Combination therapy

Abstract

Disclosed is a combination comprising a therapeutically effective amount of a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a therapeutically effective amount of a BCL-2 inhibitor, and optionally a therapeutically effective amount of at least one other anti-neoplastic agent. Also disclosed is a method of treating a subject diagnosed with a hematopoietic disorder using such a combination. The compound is represented by the following formula (I): [Formula 1] TIFF2024518497000199.tif59128 in formula, R 1a , R 1b , R 2 , R 3 , R 4 , U, Y 1 , X 1 , X 2 , n1, n2, n3 and n4 are defined herein.

Description

[Technical field]

[0001] The present invention relates to a novel combination comprising a therapeutically effective amount of a menin mixed lineage leukemia 1 (menin-MLL) inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a therapeutically effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor, and optionally, a therapeutically effective amount of at least one other anti-neoplastic agent, and to a method for treating a subject diagnosed with a hematopoietic disorder. [Background technology]

[0002] Of the 10 million cancer deaths recorded by GLOBOCAN in 2020, 7.1% were attributable to hematopoietic disorders. Thus, new therapies are urgently needed for hematopoietic disorders such as acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and acute lymphoblastic leukemia (ALL), as further detailed below.

[0003] AML is a common hematological malignancy whose incidence rises from 3:100,000 in younger adults to over 20:100,000 in older adults. In patients under 60 years of age, overall survival (OS) is 40-50%, but only 5% in patients over 60 years of age. The majority of patients newly diagnosed with AML are over 60 years of age. In this patient population, standard induction chemotherapy is often not an option due to increased treatment-related mortality as a result of age and comorbidities. The standard of care for AML patients who are not suitable for combination chemotherapy is treatment with hypomethylating agents (azacitidine or decitabine) or low-dose cytarabine. Despite these state-of-the-art treatments, the median OS is only about 10 months. In all types of AML, disease relapse is common despite initial treatment response and is the most common reason for death. Standard chemotherapy and allogeneic stem cell transplantation (when used) often fail to eradicate all tumor-propagating cells and select for chemotherapy-resistant leukemic-propagating subclones. Patients who are refractory to salvage therapy are treated palliatively since current treatment options are very limited. The median survival time for these patients is 2 months. Furthermore, patients with newly diagnosed intermediate or higher risk MDS and those who relapse after standard care have poor prognosis and high risk of progression to AML. Thus, new therapies are urgently needed for relapsed / refractory (R / R) AML and MDS patients, newly diagnosed AML patients who are ineligible for induction chemotherapy based on age and comorbidities, and newly diagnosed intermediate / high / very high risk MDS patients.

[0004] ALL is a hematological malignancy propagated by impaired differentiation, proliferation, and accumulation of lymphoid progenitor cells in the bone marrow and / or extramedullary sites. ALL represents 12% of all leukemia cases and is the most common childhood acute leukemia, with a worldwide incidence estimated at 1-4.75 per 100,000. ALL represents approximately 20% of adult leukemias. Despite high complete remission (CR) rates (80%-90%) with current therapies, the majority of adult patients with ALL will relapse. Five-year overall survival is approximately 30-40% in adult and elderly patients. Summary of the Invention

[0005] Therefore, new therapies are urgently needed for relapsed / refractory ALL, especially in adults and especially in elderly patients.

[0006] An embodiment of the present invention relates to a novel combination of a menin-MLL inhibitor of formula (I) or a pharma-ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and optionally at least one other anti-neoplastic agent.

[0007] An embodiment of the present invention relates to the use of a menin-MLL inhibitor as described herein in combination with a BCL-2 inhibitor and, optionally, at least one other anti-neoplastic agent, to treat a subject diagnosed with a hematopoietic disorder, such as, but not limited to, a hematological cancer.

[0008] Embodiments of the present invention relate to novel methods for treating a subject diagnosed with a hematopoietic disorder using such combinations. Embodiments of the novel methods include administering to the subject a therapeutically effective amount of a menin-MLL inhibitor as described herein, a therapeutically effective amount of a BCL-2 inhibitor, and, optionally, a therapeutically effective amount of at least one other anti-neoplastic agent, where the menin-MLL inhibitor is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof.

