Dihydroorotate dehydrogenase inhibitors

Abstract

To provide dihydroorotate dehydrogenase (DHODH) inhibitors that deliver a therapeutic benefit to patients suffering from cancer and / or inflammatory and immunological diseases.SOLUTION: The present invention provides a compound represented by a formula (I), where X is CH or N, Y is CH or N, R1 is a C1-6 alkyl substituted with OH or OCH3 or the like; R2 is a group represented by the formula below; R3 is H, halo, CH3, or OCH3; and R4 is a C1-6 alkyl or the like.SELECTED DRAWING: None

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application is based on U.S. Provisional Patent Application No. 62 / 835,113, filed April 17, 2019. This application claims the benefit of priority under the International Patent Application Serial No. 10 / 02 / 2005, filed on May 13, 2005, and is hereby incorporated by reference in its entirety and for all purposes. This is incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present invention relates to novel compounds that are dihydroorotate dehydrogenase (DHODH) inhibitors. These compounds are useful in treating diseases, disorders, or conditions in which inhibition of DHODH is beneficial. The present invention also includes one or more of such compounds. Pharmaceutical compositions and processes for preparing such compounds and compositions, and methods for treating cancer and autoimmune and the use of such compounds or pharmaceutical compositions for methods of treating inflammatory diseases, syndromes, and disorders. and the use of the composition. [Background technology]

[0003] Acute myeloid leukemia (AML) is a type of blood and lymphoma caused by mutations occurring in normal hematopoietic stem cells. AML is a clonal disorder of the immune system and bone marrow. It is characterized by diverse cytogenetic, morphological, and immunophenotypic features. It is a heterogeneous disease in that it presents with the present features of a clonal disorder known as myeloblastoma. It is characterized by the accumulation of abnormal myeloid progenitor cells. These cells are the result of a disruption of normal myeloid differentiation and hyperfunction. The disease remission occurs after standard induction therapy. Although treatment can be achieved using chemotherapy, refractory and relapsed disease is due to remnants of leukemic stem cells. Therefore, AML remains a challenge due to its 5-year overall survival rate of less than 30%. This is an unmet medical issue with over 20,000 new cases per year in the United States. (Stein ET et al., Health Qual Life O utcomes 16:193,2018).

[0004] Differentiation therapy is based on the knowledge that differentiation and loss of stem cell self-renewal are associated with normal cells. Based on these findings, it appears to be an attractive approach to the treatment of AML. Treatment of acute promyelocytic leukemia, which accounts for 10-15% of all cases, with all-trans retinoic acid is Retinoic acid is a paradigm for differentiation therapy. Promyelocytic leukemia protein (PML)-retinoic acid receptor-α, encoded by Targeting PML-RAR fusion proteins. Specifically reverses the blockade on transcriptionally mediated differentiation induced by protein, resulting in single-agent AT Early clinical trials in RA showed complete hematologic remission in all treated patients. (McCulloch D et al.Onco Targets Ther 20 17;10:1585-1601;Nowak D et al.Blood 113: 3655,2009).

[0005] Differentiation therapy has been successful but is only applicable to a small subset of AML patients. Research aimed at identifying the conductor has been ongoing, but with limited success. Overcomes the maturation block in primary mouse bone marrow cells expressing the meobox protein HoxA9 In phenotypic screens aimed at identifying small molecules that are Dihydroorotate dehydrogenase (DHODH) has emerged as a broadly applicable differentiation target. This protein plays a key role in balancing stem cell maintenance / differentiation. It is an essential transcription factor that is normally expressed in hematopoietic progenitor cells and is downregulated upon induction of differentiation. It has been shown to be widely overexpressed in AML (Sykes et al. l., Cell 167:171, 2016).

[0006] DHODH is a catalyzed catalysis of the fourth step in the de novo pyrimidine biosynthesis pathway, dihydropyrimidine. Flavin mononucleotide located in the inner mitochondrial membrane that catalyzes the oxidation of rotic acid to orotic acid DHODH is a flavoprotein that inhibits nucleotide synthesis. It is involved in the synthesis of pyrimidines, which are important precursors for the synthesis of glycoproteins and phospholipids, as well as in the synthesis of riboflavin. (Reis RAG et al., Archives Biochem Biophysics 632:175,2017;Vyas VK et al., Mini Rev Med Chem 11:1039,2011). DHODH is The small molecule DHODH is approved by the FDA for rheumatoid arthritis and multiple sclerosis, respectively. The inhibitors leflunomide and teriflunomide have been studied for the treatment of autoimmune diseases. (Lolli ML et al., Recent patents on Anti-Cancer Drug Discovery 13:86,2018).

[0007] As evidenced by upregulation of differentiation markers CD11b and CD14 Thus, DHODH inhibition drives AML differentiation in vitro, resulting in a dose-dependent Anti-leukemic effect, reduction of leukemic stem cells, and prolonged survival time in vivo Since the initial findings by Sykes et al. showing that DHODH inhibits the associated cellular Cell cycle arrest, upregulation of CD11b and CD14, and induction of apoptosis Additional evidence has emerged that it mediates antiproliferative activity against AML cells with induction (Wu D et al.Haematologica 103:1472,2018; Sainas S et al., J Med Chem 61:6034,2018; Cao L et al.,Mol Cancer Ther,October 23r d Epub ahead of print). In addition, in vitro and in vivo models Preclinical studies in solid tumors have demonstrated the efficacy of DHODH inhibition, and DHODH inhibits PTEN and and KRAS mutant solid tumors identified as synthetic lethality (Pharmacolo Gy and Therapeutics,Epub October 19th,20 18;Mathur D et al., Cancer Discovery 7:1, 2017;Cell Chemical Biology 25:1,2018). Summary of the Invention

[0008] Thus, it is possible to provide a therapeutic benefit to patients suffering from cancer and / or inflammatory and immune disorders. There remains a need for DHODH inhibitors that can

[0009] Embodiments of the present invention include compounds, pharmaceutical compositions containing the compounds, methods for making and administering the compounds, and the like. methods of isolating and purifying the compounds; methods of using the compounds as inhibitors of DHODH enzyme activity; and Suffering from a disease, disorder, or condition, such as an autoimmune or inflammatory disorder, or a disease, such as cancer The present invention also relates to methods of using such compounds in the treatment of subjects diagnosed with or having The novel DHODH inhibitors offer therapeutic benefit to patients suffering from cancer and / or immune disorders. It can be provided.

[0010] An embodiment of the present invention is a compound of formula (I):

[0011] [ka] During the ceremony, X is CH or N; Y is CH or N; R 1 is C 1~6 Alkyl; OH or OCH 3 C replaced with 1~6 Alkyl;C 2~6 Alkenyl; C 1~6 Haloalkyl; OH or OCH 3 C replaced with 1~6 Haloalkyl;C 2~6 Haloalkenyl; N(CH 3 ) 2 ;C 3~6 Cycloalkyl;C 1~6 Alkyl-substituted C 3~6 cycloalkyl; and phenyl. Selected; R 2 teeth,

[0012] [ka] where: R a is C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 From cycloalkyl is selected from the group consisting of R b is C 1~6Alkyl, or OH, halo, CN, OC 1~6 Alkyl, OC 1~ 6 Haloalkyl and OC 3~6 cycloalkyl; C being replaced 1~6 is alkyl, R 3 H, halo, CH 3 and OCH 3 is selected from the group consisting of R 4 teeth, (a)C 1~6 Alkyl; 1 or 2 OCH 3 C replaced with 1~6 Alkyl ;C 3~6 Cycloalkyl;CH 3 or OCH 3 C replaced with 3~6 Cycloalkane Le;CH 2 -C 3~6 Cycloalkyl; and

[0013] [ka] (b)

[0014] [ka] (c)

[0015] [ka] and (d)

[0016] [ka] is selected from the group consisting of During the ceremony, Each R c are independently: H; halo; C 1~6Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C is replaced with a member selected from the group consisting of 1~6 Alkyl;C 1~ 6 Haloalkyl; OH and OCH 3 is substituted with a member selected from the group consisting of C 1~6 Haloalkyl;NO 2 ;OH;O-CH 2 CH 2 OH; and OC 1~6 Alkyl is selected from the group consisting of R d ,H;Halo;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 from C is replaced with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Hello Aruki OH and OCH 3 C is replaced with a member selected from the group consisting of 1~6 Halo Alkyl;CN; and OC 1~6 is selected from the group consisting of alkyl, R g is H;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 A group consisting of C is replaced with a member selected from 1~6 Alkyl;C 1~6 Haloalkyl; and OH and OCH 3 C is replaced with a member selected from the group consisting of 1~6 Halo alkyl, and a compound in which n is 1 or 2; or a pharma- ceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. It is a body.

[0017] The present invention further relates to a compound of formula (I), or a pharma- ceutically acceptable salt, isotope, N-amino group, or the like thereof. and / or a combination thereof for the treatment of cancer and / or inflammatory or immune disorders. Inhibition of DHODH enzyme activity can be used to treat a variety of diseases, syndromes, and conditions, including but not limited to: or disorders, diseases, syndromes, or disorders in subjects, including mammals and / or humans, Methods for treating or ameliorating a medical condition or disorder are provided.

[0018] Further aspects of the invention will become apparent from the following detailed description and by practice of the invention. Embodiments, features and advantages will become apparent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Unless otherwise defined, all technical and scientific terms used herein are understood by those of ordinary skill in the art to be of use in the art. As used herein and in the appended claims, In this regard, unless otherwise specified, the following terms are provided to facilitate the understanding of the present invention. It has the meaning.

[0020] The singular forms "a," "an," and "the" are used unless the context clearly indicates It encompasses multiple referents.

[0021] The term "independently" used in connection with a substituent means that more than one substituent is possible. This means that when the substituents are the same or different, they may be the same or different.

[0022] The term "substituted" means that the specified group or moiety has 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 or substituted with one or more substituents. When used to describe a structural system, the substitutions are those that are valence allowed in that system. This means that the ion exchange reaction may occur in any position where the ion exchange reaction is performed.

[0023] Unless specifically limited in a particular application, the term "alkyl" refers to a group having 1 to 8 alkyl groups 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 in light of ordinary skill in the art and the teachings set forth herein, The term "C" includes groups that are considered to correspond to any one of the above examples. 1~6 "Alkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain. The word “C” 1~4 "Alkyl" means a straight or branched alkyl group having 1 to 4 carbon atoms in the chain. Refers to the base.

[0024] The term "alkenyl" refers to any alkyl group of any length and any alkyl group, except that it contains at least one double bond. The term "alkoxy" includes unsaturated aliphatic groups in which possible substitution is the same as that described above for alkyl. "Nyl" refers to a straight chain alkenyl group (e.g., ethenyl, propenyl, butenyl, pentenyl, Alkenyl and hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc. The term refers to oxygen, nitrogen, sulfur, or phosphorus atoms replacing one or more carbons of a hydrocarbon backbone. In certain embodiments, the straight or branched chain alkenyl group further comprises: Has 6 or fewer carbon atoms in its backbone (e.g., C 2~6 , in the case of branched chain C 3~6 ).

[0025] The term "cycloalkyl" refers to a saturated or partially saturated alkyl group having 3 to 12 ring atoms per carbon ring. "C" refers to partially saturated monocyclic, fused polycyclic, or spiropolycyclic carbocyclic rings. 3~6 Cycloalkane "Cycloalkyl" refers to a carbocyclic ring having 3 to 6 ring atoms per carbocyclic ring. Illustrative examples include the following entities in the form of appropriately linked moieties:

[0026] [ka]

[0027] The term "halogen" or "halo" refers to chlorine, fluorine, bromine, or iodine.

[0028] The term "cyano" refers to the group CN.

[0029] The term "haloalkyl" refers to an alkyl group within a chain, optionally where hydrogen is replaced with a halogen. As used herein, the term "alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms. When "C 1~6 The term "haloalkyl" refers to an alkyl group in which hydrogen is optionally replaced with a halogen. The present invention refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms in the chain. When used in fine print, "C 1~4The term "haloalkyl" refers to an alkyl group in which hydrogen is optionally replaced by haloalkyl. Straight or branched alkyl chain having 1 to 4 carbon atoms in the chain, substituted with aryl. An example of a "haloalkyl" group is trifluoromethyl (CF 3 ), Difluo Romethyl (CF 2 H), monofluoromethyl (CH 2 F), pentafluoroethyl (CF 2 CF 3 ), tetrafluoroethyl (CHFCF 3 ), monofluoroethyl (CH 2 CH 2 F), trifluoroethyl (CH 2 CF 3 ), tetrafluorotrifluoromethylethyl CF(CF 3 ) 2 ), and the ordinary skill in the art and the teachings provided herein. Illustrative are groups that are considered equivalent to any one of the above examples in light of the above.

[0030] The term "haloalkenyl" refers to groups analogous in length and optional substitution to the alkyls described above. However, it contains at least one double bond and optionally has hydrogen replaced with a halogen. It contains unsaturated aliphatic groups having 1 to 6 carbon atoms in the chain.

[0031] The term "aryl" refers to a monocyclic aromatic carbocyclic ring having six atoms per ring (ring atoms (The carbon atoms in an aryl group are sp2 hybridized.) (

[0032] The term "phenyl" refers to the following moiety:

[0033] [ka]

[0034] The term "heteroaryl" refers to a monocyclic or heterocyclic ring having 3 to 9 ring atoms per heterocycle. is a fused bicyclic heterocycle (having ring atoms selected from carbon atoms and not including nitrogen, oxygen, and sulfur) The heteroaryl group is a ring structure having four or less heteroatoms selected from the following: Illustrative examples include the following entities, in the form of appropriately linked moieties: do.

[0035] [ka]

[0036] The term "phenyl" refers to the following moiety:

[0037] [ka]

[0038] Those skilled in the art will appreciate that the above listed or exemplified cycloalkyl, heteroaryl, and aryl groups are The species are not exhaustive and additional species may be selected within these defined terms. will understand.

[0039] The term "variable attachment point" refers to a group that is attached at two or more alternative locations within a structure. This attachment always replaces a hydrogen atom on one of the ring atoms. Then, all permutations of bonds can be represented by a single diagram, as shown in the diagram below.

[0040] [ka]

[0041] Those skilled in the art will readily recognize that when more than one such substituent is present for a given ring, each substituent is It will be appreciated that the bonds of the substituents are independent of all others. The groups listed are not exhaustive.

[0042] As used herein, unless otherwise stated, the term "or" means "and / or." do.

[0043] As used herein, the terms "comprise," "contain," and "include" refer to a broad range of Used in a non-limiting sense.

[0044] As used herein, the term "composition" refers to a product containing specified ingredients in specified amounts. In addition, any product resulting directly or indirectly from the combination of specified ingredients in specified amounts. It is intended to be inclusive.

[0045] As used herein, any disease, condition, syndrome, or disorder can be "treated." The terms "treatment," "treating," or "treatment" are used interchangeably. In embodiments, the method comprises ameliorating the disease, condition, syndrome, or disorder (i.e., preventing or reducing the disease or condition). slowing or preventing or reducing the onset of at least one of the clinical symptoms In another embodiment, "treat," "treating," or "treatment" refers to any condition that is not consciously known to the patient. Related to or causing a disease, condition, syndrome, or disorder, including those that may not be treatable It refers to the reduction or improvement of at least one physiological or biochemical parameter. In another embodiment, "treat," "treating," or "treatment" refers to a physical (e.g., , stabilization of discernible symptoms) or physiological (e.g. stabilization of physical parameters) It also refers to modulating a disease, condition, syndrome, or disorder, either in a therapeutic or therapeutically effective manner, or both. In another embodiment, "treat", "treating" or "treatment" refers to treating a disease, condition, "Preventing or delaying the onset or development of a syndrome or disorder."

[0046] The terms "subject" and "patient" are used interchangeably herein and refer to an animal, preferably a It may refer to a mammal, most preferably a human.

[0047] As used herein, the terms active compound, drug, and active ingredient refer to those compounds that are medicamentally Used interchangeably to refer to an active compound. Other ingredients in the drug composition may be substantially or completely medicamentously inactive. The composition (also referred to herein as a composition or formulation) may comprise one or more carriers and / or one or more The active ingredient may be included in combination with the above excipients and / or one or more diluents.

[0048] The term "therapeutically effective amount" (used interchangeably herein with "effective amount") refers to an amount of an enzyme that is or reducing or inhibiting the activity of a protein, or improving symptoms, alleviating pathology, or disease progression. researchers, veterinarians, physicians, or other clinicians, including slowing or delaying the progression of, or preventing, disease. Elicit a desired biological or pharmaceutical response in a tissue system, animal, or human (e.g., (or amount of an active compound or pharmaceutical agent, such as a compound of the present invention). The term therapeutically effective amount refers to an amount that, when administered to a particular subject, effectively treats a disease, condition, or symptom in the subject. By inhibiting, alleviating, or curing a symptom or disorder, or by preventing or reducing a disease, illness, prophylactically inhibiting, preventing, or delaying the onset of a disease, syndrome, or disorder, or a symptom thereof; A therapeutically effective amount can refer to an amount that achieves a therapeutic effect by increasing the alleviating to some extent one or more of the symptoms of the disease, condition, syndrome, or disorder; and / or One or more physiological changes associated with or causing a disease, condition, syndrome, or disorder or partially or completely restores normal biochemical parameters; and / or reduces the severity of a disease, condition, or injury. The amount may be an amount that reduces the likelihood of developing a particular condition, syndrome, or disorder, or a symptom thereof.

[0049] "Pharmaceutically acceptable" means generally safe, non-toxic, and biologically or otherwise acceptable. This means that the compound is useful in the preparation of a pharmaceutical composition that is free from any undesirable properties. , including those that are acceptable for animal and human pharmaceutical use.

[0050] A "pharmaceutically acceptable salt" is a salt that is non-toxic, biologically acceptable or otherwise. The compounds represented by formula (I) (and "(I), (II)" means an acid or base salt of the compound of formula (IA), (IB) or (IC) In general, see S.M. Berge, et al., "Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Ha ndbook of Pharmaceutical Salts,Properties s,Selection,and Use,Stahl and Wermuth,Ed. s., Wiley-VCH and VHCA, Zurich, 2002 Preferred pharma- ceutically acceptable salts are those that are pharmacologically effective and do not cause undue toxicity, irritation, or acidosis. It is suitable for contacting the tissues of a patient without causing an allergic reaction.

[0051] Non-limiting examples of pharma- ceutically acceptable salts include sulfates, pyrosulfates, bisulfates, and sulfites. Acid salts, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrol Phosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate Salt, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate , oxalate, malonate, succinate, suberate, sebacate, fumarate, malate Leyne salt, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chloro Benzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate Benzoates, phthalates, sulfonates, xylene sulfonates, phenyl acetates, phenyl phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, Cholate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 -sulfonates, naphthalene-2-sulfonates, and mandelates.

[0052] The term solvate refers to the solvent addition forms, as well as the amines, which the compounds of formula (I) are able to form. Examples of such solvent addition forms include, for example, hydrates, alcoholates, etc. be.

[0053] The compounds of formula (I) contain sufficiently acidic groups, sufficiently basic groups, or both types of functional groups. Therefore, they can react with many inorganic or organic bases and inorganic and organic acids to produce pharma- ceutical acceptable compounds. Acceptable salts may be formed.

[0054] The compounds of formula (I) may contain at least one nitrogen having basic character, and therefore The desired pharma- ceutically acceptable salt can be prepared by any suitable method available in the art, e.g. For example, inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, acid, etc.), or organic acids (e.g., acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, Acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, Baltic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid carboxylic acid, palmitic acid, lauric acid, pyranosidic acid (e.g., glucuronic acid or galactosyl ronic acid), alpha-hydroxy acids (e.g., mandelic acid, citric acid, or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid, 2-acetate benzoic acid, naphthoic acid, or cinnamic acid), sulfonic acids (e.g., lauryl sulfonic acid , p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), Any compatible mixture of acids, such as those given above, as well as any mixtures that are considered equivalents. can be prepared by treating the free base with other acids and mixtures thereof.

[0055] Compounds of formula (I) may contain a carboxylic acid moiety and the desired pharma- ceutically acceptable salt may optionally be prepared by by any suitable method, for example by addition of an inorganic or organic base, such as an amine (primary, secondary or tertiary), alkali metal hydroxides, alkaline earth metal hydroxides, Any compatible mixture of bases, such as those that can be used in the preparation of glycerol, as well as any mixture of bases ... Any other bases and mixtures thereof that are considered equivalent or acceptable substitutes in accordance with the Illustrative examples of suitable salts include those prepared by treating the free acid with contains amino acids such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, Secondary and tertiary amines, as well as benzylamine, pyrrolidine, piperidine, morpholine, Derived from cyclic amines such as phosphorus, piperazine, N-methyl-glucamine, and tromethamine Organic salts of sodium, calcium, potassium, magnesium, manganese, iron, Included are inorganic salts derived from copper, zinc, aluminum, and lithium.

[0056] As used herein, each compound may be referred to interchangeably with respect to its chemical formula, chemical name, abbreviation, etc. It can be argued that:

[0057] Any formula given in this specification refers to a compound having the structure depicted by that structural formula. In addition to the above, specific modifications or configurations are also intended to be representative. Compounds of any formula may have asymmetric centers and therefore may exist as different enantiomers. Optical isomers and stereoisomers of the compounds of the general formula and mixtures thereof are all considered to be within the scope of such formula. The compounds of the present invention may have one or more asymmetric Since such compounds may have individual (R)- or (S)-stereoisomers, The term "isopropyl ether" as used herein may be used interchangeably with "isopropyl ether" or as a mixture thereof. Any given formula may represent a racemate, one or more of its enantiomeric forms, or a diastereomeric form. The term "polymer" is intended to represent one or more of the rheomeric types, and mixtures thereof. Any formula given in the specification represents such a compound even if such form is not explicitly stated. The term "hydrates," "solvates," and polymorphs of the compound, as well as mixtures thereof, are intended to refer to the compounds.

[0058] The term "R" at a stereocenter refers to the stereocenter as defined in the art. indicates that the somatic center is in a pure R-configuration. Similarly, the term "S" indicates that the somatic center is in a pure S-configuration. As used herein, the term "RS" refers to the R configuration and Refers to a stereocenter that exists as a mixture of S configurations.

[0059] Compounds containing one stereocenter that is shown without a stereochemical bond notation have two It is a mixture of enantiomers of the same compound. The two-core compound is a mixture of four diastereomers, labeled "RS" and Compounds containing two stereocenters shown with stereochemical bond notation are not shown. It is a binary mixture with the relative stereochemistry as shown. The unlabeled stereocenters depicted without are a mixture of R and S configurations. For unlabeled stereocenters shown with bond symbols, the absolute stereochemistry is given. is as shown.

[0060] Unless otherwise indicated, the description or naming of specific compounds in the specification and claims is intended to include both its individual enantiomers and mixtures, racemic or otherwise. The methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art.

[0061] Reference to a compound described herein includes (a) the recited form of such compound; and (b) the form of such compound in the medium in which it is believed to exist at the time of naming. For example, R-COO References to compounds such as H include, for example, R-COOH(s), R-COOH(sol), and R-COO-(sol). In this example, R- COOH(s) may be present, for example, in a tablet or some other solid pharmaceutical composition or preparation. R-COOH(sol) refers to the solid compound when it can exist in a solvent. R-COO-(sol) refers to the dissociated form of the compound in a solvent. For example, such dissociated form may be derived from R-COOH, a salt thereof, or in a medium. Could it come from any other entity that produces R-COO- when it is thought to have dissociated? In another example, the dissociated form of the compound may be in an aqueous environment, regardless of the dissociated form. and "exposing the entity to a compound of formula R-COOH" and the like. refers to exposing such an entity to a form(s) of the compound R-COOH present in In yet another example, a phrase such as "reacting the entity with a compound of formula R-COOH" may be used to refer to ) the chemically relevant form(s) of such entity present in the medium in which such reaction occurs (b) the chemical identity of the compound R-COOH present in the medium in which such a reaction occurs In this context, it refers to the reaction of such an entity with the relevant form(s). For example, when present in an aqueous environment, the compound R-COOH is also present in such same medium. Therefore, the entity is R-COOH(aq) and / or R-COO-(aq) (the subscript “(aq)”). q) means "aqueous solution" according to its conventional meaning in chemistry and biochemistry) In these examples of nomenclature, the carboxylic acid functional group is selected. Although the above selection is not intended to be limiting, it is merely illustrative. Hydroxyl, basic nitrogen members, such as nitrogen members in amines, and compounds containing Any other group that interacts or transforms in a known manner in the medium in which it is present may be used. It is understood that other functional groups, including but not limited to, may also be provided. and transformations include dissociation, association, tautomerization, solvolysis (including hydrolysis), solvation (water These include, but are not limited to, protonation, deprotonation, and valence. The specification does not provide further examples in this regard, because in a given medium These interactions and transformations are known to those skilled in the art.

[0062] Any formula given herein also represents unlabeled as well as isotopically labeled forms of the compounds. Isotopically labeled compounds are compounds in which one or more atoms are present in enriched form. , except as used herein, are replaced by atoms having selected atomic masses or mass numbers. The compounds of the present invention have a structure depicted by the formula given below: Examples of isotopes that can be incorporated into 2 H (or chemical symbol D), 3 H (or chemical symbol T), 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 I, hydrogen, carbon, nitrogen, oxygen, phosphorus, These include isotopes of fluorine, chlorine, and iodine. Such isotopically labeled compounds are useful in metabolic studies. (Preferably 14C), reaction kinetic studies (e.g. 2 H or 3 H), drugs or detection or imaging techniques, including substrate tissue distribution assays [e.g., positron emission tomography (PET)]. PET or SPECT)], or patients In particular, 18 F or 11 C-labeled compounds are PET or S In addition, heavier isotopes, such as deuterium (i.e. Wow, 2 Substitution with , for example, H or D, results in higher metabolic stability, e.g. The potential benefits of certain therapeutics may include longer in vivo half-lives or reduced dosage requirements. The isotopically labeled compounds of the present invention generally contain isotopes that are readily available. By using a labeling reagent instead of a nonisotopic labeling reagent, the following scheme can be implemented: Or it can be prepared by carrying out the procedures disclosed in the examples and preparations.

[0063] Term C n~m An alkyl group is any group consisting of carbon members in a chain, whether straight or branched. The total number N of aliphatic chains satisfies n≦N≦m (where m>n).

[0064] When the same substituents are assigned to various groups, the specific The assignment of specific individual substituents to the remaining groups shall be interpreted as a specific assignment of individual substituents to the remaining groups. By way of example, and not by way of limitation, the Q and R groups may be The selection of H or F for the Q group is relative to the selection of H or F for the R group, where each can be H or F. The choice of assignment for the Q group is not explicitly indicated separately since it is made independently of the choice of F. Unless otherwise specified, the present application does not determine or condition the selection of the assignment for the R group, or vice versa. In this regard, the exemplary claim recitation reads, "Each of the Q and R groups is independently H. or F," or "each of the Q and R groups is independently selected from the group consisting of H and F." will be interpreted as "selected."

[0065] In another example, a zwitterionic substance may be named in its zwitterionic form, even if it is not explicitly named in its zwitterionic form. Zwitterionic compounds by referring to compounds that are known to form ions Zwitterion(s) and its synonyms Zwitterion A term such as a chemical compound or compounds is part of a standard set of well-known and defined scientific names. The standard names are accepted by IUPAC, a division of the International Union of Chemical Associations (IUPAC). The name polar ion includes the Chemical Entities of Biolog ical Interest(ChEBI)dictionary of molecu The identification name CHEBI:27369 has been assigned by the lar entities. As is generally known, zwitterions or zwitterionic compounds have opposite polarities. These compounds are sometimes called "inner salts". Other sources refer to these compounds as "zwitterions", but The term is also misnamed in other sources. The amino acid glycine has the formula H 2 NCH 2 COOH, and some medium (in this case , neutral medium) + H 3 NCH 2 COO- These exist in the form of Zwitterions, zwitterionic compounds, molecules, etc., in the known and well-established sense of the terms Inner salts and zwitterions are in any case recognized as such by those skilled in the art. Any embodiment that would be recognized by a person skilled in the art is within the scope of the present invention. Therefore, the structures of zwitterionic compounds related to the compounds of the present invention are not necessarily named in the present specification. However, these are also part of the embodiments of the present invention. The interactions and transformations in a given medium that lead to various forms are known to those skilled in the art and are therefore within the scope of the present invention. The specification does not provide further examples in this regard.

[0066] When referring to any formula given herein, the possible species for the specified variables are The selection of a particular part from the list of In other words, if a variable appears more than once, the specified Selection of species from the given list is consistent with selection of the same variable elsewhere in the formula, unless otherwise indicated. This is independent of the species selection.

[0067] As a first example of the terminology of the substituent, the substituent S 1 example But, S 1 and S 2 and the substituent S 2 example But, S 3 and S 4 If it is one of In this case, these allocations are 1 example S 1 And S 2 example but S 3 S1 example S 1 And S 2 example S 4 That is, S 1 example S 2 And S 2 example S 3 S 1 exam ple S 2 And S 2 example S 4 The choice to be The embodiments of the present invention are given by the equivalents of each of the alternatives. Shorter "S 1 example S 1 and S 2 It is one of the S 2 example S 3 and S 4 The term "is one of" is used for brevity and not as a limitation. As used herein, the first substituting group terminology described in general terms is The examples are meant to illustrate the various substituent assignments described herein.

[0068] Furthermore, when more than one assignment is given for any member or substituent, the present invention The disclosed embodiments may be taken independently to encompass the listed assignments and their A second example of a substituent term includes the various groupings that can be made from equivalents. Group S example But, S 1 , S 2 , and S 3 It is described herein as being one of If so, this enumeration is example S1 S example S 2 Yes Ru;S example S 3 S example S 1 and S 2 It is one of Ru;S example S 1 and S 3 One of the;S example S 2 and S 3 One of the;S example S 1 , S 2 and S 3 is one of; And S example are any equivalents of each of these alternatives. It refers to the embodiment of the word "S". example S 1 , S 2 , and S 3 The term "one of" is used herein for brevity and not as a limitation. The second example above of the substituent terminology described in general terms is used herein. The above is intended to illustrate the various substituent assignments that may be made.

[0069] Nomenclature “C i ~C j " (j>i) is used herein to refer to a class of substituents. In the case where the number of carbon members is i to j, inclusive, each and every one of them is independently realized. As an example, C 1 ~C 3 The term independent and one carbon member (C 1 ), an embodiment having two carbon members (C 2 ) and an embodiment having three carbon members (C3 )

[0070] A first embodiment of the present invention (also referred to herein as embodiment 1) is a compound of formula (I) Compounds include

[0071] [ka] During the ceremony, X is CH or N; Y is CH or N; R 1 is C 1~6 Alkyl; OH and OCH 3 One substituent selected from the group consisting of C replaced with 1~6 Alkyl;C 2~6 Alkenyl; C 1~6 Haloalkyl;OH and OCH 3 C substituted with one substituent selected from the group consisting of 1~6 Haloal Kill;C 2~6 Haloalkenyl; N(CH 3 ) 2 ;C 3~6 Cycloalkyl; 1 C 1 ~6 C substituted with alkyl substituents 3~6 The group consisting of cycloalkyl; and phenyl Selected from; R 2 teeth,

[0072] [ka] where: R a is C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 From cycloalkyl is selected from the group consisting of R b is C1~6 Alkyl, or OH, halo, CN, OC 1~6 Alkyl, OC 1~ 6 Haloalkyl and OC 3~6 cycloalkyl; C being replaced 1~6 is alkyl, R 3 H, halo, CH 3 and OCH 3 is selected from the group consisting of R 4 teeth, (a)C 1~6 Alkyl; 1 or 2 OCH 3 C replaced with 1~6 Alkyl ;C 3~6 Cycloalkyl;CH 3 or OCH 3 C replaced with 3~6 Cycloalkane Le;CH 2 -C 3~6 Cycloalkyl; and

[0073] [ka] (b)

[0074] [ka] (c)

[0075] [ka] and (d)

[0076] [ka] is selected from the group consisting of During the ceremony, Each R c are independently: H; halo; C1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C is replaced with a member selected from the group consisting of 1~6 Alkyl;C 1~ 6 Haloalkyl; OH and OCH 3 is substituted with a member selected from the group consisting of C 1~6 Haloalkyl;NO 2 ;OH;O-CH 2 CH 2 OH; and OC 1~6 Alkyl is selected from the group consisting of R d ,H;Halo;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 from C is replaced with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Hello Aruki OH and OCH 3 C is replaced with a member selected from the group consisting of 1~6 Halo Alkyl;CN; and OC 1~6 is selected from the group consisting of alkyl, R g is H;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 A group consisting of C is replaced with a member selected from 1~6 Alkyl;C 1~6 Haloalkyl; and OH and OCH 3 C is replaced with a member selected from the group consisting of 1~6 Halo alkyl, and a compound in which n is 1 or 2; or a pharma- ceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. It is a body.

[0077] A further embodiment of the invention are compounds of formula (I) wherein X is CH.

[0078] A further embodiment of the invention are compounds of formula (I) wherein X is N.

[0079] A further embodiment of the invention are compounds of formula (I) wherein Y is CH.

[0080] A further embodiment of the invention are compounds of formula (I) wherein Y is N.

[0081] A further embodiment of the present invention is 1 But, C 1~4 Alkyl; OH or OCH 3 Replace with C 1~4 Alkyl;C 2~4 Alkenyl; C 1~4 Haloalkyl;OH or OCH 3 C replaced with 1~4 Haloalkyl;C 2~4 Haloalkenyl, N(CH 3 ) 2 ;Cyclopropyl;C 1~4 Alkyl-substituted cyclopropyl; or phenoxy

[0033] In another embodiment, the compound of formula (I) is

[0082] A further embodiment of the present invention is 1 But, CH 3 , C.H. 2 CH 3 ,

[0083] [ka] is a compound of formula (I)

[0084] A further embodiment of the present invention is 1 but

[0085] [ka] is a compound of formula (I)

[0086] A further embodiment of the invention is a compound of formula (I) wherein R 2 teeth,

[0087] [ka] and In the formula, R b OH, halo, CN, OC 1~4 Alkyl, OC 1~4 Haloalkyl, or OC 3~6 Cycloalkyl-substituted C 1~4 is alkyl, R a is C 1~4 Alkyl, C 1~4 Haloalkyl, or C 3~6 Cycloalkyl do.

[0088] A further embodiment of the present invention is 2 but,

[0089] [ka] is a compound of formula (I)

[0090] A further embodiment of the present invention is 3 is H.

[0091] A further embodiment of the present invention is 3 is F.

[0092] A further embodiment of the present invention is3 CH 3 is a compound of formula (I)

[0093] A further embodiment of the present invention is 3 OCH 3 is a compound of formula (I)

[0094] A further embodiment of the present invention is 4 but,

[0095] [ka] is a compound of formula (I)

[0096] A further embodiment of the invention is a compound of formula (I) wherein R 4 teeth,

[0097] [ka] and During the ceremony, Each R c are independently: H; halo; C 1~4 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C is replaced with a member selected from the group consisting of 1~ Alkyl;C 1~4 Haloalkyl; OH and OCH 3 C is replaced with a member selected from the group consisting of 1~4 Haloalkyl; and NO 2 is selected from the group consisting of R d ,H;Halo;C 1~4 Alkyl; OH, OCH 3 , S.C.H. 3 , or OCF 3 C replaced with 1~4 Alkyl;C1~4 Haloalkyl; OH or OCH 3 Place C being replaced 1~4 Haloalkyl; or OC 1~4 Alkyl; CN and OC 1~6 Al Kill; n is 1 or 2.

[0098] A further embodiment of the invention is a compound of formula (I) wherein R 4 teeth,

[0099] [ka] and Each R c are independently H, halo, and C 1~4 Alkyl, C 1~4 Haloalkyl, NO 2 , O-CH 2 CH 2 OH and OC 1~4 is selected from the group consisting of alkyl, R d H, halo, C 1~4 Alkyl, CN, and OC 1~6 From the group consisting of alkyl Selected, and n is 1 or 2.

[0100] A further embodiment of the present invention is 4 but,

[0101] [ka] is a compound of formula (I)

[0102] A further embodiment of the present invention is a compound of formula (I) in which R 4 teeth,

[0103] [ka] It is.

[0104] A further embodiment of the invention is a compound of formula (I) wherein R 4 teeth,

[0105] [ka] and During the ceremony, Each R c are independently: H; halo; C 1~4 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C is replaced with a member selected from the group consisting of 1~ Alkyl;C 1~4 Haloalkyl; OH and OCH 3 C is replaced with a member selected from the group consisting of 1~4 haloalkyl, and R d Ha, halo;C 1~4 Alkyl; OH, OCH 3 , S.C.H. 3 , or OCF 3 Place C being replaced 1~4 Alkyl;C 1~4 Haloalkyl; OH or OCH 3 Replaced with C 1~4 Haloalkyl; or OC 1~4 Alkyl;CN; and OC 1~6 Alki The compound is selected from the group consisting of

[0106] A further embodiment of the invention is a compound of formula (I) wherein R 4 teeth,

[0107] [ka] and; During the ceremony, Each R c are independently H, halo, and C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~ 4 is selected from the group consisting of alkyl, and OH; R d Halo, C 1~4 Alkyl and OC 1~4 is selected from the group consisting of alkyl, and, n is 1 or 2.

[0108] A further embodiment of the present invention is 4 but,

[0109] [ka] is a compound of formula (I)

[0110] A further embodiment of the present invention is 4 but,

[0111] [ka] is a compound of formula (I)

[0112] A further embodiment of the present invention is a compound of formula (I) in which R 4 teeth,

[0113] [ka] where: R c ,H;Halo;C 1~4 Alkyl; OH, OCH 3 , S.C.H. 3 , or OCF 3 C replaced with1~4 Alkyl;C 1~4 Haloalkyl; OH or OCH 3 Place C being replaced 1~4 Haloalkyl; or OC 1~4 is alkyl, R d Ha, halo;C 1~4 Alkyl; OH, OCH 3 , S.C.H. 3 , or OCF 3 Place C being replaced 1~4 Alkyl;C 1~4 Haloalkyl; or OH or OCH 3 Place C being replaced 1~4 is haloalkyl, R g is H;C 1~4 Alkyl; OH, OCH 3 , S.C.H. 3 , or OCF 3 Replaced with C 1~4 Alkyl;C 1~4 Haloalkyl; or OH or OCH 3 Replaced with C 1~4 It is haloalkyl.

[0114] A further embodiment of the invention is a compound of formula (I) wherein R 4 teeth,

[0115] [ka] and During the ceremony, R c is H or halo, R d is C 1~4 is alkyl, and R g is H.

[0116] A further embodiment of the present invention is 4but,

[0117] [ka] is a compound of formula (I)

[0118] Further embodiments of the present invention include compounds selected from the compounds shown in Table 1 below, and and optionally, pharma- ceutically acceptable salts, isotopes, N-oxides, solvates, and There is more than one stereoisomer.

[0119] [Table 1-1]

[0120] [Table 1-2]

[0121] [Table 1-3]

[0122] [Table 1-4]

[0123] [Table 1-5]

[0124] [Table 1-6]

[0125] [Table 1-7]

[0126] [Table 1-8]

[0127] A further embodiment of the present invention is a compound selected from the group consisting of: 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) (ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o -tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-4-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) (ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) (ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-(prop-1-en-2-yl)phthalazine-1(2H)- on; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o -tolyl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o -tolyl)297phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) (ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-isopropylphthalazin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -(Methyl-d3)phenyl)isoquinolin-1(2H)-one; (R)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrido o-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl) -4-(1,1,1-trifluoropropan-2-yl)isoquinoline-1(2H)-o hmm; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -(trifluoromethyl)phenyl)isoquinolin-1(2H)-one; 2-(2-(difluoromethyl)phenyl)-6-(4-ethyl-3-(hydroxymethyl)phenyl) (ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-isopropylisoquinolin-1(2H)-one; and, optionally, pharma- ceutically acceptable salts, isotopes, N-oxides, solvates thereof. and one or more of the stereoisomers.

[0128] A further embodiment of the present invention is a compound of formula (I) having the formula (IA):

[0129] [ka] During the ceremony, Y is CH or N; R 1 is C 1~6 Alkyl; OH or OCH 3 C replaced with 1~6 Alkyl;C 2~6 Alkenyl; C 1~6 Haloalkyl; OH or OCH 3 C replaced with 1~6 Haloalkyl;C 2~6 Haloalkenyl; N(CH 3 ) 2 ;C 3~6 Cycloalkyl;C 1~6 Alkyl-substituted C 3~6 cycloalkyl; and phenyl. Selected; R 2 teeth,

[0130] [ka] and R 3 H, halo, CH 3 and OCH 3 is selected from the group consisting of R 4 teeth, (a)C 1~6 Alkyl; 1 or 2 OCH 3 C replaced with 1~6 Alkyl ;C 3~6 Cycloalkyl;CH 3 or OCH 3 C replaced with 3~6Cycloalkane Le;CH 2 -C 3~6 Cycloalkyl; and

[0131] [ka] (b)

[0132] [ka] (c)

[0133] [ka] and (d)

[0134] [ka] is selected from the group consisting of During the ceremony, Each R c are independently: H; halo; C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C is replaced with a member selected from the group consisting of 1~6 Alkyl;C 1~ 6 Haloalkyl; OH and OCH 3 is substituted with a member selected from the group consisting of C 1~6 Haloalkyl;NO 2 ;OH;O-CH 2 CH 2 OH; and OC 1~6 Alkyl is selected from the group consisting of R d ,H;Halo;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 from C is replaced with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Hello Aruki OH and OCH 3 C is replaced with a member selected from the group consisting of 1~6 Halo Alkyl;CN; and OC 1~6 is selected from the group consisting of alkyl, R g is H;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 A group consisting of C is replaced with a member selected from 1~6 Alkyl;C 1~6 Haloalkyl; and OH and OCH 3 C is replaced with a member selected from the group consisting of 1~6 Halo alkyl, and a compound in which n is 1 or 2; or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- It is an oxide.

[0135] A further embodiment of the present invention is a compound of formula (I) having formula (IB):

[0136] [ka] During the ceremony, Y is CH or N; R 1 is C 1~6 Alkyl, C 1~6 Haloalkyl and C 2~6 The group consisting of alkenyl is selected from R 2 teeth,

[0137] [ka] and R 3 H, halo, and CH 3 is selected from the group consisting of R 4 teeth,

[0138] [ka] is selected from the group consisting of During the ceremony, R c ,H;Halo;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 from C is replaced with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Hello Aruki OH and OCH 3 C is replaced with a member selected from the group consisting of 1~6 Halo Alkyl; and NO 2 is selected from the group consisting of R d ,H;Halo;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 from C is replaced with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Hello Aruki OH and OCH 3 C is replaced with a member selected from the group consisting of 1~6 Halo Alkyl;CN; and OC 1~6 is selected from the group consisting of alkyl, R g is H;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 A group consisting of C is replaced with a member selected from 1~6 Alkyl;C 1~6 Haloalkyl; and OH and OCH 3 C is replaced with a member selected from the group consisting of 1~6 Halo alkyl, and a compound in which n is 1; or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- It is an oxide.

