-4-fluoro-3-methoxy-8-((1,1,1 -trifluoropropan-2-yl)oxy)-3,4-dihydroisoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (20 mg, 0.036 mmol) was stirred at room temperature for 1 hour. Solvent was removed in vacuo and purification (silica gel flash column system using 20-80% ethyl acetate in heptane) gave the title compound as a white solid (12 mg, 63%). MS (ESI): mass calculated _{for C24H21ClF4N4O3} ; m/z _found , _524.1 ; m/z found, 525.4 [M+H]< ₊ ^> .

Process D. 5-((benzyloxy)methyl)-2-(1-(2-chloro-6-fluorophenoxy)-4-fluoro-8-((1,1,1-trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was converted to 2-chloro-6-fluorophenol and 5-((benzyloxy)methyl)-2-(1-chloro-4-fluoro-8-(( Coupling 1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one It was prepared by MS (ESI): mass calculated _{for C30H24ClF5N4O4} , _634.1 ; m _/ z found, 635.4 [M+H]< ₊ ^> .

Process E. 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. The title compound was prepared in a manner similar to Example 1, Step B. MS (ESI): mass calculated for _{C23H18ClF5N4O4} ; 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.

Process A. 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. The title compound was converted to 6-chloro-2-fluoro-phenol and 3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-(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) -one (Intermediate 17). MS (ESI): _mass calculated _{for C28H22ClF5N6O4} ; m/z found, _636.1 ; m/z found, 637.1 [M+H]< ₊ ^> .

Process B. 1-(4-(2-chloro-6-fluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazine- 7-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner similar to Example 1, Step B. MS ( _ESI ): mass calculated, _{C21H16ClF5N6O4} ; 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 = 6.2Hz, 2H), 3.95 (q, J = 7.2Hz, 2H) ), 2.29-2.12 (m, 1H), 1.67 (d, J=6.5Hz, 3H), 1.46 (t, J=7.2Hz, 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.

Process A. (S)-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. NaH (60% purity, 418 mg, 10.44 mmol) was slowly added to a mixture of 2-chloro-6-fluorophenol (6.12 g, 41.76 mmol) in DMF (5 mL) at room temperature. After the addition, the mixture was heated to 70° C. for 0.5 hours. (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido [ 3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 18, 1.1 g crude, 2.09 mmol) at 70°C. and the reaction mixture was further stirred at 70° C. for 2 hours. The mixture was cooled, diluted with ethyl acetate (20 mL), 1 M HCl aqueous solution was added slowly, and the pH was adjusted to 6 with an ice-water bath. The mixture was separated and the organic layer was washed with brine (15 mL), dried over _Na2SO4 , 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): _mass calculated _{for C28H22ClF5N6O4} ; 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=6.6Hz, 3H), 1.36-1.29 (m, 3H).

Process 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-((1,1,1- Trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (900 mg, 1. 08 mmol) was added BCl ₃ (1 M solution in toluene, 6.52 mL, 6.52 mmol) at −78° C. under N ₂ over 1 h. The reaction mixture was quenched by adding saturated aqueous NaHCO ₃ (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 _Na2SO4 , filtered and concentrated under reduced pressure _. Purification (column chromatography, gradient elution: 0-100% ethyl acetate in petroleum ether) followed by preparative HPLC (stationary phase: Boston Prime C18, 5 μm, 150×30 mm; mobile phase: water (0.04% NH ₃ /H ₂ O + 10 mM NH ₄ HCO ₃ )(A)-MeCN(B), gradient elution: 40-70% B in A over 7 min, flow rate: 25 mL/min) to give the title compound (420 mg). , 69%) as a white solid. MS (ESI): mass calculated for _{C21H16ClF5N6O4} ; 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 = 4.6Hz, 1H) , 5.82 (br t, J=5.7 Hz, 1 H), 4.49 (d, J=5.5 Hz, 2 H), 3.79 (q, J=7.3 Hz, 2 H), 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-tri fluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.

Process 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-triazol-5(4H)-one. The title compound was treated with 3-methoxytetrahydro-2H-pyran-4-ol and (S)-3-((benzyloxy)methyl)-1-(4-chloro- 8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4 -triazol-5(4H)-one (Intermediate 18). MS (ESI): mass calculated for _C28H30F4N6O6 ; m/z found, _622.2 ; m/ _z found _, 623.1 [M+H]< ₊ ^> .