[0009] Embodiments of the present invention relate to novel methods for treating a subject diagnosed with a hematopoietic disorder using such combinations. Embodiments of the novel methods include administering to the subject a therapeutically effective amount of a menin-MLL inhibitor as described herein, a therapeutically effective amount of a BCL-2 inhibitor, and a therapeutically effective amount of at least one other anti-neoplastic agent, wherein the menin-MLL inhibitor is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0010] In some embodiments, the present invention relates to a method of treating a subject diagnosed with a hematopoietic disorder, comprising administering to the subject a therapeutically effective amount of a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, a therapeutically effective amount of venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and a therapeutically effective amount of azacitidine or a pharma- ceutical acceptable salt or solvate thereof.

[0011] In some embodiments, the invention relates to a method of treating a subject diagnosed with a hematopoietic disorder, comprising administering to the subject a therapeutically effective amount of a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, a therapeutically effective amount of venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and a therapeutically effective amount of azacitidine or a pharma- ceutical acceptable salt or solvate thereof, wherein the venetoclax or a pharma- ceutical acceptable salt or solvate thereof is administered to the subject prior to, concurrently with, or following administration of the menin-MLL inhibitor, and the azacitidine or a pharma- ceutical acceptable salt or solvate thereof is administered to the subject prior to, concurrently with, or following administration of the menin-MLL inhibitor.

[0012] In an embodiment, the menin-MLL inhibitor of formula (I) is:

[0013] [ka] and their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb , Het, or

[0014] [ka] represents Het represents a 5- or 6-membered monocyclic aromatic ring containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety; The 5- or 6-membered monocyclic aromatic ring is optionally3~6 Cycloalkyl and C 1~4 substituted with 1 or 2 substituents selected from the group consisting of alkyl; R xa and R xb is hydrogen, C 1~4 Alkyl and C 3~6 cycloalkyl; R 1b represents F or Cl, Y 1 -CR 5a R 5b -, -O-, or -NR 5c - represents R 2 is hydrogen, halo, C 1~4 Alkyl, -OC 1~4 Alkyl, and -NR 7a R 7b is selected from the group consisting of U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 5a , R 5b , R 5c , R 7a and R 7b is hydrogen, C 1~4 Alkyl and C 3~6 cycloalkyl; R 3 -C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b , -C 1~6 Alkyl-OH or -C 1~6 Alkyl-NR 11 -C(=O)-OC 1~4 Alkyl-OC(=O)-C 1~4 represents alkyl, where R3 C in the definition of 1~4 Alkyl or C 1~6 Each of the alkyl moieties, independently of the others, is selected from cyano, halo, -OH, and -OC. 1~4 and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, R 8a and R 8b is hydrogen, C 1~6 Alkyl, -C(=O)-C 1~4 Alkyl, -C(=O)-OC 1~4 Alkyl, -C(=O)-NR 12a R 12b , as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; R 9a , R 9b , R 10a , R 10b , R 10c , R 11 , R 12a , and R 12b is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0015] In certain embodiments, the menin-MLL inhibitor of formula (I) is (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide besylate (benzenesulfonate):

[0016] [ka] and solvates thereof.

[0017] One of ordinary skill in the art will understand that "and solvates thereof" refers to the besylate salt of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide.

[0018] In certain embodiments, the menin-MLL inhibitor of formula (I) is (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide besylate, or a hydrate thereof.

[0019] In certain embodiments, the menin-MLL inhibitor of formula (I) is (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate, or a solvate thereof.

[0020] In certain embodiments, the menin-MLL inhibitor of formula (I) is (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4 triazin-6-yl)oxy)benzamide bisbesylate, or a hydrate thereof.

[0021] In particular, the present invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4 triazin-6-yl)oxy)benzamide bisbesylate 0.5 to 2.0 equivalent hydrate.

[0022] In particular, the present invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4 triazin-6-yl)oxy)benzamide bisbesylate 2.0 equivalent hydrate.

[0023] In certain embodiments, the menin-MLL inhibitor of formula (I) is crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4 triazin-6-yl)oxy)benzamide bisbesylate hydrate.

[0024] In certain embodiments, the menin-MLL inhibitor of formula (I) is crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4 triazin-6-yl)oxy)benzamide bisbesylate 0.5-2.0 equivalent hydrate.