[0139] Also, the enantiomers and diastereomeric forms of the compounds of formula (I) (and formulas (IA) and (IB)) Also within the scope of the present invention are leomers. Pharmaceutically acceptable salts, N-oxides or solvates of the compounds are also within the scope of the present invention. In addition, pharma- ceutical acceptable prodrugs of the compounds of formula (I) (and formulas (IA) and (IB)) and pharma- ceutical active substitutes for the compounds of formula (I) (and formulas (IA) and (IB)). Also within the scope of the present invention are aliquots.

[0140] Also included are isotopic variants of the compounds of formula (I) (and formulas (IA) and (IB)), e.g. Deuterated compounds of formula (I) are also within the scope of the present invention. Pharmaceutically acceptable salts, N-oxides, or solvates of isotopic variants of the compounds of (IB) and (IB) are also contemplated. Solvates are also within the scope of the present invention. Pharmaceutically acceptable prodrugs of isotopic variants of the compounds of formula (I) and formula (IA) Pharmaceutically active metabolites of isotopic variations of the compounds of formula (IB) and (IB) are also within the scope of the present invention. It is.

[0141] The compounds of the present invention (including pharma- ceutical acceptable salts and pharma- ceutical acceptable solubilizers) are Although the drug may be administered alone, generally, 1. A medicament that is pharmacologic and / or veterinary compatible, selected in view of the intended route of administration and standard pharmaceutical or veterinary practice. In some embodiments, the carrier may be a pharma- ceutically acceptable excipient and / or a mixture with a pharma- ceutically acceptable diluent. It is administered as

[0142] Thus, a particular embodiment of the present invention comprises a compound of formula (I) and at least one medicament a pharma- ceutically acceptable carrier, a pharma- ceutically acceptable excipient, and / or a pharma- ceutically acceptable diluent In one embodiment of the present invention, the pharmaceutical composition of the present invention comprises In the compositions, the compound of formula (I) may be combined with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s). The composition may be mixed with an antibacterial agent, a binder, a solubilizer, and combinations thereof.

[0143] An embodiment of the present invention is a compound according to any of the embodiments described herein, comprising an effective amount of a compound of formula (I) Compounds and pharma- ceutically acceptable salts, isotopes, N-oxides, solvates, and the like thereof At least one compound selected from the group consisting of a steric isomer and at least one pharma- ceutically acceptable and an excipient.

[0144] An additional embodiment of the present invention comprises: (A) an effective amount of a compound selected from the compounds of formula (I) At least one compound:

[0145] [ka] [In the formula, X is CH or N; Y is CH or N; R 1 is C 1~6 Alkyl; OH or OCH 3 C replaced with 1~6 Alkyl;C 2~6 Alkenyl; C 1~6 Haloalkyl; OH or OCH 3 C replaced with 1~6 Haloalkyl;C 2~6 Haloalkenyl; N(CH 3 ) 2 ;C 3~6 Cycloalkyl;C 1~6 Alkyl-substituted C 3~6 cycloalkyl; and phenyl. Selected; R 2 teeth,

[0146] [ka] where: R a is C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 From cycloalkyl is selected from the group consisting of R b is C 1~6 Alkyl, or OH, halo, CN, OC 1~6 Alkyl, OC 1~ 6 Haloalkyl and OC 3~6 cycloalkyl; C being replaced 1~6 is alkyl, R 3 H, halo, CH 3 and OCH 3 is selected from the group consisting of R 4 teeth, (a)C 1~6 Alkyl; 1 or 2 OCH 3C replaced with 1~6 Alkyl ;C 3~6 Cycloalkyl;CH 3 or OCH 3 C replaced with 3~6 Cycloalkane Le;CH 2 -C 3~6 Cycloalkyl; and

[0147] [ka] (b)

[0148] [ka] (c)

[0149] [ka] and (d)

[0150] [ka] is selected from the group consisting of During the ceremony, Each R c are independently: H; halo; C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C is replaced with a member selected from the group consisting of 1~6 Alkyl;C 1~ 6 Haloalkyl; OH and OCH 3 is substituted with a member selected from the group consisting of C 1~6 Haloalkyl;NO 2 ;OH;O-CH 2 CH 2 OH; and OC 1~6 Alkyl is selected from the group consisting of R d ,H;Halo;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 from C is replaced with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Hello Aruki OH and OCH 3 C is replaced with a member selected from the group consisting of 1~6 Halo Alkyl;CN; and OC 1~6 is selected from the group consisting of alkyl, R g is H;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 A group consisting of C is replaced with a member selected from 1~6 Alkyl;C 1~6 Haloalkyl; and OH and OCH 3 C is replaced with a member selected from the group consisting of 1~6 Halo alkyl, and n is 1 or 2; or a pharma- ceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. Body and (B) at least one pharma- ceutically acceptable excipient.

[0151] Further embodiments of the present invention include administering to a subject an effective amount of a compound shown in Table 1 (e.g., Examples 1-142 or a pharma- ceutical acceptable salt, isotope, N-oxygen derivative of the compound of Table 1. side, solvate, or stereoisomer, or a pharma- ceutically acceptable prodrug of the compound of Table 1. or a pharmacokinetically active metabolite of a compound of Table 1 and at least one pharmacokinetically acceptable salt thereof. and an excipient.

[0152] Solid oral dosage forms, such as tablets or capsules, containing one or more compounds of the invention may be administered orally or in combination with other solid oral dosage forms. Depending on the need, at least one dosage form may be administered at a time. It is also possible to give

[0153] Additional oral forms in which the compounds of the present invention may be administered include elixirs, solutions, syrups, and the like. The pharmaceutical compositions include a spray, a suspending agent, and a suspending agent, each of which optionally contains flavoring and coloring agents.

[0154] Alternatively, one or more compounds of formula (I) may be administered by inhalation (intramedial or intranasal) or by saccharomyces cerevisiae. The drug may be administered in the form of a pill or pessary, or as a lotion, solution, cream, or the like. The compounds may also be applied topically in the form of a patch, ointment, or dusting powder. comprising, consisting of, and / or consisting of an aqueous emulsion of polyethylene glycol or liquid paraffin can be added to a cream consisting essentially of the compound. Waxes at a concentration of 1% to about 10% by weight, together with optional stabilizers and preservatives as required. or added to an ointment comprising, consisting of, and / or consisting essentially of a soft paraffin base. Alternatively, administration may be by using a skin or transdermal patch. Examples of administration include transdermal administration.

[0155] The pharmaceutical compositions of the present invention (as well as the compounds of the present invention alone) can be administered parenterally, for example via the penile cavernosa. It can be injected into the body, intravenously, intramuscularly, subcutaneously, intradermally, or intrathecally. The composition also includes at least one of a suitable carrier, a suitable excipient, and a suitable diluent. nothing.

[0156] For parenteral administration, the pharmaceutical compositions of the present invention may be administered, for example, in the form of a solution that is isotonic with blood. It is best used in the form of a sterile aqueous solution which may contain other substances such as sufficient salts and simple sugars. .

[0157] For buccal or sublingual administration, the pharmaceutical compositions of the present invention may be administered in the form of tablets or lozenges. Well, this can be formulated in a conventional manner.

[0158] As a further example, a pharmaceutical composition containing at least one compound of formula (I) as an active ingredient is The composition can be formulated by combining the compound, a pharma- ceutical acceptable carrier, a pharmaceutical The composition is prepared by mixing with a pharma- ceutically acceptable diluent and / or a pharma- ceutically acceptable excipient. Carriers, excipients, and diluents can be prepared according to the desired route of administration (e.g., oral, parenteral, Thus, the drug may take a wide variety of forms, depending on the dosage form (e.g., oral, etc.). For liquid oral formulations such as elixirs and solutions, suitable carriers, excipients and diluents include Contains water, glycol, oil, alcohol, fragrances, preservatives, stabilizers, colorants and similar substances. For solid oral dosage forms such as powders, capsules, and tablets, appropriate Carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, Disintegrants and the like. To control the primary site of absorption and disintegration. The solid oral formulations are optionally coated with a substance such as a sugar or are enteric coated. For parenteral administration, carriers, excipients and diluents are usually sterile water. Other ingredients may be added to enhance the solubility and storage stability of the composition. The suspension or solvent may also be an aqueous carrier, together with suitable additives, such as solubilizers and preservatives. It can also be prepared using

[0159] According to certain embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof is For an average (70 kg) person, the regimen is about 1 to about (4) times per day, 0.1 mg to about 3000 mg, or any specific amount or range therein, specifically, about The compound may contain from 1 mg to about 1000 mg, or any specific amount or range therein, but may be selected from the group consisting of the compound of formula (I The therapeutically effective amount of the compound of the present invention will vary depending on the disease, syndrome, condition, and disorder being treated. It will be apparent to those skilled in the art that the above-mentioned operation is performed.

[0160] An embodiment of the present invention is an oral administration composition comprising a compound of formula (I) in an amount of about 1 mg to about 500 mg. The purpose is to prepare a pharmaceutical composition for administration.

[0161] Advantageously, the compounds of formula (I) may be administered in a single daily dose or alternatively in multiple daily doses. The total dosage may be administered in divided doses of two, three, and (four) times daily.

[0162] The optimal dosage of the compound of formula (I) to be administered can be readily determined and used. The particular compound, mode of administration, strength of the preparation, and progression of the disease, syndrome, condition, or disorder. In addition, factors related to the particular subject being treated, e.g. The appropriate therapeutic level and desired treatment can be determined depending on the patient's sex, age, weight, diet and administration timing. Dosage adjustments may be necessary to achieve efficacy. The above dosages are therefore given as average values. Of course, there can be individual instances where higher or lower dosage ranges are effective. which are also included within the scope of the present invention.

[0163] The compounds of formula (I) may be administered to a subject in need thereof using a compound of formula (I). The composition and administration regimen may be any of those described above or may be any of those established in the art. The compositions and administration regimens described herein can be used to administer the compounds of the present invention.

[0164] According to certain embodiments, one or more compounds of formula (I) are capable of inhibiting DHODH enzyme activity. Treating, ameliorating, and / or preventing a disease, syndrome, condition, or disorder affected by The present invention is useful in the method.

[0165] Further embodiments of the invention include the use of agonists in the treatment of disorders such as inflammatory disorders, autoimmune diseases, or cancer. In the present invention, for example, by inhibiting dihydroorotate oxygenase enzyme activity, Compound I;

[0166] [ka] [In the formula, X is CH or N; Y is CH or N; R 1 is C 1~6 Alkyl; OH or OCH 3 C replaced with 1~6 Alkyl;C 2~6 Alkenyl; C 1~6 Haloalkyl; OH or OCH 3 C replaced with 1~6 Haloalkyl;C 2~6 Haloalkenyl; N(CH 3 ) 2 ;C 3~6 Cycloalkyl;C 1~6 Alkyl-substituted C 3~6 cycloalkyl; and phenyl. Selected; R 2 teeth,

[0167] [ka] where: R a is C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 From cycloalkyl is selected from the group consisting of R b is C 1~6 Alkyl, or OH, halo, CN, OC 1~6 Alkyl, OC 1~ 6 Haloalkyl and OC 3~6 cycloalkyl; C being replaced 1~6 is alkyl, R 3 H, halo, CH 3 and OCH 3 is selected from the group consisting of R 4 teeth, (a)C 1~6 Alkyl; 1 or 2 OCH 3 C replaced with 1~6 Alkyl ;C 3~6 Cycloalkyl;CH 3 or OCH 3 C replaced with 3~6 Cycloalkane Le;CH 2 -C 3~6 Cycloalkyl; and

[0168] [ka] (b)

[0169] [ka] (c)

[0170] [ka] and (d)

[0171] [ka] is selected from the group consisting of During the ceremony, Each R c are independently: H; halo; C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C is replaced with a member selected from the group consisting of 1~6 Alkyl;C 1~ 6 Haloalkyl; OH and OCH 3 is substituted with a member selected from the group consisting of C 1~6 Haloalkyl;NO 2 ;OH;O-CH 2 CH 2 OH; and OC 1~6 Alkyl is selected from the group consisting of R d ,H;Halo;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 from C is replaced with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Hello Aruki OH and OCH 3 C is replaced with a member selected from the group consisting of 1~6 Halo Alkyl;CN; and OC 1~6 is selected from the group consisting of alkyl, R g is H;C 1~6 Alkyl; OH, OCH3 , S.C.H. 3 , and OCF 3 A group consisting of C is replaced with a member selected from 1~6 Alkyl;C 1~6 Haloalkyl; and OH and OCH 3 C is replaced with a member selected from the group consisting of 1~6 Halo alkyl, and n is 1 or 2; or a pharma- ceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. Concerning the use of the body.

[0172] In a further aspect, the present invention relates to a method for producing a dihydroorotate dehydrogenase (DHODH) enzyme activity. The present invention relates to a method for inhibiting or altering the activity of DHODH, the method comprising administering DHODH to a compound of any of formula (I), and contacting the subject with any of the aspects or embodiments disclosed herein, thereby inhibiting DHODH enzyme activity. The present invention provides methods for the treatment of cancer, including damaging or otherwise altering the function of a cancer cell.

[0173] A further embodiment of the invention comprises administering a compound of formula (I) to a subject in need thereof. This is mediated by dihydroorotate dehydrogenase (DHODH) enzyme activity, The present invention provides methods for treating a disease, disorder, or condition in which the subject is susceptible to or otherwise affected by the disease, disorder, or condition.

[0174] As used herein, the term "DHODH inhibitor" refers to an agent that inhibits or reduces DHODH activity. It can also refer to a laxative.

[0175] In one embodiment, the term "therapeutically effective amount" (or "effective amount") refers to a therapeutically effective amount administered to a subject. (1) (i) mediated by DHODH enzyme activity, or (ii) DHOD H enzyme activity, or (iii) activity (normal or abnormal) of the DHODH enzyme. At least partially alleviating, inhibiting, preventing, or preventing a condition, disorder, or disease that is a symptom of the disease. and / or improve; or (2) reduce or inhibit the activity of the DHODH enzyme; or (3) reducing or inhibiting the expression of DHODH; or (4) reducing or inhibiting the expression of the DHODH protein. Without being bound to a particular theory, the term "modifying" refers to an amount of a compound of the present invention that is effective to modify the levels of Although not a direct target for DHODH inhibitors, DHODH inhibitors inhibit the transcription factors involved in the control of myeloid differentiation in progenitor tumor cells. Inhibits protein synthesis, arrests the cell cycle, or alters post-translational glycosylation It is believed that this effect occurs by

[0176] Further embodiments of the present invention relate to the use of DHODH enzyme activity mediated or otherwise affected by DHODH enzyme activity. suffer from or be diagnosed with a disease, disorder, or condition that affects A method for treating a subject suffering from a refractory disease, comprising administering to a subject in need of such treatment an effective amount of Compounds of formula (I) (as well as compounds of formula (IA) and (IB), e.g., compounds of Table 1), compounds of formula ( I) (as well as the enantiomers of the compounds of formula (IA) and (IB), e.g., the compounds of Table 1) and diastereomers, compounds of formula (I) (as well as compounds of formula (IA) and (IB), e.g., Table 1 isotopic variations of the compound of formula (I), as well as pharma- ceutically acceptable salts of all of the above. In other words, the method includes administering at least one compound that is According to embodiments, the subject is a person suffering from or suffering from a disease, disorder, or condition, such as cancer. The method of treating a subject diagnosed with a medical condition comprises administering to the subject an effective amount of a compound of formula (I) Formulae (IA) and (IB), e.g., compounds of Table 1), and all of the above, pharma- ceutically acceptable and administering to the subject at least one compound selected from the group consisting of salts thereof (e.g., inhibiting dihydroorotate oxygenase enzyme activity in a subject or (by varying it in other ways).

[0177] In another embodiment, inhibitors of DHODH of the present invention are useful for treating autoimmune and inflammatory disorders, e.g. , arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, parsley Acne, 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, dermatomyositis, psoriasis, Behcet's disease, uveitis, myasthenia gravis Graves' disease, Hashimoto's thyroiditis, Sjogren's syndrome, blistering disorders, antibody-mediated hematopoietic disorders Vasculitis syndrome, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including pulmonary edema, embolism, fibrosis, sarcoid pulmonary hypertension, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, For use in the treatment of immune disorders, including but not limited to rheumatoid arthritis, rheumatoid arthritis, and polymyositis. It is possible.

[0178] As used herein, unless otherwise noted, the terms "affect" or "affected" are used interchangeably. The term refers to a disease, disorder, or condition that is affected by inhibition or alteration of DHODH enzyme activity. (when referring to a disease, syndrome, condition, or disorder), one or more symptoms or signs of that disease, syndrome, condition, or disorder and / or reducing the frequency and / or severity of the disease, syndrome, or condition. onset of one or more symptoms or signs of a disease, condition, syndrome, or disorder, or Or preventing the onset of a disorder.

[0179] A further embodiment of the present invention is a method for treating cancer, comprising administering to a subject in need thereof a therapeutic A therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt, isotope, N-oxygen derivative thereof. The present invention provides a method of treating a patient suffering from atopic dermatitis, comprising administering to said patient a compound, a solvate, or a stereoisomer thereof, comprising administering to said patient a compound, a

[0180] According to one embodiment, the cancer is selected from lymphoma, leukemia, carcinoma, and sarcoma. However, the present invention is not limited to the above.

[0181] A further embodiment of the present invention relates to the use of compounds of formula (I) for the treatment of one or more types of cancer. or a pharma- ceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. Provides for the use of the body.

[0182] According to certain embodiments, the uses and methods of treatment described herein are intended to treat cancer. and the cancer is selected from, but not limited to, the following: Acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia Hematologic malignancies, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic ) B-myelomonocytic leukemia, chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML) ), bone marrow leukemia that can develop into large granular lymphocytic leukemia, plasma cell leukemia, and acute myeloid leukemia leukemia, including but not limited to dysplastic syndromes (MDS); 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 cells DLBCL, germinal center B-cell DLBCL, double matched lymphoma, and double expressing lymphoma Lymphomas, including but not limited to subtypes of NHL; anaplastic large cell lymphoma, Peripheral B-cell lymphoma, primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, bar Kitt'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 lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma such as T-cell NHL; Soft tissue sarcoma, neurosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma sarcomas, including but not limited to; and 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. Other cancers, such as solid tumors, that are not treated with chemotherapy.

[0183] In one embodiment, cancers that may benefit from treatment with an inhibitor of DHODH of the present invention include Examples of cancer include lymphomas, leukemias, carcinomas, and sarcomas, such as non-Hodgkin's lymphoma, diffuse large cell carcinoma, and sarcomas. Follicular 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, non-small cell Lung cancer, including lung cancer, stomach cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer Focal carcinoma, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, striated muscle cancer, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharynx cancer These include, but are not limited to, head and throat cancer, oral cancer, and GIST (gastrointestinal stromal tumor). Not determined.

[0184] In another embodiment of the invention, the compounds of the invention may be used in combination with one or more other pharmaceutical agents. More specifically, one or more anti-cancer agents, such as chemotherapeutic agents, anti-proliferative agents, or immunomodulatory agents. In combination with anti-inflammatory drugs or as adjuncts in cancer therapy, such as immunosuppressants or anti-inflammatory drugs Further examples of anti-cancer agents that may be administered in combination with the compounds of the present invention include Non-limiting examples include biological compounds, such as monoclonal antibodies (e.g., antibodies that bind to cancer cells). These receptors may mediate effector functions upon binding to associated antigens or may be expressed on cancer cells. blocking interactions with soluble or cell-bound ligands), and redirection of immune cells According to an embodiment, the method of treating cancer includes: An effective amount of a compound of the present invention (e.g., a compound of formula (I), such as a compound shown in Table 1, and optionally substituted or unsubstituted aryl groups, selected from among commercially acceptable salts, isotopes, N-oxides, solvates, and stereoisomers. and an effective amount of one or more additional anti-cancer agents, the method comprising administering to the subject a method according to the present invention. The compound and the additional anti-cancer agent are administered simultaneously (e.g., as part of the same pharmaceutical composition) or sequentially. According to an embodiment, the pharmaceutical composition comprises an effective amount of a compound of the invention (e.g., Compounds of formula (I), such as those shown in Table 1, pharma- ceutical acceptable salts thereof, isotopes, N-amino groups, and an effective amount of one or more additional and optionally one or more excipients.

[0185] Further embodiments of the present invention include the use of antitumor agents, either alone or in combination with classical antitumor compounds well known to those skilled in the art. as part of a chemotherapy regimen for the treatment of cancer, lymphoma, and leukemia, Compounds of formula (I) or pharma- ceutically acceptable salts, isotopes, N-oxides, solvates, or derivatives thereof or the use of stereoisomers thereof.

[0186] General synthesis method Exemplary compounds useful in the methods of the present invention are now described with reference to their general preparation below. This will be described by reference to exemplary synthetic schemes and specific examples that follow. To obtain the various compounds described herein, the final desired substituents must be protected as appropriate. The reaction may or may not be carried out in a manner that is carried through the reaction scheme to give the desired product. It will be appreciated by those skilled in the art that starting materials can be appropriately selected in accordance with the present invention. Alternatively, a desired substituent may be supported via the reaction scheme and used instead of the final desired substituent. It may be necessary or desirable to use suitable groups which may be optionally substituted with desired substituents. Unless otherwise specified, the variables are as defined above with reference to formula (I). The reaction is carried out at a temperature between the melting point and the reflux temperature of the solvent, preferably between 0° C. and the reflux temperature of the solvent. The reaction can be carried out under heating using conventional or microwave heating. The reaction may be carried out in a sealed pressure vessel at a temperature above the normal reflux temperature of the solvent. This is also fine.

[0187] Abbreviations used herein, particularly in the Schemes and Examples, are as set out in Table 2 below.

[0188] [Table 2-1]

[0189] [Table 2-2]

[0190] [Table 2-3]

[0191] Preparation Example Exemplary compounds useful in the methods of the present invention are then described below with respect to their general preparation. This is illustrated by reference to an exemplary synthesis scheme and the specific examples below.

[0192] [ka]

[0193] According to Scheme 1, ethyl 2-(benzyloxy)acetate can be converted to the compound of formula ( II) 1,2,4-triazol-5(4H)-one compounds (wherein PG is Bn) In the first step, a suitable solvent such as EtOH is used at a temperature in the range of 70-85°C. Ethyl 2-(benzyloxy)acetate reacts with hydrazine hydrate in a suitable solvent. 2-(benzyloxy)acetohydrazide is prepared by adding In a suitable solvent, hydrazide and a compound of formula R a -NCO isocyanate (wherein R a is C 1~6 a The reaction is then carried out with water or other suitable solvents to give the corresponding semicarbazides. By cyclization of the semicarbazide with a suitable base such as NaOH in a suitable solvent. This provides a compound of formula (II) (wherein PG is Bn).

[0194] A compound of formula (II) a is C 1~6 Haloalkyl or C 3~6 Cycloalkyl ) is expressed by the formula R a The compound was prepared as described above using a compound suitably substituted with -NCO. (wherein R a is C 1~6 Haloalkyl or C 3~6 Cycloalkyl be).

[0195] TWGreene and PGMWuts, “Protective G roups in Organic Synthesis,” 3 ed., John W. Using established methods such as those described in Elley & Sons, 1999 In two steps, a compound of formula (II) in which PG is Bn can be converted into a compound of formula (II) in which PG is TBDPS. The exchange of protecting groups to a compound of formula (II) is achieved in the first step by a method well known to those skilled in the art. Deprotection of the benzyl group is accomplished under hydrogenolysis conditions to provide the alcohol. Using a palladium catalyst such as d / C, 2 Under, EtOH, MeOH, EtOAc, or In a suitable solvent, such as a mixture thereof, preferably EtOH, in the presence or absence of HCl Deprotection is accomplished over a period of 4-72 hours without the use of tert-butyl. Diphenylsilyl chloride and imidazole, dimethylaminopyridine, pyridine, etc. and a suitable base in a solvent such as DMF or DCM at a temperature ranging from 0° C. to room temperature. and protecting the corresponding alcohol as a silyl ether to give a compound of formula (II), PG is TBDPS).

[0196] [ka]

[0197] According to Scheme 2, R 3 The compound of formula (XIV) in which is H is N-iodosuccinimide It is treated with a halogenating agent such as nisidine (NIS) and dissolved in an aprotic solvent such as acetonitrile. The halogenated compound of formula (III) (wherein HAL is iodine) is obtained by treating the compound under heating in a solvent. (which is the formula R 1 -B(OH) 2 The compound can be prepared according to Suzuki coupling conditions well known to those skilled in the art. with a compound of formula (III) under conditions to provide a compound of formula (IV). Compound (III) (wherein HAL is iodine) is reacted with R 1 -B(OH) 2 (In the formula, R 1 is optionally substituted as defined in embodiment 1; 2~6 Alkenyl or Commercially available or synthetically available boronic acids (or boronic acid esters) such as ter;Bis(triphenylphosphine)palladium(II) dichloride, tetrakis( Palladium catalysts such as triphenylphosphine palladium; potassium phosphate, Cs 2 C O 3 and a suitable solvent such as dioxane, water, ethanol, or a mixture thereof. The compound of formula (IV) (wherein R 3 teeth H) can be obtained by a copper(II)-mediated Chan-Lam coupling reaction well known to those skilled in the art. Under the conditions of formula R 4 -B(OH) 2 to give a compound of formula (V): where HAL is bromide, X is CH, and R 3 For example, the formula Compound (IV) is reacted with a compound of formula R in a suitable solvent such as DCM, ACN, dioxane, THF, etc. 4 -B(OH) 2 (wherein R 4 is as defined in embodiment 1), acetic acid Catalysts such as copper(II), pyridine, NEt 3 to give a compound of formula (V). Get something.

[0198] [ka]

[0199] According to Scheme 3, a compound of formula (V), 1 is optionally substituted C 2~6 alkenyl, R 3 is H and R 4 is preferably arranged as claimed in claim 1 (HAL is substituted phenyl, and HAL is Br) in the Ullmann-type aromatic amination reaction. In a suitable solvent such as 1,4-dioxane, DMSO, DMF, THF, ACN, etc., catalyst In the presence of CuI and a diamine (e.g., trans-1,2-diaminocyclohexane), BiK 3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , triethylamine and other bases in the presence of a commercially available or synthetically available nucleophilic compound of formula (II), a is C 1~6 alkyl) (e.g., a suitably protected triazolone (wherein PG is benzyl, 4-Methoxybenzyl, or alkoxy such as TBDPS, TBS, TES, or TIPS or arylsilane) to give a compound of formula (VI) In this case, X is CH and Y is CH.

[0200] A compound of formula (VI) 1 is C 2~6 alkenyl) under Simmons-Smith cyclopropanation reaction conditions well known to those skilled in the art to give a compound of formula (V I) compound (wherein R 1 is C 1~6 Alkyl-substituted C 3~6 Cycloalkane For example, a compound of formula (VI) (wherein R 1 teeth

[0201] [ka] ) in a suitable solvent such as toluene at a temperature ranging from 0° C. to room temperature for 3 hours. Reaction with diiodomethane and diethylzinc for ∼26 hours afforded the compound of formula (VI ) (wherein R 1 is CH 3 substituted cyclopropyl).

[0202] Next, TW Greene and PG M Huts, Groups in Organic Synthesis, 3rd ed., John Wiley Deprotection using established methods such as those described in Ley & Sons, 1999. This gives a compound of formula (I) (wherein X and Y are CH). For example, a compound of formula (VI) (wherein R 3 is H and PG is TBDPS) under conditions known to those skilled in the art. The deprotection is carried out using, preferably, TBAF in a suitable solvent such as THF. In the new method, PG is TBDPS and R a is C 1~6 Alkyl. Alternatively, T The BDPS protecting group was removed using triethylamine trihydrofluoride (Et 3 N 3HF) is achieved.

[0203] The Bn protecting group can be removed by hydrogen gas in the presence of a catalyst such as palladium on carbon (Pd / C). Removal of the protecting group Bn can also be achieved using TFA at a temperature of about 80° C. will be done.

[0204] A compound of formula (I) wherein X is CH, Y is CH, and R 2 , R 3 , R 4 Yes, that Each is defined as described in embodiment 1, and R 1 is C 2~6 alkenyl) can be reduced using hydrogenation conditions well known to those skilled in the art, e.g., H 2 Below, MeOH, THF , Pd / C or Wilkinson's catalyst [RhCl(PP h 3 ) 3 ] to give a compound of formula (I), 1 is C 2~6 (It is alkyl) get.

[0205] [ka]

[0206] According to Scheme 4, TiC l 4 and a base such as triethylamine to obtain the 3-methyl group of the compound of formula (VII). -2-butenal, 3-methylpent-2-enal and other α,β-unsaturated aldehydes Reductive amination of the above affords the enamine intermediate, which can then be reacted with NaBH 4 Such as to obtain a compound of formula (VIII), 5 is C 1~4 Alkyl R 4 is as defined in embodiment 1), to obtain a compound of formula (VIII) In an anhydrous aprotic solvent such as dichloromethane (DCM), triethylamine and 4- Using a base such as dimethylaminopyridine (DMAP), available commercially or synthetically Coupling with available 4-bromo-2-iodobenzoyl chloride to give the compound of formula (IX) The compound of formula (IX) is reacted with palladium(II) acetate under heated Heck reaction conditions to obtain a compound of formula (IX) , tetrabutylammonium bromide, and potassium acetate to give the compound of formula (V ) (wherein R 1 is optionally substituted C 2~6 Alkyl R 3 is H, X is CH, and HAL is Br), and an intramolecular ring of formula (Va): Compound (R 1 is optionally substituted C 2~6 is alkyl, R 3 is H , X is CH 2 and HAL is Br).

[0207] [ka]

[0208] According to Scheme 5, in a suitable solvent such as DMSO, DMF, THF, ACN, etc., K 3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , the presence of bases such as trimethylamine Compounds of formula (X), which are commercially available or available by synthesis, where HAL is F and R 3 is F and R 5 is H or C 1~4 alkyl), which is commercially available or synthetically available. The compound represented by formula (II) (wherein R a is C 1~6 A nucleophilic compound (e.g., a suitably supported and the like, wherein PG is benzyl, 4-methoxybenzyl, or alkyl or aryl silyl groups such as TPDPS, TBS, TES, or TIPA. The compound of formula (XI) is obtained by reacting with a compound selected from the group consisting of aryl, aryl, aryl and aryl groups. So, PG is Bn and R a is C 1~6 The ester of formula (XI) is R 5 C 1~4 If it is an alkyl group, it is hydrolyzed to its corresponding acid under acidic or basic conditions. For example, tert-butyl ester (R 5 Treatment with TFA (tert-butyl) or by hydrolysis with a base such as NaOH in an aqueous medium to give the compound of formula (XIa) (wherein R 5 Using conditions well known to those skilled in the art, a compound of formula (XIa) can be obtained. The compound of formula (XII) can be obtained by chlorinating the compound of formula (XIa). The compound is SOCl 2 or treated with oxalyl chloride in DCM. .

[0209] [ka]

[0210] According to Scheme 6, in an anhydrous aprotic solvent such as dichloromethane (DCM), Mixtures of triethylamine (TEA) and 4-dimethylaminopyridine (DMAP) Using a base, a compound of formula (XII) 3 is H or F, PG is Bn , R a is C 1~6 alkyl) to a compound of formula (VIII), 5 is C 1~4 (alkyl) to obtain a compound of formula (XIII). wherein X is CH and Y is CH) can be prepared by reacting a compound of formula (XIII) 1 teeth, C optionally substituted as described in claim 1 1~6 alkyl), Under heated Heck reaction conditions, palladium(II) acetate, tetrabutylammonium bromide and potassium acetate, thereby giving a mixture of intramolecularly cyclized compounds, which were then separated. R 1 C 2~6 is alkyl, R 3 The intermediate compound, where is H or F, is isolated.

[0211] [ka]

[0212] According to Scheme 7, a compound of formula (XIV), where R 3 is H or F) to a compound of formula (II) (e.g., a suitably protected triazolone (wherein P G is benzyl, 4-methoxybenzyl, or TBDPS, TBS, TES, or T Ullmann-type aromatic silanes selected from alkyl or aryl silanes such as IPS In amination reaction, a compound of formula (XV) is obtained. In a preferred method, PG is Bn and R a is C 1~6 The compound of formula (XV) is reacted with acetonitrile or the like under heating conditions. In any aprotic solvent, halogenating agents such as N-iodosuccinimide (NIS) to give a halogenated compound of formula (XVI), where Y is CH and HAL is iodine. (There is a certain

[0213] [ka]

[0214] According to Scheme 8, compounds of formula (XVIIa) and (XVIIb) can be prepared by reacting 5-bromoisopropyl ether with It is prepared in two steps from isobenzofuran-1,3-dione. 2 In the presence of 5-Bromoisobenzofuran-1,3-dione in an aprotic solvent such as THF Suitable substituted alkyl Grignard reagents (i- PrMgCl, EtMgBr, etc.), followed by K 2 CO 3 , Cs 2 CO 3 etc. In the presence of a base of the formula R 5 -I alkyl A compounding agent (wherein R 5 is C 1~4 alkyl) (e.g. iodomethane or iodoethane, etc.) to obtain a mixture of regioisomeric esters of formula (XVIIa) and (XVIIb). (wherein R 1 is optionally substituted C 1~6 (Alkyl) in the same way. Using an aryl Grignard reagent, compounds of formula (XVIIa) and (XIIb) can be obtained. (wherein R 1 is suitably substituted phenyl). The positional isomers of (XVIIb) and (XVIIc) were not separated but were used directly to afford the corresponding phthalazido In a suitable solvent, such as ethanol or methanol, at a temperature in the range of room temperature to 90° C. for 6 to 20 hours, The mixture of Ib) is treated with an excess of hydrazine to give the desired phthalazinone compound of formula (V). can be purified by precipitation, crystallization, or flash chromatography to obtain the other The reaction can be easily separated from the positional isomers. -1,2-diaminocyclohexane), and K 3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , 1,4-dioxane, DMSO in the presence of a base such as triethylamine , DMF, THF, ACN, or the like in a suitable solvent, ) of a suitably protected triazolone (wherein R a is C 1~6 alkyl, and PG is phenyl. benzyl, 4-methoxybenzyl, or TBDPS, TBS, TES, or TIPS, etc. alkyl or aryl silanes) in an Ullmann-type aromatic amination reaction. This gives a compound of formula (XVIII) (wherein X is N).

[0215] A compound of formula (XVIII) 1 is C 2~6 alkenyl) is known to those skilled in the art. under known Simmons-Smith cyclopropanation reaction conditions to give a compound of formula (XVIII) Compound (wherein, R 1 is C 1~6 Alkyl-substituted C 3~6 Cycloalkyl For example, 2 is obtained by subjecting the compound to reaction in a suitable solvent such as toluene at a temperature ranging from 0° C. to room temperature. The compound of formula (XVIII), 1 is C 2~6 alkenyl) , diiodomethane and diethylzinc to give a compound of formula (XVIII), 1 CH 3 cyclopropyl substituted with

[0216] [ka]

[0217] According to Scheme 9, a compound of formula (X) 3 is H , R 5 CH 3 ) by palladium catalyzed carbonylation to Available formulas R 1 -CHO aldehyde (wherein R 1 is C 1~6 alkyl) and This affords the corresponding ketone compound of formula (XIX) (a similar transformation can be carried out by Suchan d et al., J. Org. Chem. 2016, 81, 6409-6423 For example, Pd(OAc) 2 Palladium catalysts such as Ag 2 O and tert In the presence of an oxidizing agent such as an aqueous solution of butyl hydroperoxide (TBHP), the Methyl 4-bromo-2-iodobenzoate and isobutyraldehyde were mixed at a temperature of 10 to 14 °C for 10 to 14 hours. The reaction with 4-bromo-2-isobutyrylbenzoate gave methyl 4-bromo-2-isobutyrylbenzoate (XIX). The ketone compound is converted into hydrazine R 4 -NHNH 2 (In the formula, R 4 2-Chloro-6-fluoro and the like, which is a suitably substituted aryl, such as orophenylhydrazine, to give a compound of the formula ( The compound of formula (V) is preferably reacted as described above with the compound of formula (V) to obtain a compound of formula (V) in which X is N. Ullmann-type aromatic amination reaction with protected triazolone (II) to give wherein Y is CH and R 1 is C 1~6 alkyl) is obtained. .

[0218] A compound of formula (VI) 1 is phenyl and X is N) Using the method described above, methyl 4-bromo-2-isobutyrylbenzoate was reacted with commercially available or Synthetically available formula R 1 -CHO aldehyde (wherein R 1 is phenyl) and It can be prepared in a similar manner by coupling.

[0219] [ka]

[0220] According to Scheme 10, 1 -B(OH) 2 The compound was reacted with the Suzuki cuprate according to the method well known to those skilled in the art. under ring conditions with a compound of formula (XVI) to give a compound of formula (XVIII), , where X is CH. For example, dioxane, water, ethanol, or a mixture thereof in a suitable solvent, such as, for example, a compound of formula (XVI), ) to R 1 -B(OH) 2 (In the formula, R 1 is optionally as defined in embodiment 1 Replaced by C 2~6 Alkenyl or C 3~6 Commercially available or synthetic aryl groups such as cycloalkyl Boronic acids (or boronic acid esters), bis(triphenylphosphine ) Palladium catalyst such as palladium(II) dichloride, potassium phosphate, Cs 2 CO 3 with a suitable base, such as to give a compound of formula (XVIII), where X is CH During the above coupling reaction, loss of iodide during the reaction conditions gives the compound of formula (XVI II) compounds of formula (wherein X is CH and R 1 It has been found that H) can be obtained. As known to those skilled in the art or as described above, copper(II)-mediated Chang-Lam-Cu catalysts can be used to Under pulling conditions, a compound of formula (XVIII), where X is CH or N, is reacted with a compound of formula R 4 -B(OH) 2 to give a compound of formula (VI), H or N, R 1 is optionally substituted C 2~6 alkenyl, R 3 is H or F, and R 4is phenyl, suitably substituted as defined in claim 1. (obtained).

[0221] A compound of formula (XVIII) 1 is N(CH 3 ) 2 is represented by the formula (XVI) The compound is prepared from the compound of formula (XVI) where HAL is Br and PG is Bn. and NH(CH) in water 3 ) 2 and other amines at a temperature of about 110°C for 96 hours. By reacting the compound represented by formula (XVIII) 1 is N(CH 3 ) 2 and R a is C 1~6 By following the above method, a compound of R 1 N(CH 3 ) 2 in A compound of formula (I) is prepared.

[0222] A compound of formula (XVIII) 1 C is substituted with OH 1~6 Alkyl The compound of formula (XVIII) 1 is C 2~6 alkenyl, and PG is B n) in two steps. In the first step, NaIO 4 , and K 2 O so 4 .2H 2 O or OsO 4 Under oxidation conditions such as THF / H 2 In a suitable solvent such as O , a compound of formula (XVIII) 1 teeth

[0223] [ka] The reaction is carried out at a temperature ranging from 0°C to room temperature for 48 to 72 hours. In the second step, the ketone intermediate is obtained by adding a suitable solvent such as diethyl ether. The ketone intermediate is reacted with a Grignard amine such as methylmagnesium bromide in a suitable solvent. The reaction is carried out at a temperature ranging from 0°C to room temperature for 3 to 30 hours. and a compound of formula (XVIII) (wherein R 1 C is substituted with OH 1~6 With alkyl (There is a certain

[0224] [ka]

[0225] According to Scheme 11, 4,5-difluorophthalic anhydride is reacted with a compound of formula R in acetic acid. 4 -N HNH 2 (In the formula, R 4 (2-chloro-6-fluorophenyl)hydrazine hydrochloride, etc. and a hydrazine compound of about The compound of formula (XX) ( In the formula, R 3 In an aprotic solvent such as ethanol or methanol, Compounds of formula (XX) can be prepared by the addition of tetrahydrofuran under basic conditions such as thorium ethoxide or sodium methoxide. The product is subjected to a rearrangement reaction at room temperature for about 1.5 hours to obtain the ring-expanded compound of formula (XXI). The formula ( Derivatization of compounds XXI) can be carried out by reacting them with trifluoromethanesulfonyl ether in a suitable solvent such as DCM. Sulfonic anhydride (Tf 2O) and triethylamine (TEA), This is accomplished by reacting with a base such as pyridine to give a compound of formula (XXII) N-phenylbis(trifluoromethanesulfonimide) (TF 2 NPh) etc. A mild triflate agent and a base such as TEA or DIEA in a suitable solvent such as DCM. It can be used in a medium.

[0226] [ka]

[0227] According to Scheme 12, 1 -B(OH) 2 The compound was subjected to the above-mentioned Suzuki coupling conditions. under conditions with a compound of formula (XXII) to give a compound of formula (V), For example, the compound of formula (XXII) can be dissolved in dioxane, water, ethanol, or the like to obtain In a suitable solvent, such as a mixture of R 1 -B(OH) 2 wherein the formula is as defined in embodiment 1 As expected, R 1 is C 2~6 Alkenyl or C 2~6 (haloalkenyl) The boronic acid (or boronic ester) is a synthetically available boronic acid. phenylphosphino)ferrocene-palladium(II) dichloride or bis(triphenylphosphino)ferrocene-palladium(II) dichloride Palladium catalysts such as palladium(II) dichloride and potassium phosphate, C s 2 CO 3 , K 2 CO 3 With a suitable base such as to give a compound of formula (V). V), wherein R 1 is C 2~6Alkyl or C 2~6 haloalkyl) is a compound of the formula Compound (V), wherein R 1 is C 2~6 Alkenyl or C 2~6 haloalkenyl) For example, a compound of formula (V) R 1 teeth

[0228] [ka] ) under hydrogenation conditions using a catalyst such as Pd / C in a suitable solvent such as EtOAc React in an atmosphere of hydrogen gas (20-45 psi) at room temperature for 4-24 hours. to obtain a compound of formula (V), 1 teeth

[0229] [ka] By reacting a compound of formula (V) with a suitably protected compound of formula (II) using the conditions described above, Reaction with the triazolone affords a mixture of compounds of formula (VI) and (VIa). This can be separated before or after deprotection of the protecting group.

[0230] [ka]

[0231] According to Scheme 13, N-arylation of a compound of formula (XVIII) can be carried out by suitably substituted The commercially available or synthetically available fluoro compounds of formula (XXIII) c and R d is as defined in embodiment 1). 2 CO 3, Cs 2 CO 3 In the presence of a base such as , a compound of formula (XVIII) 1 is H, C 2~6 Alkenyl, C 2~6 Haloal Kenil, C. 3~6 Cycloalkyl, C 1~6 Alkyl-substituted C 3~6 Cycloa and X is CH or N), is reacted with a compound of the formula (XXI) II) at a temperature in the range of 65 to 100° C. to obtain a compound represented by the formula ( XXIV) compound is obtained.

[0232] The reduction of the compound of formula (XXIV) can be carried out in a mixture of methanol and water with zinc or iron and NH 4 This is accomplished using Cl to give the amino compound of formula (XXV).

[0233] The compound of formula (XXV) is reacted with NaNO 2 or, for example, EtOH. Diazotization with other nitrous acid reagents in a suitable solvent at a temperature of 0°C, followed by heating at 0-85°C. By reducing the diazo group with zinc at temperatures in the range of °C, or by H 3 PO 2 Process with Thus, a compound of formula (XXVI) (wherein R c and R d is defined in the description of embodiment 1. (as defined above).