Process B. 4-ethyl-1-(8-fluoro-4-((3-methoxytetrahydro-2H-pyran-4-yl)oxy)-5-(((S)-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 50, Step B. MS (ESI): mass calculated for _C2IH24F4N6O6 ; 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-naphthyridine -3-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Process A. 5-((benzyloxy)methyl)-2-(8-(2-chloro-6-fluorophenoxy)-4-fluoro-1-((1,1,1-trifluoropropan-2-yl)oxy) -2,7-naphthyridin-3-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was converted to 6-chloro-2-fluoro-phenol and 5-((benzyloxy)methyl)-2-(8-chloro-4-fluoro-1-(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-triazole-3 -one (Intermediate 19). MS ( _ESI ): mass calculated _{for C29H23ClF5N5O4} ; m/z found, _635.2 ; m/z found, 636.5 [M+H]< ₊ ^> .

Process B. 2-(8-(2-chloro-6-fluorophenoxy)-4-fluoro-1-((1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthyridin-3-yl )-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared in a manner similar to Example 1, Step B. _MS (ESI): mass calculated for _{C22H17ClF5N5O4} ; 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, 1 H), 7.55 (d, J = 7.1 Hz, 1 H), 7.32 (m, 1 H), 7.25 (m, 2H), 5.98 (m, 1H), 4.75 (s, 2H), 3.98 (m, J = 8.5Hz, 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.

Process A. (S)-3-((benzyloxy)methyl)-4-ethyl-1-(8-fluoro-4-(o-tolyloxy)-5-((1,1,1-trifluoropropan-2-yl ) oxy)pyrido[3,4-d]pyridazin-7-yl)-1H-1,2,4-triazol-5(4H)-one. The title compound was treated with o-cresol and (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 Prepared by coupling (Intermediate 18). MS (ESI): mass calcd _{, C29H26F4N6O4} ; _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, 2 H), 2.23 (s, 3 H), 1.67 (d, J = 6.6 Hz, 3 H), 1.42 (t, J = 7.2 Hz, 3 H).

Process B. (S)-4-ethyl-1-(8-fluoro-4-(o-tolyloxy)-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): mass calculated _{for C22H20F4N6O4} ; 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, 1 H), 4.72 (s, 2 H), 3.96 (q, J = 7.2 Hz, 2 H), 2.65 (br s, 1 H), 2.23 (s , 3H), 1.67 (s, 3H), 1.47 (t, J=7.2 Hz, 3H).

Example 67: (S)-4-ethyl-2-(8-fluoro-4-(4-fluoro-2-methylphenoxy)-5-((1,1,1-trifluoropropan-2-yl) Oxy)pyrido[3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Process A. (S)-3-((benzyloxy)methyl)-4-ethyl-1-(8-fluoro-4-(4-fluoro-2-methylphenoxy)-5-((1,1,1-trifluoro Propan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-1H-1,2,4-triazol-5(4H)-one. The title compound was treated with 4-fluoro-2-methylphenol and (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 Prepared by coupling (4H)-one (Intermediate 18). MS (ESI): mass _calculated for _C29H25F5N6O4 ; 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).

Process B. (S)-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)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): mass calculated for _C22H19F5N6O4 ; 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, 1 H), 4.65 (s, 2 H), 3.87 (q, J = 7.1 Hz, 2 H), 2.21 (br s, 1 H), 2.12 (s, 3 H), 1.58 (d, J=6.6 Hz, 3 H), 1.39 (t, J=7.2 Hz, 3 H).

Example 68: (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.

Process A. (S)-3-((benzyloxy)methyl)-4-ethyl-1-(8-fluoro-4-(5-fluoro-2-methylphenoxy)-5-((1,1,1-trifluoro Propan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-1H-1,2,4-triazol-5(4H)-one. The title compound was treated with 5-fluoro-2-methylphenol and (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 Prepared by coupling (4H)-one (Intermediate 18) as a yellow oil. MS (ESI): mass calculated _{for C29H25F5N6O4} , _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=6.4Hz, 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).

Process B. (S)-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)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one.
The title compound was prepared in a manner similar to Example 63, Step B, as an off-white powder. MS (ESI): mass calculated for _C22H19F5N6O4 , _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, 8.5Hz, 1H), 6.03-5.81 (m, 2H), 4.53 (d, J = 5.5Hz, 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. 2Hz, 3H).

Example 69: (S)-2-(4-(2-chloro-4,6-difluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy) Pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Process A. (S)-3-((benzyloxy)methyl)-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-1H-1,2,4-triazol-5(4H)-one. The title compound was treated with 2-chloro-4,6-difluorophenol and (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 Prepared by coupling -5(4H)-one (Intermediate 18). MS (ESI): mass calculated _{for C28H21ClF6N6O4} ; m/z found, _654.1 ; m/z found, 655.1 [M+H] ^<+ _{> .}

Process B. (S)-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-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 63, Step B. MS ( _ESI ): mass calculated _{for C21H15ClF6N6O4} ; 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, 1 H), 4.71 (d, J = 6.2 Hz, 2 H), 3.92 (q, J = 7.3 Hz, 2 H), 2.16 (br s, 1 H ), 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.