[0025] More particularly, the present invention relates to crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4 triazin-6-yl)oxy)benzamide bisbesylate 2.0 equivalent hydrate.

[0026] Additional embodiments, features, and advantages of the invention will become apparent from the following detailed description as well as through practice of the invention. [Brief description of the drawings]

[0027] [Figure 1] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of compound A4: (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bisbesylate hydrate crystalline form A. [Diagram 2] FIG. 2 shows a comparison of tumor volumes as a function of time for a control group and treatment groups treated with regimens containing various amounts of Compound A3. [Diagram 3] FIG. 3 shows a comparison of percent tumor survival as a function of time (eg, Kaplan-Meier survival curves) for a control group and treatment groups treated with regimens containing various amounts of Compound A3. [Figure 4A] FIG. 4A shows a comparison of percent survival as a function of time of mice bearing established OCI-AML3 tumors following treatment with vehicle, either venetoclax, azacitidine or Compound A1 monotherapy, either dual combinations of venetoclax and azacitidine, or Compound A1 and venetoclax, or the triple combination of Compound A1, venetoclax and azacitidine. [Figure 4B] FIG. 4B shows a comparison of percent survival as a function of time of mice bearing established MOLM-13 tumors following treatment with vehicle, either venetoclax, azacitidine or compound A1 monotherapy, either dual combinations of venetoclax and azacitidine or compound A1 and venetoclax, or the triple combination of compound A1, venetoclax and azacitidine. [Figure 5A]FIG. 5A is a contour plot of maxR showing the effect of compound A3 in combination with venetoclax on the proliferation of MOLM-13 cells in vitro. [Figure 5B] FIG. 5B is a contour plot of maxR showing the effect of Compound A3 in combination with azacytidine and venetoclax on the proliferation of MOLM-13 cells in vitro. [Figure 6A] FIG. 6A is a contour plot of maxR showing the effect of Compound A4 in combination with decitabine on the proliferation of MOLM-13 cells in vitro. [Figure 6B] FIG. 6B is a contour plot of maxR showing the effect of Compound A4 in combination with decitabine and venetoclax on the proliferation of MOLM-13 cells in vitro. [Figure 7A] FIG. 7A is a contour plot of maxR showing the effect of Compound A4 in combination with decitabine on the proliferation of OCI-AML3 cells in vitro. [Figure 7B] FIG. 7B is a contour plot of maxR showing the effect of Compound A4 in combination with decitabine and venetoclax on the proliferation of OCI-AML3 cells in vitro. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0029] As used herein, the prefix "C x~y " (where x and y are integers) refers to the number of carbon atoms in a given group. i.e., C 1~6 An alkyl group contains 1 to 6 carbon atoms, and so on.

[0030] As used herein as a group or part of a group, "C 1~4The term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, and the like.

[0031] As used herein as a group or part of a group, "C 1~6 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0032] As used herein as a group or part of a group, "C 3~6 The term "cycloalkyl" defines a saturated cyclic hydrocarbon radical having three to six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0033] S(=O) 2 or SO 2 It will be apparent to those skilled in the art that represents a sulfonyl moiety.

[0034] It will be apparent to one skilled in the art that CO or C(=O) represent a carbonyl moiety.

[0035] Groups such as -CRR-

[0036] [ka] It will be clear to those skilled in the art that the aryl group represents -CR 5a R 5b -It is.

[0037] Groups such as -NR-

[0038] [ka] It will be clear to one skilled in the art that the aryl group represents -NR5c -It is.

[0039] Non-limiting examples of "monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and optionally a carbonyl moiety" include, but are not limited to, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or 1,2-dihydro-2-oxo-4-pyridinyl.

[0040] Those skilled in the art will recognize the term as a 5- or 6-membered monocyclic aromatic ring containing 1, 2, or 3 nitrogen atoms and a carbonyl moiety:

[0041] [ka] It will be understood that these include, but are not limited to:

[0042] When any variable occurs more than one time in any constituent, each definition is independent.

[0043] When any variable occurs more than one time in any formula (eg, formula (I)), each definition is independent.