[0234] [ka]

[0235] According to Scheme 14, K 2 CO 3 , Cs2 CO 3 In the presence of bases such as DMSO, D In a suitable solvent such as MF, THF, ACN, etc., a compound of formula (X), R 5 is H and R 3 is F), II) compound (wherein R 1a and R 1b are each independently H or C 1~4 Alkyl and for example 1-bromo-3-methyl-2-butene) to give a compound of the formula (XXV III) ester compounds (wherein R 3 is F and HAL is F). XVIII), wherein R 1a and R 1b are each independently C 1~4 Hello Aruki Ru or C 3~6 Cycloalkyl) can be prepared in a similar manner. XVIII) with a suitably protected triazolone compound of formula (II) 3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 In the presence of a base such as triethylamine, The reaction is carried out in a suitable solvent such as 1,4-dioxane, DMSO, DMF, THF, or ACN. In a preferred method, PG is Bn and R a is C 1~6 The compound of formula (XXIX) (wherein R 3 is H or F) Under Heck reaction conditions, for example, chloro[(tri-tert-butylphosphine)- 2-(2-aminobiphenyl)]palladium(II)(P(tBu 3 )PdG 2 ), N- A catalyst such as cyclohexyl-N-methyl-cyclohexanamine is added to a suitable solvent such as toluene. Intramolecular cyclization is carried out in a suitable solvent at a temperature of about 15 to 80° C. for about 18 to 36 hours. and isocoumarin compounds of the formula (XXX), 1 is isopropyl Yes, R 3 is H or F, and R a and PG is defined as above).

[0236] An isocoumarin compound of formula (XXX) 1 teeth

[0237] [ka] is a compound of formula (XIa) and methylbuta-1,2-dien-1-ylacetate Methyl buta-1,2-dien-1-yl acetate is commercially available. It can be prepared in two steps from 2-methyl-3-butyn-2-ol or from Mg(C lO 4 ) 2 Acetic anhydride is reacted with 2-methyl- Reaction with 3-butyn-2-ol to give 2-methylbut-3-yn-2-yl acetate 2-Methylbut-3-yn-2-yl acetate is reacted with a catalytic amount of Lewis acid (AgB F 4 , AgClO 4 , PtCl 2 etc.) to form 3-methylbuta-1,2-diene 3-Methylbuta-1,2-dien-1-yl acetate is obtained. Using intermolecular cyclization under Heck reaction conditions as described above, a compound of formula (XIa),5 is H). For example, Catacxium A Pd G2, and And Cy 2 Catalysts such as NMe palladium(II), tetrabutylammonium bromide, and a base such as potassium acetate in a suitable solvent such as DMF. The reaction is carried out at a temperature of 70 to 90°C for 10 to 16 hours to obtain a compound represented by the formula (XXX) isocoumarin compound of the formula 1 teeth,

[0238] [ka] ) is obtained.

[0239] A compound of formula (XXX) where Y is CH and R 1 teeth

[0240] [ka] ) was reacted with Wilkinson's catalyst [RhCl(PPh 3 ) 3 Water using a catalyst such as Selective reduction under halogenation conditions at room temperature in a suitable solvent such as THF to give compounds of formula (X XX) isocoumarin compounds (wherein R 1 is isopropyl).

[0241] [ka]

[0242] According to Scheme 15, 2-butanone can be prepared using Wittig reaction conditions well known to those skilled in the art. is converted to ethyl 3-methylpent-2-enoate. For example, 2-butanone can be converted to ethyl 3-methylpent-2-enoate by In a suitable solvent, such as benzoic acid, LiCl, etc., at temperatures ranging from room temperature to the reflux temperature of the solvent, Cl, and sodium dodecyl sulfate (SDS), with or without additives (Carbethes Triphenylphosphonium ylides such as 12-(2-methoxymethylene)triphenylphosphorane and The reaction is allowed to proceed for 24 hours. Ethyl 3-methylpent-2-enoate is dissolved in a suitable solvent such as toluene. In a suitable solvent, at temperatures ranging from -78°C to room temperature, using a suitable reducing agent such as DIBAL-H. and reduced to 3-methylpent-2-en-1-ol. The 1-ol can be prepared by oxidation under conditions well known to those skilled in the art, e.g., in EtOAc, DMSO, DCM, etc. In a solvent of DMP (Dess-Martin-Penetration-Method) at temperatures ranging from about -78°C to room temperature (about 23°C), Leuyogenan), SO 3 -Pyridine, Swern conditions [(COCl) 2 , DMSO, Et 3 N], PCC, etc. to give 3-methylpent-2-enal. In the method, 3-methylpent-2-en-1-ol was reacted with Dess-Martin periodinator The mixture is then oxidized with pentane at 25°C for 1-4 hours to give 3-methylpent-2-enal.

[0243] [ka]

[0244] According to Scheme 16, in a suitable aprotic solvent such as DCM or toluene, XX) isocoumarin (wherein Y is CH) is commercially available or obtained by synthesis. Possible formula R 4 -NH 2 (wherein R 4 is as defined in embodiment 1 ), and AlMe3 , AlCl 3 and the like, to give a compound of formula (XXXI) wherein Y is CH and R 1 , R 3 , R 4 and R a As described in embodiment 1 It is defined as follows.

[0245] [ka]

[0246] Isocoumarin compounds of formula (XXX) can be prepared according to Scheme 17. ,5-Difluoro-2-iodobenzoyl chloride is oxalyl chloride or thionyl chloride. Using conditions well known to those skilled in the art, dichloromethane (DCM) in the presence of a catalytic amount of DMF ), tetrahydrofuran (THF), acetonitrile (ACN), toluene, and other non-proline solvents. In a suitable solvent, such as a volatile non-polar solvent, at a temperature ranging from 0° C. to room temperature, a compound of formula (X) is (wherein HAL is F and R 5 is H and R 3 is F), Form 4,5-difluoro-2-iodobenzoyl chloride. -Iodobenzoyl chloride is reacted with triethylamine and DCM in a suitable solvent. In the presence of a base such as AP, commercially available or synthetically available 2-methylbut-3-ene is 3-2-ol to give an ester compound of formula (XXXIII). Reacting a compound of formula (XXXIII) with a compound of formula (II) using the method described above. Compound (XXXIV) can be obtained by the above reaction. Compound (XXXIV) with a catalytic amount of Lewis acid (e.g., AgClO 4, PtCl 2 By processing with A rearranged compound of formula (XXXV) can be obtained. , R 3 is H or F), can be prepared by the use of a catalyst such as palladium(II) acetate, tetrabutylammonium using a phase transfer reagent such as hexafluoroammonium bromide and a base such as potassium acetate. Under the reaction conditions, the intramolecular cyclization can be carried out at a temperature of 70 to 90°C for 1 to 3 hours. This gives an isocoumarin compound of formula (XXX), where Y is CH.

[0247] [ka]

[0248] According to Scheme 18, a compound of formula (Xa) (wherein HAL is Cl and R 5 CH (CH 3 ) 2 and R 3 (wherein F) is disclosed in U.S. Patent Application Publication No. 2016-013322 by Chen et al. They are available commercially or synthesized according to the methods described in US Pat. No. 5,639,369. K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 In the presence of a base such as triethylamine, In a suitable solvent such as diethyl sulfoxide (DMSO), DMF, THF, ACN, etc., a compound of formula (X a) is reacted with a commercially available or synthetically available nucleophilic compound of formula (II), is benzyl, and R c is C 1~6 By reacting with a compound of the formula (XX A compound of formula (XXXIX) or formula (XIX) (wherein Y is N) is obtained. I) compound (wherein R 3 is F and R 5 is C 1~4 alkyl) is dioxane In a suitable solvent, such as ethanol, water, or a mixture thereof, conventional heating or micro-dispersion may be used. Using microwave heating, commercially available 1-ethoxyethene-2-boronic acid pinacol ester and bis(1-ethoxyethene-2-boronic acid pinacol ester were synthesized. (Triphenylphosphine)palladium(II) dichloride, 1,1'-bis(diphenyl palladium catalysts such as phenylphosphino)ferrocene-palladium(II) dichloride and C s 2 CO 3 to give a compound of formula (XL), H).

[0249] [ka]

[0250] According to Scheme 19, 4 -NH 2 (In the formula, R 4 is as defined in embodiment 1 The compound (which is a methyl group) is dissolved in trimethylaluminum and dichloromethane, toluene, or the like. and reacting the resulting solution with a compound of formula (XL), , Y is CH or N) to obtain a compound of formula (XLI). The compound (wherein Y is CH or N) is heated at 50°C to 90°C with acetic acid or trifluoroacetate. The compound of formula (XLII) is then treated with fluoroacetic acid to give the compound of formula (XLII). Halogenation with N-bromosuccinimide in anhydrous dimethylformamide at room temperature This gives a compound of formula (XVI) where HAL is Br. 1 -B( OH)2 under Suzuki coupling conditions as known to those skilled in the art or as described above. with a compound of formula (XVI) to give a compound of formula (VI), 1 In embodiment 1, C, optionally substituted as defined 2~6 Alkenyl, C 2~6 Haloal To obtain a compound of formula (VI), 1 is optional C has been replaced by 2~6 Alkenyl, C 2~6 haloalkenyl) by Wilkin Son catalyst ((PPh 3 ) 3 RhCl) under hydrogenation conditions to give a compound of formula (VI) Compound (wherein, R 1 is C 2~6 Alkyl or C 2~6 haloalkyl).

[0251] [ka]

[0252] According to Scheme 20, 3-methylbutanal can be condensed with a solvent such as molecular sieves (4A). In the presence of a water scavenger, in a suitable solvent such as dioxane, a compound of formula (XXXIX), , Y is N and R 5 is CH(CH 3 ) 2 ), and palladium catalysts (e.g., aryl palladium(II) chloride dimer, etc.) and 1,1'-bis(diphenylphosphino) Ligands such as ferrocene (dppf), Cs 2 CO 3 Reacting with a suitable base such as Thus, a compound of formula (XV) (wherein R 1 is isopropyl). 4-NH 2 (In the formula, R 4 is as defined in embodiment 1) with trimethylalkane. React with dimethylaminoethylamine in a suitable solvent such as dichloromethane, toluene, or a mixture thereof. The resulting solution is combined with the compound of formula (XXX) and then heated at 80 to 100° C. Treatment with acetic acid at elevated temperature for a period ranging from 5 to 24 hours affords the compound of formula (VI) wherein X is CH, Y is N, and R 1 is isopropyl, R 3 is F ) is obtained.

[0253] [ka]

[0254] According to Scheme 21, a compound of formula (XXXIX) or (XI) 3 is F Yes, R 5 is C 1~4 (alkyl) to commercially available vinyl boronic acid pinacol ester, and bis(triphenylphosphine)palladium(II) dichloride, or 1,1'-biphenylphosphine Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane Palladium catalysts such as Cs complexes 2 CO 3 and a suitable base such as dioxane, water, or ethanol. ethanol, or a mixture thereof to give a compound of formula (XLIII) In the compound of formula (XLIII), the vinyl group is potassium periodate(VI) dihydrate / sodium periodate, or ozonolysis. The compound of formula (XLIV) is selectively converted to an aldehyde group of formula (XLIV). Suitable substituted alkyl Grignard reagents (i) are commercially available or available by synthesis. -PrMgCl, etc.) in an aprotic solvent such as THF, followed by des By subsequent treatment with an oxidizing reagent, such as Martin's reagent or Swern oxidation conditions to obtain a ketone compound of formula (XLV).

[0255] Compounds of formula (XLV) are prepared in two steps from compounds of formula (XXXIX). Compound (XLa) (R 3 is F and R 5 C 1~4 (alkyl) was added to commercially available triphenylphosphine Butyl(1-ethoxyvinyl)tin and bis(triphenylphosphine)palladium ( II) dichloride, 1,1'-bis(diphenylphosphino)ferrocene-palladium ( II) A palladium catalyst such as dichloride and dioxane, water, ethanol, or any of these The reaction is then carried out in a suitable solvent, such as a mixture of 1,2-dichlorophenyl ether, ... and 1,2-dichlorophenyl ether. By acidic hydrolysis using conditions, a compound of formula (XLV) (wherein X is N and Y is N or CH, R 1 is methyl).

[0256] Commercially available or synthetically available hydrazine R 4 -NHNH 2 (In the formula, R 4 is an embodiment 1) (e.g., 2-chloro-6-fluorophenylhydrazine , o-tolylhydrazine) in the presence of a suitably selected base such as potassium carbonate, Under heating conditions such as 0 to 120°C, in a suitable solvent such as toluene or a mixture thereof and a compound of formula (XLV) to give a compound of formula (VI) Y is CH or N; R 4 is as defined in embodiment 1).

[0257] [ka]

[0258] According to Scheme 22, K 3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , Tori In the presence of a suitable base such as ethylamine, 1,4-dioxane, DMSO, DMF, TH F, methyl 2-bromo-4,5-difluorobenzoate in a suitable solvent such as ACN with a suitably protected triazolone compound of formula (II) to give a compound of formula (XLVI) In a preferred method, PG is Bn and R a is C 1~6 Alkyl (As previously described in Scheme 14). In the absence of a water scavenger such as LA-4A, 3-methylbutanal was with an allylpalladium(II) chloride dimer, I) and 1,1'-bis(diphenylphosphino)ferrocene (dppf), etc. and Cs 2 CO 3 to give a compound of formula (XLVII) We obtain the formula R 4 -NH 2 (In the formula, R 4 is as defined in embodiment 1 The material is dissolved in a suitable solvent such as dichloromethane, dichloroethane, toluene, or mixtures thereof. The resulting solution is reacted with trimethylaluminum in a solvent to give a compound of formula (XLVII). Then, the mixture is heated at a temperature of 80 to 100°C for a period of time ranging from 5 to 24 hours. and treating with acetic acid to give a compound of formula (VI), and R 1 is isopropyl, R 3 In a particular case, o -Toluidine, etc., with formula R 4 -NH 2 The compound is heated to 80-100°C and then cooled to 10-2 Direct condensation with the compound of formula (XLVII) in acetic acid for a period ranging from 4 hours. and forming a compound of formula (VI) (wherein X, Y, R 1 , R 3 is defined above).

[0259] [ka]

[0260] According to Scheme 23, a compound of formula (XXXIX), 5 is C 1~4 With alkyl Y is N and R 3 (F) in a suitable solvent such as ACN or toluene. Palladium catalysts such as radium(II) bis(triphenylphosphine) dichloride, A copper catalyst such as copper iodide and a suitable base (e.g., triethylamine) can be used to prepare trimethylsilyl The silyl-protected alkyne, such as acetylene, is subjected to the Sonogashira coupling reaction. Deprotection is carried out using TBAF in a suitable solvent at room temperature to give a compound of formula (XLVIII). The compound of formula (XLIX) can be prepared by reacting a gold catalyst (preferably Or AuCl 3) is obtained using AuCl 3 A similar transformation by catalytic cyclization can be carried out using M archal,E.et al in Tetrahedron 2007,63,99 79-9990. Formula R 4 -NH 2 (In the formula, R 4 In embodiment 1 The compound (as defined above) is dissolved in trimethylaluminum, dichloromethane, dichloromethane, and The reaction is carried out in a suitable solvent such as chloroethane, toluene, or a mixture thereof, and the resulting The solution is combined with a compound of formula (XLIX) and then heated to a temperature of 80-100° C. for 5 Treatment with acetic acid for a period ranging from -24 hours gives compound of formula (L). NBS is used at room temperature in a suitable solvent (preferably DMF) followed by the procedure well known to those skilled in the art. and carrying out cross-coupling using conditions, preferably palladium(II) bis(triphenylphosphine) palladium catalysts such as Cs(2-phenylphosphine)dichloride, 2 CO 3 , Na 2 CO 3 etc. Using a base, chloroform is synthesized in a solvent mixture consisting of 1,4-dioxane and water at a temperature of 100°C. By coupling, a compound of formula (VI) (wherein X is CH and Y is N and R 3 is F and R 1 , R a and PG is defined as above).

[0261] [ka]

[0262] According to Scheme 24, a compound of formula (VI), where PG is Bn, can be prepared by one skilled in the art. Using well-known conditions, preferably in a sealed tube in neat TFA at a temperature of about 60-90° C. or in a suitable solvent such as DCM at a temperature of about -78 °C. 3 of Deprotection is carried out using palladium on carbon (Pd / C) or in the presence of a catalyst such as and treating with hydrogen gas to obtain the compound of formula (I).

[0263] In a similar manner, a compound of formula (XVIII) 1 is I and PG is TBDPS and Z is NO 2 and X is N) and in situ TBDPS Deprotection is accomplished using conditions well known to those skilled in the art or described above to give compounds of formula (I). It is possible.

[0264] A compound of formula (I) 3 is F) in an aromatic nucleophilic substitution reaction. and a compound of formula (I) (wherein R 3 OCH 3 For example, the compound of formula (I) thing (in the formula, R 3 is F) in a suitable solvent, such as MeOH, with a suitable Reacting with a base to give a compound of formula (I), 3 OCH 3 (which is .

[0265] Compounds of formula (I) may be converted to their corresponding salts using methods well known to those skilled in the art. For example, the amine of formula (I) can be reacted with, for example, Et 2 O, C.H. 2 Cl 2 , THF, MeOH, Trifluoroacetic acid, HCl, or quenching in a solvent such as chloroform or isopropanol Alternatively, the reverse phase HPLC purification conditions may be followed to provide the corresponding salt form. The pharma- ceutically acceptable salts of the compounds of formula (I) can be prepared by reacting the compounds of formula (I) with the trifluoroacetate or formate salts. The crystalline forms of the salts can be dissolved in polar solvents (mixtures of polar solvents and aqueous mixtures of polar solvents). recrystallization from a polar solvent (including a mixture of a polar solvent) or from a non-polar solvent (including a mixture of a polar solvent) It can be obtained in crystalline form by

[0266] When the compounds according to the invention have at least one chiral centre, they are consequently It may exist as an enantiomer. When a compound has two or more chiral centers, they may additionally exist as diastereomers. All such isomers and mixtures thereof are within the scope of the present invention. It is understood to be within the scope of the invention.

[0267] Compounds prepared according to the above schemes may be prepared by form-specific synthesis or by decomposition. Alternatively, the compounds may be obtained in a single form, such as a single enantiomer, by the methods described above. Compounds prepared according to this scheme may be racemic (1:1) or non-racemic (not 1:1). It may also be obtained as a mixture of various forms, including mixtures of enantiomers, racemic and non-racemic. If a chiral mixture is obtained, conventional isolation methods known to those skilled in the art, such as chiral chromatography, may be used. Fi, recrystallization, diastereomeric salt formation, derivatization to diastereomeric adducts, biomolecular Alternatively, internal or enzymatic conversion or the like can be used to isolate the single enantiomers. When regioisomeric or diastereomeric mixtures are obtained, if applicable, Conventional methods, such as chromatography or crystallization, can be used to separate the single isomers. good.

[0268] The following specific examples are provided to further illustrate the invention and various preferred embodiments. It will be offered. EXAMPLES

[0269] The compounds described in the following examples and the corresponding analytical data were obtained using the methods described herein, unless otherwise indicated. The following experimental and analytical protocols were followed.

[0270] Unless otherwise noted, reaction mixtures were magnetically stirred under a nitrogen atmosphere at room temperature (rt). When a solution is "dried", generally Na 2 SO 4 or MgSO 4 Dry with a desiccant such as Mixtures, solutions, and extracts are "concentrated," typically by using a rotor The mixture was concentrated using a rotary evaporator.

[0271] Normal phase silica gel chromatography (FCC) uses prepacked cartridges Then, silica gel (SiO 2 ) was carried out.

[0272] Preparative reverse-phase high performance liquid chromatography Liquid chromatography, RP HPLC) were performed by one of the following methods: Method A. Phenomenex Synergi C18(10μm, 150×25m m) or Boston Green ODS C18 (5 μm, 150 × 30 mm) Gilson GX-281 semi-prep-HPLC with a flow rate of 25 mL / min 5 → 99% ACN (containing 0.225% FA) in water for 10 min, then 10 Mobile phase with 0% ACN and a 2 min hold. or Method B. Phenomenex Synergi C18(10μm, 150×25m m) or Boston Green ODS C18 (5 μm, 150 × 30 mm) Gilson GX-281 semi-prep-HPLC with a flow rate of 25 mL / min , 5 → 99% ACN (0.1% TFA) in water for 10 min, then 100% AC Mobile phase with N hold for 2 min. or Method C. Phenomenex Synergi C18(10μm, 150×25m m) or Boston Green ODS C18 (5 μm, 150 × 30 mm) Gilson GX-281 semi-prep-HPLC with a flow rate of 25 mL / min , 5 → 99% ACN (0.05% HCl) in water for 10 min, then 100% A Mobile phase with CN hold for 2 min. or Method D. Phenomenex Gemini C18 (10μm, 150×25mm ), AD (10 μm, 250 mm × 30 mm), or Waters XBridge C Gilson GX-281semi with 18 columns (5μm, 150×30mm) -prep-HPLC, 0→99% AC in water for 10 min at a flow rate of 25 mL / min N (containing 0.05% ammonium hydroxide v / v), followed by 100% ACN for 2 min. Mobile phase of interest. or Method E. Phenomenex Gemini C18 (10μm, 150×25mm ) or a Waters XBridge C18 column (5 μm, 150 × 30 mm). Gilson GX-281 semi-prep-HPLC with a flow rate of 25 mL / min , 5 → 99% ACN (10 mM NH) in water for 10 min.4 HCO 3 ), then 1 Mobile phase with 00% ACN for 2 min hold.

[0273] Preparative supercritical fluid high performance liquid chromatography erformance liquid chromatography (SFC) is the Thar 80 Prep-SFC system. either the Waters 80Q Prep-SFC system or the Waters 80Q Prep-SFC system The ABPR was set at 100 bar to maintain CO2 at SF conditions, and the flow rate was , flow rates ranging from 50 g / min to 70 g / min can be verified according to compound properties. The column temperature was ambient.

[0274] Unless otherwise stated, electrospray ionization (ESI) in positive mode was used. SHIMADZU LCMS-2020 MSD or Agilent 1200\G Mass spectra (MS) were obtained on a 6110A MSD. Calculated masses (calcd.) were , corresponds to the exact mass.

[0275] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker AVIII 400 spectrometer. The definitions of multiplicity are as follows: s = singlet, d = doublet, t = triplet, q = quadruplet. line, dd=double double line, ddd=double double line, td=triple double line, dt= Double triplet, spt=septuplet, quin=quintuplet, m=multiplet, br=broad. Interchangeable In compounds that contain protons that can be used to perform NMR spectroscopy, the protons Depending on the choice of solvent and the concentration of the compound in solution, it may be visible in the NMR spectrum. It will be appreciated that this may or may not be the case.

[0276] Chemical names: ChemDraw Ultra12.0, ChemDraw Ultra1 4.0 (CambridgeSoft Corp., Cambridge, MA) or A CD / Name Version 10.01(Advanced Chemistry ) was used to create the model.

[0277] R * Or S * The compounds denoted as It is a compound.

[0278] Intermediate 1: 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-trimethyl- Azol-5(4H)-one.

[0279] [ka]

[0280] Step A. 2-(Benzyloxy)acetohydrazide. To a solution of ethyl 2-(benzyloxy)acetate (55 g, 283.17 mmol), H 2 NH 2 H 2 28.3 g, 566 mmol, 27.5 mL of 1H2O was added to the reaction mixture. The mixture was heated at 78° C. for 6 h. The reaction mixture was concentrated under reduced pressure to give the title product (52 g, Crude) was obtained as a colorless oil, which was used directly in the next step without further purification. Used.

[0281] Step B. 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-tetramethyl- Riazol-5(4H)-one. H 2 2-(Benzyloxy)acetone in O (500 mL) A solution of hydrazide (52 g, 288 mmol) was added to isocyanatoethane (25.1 g, 346 mmol, 27.9 mL) was added dropwise. After the addition was complete, the mixture was cooled to 25° C. The mixture was stirred for 12 hours. 2 O (20 mL) and NaOH (57.7 g, 1.44 m An aqueous solution (120 mL) of 1,2-dichlorophenyl ether was added. The mixture was stirred at 95° C. for 12 hours. The mixture was cooled to room temperature and then quenched with HCl (12 M) at 0 °C to adjust the pH to 6. The solid was filtered and dried under vacuum to give the title compound as a white solid (61 g, yield 91%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.23-9.09 (m,1H),7.41-7.31(m,5H),4.58-4.53(m,2H),4 .45-4.42(m,2H),3.82-3.75(m,2H),1.33-1.29 (m,3H) ppm.

[0282] Intermediate 2: 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl Thiol-2,4-dihydro-3H-1,2,4-triazol-3-one.

[0283] [ka]

[0284] Step A. 4-Ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1, 2,4-Triazol-3-one. 5-[(benzyloxy)methyl]-4-methyl-2,4 in methanol (200 mL) -Dihydro-3H-1,2,4-triazol-3-one (8 g, 34.3 mmol, 1 To a solution of 1.0 eq. of 1,000 sulphate (1.0 eq.) was added Pd / C (2 g). The resulting mixture was kept under hydrogen and heated at room temperature. The mixture was stirred at room temperature for 6 hours. The resulting mixture was then filtered, and the filtrate was concentrated to give a white solid. The crude product 4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2 , 4-triazol-3-one was obtained (4.3 g, yield 88%). 1 H NMR(400 MHz,DMSO-d 6 )δ 11.52(s,1H),5.55(t,J=5.50H z,1H),4.32(d,J=5.50Hz,2H),3.64(q,J=6.97H z,2H),1.18(t,J=6.97Hz,3H)ppm.

[0285] Step B. 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4- Ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. 4-Ethyl-5-(hydroxymethyl)-2,4-dihydro-3 in DCM (30 mL) To a solution of H-1,2,4-triazol-3-one (3 g, 21 mmol, 1.0 equiv.) , tert-butylchlorodiphenylsilane (6.5 mL, 25 mmol, 1.2 equiv.) and pyridine (1.86 mL, 23 mmol, 1.1 equiv.) were added. The resulting mixture The mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (100 mL). The mixture was extracted with DCM (3×100 mL). The organic layers were combined and washed with anhydrous sodium sulfate. The residue was purified by silica gel chromatography (SiO 2 , 50~ 80% ethyl acetate / petroleum ether) to give 5-(((te rt-Butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3 H-1,2,4-triazol-3-one was obtained (4.9 g, 61% yield). LCMS( ES-API):C 21 H 27 N 3 O 2 Calculated mass of Si, 381.2; measured m / z, 382.2[M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.98(s ,1H),7.61-7.72(m,4H),7.32-7.54(m,6H),4.5 4(s,2H),3.84(q,J=7.34Hz,2H),1.33(t,J=7.3 4Hz,3H),1.07(s,9H)ppm.

[0286] Intermediate 3: 5-((benzyloxy)methyl)-4-ethyl-2-(7-fluoro-1 -Oxo-4-(prop-1-en-2-yl)-1H-isochromen-6-yl)-2 ,4-Dihydro-3H-1,2,4-triazol-3-one.

[0287] [ka]

[0288] Step A. tert-Butyl 4,5-difluoro-2-iodobenzoate. 4,5 -Difluoro-2-iodobenzoic acid (3 g, 11 mmol) was dissolved in THF (30 mL). Then di-tert-butyl dicarbonate (4.6 g, 21 mmol) was added. The reaction mixture was stirred under nitrogen for 1 hour at room temperature for 2 hours, followed by the addition of DMAP (645 mg, 5.3 mmol). The mixture was stirred at 50° C. overnight and then cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was The mixture was diluted with tOAc and washed with brine. The organic layer was separated and 2 SO 4 Dry and filter. The residue was purified by silica column chromatography (gradient elution: 0 to 100 ml of petroleum ether). 5% EtOAc) to give the title compound as a yellow oil (2.9 g, yield: 79%). 1 H NMR (400 MHz, CDCl 3 )δ 7.77(dd,J=10. 2,7.9Hz,1 H),7.63(dd,J=10.2,7.9Hz,1 H),1 .62(s,9H)ppm; 19 F NMR (376 MHz, CDCl 3 )δ-131 .55--131.13(m,1 F),-136.97--136.65(m,1 F ) ppm.

[0289] Step B. tert-Butyl 4-(3-((benzyloxy)methyl)-4-ethyl -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5- Fluoro-2-iodobenzoate. tert-Butyl 4, 5-Difluoro-2-iodobenzoate (3.2 g, 9.4 mmol), 3-((benzoyl) (4H)-dimethyl)-4-ethyl-1H-1,2,4-triazole-5(4H)-o (Intermediate 1, 2.6 g, 11.2 mmol), and Cs 2 CO 3 (6.1g, 18.7 The mixture of 1 mmol) was stirred at 75° C. under nitrogen for 1 h and then cooled to room temperature. The material was filtered through a pad of Celite® and the pad was washed with EtOAc. The extract was combined, washed with brine and concentrated. The residue was purified by silica column chromatography (gradient elution). Extraction: 0-40% EtOAc in petroleum ether) to give the title compound as a colorless amorphous solid. It was obtained as a solid (5 g, yield: 96%). ESI-MS: 23 H 25 FIN 3 O 4 of Calculated mass, 553.1; measured m / z, 554.1 [M+H] + . 1 H NMR(40 0MHz,CDCl 3 )δ 8.16(d,J=7.1Hz,1 H),7.62(d, J=10.8Hz,1H),7.29-7.45(m,5H),4.61(s,2 H),4.50(s,2 H),3.84(q,J=7.2Hz,2 H),1.63( s,9 H),1.35(t,J=7.2Hz,3 H)ppm; 19 F NMR(37 6MHz, CDCl 3 )δ-119.09(dd,J=10.6,7.0Hz,1 F) ppm.

[0290] Step C. 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-io Benzyloxymethyl-4-tert-butyl ester -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5- To a solution of fluoro-2-iodobenzoate (5 g, 9 mmol) in DCM (50 mL) Then TFA (10 mL) was added slowly. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the resulting residue was triturated with petroleum ether at room temperature for 30 min. The mixture was filtered and the solid was rinsed with petroleum ether. The precipitate was collected and dried under reduced pressure to give The title compound was obtained as a white solid (4.1 g, yield: 91%). ESI-MS: 19 H 17 FIN 3 O 4 Calculated mass, 497.0; measured m / z, 498.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.16(d,J=7.3Hz, 1 H),7.78(d,J=11.0Hz,1 H),7.28-7.43(m,5 H),4.60(s,2 H),4.57(s,2 H),3.74(q,J=7.2H z,2 H),1.23(t,J=7.2Hz,3 H)ppm; 19 F NMR(37 6MHz,DMSO-d 6 ) δ-119.91(s,1F)ppm.

[0291] Step D. 5-((benzyloxy)methyl)-4-ethyl-2-(7-fluoro- 1-Oxo-4-(prop-1-en-2-yl)-1H-isochromen-6-yl)- 2,4-Dihydro-3H-1,2,4-triazol-3-one. 3-Methylbuta-1, 2-Dien-1-yl acetate (Intermediate 12, 280 mg, 2.2 mmol), 4-( 3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-5-fluoro-2-iodobenzoic acid (1.1 g, 2.2 mmol) and Cy 2 NMe (867 mg, 4.4 mmol) in DMF (7 mM To the mixture in 10 mL of water was added Catacxium A Pd G2 (74.2 mg, 0. 11 mmol) was added. The reaction mixture was stirred under nitrogen at 90° C. overnight. The mixture was then The mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The organic layer was separated and the aqueous layer was The combined organic layer was extracted with EtOAc. 2 SO 4 Dry, filter and concentrate The residue was purified by silica column chromatography (gradient elution: 0–80% E in petroleum ether). tOAc) to give the title compound as a yellow solid (240 mg, yield: 25 %). ESI-MS:C 24 H 22 FN 3 O 4 Calculated mass, 435.2; m / z 43 6.2[M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.15(d,J =10.5Hz,1 H),7.86(d,J=6.8Hz,1 H),7.30-7. 45(m,5 H),7.19(s,1 H),5.37-5.39(m,1 H),5 .18(s,1 H),4.62(s,2 H),4.53(s,2 H),3.87( q,J=7.1Hz,2H),2.11(s,3H),1.37(t,J=7.2H z,3H) ppm.

[0292] Intermediate 4: 5-((benzyloxy)methyl)-4-ethyl-2-(7-fluoro-4 -isopropyl-1-oxo-1H-isochromen-6-yl)-2,4-dihydro-3 H-1,2,4-triazol-3-one.

[0293] [ka]

[0294] Method I: Step A. 3-Methylbut-2-en-1-yl 4,5-difluoro-2-iodobenzyl 4,5-Difluoro-2-iodobenzoic acid (1.4 g, 4.9 mmol) and Cs 2 CO 3 To a mixture of (4.8 g, 14.8 mmol) in anhydrous DMF (20 mL), 1-Bromo-3-methyl-2-butene (1.5 g, 9.9 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 18 h. The mixture was diluted with water and this mixture was diluted with DCM and EtOAc. The combined organic extracts were washed with Na 2 SO 4 The residue was dried over 1000 ml of ethyl acetate, filtered and concentrated. The SiO 2 , Gradient elution: 10-20% EtO in heptane Ac) to give the desired product as a colorless oil (1.6 g, yield: 92%) . 1 H NMR (400 MHz, CDCl 3 )δ 7.80(dd,J=7.58,9. 54Hz,1H),7.73(dd,J=7.83,10.76Hz,1H),5.42 -5.52(m,1H),4.82(d,J=7.34Hz,2H),1.80(s,3 H), 1.78(s,3H) ppm.

[0295] Step B. 3-Methylbut-2-en-1-yl 4-(3-((benzyloxy)methyl) (ethyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-5-fluoro-2-iodobenzoate. 3-Methylbut-2-ene-1 -yl 4,5-difluoro-2-iodobenzoate (1.6 g, 4.5 mmol), 3 -((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazole-5( 4H)-one (Intermediate 1, 2.1 g, 9.1 mmol) in anhydrous DMF (25 mL) To things、 Cs 2 CO 3 (2.9 g, 9.1 mmol) was added. The reaction mixture was stirred under nitrogen for 8 After heating at 5° C. for 1 h, the mixture was cooled to room temperature. The mixture was diluted with water and the mixture was diluted with DCM and The combined organic extracts were washed with Na 2 SO 4 Dry, filter and concentrate The residue was purified by flash chromatography (SiO 2 , Gradient elution: 20-50 in heptane % EtOAc) to give the title compound as a white solid (2.4 g, yield: 93%). LCMS(ES-API):C 24 H 25 FIN 3 O 4 Calculated mass of 565 .1; m / z measured value, 566.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ 8.21(d,J=6.85Hz,1H),7.73(d,J=11.25Hz ,1H),7.29-7.44(m,5H),5.41-5.53(m,1H),4.8 4(d,J=7.34Hz,2H),4.60(s,2H),4.50(s,2H),3 .84(q,J=7.22Hz,2H),1.80(s,3H),1.78(d,J=0 .98Hz,3H),1.34(t,J=7.22Hz,3H)ppm.

[0296] Step C. 5-((benzyloxy)methyl)-4-ethyl-2-(7-fluoro- 4-Isopropyl-1-oxo-1H-isochromen-6-yl)-2,4-dihydro- 3H-1,2,4-Triazol-3-one. 3-Methylbut-2-en-1-yl 4- (3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazol-1-yl)-5-fluoro-2-iodobenzoate ( To a mixture of (tBu 3 P)PdG 2 (351 mg, 0.69 mmol, 0.1 equiv.), N-cyclohexyl-N -Methyl-cyclohexanamine (1.60 mL, 7.54 mmol, 1.1 equiv.) The reaction mixture was degassed with nitrogen three times and then heated at 80° C. under a nitrogen atmosphere for 18 hours. The mixture was heated for 15 min. LCMS analysis indicated that approximately 18% of the starting material remained. Cool to 0.4 °C and add additional N-cyclohexyl-N-methyl-cyclohexanamine (0.72 mL, 3.43 mmol, 0.5 equiv.) and tBu 3 PPdG 2 (176 mg, 0.34 The reaction mixture was degassed with nitrogen and then cooled to 50° C. The mixture was heated at 80° C. for 16 h. The mixture was concentrated under reduced pressure and then 2 O (200 mL) Dilute and extract with EtOAc (150 mL x 3). Wash the combined organic layers with brine. (100mL x 2 times), anhydrous sodium 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. Rush Chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1~3 / 1) The residue was purified by ESI-M to give the title compound as a yellow oil (1.1 g, 35%). S:C 24 H 24 FN 3 O 4 Calculated mass, 437.2; measured m / z, 438.5 [M +H]+ . 1 H NMR (400 MHz, CDCl 3 ) δ 8.16(d,J=6.6H z,1H),7.96(d,J=6.6Hz,1H),7.42-7.34(m,5H) ,7.13(s,1H),4.63(s,2H),4.54(s,2H),3.88(d d,J = 7.2,14.4Hz,2H),3.13-3.06(m,1H),1.38( t,J=7.2Hz,3H),1.32(d,J=6.8Hz,6H)ppm.

[0297] Method II: 5-((benzyloxy)methyl)-4-ethyl-2-(7-fluoro-1-oxo- 4-(Prop-1-en-2-yl)-1H-isochromen-6-yl)-2,4-dihydro- Doro-3H-1,2,4-triazol-3-one (Intermediate 3, 5.9 g, 13.5 mm A solution of 100 mL of RhCl(PPh) in THF (100 mL) at room temperature was treated with Wilkinson's catalyst [RhCl(PPh 3 ) 3 ] (3.8 g, 4.1 mmol) was added. The mixture was degassed and purged with hydrogen gas. The reaction mixture was stirred under hydrogen atmosphere (15 Psi) at room temperature for 12 hours. The residue was purified by silica column chromatography (elution: 0-25% petroleum ether EtOAc) to give the title compound as a yellow solid (1.5 g, yield: 77 %). ESI-MS:C 24 H 24 FN 3 O 4 Calculated mass, 437.2; measured m / z 438.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.10 (d,J=10.5Hz,1H),8.01(d,J=7.0Hz,1H),7.4 6(s,1 H),7.26-7.42(m,5 H),4.61(s,2 H),4. 59(s,2H),3.77(q,J=7.3Hz,2H),3.08(dt,J= 13.4,6.8Hz,1H),1.22-1.28(m,9H)ppm; 19 F NMR (376MHz, DMSO-d 6 ) δ-118.29(br s,1 F)ppm .

[0298] Intermediate 5: 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4, 5-Dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-iso Benzoyl chloride.

[0299] [ka]

[0300] Step A. tert-Butyl 4,5-difluoro-2-iodobenzoate. 4,5 -Difluoro-2-iodobenzoic acid (3 g, 11 mmol) was dissolved in THF (30 mL). Then di-tert-butyl dicarbonate (4.6 g, 21 mmol) was added. The reaction mixture was stirred under nitrogen for 1 hour at room temperature for 2 hours, followed by the addition of DMAP (645 mg, 5.3 mmol). The mixture was stirred at 50° C. overnight and then cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was The mixture was diluted with tOAc and washed with brine. The organic layer was separated and 2 SO 4 Dry and filter. The residue was purified by silica column chromatography (gradient elution: 0 to 100 ml of petroleum ether). 5% EtOAc) to give the title compound as a yellow oil (2.9 g, yield: 79%). 1 H NMR (400 MHz, CDCl 3 )δ 7.77(dd,J=10. 2,7.9Hz,1 H),7.63(dd,J=10.2,7.9Hz,1 H),1 .62(s,9H)ppm; 19 F NMR (376 MHz, CDCl 3 )δ-131 .55--131.13(m,1 F),-136.97--136.65(m,1 F ) ppm.

[0301] Step B. tert-Butyl 4-(3-((benzyloxy)methyl)-4-ethyl -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5- Fluoro-2-iodobenzoate. tert-Butyl 4, 5-Difluoro-2-iodobenzoate (3.2 g, 9.4 mmol), 3-((benzoyl) (4H)-dimethyl)-4-ethyl-1H-1,2,4-triazole-5(4H)-o (Intermediate 1, 2.6 g, 11.2 mmol), and Cs 2 CO 3 (6.1g, 18.7 The mixture of 1 mmol) was stirred at 75° C. under nitrogen for 1 h and then cooled to room temperature. The material was filtered through a pad of Celite® and the pad was washed with EtOAc. The extract was combined, washed with brine and concentrated. The residue was purified by silica column chromatography (gradient elution). Extraction: 0-40% EtOAc in petroleum ether) to give the title compound as a colorless amorphous solid. It was obtained as a solid (5 g, yield: 96%). ESI-MS: 23 H 25 FIN 3 O 4 of Calculated mass, 553.1; measured m / z, 554.1 [M+H] + . 1 H NMR(40 0MHz,CDCl 3 )δ 8.16(d,J=7.1Hz,1 H),7.62(d, J=10.8Hz,1H),7.29-7.45(m,5H),4.61(s,2 H),4.50(s,2 H),3.84(q,J=7.2Hz,2 H),1.63( s,9 H),1.35(t,J=7.2Hz,3 H)ppm; 19 F NMR(37 6MHz, CDCl 3 )δ-119.09(dd,J=10.6,7.0Hz,1 F) ppm.

[0302] Step C. 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-io Benzyloxymethyl-4-tert-butyl ester -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5- To a solution of fluoro-2-iodobenzoate (5 g, 9 mmol) in DCM (50 mL) Then TFA (10 mL) was added slowly. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the resulting residue was triturated with petroleum ether at room temperature for 30 min. The mixture was filtered and the solid was rinsed with petroleum ether. The precipitate was collected and dried under reduced pressure to give The title compound was obtained as a white solid (4.1 g, yield: 91%). ESI-MS: 19 H 17 FIN 3 O 4 Calculated mass, 497.0; measured m / z, 498.0 [M+H]+ . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.16(d,J=7.3Hz, 1 H),7.78(d,J=11.0Hz,1 H),7.28-7.43(m,5 H),4.60(s,2 H),4.57(s,2 H),3.74(q,J=7.2H z,2 H),1.23(t,J=7.2Hz,3 H)ppm; 19 F NMR(37 6MHz,DMSO-d 6 ) δ-119.91(s,1F)ppm.

[0303] Step D. 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-io Benzoyl chloride. 4-(3-((benzyloxy)methyl)-4-ethyl-5- Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro 2-iodobenzoic acid (3.5 g, 7 mmol) SOCl 2 (14 mL) solution, The mixture was heated under reflux for 15 minutes. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with anhydrous toluene. After addition of ethanol the mixture was evaporated to give the crude product as a yellow gum (3.6g). It was used directly in the next step without further purification.

[0304] Intermediate 6: 2-Chloro-6-fluoro-N-(3-methylpent-2-en-1-yl )Aniline.