Process A. (S)-3-((benzyloxy)methyl)-4-ethyl-1-(8-fluoro-4-(2-methoxyphenoxy)-5-((1,1,1-trifluoropropane-2- yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-1H-1,2,4-triazol-5(4H)-one. The title compound was treated with 2-methoxyphenol and (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)- Prepared by coupling on (intermediate 18). MS (ESI): mass _calculated for _C29H26F4N6O5 ; 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=1.5Hz, 1H),7. 23 (br s, 1H), 7.05-6.99 (m, 2H), 5.88 (quin, J=6.4Hz, 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=6.4Hz, 3H), 1.37 (t, J=7.3 Hz, 3H).

Process 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 ): mass calculated for _C22H20F4N6O5 ; 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, 1 H), 5.93 (quin, J=6.5 Hz, 1 H), 5.87 (t, J=5.8 Hz, 1 H), 4.53 (d, J = 5.7Hz, 2H), 3.83 (q, J = 7.0Hz, 2H), 3.69 (s, 3H), 1.60 (d, J = 6.4Hz, 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-triazole-3 -on.

Process 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. The title compound was treated with 2-methoxy-3,5-dimethylpyridin-4-ol and (S)-3-((benzyloxy)methyl)-1-(4- Chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2 , 4-triazol-5(4H)-one (Intermediate 18). MS (ESI) _: mass calculated for _C30H29F4N7O5 , _643.2 ; m _/ z found, 644.1 [M+H] ^<+> _.

Process B. (S)-4-ethyl-1-(8-fluoro-4-((2-methoxy-3,5-dimethylpyridin-4-yl)oxy)-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): mass calculated _{for C23H23F4N7O5} , _553.2 ; m _{/ z} found, 554.5 [M+H] ^<+> . ¹ H NMR (400 MHz, CDCl ₃ ) δ=9.57 (s, 1 H), 7.96 (s, 1 H), 5.95 (dq, J=4.5, 6.4 Hz, 1 H), 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=6.6Hz, 3H), 1.48 (t, J=7.2Hz, 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 .

Process 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-triazol-5(4H)-one. The title compound was treated with 2-chloro-4-methylpyridin-3-ol and (S)-3-((benzyloxy)methyl)-1-(4-chloro- 8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4 -triazol-5(4H)-one (Intermediate 18). _MS (ESI): mass calculated for _{C28H24ClF4N7O4} ; m/z found, _633.2 ; m/ _z found, 634.1 [M+H]< ₊ ^> .

Process B. (S)-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-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): mass calculated for _{C21H18ClF4N7O4} ; 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, 12.6Hz, 1H), 4.71 (d, J = 6.2Hz, 2H), 3.93 (q, J = 7.1Hz, 2H), 2.33 -2.23 (m, 3H), 2.17 (s, 1H), 1.65 (dd, J = 3.1, 6.4Hz, 3H), 1.44 (t, J = 7.2Hz, 3H).

Example 73: (S)-2-(4-((5-chloro-3-methyl-1H-pyrazol-4-yl)oxy)-8-fluoro-5-((1,1,1-trifluoro Propan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazole- 3-on.

Process A. (S)-3-((benzyloxy)methyl)-1-(4-((5-chloro-3-methyl-1-((2-(trimethylsilyl)ethoxy)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-1H-1 , 2,4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 63, Step A, to give 5-chloro-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol (Intermediate 9). and (S)-3-((benzyloxy)methyl)-1-(4-chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido [3, Prepared by coupling 4-d]pyridazin-7-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 18). MS (ESI) _: mass calculated for _{C32H37ClF4N8O5Si} , _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=6.4Hz, 1H), 5. 37 (s, 2H), 4.63 (s, 2H), 4.54 (s, 2H), 3.87 (q, J=7.2Hz, 2H), 3.72-3.61 (m, 2H), 2.29 (s, 3H), 1.68-1.62 (m, 3H), 1.37 (t, J = 7.2Hz, 3H), 0.96-0.87 (m, 2H), 0.00 (s, 9H).

Process B. (S)-1-(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-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): mass calculated for _{C19H17ClF4N8O4} , _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 = 7.2Hz, 2H), 2.72 (br s, 1H), 2.20 (s, 3H), 1.60 (br s, 3H), 1.38 (t, J = 7.2Hz, 3H).

Example 74: (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-triazol-3-one.