[0044] In general, whenever the term "substituted" is used in the present invention, unless otherwise indicated or apparent from the context, it is meant to indicate that one or more hydrogens, particularly 1 to 4 hydrogens, more particularly 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical shown in the expression are replaced with a selection from the group shown, provided that the normal valences are not exceeded, and that the replacement results in a chemically stable compound, i.e., a compound that is sufficiently robust to withstand isolation to a useful purity from the reaction mixture (isolation after the reaction, for example, purification by silica gel chromatography). In certain embodiments, when the number of substituents is not explicitly specified, the number of substituents is 1.

[0045] Combinations of substituents and / or variables are permissible only if such combinations result in chemically stable compounds. "Stable compound," in this context, is meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture (post-reaction isolation, e.g., purification by silica gel chromatography).

[0046] Those of skill in the art will understand that the term "optionally substituted" means that the atom or radical designated in the expression using "optionally substituted" may be substituted or unsubstituted (which means substituted or unsubstituted, respectively).

[0047] When two or more substituents are present on a moiety, they may replace hydrogen atoms on the same atom or they may replace hydrogen atoms on different atoms in the moiety, unless otherwise stated or apparent from the context.

[0048] Within the context of the present invention, "saturated" means "fully saturated" unless otherwise stated.

[0049] Unless otherwise stated or apparent from the context, the aromatic ring group may be attached to the remainder of the molecule of formula (I) by any available ring carbon atom (C-bonded) or nitrogen atom (N-bonded).

[0050] Unless otherwise specified or apparent from the context, aromatic ring groups may be optionally substituted on carbon and / or nitrogen atoms in accordance with embodiments where such is possible.

[0051] As used herein, the term "comprising" encompasses the terms "consisting of" and "consisting essentially of." All embodiments described herein using the term "comprising" are also applicable to embodiments of the invention where the term "comprising" is limited to "consisting of." Similarly, all embodiments described herein using the term "comprising" are also applicable to embodiments of the invention where the term "comprising" is limited to "consisting essentially of."

[0052] As used herein, the term "subject" refers to an animal, preferably a mammal (e.g., a cat, dog, primate, or human), more preferably a human, who is or has been the object of treatment, observation, or experiment.

[0053] The term "therapeutically effective amount," as used herein, means that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician, including alleviation or reversal of the symptoms of the disease or disorder being treated.

[0054] The term "composition" is intended to encompass a product comprising specified ingredients in specified amounts, and any product that results directly or indirectly from a combination of the specified ingredients in the specified amounts.

[0055] As used herein, the terms "treatment" and "treating" are intended to refer to any process that may slow, interrupt, halt or stop the progression of a disorder, or ameliorate one or more symptoms thereof, but does not necessarily indicate the complete elimination of all symptoms.

[0056] As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedge bonds or hashed wedge bonds, or otherwise shown as having a particular configuration (e.g., R, S) around one or more atoms contemplates each possible stereoisomer, or a mixture of two or more stereoisomers.

[0057] In the above and below, the term "compounds of formula (I)" is meant to include the tautomers thereof and their stereoisomeric forms.

[0058] Above and below, the term "compounds of formula (Z)" is meant to include tautomers thereof and their stereoisomeric forms.

[0059] Above and below, the terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" are used interchangeably.

[0060] The present invention includes all stereoisomers of the compounds of the present invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.

[0061] Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

[0062] Atropisomers (or atropoisomers) are stereoisomers with specific spatial configurations resulting from restricted rotation about a single bond due to significant steric hindrance. All atropisomers of the compounds of formula (I) are intended to be included within the scope of the present invention.

[0063] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related as mirror images. When a compound contains double bonds, the substituents may be in the E or Z configuration.

[0064] Substituents on a divalent cyclic saturated or partially saturated radical can have either the cis or trans configuration; for example, if the compound contains a disubstituted cycloalkyl group, the substituents can be in either the cis or trans configuration.

[0065] Thus, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, whenever chemically possible.

[0066] The meanings of all terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, are known to the person skilled in the art.

[0067] Absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at the asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated (+) or (-) depending on the direction they rotate plane polarized light. For example, resolved enantiomers whose absolute configuration is not known can be designated (+) or (-) depending on the direction they rotate plane polarized light.