[0305] [ka]

[0306] Step A. Ethyl 3-methylpent-2-enoate. 2-Butanone (52 g, 71 7.6 mmol) and (carbethoxymethylene)triphenylphosphorane (50 g, 14 To a solution of benzoic acid (3.5 g, 28.7 mmHg) in toluene (65 mL), ol) was added. The reaction mixture was heated at reflux for 16 hours. The mixture was diluted with petroleum ether The mixture was diluted with hexane and filtered through a short pad of silica gel. The filtrate was concentrated under reduced pressure at 0-2°C. The residue was purified by silica column chromatography (solvent). Extraction: 0-10% EtOAc in petroleum ether) to give the title compound as a colorless liquid. To obtain 23.3 g (crude). 1 H NMR (400 MHz, CDCl 3 ) δ 5.58 -5.69(m,1 H),4.13(qd,J=7.1,4.9Hz,2 H),2. 62(q,J=7.5Hz,1H),2.09-2.20(m,3H),1.86( d,J=1.2Hz,1H),1.24-1.28(m,3H),1.01-1.0 9(m,3H)ppm.

[0307] Step B. 3-Methylpent-2-en-1-ol. DIBAL-H( A solution of 118 mL (118 mmol) of ethyl 3-methylpropanediol in toluene (1 M) was A solution of pent-2-enoate (20 g, crude) in toluene (40 mL) was added dropwise to the reaction mixture. The mixture was stirred at -78°C for 2 h. The mixture was warmed to room temperature and diluted with potassium sodium tartrate at 0°C. The mixture was stirred for 2 hours and then poured slowly into a saturated aqueous solution of sodium chloride. The mixture was filtered through a pad of DCM / EtOAc (v / v, 3 / 1), and the pad was washed with DCM / EtOAc (v / v, 3 / 1). The filtrate was extracted with DCM. The organic extract was separated and2 SO 4 Dry, filter and concentrate The residue was purified by silica column chromatography (elution: 0-100% DC in petroleum ether). M, followed by 0-30% EtOAc in DCM) to give the title compound as a colorless liquid. (7 g, 2-step yield: 57%). 1 H NMR (400 MHz, CDCl 3 )δ 5.35-5.46(m,1 H),4.11-4.21(m,2 H),2. 02-2.13(m,2 H),1.67-1.76(m,3 H),0.98-1.0 6(m,3H)ppm.

[0308] Step C. 3-Methylpent-2-enal. 3-Methylpent-2-en-1-ol A solution of 2 g (20.0 mmol) of ethanol in 20 mL of DCM was Iodinane (10 g, 24.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered through a short pad of Celite®. The combined filtrate was washed with saturated NaHCO 3 The organic layer was separated and washed with N a 2 SO 4 The crude product was dried over 1000 ml of silica gel, filtered and concentrated under reduced pressure at 0-2° C. Purify by column chromatography (eluent: DCM) to obtain the title compound as a colorless liquid. (1.5 g, yield: 77%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.9 1-10.04(m,1 H),5.78-5.90(m,1 H),2.58(q,J =7.6Hz,1 H),2.23(d,J=7.3Hz,1 H),2.16(s,2 H),1.96(d,J=1.1Hz,1 H),1.16(t,J=7.6Hz,1 H), 1.09 (t, J = 7.4 Hz, 2 H) ppm.

[0309] Step D. N-(2-chloro-6-fluorophenyl)-3-methylpent-2-ene 2-Chloro-6-fluoroaniline (1.2 g, 8.2 mmol) and 3-Methylpent-2-enal (0.97 g, 9.9 mmol) in DCM (18 mL) To the mixture was added triethylamine (4.6 mL, 33 mmol) at 0° C. under nitrogen. Next, TiCl 4 (5 mL, 5 mmol) in DCM (1 M) was added dropwise. The mixture was stirred at 0° C. for 1 h, then warmed to room temperature and stirred for 4 h. The mixture was diluted with NH 4 Cl The mixture became cloudy and was filtered through a pad of Celite®. The pad was washed with EtOAc. The combined filtrate was diluted with DCM and water. The organic layer was The aqueous layer was separated and extracted with DCM. The combined organic layers were washed with brine and added Na 2 SO 4 in It was dried, filtered and concentrated. The residual product was purified by silica gel column chromatography (gradient elution). Extraction: 0-5% DCM in petroleum ether) to give the title compound as a pale yellow oil. Obtained (1.3 g, yield: 70%).

[0310] Step E. 2-Chloro-6-fluoro-N-(3-methylpent-2-en-1-yl) N-(2-chloro-6-fluorophenyl)-3-methylpenta-2-enyl aniline. To a solution of 1.3 g (5.76 mmol) of phenyl-1-imine in 20 mL of MeOH was added Na BH 4(218 mg, 5.8 mmol) was added and after 1 h another batch of NaBH 4 ( A total of 218 mg, 5.8 mmol) of NaBH 4 (1.1 g, 29 mmol ) was added. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and then diluted with water. The organic layer was separated, washed with brine and extracted with Na 2 SO 4 Dry with The residue was purified by CombiFlash column chromatography on silica gel ( Purification with 0-5% DCM in petroleum ether gave the title compound as a yellow oil. Obtained (430 mg, yield: 33%). 1 H NMR (400 MHz, CDCl 3 ) δ 6 .95-7.02(m,1 H),6.84(ddd,J=12.2,8.3,1.3H z,1 H),6.52-6.63(m,1 H),5.17-5.28(m,1 H) ,3.85(d,J=5.6Hz,2 H),3.73(s,1 H),1.91-2. 07(m,2 H),1.58-1.68(m,3 H),0.89-0.96(m,3 H).

[0311] Intermediate 7: 5-Chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl) -1H-Pyrazol-4-amine.

[0312] [ka]

[0313] Step A. 5-Chloro-3-methyl-4-nitro-1-(tetrahydro-2H-pyrazol-2-yl) 3-Methyl-4-nitropyrazole (2g, 15. 7 mmol) in EtOAc (20 mL), TsOH.H 2 O (150 mg, 0.79 mmol) was added at room temperature. The mixture was stirred at room temperature. Stirred overnight. 3 N (0.4 mL) was added and the mixture was washed with brine. The organic layer was separated and diluted with anhydrous sodium 2 SO 4 The residue was diluted with THF (45m LiHMDS (10.6 mL, 13.8 mmol) was dissolved in 10.6 mL of LiHMDS and the temperature was lowered to -78 °C. A solution of 1M of 1) in THF was added to the mixture under nitrogen. After 45 min at -78°C, hexa A solution of chloroethane (8.9 g, 37.8 mmol) in THF (20 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with saturated NH 4 Pour into aqueous Cl solution and add Et The organic phase was separated, washed with brine and extracted with anhydrous Na 2 SO 4 Dry with The residue was purified by silica column chromatography (gradient elution: 0.05 ml of petroleum ether). ~40% EtOAc) to give the title compound as a white solid (1.8 g, Yield: 58%). 1 H NMR (400 MHz, CDCl 3 ) δ 5.52(dd,J= 10.0,2.7Hz,1H),4.07-4.15(m,1H),3.70(td ,J=11.3,2.8Hz,1H),2.57(s,3H),2.37-2.47 (m,1 H),2.11-2.19(m,1 H),1.86-1.90(m,1 H ),1.72-1.75(m,1 H),1.64(d,J=2.0Hz,1 H),1 .53(d,J=6.6Hz,1H)ppm.

[0314] Step B. 5-Chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl) )-1H-Pyrazol-4-amine. 5-Chloro-3-methyl-4-nitro-1-(tetrahydrofuran) Lahydro-2H-pyran-2-yl)-1H-pyrazole (100 mg, 0.4 mmol ) in MeOH / THF / H 2 A solution of iron powder ( 114 mg, 2.0 mmol) and NH 4 Cl (109 mg, 2.0 mmol) was added. The mixture was stirred at 70° C. for 1.5 h. The mixture was cooled to room temperature and The mixture was filtered through a pad of ethyl acetate. The pad was washed with EtOAc. The combined filtrate was diluted with saturated NaHCO 3 The organic layer was separated and the aqueous layer was extracted with EtOAc. The organic extract was washed with brine and anhydrous Na 2 SO 4 The residue was dried over 1000 ml of ethyl acetate, filtered and concentrated. Silica column chromatography (gradient elution: 0-50% EtOAc in petroleum ether) The title compound was obtained as a yellow oil (70 mg, yield: 79%). MS:C 9 H 14 ClN 3 Calculated mass of O, 215.1; measured m / z, 216.1 [M +H] + .

[0315] Intermediate 8: 3-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)- 2-Chloroaniline.

[0316] [ka]

[0317] Step A. tert-Butyl(2-(2-chloro-3-nitrophenoxy)ethoxy) ) diphenylsilane. 2-Chloro-3-nitrophenol (200 mg, 1.2 mmol ), 2-((tert-butyldiphenylsilyl)oxy)ethane-1-ol (554 mg, 1.8 mmol) and PPh 3 (453 mg, 1.7 mmol) of THF (10 To the mixture in 100 mL was added DEAD (281 mg, 161 mmol) under nitrogen at 0° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 12 h. 4 A Cl solution was added, The mixture was extracted with EtOAc. The organic layer was separated, washed with brine and dried over Na2SO4. The residue was purified by silica column chromatography (gradient elution: petroleum ether). Purification by elution with 0-10% EtOAc in ether afforded the title compound as a yellow oil (24 0mg, yield: 46%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.72(d d,J=7.8,1.5Hz,4H),7.35-7.49(m,7H),7.30 (t,J=8.2Hz,1H),7.12(dd,J=8.3,1.2Hz,1H) ,4.20-4.25(m,2 H),4.06(t,J=4.9Hz,2 H),1. 06(s,9H)ppm.

[0318] Step B. 3-(2-((tert-butyldiphenylsilyl)oxy)ethoxy) -2-Chloroaniline. tert-Butyl(2-(2-chloro-3-nitrophenoxy) Ethoxy)diphenylsilane (220 mg, 0.5 mmol), NH 4 Cl(258mg , 4.8 mmol) in THF (3 mL), MeOH (3 mL) and HO (3 mL). To the mixture was added iron powder (269 mg, 4.8 mmol). The reaction mixture was heated at 70° C. for 2 The mixture was cooled to room temperature, diluted with EtOAc, and washed with Celite®. The mixture was filtered through a pad of Celite®. The Celite® was washed with EtOAc. The filtrate was washed with brine and 2 SO 4 The residue was dried over silica gel, filtered and concentrated. Purification was performed by column chromatography (gradient elution: 0-11% EtOAc in petroleum ether). The title compound was obtained as a yellow solid (192 mg, yield: 92%). ESI-MS :C 24 H 28 ClNO 2 Calculated mass of Si, 425.2; measured m / z, 426.1 M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ 7.75(dd,J=7. 9,1.6Hz,4H),7.35-7.48(m,6H),6.97(t,J=8 .1Hz,1H),6.42(dd,J=8.2,1.1Hz,1H),6.33( dd,J=8.2,1.1Hz,1H),4.13-4.17(m,2H),4.0 7-4.13(m,2 H),4.01-4.06(m,2 H),1.06(s,9 H) ppm.

[0319] Intermediate 9: 5-((benzyloxy)methyl)-4-ethyl-2-(7-methyl-1- Oxo-4-(prop-1-en-2-yl)-1H-isochromen-6-yl)-2, 4-Dihydro-3H-1,2,4-triazol-3-one.

[0320] [ka]

[0321] Step A. tert-Butyl 2-bromo-4-fluoro-5-methylbenzoate. 2-Bromo-4-fluoro-5-methylbenzoic acid (1 g, 4.3 mmol) in THF (1 0 mL) (Boc) 2 O (1.9 g, 8.6 mmol) was added, followed by DM AP (262 mg, 2.1 mmol) was added. The reaction mixture turned orange and was stirred for 5 h under nitrogen. The mixture was stirred overnight at 0° C. The mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The organic layer was separated and 2 SO 4 The mixture was dried over 1000 ml of sodium hydroxide, filtered and concentrated. The residue was purified by silica column chromatography. The product was purified by chromatography (elution: 0-3% EtOAc in petroleum ether) to give the title compound. The product was obtained as a colorless oil (900 mg, yield: 72%). 1 H NMR (400MHz, CDCl 3 )δ 7.57(d,J=8.1Hz,1 H),7.24(d,J=4.6 Hz,1 H),2.22(d,J=1.5Hz,3 H),1.58(s,9 H)p pm.

[0322] Step B. tert-Butyl 4-(3-((benzyloxy)methyl)-4-ethyl -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2- Bromo-5-methylbenzoate. tert-Butyl 2-bromo-4-fluoro-5-methylbenzoate Tylbenzoate (750 mg, 2.6 mmol), 5-((benzyloxy)methyl) -4-Ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (800 mg, 3.4 mmol), and Cs 2 CO 3 (1.7 g, 5.2 mmol) of DMF (8 The mixture in 1 mL) was stirred at 90° C. for 16 h. The reaction was diluted with saturated NH 4 Add Cl solution The reaction was quenched by extracting the mixture with EtOAc. The organic layer was separated and Wash with brine and add Na 2 SO 4 The residue was purified by CombiFlash. Chromatography (SiO 2 eluent: 0-22% EtOAc in petroleum ether) The product was purified by HPLC to give the title compound as a colorless gum (1 g, yield: 71%). ESI-MS: C 24 H 28 BrN 3 O 4 Calculated mass, 501.1; measured m / z, 502.1 [M+ H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.64(d,J=6.1Hz ,2 H),7.33-7.43(m,5 H),4.61(s,2 H),4.50( s,2 H),3.85(q,J=7.3Hz,2 H),2.31(s,3 H),1 .62(s,9H),1.36(t,J=7.2Hz,3H)ppm.

[0323] Step C. 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-bromo-5-methyl tert-Butyl 4-(3-((benzyloxy)methyl)-4-ethyl- 5-Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-bromo Bromo-5-methylbenzoate (500 mg, 0.90 mmol) in DCM (5 mL) To the solution was added TFA (1 mL). The mixture was stirred at room temperature for 12 h. The mixture was concentrated. The residue was dissolved in DCM and petroleum ether was added slowly. The mixture was stirred at room temperature for 30 The mixture was filtered and the precipitate was rinsed with petroleum ether. The solid was collected and concentrated under reduced pressure. The title compound was obtained as a white solid (360 mg, yield: 86%). -MS:C 20 H 20 BrN 3 O 4 Calculated mass, 445.1; measured m / z, 446. 0[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.77(s,1 H),7.70(s,1 H),7.29-7.41(m,5 H),4.59(s, 2 H),4.56(s,2 H),3.74(q,J=7.0Hz,2 H),2.2 4(s,3H),1.23(t,J=7.2Hz,3H)ppm.

[0324] Step D. 5-((benzyloxy)methyl)-4-ethyl-2-(7-methyl-1 -Oxo-4-(prop-1-en-2-yl)-1H-isochromen-6-yl)-2 ,4-Dihydro-3H-1,2,4-triazol-3-one. 4-(3-((benzyl 4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl-4-oxo riazol-1-yl)-2-bromo-5-methylbenzoic acid (560 mg, 1.26 mm ol), 3-methylbuta-1,2-dien-1-yl acetate (Intermediate 12, 1.58 g, 12.5 mmol), AcOK (369 mg, 3.76 mmol) and TBAB (8 To a mixture of Pd(O Ac) 2 (141 mg, 0.63 mmol) was added. The reaction mixture was heated under nitrogen at 90° C. The mixture was stirred at rt overnight. The mixture was cooled to rt, diluted with EtOAc and washed with brine. The organic layers were separated and the aqueous layer was extracted with EtOAc. 2 SO 4 in The residue was purified by silica column chromatography (gradient elution: petroleum ether). Purification by elution with 0% EtOAc in ether (0 to 70%) afforded the title compound as a yellow solid ( 410 mg, yield: 73%). ESI-MS:C 25 H 25 N 3 O 4 Calculated mass of 43 1.2; m / z measured value, 432.1 [M+H] + . 1 H NMR (400MHz, CDC l 3 )δ 8.28(s,1 H),7.59(s,1 H),7.31-7.46(m ,5 H),7.17(s,1 H),5.30-5.37(m,1 H),5.15( s,1 H),4.63(s,2 H),4.52(s,2 H),3.87(q,J= 7.1Hz,2H),2.46(s,3H),2.10(s,3H),1.38( t, J = 7.2 Hz, 3 H) ppm.

[0325] Intermediate 10: Isopropyl 6-(3-((benzyloxy)methyl)-4-ethyl- 5-Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-chloride Rolo-5-fluoronicotinate.

[0326] [ka]

[0327] Step A. 2,6-Dichloro-5-fluoronicotinoyl chloride. To a solution of 5-fluoronicotinic acid (20 g, 95 mmol) in THF (200 mL) , at 0°C (COCl) 2 (12.7 g, 10.0 mmol) and DMF (69.6 mg, The mixture was stirred at 0°C for 30 min and then heated to 25°C. The reaction mixture was concentrated under reduced pressure to give the desired product as a colorless oil. The product (21.7 g, crude) was obtained and used without further purification.

[0328] Step B. Isopropyl 2,6-dichloro-5-fluoronicotinate. Propane- 2-ol (8.56 g, 142 mmol, 10.9 mL) and pyridine (9.02 g, To a mixture of 2,6-dichloro-5-(114 mmol) tetrahydrofuran (THF) (200 mL) at 0° C. Fluoronicotinoyl chloride (21.7 g, 96.0 mmol) in THF (50 mL) The mixture was stirred at 25° C. for 1 h. The mixture was poured into water (300 mL). The aqueous phase was extracted with ethyl acetate (300 mL). The combined organic phase was washed with anhydrous Na 2 SO 4 in It was dried, filtered and concentrated. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 1 to 10:1) to obtain the title compound (21 g, yield 86.8 2%) was obtained. MS(ESI): C 9 H 8 Cl 2 FNO 2 Calculated mass of 250.1 m Measured value / z: 252.0[M+H]+. 1H NMR (400 MHz, CDCl 3 ) δ 7.97-7.95(d,J=7.2Hz,1H),5.32-5.25(m,1H), 1.58-1.39(m,6H)ppm.

[0329] Step C. Isopropyl 6-(3-((benzyloxy)methyl)-4-ethyl-5 -Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-chloro 5-fluoro-nicotinate. Isopropyl 2,6-dichloroacetate in DMSO (40 mL) To a mixture of 3-((benzoyl)-5-fluoronicotinate (4 g, 15.87 mmol), (peroxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (3.89 g, 16.66 mmol) and K 2 CO 3 (3.29g, 23.80mmol ) was added. The mixture was stirred at 80 °C for 3 h. LCMS showed that the starting material was consumed and the desired The mixture was then mixed with H 2 Dilute with HO (30 mL) and EtOAc. The combined organic layers were washed with brine (100 mL), and Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by column chromatography ( SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 1:1) to obtain the title compound ( 5.7 g, 79.86% yield was obtained. MS(ESI):C 21 H 22 ClFN 4 O 4 of Calculated mass, 448.1; observed m / z, 449.2 [M+H]+. 1 H NMR(40 0MHz,CDCl 3)δ 8.10(d,J=8.8Hz,1H),7.43-7.3 1(m,5H),5.30(td,J=6.3,12.5Hz,1H),4.61(s, 2H),4.54(s,2H),3.85(q,J=7.2Hz,2H),1.41(d ,J=6.2Hz,6H),1.37-1.31(m,3H)ppm.

[0330] Intermediate 11: 5-((benzyloxy)methyl)-4-ethyl-2-(7-fluoro- 3-Hydroxy-4-isopropyl-1-oxoisochroman-6-yl)-2,4-di Hydro-3H-1,2,4-triazol-3-one.

[0331] [ka]

[0332] Step A. Methyl 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo So-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-bromo-5 -Fluorobenzoate. Methyl 2-bromo-4,5-difluorobenzoate (100 .0g, 398mmol), 5-((benzyloxy)methyl)-4-ethyl-2,4- Dihydro-3H-1,2,4-triazol-3-one (Intermediate 1, 113.5 g, 50 8mmol) and K 2 CO 3 (100.0 g, 724 mmol) in a flask. Water DMF (1000 mL) was added. The reaction mixture was heated under nitrogen at 50° C. for 16 h. Then, 5-((benzyloxy)methyl)-4-ethyl-2,4-dihydro-3H-1 ,2,4-triazol-3-one (11 g, 51 mmol) was added. The reaction mixture was stirred for 1 hour at 4°C for 2 hours. Stirring was continued at 50° C. The mixture was cooled to room temperature and stirred for 10 min. Water (1000 ml) was added. L) was added dropwise and the mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration and dried. The crude product was obtained (190 g). After stirring the product in DMF (500 mL) for 30 min, Then water (500 mL) was added. The mixture was stirred for 2 hours. The precipitate was collected by filtration. After drying, the title compound was obtained (180 g, yield: 90%). 1 H NMR (300MH z,CDCl 3 )δ 7.95(d,J=6.7Hz,1H),7.73(d,J=10 .7Hz,1H),7.44-7.27(m,5H),4.60(s,2H),4. 50(s,2H),3.95(s,3H),3.84(q,J=7.2Hz,2H) , 1.34(t,J=7.2Hz,3H)ppm.

[0333] Step B. 5-((benzyloxy)methyl)-4-ethyl-2-(7-fluoro- 3-Hydroxy-4-isopropyl-1-oxoisochroman-6-yl)-2,4-di Hydro-3H-1,2,4-triazol-3-one. Methyl 4-(3-((benzyloxy) 4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-trimethyloxy Azol-1-yl)-2-bromo-5-fluorobenzoate (30 g, 65.9 mm ol), Xantphos (4.02 g, 6.6 mmol), [Pd(allyl)Cl] 2 (1 .38g, 3.77mmol), Cs 2 CO 3 (42.6g, 130mmol) Dimethy To the mixture was added 3-methylbutanal (41.4 mL, 38 6 mmol) was slowly added, and the reaction mixture was heated at 80° C. under nitrogen for 22 h. Filter the mixture and add NH until the pH is 7-8. 4 The reaction was quenched by adding aqueous Cl solution. The mixture was extracted with ethyl acetate (2000 mL x 2). The combined organic extracts were concentrated. The residue was purified by column chromatography (SiO 2 Gradient elution: 1–33% in petroleum ether ethyl acetate) to give the title compound as an oil (61.7 g, yield: 56%) . 1 H NMR (300 MHz, CDCl 3 ) δ 7.93(d,J=10.4Hz,1 H),7.55(d,J=6.7Hz,1H),7.44-7.28(m,5H),5. 92(s,1H),4.61(s,2H),4.51(s,2H),4.37(br s ,1H),3.85(q,J=7.2Hz,2H),2.80(d,J=7.1Hz,1 H),1.92(spt,J=6.8Hz,1H),1.35(t,J=7.2Hz,3 H),1.05(d,J=6.8Hz,3H),0.93(d,J=6.8Hz,3H) ppm.

[0334] Intermediate 12: 3-Methylbuta-1,2-dien-1-yl acetate.

[0335] [ka]

[0336] Step A. 2-Methylbut-3-yn-2-yl acetate. Acetic anhydride (38 g, 371 mmol) in Mg(ClO 4 ) 2 (796mg, 3.6mmol) mixture 2-Methyl-3-butyn-2-ol (30 g, 357 mmol) was added dropwise to the reaction. The mixture was stirred at 0° C. for 10 min, then warmed to room temperature and stirred overnight. The reaction mixture was diluted with DCM Dilute with saturated NaHCO 3 Aqueous and saturated Na 2 CO 3 Washed with aqueous solution. Separate the layers and add Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated at 0° C. The residue was purified by silica column chromatography. The product was purified by chromatography (elution: DCM) to give the title compound as a pale yellow oil (3 5.8g, yield: 80%). 1 H NMR (400 MHz, CDCl 3 )δ 2.54( s,1 H),2.03(s,3 H),1.67(s,6 H)ppm.

[0337] Step B. 3-Methylbut-1,2-dien-1-yl acetate. Dissolve 1,2-dihydro-3-yn-2-yl acetate (2.5 g, 20 mmol) in DCM (20 mL). In the liquid, AgBF 4 (117 mg, 0.6 mmol) was added under nitrogen. The mixture was stirred at 35° C. under nitrogen for 2 hours until the mixture became a black solution. The organic layer was separated and the aqueous layer was extracted with DCM. The organic layer was separated using Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica column chromatography. The title compound was purified by chromatography (gradient elution: 0-3% EtOAc in petroleum ether) to give the yellow solid. Obtained as a coloured oil (650mg, yield: 26%). 1 H NMR (400 MHz, CDCl 3 )δ 7.20(dt,J=4.1,2.0Hz,1 H),2.11(s,3 H) , 1.81(d,J=2.0Hz,6H)ppm.

[0338] Example 2: 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- 1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)- 4-(Prop-1-en-2-yl)isoquinolin-1(2H)-one.

[0339] [ka]

[0340] Step A. 6-Bromo-4-iodoisoquinolin-1(2H)-one. 6-Bromo-2H-isoquinolin-1-one (2.9 g, 12.9 mmol) anhydrous N-iodosuccinimide (NIS) in suspension in acetonitrile (ACN) (50 mL) (4.4 g, 19.4 mmol) was added. The reaction mixture was heated at 80° C. under nitrogen for 2 h. The mixture was filtered through a sintered funnel to remove the precipitate. The resulting mixture was collected, washed with water and dried in vacuum to give the desired product (3.5 g) as a brown solid. , crude, 77%) which was used crude in the next step without further purification. LCMS(ES-API):C 9 H 5 BrINO calculated mass, 348.9; m / z measured Value, 349.8[M+H] + .

[0341] Step B. 6-Bromo-4-(prop-1-en-2-yl)isoquinoline-1(2 H)-one. 1,4-dioxane (20 mL) and ethanol (20 mL) and water (10 6-Bromo-4-iodoisoquinolin-1(2H)-one (0.7 g, 2 mm ol) and Cs 2 CO 3 (3.3 g, 10 mmol), bis(trifluoromethyl) (phenylphosphine)palladium(II) dichloride (0.7 g, 1 mmol) and isopropyl Then, 1.3 g (4 mmol) of pyropenylphenylboronic acid pinacol ester was added to the reaction mixture. The reaction mixture was degassed with nitrogen and then stirred at 25° C. for 24 h. The mixture was diluted with water (50 mL) The aqueous phase was poured into ethyl ether (100 mL) and ethyl acetate (EtOAc) (100 The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 Dry with The residue was purified by flash column chromatography (SiO 2 , Hep Purification by elution with 10% ethyl acetate in ethanol (10 to 70% ethyl acetate) gave the desired product as a white solid. (0.12 g, 23% yield). LCMS (ES-API): C 12 H 10 Quality of BrNO Calculated mass, 263.0; measured m / z, 264.0 [M+H] + . 1 H NMR(400 MHz, CDCl 3 )δ 11.15(br s,1H),8.30(d,J=8.42 Hz,1H),7.85(d,J=1.59Hz,1H),7.62(br dd,J= 1.59,8.42Hz,1H),7.06(s,1H),5.37(s,1H),5. 09(s,1H),2.11(s,3H)ppm.

[0342] Step C. 6-Bromo-2-(3-fluorophenyl)-4-(prop-1-ene- 2-yl)isoquinolin-1(2H)-one. Dichloromethane (DCM) (20 mL) and and triethylamine (3 mL), Soquinolin-1(2H)-one (120 mg, 0.45 mmol) and 3-fluorophenyl A mixture of 191 mg (1.4 mmol) of 2-phenylboronic acid was added to copper(II) acetate (82.5 mg, 1.4 mmol). g, 0.45 mmol) and pyridine (0.11 mL, 1.36 mmol) were added. The reaction mixture was stirred at 25° C. for 18 h. The mixture was passed through a short pad of silica gel. The silica gel was filtered and washed with ethyl acetate (100 mL). The filtrate was concentrated. The residue was Rush column chromatography (SiO 2 20-50% EtOAc in heptane) Purification by LCM afforded the crude desired product as an amorphous gum (118 mg, 72%). S(ES-API):C 18 H 13 Calculated mass of BrFNO, 358.0; measured m / z , 358.0[M] + .

[0343] Step D. 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl) -4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1- (yl)-2-(3-fluorophenyl)-4-(prop-1-en-2-yl)isoquino Phosph-1(2H)-one. 6-Bromo-2-(3 -fluorophenyl)-4-(prop-1-en-2-yl)isoquinoline-1(2H) -one (product of Example 1, Step C, 114 mg, 0.32 mmol) and K 3 PO 4 (338 mg, 1.6 mmol) of 5-(((tert-butyldiphenyl Phenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4 -triazol-3-one (intermediate product 2, 304 mg, 0.8 mmol), CuI(6 0 mg, 0.32 mmol), and trans-N,N'-dimethylcyclohexane-1, 2-Diamine (45 mg, 0.32 mmol) was added. The mixture was slowly heated, Stir under nitrogen at 95° C. for 2 hours, then cool to 25° C. and quench the reaction by the addition of water. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic extracts were Wash with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography. Purification by chromatography (20-50% EtOAc in heptane) gave a white solid The desired product was obtained as (125 mg, 60%). LCMS (ES-API): C 39 H 39 FN 4 O 3 Calculated mass of Si, 658.3; measured m / z, 659.4 [M+H] + .

[0344] Step E. 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl) -4-(prop-1-en-2-yl)isoquinolin-1(2H)-one. Tetrahydro 6-(3-(((tert-butyldiphenylsilyl)) in furan (THF) (10 mL) 4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl-4-oxo 2-(3-fluorophenyl)-4-(prop-1-en-2-yl)- To a solution of tetrahydrofuran-1(2H)-isoquinolinone (92 mg, 0.14 mmol), Tetrabutylammonium fluoride (0.14 mL, 0.14 mmol) A solution of furan (THF) (1M) was added. The mixture was stirred at 25° C. for 0.5 h. H 2 The mixture was diluted with 200 mL of ethyl acetate (15 mL) and extracted with ethyl acetate (2 x 50 mL). The organic extract was washed with brine (20 mL) and Na 2 SO 4 Dry, filter and concentrate. The residue was purified by flash column chromatography (30-100% EtOAc in heptane). and then purified by preparative HPLC (C18 column, 10-90% gradient MeCN in water). ) to give the title compound as a white solid (35 mg, 60% yield). LCMS(ES-API):C 23 H 21 FN 4 O 3 Calculated mass: 420.2 m / Actual z value: 421.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )d 8.40(br s,2H),8.15(br d,J=9.09Hz,1H),7. 55-7.59(m,1H),7.49(br d,J=9.60Hz,1H),7.2 5-7.42(m,3H),5.40(br s,1H),5.17(s,1H),4. 53(s,2H),3.81(q,J=6.87Hz,2H),2.14(s,3H), 1.29(br t,J=6.87Hz,3H)ppm.

[0345] Example 2: 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- 1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)- 4-Isopropylisoquinolin-1(2H)-one.

[0346] [ka]

[0347] 6-(4-ethyl-3-(hydroxymethyl)-5-oxo- 4,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluoro phenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one(3 To a solution of 5 mg, 0.08 mmol) was added Pd / C (18 mg, 10%). The mixture was degassed and purged with hydrogen gas three times. The reaction mixture was then cooled under a hydrogen atmosphere (15 ps i) and stirred at 25° C. for 12 hours. The mixture was then poured onto a short pad of Celite®. The residue was purified by preparative HPLC (C18 column, 10–9 ml of water). 0% gradient ACN) to give the title compound as a white solid (8 mg, yield 42%). LCMS(ES-API):C 23 H 23 FN 4 O 3 Calculated mass of, 422. 2; m / z measured value, 423.1 [M+H] + . 1 H NMR (400MHz, DMSO- d 6 )d 8.51(s,1H),8.41(d,J=8.84Hz,1H),8.13 (br d,J=8.84Hz,1H),7.54-7.64(m,1H),7.28- 7.41(m,3H),7.20(s,1H),4.54(s,2H),3.76-3. 87(m,2H),3.16-3.28(m,1H),1.23-1.41(m,9H) ppm.

[0348] Racemic 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine 1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4 -Isopropyl-3,4-dihydroisoquinolin-1(2H)-one was also found to be a white solid. The product was isolated (15 mg, 42% yield). LCMS (ES-API): C 23 H 25 FN 4 O 3 Calculated mass, 424.2; measured m / z, 425.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )d 7.94-8.10(m,2H), 7.92(s,1H),7.45-7.51(m,1H),7.31(br d,J=1 1.12Hz,1H),7.26(br d,J=8.08Hz,1H),7.11(b rt,J=8.34Hz,1H),5.82(br s,1H),4.51(s,2H ),4.27(br d,J=10.61Hz,1H),3.59-3.98(m,3H ),1.92-2.16(m,1H),1.28(br t,J=6.82Hz,3H) ,0.92(br d,J=6.57Hz,3H),0.88(br d,J=6.57 Hz,3H) ppm.

[0349] Example 3: 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(phenyl) hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole 1-yl)-4-isopropylisoquinolin-1(2H)-one.

[0350] [ka]

[0351] Step A. N-(2-chloro-6-fluorophenyl)-3-methylbut-2-ene 2-Chloro-6-fluoroaniline in anhydrous dichloromethane (50 mL) at 0°C. Phosphorus (2.9 g, 20 mmol) and 3-methyl-2-butenal (2 g, 23.9 mmol) To a solution of 1.2 mmol of ethyl amine was added (8.3 mL, 60 mmol), followed by addition of T iCl 4 (3 g, 16 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h, then The mixture was then heated to 25° C. and stirred for 4 hours. The mixture was filtered through a filter, and the filtrate was partitioned between dichloromethane and water. The organic layer was separated, and the aqueous layer was The combined organic extracts were washed with MgSO 4 Dry, filter and concentrate. This gave the crude desired product as a yellow oil (3.3 g, 78%), which was further purified. Used crude in the next step without purification. 1 H NMR (400MHz, CDC l 3 )δ 8.36(dd,J=2.20,9.66Hz,1H),7.20(d,J= 7.83Hz,1H),6.94-7.09(m,2H),6.32(br d,J=9 .66Hz,1H),5.30(s,1H),2.00(s,6H).

[0352] Step B. 2-Chloro-6-fluoro-N-(3-methylbut-2-en-1-yl) ) aniline. Crude N-(2-chloro-6-fluorophenyl)- in methanol (25 mL) A solution of 3-methylbut-2-en-1-imine (3.3 g, 15.6 mmol) was added to 25 °C NaBH 4 (0.59 g, 15.6 mmol) was added, and after an interval of 1 h, another batch Chi's NaBH 4 (0.59 g, 15.6 mmol) was added. A total of 3 equivalents of NaBH 4 (1.8 g, 47 mmol) was added. The reaction mixture was stirred at 25° C. for 16 h. The mixture was concentrated to dryness. The mixture was partitioned between ethyl acetate and water. The organic layer was separated and The layers were extracted with ethyl acetate. The combined organic extracts were washed with MgSO 4 Dry, filter and concentrate The residue was purified by flash column chromatography (SiO 2 , 5-25% Et in heptane OAc) to give the desired product (yield, 1.9 g, 57%) as a yellow oil. Got it. 1 H NMR (400 MHz, CDCl 3 ) δ 7.05(br d,J=7.5 8Hz,1H),6.83-6.97(m,1H),6.55-6.73(m,1H), 5.32(br s,1H),3.91(br d,J=6.57Hz,2H),3.8 2(br s,1H),1.73(s,3H),1.68(s,3H)ppm.

[0353] Step C. 4-Bromo-2-iodobenzoyl chloride. 4-Bromo-2-iodobenzoyl chloride. In a flask containing benzoic acid (2.5 g, 7.7 mmol), SOCl 2 (7mL) was added The mixture was heated at 80° C. for 15 min, then cooled to 25° C. and concentrated to give off-white The crude 4-bromo-2-iodobenzoyl chloride was obtained as a thiocyanate solid. It was used in the next step without any modification.

[0354] Step D: 4-Bromo-N-(2-chloro-6-fluorophenyl)-2-iodo- N-(3-methylbut-2-en-1-yl)benzamido)-one. Crude 4-bromo-2 -Iodobenzoyl chloride was dissolved in dichloromethane (10 mL) and then cooled to 0°C. 2-Chloro-6-fluoro-N-(3-methylbut-2-en-1-yl)aniline(1 .1g, 5.1mmol) and triethylamine (2.1mmol, 15mmol) Slowly add dropwise to a cold dichloromethane solution (20 mL), followed by a catalytic amount of 4-dimethylazo The reaction mixture was stirred for 25 min at 4° C. for 1 hour at 4° C. for 2 hours. The mixture was heated and stirred at ℃ for 3 hours. 3 The reaction was stopped by adding aqueous The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water, Line washed with MgSO 4 Dry at 40° C., filter, and concentrate to give the desired product as a brown oil. The crude product was obtained (2.4 g, 89%). LCMS (ES-API): C 18 H 15 BRC Calculated mass of lFINO, 520.9; measured m / z, 522.0 [M+H] + .

[0355] Step E. Racemic-6-bromo-2-(2-chloro-6-fluorophenyl)-4 -(Prop-1-en-2-yl)-3,4-dihydroisoquinolin-1(2H)-one , and 6-bromo-2-(2-chloro-6-fluorophenyl)-4-isopropyliso Quinolin-1(2H)-one. 4-Bromoquinolin-1(2H)-one in anhydrous N,N-dimethylformamide (30 mL) Bromo-N-(2-chloro-6-fluorophenyl)-2-iodo-N-(3-methylbutanoate) -2-en-1-yl)benzamido)-one (1.2 g, 2.3 mmol), tetrabromo ethylammonium bromide (1.48 g, 4.6 mmol), and potassium acetate (0.6 A mixture of palladium(II) acetate (0.26 g, 1 The reaction mixture was heated and stirred under nitrogen at 80° C. for 1.5 hours. It was then cooled to 25° C. and water (100 mL) was added. The mixture was diluted with ethyl ether (10 The mixture was extracted with ethyl acetate (100 mL) and ethyl acetate (100 mL). The combined organic extracts were washed with brine. Purified, anhydrous sodium 2 SO 4 The residue was purified by flash column chromatography. Topography (SiO 2 , 30-60% EtOAc in heptane) to give a white The two isomeric products were obtained as a mixture of solids (approximately 3:1, 590 mg, 65%). The mixture was used directly in the next step without further separation. LCMS (ES-API ):C 18 H 14 Calculated mass of BrClFNO, 393.0; observed m / z, 394.0 [M+H] + .

[0356] Step F. Racemic 6-(3-(((tert-butyldiphenylsilyl)oxy) Methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazo (2-chloro-6-fluorophenyl)-4-(propane-1-yl)-2-(2-chloro-6-fluorophenyl)-4-(propane-1-yl) -2-yl)-3,4-dihydroisoquinolin-1(2H)-one, and 6-(3-(( (tert-Butyldiphenylsilyl)oxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-6 -fluorophenyl)-4-isopropylisoquinolin-1(2H)-one. Anhydrous 1,4 - Racemic 6-bromo-2-(2-chloro-6-fluorophenyl)propane in dioxane (8 mL) phenyl)-4-(prop-1-en-2-yl)-3,4-dihydroisoquinoline-1( 2H)-one and 6-bromo-2-(2-chloro-6-fluorophenyl)-4-isopropanol propylisoquinolin-1(2H)-one (ca. 3:1, 590 mg, 1.49 mmol), And K 3 PO 4 (946 mg, 4.5 mmol) of 5-(((tert-butyl ether) (ethyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1, 2,4-Triazol-3-one (Intermediate 2, 1063 mg, 2.8 mmol), CuI (212 mg, 1.1 mmol), and trans-N,N'-dimethylcyclohexane- 1,2-diamine (159 mg, 1.1 mmol) was added to each reaction mixture. The mixture was heated to 95° C. for 3 hours under nitrogen, then cooled to 25° C. and diluted with water. The reaction was quenched with ethyl acetate (40 mL). The mixture was extracted with ethyl acetate (200 mL x 2). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 Dry, filter and concentrate The residue was purified by flash column chromatography (SiO 2 , 0-40% Et in heptane OAc) to give two isomeric products as a mixture of white foams (ca. 4 :1, 620 mg, 79%). LCMS(ES-API):C 39 H 40 ClFN 4 O 3 Calculated mass of Si, 694.3; measured m / z, 695.4 [M+H] + .

[0357] Step G. 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-4-isopropylisoquinolin-1(2H)-one. Racemic 6-(3- (((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-5-oxo -4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro -6-fluorophenyl)-4-(prop-1-en-2-yl)-3,4-dihydro- Soxinoline-1(2H)-one and 6-(3-(((tert-butyldiphenylsilyl 4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl-oxy -triazol-1-yl)-2-(2-chloro-6-fluorophenyl)-4-isopropyl of propylisoquinolin-1(2H)-one (approximately 4:1, 620 mg, 0.85 mmol) To the mixture in tetrahydrofuran (THF) (10 mL) was added tetrabutylammonium fluoride. A solution of 0.8 mL (0.8 mmol) in tetrahydrofuran (THF) (1 M) was The reaction mixture was stirred at 25° C. for 0.5 h. The mixture was 2 Dilute with ethyl acetate and The combined organic extracts were washed with brine and 2 SO 4 Dry and filter. The residue was purified by flash column chromatography (50-100% in heptane). EtOAc) and then purified by preparative HPLC (C18 column, 20-80% in water). Further purification by MeCN gradient gave 2-(2-chloro-6-fluorophenyl) (4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-diphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-diphenyl Hydro-1H-1,2,4-triazol-1-yl)-4-isopropylisoquinoline 36 mg, 11%. LCMS (ES-API): 23 H 22 ClFN 4 O 3 Calculated mass, 456.1; measured m / z, 457.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )d 8.61(d,J=1.96Hz,1 H),8.56(d,J=8.80Hz,1H),8.10(dd,J=1.96,8. 80Hz,1H),7.34-7.46(m,1H),7.16-7.33(m,2H) ,6.77(s,1H),4.70(s,2H),3.85-3.97(m,2H),3 .27-3.44(m,1H),1.40-1.46(m,3H),1.30-1.40 (m,6H) ppm.

[0358] Racemic 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(phenyl) hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole 1-yl)-4-(prop-1-en-2-yl)-3,4-dihydroisoquinoline-1 The (2H)-one was isolated as a second crop of white solid (280 mg, 85% yield). LCMS(ES-API):C 23 H 22 ClFN 4 O 3 Calculated mass, 456.1; Measured m / z: 457.2 [M+H] +. 1 H NMR (400 MHz, CDCl 3 )d 8.24(br d,J=9.09Hz,1H),7.98(br s,2H),7. 27-7.35(m,2H),7.06-7.16(m,1H),5.15(br d, J=4.04Hz,1H),4.85,4.75(2s,1H),4.68(s,2H ),3.97-4.07(m,1H),3.84-3.95(m,4H),1.87,1 .84(2s,3H),1.40(br t,J=7.07Hz,3H)ppm.

[0359] Example 4: 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- 1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)- 4-Phenylisoquinolin-1(2H)-one.