Process A. (S)-3-((benzyloxy)methyl)-1-(4-((1,3-dimethoxypropan-2-yl)oxy)-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. The title compound was purified with 1,3-dimethoxypropan-2-ol and (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 Prepared by coupling -5(4H)-one (Intermediate 18). MS ( _ESI ): mass calculated _{for C27H30F4N6O6} ; m/z found, _610.2 ; m/z found, 611.1 [M+H]< ₊ ^> .

Process B. (S)-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-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner analogous to Example 63, Step B. MS (ESI): mass calculated, _C20H24F4N6O6 ; _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 .9Hz, 6H), 2.15 (t, J = 6.3Hz, 1H), 1.56 (d, J = 6.4Hz, 3H), 1.37 (t, J = 7.2Hz, 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.

Process 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.
The title compound was treated in a manner analogous to Example 63, Step A, with 2-chloro-6-fluorophenol and 5-((benzyloxy)methyl)-2-(4-chloro-8-fluoro-5-isopropoxy By coupling pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (intermediate 29) prepared. MS (ESI): mass calculated _{for C28H25ClF2N6O4} ; m/z _found , _582.9 ; m/z found, _583.9 [M+H] ^<+> .

Process 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. The title compound was prepared in a manner similar to Example 63, Step B, as an off-white solid. MS (ESI): mass calculated for _{C21H19ClF2N6O4} ; m/z _found , _492.8 ; m/z found, 493.6 _[ M+H]< ₊ ^> . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.24 (s, 1 H), 7.02 (d, J = 7.5 Hz, 1 H), 6.91 (d, J = 7.0 Hz, 1 H), 6.82 (m, J = 6.2 Hz, 1 H), 4.90 (br, s, 1 H), 4.72 (m, J = 5.6 Hz, 1 H), 4.52 (t, J = 7 .5Hz, 2H), 3.92 (q, J = 9.5Hz, 2H), 1.34 (d, J = 9.5Hz, 6H), 1.21 (t, J = 8.5Hz, 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.

Process A. (S)-5-((benzyloxy)methyl)-4-ethyl-2-(8-fluoro-4-(o-tolylamino)-5-((1,1,1-trifluoropropan-2-yl ) oxy)pyrido[3,4-d]pyridazin-7-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one. NaH (60% purity, 200 mg, 4.27 mmol) was slowly added to a mixture of o-toluidine (1.76 g, 16.4 mmol) in DMF (10 mL) at room temperature. After the addition, the mixed reaction was heated to 60° C. for 0.5 hours. (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 (900 mg, 1.09 mmol) was slowly added to the mixed solution at 60° C., The reaction mixture was allowed to stir at 60° C. for an additional hour. The mixture was cooled, diluted with ethyl acetate (20 mL), 1 M HCl aqueous solution was added slowly, and the pH was adjusted to 6 with an ice-water bath. The mixture was separated and the organic layer was washed with brine (45 mL), dried over _Na2SO4 , filtered and evaporated _. The residue was purified by column chromatography (SiO ₂ , gradient elution: 0-100% ethyl acetate/petroleum ether) to give the title compound (163 mg, 25% yield) as a yellow oil. MS (ESI) _: mass calculated _{for C29H27F4N7O3} , _597.6 ; m _/ z found, 598.5 [M+H] ^<+> .

Process B. (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. The title compound was prepared as a white powder in a manner similar to Example 63, Step B. MS (ESI) _: mass calculated _{for C22H21F4N7O3} , _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=6.4Hz, 1H), 4.52 (d, J=6.2Hz, 2H), 3.92 (q, J=7.3 Hz, 2H), 2.12 (s, 3H), 1.45 (d, J=6.6 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H).

Example 77: (S)-2-(4-((2-chloro-6-fluorophenyl)amino)-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy ) pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Process A. (S)-3-((benzyloxy)methyl)-1-(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-1H-1,2,4-triazol-5(4H)-one. NaH (60% purity, 57 mg, 1.43 mmol) was slowly added to a mixture of 2-chloro-6-fluoroaniline (797 mg, 5.48 mmol) in DMF (3 mL) at room temperature. After the addition, the mixed reaction was heated to 60° C. for 0.5 hours. (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 (300 mg, 364.42 μmol) was slowly added to the mixed solution at 60° C., The reaction mixture was further stirred at 60° C. for 1 hour. The mixture was cooled, diluted with ethyl acetate (20 mL), 1 M HCl aqueous solution was added slowly, and the pH was adjusted to 6 with an ice-water bath. The mixture was separated and the organic layer was washed with brine (15 mL), dried over _Na2SO4 , 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) _: mass calculated _{for C28H23ClF5N7O3} , _635.1 ; m _/ z found, 636.1 [M+H] ^<+> .