[0068] When a particular stereoisomer is specified, this means that the stereoisomer is substantially free of other stereoisomers, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, particularly less than 2%, and most preferably less than 1% of other stereoisomers. Thus, when a compound of formula (I) is specified, for example, as (R), this means that the compound is substantially free of the (S) isomer, when a compound of formula (I) is specified, for example, as E, this means that the compound is substantially free of the Z isomer, and when a compound of formula (I) is specified, for example, as cis, this means that the compound is substantially free of the trans isomer.

[0069] Some of the compounds according to formula (I) may also exist in their tautomeric forms. Such forms, to the extent that they may exist, are intended to be included within the scope of the present invention even if not explicitly shown in formula (I) above. Thus, a single compound may exist in both stereoisomeric and tautomeric forms.

[0070] Pharmaceutically acceptable salts include acid addition salts and base addition salts.Such salts can be formed by conventional means, for example, by reacting free acid form or free base form with one or more equivalents of suitable base or acid, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (for example, in vacuum, by lyophilization, or by filtration).Salts can also be prepared by exchanging the counterion of the compound of the present disclosure in the form of a salt with another counterion, for example, by using a suitable ion exchange resin.

[0071] The pharma- ceutically acceptable salts referred to above and hereinafter are meant to include the therapeutically active non-toxic acid and base salt forms that the compounds of formula (I) and their solvates are able to form.

[0072] Suitable acids include, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acids, sulfuric, nitric, phosphoric acids, and the like, or organic acids such as, for example, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like. Conversely, the above salt forms can be converted to the free base form by treatment with an appropriate base.

[0073] The compounds of formula (I) or solvates thereof containing acidic protons may be converted into their non-toxic metal or amine salt forms by treatment with appropriate organic and inorganic bases.

[0074] Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, cesium, magnesium, calcium salts, and the like, organic bases such as primary, secondary and tertiary aliphatic amines and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline, and isoquinoline, benzathine, N-methyl-glucamine, hydrabamine salts, and salts with amino acids such as arginine, lysine, and the like. Conversely, the base forms can be converted to the free base forms by treatment with acid.

[0075] The term "prodrug" includes any compound which, following oral or parenteral administration, in particular following oral administration, is metabolized to a (more) active form in an experimentally detectable amount and within a given time (e.g. within a 0.5 to 24 hour dosing interval, or, for example, within a 6 to 24 hour dosing interval (i.e., once to four times daily)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration, in particular intravenous (IV), intramuscular (IM) and subcutaneous (SC) injections.

[0076] Prodrugs can be prepared by modifying functional groups present on the compound such that the modifications are cleaved in vivo when such prodrug is administered to a mammalian subject. The modification is typically accomplished by synthesizing the parent compound with a prodrug substituent. In general, prodrugs include compounds in which a hydroxyl, amino, sulfhydryl, carboxy, or carbonyl group is bonded to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy, or carbonyl group, respectively.

[0077] Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, ester groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs can be found, for example, in Bundegaard, H. "Design of Prodrugs" pl-92, Elsevier, New York-Oxford (1985).

[0078] The term solvates comprises the solvent addition forms, which the compounds of formula (I) are able to form, as well as the salts thereof. Examples of such solvent addition forms are, for example, hydrates, alcoholates, etc.

[0079] The compounds of the present invention prepared by the process described below may be synthesized in the form of a mixture of enantiomers, in particular a racemic mixture of enantiomers, which can be separated from each other according to resolution procedures known in the art. Methods for separating the enantiomeric forms of the compounds of formula (I) and their pharma-ceutically acceptable salts and solvates include liquid chromatography using chiral stationary phases. Said pure stereochemically isomers may also be derived from the corresponding pure stereochemically isomers of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, when a specific stereoisomer is desired, said compound will be synthesized by stereospecific preparation methods. These methods will advantageously employ enantiomerically pure starting materials.

[0080] As used herein, the term "enantiomerically pure" means that the product contains at least 80% by weight of one enantiomer and no more than 20% by weight of the other enantiomer. Preferably, the product contains at least 90% by weight of one enantiomer and no more than 10% by weight of the other enantiomer. In the most preferred embodiment, the term "enantiomerically pure" means that the composition contains at least 99% by weight of one enantiomer and no more than 1% of the other enantiomer.

[0081] The present invention also includes isotopically labeled compounds which are identical to those enumerated herein, but by virtue of the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (or the most abundant atom found in nature).