[0360] [ka]

[0361] Step A. 6-Bromo-4-phenylisoquinolin-1(2H)-one. 1,4-Di 6-Bromo-4-iodoisoquinolin-1(2H)-one (pure) in oxane (20 mL) Example 1 Step A, 0.55 g, 1.7 mmol) and Cs 2 CO 3 (1.3g, 3.9 1 mmol) of bis(triphenylphosphine)palladium(II) di Chloride (0.22 g, 0.31 mmol) and phenylboronic acid (0.29 g, 2.4 The reaction mixture was degassed with nitrogen and then heated at 85° C. The progress was closely monitored by TLC. After 0.5 h, TLC analysis showed nearly complete conversion of the starting material. Complete consumption and formation of the desired product was noted. The mixture was cooled to 25° C. and precipitated on silica gel. The mixture was filtered through a pad of silica gel. The silica gel was washed with ethyl acetate. The combined filtrate was concentrated. The residue was purified by flash column chromatography (SiO 2 , 10-70% in heptane ethyl acetate) to give the desired product as a white solid (0.16 g, yield LCMS(ES-API):C 15 H 10 Calculated mass of BrNO: 299. 0; m / z measured value, 298.1 [MH] + . 1 H NMR (400MHz, DMSO- d 6 )δ 11.65(br d,J=4.04Hz,1H),8.21(d,J=8. 59Hz,1H),7.71(br d,J=8.59Hz,1H),7.56(s,1 H),7.41-7.53(m,5H),7.18(br d,J=5.56Hz,1H ) ppm.

[0362] Step B. 6-Bromo-2-(3-fluorophenyl)-4-phenylisoquinoline -1(2H)-one. Dichloromethane (DCM) (20 mL) and triethylamine (2 6-Bromo-4-phenylisoquinolin-1(2H)-one (160 mg, 0 mL) .53 mmol) and 3-fluorophenylboronic acid (224 mg, 1.6 mmol) The mixture was added with copper(II) acetate (48 mg, 0.26 mmol) and pyridine (0.13 mL The reaction mixture was stirred at 25° C. for 48 hours. Filter the mixture through a short pad and wash the silica gel with ethyl acetate (100 mL). The filtrate was concentrated, and the residue was purified by flash column chromatography (SiO2 , heptane Purify by elution with 20-50% EtOAc to give the crude desired product as a yellow amorphous gum. (180 mg, 86%). LCMS (ES-API): 21 H 13 BrFNO Calculated mass, 393.0; measured m / z, 394.0 [M+H] + .

[0363] Step C. 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl) -4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1- 2-(3-fluorophenyl)-4-phenylisoquinolin-1(2H)-one 6-Bromo-2-(3-fluorophenyl)- in anhydrous 1,4-dioxane (6 mL) 4-Phenylisoquinolin-1(2H)-one (100 mg, 0.25 mmol) and K 3 PO 4 (161 mg, 0.7 mmol), 5-(((tert-butyldiphenyl (phenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4- Triazol-3-one (Intermediate 2, 194 mg, 0.5 mmol), CuI (48 mg , 0.25 mmol), and trans-N,N'-dimethylcyclohexane-1,2-di Amine (36 mg, 0.25 mmol) was added to each. The mixture was slowly heated. The mixture was stirred at 95° C. under nitrogen for 2 hours, then cooled to 25° C. and quenched by the addition of water. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine. Wash with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography. Purification by chromatography (20-50% EtOAc in heptane) gave a white solid. The desired product was obtained (120 mg, 68%). LCMS (ES-API): 42 H 39 FN 4 O 3 Calculated mass of Si, 694.3; measured m / z, 695.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.60(d,J=8.59Hz,1 H),8.28(s,1H),8.15(br d,J=8.59Hz,1H),7.6 6(br d,J=7.07Hz,4H),7.34-7.53(m,12H),7.2 7-7.33(m,2H),7.08-7.19(m,2H),4.62(s,2H), 3.88(br q,J=6.82Hz,2H),1.34(br t,J=6.82H z,3H), 1.07(s,9H)ppm.

[0364] Step D. 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl) -4-phenylisoquinolin-1(2H)-one. Tetrahydrofuran (THF) (10 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4- Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl -2-(3-fluorophenyl)-4-phenylisoquinolin-1(2H)-one (12 A solution of 0.0 mg, 0.17 mmol) of tetrabutylammonium fluoride (0.17 A tetrahydrofuran (THF) solution (1M) of 1.5 mL, 0.17 mmol was added. The mixture was stirred at 25° C. for 0.5 h. The mixture was 2 Dilute with 200 (15 mL) and ethyl acetate. (50 mL x 2). The combined organic extracts were washed with brine (20 mL), Na 2 SO 4 The residue was purified by flash column chromatography. (30-100% EtOAc in heptane) to give the title compound as a white solid. The product was obtained (50 mg, 63% yield). LCMS (ES-API): C 26 H 21 FN 4 O 3 Calculated mass, 456.2; measured m / z, 457.2 [M+H] + . 1 H NMR( 400MHz, CDCl 3 )d 8.55-8.65(m,1H),8.30(s,1H ),8.20(br d,J=8.59Hz,1H),7.39-7.56(m,6H) ,7.28-7.32(m,2H),7.17(s,1H),7.10-7.16(m, 1H),4.64(br d,J=6.19Hz,2H),3.86(q,J=7.07 Hz,2H),2.27(t,J=6.19Hz,1H),1.37(br t,J=7 .07Hz,3H)ppm.

[0365] Example 5: 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(phenyl) hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole 1-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one.

[0366] [ka]

[0367] Step A. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-isoquinoline-1(2 H)-one. 6-Bromo-2-(3-fluoro)-2-(phenylenediamine) in anhydrous 1,4-dioxane (37 mL) phenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one (act The product of Example 1, Step C, 1.8 g, 8.0 mmol) and K 3 PO 4 (3.4g, 16mmol) of 3-((benzyloxy)methyl)-4-ethyl-1H-1 , 2,4-triazol-5(4H)-one (intermediate product 1, 2.2 g, 9.6 mmol) ), CuI (1.5 g, 8.0 mmol), and trans-N,N'-dimethylcyclohexane Xanthane-1,2-diamine (1.1 g, 8.0 mmol) was added to each mixture. Slowly heat and stir under nitrogen at 95°C for 24 hours, then cool to 25°C and add water. The reaction was quenched by adding dichloromethane (200 mL x 2) and ethyl acetate. The combined organic extracts were washed with brine and anhydrous NaCl. 2 SO 4 The residue was purified by flash column chromatography (heptane Purification by 50-100% EtOAc) gave the desired product as a white solid. (2.5g, 82%). LCMS(ES-API):C 21 H 20 N 4 O 3 Calculated mass value , 376.2; m / z measured, 377.3 [M+H] + . 1 H NMR (400MHz, CDCl 3 )δ 10.58(br s,1H),8.47(d,J=8.80Hz,1 H),8.29(s,1H),8.17(br d,J=8.80Hz,1H),7.2 9-7.45(m,5H),7.15(br d,J=6.85Hz,1H),6.60 (br d,J=6.85Hz,1H),4.62(s,2H),4.55(s,2H) ,3.87(q,J=6.92Hz,2H),1.36(t,J=6.92Hz,3H) ppm.

[0368] Step B. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-4-iodoisoquinol 6-(3-((benzyloxy)methyl)-4-ethyl-5-one Xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-isoquinoline -1(2H)-one (2.5 g, 6.6 mmol) in anhydrous acetonitrile (60 mL) To the suspension was added N-iodosuccinimide (NIS) (2.9 g, 13 mmol). The reaction mixture was heated and stirred under nitrogen at 80°C for 2 hours and then cooled to 25°C. The mixture was filtered through a sintered funnel and the precipitate was collected, washed with water and dried in vacuum. This afforded the desired product (1.2 g, crude, 36%) as an off-white solid, which was further purified. Used crude in the next step without purification. LCMS (ES-API): 21 H 19 IN 4 O 3 Calculated mass, 502.1; measured m / z, 503.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3) δ 10.97(br s,1H),8.5 5(d,J=1.96Hz,1H),8.44(d,J=8.80Hz,1H),8.2 3(dd,J=1.96,8.80Hz,1H),7.61(s,1H),7.30-7 .48(m,5H),4.63(s,2H),4.57(s,2H),3.88(q,J =7.34Hz,2H),1.37(t,J=7.34Hz,3H)ppm.

[0369] Step C. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-yl) 1,4-dioxane (20 mL) and 6-(3-((benzyloxy)methyl)-2-(2-methylphenyl)-1,3-dihydro-1,4-trimethylphenyl)-1,4-dihydro-1,5-trimethylphenyl)-1,5-dihydro-1,6-trimethylphenyl )-4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-4-iodoisoquinolin-1(2H)-one (0.8 g, 1.6 mmol) and Cs 2 CO 3 (1.6 g, 4.8 mmol) of bis(triphenyl Phosphine)palladium(II) dichloride (0.56 g, 0.8 mmol) and isoprene Ropenylphenylboronic acid pinacol ester (0.67 g, 4 mmol) was added. The reaction mixture was degassed with nitrogen and then heated at 85° C. for 1 h. The mixture was diluted with water (50 mL) The aqueous phase was poured into ethyl ether (100 mL) and ethyl acetate (EtOAc) (100 The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 Dry with The residue was purified by flash column chromatography (SiO 2, Hep Purification by elution with 50% ethyl acetate in ethanol (50-100% ethyl acetate in ethanol) afforded the desired product as a white solid. Obtained (0.45 g, yield 68%). LCMS (ES-API): C 24 H 24 N 4 O 3 of Calculated mass, 416.2; measured m / z, 417.3 [M+H] + . 1 H NMR(40 0MHz,CDCl 3 )δ 10.59(br s,1H),8.51(d,J=8.8 0Hz,1H),8.48(d,J=2.03Hz,1H),8.14(dd,J=2. 03,8.80Hz,1H),7.30-7.43(m,5H),7.06(br s, 1H),5.35-5.39(m,1H),5.15(d,J=0.98Hz,1H), 4.61(s,2H),4.55(s,2H),3.87(q,J=7.22Hz,2H ),2.18(s,3H),1.36(t,J=7.22Hz,3H)ppm.

[0370] Step D. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-6 -Fluoro-4-nitrophenyl)-4-(prop-1-en-2-yl)isoquinoline -1(2H)-one. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo So-4,5-dihydro)-1H-1,2,4-triazol-1-yl)-4-(propanediol) -1-en-2-yl)isoquinolin-1(2H)-one (0.2 g, 0.48 mmol ) and Cs 2 CO 3 (0.47 g, 1.4 mmol) in anhydrous DMF (8 mL) , 3-chloro-4,5-difluoronitrobenzene (0.17 g, 0.86 mmol) The reaction mixture was stirred under nitrogen at 85° C. for 1 h. The reaction mixture was diluted with NaHCO 3 The aqueous phase was poured into a saturated aqueous solution (50 mL). The combined organic extracts were washed with brine and then extracted with anhydrous tOAc (50 mL). Na 2 SO 4 The residue was purified by flash column chromatography. (SiO 2 , 20-50% ethyl acetate in heptane) to give a white solid. The desired product was obtained (0.15 g, 53% yield). LCMS (ES-API): 30 H 25 ClFN 5 O 5 Calculated mass, 589.2; measured m / z, 590.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.53(d,J=8.80Hz,1 H),8.51(d,J=2.45Hz,1H),8.29-8.32(m,1H),8 .17(dd,J=1.96,8.80Hz,1H),8.09(dd,J=2.45, 8.31Hz,1H),7.29-7.46(m,5H),6.80(s,1H),5. 40(t,J=1.71Hz,1H),5.14-5.25(m,1H),4.63(s ,2H),4.55(s,2H),3.87(q,J=7.01Hz,2H),2.21 (s,3H),1.37(t,J=7.01Hz,3H)ppm.

[0371] Step E. 2-(4-amino-2-chloro-6-fluorophenyl)-6-(3-( (benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1, 2,4-Triazol-1-yl)-4-(prop-1-en-2-yl)isoquinoline -1(2H)-one. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo So-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro 2-(6-fluoro-4-nitrophenyl)-4-(prop-1-en-2-yl)isox Neutral-1(2H)-one (1.4 g, 2.4 mmol) in methanol (100 mL) To a mixture of 1,2-dichlorophenyl ether and ethyl acetate (40 mL), NH 4 Cl(1 . 1g, 21mmol) and zinc (1.55 g, 23 mmol) of each was added to an aqueous solution (20 mL). The mixture was stirred for 1 hour at 25° C. and passed through a short pad of Celite®. The filtrate was concentrated to a small volume and then partitioned between ethyl acetate (EtOAc) and water. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (EtOAc). Wash with anhydrous Na 2 SO 4 Dry at 40° C., filter, and concentrate to give the crude product as a white foam. (1.3 g, crude, 97% yield), which was carried to the next step without further purification. Used crude in this study. LCMS (ES-API): 30 H 27 ClFN 5 O 3 Mass meter Calculated value, 559.2; measured m / z value, 560.3 [M+H] + .

[0372] Step F. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-6 -fluorophenyl)-4-(prop-1-en-2-yl)isoquinoline-1(2H) -one. Crude 2-(4-amino-2-chloro-6-fluorophenyl)-6-(3 -((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H- 1,2,4-Triazol-1-yl)-4-(prop-1-en-2-yl)isoquino Phosphin-1(2H)-one (0.5 g, 0.89 mmol, estimated) in ethanol (25 mL ) and dark H 2 SO 4 (5 mL) solution of NaNO 2 (0.22g, 3.1mmol) Aqueous solution (10 mL) was added. The mixture was stirred at 0° C. for 0.5 h, and then hypophosphorous acid (2 The reaction mixture was stirred at 0° C. for 0.5 h and then cooled to room temperature. The mixture was stirred at rt for 1 h. The mixture was poured into water (50 mL) and diluted with dichloromethane (50 mL) and vinegar (10 mL). The combined organic extracts were washed with brine. Wash and add anhydrous Na 2 SO 4 The residue was purified by flash column chromatography. Mathography (SiO 2 , 20-70% ethyl acetate in heptane) to give a white The title compound was obtained as a solid (0.11 g, 23% yield). LCMS (ES-API) :C 30 H 26 ClFN 4 O 3 Calculated mass, 544.2; measured m / z, 545.3 M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.55(d,J=8.8 0Hz,1H),8.49(d,J=1.96Hz,1H),8.14(dd,J=1. 96,8.80Hz,1H),7.30-7.43(m,7H),7.15-7.23( m,1H),6.86(s,1H),5.36-5.39(m,1H),5.20(dd ,J=0.98,1.96Hz,1H),4.62(s,2H),4.55(s,2H) ,3.87(q,J=7.22Hz,2H),2.20(s,3H),1.36(t,J =7.22Hz,3H)ppm.

[0373] Step G. 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro -1H-1,2,4-triazol-1-yl)-2-(2-chloro-6-fluorophenyl nyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one(0.1 1 g, 0.2 mmol) was dissolved in trifluoroacetic acid (5 mL) and the reaction mixture was placed in a sealed tube. The mixture was transferred to a 250° C. flask and heated at 80° C. for 17 h, then cooled to room temperature, and the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , 50-100% EtO in heptane Ac) and then purified by preparative HPLC (C18 column, 20-80% gradient M in water) Further purification by hexane (ECN) afforded the desired product as a white solid (45 mg, yield 49%). LCMS(ES-API):C 23 H 20 ClFN 4 O 3 Calculated mass of 54 4.2; m / z measured value, 545.1 [M+H] + . 1 H NMR (400MHz, CDC l 3 )δ 8.55(d,J=8.80Hz,1H),8.48(d,J=1.96Hz ,1H),8.12(dd,J=1.96,8.80Hz,1H),7.31-7.46 (m,2H),7.16-7.25(m,1H),6.86(s,1H),5.37(t ,J=1.83Hz,1H),5.30(s,1H),5.20(dd,J=0.98, 1.83Hz,1H),4.70(s,2H),3.92(q,J=7.34Hz,2H ),2.20(s,3H),1.42(t,J=7.34Hz,3H)ppm.

[0374] Example 6: 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(phenyl) hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole 1-yl)-4-(3,3,3-trifluoroprop-1-en-2-yl)isoquinol N-1(2H)-On.

[0375] [ka]

[0376] Step A. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-4-(3,3,3-triazol-1-yl) Trifluoroprop-1-en-2-yl)isoquinolin-1(2H)-one. 1,4-Difluoroprop-1-en-2-yl In oxane (20 mL) and ethanol (20 mL) and water (10 mL), 6-(3-( (benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1, 2,4-Triazol-1-yl)-4-iodoisoquinolin-1(2H)-one (exemplified The product of Example 5, Step B, 0.5 g, 1.0 mmol) and Cs 2 CO 3 (0.97g , 2.98 mmol) to a mixture of bis(triphenylphosphine)palladium(II) dichloride (0.35 g, 0.5 mmol) and 1-(trifluoromethyl)vinylborate hexylene glycol ester (0.55 g, 2.5 mmol) was added to each The reaction mixture was degassed with nitrogen and then heated at 85° C. for 2 h. The mixture was diluted with water (50 mL The aqueous phase was poured into ethyl ether (100 mL) and ethyl acetate (EtOAc) (10 The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 in It was dried, filtered and concentrated. The residue was purified by flash column chromatography (SiO 2 , He Purify with ethyl acetate (30 to 100% ethyl acetate in butane) to give the desired product as a white solid. (0.45 g, 96% yield). LCMS (ES-API): 24 H 21 F 3 N 4 O 3 Calculated mass, 470.2; measured m / z, 417.3 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ 10.42(br s,1H),8.51(d,J= 8.80Hz,1H),8.35(d,J=1.96Hz,1H),8.14-8.28 (m,1H),7.30-7.50(m,5H),7.15(br d,J=4.40H z,1H),6.40(d,J=1.24Hz,1H),5.81(d,J=1.24H z,1H),4.61(s,2H),4.54(s,2H),3.86(q,J=7.1 7Hz,2H),1.36(t,J=7.17Hz,3H)ppm.

[0377] Step B. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-6 -Fluoro-4-nitrophenyl)-4-(3,3,3-trifluoroprop-1-ene -2-yl)isoquinolin-1(2H)-one. -(3-((benzyloxy)methyl) -4-Ethyl-5-oxo-4,5-dihydro)-1H-1,2,4-triazole-1 -yl)-4-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline -1(2H)-one (0.45 g, 0.96 mmol) and Cs 2 CO 3 (0.93g, To a mixture of 2.9 mmol) of 3-chloro-4,5-difluorophenyl Nitronitrobenzene (0.33 g, 1.7 mmol) was added. The reaction mixture was stirred under nitrogen for 8 h. The mixture was stirred at 5° C. for 1 h. The reaction mixture was diluted with NaHCO 3 Poured into saturated aqueous solution (100 mL) The aqueous phase was washed with ethyl ether (100 mL) and ethyl acetate (EtOAc) (100 mL). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 Dry with It was filtered and concentrated. The residue was purified by flash column chromatography (SiO 2 , 2 in heptane 0 to 50% ethyl acetate) to give the desired product as a white solid (0. 22g, 35% yield. LCMS (ES-API): C 30 H 22ClF 4 N 5 O 5 Quality Calculated mass, 643.1; measured m / z, 590.3 [M+H] + . 1 H NMR(400 MHz, CDCl 3 )δ 8.54(d,J=8.80Hz,1H),8.41(d,J =1.96Hz,1H),8.30-8.32(m,1H),8.26(dd,J=1. 96,8.80Hz,1H),8.10(dd,J=2.45,8.31Hz,1H), 7.31-7.41(m,5H),6.94(s,1H),6.44(d,J=1.22 Hz,1H),5.90(d,J=1.22Hz,1H),4.62(s,2H),4. 55(s,2H),3.87(d,J=6.85Hz,3H),1.36(t,J=6. 85Hz,3H)ppm.

[0378] Step C. 2-(4-amino-2-chloro-6-fluorophenyl)-6-(3-( (benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1, 2,4-Triazol-1-yl)-4-(3,3,3-trifluoroprop-1-ene -2-yl)isoquinolin-1(2H)-one. 6-(3-((benzyloxy)methyl )-4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-2-(2-chloro-6-fluoro-4-nitrophenyl)-4-(3,3,3 -trifluoroprop-1-en-2-yl)isoquinolin-1(2H)-one(0.2 2 g, 0.34 mmol) in methanol (40 mL) and ethyl acetate (20 mL) To,NH 4 Cl (0.16 g, 3 mmol) and Zn (0.22 g, 3.4 mmol) Each aqueous solution (5 mL) was added. The reaction mixture was stirred at 25° C. for 1 hour. The mixture was filtered through a short pad of Celite®. The filtrate was concentrated to a small volume. The organic layer was separated and the aqueous phase was diluted with ethyl acetate (Et0Ac) and water. The combined organic layers were washed with brine and extracted with anhydrous Na 2 SO 4 Dry in The mixture was then cooled to room temperature, filtered and concentrated to give the crude product as a white foam (0.2 g, crude, 97% yield). ). This was used crude in the next step without further purification. LCMS (ES- API):C 30 H 24 ClF 4 N 5 O 3 Calculated mass, 613.2; measured m / z, 6 14.3[M+H] + .

[0379] Step D. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-6 -fluorophenyl)-4-(3,3,3-trifluoroprop-1-en-2-yl) Isoquinolin-1(2H)-one. Crude 2-(4-amino-2-chloro-6-fluoro-1,4-dihydro-1,5-dihydro-2,6-dihydro-1,7-dihydro-1,8-dihydro-1,9-dihydro-1,1,1,2,3,4,5,6,7,8 (3-((benzyloxy)methyl)-4-ethyl-5-oxo- 4,5-Dihydro-1H-1,2,4-triazol-1-yl)-4-(3,3,3- Trifluoroprop-1-en-2-yl)isoquinolin-1(2H)-one (0.2g , 0.33 mmol, estimated) in ethanol (20 mL) and concentrated H 2 SO 4 (4mL) medium solution In the liquid, NaNO 2(0.03 g, 0.5 mmol) in water (10 mL) was added. The mixture was stirred at 0° C. for 0.5 h, then hypophosphorous acid (20 mL, 50% w / w) was added. The reaction mixture was stirred at 0°C for 0.5 h and then at room temperature for 1 h. The mixture was diluted with water (5 0 mL) and dichloromethane (50 mL) and ethyl acetate (EtOAc) (50 mL The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 Dry in The residue was purified by flash column chromatography (SiO 2 , heptane in 20-70% ethyl acetate) to give the desired product as a white solid ( 21mg, 10% yield. LCMS (ES-API): C 30 H 23 ClF 4 N 4 O 3 of Calculated mass, 598.1; measured m / z, 599.3 [M+H] + . 1 H NMR(40 0MHz,CDCl 3 )δ 8.56(d,J=8.80Hz,1H),8.38(d, J=1.96Hz,1H),8.22(dd,J=1.96,8.80Hz,1H),7 .33-7.44(m,7H),7.13-7.28(m,1H),7.00(s,1H ),6.41(d,J=1.47Hz,1H),5.89(d,J=1.47Hz,1H ),4.62(s,2H),4.55(s,2H),3.86(q,J=7.01Hz, 3H), 1.36(t,J=7.01Hz,3H)ppm.

[0380] Step E. 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-4-(3,3,3-trifluoroprop-1-en-2-yl)isoquino Phosph-1(2H)-one. 6-(3-((benzyloxy)methyl)-4-ethyl-5- Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(2- Chloro-6-fluorophenyl)-4-(3,3,3-trifluoroprop-1-ene- 2-yl)isoquinolin-1(2H)-one (21 mg, 0.03 mmol) was added to trifluoroacetate. The mixture was dissolved in oroacetic acid (5 mL) and the reaction mixture was transferred into a sealed tube and heated at 80° C. for 17 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography. Raffi (SiO 2 , 50-100% EtOAc in heptane) and then fractionated. Further purification by preparative HPLC (C18 column, 20-80% gradient MeCN in water) gave white The desired product was obtained as a colored solid (9 mg, 50% yield). LCMS (ES-API) :C 23 H 17 ClF 4 N 4 O 3 Calculated mass, 508.1; measured m / z, 509.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.56(br d,J =8.80Hz,1H),8.36(s,1H),8.21(br dd,J=1.47 ,8.80Hz,1H),7.33-7.51(m,2H),7.16-7.26(m, 1H),7.00(s,1H),6.41(s,1H),5.88(s,1H),4.7 0(br d,J=6.24Hz,2H),3.90(q,J=7.09Hz,2H), 2.14(br t,J=6.24Hz,1H),1.42(br t,J=7.09H z,3H) ppm.

[0381] Example 7: 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxyphenyl) Methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl )-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one.

[0382] [ka]

[0383] Step A. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-4-(1-methylcyclohexyl) 6-(3-((benzyloxy)methyl)methyl)isoquinolin-1(2H)-one, (ethyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one. A mixture of diiodomethane (1.6 g, 6 mmol) in anhydrous toluene (10 mL) at 0 °C To this was added a solution of diethylzinc (3.9 g, 4.8 mmol) in toluene (15%). The mixture was heated at 0° C. under nitrogen for 15 min, after which 6-(3-((benzyloxy)methyl)- 4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl (1-propen-2-yl)-4-(propan-1-yl)isoquinolin-1(2H)-one (250m g, 0.6 mmol) in toluene (20 mL) was added. The reaction mixture was stirred at 0° C. After stirring for 0.5 h, the reaction mixture was warmed to room temperature and stirred for 24 h. 3 The aqueous phase was poured into saturated aqueous solution (50 mL). The aqueous phase was diluted with DCM (50 mL) and ethyl acetate (EtOAc The combined organic extracts were washed with brine and anhydrous Na 2 S O 4 The residue was purified by flash column chromatography (SiO 2 , 50 to 100% ethyl acetate in heptane) to give 6-(3-((benzyloxy) 4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-trimethyloxy Azol-1-yl)-4-(1-methylcyclopropyl)isoquinoline-1(2H)- ion, and unreacted 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo- 4,5-Dihydro-1H-1,2,4-triazol-1-yl)-4-(propan-1-yl) The resulting mixture of (en-2-yl)isoquinolin-1(2H)-ones was purified further. Used directly in the next step without purification. White solid (approximately 1:4 ratio, 190 mg, yield 70%).

[0384] Step B. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2,6-dichloro 2H-4-nitrophenyl)-4-(1-methylcyclopropyl)isoquinoline-1(2H )-one, and 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2,6-dichloro 4-(4-nitrophenyl)-4-(prop-1-en-2-yl)isoquinoline-1(2 H)-one. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4, 5-Dihydro-1H-1,2,4-triazol-1-yl)-4-(1-methylcyclo propyl)isoquinolin-1(2H)-one, and 6-(3-((benzyloxy)methyl (ethyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole 1-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one (approximately 1:4, 0.19 g, 0.45 mmol) and Cs 2 CO 3 (0.35g, 1.1mmol l) in anhydrous DMF (6 mL) was added 3,5-dichloro-4-fluoronitrobenzene The reaction mixture was stirred under nitrogen at 85° C. for 1 h. The reaction mixture was diluted with NaHCO 3 The aqueous phase was poured into ethyl acetate (50 mL). The mixture was extracted successively with tert-butyl ether (50 mL) and ethyl acetate (EtOAc) (50 mL). The organic extract was washed with brine and anhydrous Na 2 SO 4 The residue was dried over 1000 ml of ethyl acetate, filtered and concentrated. The mixture was subjected to flash column chromatography (SiO 2 , 20-50% ethyl acetate in heptane) This was purified by HPLC to give two products as a mixture, which were carried on to the next step without further purification. Used directly in the flask: White solid (112 mg, 51% yield).

[0385] 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydrazine 1H-1,2,4-triazol-1-yl)-2-(2,6-dichloro-4-nitro (1-methylcyclopropyl)-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one: CMS(ES-API):C31 H 27 Cl 2 N 5 O 5 Calculated mass of 619.1 m / Actual z value: 620.2 [M+H] + ; 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydrazine 1H-1,2,4-triazol-1-yl)-2-(2,6-dichloro-4-nitro (2H)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one: LCMS(ES-API):C 30 H 25 Cl 2 N 5 O 5 Calculated mass of 605.1 m / z measured value: 606.3 [M+H] + .

[0386] Step C. 2-(4-amino-2,6-dichlorophenyl)-6-(3-((benzene (4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-dimethyl-4-methyl- Triazol-1-yl)-4-(1-methylcyclopropyl)isoquinoline-1(2H )-one, and 2-(4-amino-2,6-dichlorophenyl)-6-(3-((benzene (4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-dimethyl-4-methyl- Triazol-1-yl)-4-(prop-1-en-2-yl)isoquinoline-1(2 H)-one. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4, 5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2,6-dichloro -4-nitrophenyl)-4-(1-methylcyclopropyl)isoquinoline-1(2H) -one, and 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4, 5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2,6-dichloro -4-nitrophenyl)-4-(prop-1-en-2-yl)isoquinoline-1(2H )-one (ca. 1:4, 112 mg, 0.18 mmol) in methanol (40 mL) and acetic acid To the mixture in ethyl acetate (20 mL), NH 4 Cl (71 mg, 1.3 mmol) and Zn ( The reaction mixture was mixed with 2 The mixture was stirred for 1 hour at 5° C. and filtered through a short pad of Celite®. The filtrate was concentrated to a small volume and then partitioned between ethyl acetate (EtOAc) and water. The layers were separated and the aqueous phase was extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine. Purified, anhydrous sodium 2 SO 4 The crude product was obtained by drying at 40° C., filtering and concentrating the mixture to give a white foam. (approximately 1:5 ratio, 96 mg, crude, 97% yield) was obtained without further purification. Used crude in the next step. 2-(4-amino-2,6-dichlorophenyl) -6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydrido 1H-1,2,4-triazol-1-yl)-4-(1-methylcyclopropyl) Isoquinolin-1(2H)-one: LCMS (ES-API): C 31 H 29 Cl 2 N 5 O 3 Calculated mass, 589.2; measured m / z, 590.2 [M+H] + ;2-(4-A Benzyloxymethyl)-4-amino-2,6-dichlorophenyl (ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)- 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one LCMS (ES- API):C 30 H 27 Cl 2 N 5 O 3 Calculated mass, 575.2; measured m / z, 57 6.3[M+H] + .

[0387] Step D. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2,6-dichloro (1-methylcyclopropyl)-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one, and 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydr 1H-1,2,4-triazol-1-yl)-2-(2,6-dichlorophenyl) -4-(prop-1-en-2-yl)isoquinolin-1(2H)-one. -(4-amino-2,6-dichlorophenyl)-6-(3-((benzyloxy)methyl) )-4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one, and 2 -(4-amino-2,6-dichlorophenyl)-6-(3-((benzyloxy)methyl) )-4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one (approximately 1 1:5 ratio, 96 mg, 0.17 mmol, estimated) in ethanol (20 mL) and concentrated H 2 S O 4(4 mL) solution of NaNO 2 (34 mg, 0.49 mmol) in water (4 mL The reaction mixture was stirred at 0° C. for 1 h, then zinc powder (91 mg, 1.4 mm The reaction mixture was heated at room temperature for 0.5 h and then at 85° C. for 1 h. The mixture was cooled to room temperature, poured into water (50 mL) and diluted with aqueous NaOH and NaHCO 3 water soluble The pH was adjusted to 7-8 with dichloromethane (50 mL) and ethyl acetate. (EtOAc) (50 mL) in turn. The combined organic extracts were washed with brine, Anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated. The residue was purified by flash column chromatography. Fi(SiO 2 , 20-70% ethyl acetate in heptane) as a mixture The two desired products were obtained as white solids (approximately 1:4, 50 mg, 64% yield). -((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H- 1,2,4-triazol-1-yl)-2-(2,6-dichlorophenyl)-4-(1 -methylcyclopropyl)isoquinolin-1(2H)-one: LCMS (ES-API) :C 31 H 28 Cl 2 N 4 O 3 Calculated mass, 574.2; measured m / z, 575.2 M+H] + ;6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4, 5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2,6-dichloro Phenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one: L CMS(ES-API):C 30H 26 Cl 2 N 4 O 3 Calculated mass: 560.1 m / s Actual z value: 561.1 [M+H] + .

[0388] Step E. 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxyphenyl) Dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-isopropyl 6-(3-methylcyclopropyl)-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one. ((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1 ,2,4-triazol-1-yl)-2-(2,6-dichlorophenyl)-4-(1- methylcyclopropyl)isoquinolin-1(2H)-one, and 6-(3-((benzyl 4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl-4-oxo 2-(2,6-dichlorophenyl)-4-(prop-1-yl)- -2-yl)isoquinolin-1(2H)-one (ca. 1:4, 50 mg, 0.09 mmol The mixture was dissolved in trifluoroacetic acid (3 mL) and the reaction mixture was transferred to a sealed tube and diluted with 80 After heating at 5° C. for 17 hours, the mixture was cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was Column chromatography (SiO 2 , 50-100% EtOAc in heptane) and then purified by preparative HPLC (C18 column, 20-80% gradient MeCN in water). This was further purified by HPLC to give the desired product as a white solid (2 mg, 24% yield). MS(ES-API):C 24 H 22 Cl 2 N 4 O 3Calculated mass, 484.1; m / z Measured value: 485.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ 8. 92(d,J=2.21Hz,1H),8.54(d,J=8.80Hz,1H),8. 09(dd,J=2.21,8.80Hz,2H),7.48-7.54(m,2H), 7.32-7.39(m,1H),6.89(s,1H),4.72(d,J=6.36 Hz,2H),3.94(q,J=7.34Hz,2H),2.17(t,J=6.36 Hz,1H),1.50(s,3H),1.44(t,J=7.34Hz,3H),0. 81-0.97(m,4H)ppm.

[0389] Example 8: 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxyphenyl) Methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl )-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one.

[0390] [ka]

[0391] 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)- 5-Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-( 1-Methylcyclopropyl)isoquinolin-1(2H)-one (Example 7, Step E) The title compound was obtained as a second crop in the preparation of %). LCMS(ES-API):C 23 H 20 Cl 2 N 4 O3 Calculated mass of 470. 1; m / z measured value, 471.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ 8.55(d,J=8.80Hz,1H),8.49(d,J=2.21Hz,1 H),8.12(dd,J=2.21,8.80Hz,1H),7.47-7.53(m ,2H),7.33-7.40(m,1H),6.80(s,1H),5.35-5.3 8(m,1H),5.20(s,1H),4.70(d,J=6.36Hz,3H),3 .92(q,J=7.34Hz,3H),2.20(t,J=6.36Hz,1H),2 .20(s,3H),1.42(t,J=7.34Hz,3H)ppm.

[0392] Example 9: 2-(2-chloro-6-fluorophenyl)-4-cyclopropyl-6-( 4-Ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2 ,4-triazol-1-yl)isoquinolin-1(2H)-one.

[0393] [ka]

[0394] Step A. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-4-cyclopropyl Soquinolin-1(2H)-one and 6-(3-((benzyloxy)methyl)-4-en 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl Soquinoline-1(2H)-one. 1,4-Dioxane (20 mL) and ethanol (20 mL) and 6-(3-((benzyloxy)methyl)-4-ethyl- 5-Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-io Triisoquinolin-1(2H)-one (product of Example 5, Step B, 0.6 g, 1. 2mmol) and Cs 2 CO 3 (1.2 g, 3.6 mmol) was added to a mixture of bis(trifluoroacetate) (phenylphosphine)palladium(II) dichloride (0.42 g, 0.6 mmol) and Cyclopropylboronic acid (0.26 g, 2.9 mmol) was added to each reaction mixture. The mixture was degassed with nitrogen and then heated at 85° C. for 24 h. The mixture was poured into water (50 mL). The aqueous phase was diluted with ethyl ether (100 mL) and ethyl acetate (EtOAc) (100 mL). The combined organic extracts were washed with brine and then with anhydrous Na 2 SO 4 Dry with The residue was purified by flash column chromatography (SiO 2 , in heptane Purification with 30% to 100% ethyl acetate gave two products as a mixture, which was further Used directly in the next step without purification. White solid (approximately 1:2.5, 0.35 g , yield 75%). 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo- 4,5-Dihydro-1H-1,2,4-triazol-1-yl)-4-cyclopropyl Isoquinolin-1(2H)-one: LCMS (ES-API): C 24 H 24 N 4 O 3 of Calculated mass, 416.2; measured m / z, 417.3 [M+H] + ;6-(3-((Ben (Dimethyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4 -triazol-1-yl)isoquinolin-1(2H)-one: LCMS (ES-API ):C 21 H 20 N 4 O 3 Calculated mass, 376.2; measured m / z, 377.2 [M+ H] + .

[0395] Step B. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-6 -fluoro-4-nitrophenyl)-4-cyclopropylisoquinoline-1(2H)-o and 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5- Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-6-fluoro (4-nitrophenyl)isoquinolin-1(2H)-one. 6-(3-((benzyl 4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl-4-oxo riazol-1-yl)-4-cyclopropylisoquinolin-1(2H)-one, and 6 -(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro- 1H-1,2,4-triazol-1-yl)isoquinolin-1(2H)-one. (Approximately 1 : 2.5, 0.35g, 0.9mmol) and Cs 2 CO 3 (0.39g, 1.2mmol l) in anhydrous DMF (6 mL) was treated with 3-chloro-4,5-difluoronitrobenzene The reaction mixture was stirred under nitrogen at 85° C. for 1 h. The reaction mixture was diluted with NaHCO 3The aqueous phase was poured into ethyl acetate (50 mL). The mixture was extracted successively with tert-butyl ether (50 mL) and ethyl acetate (EtOAc) (50 mL). The organic extract was washed with brine and anhydrous Na 2 SO 4 The residue was dried over 1000 ml of ethyl acetate, filtered and concentrated. The mixture was subjected to flash column chromatography (SiO 2 , 20-50% ethyl acetate in heptane) This was purified by HPLC to give two products as a mixture, which were carried on to the next step without further purification. Used directly in the cup. White solid (approximately 1:2.3, 330 mg, 70% yield). 6-(3- ((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1 ,2,4-triazol-1-yl)-2-(2-chloro-6-fluoro-4-nitrophenyl) phenyl)-4-cyclopropylisoquinolin-1(2H)-one: LCMS (ES-AP I C 30 H 25 ClFN 5 O 5 Calculated mass, 589.2; measured m / z, 590. 3[M+H] + ;6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo- 4,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro- 6-Fluoro-4-nitrophenyl)isoquinolin-1(2H)-one: LCMS (ES -API):C 27 H 21 ClFN 5 O 5 Calculated mass, 549.1; measured m / z, 5 50.2[M+H] + .

[0396] Step C. 2-(4-amino-2-chloro-6-fluorophenyl)-6-(3-( (benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1, 2,4-Triazol-1-yl)-4-cyclopropylisoquinoline-1(2H)-o Benzene, and 2-(4-amino-2-chloro-6-fluorophenyl)-6-(3-((benzoyl) (Dimethyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4 -triazol-1-yl)isoquinolin-1(2H)-one. 6-(3-((benzyl 4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl-4-oxo 2-(2-chloro-6-fluoro-4-nitrophenyl)-4-riazol-1-yl -cyclopropylisoquinolin-1(2H)-one, and 6-(3-((benzyloxy )Methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazo (2-chloro-6-fluoro-4-nitrophenyl)isoquinol of 1(2H)-one (ca. 1:2.3, 330 mg, 0.58 mmol) in methanol (40 mL) and ethyl acetate (20 mL), 4 Cl (82 mg, 1.5 m mol) and zinc (111 mg, 1.7 mmol) in water (10 mL), respectively. The reaction mixture was stirred at 25°C for 1 h. The mixture was then filtered through a Celite® filter. The filtrate was concentrated to a small volume and then washed with ethyl acetate (EtOAc) and water. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (EtOAc). The organic layer was washed with brine and anhydrous Na 2 SO 4 Dry at 400 C, filter, and concentrate to give two crude The product was obtained as a white foam of a mixture (approximately 1:2 ratio, 270 mg, crude, 86% yield). ), which was used crude in the next step without further purification. -2-chloro-6-fluorophenyl)-6-(3-((benzyloxy)methyl)-4 -Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl )-4-Cyclopropylisoquinolin-1(2H)-one: LCMS (ES-API): C 30 H 27 ClFN 5 O 3 Calculated mass, 559.2; measured m / z, 560.3 [M +H] + ;2-(4-amino-2-chloro-6-fluorophenyl)-6-(3-((beta 4-ethyl-5-oxo-4,5-dihydro-1H-1,2, 4-Triazol-1-yl)isoquinolin-1(2H)-one: LCMS (ES-AP I C 27 H 23 ClFN 5 O 3 Calculated mass, 519.2; measured m / z, 520. 2[M+H] + .

[0397] Step D. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-6 -fluorophenyl)-4-cyclopropylisoquinolin-1(2H)-one, and 6- (3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazol-1-yl)-2-(2-chloro-6-fluorophenyl ) isoquinolin-1(2H)-one. Crude 2-(4-amino-2-chloro-6-fluorophenyl)-2-(4H)-isoquinolin-1(2H)-one at 0°C. (fluorophenyl)-6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo -4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-cyclopropyl Isoquinolin-1(2H)-one, and 2-(4-amino-2-chloro-6-fluoro phenyl)-6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4, 5-Dihydro-1H-1,2,4-triazol-1-yl)isoquinoline-1(2H) -one (approximately 1:2 ratio, 270 mg, 0.5 mmol, estimated) in ethanol (25 mL) And dark H 2 SO 4 (5 mL) solution of NaNO 2 (39 mg, 0.56 mmol) of water The reaction mixture was stirred at 0° C. for 1 h and then zinc dust (105 The reaction mixture was heated at room temperature for 0.5 h and then at 85° C. The mixture was cooled to room temperature, poured into water (50 mL), and diluted with aqueous NaOH and NaHCO 3 The pH was adjusted to 7-8 with aqueous solution. The mixture was diluted with dichloromethane (50 mL The combined organic extracts were then extracted with 50 mL of ethyl acetate (EtOAc) (50 mL). Line washing, anhydrous Na 2 SO 4 The residue was dried over flash chromatograms, filtered, and concentrated. Chromatography (SiO 2 , 20-70% ethyl acetate in heptane) The two desired products were obtained as a mixture: a white solid (approximately 1:2, 180 mg, yield 68%). 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5 -Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-6-fluoro (fluorophenyl)-4-cyclopropylisoquinolin-1(2H)-one: LCMS (E S-API):C 30 H 26 ClFN 4 O 3 Calculated mass, 544.2; measured m / z, 545.3[M+H] + ;6-(3-((benzyloxy)methyl)-4-ethyl-5- Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(2- Chloro-6-fluorophenyl)isoquinolin-1(2H)-one: LCMS (ES-A PI):C 27 H 22 ClFN 4 O 3 Calculated mass, 504.1; measured m / z, 505 .2[M+H] + .

[0398] Step E. 2-(2-chloro-6-fluorophenyl)-4-cyclopropyl-6- (4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1, 2,4-Triazol-1-yl)isoquinolin-1(2H)-one. 6-(3-((benzyl) 4-ethyl-5-oxo-4,5-dihydro-1H-1,2, 4-Triazol-1-yl)-2-(2-chloro-6-fluorophenyl)-4-cyclohexyl 6-(3-((benzyloxy)methyl)isoquinolin-1(2H)-one, (ethyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole 1-yl)-2-(2-chloro-6-fluorophenyl)isoquinoline-1(2H)-o Dissolve 180 mg (approximately 1:2, 0.35 mmol) in trifluoroacetic acid (8 mL). The reaction mixture was transferred to a sealed tube and heated at 80° C. for 17 h, then cooled to room temperature. The residue was purified by flash column chromatography (SiO2 , in heptane 50-100% EtOAc) and then purified by preparative HPLC (C18 column, water Further purification by elution with 20-80% gradient MeCN afforded the desired product as a white solid. Obtained (17 mg, yield 34%). LCMS (ES-API): C 23 H 20 ClFN 4 O 3 Calculated mass, 454.1; measured m / z, 455.1 [M+H] + . 1 H NMR( 400MHz, CDCl 3 ) δ 8.83(d,J=1.96Hz,1H),8.52( d,J=8.80Hz,1H),8.16(dd,J=1.96,8.80Hz,1H) ,7.33-7.44(m,2H),7.16-7.23(m,1H),6.79(d, J=0.98Hz,1H),4.72(d,J=6.36Hz,2H),3.93(q, J=7.25Hz,2H),2.17(t,J=6.36Hz,1H),1.94-2. 02(m,1H),1.44(t,J=7.25Hz,3H),0.96-1.05(m ,2H),0.58-0.65(m,2H)ppm.