Process 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-triazol-5(4H)-one. The title compound was prepared as a white powder in a manner similar to Example 63, Step B. MS (ESI) _: mass calculated for _{C21H17ClF5N7O3} , _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=6.4Hz, 1H), 4.64 (d, J=6.2Hz, 2H), 3. 87 (q, J = 7.3Hz, 2H), 2.47-2.26 (m, 1H), 1.65 (d, J = 6.6Hz, 3H), 1.38 (t, J = 7 .2Hz, 3H).

Example 78: (S)-2-(4-(4,5-difluoro-2-methylphenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy) Pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Process A. (S) -3-((benzyloxy)methyl)-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-1H-1,2,4-triazol-5(4H)-one. The title compound was treated with 4,5-difluoro-2-methylphenol and (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 Prepared by coupling -5(4H)-one (Intermediate 18). MS (ESI): mass calculated for _C29H24F6N6O4 , _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 = 7.3Hz, 2H), 2.17 ( s, 3H), 1.68 (d, J=6.5Hz, 3H), 1.42 (t, J=7.3Hz, 3H).

Process B. (S)-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-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one. The title compound was prepared in a manner similar to Example 63, Step B, as an off-white solid. MS (ESI): mass calculated _{for C22H18F6N6O4} , _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=6.4Hz, 1H), 4. 65 (d, J = 6.3Hz, 2H), 3.87 (q, J = 7.2Hz, 2H), 2.22 (t, J = 6.3Hz, 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. Half-maximal inhibitory concentration values (IC ₅₀ ) are summarized in Table 2.

Biological Assays In Vitro Assay: DHODH Enzyme Assay To detect DHODH enzymatic activity, dichloroindophenol (DCIP) is added as the final electron acceptor in the assay. DCIP can accept electrons from reduced coenzyme Q generated in the assay or from dihydroorotate (DHO) via FMN, presumably by binding to the ubiquinone pocket. DCIP solutions are blue and have a strong absorbance at about 600 nm, but become colorless upon reduction (J. Biol. Chem. 1986:261, 11386). 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. The assay is performed in endpoint mode by stopping 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 (catalog number PR-0044). Chemicals were purchased from Sigma-Aldrich, Teknova, and Avanti Polar Lipids. Liquid handling was performed using a Labcyte Echo and a Formulatrix Tempest.

In Vitro Assay: MOLM-13 Cellular Assay MOLM-13 cells were obtained from DSMZ in RPMI 1640 + Glutamax + 25 mM HEPES (Invitrogen, Cat. No. 72400) supplemented with 10% heat-inactivated Fetal Bovine Serum (FBS; Invitrogen, Cat. No. 16140). maintained with The day before assay setup, cells were pelleted, resuspended in fresh medium, counted, and cells plated at 0.4 x ¹⁰⁶ cells/mL in T150 flasks. On the day of the assay, cells were pelleted, resuspended in fresh medium, counted, and plated at 5,000 cells/well in white, opaque 96-well tissue culture treated microplates (Perkin Elmer, Catalog No. 6005680). Cells were exposed to various concentrations of test compounds for 72 hours at 37° C., 5% CO ₂ immediately after seeding. Cell viability was obtained on a Perkin Elmer Envision 2104 multilabel reader using the CellTiter-Glo assay (Promega) according to the manufacturer's instructions.

ＮＴ又はｎｔは未試験を意味する。

NT or nt means not tested.

Claims (60)

Formula (I):

[In the 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;
^R2 is

(In the formula,
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;
^R4 is
(a) C _1-6 alkyl; C _1-6 alkyl substituted with one or two 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;
(b)

(In the formula,
R ^d is 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 and OCH ₃ ; _CN ; OH; CO ₂ H; N(CH ₃ ) ₂ ; _{2 CH} ; 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 _{; 6} haloalkyl; C _1-6 haloalkyl substituted with a member selected from the group consisting of OH and OCH ₃ ;
n is 1 or 2),
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein X ¹ is CH. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein X ¹ is N. 4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein ^X2 is CH. 4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein ^X2 is N. 6. The compound of any one of claims 1-5, wherein Y is O, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein Y is NH. 6. The compound of any one of claims 1-5, wherein Y is S, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 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, according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, a solvent. hydrates, stereoisomers, isotopic variants, or N-oxides. 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 ; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant _thereof , or N - oxide. 6. 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. 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 salts, solvates, stereoisomers, isotopic variants, or N-oxides. R ¹ is

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant or N-oxide thereof, which is ^R2 is

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant or N-oxide thereof, which is ^R2 is

and
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;
14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R ^c is C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl , solvates, stereoisomers, isotopic variants, or N-oxides. ^R2 is