[0082] All isotopes and isotopic mixtures of any particular atom or element identified herein, whether naturally occurring or synthetically produced, either at natural abundance or in isotopically enriched form, are contemplated within the scope of the present invention. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine; 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 Br. Preferably, the isotope is 2 H, 3 H, 11 C. 13 C, and 18 F. Preferably, the isotope is selected from the group 2 H, 3 H, 11 C, and 18 F. More preferably, the isotope is selected from the group 2 H, 3 H or 13 C. More preferably, the isotope is 2 H or 13 C. More preferably, the isotope is 2H. In particular, deuterated compounds and 13 C-enriched compounds are intended to be included within the scope of the present invention. In particular, deuterium compounds are intended to be included within the scope of the present invention.

[0083] Certain isotopically labeled compounds (e.g. 3 H and 14 C) can be useful, for example, in substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability. Additionally, heavier isotopes, such as deuterium (i.e., 2 H) or the like may result in greater metabolic stability (e.g., increased half-life in vivo or reduced dosage requirements), which may result in certain therapeutic advantages and therefore may be preferred in some circumstances. For example, 15 O. 13 N, 11 C, and 18 Positron-emitting isotopes such as F are useful in positron emission tomography (PET) studies. PET imaging in cancer finds utility in helping to localize and identify tumors, stage disease, and determine suitable treatments. Human cancer cells overexpress many receptors or proteins that are potential disease-specific molecular targets. Radiolabeled tracers that bind with high affinity and specificity to such receptors or proteins on tumor cells have great potential for diagnostic imaging and targeted radionuclide therapy (Charron, Carlie L. et al. Tetrahedron Lett. 2016, 57(37), 4119-4127). Furthermore, target-specific PET radiotracers can be used as biomarkers to investigate and evaluate pathology, for example, by measuring target expression and treatment response (Austin R. et al. Cancer Letters (2016), doi:10.1016 / j.canlet.2016.05.008).

[0084] Solid oral dosage forms, such as tablets or capsules, containing one or more compounds described herein may be administered in at least one dosage form at a time, if desired. It is also possible to administer the compounds in sustained release formulations.

[0085] Additional oral forms in which the compounds described herein can be administered include elixirs, solutions, syrups, and suspensions, each optionally containing flavoring and coloring agents.

[0086] Alternatively, one or more compounds described herein may be administered by inhalation (intratracheal or intranasal) or in the form of a suppository or pessary, or may be applied topically in the form of a lotion, solution, cream, ointment, or dusting powder. For example, the compounds may be added to a cream comprising, consisting of, and / or consisting essentially of an aqueous emulsion of polyethylene glycol or liquid paraffin. The compounds may also be added to an ointment comprising, consisting of, and / or consisting essentially of a wax or soft paraffin base, together with optional stabilizers and preservatives as required, at a concentration of about 1% to about 10% by weight of the cream. Alternative means of administration include transdermal administration by using a skin or transdermal patch.

[0087] The pharmaceutical compositions used in the methods of the present invention (as well as the compounds alone) can be injected parenterally, for example, intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally, or intrathecally, in which case the composition also includes at least one of a suitable carrier, a suitable excipient, and a suitable diluent.

[0088] For parenteral administration, the pharmaceutical compositions of the invention are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts and monosaccharides to make the solution isotonic with blood.

[0089] For buccal or sublingual administration, the pharmaceutical compositions of the invention may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.

[0090] As a further example, a pharmaceutical composition containing a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and optionally at least one other anti-neoplastic agent as an active ingredient can be prepared by mixing the compound with a pharma- ceutically acceptable carrier, a pharma- ceutically acceptable diluent, and / or a pharma- ceutically acceptable excipient according to conventional pharmaceutical compounding techniques. Carriers, excipients, and diluents can take a wide variety of forms, depending on the desired route of administration (e.g., oral, parenteral, etc.). Thus, for liquid oral formulations such as suspensions, syrups, elixirs, and solutions, suitable carriers, excipients, and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, and the like. For solid oral formulations such as powders, capsules, and tablets, suitable carriers, excipients, and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. To control the primary site of absorption and disintegration, solid oral preparations can be optionally coated with substances such as sugars or enteric coated. For parenteral administration, carriers, excipients and diluents usually comprise sterile water, and other ingredients may be added to enhance the solubility and preservability of the composition. Injectable suspensions or solutions can also be prepared using aqueous carriers with suitable additives, such as solubilizers and preservatives.