[0399] Example 10: 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)isoquinolin-1(2H)-one.

[0400] [ka]

[0401] 2-(2-chloro-6-fluorophenyl)-4-cyclopropyl-6-(4-ethyl -3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl Preparation of azol-1-yl)isoquinolin-1(2H)-one (Example 9, Step E) The title compound was obtained as a second crop in a white solid (34 mg, 74% yield). LCMS(ES-API):C 20 H 16 ClFN 4 O 3 calculated mass, 414.1; Measured m / z: 415.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ 8.49(d,J=8.80Hz,1H),8.30(d,J=1.96Hz,1H) ,8.15(dd,J=1.96,8.80Hz,1H),7.31-7.47(m,2 H),7.15-7.27(m,1H),6.96(d,J=7.59Hz,1H),6 .65(d,J=7.59Hz,1H),4.70(s,2H),3.92(d,J=7 .22Hz,2H),1.43(t,J=7.22Hz,3H)ppm.

[0402] Example 11: 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one.

[0403] [ka]

[0404] Step A. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-6 -fluorophenyl)-7-fluoro-4-isopropylisoquinoline-1(2H)-o 2-Chloro-6-fluoroaniline (399 mg, 2.7 mmol) in DCM (6 mL) l) was added to a stirred solution of AlMe under nitrogen. 3 (2M toluene solution, 1.03mL, 2.06m The mixture was stirred at room temperature for 0.5 hours, and then 5-((benzyloxy) methyl)-4-ethyl-2-(7-fluoro-4-isopropyl-1-oxo-1H-iso Sochromen-6-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ol A solution of 1,2-dichlorophenyl ether (Intermediate 4, 300 mg, 0.69 mmol) in DCM (6 mL) was added. The mixture was stirred at room temperature overnight. Aqueous HCl (1N, 1.8 mL) was added and the mixture was cooled to room temperature for 2 min. After stirring for 1 h, it was poured into water and extracted with DCM. The organic extract was separated, washed with brine, Anhydrous Na 2 SO 4 The residue was dissolved in AcOH (15 mL) and heated at 90° C. The mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were Wash with brine and add anhydrous Na 2 SO 4 The residue was purified by flash chromatography. Graphy (SiO 2 , gradient elution: 0-70% EtOAc in petroleum ether) The title compound was obtained as a yellow oil (320 mg, yield: 82%). MS(ESI): 30 H 27 ClF 2 N 4 O 3 Calculated mass, 564.2; measured m / z, 565.1 [M +H]+ . 1 H NMR (400 MHz, CDCl 3 ) δ 8.33(d,J=11.0 Hz,1 H),8.09(d,J=7.0Hz,1 H),7.36-7.45(m, 7 H),7.19-7.26(m,1 H),6.74(s,1 H),4.64(s ,2 H),4.56(s,2 H),3.90(q,J=7.3Hz,2 H),3. 28(dt,J=13.6,6.6Hz,1 H),1.40(t,J=7.2Hz,3 H), 1.34(dd, J=6.8, 4.0Hz, 6H); 19 F NMR(376 MHz, CDCl 3 )δ-116.47--116.23(m,1 F),-120.5 2(s,1F)ppm.

[0405] Step B. 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one. (3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazol-1-yl)-2-(2-chloro-6-fluorophenyl )-7-Fluoro-4-isopropylisoquinolin-1(2H)-one (1.52g, 2 To a stirred solution of 1.7 mmol) of BCl in DCM (62 mL) at -78 °C 3 (1M toluene The reaction mixture was stirred at -78°C for 1 h. Aqueous MeOH (17 mL) was added and the mixture was then stirred at -78°C for 0.5 h. The mixture was diluted with DCM and saturated NaHCO 3The organic extract was separated and washed with water. , washed with brine, and then washed with anhydrous Na 2 SO 4 The residue was dried over 1000 ml of ethyl acetate, filtered and concentrated. HPLC (stationary phase: Boston Prime C18, 5 μm, 150 × 30 mm; transfer Motion phase: Water (0.04% NH 3 .H 2 O + 10 mM NH 4 HCO 3 )(A)-MeCN (B), gradient elution: 45–75% B in A over 8 min, flow rate: 25 mL / min). The title compound was obtained as a white powder (875 mg, 69% yield). MS(ES I C 23 H 21 ClF 2 N 4 O 3 Calculated mass, 474.1; measured m / z, 475 .2[M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.32(d,J= 11.0Hz,1H),8.09(d,J=6.8Hz,1H),7.37-7.4 8(m,2 H),7.20-7.25(m,1 H),6.74(s,1 H),4. 69(d,J=6.2Hz,2H),3.94(q,J=7.1Hz,2H),3. 27(dt,J=13.4,6.6Hz,1 H),2.57(t,J=6.4Hz,1 H),1.44(t,J=7.3Hz,3 H),1.33(dd,J=6.8,4. 0Hz,6H); 19 F NMR (376 MHz, CDCl 3 )δ ppm-116. 37(dd,J=9.5,5.1Hz,1 F),-120.58(dd,J=11.7 ,7.3Hz,1F)ppm.

[0406] Example 12: 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-ene-2- 2-(2-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one .

[0407] [ka]

[0408] Step A. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-yl) 2-(2-(trifluoromethyl)phenyl)isoquinoline-1(2H )-one. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5 -dihydro)-1H-1,2,4-triazol-1-yl)-4-(prop-1-ene 300 mg, 0.57 mmol) and C s 2 CO 3 To a solution of (369 mg, 1.13 mmol) in anhydrous DMF (1.5 mL), 2 -fluorobenzotrifluoride (111 mg, 0.68 mmol) was added to the mixture. The mixture was stirred under nitrogen at 130° C. for 4 days and then cooled to room temperature. Water was added and the mixture was diluted with DCM. The combined organic layer was extracted with anhydrous Na 2 SO 4 The residue was dried over 1000 ml of ethyl acetate, filtered and concentrated. Purification was performed by silica column chromatography (eluent: 0-1% MeOH in DCM). The title compound was obtained as a yellow solid (177 mg, yield: 49%). ESI-MS: 3 1 H 27 F 3 N 4 O 3 Calculated mass, 560.2; measured m / z, 561.2 [M+H] + .

[0409] Step B. 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-ene-2- 2-(2-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro 1H-1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl )-2-(2-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one(1 A mixture of 77 mg, 0.26 mmol) in TFA (3 mL) was added to a sealed tube under nitrogen. Heated at 0° C. overnight and then cooled to room temperature. 3 Reaction of the solution with aqueous solution The aqueous layer was extracted with DCM. The combined organic layers were washed with Na 2 SO 4 Dry and filter. The residue was purified by silica column chromatography (gradient elution: 0-40% in DCM). EtOAc) and then preparative reverse-phase HPLC (stationary phase: Boston Prim e C18, 5 μm, 150 × 25 mm; Mobile phase: water (0.04% NH 3 .H 2 O+1 0 mM NH 4 HCO 3 ) (A)-MeCN (B), gradient elution: in A over 8 min. The title compound was obtained as a white powder by further purification using 45-75% B, flow rate: 25 mL / min. (50 mg, 35% yield). ESI-MS: 24 H 21 F 3 N 4 O 3 Mass calculation value, 470.2; m / z actual value, 471.2 [M+H] + . 1 H NMR (400MHz ,DMSO-d 6 )δ 8.42(d,J=2.1Hz,1 H),8.35(d,J= 8.8Hz,1H),8.13(dd,J=8.8,2.1Hz,1H),7.94 (d,J=8.2Hz,1 H),7.84-7.90(m,1 H),7.72-7. 78(m,1 H),7.67(d,J=8.2Hz,1 H),7.27(s,1 H ),5.83(t,J=5.8Hz,1H),5.36(s,1H),5.07(s ,1 H),4.52(d,J=5.8Hz,2 H),3.80(q,J=7.0Hz ,2 H),2.10(s,3 H),1.28(t,J=7.0Hz,3 H)ppm ; 19 F NMR (376MHz, DMSO-d 6 )δ-59.37(s,1 F)pp m.

[0410] Example 13: 2-(6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4, 5-Dihydro-1H-1,2,4-triazol-1-yl)-1-oxo-4-(pro Per-1-en-2-yl)isoquinolin-2(1H)-yl)benzonitrile.

[0411] [ka]

[0412] Step A. 2-(6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo So-4,5-dihydro-1H-1,2,4-triazol-1-yl)-1-oxo-4 -(Prop-1-en-2-yl)isoquinolin-2(1H)-yl)benzonitrile. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro )-1H-1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl ) isoquinolin-1(2H)-one (300 mg, 0.57 mmol) and Cs 2 CO 3 To a mixture of (369 mg, 1.13 mmol) of 2-fluorobenzyl ether (1.5 mL) in DMF (1.5 mL), The reaction mixture was then cooled to 85° C. The mixture was heated at 5° C. for 20 h. The mixture was cooled to room temperature, poured into water and extracted with EtOAc. The organic layer was washed with Na 2 SO 4 The residue was purified by silica column chromatography. The crude product was purified by chromatography (gradient elution: 0-10% EtOAc in DCM). The title compound was obtained, which was used without further purification. A red gum (580 mg, crude ). ESI-MS:C 31 H 27 N 5 O 3 Calculated mass, 517.2; measured m / z, 5 18.2[M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.56(d, J=8.8Hz,1H),8.49(d,J=2.0Hz,1H),8.16(dd ,J=8.8,2.0Hz,1 H),7.82-7.86(m,1 H),7.77( td,J=7.9,1.3Hz,1H),7.54-7.60(m,2H),7.3 4-7.42(m,5 H),7.01(s,1 H),5.38(s,1 H),5. 22(s,1 H),4.62(s,2 H),4.55(s,2 H),3.87(q ,J=7.3Hz,2H),2.21(s,3H),1.36(t,J=7.3Hz ,3H) ppm.

[0413] Step B. 2-(6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4, 5-Dihydro-1H-1,2,4-triazol-1-yl)-1-oxo-4-(pro Per-1-en-2-yl)isoquinolin-2(1H)-yl)benzonitrile. -78℃ 2-(6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5 -Dihydro-1H-1,2,4-triazol-1-yl)-1-oxo-4-(propane -1-en-2-yl)isoquinolin-2(1H)-yl)benzonitrile (500mg Crude, 0.89 mmol) in DCM (27 mL) was added under nitrogen to 3 (4.5mL A solution of 4.5 mmol) in toluene (1M) was added. The reaction mixture was incubated at -78°C for 1 h. MeOH (3 mL) was added at -78°C, and the mixture was then stirred for 0.5 h. The mixture was diluted with DCM and saturated NaHCO 3 The organic layer was separated and washed with Na 2 SO 4 The residue was purified by preparative reverse phase HPLC (stationary phase: Bosto n Prime C18, 5 μm, 150 × 25 mm; Mobile phase: H2O (0.04% N H 3 .H 2 O + 10 mM NH 4 HCO 3 ) (A)-MeCN (B), gradient elution: 8 min The title compound was purified by elution with 40-70% B in A (flow rate: 25 mL / min) over a period of 10 min to give the title compound. Obtained as a white solid (48 mg, 14% yield over two steps). ESI-MS: 24 H 2 1 N 5 O 3 Calculated mass, 427.2; measured m / z, 428.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.41(d,J=2.0Hz,1H) ,8.37(d,J=8.8Hz,1H),8.17(dd,J=8.8,2.0Hz ,1 H),8.06(d,J=8.0Hz,1 H),7.88-7.94(m,1 H),7.75(d,J=8.0Hz,1 H),7.66(t,J=7.7Hz,1 H),7.44(s,1 H),5.79(br t,J=5.0Hz,1 H),5. 42(s,1 H),5.17(s,1 H),4.53(br d,J=5.0Hz, 2 H),3.81(q,J=7.2Hz,2 H),2.14(s,3 H),1.2 9(t,J=7.2Hz,3H)ppm.

[0414] Example 14: 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl) 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)- 4-(Prop-1-en-2-yl)isoquinolin-1(2H)-one.

[0415] [ka]

[0416] Step A. 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl) -4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1- 6 in anhydrous 1,4-dioxane (10 mL). -Bromo-2H-isoquinolin-1-one (1 g, 4.5 mmol) was added to a mixture of 5-( ((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-diphenyl 3H-1,2,4-triazol-3-one (Intermediate 2, 2.1 g, 5.4 mmol) l) 、 Cs 2 CO 3 (2.6g, 8mmol), CuI (0.4g, 2.2mmol), KI (0.5 mg, 3.1 mmol) and trans-1,2-diaminocyclohexane ( 0.3 g, 2.7 mmol) was added. The reaction was heated under nitrogen at 110° C. overnight. The mixture was filtered through a short pad of Celite® and the filtrate was evaporated under reduced pressure. The crude product was purified by silica column chromatography (gradient elution: 0–30 in petroleum ether). % EtOAc) to give the title compound as a yellow solid (1.2 g, yield: 46%). ESI-MS:C 30 H 32 N 4 O 3 Calculated mass of Si, 524.2; m / z Measured value: 525.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ 11.23(br d,J=5.1Hz,1 H),8.23(d,J=8.8Hz,1 H),8.06(d,J=2.0Hz,1 H),7.97(dd,J=8.8,2. 0Hz,1H),7.62-7.70(m,4H),7.41-7.51(m,6 H),7.14-7.22(m,1 H),6.57(d,J=7.1Hz,1 H), 4.75(s,2H),3.82(q,J=7.1Hz,2H),1.29(t,J =7.1Hz,3H),1.03(s,9H)ppm.

[0417] Step B. 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl) -4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1- 6-(3-(((tert-butyl)-4-iodoisoquinolin-1(2H)-one (diphenylsilyl)oxy)methyl)-4-ethyl-5-oxo-4,5-dihydro- 1H-1,2,4-triazol-1-yl)-isoquinolin-1(2H)-one (1. To a mixture of N-iodophenyl ether (2 g, 2 mmol) in anhydrous acetonitrile (MeCN) (30 mL), Nisuccinimide (NIS) (0.5 g, 2.4 mmol) was added to the reaction mixture. The mixture was then cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica column chromatography (gradient elution: 0–30% EtOAc in petroleum ether). ) to give the title compound as a yellow solid (1.1 g, yield: 74%). I-MS:C 30 H 31 IN 4 O 3 Calculated mass of Si, 650.1; measured m / z, 65 1.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 11.49( br s,1 H),8.22-8.31(m,2 H),8.03(dd,J=8.8 ,2.0Hz,1H),7.64-7.72(m,5H),7.44-7.49(m ,6 H),4.77(s,2 H),3.83(q,J=7.2Hz,2 H),1. 30(t,J=7.2Hz,3H),1.04(s,9H)ppm.

[0418] Step C. 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-ene-2- 6-(3-(((tert-butyldiphenyl)isoquinolin-1(2H)-one under nitrogen Phenylsilyl)oxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-4-iodoisoquinolin-1(2H)-one (500 mg, 0.69 mmol) in EtOH (20 mL) and H 2 Mix in O (5 mL) To the mixture, isopropenylboronic acid pinacol ester (288 mg, 1.71 mmol) , PdCl 2 (PPh 3 ) 2 (241 mg, 0.34 mmol) and Cs 2 CO 3 (67 The reaction mixture was heated under nitrogen at 100° C. for 12 hours. The mixture was concentrated to a small volume, and then water was added. The mixture was extracted with EtOAc. The organic layer was separated and washed with brine and 2 SO 4 Dry at 40° C., filter, and evaporate under reduced pressure. The residue was purified by silica column chromatography (gradient elution: 0-10% Me in DCM). OH) to give the title compound as a yellow solid (105 mg, yield: 47%) ESI-MS:C 17 H 18 N 4 O 3 Calculated mass, 326.1; measured m / z, 32 7.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ 11.27( br d,J=5.3Hz,1 H),8.23-8.39(m,2 H),8.06( dd,J=8.8,2.0Hz,1H),7.03(d,J=5.8Hz,1H), 5.79(t,J=5.9Hz,1 H),5.34(s,1 H),5.07(s,1 H),4.51(d,J=5.9Hz,2 H),3.79(q,J=7.3Hz,2 H),2.09(s,3 H),1.27(t,J=7.3Hz,3 H)ppm.

[0419] Step D. 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl) 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)- 4-(Prop-1-en-2-yl)isoquinolin-1(2H)-one. 6-(4-Ethyl 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-tetrahydrofuran 2H-riazol-1-yl)-4-(prop-1-en-2-yl)isoquinoline-1 To a mixture of 2-chloro-1,4-dihydro-1,4-dihydro-2,5-dihydro-1,6 ... Phenylboronic acid (201 mg, 1.3 mmol), Et 3 N (65 mg, 0.64 mm ol) and Cu(OAc) 2 (58 mg, 0.32 mmol) was added to each reaction. O mixture 2 (15 Psi) at room temperature for 72 h. The reaction was diluted with saturated NH 4 Cl The reaction was quenched by adding aqueous solution of 1,2-dichloromethane and the mixture was extracted with EtOAc. The layers were separated and washed with brine and Na 2 SO4 The residue was dried over 1000 ml of ethyl acetate, filtered and concentrated. Reversed phase HPLC (stationary phase: Xtimate C18, 5 μm, 150 x 25 mm; mobile phase : Water (0.225% formic acid) (A)-MeCN (B), gradient elution: in A over 7 min The title compound was obtained as a yellow solid by purification using 57-87% B, flow rate: 30 mL / min. Obtained (4.7 mg, yield: 3%).

[0420] ESI-MS:C 23 H 21 ClN 4 O 3 Calculated mass, 436.1; measured m / z, 437.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.40 (d,J=1.96Hz,1H),8.35(d,J=8.80Hz,1H),8.12 (dd,J=1.96,8.80Hz,1H),7.64-7.70(m,1H),7. 55-7.61(m,1H),7.47-7.53(m,2H),7.22(s,1H) ,5.79(t,J=5.87Hz,1H),5.37(s,1H),5.11(s,1 H),4.50(d,J=5.87Hz,2H),3.78(q,J=7.09Hz,2 H),2.10(s,3H),1.26(br t,J=7.09Hz,3H)ppm.

[0421] Example 15: 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-ene-2- yl)-2-(o-tolyl)isoquinolin-1(2H)-one.

[0422] [ka]

[0423] 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)isox A mixture of norin-1(2H)-one (200 mg, 0.6 mmol) in DMF (6 mL) Into 2-methylphenylboronic acid (304 mg, 2.2 mmol), Et 3 N(227m g, 2.2 mmol) and Cu(OAc) 2 (102 mg, 0.6 mmol), respectively. The reaction mixture was stirred for 2 hours. 2 (15 Psi) at room temperature for 72 hours. saturated NH 4 The reaction was quenched by adding aqueous Cl. The mixture was diluted with EtOAc. The organic layer was separated and washed with brine and 2 SO 4 Dry, filter and concentrate The residue was purified by preparative reversed-phase HPLC (stationary phase: Phenomenex Gemini-NX, 5μm, 150×30mm; Mobile phase: water (0.04% NH 3 .H 2 O + 10 mM NH 4 HCO 3 ) (A)-MeCN (B), gradient elution: 42-72% in A over 8 min. B, flow rate: 25 mL / min) to give the title compound as a yellow solid (28 mg , yield 12%).

[0424] ESI-MS:C 24 H 24 N 4 O 3 Calculated mass, 416.2; measured m / z, 41 7.3[M+H] + . 1H NMR (400MHz, DMSO-d 6 ) δ 8.39(d ,J=1.71Hz,1H),8.35(d,J=8.80Hz,1H),8.10(d d,J=1.71,8.80Hz,1H),7.27-7.42(m,4H),7.16 (s,1H),5.79(t,J=5.87Hz,1H),5.35(s,1H),5. 11(s,1H),4.49(d,J=5.87Hz,2H),3.77(q,J=7. 09Hz,2H),2.09(s,3H),2.05(s,3H),1.25(t,J= 7.09Hz,3H)ppm.

[0425] Example 16: 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-2-(2-fluoro-4-nitro (2H)-4-iodoisoquinolin-1(2H)-one.

[0426] [ka]

[0427] 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4- Iodoisoquinolin-1(2H)-one (120 mg, 0.18 mmol) and Cs 2 C O 3 To a mixture of (63 mg, 0.45 mmol) in anhydrous DMF (1.2 mL), 3,4- Difluoronitrobenzene (29 mg, 0.18 mmol) was added under nitrogen. The mixture was stirred under nitrogen at room temperature for 2 days. The mixture was filtered through a pad of Celite®. The pad was filtered and washed with EtOAc. The filtrates were combined and concentrated. The residue was purified by preparative reverse phase HPLC. C (stationary phase: Boston Green ODS, 5 μm, 150 x 30 mm; mobile phase: H 2 O(0.04% NH 3 .H 2 O + 10 mM NH 4 HCO 3 )(A)-MeCN( B), gradient elution: 45–75% B in A over 8 min, flow rate: 25 mL / min This was purified by hexanes extraction to give the title compound as a yellow solid (25 mg, 29% yield).

[0428] ESI-MS:C 20 H 15 IN 5 O 5 Calculated mass, 551.0; measured m / z, 5 51.8[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ 8.43( d,J=1.96Hz,1H),8.37(dd,J=2.27,9.24Hz,1H) ,8.32(d,J=8.80Hz,1H),8.21-8.25(m,1H),8.1 9(dd,J=2.27,9.24Hz,1H),8.04(s,1H),7.91-7 .98(m,1H),4.51(s,2H),3.79(q,J=7.09Hz,2H) ,1.27(t,J=7.09Hz,3H)ppm; 19 F NMR (376MHz, D MSO-d 6 )δ-115.27(br t,J=8.4Hz,1 F)ppm.

[0429] Example 17: 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl) 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)- 4-Isopropylphthalazin-1(2H)-one.

[0430] [ka]

[0431] Step A. 4-Bromo-2-isobutyrylbenzoic acid and 5-Bromo-2-isobutyryl Benzoic acid. CdCl in THF (30 mL) 2 (3.8g, 20.5mmol) suspension A solution of i-PrMgCl (20.5 mL, 41 mmol) in THF (2 M) was added to the mixture at 0°C. The mixture was heated at 45° C. under nitrogen for 1 h, then cooled to 0° C. and stirred for 4 h under nitrogen. -Add bromophthalic anhydride (3.5 g, 15.4 mmol) in THF (7 mL) The reaction mixture was stirred at 45° C. for 12 h and then concentrated. Then, aqueous HCl (1M ) was added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with anhydrous Na 2 SO 4 Dry at 40° C., filter, and concentrate to give a crude mixture of the regioisomers of the two title compounds as a yellow oil. This was used in the next step without further purification.

[0432] Step B. Ethyl 4-bromo-2-isobutyrylbenzoate and Ethyl 5-bromo 4-Bromo-2-isobutyrylbenzoic acid and 5-isobutyrylbenzoate. A mixture of 2-bromo-isobutyrylbenzoic acid (4.9 g, 9.1 mmol) in DMF (14 mL) solution of K 2 CO 3 (3.8 g, 27 mmol) and iodoethane (2.2 mL , 27 mmol) was added. The reaction was stirred at room temperature overnight. The suspension was poured onto Celite ( The mixture was filtered through a pad of ethyl acetate and the filtrate was concentrated. The residue was purified by silica column chromatography ( Purification by gradient elution: 0-4% EtOAc in petroleum ether afforded the two title compounds A mixture of regioisomers of was obtained as an orange oil (4 g).

[0433] Step C. 6-Bromo-4-isopropylphthalazin-1(2H)-one. Ethyl 4 -Bromo-2-isobutylbenzoate and Ethyl 5-bromo-2-isobutylbenzoate A solution of 4 g of mixture of tetrahydrofuran (6.7 mmol) in EtOH (28 mL) was added with NH 2 NH 2 .H 2 2H2O (6.1 mL, 107 mmol, 98%) was added. The reaction mixture was stirred for 90 The mixture was refluxed at ℃ overnight. The mixture was cooled to room temperature and the precipitate was collected by filtration. The filtrate was concentrated. The residue was triturated with EtOAc. The solid was collected by filtration. Two batches of precipitate were Combine, rinse with water, and dry under vacuum to give the title compound as a yellow solid (819 mg, yield for 3 steps: 20%). ESI-MS: C 11 H 11 BrN 2 Mass calculation of O value, 266.0; m / z actual value, 267.0 [M+H] + . 1 H NMR (400MHz ,DMSO-d 6 )δ 12.63(s,1H),8.25(s,J=1.47Hz,1 H),8.18(d,J=8.56Hz,1H),8.02(dd,J=1.47,8. 56Hz,1H),3.58(q,J=6.51Hz,1H),1.25(d,J=6. 51Hz,6H)ppm.

[0434] The filtrate was concentrated, and the residue was purified by flash column chromatography (20-75% E in heptane). The second compound, 7-bromo-4-isopropylphthalazine- The 1(2H)-one was obtained as a white solid (320 mg, 8% yield over three steps). I-MS:C 11 H 11 BrN 2 Calculated mass of O, 266.0; observed m / z, 267. 0[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ 12.68(s, 1H),8.36(s,1H),8.09-8.17(m,1H),7.95-8.07 (m,1H),3.46-3.63(m,1H),1.26(d,J=6.57Hz,6 H) ppm.

[0435] Step D. 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl) -4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1- yl)-4-isopropylphthalazin-1(2H)-one. 1,4-Dioxane (18. 6-Bromo-4-isopropylphthalazin-1(2H)-one (619 mg) in 5 mL , 2.3 mmol) was added to a mixture of 5-(((tert-butyldiphenylsilyl)oxy )Methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-o (Intermediate 2, 1.06 g, 2.8 mmol) 、 Cs 2 CO 3 (1.4g, 4.2mmol l), CuI (221 mg, 1.2 mmol), KI (269 mg, 1.6 mmol) and and trans-1,2-diaminocyclohexane (159 mg, 1.4 mmol) under nitrogen. The reaction was heated under nitrogen at 110° C. overnight. The mixture was cooled to room temperature and diluted with water. The combined organic extracts were washed with anhydrous Na 2 SO 4 Dry and filter The residue was purified by silica column chromatography (gradient elution: 0 to 3 ml of petroleum ether). 2% EtOAc) to give the title compound as a yellow solid (410 mg, yield rate: 31%). ESI-MS:C 32 H 37 N 5 O 3 Calculated mass of Si: 567.3 m / z measured value: 568.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ 9.89(s,1H),8.65(d,J=1.9Hz,1H),8.50(d,J =8.8Hz,1 H),8.31(dd,J=8.8,1.9Hz,1 H),7.7 1(dd,J=7.8,1.5Hz,4H),7.38-7.52(m,6H),4 .70(s,2 H),3.94(q,J=7.0Hz,2 H),3.53(q,J= 7.0Hz,1H),1.35-1.44(m,9H),1.11(s,9H)p pm.

[0436] Step E. 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl) -4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1- 2-(2-chlorophenyl)-4-isopropylphthalazin-1(2H)-one 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4- Isopropylphthalazin-1(2H)-one (881 mg, 1.6 mmol) in DMF ( In a solution of 2-chlorophenylboronic acid (971 mg, 6.2 mmol), C u(OAc) 2 (282 mg, 1.6 mmol) and Et 3 N (0.4 mL, 3.1 mm The reaction mixture was stirred for 1 hour at 37°C for 2 hours. 2 The reaction was stirred at room temperature for 5 days under (15 Psi). saturated NH 4 The reaction was quenched by adding aqueous Cl. The mixture was diluted with EtO The mixture was extracted twice with Ac and the organic layer was separated. The combined organic extracts were washed with anhydrous Na 2 SO 4 Dry in The residue was purified by silica column chromatography (gradient elution: petroleum ether in 0-32% EtOAc) to give the title compound as a brown oil (36m g, yield: 3%). ESI-MS:C 38 H 40 ClN 5 O 3 Calculated mass of Si: 677 .3; m / z measured, 678.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ 8.64(d,J=1.9Hz,1 H),8.52(d,J=8.8Hz,1 H),8.29(dd,J=8.8,1.9Hz,1 H),7.63-7.71(m ,4 H),7.33-7.56(m,10 H),4.67(s,2 H),3.91 (q,J=7.0Hz,2H),3.54(q,J=6.7Hz,1H),1.33 -1.41(m,9 H),1.08(s,9 H)ppm.

[0437] Step F. 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl) 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)- 4-Isopropylphthalazin-1(2H)-one. 6-(3-(((tert-butyldi Phenylsilyl)oxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(2-chlorophenyl)-4-isopropyl Pyrphthalazin-1(2H)-one (18 mg, 0.03 mmol) in THF (2.5 mM L), triethylamine trihydrofluoride (Et 3 N 3HF) (64.2 mg, 0 0.40 mmol) was added. The reaction mixture was stirred at 60° C. for 4 h. The mixture was allowed to warm to room temperature. It was cooled and concentrated. The residue was diluted with water and the mixture was extracted twice with EtOAc. The organic layers were combined. The residue was purified by preparative reverse phase HPLC (stationary phase: HT C18 Highload, 5μm, 150×25mm; Mobile phase: Water (0.04% NH 3 .H 2 O + 10 mM NH 4 HCO 3 ) (A)-MeCN (B), gradient elution: over 7.5 min The title compound was purified by elution with 38-68% B in A (flow rate: 30 mL / min) to give a white solid. The compound was obtained as a tetrahydrofuran (2.6 mg, yield 22%). ESI-MS: 22 H 22 ClN 5 O 3 of Calculated mass, 439.1; measured m / z, 440.2 [M+H] + . 1 H NMR(40 0MHz,CDCl 3 )δ 8.73(d,J=1.8Hz,1 H),8.58(d, J=8.8Hz,1 H),8.38(dd,J=8.7,1.8Hz,1 H),7. 54-7.60(m,1 H),7.49-7.54(m,1 H),7.37-7.4 7(m,2H),4.72(s,2H),3.94(q,J=7.3Hz,2H) ,3.59(q,J=6.7Hz,1 H),2.37(s,1 H),1.45(t, J=7.3Hz,3H),1.39(d,J=6.7Hz,6H)ppm.

[0438] Example 18: 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl) -4-Isopropylphthalazin-1(2H)-one.

[0439] [ka]

[0440] Step A. 6-Bromo-2-(3-fluorophenyl)-4-isopropylphthalazine 6-Bromo-4-isopropylphthalazin-1(2H)-one ( A solution of 3-fluorophenylboronic acid (300 mg, 1.1 mmol) in DCM (20 mL) was Rhonic acid (471 mg, 3.4 mmol), Cu(OAc) 2 (245mg, 1.3mmol l), pyridine (0.27 mL, 3.3 mmol) and Et 3 N (3 mL, 22 mmol The reaction mixture was stirred in air at room temperature for 18 hours. It was filtered through a pad of silica gel and the silica gel was washed with EtOAc. The combined filtrate was concentrated. The residue was purified by silica column chromatography (gradient elution: 20-50% EtOAc in heptane). ) to give the title compound as a colorless gum (250 mg, yield: 62%). LCMS(ES-API):C 17 H 14 BrFN 2 Calculated mass of O: 360.0 m / s Actual z value: 361.0 [M+H] + .

[0441] Step B. 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl) -4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1- 2-(3-fluorophenyl)-4-isopropylphthalazine-1(2H)-o 6-Bromo-2-(3-fluorophenyl) in anhydrous 1,4-dioxane (8 mL) -4-isopropylphthalazin-1(2H)-one (250 mg, 0.69 mmol) and BiK 3 PO 4 (441 mg, 2.1 mmol) of 5-(((tert-butyl Diphenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2, 4-Triazol-3-one (Intermediate 2, 528 mg, 1.4 mmol), CuI(13 2 mg, 0.69 mmol), and trans-N,N'-dimethylcyclohexane-1, 2-Diamine (98 mg, 0.69 mmol) was added to each. The mixture was slowly Heat and stir under nitrogen at 95° C. for 2 hours, then cool to 25° C. and react by addition of water. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts Wash with brine and add anhydrous Na 2 SO 4 The mixture was dried over sodium hydroxide, filtered and concentrated. The residue was concentrated to silica gel. Purification by column chromatography (20-50% EtOAc in heptane) gave a white solid. The desired product was obtained as a chloroform (200 mg, 43%). LCMS (ES-API): 3 8 H 40 FN 5 O 3 Calculated mass of Si, 661.3; measured m / z, 662.4 [M+H ] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.66(br s,1H),8 .58(d,J=8.59Hz,1H),8.33(br d,J=8.59Hz,1H ),7.70(br d,J=6.57Hz,4H),7.65(br d,J=8.0 8Hz,1H),7.58(br d,J=10.61Hz,1H),7.38-7.5 1(m,7H),7.05(br t,J=8.08Hz,1H),4.70(s,2H ),3.94(q,J=7.07Hz,2H),3.59(q,J=6.76Hz,1H ),1.36-1.46(m,9H),1.11(s,9H)ppm.

[0442] Step C. 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl) -4-isopropylphthalazin-1(2H)-one. Tetrahydrofuran (THF) (1 0 mL) in 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl)- 4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl (3-fluorophenyl)-2-(3-fluorophenyl)-4-isopropylphthalazin-1(2H)-one (200 mg, 0.3 mmol) was added to a solution of tetrabutylammonium fluoride (0. 45 mL, 0.45 mmol) of tetrahydrofuran (THF) solution (1 M) was added. The mixture was stirred at 25° C. for 0.5 h. The mixture was 2Dilute with ethyl acetate (15 mL). The combined organic extracts were washed with brine (20 mL). ), Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated. The residue was purified by flash column chromatography. Fi(SiO 2 , 30-70% EtOAc in heptane) to give a white solid. The title compound was obtained as a compound (120 mg, yield 94%). LCMS (ES-API): 22 H 22 FN 5 O 3 Calculated mass, 423.2; measured m / z, 424.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.65(d,J=1.96H z,1H),8.49(d,J=8.80Hz,1H),8.42(dd,J=1.96 ,8.80Hz,1H),7.52-7.64(m,3H),7.22-7.31(m, 1H),5.87(br s,1H),4.55(br s,2H),3.83(q,J =7.18Hz,2H),3.54(q,J=6.56Hz,1H),1.35(d,J =6.56Hz,6H),1.31(t,J=7.18Hz,3H)ppm.

[0443] Example 19: 2-(2-chloro-6-fluorophenyl)-1-(cyclohexylmethyl) 4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- 1H-1,2,4-triazol-1-yl)-4-isopropylphthalazine-1(2H )-on.

[0444] [ka]

[0445] Step A. Methyl 4-bromo-2-isobutyrylbenzoate. Methyl 4-bromo- A test tube containing 2-iodobenzoate (1420 mg, 4.2 mmol) was Citraldehyde (1201 mg, 17 mmol), Pd(OAc) 2 (94mg, 0.4 mmol), Ag 2 O (1255 mg, 5.4 mmol) and aqueous solution (70% w / w) tert-Butyl hydroperoxide (TBHP) (2681 mg, 21 mmol) was added. The reaction mixture was degassed with nitrogen, sealed, and heated with stirring at 120° C. for 12 h. The reaction was cooled to room temperature and then added NaHCO 3 water (50 mL) and ethyl acetate ( The combined organic extracts were washed with brine (20 mL) and a 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica column chromatography (gradient Elution: 10-30% EtOAc in heptane) to give the title compound as a white solid (167 mg, yield: 14%). LCMS (ES-API): C 12 H 13 B rO 3 Calculated mass, 284.0; measured m / z, 285.0 [M+H] + . 1 H.N.M. R (400MHz, CDCl 3 ) δ 7.83(d,J=8.31Hz,1H),7.6 2(dd,J=1.96,8.31Hz,1H),7.42(d,J=1.96Hz,1 H),3.88(s,3H),3.02(spt,J=6.89Hz,1H),1.21 (d, J = 6.89 Hz, 6H) ppm.

[0446] Step B. 6-Bromo-2-(2-chloro-6-fluorophenyl)-4-isopropyl Pyrphthalazin-1(2H)-one. Methyl 4-bromo in absolute ethanol (20 mL) To a solution of 2-isobutyl benzoate (167 mg, 0.6 mmol), 2-chloro- 6-Fluorophenylhydrazine (658 mg, 4.1 mmol) and concentrated H 2 SO 4 (1 0 mL) was added. The reaction mixture was heated at 70° C. for 2 days. The reaction was cooled to room temperature and Dilute with water (50 mL) and extract with DCM (50 mL) and ethyl acetate (100 mL x 2). The combined organic extracts were washed with brine (75 mL) and sodium 2 SO 4 Dry with The residue was purified by silica gel column chromatography (gradient elution: in heptane 20-50% EtOAc) to give the title compound as a white solid (21 mg, yield: 9%). LCMS (ES-API): C 17 H 13 BrClFN 2 Mass of O Calculated value, 394.0; m / z measured value, 395.0 [M+H] + . 1 H NMR (400M Hz, CDCl 3 )δ 8.40(br d,J=8.34Hz,1H),8.06(s ,1H),7.90(br d,J=8.34Hz,1H),7.32-7.45(m, 2H),7.19(br t,J=8.34Hz,1H),3.47(spt,J=7. 14Hz,1H),1.36(br d,J=7.14Hz,6H)ppm.

[0447] Step C. 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl) -4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1- (yl)-2-(2-chloro-6-fluorophenyl)-4-isopropylphthalazine-1 (2H)-one. 6-Bromo-2-(2-chloro)-1,3-dioxane (3 mL) -6-fluorophenyl)-4-isopropylphthalazin-1(2H)-one (17 mg , 0.04 mmol) and K 3 PO 4 (36 mg, 0.17 mmol) of 5- (((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-di Hydro-3H-1,2,4-triazol-3-one (Intermediate 2, 49 mg, 0.12 m mol), CuI (16 mg, 0.08 mmol), and trans-N,N'-dimethyl Cyclohexane-1,2-diamine (12 mg, 0.08 mmol) was added to each The mixture was slowly heated and stirred under nitrogen at 95° C. for 3 hours, then cooled to 25° C. The reaction was quenched by the addition of water. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 Dry, filter and concentrate The residue was purified by silica gel column chromatography (SiO 2 , in heptane, 20-50% EtOAc) to give the desired product as a white solid (17 mg, 5 7%). LCMS(ES-API):C 38 H 39 ClFN 5 O 3 Calculated mass of Si, 6 95.3; m / z measured, 696.3 [M+H] + . 1H NMR (400MHz, CD Cl 3 )δ 8.68(s,1H),8.56(br d,J=8.59Hz,1H), 8.32(br d,J=8.59Hz,1H),7.70(br d,J=6.06H z,4H),7.33-7.51(m,8H),7.20(br d,J=8.08Hz ,1H),4.70(s,2H),3.94(br d,J=7.07Hz,3H),3 .57(spt,J=7.01Hz,1H),1.34-1.44(m,9H),1.1 0(br s,9H)ppm.

[0448] Step D. 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-4-isopropylphthalazin-1(2H)-one. Tetrahydrofuran ( 6-(3-(((tert-butyldiphenylsilyl)oxy)) in THF (1 mL) Methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazo (2-chloro-6-fluorophenyl)-4-isopropylphthalate A solution of di-n-1(2H)-one (17 mg, 0.02 mmol) was added to tetrabutylammonium chloride. A solution of nium fluoride (0.1 mL, 0.1 mmol) in tetrahydrofuran (THF) (1M) was added. The mixture was stirred at 25° C. for 0.5 h. The mixture was diluted with H 2 O(15mL ) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were (20 mL), and then washed with Na 2 SO 4 The residue was evaporated, dried, filtered and concentrated. Column chromatography (SiO2 , 30-70% EtOAc in heptane) The product was purified and then purified by preparative HPLC (C18 column, 10-90% gradient MeCN in water). This was further purified by LCM to give the title compound as a white solid (8 mg, yield: 71%). S(ES-API):C 22 H 21 ClFN 5 O 3 Calculated mass, 457.1; actual m / z Measured value, 458.1[M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.7 4(br s,1H),8.58(br d,J=8.59Hz,1H),8.39(b rd,J=8.59Hz,1H),7.34-7.45(m,2H),7.20(br d,J=8.08Hz,1H),4.73(br s,2H),3.94(t,J=6 .57Hz,2H),3.52-3.65(m,1H),2.06(br s,1H), 1.44(br t,J=6.57Hz,3H),1.38(br d,J=7.14H z,6H) ppm.

[0449] Example 20: 4-Ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo -4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluoro (2H)-phthalazin-1(3H)-one.

[0450] [ka]

[0451] Step A. 4-Bromo-2-propionylbenzoic acid and 5-Bromo-2-propionyl Benzoic acid. CdCl in THF (10 mL) 2(3.6g, 20mmol) , EtMgBr (13.3 mL, 40 mmol) in diethyl ether (3 M) at 0 °C The mixture was stirred at 45° C. for 1 hour, and then 4-bromophthalic anhydride (3.4 g A solution of 1,5-dichlorophenyl ether (15 mmol) in THF (5 mL) was added under nitrogen. The reaction mixture was stirred at 45° C. for 1 The mixture was stirred for 2 h. The mixture was cooled to room temperature and concentrated. Aqueous HCl (1N) was added and The mixture was extracted with EtOAc. The combined organic layers were separated and washed with anhydrous Na 2 SO 4 Dry with , filtered, and concentrated to give a crude mixture of the regioisomers of the two title compounds as a yellow oil (4 0 g), which was used in the next step without further purification.

[0452] Step B. Ethyl 4-bromo-2-propionylbenzoate and Ethyl 5-bromo -2-propionylbenzoate. 4-Bromo-2-propionylbenzoic acid and 5-bromo A mixture of 4 g of 2-propionylbenzoic acid (7.7 mmol) in anhydrous DMF (15 ml To the mixture in 1.2 mL of iodoethane (1.9 mL, 23 mmol) and K 2 CO 3 (3.2g The reaction mixture was stirred at room temperature overnight. The mixture was filtered through a short pad of silica gel and the silica gel was washed with EtOAc. The filtrates were combined and concentrated. The residue was purified by silica column chromatography (SiO 2 Gradient elution: 0 to 100 ml of petroleum ether 3% EtOAc) to give a regioisomeric mixture of the two title compounds as a yellow oil. This was used in the next step without further purification. It was used in the

[0453] Step C. 6-Bromo-4-ethylphthalazin-1(2H)-one. Ethyl 4-bromo 5-bromo-2-propionylbenzoate and ethyl 5-bromo-2-propionylbenzoate To a mixture of 2.4 g (4.2 mmol) of ethyl acetate in 15 mL of EtOH, 2 NH 2 .H 2 O (924 mg, 18 mmol, 98%) was added. The reaction mixture was stirred at room temperature for 6 h. The solid was collected by filtration. The filtrate was concentrated and the residue was triturated with petroleum ether. Precipitation The collected precipitates were combined, washed with water, and dried under reduced pressure to give the title compound. was obtained as a white solid (320 mg, 24% yield). ESI-MS: 10 H 9 BrN 2 Calculated mass of O, 252.0; measured m / z, 252.8 [M+H] + . 1 H NMR( 400MHz,DMSO-d 6 ) δ 12.55(s,1 H),8.11-8.15( m,2 H),7.98(dd,J=8.3,1.7Hz,1 H),2.92(q,J = 7.5Hz, 2H), 1.20(t, J = 7.4Hz, 3H) ppm. Second generation Product 7: Bromo-4-ethylphthalazin-1(2H)-one was purified by flash column chromatography. It can be obtained by purification of the filtrate by elution with 20-75% EtOAc in heptane. But it cannot be characterized.