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant or N-oxide thereof, which is 17. The compound of any one of claims 1-16, wherein ^R3 is H, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein R ³ is Cl. 17. The compound of any one of claims 1-16, wherein ^R3 is F, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. ^R4 is

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

(In the formula,
^CH2OH ; CN; _{OH ; CO2H} ; N( _CH3 ) ₂ ; (C ₌ O)NH _{- CH2CH2OH} ; _NHSO2CH3 ; _{OCH3 , OCH2CH2OH , and OCH2CH2OCH3} ;
R ^e is selected from the group consisting of Cl, F, _CH3 , and _OCH3 ;
n is 1 or 2),
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. ^R4 is

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

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

[In the formula,
R ^d is independently selected from the group consisting of H, Cl, _CH3 , OH and _OCH3 ;
R ^e is F, Cl, or _CH3 ;
n is 1 or 2], the compound according to any one of claims 1 to 19,
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. ^R4 is

A compound according to any one of claims 1 to 19, which is
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. ^R4 is

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant or N-oxide thereof, which is 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. 25. The compound of any one of claims 1-19, 21 and 24, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- oxide. Y is NH and ^R4 is

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant or N-oxide thereof, which is Y is S and ^R4 is

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant or N-oxide thereof, which is Formula (IA):

[In the 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;
^R4 is
(a) C _1-6 alkyl; C _1-6 alkyl substituted with one or two 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;
(b)

(wherein R ^d is 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 ( (C= _O )NH—CH ₂ CH ₂ OH; NHSO _{2 CH 3} ; OC _1-6 alkyl; and OC _1- substituted with a member selected from the group consisting of OH and OCH _{3 6} alkyl, independently selected from the group consisting of
R ^e is selected from the group consisting of halo, C _1-6 alkyl and OC _1-6 alkyl;
n is 1 or 2)],
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. Formula (IB):

[In the 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;
^R2 is

(In the formula,
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;
^R4 is

(wherein R ^d is independently selected from the group consisting of H, Cl, and F;
R ^e is selected from the group consisting of F, _CH3 , and _OCH3 ;
n is 1 or 2)],
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 32. The compound of claim 31, wherein Y is O. A compound according to 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. Formula (II):

[In the formula,
X ³ and X ⁴ are each independently CH or N, when X ³ is N, X ⁴ is CH, 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 ;} is selected from the group consisting of alkyl,
^R6 is

and
R ⁷ is H or F;
^R8 is

(In the formula,
R ^f is H; halo; C _1-6 alkyl _; C _1-6 alkyl substituted with _a member selected from the group consisting of OH and OCH _{3 ;} (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)],
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 38. The compound of Claim 37, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein ^X3 is N and ^X4 is CH. 38. The compound of Claim 37, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein ^X3 is CH and ^X4 is N. 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. the compound of any one of claims 37-40, or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, wherein R ⁵ is C _1-6 alkyl or C _1-6 haloalkyl; Isotopic variants or N-oxides. 42. The compound of any one of claims 37-41, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein ^R7 is H. ^R8 is