[0454] Step D. 6-Bromo-4-ethyl-2-(3-fluorophenyl)phthalazine-1 (2H)-one. 6-Bromo-4-ethylphthalazin-1(2H)-one (50 mg, 0 To a mixture of 1.16 mmol) of 3-fluorophenylboronic acid (45 mg, 0.32 mmol), Et 3 N (32 mg, 0.32 mmol) and Cu(OAc ) 2 (29 mg, 0.16 mmol) was added. The reaction mixture was cooled to 0 2 (15 Psi) The mixture was stirred at room temperature for 12 hours. Water was added and the mixture was extracted with EtOAc. The organic phase was separated. S,Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography. Raffi (SiO 2 , gradient elution: 0-5% EtOAc in petroleum ether) to give The title compound was obtained as a white solid (60 mg, yield: 95%). ESI-MS: 16 H 12 BrFN 2 Calculated mass of O, 346.0; measured m / z, 347.0 [M+H] + .

[0455] Step E. 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl) -4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1- yl)-4-ethyl-2-(3-fluorophenyl)phthalazin-1(2H)-one. 6-Bromo-4-ethyl-2-(3-fluorophenyl)propane in water (4 mL) To a mixture of 5-(2H)-phenylphthalazin-1(2H)-one (120 mg, 0.3 mmol), (((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-di Hydro-3H-1,2,4-triazol-3-one (Intermediate 2, 141 mg, 0.36 mmol) 、 Cs 2 CO 3 (177mg, 0.54mmol), CuI (29mg, 0. 15 mmol), KI (35 mg, 0.21 mmol) and trans-1,2-diamino Cyclohexane (21 mg, 0.18 mmol) was added under nitrogen. The reaction mixture was then cooled to 37° C. The mixture was cooled to room temperature and washed with Celite®. The mixture was filtered through a gel pad. The filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography. Raffi (SiO 2 , gradient elution: 0-14% EtOAc in petroleum ether) The title compound was obtained as a colorless gum (130 mg, yield: 66%). ESI-MS: 37 H 38 FN 5 O 3 Calculated mass of Si, 647.3; measured m / z, 648.3 [M+ H] + .

[0456] Step F. 4-Ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo -4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluoro 6-(3-(((t ert-Butyldiphenylsilyl)oxy)methyl)-4-ethyl-5-oxo-4,5 -Dihydro-1H-1,2,4-triazol-1-yl)-4-ethyl-2-(3-fluoro Solution of (fluorophenyl)phthalazin-1(2H)-one (20 mg, 0.03 mmol) To, Et 3 N.3HF (74 mg, 0.46 mmol) was added. The reaction mixture was heated to 60° C. The mixture was stirred at rt for 1.5 h. The mixture was cooled to room temperature and concentrated. The residue was purified by preparative reverse phase HPLC ( Stationary phase: Boston Prime C18, 5 μm, 150 × 30 mm; Mobile phase: water ( 0.05% ammonium hydroxide) (A)-MeCN (B), gradient elution: over 9 min , 45-75% B in A, flow rate: 25 mL / min) to give the title compound as a yellow solid. (9 mg, yield: 71%). ESI-MS: 21 H 20 FN 5 O 3 Mass meter Calculated value, 409.2; measured m / z value, 410.2 [M+H] + . 1 H NMR (400MH z,DMSO-d 6 )δ 8.51(s,1H),8.37-8.46(m,2H),7 .47-7.60(m,3H),7.16-7.28(m,1H),5.82(br s ,1H),4.52(br d,J=3.91Hz,2H),3.80(q,J=6.8 5Hz,2H),2.98(q,J=7.42Hz,2H),1.28(q,J=7.4 2Hz,6H)ppm; 19 F NMR (376MHz, DMSO-d 6 )δ-112. 70(br s,1F)ppm.

[0457] Example 21: 4-Ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo -4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl ) Phthalazin-1(2H)-one.

[0458] [ka]

[0459] Step A. 6-Bromo-4-ethyl-2-(o-tolyl)phthalazine-1(2H)- 6-Bromo-4-ethylphthalazin-1(2H)-one (50 mg, 0.16 mm To a mixture of 2-methylphenylboronic acid (43 mg, 0.3 ml) in DCM (2 mL) was added 2mmol), Et 3 N (32 mg, 0.32 mmol) and Cu(OAc) 2 (29mg The reaction mixture was diluted with O 2 (15 Psi) at room temperature for 12 hours The mixture was stirred for 1 h. 4 Aqueous Cl solution was added and the mixture was extracted with EtOAc. Separate and add Na 2 SO 4 The residue was analyzed by preparative TLC (petroleum 17% EtOAc in ether) to give the title compound as a yellow gum ( 23 mg, yield: 36%). ESI-MS:C 17 H 15 BrN 2 Calculated mass of O: 34 2.0; m / z measured value, 343.0 [M+H] + .

[0460] Step B. 6-(3-(((tert-butyldiphenylsilyl)oxy)methyl) -4-Ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1- 1,4-(2-(o-tolyl)phthalazin-1(2H)-one. 6-Bromo-4-ethyl-2-(o-tolyl)phthalazine in dioxane (1.5 mL) To a mixture of tert-(1(2H)-one (23 mg, 0.06 mmol), 5-(((tert- Butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1 ,2,4-Triazol-3-one (Intermediate 2, 27 mg, 0.07 mmol) 、 Cs 2 CO 3 (33 mg, 0.1 mmol), CuI (5 mg, 0.03 mmol), KI (7 mg, 0.04 mmol) and trans-1,2-diaminocyclohexane (4 mg, 0 0.03 mmol) was added. The reaction was heated under nitrogen at 110° C. overnight. The mixture was allowed to cool to room temperature. The mixture was cooled to rt and filtered through a short pad of silica gel, and the silica gel was washed with EtOAc. The combined filtrate was concentrated. The residue was purified by preparative TLC (25% EtOAc in petroleum ether). The title compound was obtained as a white solid (15 mg, yield: 35%). MS:C 38 H 41 N 5 O 3 Calculated mass of Si, 643.3; measured m / z, 644.3 [M+H] + .

[0461] Step C. 4-Ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo -4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl ) phthalazin-1(2H)-one. 6-(3-(((tert-Br) in THF (2 mL) 4-ethyl-5-oxo-4,5-dihydro-2,4-diphenylsilyloxymethyl -1H-1,2,4-triazol-1-yl)-4-ethyl-2-(o-tolyl)phthalate A solution of radin-1(2H)-one (15 mg, 0.02 mmol) was added to Et 3 N.3HF (49 mg, 0.3 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h. The mixture was cooled to room temperature and concentrated. The residue was purified by preparative reversed-phase HPLC (stationary phase: Xtimate C 18, 5 μm, 150 × 25 mm; mobile phase: water (0.225% formic acid) (A)-MeCN( B), gradient elution: 44–74% B in A over 7 min, flow rate: 30 mL / min. The title compound was obtained as a yellow solid (7.3 mg, yield: 89%). MS:C 22 H 23 N 5 O 3 Calculated mass, 405.2; measured m / z, 406.2 [M +H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.58(s,1H) ,8.45(s,2 H),7.31-7.42(m,4 H),5.86(t,J=5 .9Hz,1H),4.56(d,J=5.9Hz,2H),3.84(q,J=7 .1Hz,2H),3.00(q,J=7.4Hz,2H),2.09(s,3H ),1.30-1.34(m,3 H),1.26-1.30(m,3 H)ppm.

[0462] Example 22: 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl 2-(o-tolyl)isoquinolin-1(2H)-one.

[0463] [ka]

[0464] Step A. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-iso 5-((benzyloxy)propyl)-2-(o-tolyl)isoquinolin-1(2H)-one. 2-(7-fluoro-3-hydroxy-4-isopropyl)-4-ethyl -1-Oxoisochroman-6-yl)-2,4-dihydro-3H-1,2,4-trimethyl- zoll-3-one (intermediate 11, 56 g, 123 mmol) in AcOH (160 mL) To the mixture was added o-toluidine (14.8 g, 138 mmol). The mixture was heated at 0° C. for 16 h. The mixture was concentrated and diluted with NaHCO 3 Adjust the pH to 7-8 with an aqueous solution. The mixture was extracted with ethyl acetate (160 mL x 2). The combined organic extracts were concentrated. The residue was purified by flash chromatography (SiO 2 , 0-20% ethyl acetate in DCM) The title compound was obtained as an oil (32.5 g, yield: 50%). MS (ES I C 31 H 31 FN 4 O 3 Calculated mass, 526.2; measured m / z, 527.4 M+H] + . 1 H NMR (300 MHz, CDCl 3 )δ 8.33(d,J=10. 9Hz,1H),8.07(d,J=6.8Hz,1H),7.44-7.27(m,9 H),6.84(s,1H),4.64(s,2H),4.55(s,2H),3.89 (q,J=7.2Hz,2H),3.23(spt,J=6.8Hz,1H),2.16 (s,3H),1.39(t,J=7.2Hz,3H),1.31(dd,J=6.8, 2.1Hz,6H)ppm.

[0465] Step B. 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl 2-(o-tolyl)isoquinolin-1(2H)-one. At -78°C, 6-(3-(( Benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2 ,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o-tolyl ) Isoquinolin-1(2H)-one (26.5 g, 50.3 mmol) in DCM (230 To a stirred solution of BCl 3 (290 mL, 290 mL) of DCM solution (1 M) was added. The reaction mixture was stirred at 15°C for 0.5 h. MeOH (1 The reaction was quenched with 0.05 mL of ethyl acetate. The mixture was partitioned between water and DCM. The organic layer was separated. The aqueous layer was separated and extracted with DCM (2×110 mL). The combined organic extracts were washed with brine. Wash (30mL x 2) with anhydrous Na 2 SO 4 Dry at 40° C., filter, and concentrate to give the crude product. The product was diluted with methyl ethyl ketone (82 mL) and heptane (290 mL). Trituration with water (100 mL) gave the pure product (17.5 g), which was recrystallized from ethanol and water. The title compound was obtained as a white solid (16 g, yield: 73%). MS (ESI): C 24 H 25 FN 4 O 3 Calculated mass, 436.2; measured m / z, 437.2 [M+H ] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.33(d,J=11.2,1 H),8.08(d,J=6.8,1 H),7.39-7.33(m,3 H),7 .28(s,1 H),6.85(s,1 H),4.69(br s,2 H),3. 94(q,J=7.11Hz,2H),3.27(td,J=13.66,6.82H z,1 H),2.32(br s,1 H),2.17(s,3 H),1.45(t ,J=7.11Hz,3H),1.32(dd,J=6.82,1.83Hz,6H ) ppm.

[0466] Example 23: 2-(2-chloro-4-methylpyridin-3-yl)-6-(4-ethyl -3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl Azol-1-yl)-7-fluoro-4-isopropylisoquinoline-1(2H)-o hmm.

[0467] [ka]

[0468] Step A. 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-N-(2-chloro-4 -methylpyridin-3-yl)-5-fluoro-2-(1-hydroxy-3-methylbut 3-amino-2-chloro-4-methylpiperidinyl) A solution of lysine (310 mg, 2.2 mmol) in DCM (4.0 mL) was added Aluminium (0.82 mL, 2 M in toluene, 1.6 mmol) was added. The mixture was stirred for 5 After stirring for 1 min, 5-((benzyloxy)methyl)-4-ethyl-2-(7-fluoro -4-isopropyl-1-oxo-1H-isochromen-6-yl)-2,4-dihydro -3H-1,2,4-triazol-3-one (Intermediate 4, 238 mg, 0.5 mmol) A solution of 1.0 mL of DCM was added. The reaction mixture was allowed to warm slowly to room temperature, and then The mixture was heated to 60° C. and stirred overnight. The reaction was quenched by dropwise addition of MeOH followed by dropwise addition of water. The reaction was carefully quenched. The organics were extracted with EtOAc (3 times). The combined organic layers were The crude product was washed with brine, dried over sodium sulfate, filtered and concentrated. Used without modification. LCMS (ES-API): 30 H 31 ClFN 5 O 4 Quality Calculated mass, 579.2; measured m / z, 580.2 [M+H] + .

[0469] Step B. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-4 -methylpyridin-3-yl)-7-fluoro-4-isopropylisoquinoline-1(2 H)-one. 4-(3-((benzyloxy)methyl)-4-ethyl-5- Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2 -Chloro-4-methylpyridin-3-yl)-5-fluoro-2-(1-hydroxy-3 -Methylbut-1-en-2-yl)benzamide (316 mg, 0.54 mmol) The mixture was stirred at 90° C. for 48 hours, then cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography. Chromatography (SiO 2 , 20~70% EtOAc / heptane) The title compound was obtained (155 mg, 51% yield for two steps). I C 30 H 29 ClFN 5 O 3 Calculated mass, 561.2; measured m / z, 562. 2[M+H] + .1 H NMR (400 MHz, CDCl 3 ) δ: 8.28-8.39 (m,2H),8.11(d,J=6.8Hz,1H),7.32-7.44(m,5H ),7.29(d,J=5.4Hz,1H),6.67(s,1H),4.64(s,2 H),4.56(s,2H),3.83-3.96(m,2H),3.21-3.38( m,1H),2.24(s,3H),1.39(t,J=7.3Hz,3H),1.33 (t, J = 7.1 Hz, 6H) ppm.

[0470] Step C. 2-(2-chloro-4-methylpyridin-3-yl)-6-(4-ethyl -3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl Azol-1-yl)-7-fluoro-4-isopropylisoquinoline-1(2H)-o 6-(3-((benzyloxy)methyl)-4-ethyl-5-methyl-1,2-dichloro-1,2-diphenyl-2,4-diaminetetraacetate) in DCM at -78 °C. -Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(2 -Chloro-4-methylpyridin-3-yl)-7-fluoro-4-isopropylisoquinoline A solution of phosphorus-1(2H)-one (100 mg, 0.18 mmol) was added to boron trichloride (0 0.53 mL, 1M DCM, 0.53 mmol) was added. The mixture was stirred for 1.5 h. Then, an additional 0.25 mL of boron trichloride was added. After stirring for an additional hour, MeOH was added. The reaction was carefully quenched by dropwise addition of 1,2-dichloromethane followed by water. The organics were washed with DCM and Extract, wash with brine, dry over sodium sulfate, filter and concentrate. Mathography (SiO 2 , 60~100% EtOAc / heptane) to give The title compound was obtained (72 mg, 86% yield) along with trace impurities. This impure product was purified by RP HPLC (Isco AcuuPrep, 30×100mm C18, 10~70% ACN / 10mM NH 4 The pure title compound was obtained as a white solid. (36.5 mg, 43% yield). LCMS (ES-API): C 23 H 23 C IFN 5 O 3 Calculated mass, 471.2; measured m / z, 472.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ: 8.24-8.44(m,2H),8.1 1(d,J=6.8Hz,1H),7.29(d,J=4.9Hz,1H),6.67( s,1H),4.72(d,J=6.4Hz,2H),3.95(q,J=7.3Hz, 2H),3.19-3.36(m,1H),2.24(s,3H),2.10(t,J= 6.4Hz,1H),1.45(t,J=7.3Hz,3H),1.33(app.t , J = 6.8 Hz, 6H) ppm.

[0471] Example 24: 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one.

[0472] [ka]

[0473] Step A. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-6 -fluorophenyl)-4-(1-methylcyclopropyl)isoquinoline-1(2H)- On. Diiodomethane (373 mg, 14 mmol) in anhydrous toluene (20 mL) at 0 °C. l) was added to a mixture of diethylzinc (918 mg, 1.1 mmol) in toluene (15% The mixture was heated at 0° C. under nitrogen for 15 minutes, after which 6-(3-((benzyloxy) methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl 2-(2-chloro-6-fluorophenyl)-4-(1-methylphenyl)- (chloropropyl)isoquinolin-1(2H)-one (38 mg, 0.6 mmol) The reaction mixture was stirred at 0°C for 0.5 h and then cooled to room temperature. The reaction mixture was warmed and stirred for 24 h. 3 Poured into saturated solution (50 mL) The aqueous phase was extracted successively with DCM (50 mL) and ethyl acetate (EtOAc) (50 mL). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 Dry, filter and concentrate The residue was purified by flash column chromatography (SiO 2 , 50-100% in heptane ethyl acetate) to give the title product and unreacted 6-(3-((benzyloxy) Methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazo 2-(2-chloro-6-fluorophenyl)-4-(1-methylcyclophenyl)-1-yl This gave a mixture of 2H-propyl isoquinolin-1(2H)-ones, which could not be further purified. Used directly in the next step without further purification: White solid (approximately 1:4 ratio, 15 mg, 38% yield). .

[0474] Step B. 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one. 6 -(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro- 1H-1,2,4-triazol-1-yl)-2-(2-chloro-6-fluorophenyl 1-methylcyclopropyl)-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one, and 6-( 3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(2-chloro-6-fluorophenyl) -4-(1-methylcyclopropyl)isoquinolin-1(2H)-one mixture (approximately 1: 4, 15 mg, 0.03 mmol) was dissolved in trifluoroacetic acid (3 mL) and the reaction mixture The mixture was transferred to a sealed tube and heated at 80° C. for 17 h and then cooled to room temperature. The residue was purified by flash column chromatography (SiO 2 , 50-100 in heptane % EtOAc) and then purified by preparative HPLC (C18 column, 20-80% in water). % gradient MeCN) to give the desired product as a white solid (1 mg , yield 11%). LCMS (ES-API): C 24 H 22 ClFN 4 O 3 Calculated mass value , 468.1; m / z measured, 469.2 [M+H] + . 1 H NMR (400MHz, CDCl 3)δ 8.91(d,J=2.08Hz,1H),8.52(d,J=8.8 0Hz,1H),8.09(dd,J=2.08,8.80Hz,1H),7.33-7 .48(m,2H),7.17-7.24(m,1H),6.95(s,1H),4.7 1(d,J=6.61Hz,2H),3.84-4.02(m,2H),2.41(t, J=6.61Hz,1H),1.49(s,3H),1.44(t,J=7.34Hz, 3H), 0.78-0.88(m,4H)ppm.

[0475] Example 25: 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl) -4-(2-hydroxypropan-2-yl)isoquinolin-1(2H)-one.

[0476] [ka]

[0477] Step A. 4-Acetyl-6-(3-((benzyloxy)methyl)-4-ethyl- 5-Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-isox Norin-1(2H)-one. 6-(3-((benzyloxy)methyl) -4-Ethyl-5-oxo-4,5-dihydro)-1H-1,2,4-triazole-1 -yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one(10 0 mg, 0.19 mmol) in THF / H 2 A solution of N2O (v / v, 4:1, 5 mL) aIO 4 (121 mg, 0.57 mmol) and K 2 OsO 4 .2H2 O(3.5 mg, 0.01 mmol) was added. The resulting light brown suspension was stirred at room temperature for 3 days. The mixture was diluted with water, stirred at room temperature for 30 minutes, and then filtered. The solid was collected and dried under reduced pressure. The crude product was purified by preparative reversed-phase HPLC (stationary phase: Phenomenex Gemini-N X, 5 μm, 150 × 30 mm; Mobile phase: water (0.05% HCl) (A)-MeCN ( B), gradient elution: 40–70% B in A over 8 min, flow rate: 25 mL / min This was further purified to give the title compound as an off-white solid (20 mg, yield: 23%). ). ESI-MS:C 23 H 22 N 4 O 4 Calculated mass, 418.2; measured m / z, 4 19.1[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ) δ 11.96 (br d,J=5.6Hz,1H),9.48(d,J=2.0Hz,1H),8 .31(d,J=8.8Hz,1H),8.17-8.23(m,2H),7.36 -7.41(m,4 H),7.29-7.36(m,1 H),4.62(d,J=3 .9Hz,4H),3.77(q,J=7.1Hz,2H),2.54(s,3H) , 1.24(t,J=7.1Hz,3H)ppm.

[0478] Step B. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-4-(2-hydroxy propan-2-yl)isoquinolin-1(2H)-one. At 0°C, 4-acetyl-6-( 3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-isoquinolin-1(2H)-one (20mg To a stirred solution of 1,2-dimethyl-3,4-tetramethyl-1,2,4-tetramethyl-2,4-tetramethyl-1, ... A solution of romide (21 μL, 0.06 mmol) in diethyl ether (3 M) was added dropwise. The resulting yellow suspension was stirred at 0°C for 3 h, then allowed to warm slowly to room temperature and stirred for 24 h. The mixture was slowly added with saturated NH 4 Poured into aqueous Cl and extracted with EtOAc. Separate the layers and add Na 2 SO 4 The residue was purified by flash chromatography. Raffi (SiO 2 , gradient elution: 1-4% MeOH in DCM) to give the title compound as a white solid. Obtained as a solid (10 mg, yield: 50%). ESI-MS: 24 H 26 N 4 O 4 Quality Calculated mass, 434.2; measured m / z, 435.2 [M+H] + . 1 H NMR(400 MHz,DMSO-d 6 )δ 11.13(br d,J=5.8Hz,1 H),9. 03(s,1H),8.32(d,J=8.8Hz,1H),8.01(d,J=9 .0Hz,1H),7.26-7.45(m,5H),7.10(d,J=5.8H z,1 H),5.12(s,1 H),4.61(s,4 H),3.77(q,J= 7.0Hz,2H),1.60(s,6H),1.23-1.27(m,3H)p pm.

[0479] Step C. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl (phenyl)-4-(2-hydroxypropan-2-yl)isoquinolin-1(2H)-one 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro 1H-1,2,4-triazol-1-yl)-4-(2-hydroxypropane-2 -yl)isoquinolin-1(2H)-one (100 mg, 0.23 mmol), Et 3 N (64 μL, 0.46 mmol), 3-fluorophenylboronic acid (64.4 mg, 0. To a mixture of 46 mmol) of 4 Å MS powder (0.1 g) and Cu( OAc) 2 (41.8 mg, 0.23 mmol) was added. The reaction mixture was stirred at 37° C. for 1 hour .... 2 Bottom, room temperature The mixture was stirred at rt for 2 days. The mixture was diluted with EtOAc and then washed with Celite® The mixture was filtered through a short pad. The pad was washed with EtOAc and the combined filtrate was diluted with H 2 O The organic layer was separated and washed with Na 2 SO 4 The residue was dried over sodium hydroxide, filtered and concentrated. Chromatography (SiO 2 , gradient elution: 1-5% MeOH in DCM) The title compound was obtained as a yellow solid (40 mg, yield: 25%). ESI-MS: 30 H 29 FN 4 O 4 Calculated mass, 528.2; measured m / z, 529.3 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.15(d,J=1.8Hz,1 H),8.61(d,J=8.9Hz,1 H),8.11(dd,J=8.9,1. 8Hz,1H),7.83-8.05(m,1H),7.44-7.55(m,2 H),7.36-7.40(m,5 H),7.22-7.26(m,1 H),7.1 3-7.19(m,1 H),4.63(s,2 H),4.57(s,2 H),3. 89(q,J=7.1Hz,2H),1.85(s,6H),1.38(t,J=7 .1Hz,3H)ppm; 19 F NMR (376 MHz, CDCl 3 )δ-111. 17(s,1F)ppm.

[0480] Step D. 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl) -4-(2-hydroxypropan-2-yl)isoquinolin-1(2H)-one. , -78°C, 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl (phenyl)-4-(2-hydroxypropan-2-yl)isoquinolin-1(2H)-one (40 mg, 0.057 mmol) in DCM (2 mL) 3 (in toluene 1 M solution, 283 μL, 0.28 mmol) was added. The reaction mixture was stirred at -78° C. for 1 h. The mixture was quenched with MeOH (1 mL) at -78 °C and stirred for 0.5 h. The mixture was diluted with DCM and saturated NaHCO 3 The organic layer was separated and washed with water. , Na 2 SO 4The residue was purified by preparative reverse phase HPLC (stationary phase: Wa ters Xbridge Prep OBD C18, 10μm, 150×40mm; Mobile phase: H 2 O(10 mM NH 4 HCO 3 ) (A)-MeCN (B), gradient elution: 25 The title compound was purified by elution with 0-70% B in A over 2 min (flow rate: 25 mL / min). was obtained as a white solid (20 mg, yield: 40%). ESI-MS: 23 H 23 FN 4 O 4 Calculated mass, 438.2; measured m / z, 439.2 [M+H] + ; 1 H NMR (400MHz,DMSO-d 6 ) δ 9.08(d,J=2.0Hz,1H),8. 41(d,J=8.8Hz,1 H),8.11(dd,J=9.0,2.0Hz,1 H),7.55-7.64(m,1 H),7.47(dt,J=9.9,2.2Hz, 1 H),7.29-7.39(m,3 H),5.83(t,J=5.9Hz,1 H ),5.25(s,1 H),4.52(d,J=5.9Hz,2 H),3.82(q ,J=7.1Hz,2H),1.64(s,6H),1.29(t,J=7.1Hz ,3H) ppm.

[0481] Example 26: 4-(Dimethylamino)-6-(4-ethyl-3-(hydroxymethyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2- (o-Tolyl)isoquinolin-1(2H)-one.

[0482] [ka]

[0483] Step A. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-4-bromoisoquinol 6-(3-((benzyloxy)methyl)-4-ethyl-5-one Xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-isoquinoline To a mixture of 1(2H)-1-one (2 g, 3.9 mmol) in MeCN (20 mL), NB S (842 mg, 4.7 mmol) was added. The reaction mixture was refluxed for 16 h. The mixture was cooled to room temperature and filtered. The collected precipitate was washed with DCM to give the title compound. The compound was obtained as a yellow solid (980 mg, yield: 55%). ESI-MS: 21 H 19 BrN 4 O 3 Calculated mass, 454.1; measured m / z, 455.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ) δ 11.59(br d,J=5.8 Hz,1 H),8.42(d,J=2.1Hz,1 H),8.32(d,J=8.9 Hz,1 H),8.17(dd,J=8.9,2.1Hz,1 H),7.61(d, J=5.8Hz,1H),7.37-7.62(m,5H),4.64(s,2H) ),4.62(s,2 H),3.78(q,J=7.3Hz,2 H),1.25(t , J = 7.3 Hz, 3 H) ppm.

[0484] Step B. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-4-(dimethylamino ) Isoquinolin-1(2H)-one. 6-(3-((benzyloxy)methyl)-4-en (ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)- A flask containing 4-bromoisoquinolin-1(2H)-one (930 mg, 2 mmol) was Dimethylamine (40% in water, 5 mL) was added to the mixture. The mixture was heated in a toclave at 110° C. for 4 days. The mixture was cooled to room temperature and diluted with DCM and water. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated. The residue was purified by silica column chromatography (SiO 2 , slope Purification by dilution (elution: 0-1% MeOH in DCM) gave the title compound as a yellow solid. (161 mg, yield: 18%). ESI-MS: 23 H 25 N 5 O 3 The calculated mass of 419.2; m / z measured, 420.2 [M+H] + .

[0485] Step C. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-4-(dimethylamino )-2-(o-tolyl)isoquinolin-1(2H)-one. 6-(3-((benzyloxy) methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl (1-isoquinolin-1-yl)-4-(dimethylamino)isoquinolin-1(2H)-one (160 mg, 0.36 mmol), Et 3N (72 mg, 0.71 mmol), 2-methylphenyl To a mixture of 4 Å M boronic acid (97 mg, 0.71 mmol) in DCM (9 mL), S powder (300 mg) and Cu(OAc) 2 (64 mg, 0.36 mmol) was added. The reaction mixture is 2 The mixture was stirred at 30°C for 2 days under H 2 O was added and the mixture was cooled to room temperature. The organic layer was separated and extracted with Na 2 SO 4 The residue was dried over 1000 ml of ethyl acetate, filtered and concentrated. Rush Chromatography (SiO 2 , Gradient elution: 0–100% EtO in petroleum ether Ac) to afford the title compound as a yellow solid (31 mg, yield: 14%). ESI-MS:C 30 H 31 N 5 O 3 Calculated mass, 509.2; measured m / z, 510 .3[M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.68(d,J= 2.2Hz,1H),8.55(d,J=8.8Hz,1H),8.16(dd,J =8.8,2.2Hz,1 H),7.33-7.43(m,9 H),6.68(s, 1 H),4.64(s,2 H),4.57(s,2 H),3.89(q,J=7. 0Hz,2H),2.78(s,6H),2.20(s,3H),1.36-1. 41(m,3H)ppm.

[0486] Step D. 4-(Dimethylamino)-6-(4-ethyl-3-(hydroxymethyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2- (o-Tolyl)isoquinolin-1(2H)-one. 6-(3-(( Benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2 ,4-Triazol-1-yl)-4-(dimethylamino)-2-(o-tolyl)isoxy To a solution of norin-1(2H)-one (31 mg, 0.05 mmol) in DCM (2 mL) , BCl 3 (1M solution in toluene, 254 μL, 0.25 mmol) was added to the reaction mixture. The mixture was stirred at -78 °C for 1 h. The reaction was then quenched with MeOH (1 mL) at -78 °C. The mixture was then cooled to -78 °C and stirred for 0.5 h. Then saturated NaHCO 3 Add aqueous solution The mixture was extracted with DCM. 2 SO 4 It was dried, filtered and concentrated. The residue was purified by preparative reversed-phase HPLC (stationary phase: Waters Xbridge Prep OBD C18, 10μm, 150×40mm; Mobile phase: H 2 O(10 mM NH 4 HCO 3 )( A) -MeCN(B), gradient elution: 0-60% B in A over 30 min, flow rate: 2 5 mL / min) to give the title compound as a white solid (13 mg, yield: 53%) ). ESI-MS:C 23 H 25 N 5 O 3 Calculated mass, 419.2; measured m / z, 4 20.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ 8.54( d,J=2.1Hz,1H),8.35(d,J=9.0Hz,1H),8.15( dd,J=9.0,2.1Hz,1H),7.29-7.44(m,4H),6.9 3(s,1 H),5.83(br t,J=5.8Hz,1 H),4.54(d,J =5.8Hz,2H),3.82(q,J=7.2Hz,2H),3.31(s,6 H),2.69(s,3 H),1.30(t,J=7.2Hz,3 H)ppm.

[0487] Example 27: 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-7-fluoro-4-(prop-1-en-2-yl)phthalazine-1(2 H)-On.

[0488] [ka]

[0489] Step A. 2-((2-chloro-6-fluorophenyl)amino)-5,6-difluoro Oloisoindoline-1,3-dione. 4,5-Difluorophthalic anhydride (1.83g , 9.94 mmol) and (2-chloro-6-fluorophenyl)hydrazine hydrochloride (2 The reaction mixture of 0.40 g, 12.2 mmol) in AcOH (45 mL) was heated at 125 °C for 1 Heated for 0.5 h and then concentrated to about 15 mL. The clear mixture was poured into 50 mL of water. The off-white solid that formed was filtered and then diluted with NaHCO 3 Stir in the aqueous solution and filter again. Filtered, washed with water, and dried under vacuum overnight to give the title compound (2.93 g, 90%). LCMS(ES-API):C 14 H 6 ClF 3 N 2 O 2 Calculated mass, 326.0; Measured m / z: 327.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.73(t,J=7.3Hz,2H),7.20-7.13(m,1H),6.97 -6.90(m,2H),6.48(d,J=2.9Hz,1H)ppm.

[0490] Step B. 2-(2-chloro-6-fluorophenyl)-6,7-difluoro-2, 3-Dihydrophthalazine-1,4-dione. 2-((2-chloro-6-fluorophenyl )amino)-5,6-difluoroisoindoline-1,3-dione (1.51 g, 4.6 2 mmol) in EtOH (28 mL), After stirring at room temperature for 1.5 hours, a few drops of water were added. The pH was adjusted to about 4 by adding 3.8 mL of 2N HCl under reduced pressure. After removing the solvent, DCM and water were added to the residue. The white solid was filtered and the filtrate was separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with Na 2 SO 4 Dry, filter and concentrate The residue was purified by solid-loaded flash column chromatography (SiO 2 , in heptane 0-6 0% EtOAc) to give the title compound as a white crystalline solid (25 0 mg, 17%). LCMS (ES-API): C 14 H 6 ClF 3 N 2 O 2 Mass calculation value, 326.0; m / z actual value, 327.0 [M+H] + . 1 H NMR (400MHz ,CDCl 3)δ 9.26(br s,1H),8.23(dd,J=7.6,9.5 Hz,1H),7.68(dd,J=7.3,9.3Hz,1H),7.47(dt,J =5.9,8.3Hz,1H),7.43-7.35(m,1H),7.23(dt,J =1.5,8.6Hz,1H)ppm.

[0491] Step C. 3-(2-chloro-6-fluorophenyl)-6,7-difluoro-4- Oxo-3,4-dihydrophthalazin-1-yl trifluoromethanesulfonate. 4 2-(2-chloro-6-fluorophenyl)-6,7-difluoro-2,3-dihydro- Dorophthalazine-1,4-dione (377 mg, 1.15 mmol) in DCM (35 mL ) into the mixture, Tf 2 HO (0.30 mL, 1.83 mmol) was added, followed by Et 3 N (0.42 mL, 3.03 mmol) was added. The reaction mixture was stirred at room temperature for 17.5 h. The mixture was stirred for 1 h and then concentrated. The residue was purified by flash column chromatography (Si O 2 , 0 to 50% EtOAc in heptane) to give the title compound as a viscous yellow oil. The compound was obtained (460 mg, 87%). LCMS (ES-API): C 15 H 5 ClF 6 N 2 O 4 Calculated mass, 458.0; measured m / z, 459.0 [M+H] + . 1 HN MR (400MHz, CDCl 3 ) δ 8.32(dd,J=7.3,9.3Hz,1H ),7.72(dd,J=6.8,9.3Hz,1H),7.47(dt,J=5.9, 8.3Hz,1H),7.42-7.36(m,1H),7.22(dt,J=1.0, 8.6Hz,1H)ppm.

[0492] Step D. 2-(2-chloro-6-fluorophenyl)-6,7-difluoro-4- (Prop-1-en-2-yl)phthalazin-1(2H)-one. Dioxane (3 mL) 3-(2-chloro-6-fluorophenyl)-6,7-difluoro-4-oxo- 3,4-Dihydrophthalazin-1-yl trifluoromethanesulfonate (141mg , 0.310 mmol), isopropenylboronic acid pinacol ester (78 mg, 0. 46mmol), bis(triphenylphosphine)palladium(ii) dichloride (25 mg, 0.036 mmol) was added to the mixture of K 2 CO 3 Aqueous solution of (2M, 0.30mL, 0 The reaction mixture was purged with argon for about 5 minutes and then heated to 85° C. The mixture was heated at rt for 3 h. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between EtOAc and water. The organic layer was washed with Na 2 SO 4 The residue was purified by flash column chromatography. Mathography (SiO 2 , 0~50% EtOAc in heptane) to give off- The title compound was obtained as a white solid (101 mg, 94%). ):C 17 H 10 ClF 3 N 2 Calculated mass of O, 350.0; observed m / z, 351.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.32(dd,J=7 .6,10.0Hz,1H),7.78(dd,J=7.3,10.8Hz,1H),7 .47-7.32(m,2H),7.24-7.13(m,1H),5.67-5.58 (m,1H),5.34(t,J=1.0Hz,1H),2.19(s,3H)ppm.

[0493] Step E. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4 ,5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-6 -fluorophenyl)-7-fluoro-4-(prop-1-en-2-yl)phthalazine -1(2H)-one, and 7-(3-((benzyloxy)methyl)-4-ethyl-5- Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(2- Chloro-6-fluorophenyl)-6-fluoro-4-(prop-1-en-2-yl) Phthalazin-1(2H)-one. 2-(2-chloro-6-fluoro) Phenyl)-6,7-difluoro-4-(prop-1-en-2-yl)phthalazine-1 (2H)-one (56 mg, 0.16 mmol), 5-((benzyloxy)methyl)- 4-Ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (51mg , 0.22 mmol) and K 2 CO 3 (45 mg, 0.33 mmol) of the reaction mixture The crude residue was heated at 85° C. for 4 h, then cooled to room temperature and concentrated. Chromatography (SiO 2 , 0 to 50% EtOAc in heptane) to give two of the title compound (58 mg, 64% and 19 mg, 21%, respectively).

[0494] 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydrazine 1H-1,2,4-triazol-1-yl)-2-(2-chloro-6-fluorophenyl) (phenyl)-7-fluoro-4-(prop-1-en-2-yl)phthalazine-1(2H) -On:LCMS(ES-API):C 29 H 24 ClF 2 N 5 O 3 Calculated mass of 56 3.2; m / z measured value, 564.2 [M+H] + . 1 H NMR (400MHz, CDC l 3 )δ 8.34(s,1H),8.32(d,J=3.9Hz,1H),7.44- 7.31(m,7H),7.23-7.16(m,1H),5.67-5.60(m,1 H),5.41(t,J=1.0Hz,1H),4.63(s,2H),4.54(s, 2H),3.88(q,J=7.2Hz,2H),2.21(t,J=1.2Hz,3H ), 1.38(t,J=7.3Hz,3H)ppm.

[0495] 7-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydrazine 1H-1,2,4-triazol-1-yl)-2-(2-chloro-6-fluorophenyl) (phenyl)-6-fluoro-4-(prop-1-en-2-yl)phthalazine-1(2H) -On:LCMS(ES-API):C 29 H 24 ClF 2 N 5 O 3 Calculated mass of 56 3.2; m / z measured value, 564.3 [M+H] + . 1 H NMR (400MHz CDC l 3)δ 8.72(d,J=7.3Hz,1H),7.78(d,J=10.8Hz, 1H),7.46-7.29(m,7H),7.23-7.12(m,1H),5.67 -5.60(m,1H),5.37(t,J=1.0Hz,1H),4.62(s,2H ),4.52(s,2H),3.87(q,J=7.2Hz,2H),2.20(s,3 H), 1.37(t,J=7.1Hz,3H)ppm.

[0496] Step F. 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-7-fluoro-4-(prop-1-en-2-yl)phthalazine-1(2 H)-one. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4, 5-Dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro-6- Fluorophenyl)-7-fluoro-4-(prop-1-en-2-yl)phthalazine- 1(2H)-one and 7-(3-((benzyloxy)methyl)-4-ethyl-5-oxo So-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(2-chloro (6-fluorophenyl)-6-fluoro-4-(prop-1-en-2-yl) phthalate Radin-1(2H)-one (40 mg, 0.071 mmol) in TFA (0.3 mL) The solution was heated at 70° C. for 8 h, then cooled to room temperature and concentrated. 0.5 mL of MeO H and the residue in 0.5 mL of THF was treated with 0.15 mL of 3M NaOH for 1.5 h. After concentration, the residue was purified by RP-HPLC (Gemini C18 110A, 5uM 10 0×30mm, 10mM NH 4In water containing OH, 20-100% CH 3 CN, 60m L / min) to give one of two products as the title compound (15 mg, 45%). LCMS(ES-API):C 22 H 18 ClF 2 N 5 O 3 Calculated mass of 4 73.1; m / z measured value, 474.1 [M+H] + . 1 H NMR (400MHz, CD Cl 3 )δ 8.39-8.27(m,2H),7.50-7.28(m,2H),7. 20(t,J=8.5Hz,1H),5.70-5.56(m,1H),5.40(s, 1H),4.67(d,J=5.9Hz,2H),3.93(q,J=7.0Hz,2H ),2.71-2.55(m,1H),2.20(s,3H),1.42(t,J=7. 3Hz,3H) ppm.

[0497] Example 28: 2-(2-chloro-6-fluorophenyl)-7-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-6-fluoro-4-(prop-1-en-2-yl)phthalazine-1(2 H)-On.

[0498] [ka]

[0499] 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) (ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-(prop-1-en-2-yl)phthalazin-1(2H)-one ( In the preparation of Example 27, Step F), the title compound was obtained as a second crop (3m g). LCMS(ES-API):C 22 H 18 ClF 2 N 5 O 3 Calculated mass of 473 .1; m / z measured value, 474.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ 8.69(d,J=7.3Hz,1H),7.78(d,J=10.8Hz,1 H),7.46-7.28(m,2H),7.25-7.13(m,1H),5.68- 5.55(m,1H),5.37(s,1H),4.67(s,2H),3.91(q, J=7.2Hz,2H),2.37(br s,1H),2.20(s,3H),1.4 2(t,J=7.3Hz,3H)ppm.

[0500] Example 29: 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-7-methoxy-4-(prop-1-en-2-yl)phthalazine-1(2 H)-On.

[0501] [ka]

[0502] Step A: 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-7-fluoro-4-(prop-1-en-2-yl)phthalazine-1(2 H)-one, and (1-(2-(2-chloro-6-fluorophenyl)-7-fluoro- 1-Oxo-4-(prop-1-en-2-yl)-1,2-dihydrophthalazine-6- 4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole -3-yl)methyl 2,2,2-trifluoroacetate. 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro -1H-1,2,4-triazol-1-yl)-2-(2-chloro-6-fluorophenyl 7-fluoro-4-(prop-1-en-2-yl)phthalazine-1(2H)- A solution of 100 mg (25 mg, 0.044 mmol) was heated at 70° C. for 8 h and then cooled to room temperature. The mixture was cooled at rt and concentrated to give the crude title compound, which was carried on to the next step without further purification. It was used as is.

[0503] Step B: 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-7-methoxy-4-(prop-1-en-2-yl)phthalazine-1(2 H)-one. 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-( hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole 1-yl)-7-fluoro-4-(prop-1-en-2-yl)phthalazine-1(2H )-one, and (1-(2-(2-chloro-6-fluorophenyl)-7-fluoro-1 -Oxo-4-(prop-1-en-2-yl)-1,2-dihydrophthalazine-6-yl (ethyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole 3-yl)methyl 2,2,2-trifluoroacetate (crude product obtained from step A) A solution of 0.5 mL of MeOH and 0.5 mL of THF was added to 0.10 mL of 3M The mixture was treated with NaOH for 1.5 h. After concentration, the residue was purified by RP-HPLC (Gemini C1 8 110A, 5uM 100×30mm, 10mM NH 4 In water containing OH, 20-1 00% of CH 3 CN, 60 mL / min) to give the title compound (6.7 mg, 3 1%). LCMS(ES-API):C 23 H 21 ClFN 5 O 4 Calculated mass of 485 .1; m / z measured value, 486.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ 8.05(d,J=9.3Hz,2H),7.45-7.33(m,2H),7 .25-7.14(m,1H),5.58(s,1H),5.37(s,1H),4.6 7(d,J=4.9Hz,2H),4.04(s,3H),3.92(q,J=7.3H z,2H),2.32(br t,J=5.6Hz,1H),2.19(s,3H),1 .43(t,J=7.1Hz,3H)ppm.