43. The compound of any one of claims 37-42, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant or N-oxide thereof, which is 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)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-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 -(hydroxymethyl)-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-(hydroxymethyl)-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)isoquinolin-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-(hydroxymethyl)-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)isoquinoline-6- yl)-4-ethyl-3-(hydroxymethyl)-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-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-(4-(2-chloro-6-fluorophenoxy)-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl) -4-ethyl-5-(hydroxymethyl)-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-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-2-(1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)phthalazin-6-yl)-4-ethyl -5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-1-(1-((2,5-dichloropyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl )-4-ethyl-3-(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)isoquinoline-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)isoquinoline-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)isoquinoline- 6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-4-ethyl-1-(1-(2-fluoro-5-methylphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl) -3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-(2-chloro-6-fluoro-3-(2-methoxyethoxy)phenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline -6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-(2-chloro-6-fluoro-3-(2-hydroxyethoxy)phenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline -6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-(2-chloro-6-fluoro-3-hydroxyphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl) -4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-(2,5-dimethylphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3 -(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((3-chloro-1-methyl-1H-pyrazol-4-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-N-(2-chloro-3-((6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-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)isoquinoline-6 -yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((3,6-dichloropyridin-2-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl )-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-(2-chloro-6-fluoro-3-methoxyphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl) -4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((3-chloro-2-methoxy-5-methylpyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy ) isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((3-chloro-2-methoxypyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-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)isoquinoline -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-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)-4-ethyl-3-(hydroxymethyl)-1-(1-((1-methyl-1H-pyrazol-5-yl)oxy)-8-((1,1,1-trifluoropropane -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)isoquinoline-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)isoquinoline- 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)isoquinoline-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-trifluoropropane-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)isoquinoline- 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)isoquinolin-6-yl )-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
4-ethyl-3-(hydroxymethyl)-1-(1-trans-2-methylcyclohexyl)oxy)-8-(((S)-1,1,1-trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((1,3-dihydroxypropan-2-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl )-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-4-ethyl-3-(hydroxymethyl)-1-(1-isobutoxy-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H -1,2,4-triazol-5(4H)-one;
(S)-4-ethyl-3-(hydroxymethyl)-1-(1-(2-methoxyethoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-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-trifluoro propan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one;
4-ethyl-1-(1-((1-hydroxy-3-methoxypropan-2-yl)oxy)-8-(((S)-1,1,1-trifluoropropan-2-yl)oxy ) isoquinolin-6-yl)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((tetrahydro-2H-thiopyran 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;
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]pyridazine- 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-trifluoropropane-2 -yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
2-(8-(2-chloro-6-fluorophenoxy)-4-fluoro-1-((1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthyridin-3-yl )-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-4-ethyl-2-(8-fluoro-4-(o-tolyloxy)-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d ] pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-4-ethyl-2-(8-fluoro-4-(4-fluoro-2-methylphenoxy)-5-((1,1,1-trifluoropropan-2-yl)oxy) pyrido [ 3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-4-ethyl-2-(8-fluoro-4-(5-fluoro-2-methylphenoxy)-5-((1,1,1-trifluoropropan-2-yl)oxy) pyrido [ 3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-2-(4-(2-chloro-4,6-difluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido [3, 4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-4-ethyl-2-(8-fluoro-4-(2-methoxyphenoxy)-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4- d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-4-ethyl-2-(8-fluoro-4-((2-methoxy-3,5-dimethylpyridin-4-yl)oxy)-5-((1,1,1-trifluoropropane -2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-2-(4-((2-chloro-4-methylpyridin-3-yl)oxy)-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy ) pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-2-(4-((5-chloro-3-methyl-1H-pyrazol-4-yl)oxy)-8-fluoro-5-((1,1,1-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-triazol-3-one;
2-(4-(2-chloro-6-fluorophenoxy)-8-fluoro-5-isopropoxypyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl) -2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-4-ethyl-2-(8-fluoro-4-(o-tolylamino)-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d ] pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-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]pyridazine- 7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; a compound selected from the group consisting of;
and pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants and N-oxides thereof. (A) a compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof; and (B) at least and one pharmaceutically acceptable excipient. (A) a compound of any one of claims 37-43, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof; and (B) at least and one pharmaceutically acceptable excipient. 45. A pharmaceutical composition comprising an effective amount of a compound of claim 44 and at least one pharmaceutically acceptable excipient. 37. A method of treating a subject suffering from or diagnosed with a disease, disorder or condition, comprising an effective amount of at least one of any one of claims 1-36. or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, to inhibit dihydroorotate oxygenase enzymatic activity in said subject or changing. A method of treating a subject suffering from or diagnosed with a disease, disorder or condition, comprising an effective amount of at least one according to any one of claims 37-43. or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, to inhibit dihydroorotate oxygenase enzymatic activity in said subject or changing. 49. The method of claim 48, wherein said disorder, disease or condition is selected from the group consisting of inflammatory disorders and autoimmune disorders. 49. The method of claim 48, wherein said disorder, disease or condition is cancer. 