[0504] Example 30: 2-(2-chloro-6-fluorophenyl)-7-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-6-methoxy-4-(prop-1-en-2-yl)phthalazine-1(2 H)-On.

[0505] [ka]

[0506] Step A: 2-(2-chloro-6-fluorophenyl)-7-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-6-fluoro-4-(prop-1-en-2-yl)phthalazine-1(2 H)-one, and (1-(3-(2-chloro-6-fluorophenyl)-7-fluoro- 4-Oxo-1-(prop-1-en-2-yl)-3,4-dihydrophthalazine-6- 4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole -3-yl)methyl 2,2,2-trifluoroacetate. 7-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro -1H-1,2,4-triazol-1-yl)-2-(2-chloro-6-fluorophenyl 6-fluoro-4-(prop-1-en-2-yl)phthalazine-1(2H)- A solution of 12 mg (0.021 mmol) was heated at 70° C. for 8 h and cooled to room temperature. The crude title compound was then subjected to purification and concentrated to give the crude title compound, which was directly carried to the next step without further purification. Used.

[0507] Step B: 2-(2-chloro-6-fluorophenyl)-7-(4-ethyl-3-( Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole -1-yl)-6-methoxy-4-(prop-1-en-2-yl)phthalazine-1(2 H)-one. 2-(2-chloro-6-fluorophenyl)-7-(4-ethyl-3-( hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole 1-yl)-6-fluoro-4-(prop-1-en-2-yl)phthalazine-1(2H )-one, and (1-(3-(2-chloro-6-fluorophenyl)-7-fluoro-4 -Oxo-1-(prop-1-en-2-yl)-3,4-dihydrophthalazine-6-yl (ethyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole 3-yl)methyl 2,2,2-trifluoroacetate (crude product obtained from step A) A solution of 0.5 mL of MeOH and 0.5 mL of THF was added to 0.10 mL of 3M The mixture was treated with NaOH for 1.5 h. After concentration, the residue was purified by RP-HPLC (Gemini C1 8 110A, 5uM 100×30mm, 10mM NH 4 In water containing OH, 20-1 00% of CH 3 CN, 60 mL / min) to give the title compound (3 mg, 29%) LCMS(ES-API):C 23 H 21 ClFN 5 O 4 Calculated mass of 485.1 ; m / z measured value, 486.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.51(s,1H),7.43(s,1H),7.42-7.32(m,2H), 7.24-7.12(m,1H),5.64-5.60(m,1H),5.39(s,1 H),4.66(d,J=6.4Hz,2H),4.00(s,3H),3.90(q, J=7.3Hz,2H),2.22(s,3H),2.18(br s,1H),1.4 6-1.38(m,3H)ppm.

[0508] Example 31: 2-(5-chloro-3-methyl-1H-pyrazol-4-yl)-6-( 4-Ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2 ,4-triazol-1-yl)-7-fl...

Claims

1. Formula (I): 【Chemistry 1】 wherein: X is CH or N; Y is CH or N; R １ is C １～６ Alkyl; OH or OCH ３ C substituted with １～６ Alkyl; C ２～６ Alkenyl; C １～６ Haloalkyl; OH or OCH ３ C substituted with １～６ Haloalkyl; C ２～６ Haloalkenyl; N(CH ３ ) ２ ; C ３～６ Cycloalkyl; C １～６ Alkyl-substituted C ３～６ cycloalkyl; and phenyl. Selected; R ２ teeth, 【Chemistry 2】 where: R ａ is C １～６ Alkyl, C １～６ Haloalkyl and C ３～６ From cycloalkyl is selected from the group consisting of R ｂ is C １～６ Alkyl, or OH, halo, CN, OC １～６ Alkyl, O.C. １～ ６ Haloalkyl and O.C. ３～６ cycloalkyl; C being replaced １～６ is alkyl, R ３ H, halo, CH ３ and O.C.H. ３ is selected from the group consisting of R ４ teeth, (e) C １～６ Alkyl; 1 or 2 OCH ３ C substituted with １～６ Alkyl ; C ３～６ Cycloalkyl; CH ３ Or OCH ３ C substituted with ３～６ Cycloalkane Ru;CH ２ -C ３～６ cycloalkyl; and 【Chemistry 3】 is selected from the group consisting of During the ceremony, Each R ｃ are independently H; halo; C １～６ Alkyl; OH, OCH ３ , S.C.H. ３ , and O.C.F. ３ C is substituted with a member selected from the group consisting of １～６ Alkyl; C １～ ６ Haloalkyl; OH and OCH ３ is substituted with a member selected from the group consisting of C １～６ Haloalkyl; NO ２ ;OH;O-CH ２ CH ２ OH; and OC １～６ Alkyl is selected from the group consisting of R ｄ is H; halo; C １～６ Alkyl; OH, OCH ３ , S.C.H. ３ , and O.C.F. ３ from C is substituted with a member selected from the group consisting of １～６ Alkyl; C １～６ Hello Aruki OH and OCH ３ C is substituted with a member selected from the group consisting of １～６ Halo Alkyl; CN; and OC １～６ is selected from the group consisting of alkyl, R ｇ is H;C １～６ Alkyl; OH, OCH ３ , S.C.H. ３ , and O.C.F. ３ A group consisting of C is substituted with a member selected from １～６ Alkyl; C １～６ Haloalkyl; and OH and OCH ３ C is substituted with a member selected from the group consisting of １～６ Halo alkyl, and A compound wherein n is 1 or 2; or a pharma- ceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. body.

2. 2. The compound of claim 1, wherein X is CH; or a pharma- ceutically acceptable salt or solvate thereof. , stereoisomers, isotopic variants, or N-oxides.

3. 2. The compound of claim 1, wherein X is N; or a pharma- ceutically acceptable salt or solvate thereof. Stereoisomers, isotopic variants, or N-oxides.

4. A compound according to any one of claims 1 to 3, wherein Y is N; or a pharma- ceutical acceptable salt thereof. Salts, solvates, stereoisomers, isotopic variants, or N-oxides thereof.

5. A compound according to any one of claims 1 to 3, wherein Y is CH; or a pharma- ceutical acceptable salt thereof. salts, solvates, stereoisomers, isotopic variants, or N-oxides thereof.

6. R １ But, C １～４ Alkyl; OH or OCH ３ C substituted with １～４ Alkyl ; C ２～４ Alkenyl; C １～４ Haloalkyl; OH or OCH ３ has been replaced with C １～４ Haloalkyl; C ２～４ Haloalkenyl, N(CH ３ ) ２ cyclopropyl; C １～４ cyclopropyl substituted with alkyl; or phenyl. A compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. Isotopic variants, or N-oxides.

7. R １ が、CH ３ 、CH ２ CH ３ 、 【Chemistry 4】 6. The compound according to any one of claims 1 to 5, which is: , solvates, stereoisomers, isotopic variants, or N-oxides.

8. R １ but, 【Chemistry 5】 6. The compound according to any one of claims 1 to 5, which is: , solvates, stereoisomers, isotopic variants, or N-oxides.

9. R ２ but, 【Chemistry 6】 and During the ceremony, R ｂ OH, halo, CN, OC １～４ Alkyl, O.C. １～４ Haloalkyl, or O ３～６ Cycloalkyl-substituted C １～４ is alkyl, R ａ is C １～４ Alkyl, C １～４ Haloalkyl, or C ３－６ Cycloalkyl The compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- Oxide.

10. R ２ but, 【Chemistry 7】 9. The compound according to any one of claims 1 to 8, which is: , solvates, stereoisomers, isotopic variants, or N-oxides.

11. R ３ is H; or a medicament thereof; Acceptable salts, solvates, stereoisomers, isotopic variants, or N-oxides.

12. R ３ is F; or a medicament thereof according to any one of claims 1 to 10, Acceptable salts, solvates, stereoisomers, isotopic variants, or N-oxides.

13. R ３ But, CH ３ or a medicament thereof; A commercially available salt, solvate, stereoisomer, isotopic variant, or N-oxide.

14. R ３ But OCH ３ The compound according to any one of claims 1 to 10, A pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide.

15. R ４ but, 【Chemistry 8】 15. The compound according to any one of claims 1 to 14, Salts, solvates, stereoisomers, isotopic variants, or N-oxides.

16. R ４ but, 【Chemistry 9】 and During the ceremony, Each R ｃ are independently H, halo, C １～４ Alkyl, C １～４ Haloalkyl, NO ２ , O-CH ２ CH ２ OH and OC １～４ is selected from the group consisting of alkyl, R ｄ H, halo, C １～４ Alkyl, CN, and OC １～６ From the group consisting of alkyl Selected, and The compound according to any one of claims 1 to 14, wherein n is 1 or 2; or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- Oxide.

17. R ４ but, 【Chemistry 10】 15. The compound according to any one of claims 1 to 14, Salts, solvates, stereoisomers, isotopic variants, or N-oxides.

18. R ４ but, 【Chemistry 11】 15. The compound according to any one of claims 1 to 14, Salts, solvates, stereoisomers, isotopic variants, or N-oxides.

19. R ４ but, 【Chemistry 12】 and During the ceremony, Each R ｃ are independently H, halo, C １～４ Alkyl, C １～４ Haloalkyl, O.C. １～ ４ is selected from the group consisting of alkyl, and OH; R ｄ Ha, Haro, C １～４ Alkyl and O.C. １～４ is selected from the group consisting of alkyl, and, The compound according to any one of claims 1 to 14, wherein n is 1 or 2; or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- Oxide.

20. R ４ but, 【Chemistry 13】 A compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- Oxide.

21. R ４ but, 【Chemistry 14】 15. The compound according to any one of claims 1 to 14, Salts, solvates, stereoisomers, isotopic variants, or N-oxides.

22. R ４ but, 【Chemistry 15】 and During the ceremony, R ｃ is H or halo, R ｄ is C １～４ is alkyl, and R ｇ is H; or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- Oxide.

23. R ４ but, 【Chemistry 16】 A compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- Oxide.

24. Formula (IA) 【Chemistry 17】 wherein: Y is CH or N; R １ is C １～６ Alkyl; OH or OCH ３ C substituted with １～６ Alkyl; C ２～６ Alkenyl; C １～６ Haloalkyl; OH or OCH ３ C substituted with １～６ Haloalkyl; C ２～６ Haloalkenyl; N(CH ３ ) ２ ; C ３～６ Cycloalkyl; C １～６ Alkyl-substituted C ３～６ cycloalkyl; and phenyl. Selected; R ２ teeth, 【Chemistry 18】 and R ３ H, halo, CH ３ and O.C.H. ３ is selected from the group consisting of R ４ teeth, (e) C １～６ Alkyl; 1 or 2 OCH ３ C substituted with １～６ Alkyl ; C ３～６ Cycloalkyl; CH ３ Or OCH ３ C substituted with ３～６ Cycloalkane Ru;CH ２ -C ３～６ cycloalkyl; and 【Chemistry 19】 wherein: Each R ｃ are independently H; halo; C １～６ Alkyl; OH, OCH ３ , S.C.H. ３ , and O.C.F. ３ C is substituted with a member selected from the group consisting of １～６ Alkyl; C １～ ６ Haloalkyl; OH and OCH ３ is substituted with a member selected from the group consisting of C １～６ Haloalkyl; NO ２ ;OH;O-CH ２ CH ２ OH; and OC １～６ Alkyl is selected from the group consisting of R ｄ is H; halo; C １～６ Alkyl; OH, OCH ３ , S.C.H. ３ , and O.C.F. ３ from C is substituted with a member selected from the group consisting of １～６ Alkyl; C １～６ Hello Aruki OH and OCH ３ C is substituted with a member selected from the group consisting of １～６ Halo Alkyl; CN; and OC １～６ is selected from the group consisting of alkyl, R ｇ is H;C １～６ Alkyl; OH, OCH ３ , S.C.H. ３ , and O.C.F. ３ A group consisting of C is substituted with a member selected from １～６ Alkyl; C １～６ Haloalkyl; and OH and OCH ３ C is substituted with a member selected from the group consisting of １～６ Halo alkyl, and The compound of claim 1, wherein n is 1 or 2; or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- Oxide.

25. Formula (IB) 【Chemistry 20】 wherein: Y is CH or N; R １ is C １～６ Alkyl, C １～６ Haloalkyl and C ２～６ The group consisting of alkenyl is selected from R ２ teeth, 【Chemistry 21】 and R ３ is H, halo, and CH ３ is selected from the group consisting of R ４ teeth, 【Chemical 22】 is selected from the group consisting of During the ceremony, R ｃ is H; halo; C １～６ Alkyl; OH, OCH ３ , S.C.H. ３ , and O.C.F. ３ from C is substituted with a member selected from the group consisting of １～６ Alkyl; C １～６ Hello Aruki OH and OCH ３ C is substituted with a member selected from the group consisting of １～６ Halo Alkyl; and NO ２ is selected from the group consisting of R ｄ is H; halo; C １～６ Alkyl; OH, OCH ３ , S.C.H. ３ , and O.C.F. ３ from C is substituted with a member selected from the group consisting of １～６ Alkyl; C １～６ Hello Aruki OH and OCH ３ C is substituted with a member selected from the group consisting of １～６ Halo Alkyl; CN; and OC １～６ is selected from the group consisting of alkyl, R ｇ is H;C １～６ Alkyl; OH, OCH ３ , S.C.H. ３ , and O.C.F. ３ A group consisting of C is substituted with a member selected from １～６ Alkyl; C １～６ Haloalkyl; and OH and OCH ３ C is substituted with a member selected from the group consisting of １～６ Halo alkyl, and The compound according to claim 1, wherein n is 1. or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- Oxide.

26. 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-(pro (per-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-isopropyl propylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-phenyl lysoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline-1(2 H) -on; 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)- 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-( 1-Methylcyclopropyl)isoquinolin-1(2H)-one; 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)- 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-( prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-4-cyclopropyl-6-(4-ethyl -3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl azo-1-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) Isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)-2- (2-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one; 2-(6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro -1H-1,2,4-triazol-1-yl)-1-oxo-4-(prop-1-ene 1H-(2-yl)isoquinolin-2(1H)-yl)benzonitrile; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-phenyl xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(propanol -1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)-2- (o-tolyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(2-fluoro-4-nitrophenyl) -4-iodoisoquinolin-1(2H)-one; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-phenyl xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-isopropyl Pirphthalazin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-isopropyl Lopyrphthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-isopropylphthalazin-1(2H)-one; 4-Ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl) Phthalazin-1(2H)-one; 4-Ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl)phthalazine -1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o -tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-4-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-(2- Hydroxypropan-2-yl)isoquinolin-1(2H)-one; 4-(Dimethylamino)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo -4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl ) isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-7-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -6-fluoro-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Methoxy-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-7-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -6-Methoxy-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(5-chloro-3-methyl-1H-pyrazol-4-yl)-6-(4-ethyl-3 -(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazo (2H)-phenyl-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-(prop-1-ene-2 -yl)-6-(o-tolyl)-1,6-naphthyridin-5(6H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-methyl-6-(o-triazol-1-yl) pyrido[2,3-d]pyridazin-5(6H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o -tolyl)pyrido[2,3-d]pyridazin-5(6H)-one; 6-(2-chloro-6-fluorophenyl)-2-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -3-fluoro-8-(prop-1-en-2-yl)-1,6-naphthyridine-5(6 H) -on; 6-(2-chloro-6-fluorophenyl)-2-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -3-fluoro-8-isopropyl-1,6-naphthyridin-5(6H)-one; (S)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine o-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl) -8-(1,1,1-trifluoropropan-2-yl)-1,6-naphthyridine-5 ( 6H)-on; (R)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine o-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl) -8-(1,1,1-trifluoropropan-2-yl)-1,6-naphthyridine-5 ( 6H)-on; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4 -methylthiazol-5-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o -tolyl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methyl 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 2-(2-chloro-5-methylphenyl)-6-(4-ethyl-3-(hydroxymethyl) 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)- 7-Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methyl (2H)-isoquinoline)-4-(prop-1-en-2-yl)isoquinoline-1(2H)-phenyl hmm; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-phenyl xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro -4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-ene-2 -yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methoxyphenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； Racemic 4-(sec-butyl)-2-(2-chloro-6-fluorophenyl)-6 -(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1 ,2,4-triazol-1-yl)-7-fluoroisoquinolin-1(2H)-one; 2-(3-chloro-6-methoxypyridin-2-yl)-6-(4-ethyl-3-( hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole- 1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxy-4-methylpyridin-3-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluoro-3-methoxyphenyl)-6-(4-ethyl-3- (Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazo (1-phenyl)-7-fluoro-4-(prop-1-en-2-yl)isoquinoline-1 (2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o -tolyl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-isopropylphthalazin-1(2H)-one; Racemic 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- d-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl )-4-(1,1,1-trifluoropropan-2-yl)phthalazine-1(2H)-o hmm; (S ＊ )-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro d-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl )-4-(1,1,1-trifluoropropan-2-yl)phthalazine-1(2H)-o hmm; (R ＊ )-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro d-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl )-4-(1,1,1-trifluoropropan-2-yl)phthalazine-1(2H)-o hmm; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxy-4-methyl 2-(2-ethylpyridin-3-yl)-4-(prop-1-en-2-yl)isoquinoline-1(2 H) -on; 2-(5-chloro-3-methyl-1H-pyrazol-4-yl)-6-(4-ethyl-3 -(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazo 7-fluoro-4-(prop-1-en-2-yl)isoquinoline- 1(2H)-one; 2-(3-chloro-2-methoxy-5-methylpyridin-4-yl)-6-(4-ethyl 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-tetrahydro- riazol-1-yl)-7-fluoro-4-isopropylisoquinoline-1(2H)- on; 2-(3-chloro-2-methoxy-5-methylpyridin-4-yl)-6-(4-ethyl 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-tetrahydro- riazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquino Phosph-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(4-fluoro-2-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-3-(2-hydroxyethoxy)phenyl)-6-(4-ethyl- 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl 7-fluoro-4-(prop-1-en-2-yl)isoquinoline -1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluorophenyl )-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-difluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7- Fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-6-methyl- ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-3-methoxyphenyl)-6-(4-ethyl-3-(hydroxyphenyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxy-3,5 -Dimethylpyridin-4-yl)-4-(prop-1-en-2-yl)isoquinoline- 1(2H)-one; 2-(2,5-difluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7- Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-6-methyl- 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-2-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-dimethylphenyl)-6-(4-ethyl-3-(hydroxymethyl)- 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro Fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(4-fluoro-2-methyl 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluorophenyl )-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxy-3,5-dimethylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-methyl-4-(prop-1-ene-2- yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluoro-3-methoxyphenyl)-6-(4-ethyl-3- (Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazo (1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-( 3,3,3-trifluoroprop-1-en-2-yl)isoquinoline-1(2H)-o hmm; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methyl 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxyphenyl )-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinoline-1(2H )-on; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methyl (4-(2-methoxypyridin-4-yl)-4-(prop-1-en-2-yl)isoquinoline-1( 2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-2-methyl 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 2-(2,5-dimethylphenyl)-6-(4-ethyl-3-(hydroxymethyl)- 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; Racemic 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- d-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl )-4-(1,1,1-trifluoropropan-2-yl)isoquinoline-1(2H)- on; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(2-ethylphenyl)-7-fluoro -4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxypyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methyl (2H)-thoxypyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -(methyl-d3)phenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4 -methylpyridin-5-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -methoxyphenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-6-methyl- (2H)-thoxypyridin-2-yl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3 -methylpyrazin-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-3-fluoro-6-(2-fluoro-5-methyl (6H)-ethylphenyl)-8-isopropyl-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4- Methylpyridazin-3-yl)isoquinolin-1(2H)-one; (S)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine o-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl) -4-(1,1,1-trifluoropropan-2-yl)isoquinoline-1(2H)-o hmm; (R)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine o-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl) -4-(1,1,1-trifluoropropan-2-yl)isoquinoline-1(2H)-o hmm; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -(trifluoromethyl)phenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(5 -methylpyridin-4-yl)isoquinolin-1(2H)-one; 2-(2-(difluoromethyl)phenyl)-6-(4-ethyl-3-(hydroxymethyl)phenyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(3-chloro-2-methoxypyridin-4-yl)-6-(4-ethyl-3-( hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole- 1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-Cyclohexyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4 ,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-yl isopropylisoquinolin-1(2H)-one; 2-(3-chloro-6-methylpyridin-2-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-Cyclopentyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4 ,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-yl isopropylisoquinolin-1(2H)-one; 2-(3-chloro-4-methoxypyridin-2-yl)-6-(4-ethyl-3-( hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole- 1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1R,2S)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 2-(1,3-dimethoxypropan-2-yl)-6-(4-ethyl-3-(hydroxy Dimethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl 2H)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxy-5-methylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1S,2R)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 2-(cyclopropylmethyl)-6-(4-ethyl-3-(hydroxymethyl)-5- Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro rho-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(1 -Methoxybutan-2-yl)isoquinolin-1(2H)-one; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-phenyl xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro -4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3 -methylpyridin-2-yl)isoquinolin-1(2H)-one; Racemic 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- d-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl -2-((cis)-3-methoxycyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1R ＊ , 2R ＊ )-2-methylcyclohexyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1S ＊ , 2S ＊ )-2-methylcyclohexyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(phenyl 2H-methyl-3-phenyl-2H-isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1R ＊ , 2R ＊ )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1S ＊ , 2S ＊ )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1R ＊ , 2S ＊ )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1S ＊ , 2R ＊ )-2-methylcyclopentyl)isoquinolin-1(2H)-one; Racemic 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- d-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl -2-((cis)-3-methoxycyclohexyl)isoquinolin-1(2H)-one; 2-(bicyclo[2.2.1]heptan-1-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxy-3-methylpyridin-4-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(2 -methoxyphenyl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3 -methylisothiazol-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(5 -methylisothiazol-4-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(2 -(trifluoromethyl)phenyl)-1,6-naphthyridin-5(6H)-one; 2-(3,6-dimethylpyridin-2-yl)-6-(4-ethyl-3-(hydroxy methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl )-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-dimethylpyridin-4-yl)-6-(4-ethyl-3-(hydroxy methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl )-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4 -methylpyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3 -methylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -methylpyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-hydroxy-5- Methylpyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; 6-(2-(difluoromethyl)phenyl)-2-(4-ethyl-3-(hydroxymethyl)phenyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -3-fluoro-8-isopropyl-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-hydroxy-3- Methylpyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; and 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o -D ３ -tolyl)-1,6-naphthyridin-5(6H)-one; A compound selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- Oxide.

27. 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o -tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-4-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o -tolyl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o -tolyl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-isopropylphthalazin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -(methyl-d3)phenyl)isoquinolin-1(2H)-one; (R)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine o-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl) -4-(1,1,1-trifluoropropan-2-yl)isoquinoline-1(2H)-o hmm; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -(trifluoromethyl)phenyl)isoquinolin-1(2H)-one; 2-(2-(difluoromethyl)phenyl)-6-(4-ethyl-3-(hydroxymethyl)phenyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1(2H)-one; A compound selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- Oxide.

28. (A) A compound according to any one of claims 1 to 27, or a pharma- ceutical acceptable salt thereof. , solvate, stereoisomer, isotopic variant, or N-oxide; and (B) at least one and a pharma- ceutical acceptable excipient.

29. 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-(pro (per-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-isopropyl propylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-phenyl lysoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline-1(2 H) -on; 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)- 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-( 1-Methylcyclopropyl)isoquinolin-1(2H)-one; 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)- 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-( prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-4-cyclopropyl-6-(4-ethyl -3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl azo-1-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) Isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)-2- (2-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one; 2-(6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro -1H-1,2,4-triazol-1-yl)-1-oxo-4-(prop-1-ene 1H-(2-yl)isoquinolin-2(1H)-yl)benzonitrile; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-phenyl xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(propanol -1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)-2- (o-tolyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(2-fluoro-4-nitrophenyl) -4-iodoisoquinolin-1(2H)-one; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-phenyl xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-isopropyl Pirphthalazin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-isopropyl Lopyrphthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-isopropylphthalazin-1(2H)-one; 4-Ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl) Phthalazin-1(2H)-one; 4-Ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl)phthalazine -1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o -tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-4-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-(2- Hydroxypropan-2-yl)isoquinolin-1(2H)-one; 4-(Dimethylamino)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo -4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl ) isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-7-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -6-fluoro-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Methoxy-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-7-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -6-Methoxy-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(5-chloro-3-methyl-1H-pyrazol-4-yl)-6-(4-ethyl- 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl 2H-isopropyl-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one ； 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-(prop-1-ene-2 -yl)-6-(o-tolyl)-1,6-naphthyridin-5(6H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-methyl-6-(o-triazol-1-yl) pyrido[2,3-d]pyridazin-5(6H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o -tolyl)pyrido[2,3-d]pyridazin-5(6H)-one; 6-(2-chloro-6-fluorophenyl)-2-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -3-fluoro-8-(prop-1-en-2-yl)-1,6-naphthyridine-5(6 H) -on; 6-(2-chloro-6-fluorophenyl)-2-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -3-fluoro-8-isopropyl-1,6-naphthyridin-5(6H)-one; (S)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine o-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl) -8-(1,1,1-trifluoropropan-2-yl)-1,6-naphthyridine-5 ( 6H)-on; (R)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine o-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl) -8-(1,1,1-trifluoropropan-2-yl)-1,6-naphthyridine-5 ( 6H)-on; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4 -methylthiazol-5-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o -tolyl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methyl 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 2-(2-chloro-5-methylphenyl)-6-(4-ethyl-3-(hydroxymethyl) 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)- 7-Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methyl (2H)-isoquinoline)-4-(prop-1-en-2-yl)isoquinoline-1(2H)-phenyl hmm; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-phenyl xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro -4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-ene-2 -yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methoxyphenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； Racemic 4-(sec-butyl)-2-(2-chloro-6-fluorophenyl)-6 -(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1 ,2,4-triazol-1-yl)-7-fluoroisoquinolin-1(2H)-one; 2-(3-chloro-6-methoxypyridin-2-yl)-6-(4-ethyl-3-( hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole- 1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxy-4-methylpyridin-3-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluoro-3-methoxyphenyl)-6-(4-ethyl-3- (Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazo (1-phenyl)-7-fluoro-4-(prop-1-en-2-yl)isoquinoline-1 (2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o -tolyl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-isopropylphthalazin-1(2H)-one; Racemic 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- d-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl )-4-(1,1,1-trifluoropropan-2-yl)phthalazine-1(2H)-o hmm; (S ＊ )-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro d-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl )-4-(1,1,1-trifluoropropan-2-yl)phthalazine-1(2H)-o hmm; (R ＊ )-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro d-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl )-4-(1,1,1-trifluoropropan-2-yl)phthalazine-1(2H)-o hmm; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxy-4-methyl 2-(2-ethylpyridin-3-yl)-4-(prop-1-en-2-yl)isoquinoline-1(2 H) -on; 2-(5-chloro-3-methyl-1H-pyrazol-4-yl)-6-(4-ethyl- 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl 7-fluoro-4-(prop-1-en-2-yl)isoquinoline -1(2H)-one; 2-(3-chloro-2-methoxy-5-methylpyridin-4-yl)-6-(4-ethyl 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-tetrahydro- riazol-1-yl)-7-fluoro-4-isopropylisoquinoline-1(2H)- on; 2-(3-chloro-2-methoxy-5-methylpyridin-4-yl)-6-(4-ethyl 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-tetrahydro- riazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquino Phosph-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(4-fluoro-2-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-3-(2-hydroxyethoxy)phenyl)-6-(4-ethyl- 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl 7-fluoro-4-(prop-1-en-2-yl)isoquinoline -1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluorophenyl )-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-difluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7- Fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-6-methyl- ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-3-methoxyphenyl)-6-(4-ethyl-3-(hydroxyphenyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxy-3,5 -Dimethylpyridin-4-yl)-4-(prop-1-en-2-yl)isoquinoline- 1(2H)-one; 2-(2,5-difluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7- Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-6-methyl- 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-2-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-dimethylphenyl)-6-(4-ethyl-3-(hydroxymethyl)- 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro Fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(4-fluoro-2-methyl 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluorophenyl )-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxy-3,5-dimethylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-methyl-4-(prop-1-ene-2- yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluoro-3-methoxyphenyl)-6-(4-ethyl-3- (Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazo (1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-( 3,3,3-trifluoroprop-1-en-2-yl)isoquinoline-1(2H)-o hmm; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methyl 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxyphenyl )-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinoline-1(2H )-on; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methyl (4-(2-methoxypyridin-4-yl)-4-(prop-1-en-2-yl)isoquinoline-1( 2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-2-methyl 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 2-(2,5-dimethylphenyl)-6-(4-ethyl-3-(hydroxymethyl)- 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; Racemic 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- d-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl )-4-(1,1,1-trifluoropropan-2-yl)isoquinoline-1(2H)- on; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(2-ethylphenyl)-7-fluoro -4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxypyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methyl (2H)-thoxypyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -(methyl-d3)phenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4 -methylpyridin-5-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -methoxyphenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-6-methyl- (2H)-thoxypyridin-2-yl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3 -methylpyrazin-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-3-fluoro-6-(2-fluoro-5-methyl (6H)-ethylphenyl)-8-isopropyl-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4- Methylpyridazin-3-yl)isoquinolin-1(2H)-one; (S)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine o-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl) -4-(1,1,1-trifluoropropan-2-yl)isoquinoline-1(2H)-o hmm; (R)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine o-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl) -4-(1,1,1-trifluoropropan-2-yl)isoquinoline-1(2H)-o hmm; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -(trifluoromethyl)phenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(5 -methylpyridin-4-yl)isoquinolin-1(2H)-one; 2-(2-(difluoromethyl)phenyl)-6-(4-ethyl-3-(hydroxymethyl)phenyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(3-chloro-2-methoxypyridin-4-yl)-6-(4-ethyl-3-( hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole- 1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-Cyclohexyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4 ,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-yl isopropylisoquinolin-1(2H)-one; 2-(3-chloro-6-methylpyridin-2-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-Cyclopentyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4 ,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-yl isopropylisoquinolin-1(2H)-one; 2-(3-chloro-4-methoxypyridin-2-yl)-6-(4-ethyl-3-( hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole- 1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1R,2S)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 2-(1,3-dimethoxypropan-2-yl)-6-(4-ethyl-3-(hydroxy Dimethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl 2H)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxy-5-methylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1S,2R)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 2-(cyclopropylmethyl)-6-(4-ethyl-3-(hydroxymethyl)-5- Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro rho-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(1 -Methoxybutan-2-yl)isoquinolin-1(2H)-one; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-phenyl xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro -4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3 -methylpyridin-2-yl)isoquinolin-1(2H)-one; Racemic 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- d-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl -2-((cis)-3-methoxycyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1R ＊ , 2R ＊ )-2-methylcyclohexyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1S ＊ , 2S ＊ )-2-methylcyclohexyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(phenyl 2H-methyl-3-phenyl-2H-isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1R ＊ , 2R ＊ )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1S ＊ , 2S ＊ )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1R ＊ , 2S ＊ )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1S ＊ , 2R ＊ )-2-methylcyclopentyl)isoquinolin-1(2H)-one; Racemic 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- d-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl -2-((cis)-3-methoxycyclohexyl)isoquinolin-1(2H)-one; 2-(bicyclo[2.2.1]heptan-1-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxy-3-methylpyridin-4-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(2 -methoxyphenyl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3 -methylisothiazol-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(5 -methylisothiazol-4-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(2 -(trifluoromethyl)phenyl)-1,6-naphthyridin-5(6H)-one; 2-(3,6-dimethylpyridin-2-yl)-6-(4-ethyl-3-(hydroxy methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl )-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-dimethylpyridin-4-yl)-6-(4-ethyl-3-(hydroxy methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl )-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4 -methylpyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3 -methylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -methylpyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-hydroxy-5- Methylpyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; 6-(2-(difluoromethyl)phenyl)-2-(4-ethyl-3-(hydroxymethyl)phenyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -3-fluoro-8-isopropyl-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-hydroxy-3- Methylpyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; and 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o -D ３ -tolyl)-1,6-naphthyridin-5(6H)-one; or a pharma- ceutically acceptable salt or solvate thereof, and at least one phenylmethylsulfonyl ether, stereoisomer, isotopic variant, or N-oxide, and an excipient compatible with said pharmaceutical composition.

30. Suffering from or having a disease, disorder, or medical condition A method of treating a subject diagnosed with a medical condition comprising administering to said subject an effective amount of any one of claims 1 to 27. At least one compound according to the above item, or a pharma- ceutically acceptable salt, solvate, stereoisomer thereof administering to a subject a compound, isotopic variant, or N-oxide of the compound to said subject, The method comprises inhibiting or altering dihydroorotate oxygenase enzyme activity in said organism.

31. The disease, disorder, or condition is selected from the group consisting of inflammatory disorders and autoimmune disorders. The method of claim 30.

32. 31. The method of claim 30, wherein the disease, disorder, or condition is cancer.

33. The disease, disorder, or condition is selected from the group consisting of lymphoma, leukemia, carcinoma, and sarcoma. The method of claim 30,

34. The disease, disorder, or condition is acute lymphoblastic leukemia, acute myeloid leukemia, (acute) T-cell leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute monocytic leukemia, acute Promyelocytic leukemia, biphenotypic B myelomonocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia chronic myeloid leukemia, chronic myelomonocytic leukemia, large granular lymphocytic leukemia, plasma cell leukemia and myelodysplastic syndromes, which may progress to acute myeloid leukemia. The method according to claim 30.

35. 31. The method of claim 30, wherein the disease, disorder, or condition is acute myeloid leukemia.

36. The at least one compound is 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-(pro (per-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-isopropyl propylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-phenyl lysoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline-1(2 H) -on; 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)- 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-( 1-Methylcyclopropyl)isoquinolin-1(2H)-one; 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)- 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-( prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-4-cyclopropyl-6-(4-ethyl -3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl azo-1-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) Isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)-2- (2-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one; 2-(6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro -1H-1,2,4-triazol-1-yl)-1-oxo-4-(prop-1-ene 1H-(2-yl)isoquinolin-2(1H)-yl)benzonitrile; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-phenyl xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(propanol -1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)-2- (o-tolyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(2-fluoro-4-nitrophenyl) -4-iodoisoquinolin-1(2H)-one; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-phenyl xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-isopropyl Pirphthalazin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-isopropyl Lopyrphthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-isopropylphthalazin-1(2H)-one; 4-Ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl) Phthalazin-1(2H)-one; 4-Ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-di Hydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl)phthalazine -1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o -tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-4-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-(2- Hydroxypropan-2-yl)isoquinolin-1(2H)-one; 4-(Dimethylamino)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo -4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl ) isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-7-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -6-fluoro-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Methoxy-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-7-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -6-Methoxy-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(5-chloro-3-methyl-1H-pyrazol-4-yl)-6-(4-ethyl- 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl 2H-isopropyl-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one ； 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-(prop-1-ene-2 -yl)-6-(o-tolyl)-1,6-naphthyridin-5(6H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-methyl-6-(o-triazol-1-yl) pyrido[2,3-d]pyridazin-5(6H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o -tolyl)pyrido[2,3-d]pyridazin-5(6H)-one; 6-(2-chloro-6-fluorophenyl)-2-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -3-fluoro-8-(prop-1-en-2-yl)-1,6-naphthyridine-5(6 H) -on; 6-(2-chloro-6-fluorophenyl)-2-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -3-fluoro-8-isopropyl-1,6-naphthyridin-5(6H)-one; (S)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine o-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl) -8-(1,1,1-trifluoropropan-2-yl)-1,6-naphthyridine-5 ( 6H)-on; (R)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine o-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl) -8-(1,1,1-trifluoropropan-2-yl)-1,6-naphthyridine-5 ( 6H)-on; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4 -methylthiazol-5-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o -tolyl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methyl 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 2-(2-chloro-5-methylphenyl)-6-(4-ethyl-3-(hydroxymethyl) 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)- 7-Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methyl (2H)-isoquinoline)-4-(prop-1-en-2-yl)isoquinoline-1(2H)-phenyl hmm; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-phenyl xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro -4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-ene-2 -yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methoxyphenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； Racemic 4-(sec-butyl)-2-(2-chloro-6-fluorophenyl)-6 -(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1 ,2,4-triazol-1-yl)-7-fluoroisoquinolin-1(2H)-one; 2-(3-chloro-6-methoxypyridin-2-yl)-6-(4-ethyl-3-( hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole- 1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxy-4-methylpyridin-3-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluoro-3-methoxyphenyl)-6-(4-ethyl-3- (Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazo (1-phenyl)-7-fluoro-4-(prop-1-en-2-yl)isoquinoline-1 (2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o -tolyl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-isopropylphthalazin-1(2H)-one; Racemic 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- d-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl )-4-(1,1,1-trifluoropropan-2-yl)phthalazine-1(2H)-o hmm; (S ＊ )-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro d-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl )-4-(1,1,1-trifluoropropan-2-yl)phthalazine-1(2H)-o hmm; (R ＊ )-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro d-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl )-4-(1,1,1-trifluoropropan-2-yl)phthalazine-1(2H)-o hmm; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxy-4-methyl 2-(2-ethylpyridin-3-yl)-4-(prop-1-en-2-yl)isoquinoline-1(2 H) -on; 2-(5-chloro-3-methyl-1H-pyrazol-4-yl)-6-(4-ethyl- 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl 7-fluoro-4-(prop-1-en-2-yl)isoquinoline -1(2H)-one; 2-(3-chloro-2-methoxy-5-methylpyridin-4-yl)-6-(4-ethyl 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-tetrahydro- riazol-1-yl)-7-fluoro-4-isopropylisoquinoline-1(2H)- on; 2-(3-chloro-2-methoxy-5-methylpyridin-4-yl)-6-(4-ethyl 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-tetrahydro- riazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquino Phosph-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(4-fluoro-2-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-3-(2-hydroxyethoxy)phenyl)-6-(4-ethyl- 3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-trimethyl 7-fluoro-4-(prop-1-en-2-yl)isoquinoline -1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluorophenyl )-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-difluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7- Fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-6-methyl- ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-3-methoxyphenyl)-6-(4-ethyl-3-(hydroxyphenyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxy-3,5 -Dimethylpyridin-4-yl)-4-(prop-1-en-2-yl)isoquinoline- 1(2H)-one; 2-(2,5-difluorophenyl)-6-(4-ethyl-3-(hydroxymethyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7- Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-6-methyl- 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-2-methyl ethylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-dimethylphenyl)-6-(4-ethyl-3-(hydroxymethyl)- 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro Fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(4-fluoro-2-methyl 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluorophenyl )-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxy-3,5-dimethylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-methyl-4-(prop-1-ene-2- yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluoro-3-methoxyphenyl)-6-(4-ethyl-3- (Hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazo (1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-( 3,3,3-trifluoroprop-1-en-2-yl)isoquinoline-1(2H)-o hmm; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methyl 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxyphenyl )-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinoline-1(2H )-on; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methyl (4-(2-methoxypyridin-4-yl)-4-(prop-1-en-2-yl)isoquinoline-1( 2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-2-methyl 4-(prop-1-en-2-yl)isoquinolin-1(2H)-one ； 2-(2,5-dimethylphenyl)-6-(4-ethyl-3-(hydroxymethyl)- 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro Fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; Racemic 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- d-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl )-4-(1,1,1-trifluoropropan-2-yl)isoquinoline-1(2H)- on; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-2-(2-ethylphenyl)-7-fluoro -4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxypyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methyl (2H)-thoxypyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -(methyl-d3)phenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4 -methylpyridin-5-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -methoxyphenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-6-methyl- (2H)-thoxypyridin-2-yl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3 -methylpyrazin-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H 1,2,4-triazol-1-yl)-3-fluoro-6-(2-fluoro-5-methyl (6H)-ethylphenyl)-8-isopropyl-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4- Methylpyridazin-3-yl)isoquinolin-1(2H)-one; (S)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine o-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl) -4-(1,1,1-trifluoropropan-2-yl)isoquinoline-1(2H)-o hmm; (R)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydrazine o-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl) -4-(1,1,1-trifluoropropan-2-yl)isoquinoline-1(2H)-o hmm; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -(trifluoromethyl)phenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(5 -methylpyridin-4-yl)isoquinolin-1(2H)-one; 2-(2-(difluoromethyl)phenyl)-6-(4-ethyl-3-(hydroxymethyl)phenyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(3-chloro-2-methoxypyridin-4-yl)-6-(4-ethyl-3-( hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole- 1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-Cyclohexyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4 ,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-yl isopropylisoquinolin-1(2H)-one; 2-(3-chloro-6-methylpyridin-2-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-Cyclopentyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4 ,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-yl isopropylisoquinolin-1(2H)-one; 2-(3-chloro-4-methoxypyridin-2-yl)-6-(4-ethyl-3-( hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole- 1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1R,2S)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 2-(1,3-dimethoxypropan-2-yl)-6-(4-ethyl-3-(hydroxy Dimethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl 2H)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxy-5-methylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1S,2R)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 2-(cyclopropylmethyl)-6-(4-ethyl-3-(hydroxymethyl)-5- Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro rho-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(1 -Methoxybutan-2-yl)isoquinolin-1(2H)-one; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-phenyl xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro -4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3 -methylpyridin-2-yl)isoquinolin-1(2H)-one; Racemic 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- d-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl -2-((cis)-3-methoxycyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1R ＊ , 2R ＊ )-2-methylcyclohexyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1S ＊ , 2S ＊ )-2-methylcyclohexyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(phenyl 2H-methyl-3-phenyl-2H-isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1R ＊ , 2R ＊ )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1S ＊ , 2S ＊ )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1R ＊ , 2S ＊ )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(( 1S ＊ , 2R ＊ )-2-methylcyclopentyl)isoquinolin-1(2H)-one; Racemic 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro- d-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl -2-((cis)-3-methoxycyclohexyl)isoquinolin-1(2H)-one; 2-(bicyclo[2.2.1]heptan-1-yl)-6-(4-ethyl-3-(hydrogen (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -Methoxy-3-methylpyridin-4-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(2 -methoxyphenyl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3 -methylisothiazol-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(5 -methylisothiazol-4-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(2 -(trifluoromethyl)phenyl)-1,6-naphthyridin-5(6H)-one; 2-(3,6-dimethylpyridin-2-yl)-6-(4-ethyl-3-(hydroxy methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl )-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-dimethylpyridin-4-yl)-6-(4-ethyl-3-(hydroxy methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl )-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4 -methylpyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3 -methylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2 -methylpyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-hydroxy-5- Methylpyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; 6-(2-(difluoromethyl)phenyl)-2-(4-ethyl-3-(hydroxymethyl)phenyl) ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -3-fluoro-8-isopropyl-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-7-fluoro-2-(2-hydroxy-3- Methylpyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; and 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H -1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o -D ３ -tolyl)-1,6-naphthyridin-5(6H)-one; or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N- The method of any one of claims 30 to 35, wherein the compound is an oxide.

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