49. The method of claim 48, wherein said disorder, disease or condition is selected from the group consisting of lymphoma, leukemia, carcinoma and sarcoma. said disorder, disease or condition is acute lymphoblastic leukemia, acute myeloid leukemia, (acute) T-cell leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute monocytic leukemia, acute promyelocytic biphenotypic B myelomonocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, large granular lymphocytic leukemia, plasma cell leukemia, and also acute myeloid leukemia 49. The method of claim 48, selected from the group consisting of myelodysplastic syndromes that can develop into leukemia. 49. The method of claim 48, wherein said disorder, disease or condition is acute myelogenous leukemia. 50. The method of claim 49, wherein said disorder, disease or condition is selected from the group consisting of inflammatory disorders and autoimmune disorders. 50. The method of claim 49, wherein said disorder, disease or condition is cancer. 50. The method of claim 49, wherein said disorder, disease or condition is selected from the group consisting of lymphoma, leukemia, carcinoma and sarcoma. said disorder, disease or condition is acute lymphoblastic leukemia, acute myeloid leukemia, (acute) T-cell leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute monocytic leukemia, acute promyelocytic biphenotypic B myelomonocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, large granular lymphocytic leukemia, plasma cell leukemia, and also acute myeloid leukemia 50. The method of claim 49, selected from the group consisting of myelodysplastic syndromes that can develop into leukemia. 50. The method of claim 49, wherein said disorder, disease or condition is acute myelogenous leukemia. The at least one compound is
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)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-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 -(hydroxymethyl)-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-(hydroxymethyl)-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)isoquinolin-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-(hydroxymethyl)-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)isoquinoline-6- yl)-4-ethyl-3-(hydroxymethyl)-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-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-(4-(2-chloro-6-fluorophenoxy)-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl) -4-ethyl-5-(hydroxymethyl)-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-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-2-(1-(2-chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)phthalazin-6-yl)-4-ethyl -5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-1-(1-((2,5-dichloropyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl )-4-ethyl-3-(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)isoquinoline-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)isoquinoline-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)isoquinoline- 6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-4-ethyl-1-(1-(2-fluoro-5-methylphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl) -3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-(2-chloro-6-fluoro-3-(2-methoxyethoxy)phenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline -6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-(2-chloro-6-fluoro-3-(2-hydroxyethoxy)phenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline -6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-(2-chloro-6-fluoro-3-hydroxyphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl) -4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-(2,5-dimethylphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3 -(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((3-chloro-1-methyl-1H-pyrazol-4-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-N-(2-chloro-3-((6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-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)isoquinoline-6 -yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((3,6-dichloropyridin-2-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl )-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-(2-chloro-6-fluoro-3-methoxyphenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl) -4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((3-chloro-2-methoxy-5-methylpyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy ) isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((3-chloro-2-methoxypyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-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)isoquinoline -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-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)-4-ethyl-3-(hydroxymethyl)-1-(1-((1-methyl-1H-pyrazol-5-yl)oxy)-8-((1,1,1-trifluoropropane -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)isoquinoline-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)isoquinoline- 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)isoquinoline-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-trifluoropropane-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)isoquinoline- 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)isoquinolin-6-yl )-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
4-ethyl-3-(hydroxymethyl)-1-(1-trans-2-methylcyclohexyl)oxy)-8-(((S)-1,1,1-trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((1,3-dihydroxypropan-2-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl )-4-ethyl-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-4-ethyl-3-(hydroxymethyl)-1-(1-isobutoxy-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H -1,2,4-triazol-5(4H)-one;
(S)-4-ethyl-3-(hydroxymethyl)-1-(1-(2-methoxyethoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinoline-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-trifluoro propan-2-yl)oxy)isoquinolin-6-yl)-1H-1,2,4-triazol-5(4H)-one;
4-ethyl-1-(1-((1-hydroxy-3-methoxypropan-2-yl)oxy)-8-(((S)-1,1,1-trifluoropropan-2-yl)oxy ) isoquinolin-6-yl)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
(S)-1-(1-((tetrahydro-2H-thiopyran 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;
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]pyridazine- 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-trifluoropropane-2 -yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-3-(hydroxymethyl)-1H-1,2,4-triazol-5(4H)-one;
2-(8-(2-chloro-6-fluorophenoxy)-4-fluoro-1-((1,1,1-trifluoropropan-2-yl)oxy)-2,7-naphthyridin-3-yl )-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-4-ethyl-2-(8-fluoro-4-(o-tolyloxy)-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d ] pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-4-ethyl-2-(8-fluoro-4-(4-fluoro-2-methylphenoxy)-5-((1,1,1-trifluoropropan-2-yl)oxy) pyrido [ 3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-4-ethyl-2-(8-fluoro-4-(5-fluoro-2-methylphenoxy)-5-((1,1,1-trifluoropropan-2-yl)oxy) pyrido [ 3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-2-(4-(2-chloro-4,6-difluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido [3, 4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-4-ethyl-2-(8-fluoro-4-(2-methoxyphenoxy)-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4- d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-4-ethyl-2-(8-fluoro-4-((2-methoxy-3,5-dimethylpyridin-4-yl)oxy)-5-((1,1,1-trifluoropropane -2-yl)oxy)pyrido[3,4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-2-(4-((2-chloro-4-methylpyridin-3-yl)oxy)-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy ) pyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-2-(4-((5-chloro-3-methyl-1H-pyrazol-4-yl)oxy)-8-fluoro-5-((1,1,1-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-triazol-3-one;
2-(4-(2-chloro-6-fluorophenoxy)-8-fluoro-5-isopropoxypyrido[3,4-d]pyridazin-7-yl)-4-ethyl-5-(hydroxymethyl) -2,4-dihydro-3H-1,2,4-triazol-3-one;
(S)-4-ethyl-2-(8-fluoro-4-(o-tolylamino)-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d ] pyridazin-7-yl)-5-(hydroxymethyl)-2,4-dihydro-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]pyridazine- 7-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
and pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants and N-oxides thereof.