[0091] According to certain embodiments, the method of using a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and optionally at least one other anti-neoplastic agent, may include a dose range of about 0.1 mg to about 3000 mg of active ingredient, or any particular amount or range therein, particularly a dose range of about 1 mg to about 1000 mg, or any particular amount or range therein, in a regimen of about 1 to about (4x) per day for an average (70 kg) human, although it will be apparent to one of skill in the art that the therapeutically effective amounts of the compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and optionally at least one other anti-neoplastic agent will vary depending on the disease, syndrome, condition, and disorder being treated.

[0092] One embodiment of the present invention relates to a method of using a pharmaceutical composition for oral administration comprising a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof in an amount of about 1 mg to about 500 mg. Advantageously, the compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof may be administered in a single dose per day, or the total daily dosage may be administered in 2, 3 and (4x) divided doses per day.

[0093] The optimal dosage of the compound of formula (I) or its pharmacologic acceptable salt or solvate to be administered can be easily determined and varies according to the specific compound used, the mode of administration, the strength of the preparation, and the progression of hematopoietic disorder.In addition, factors related to the specific subject to be treated, such as the subject's sex, age, weight, diet, and administration time, may require adjustment of the dosage to achieve appropriate therapeutic level and desired therapeutic effect.Therefore, the dosages above are examples of the average case.It goes without saying that there may be individual cases in which higher or lower dosage ranges are effective, and these are also within the scope of the present invention.

[0094] The compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof may be administered in any of the compositions and dosing regimens described above, or by compositions and dosing regimens established in the art, whenever the compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof is administered to a subject in need thereof for use.

[0095] One embodiment of the present invention relates to a method of using a pharmaceutical composition for intravenous or subcutaneous administration comprising a BCL-2 inhibitor in an amount of about 1 mg to about 500 mg. Advantageously, the BCL-2 inhibitor can be administered in a single daily dose, or the total daily dose can be administered in 2, 3 and (4x) divided doses per day.

[0096] The optimal dose of the BCL-2 inhibitor to be administered can be easily determined and depends on the specific compound used, the form of administration, the strength of the formulation, and the progression of the disease, syndrome, condition, or disorder.In addition, factors related to the specific subject to be treated, such as the subject's sex, age, weight, diet, and administration time, may require adjustment of the dose to achieve an appropriate therapeutic level and the desired therapeutic effect.The above dosage amounts are therefore examples of the average case.It goes without saying that there may be individual cases in which higher or lower dosage ranges are effective, and these are also within the scope of the present invention.

[0097] The BCL-2 inhibitor can be administered in any of the compositions and administration regimens described above, or using compositions and administration regimens established in the art, whenever a BCL-2 inhibitor is administered to a subject in need thereof.

[0098] As used herein, the term "menin-MLL inhibitors" refers to inhibitors of the protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1), also known in the scientific art as histone-lysine N-methyltransferase 2A (KMT2A) protein (UniProt Accession No. Q03164), which inhibit or reduce menin-MLL1 activity. The menin-MLL inhibitors described herein are disclosed in International Application No. CN2020 / 137266 (published as WO 2021 / 121327 on June 24, 2021), which is incorporated herein by reference in its entirety, and which also disclose corresponding synthetic schemes and analytical characterization.

[0099] As used herein, the term "BCL-2 inhibitor" refers to an agent that inhibits or reduces BCL-2 activity.

[0100] As used herein, the term "anti-neoplastic agent" refers to any agent that treats cancer.

[0101] As used herein, the term "hypomethylating agent" refers to an agent that inhibits or reduces DNA methylation.

[0102] As used herein, the term "kinase inhibitor" refers to an agent that inhibits or reduces the activity of at least one kinase (e.g., tyrosine and / or serine kinases, such as fms-like receptor tyrosine kinase-3 (FLT3), Bruton's tyrosine kinase (BTK), Abelson tyrosine kinase 1 (ABL), Aurorace serine / tyrosine kinase, etc.).

[0103] As used herein, the term "FLT-3 inhibitors" refers to tyrosine kinase inhibitors (TKIs) that are classified into first-generation and next-generation inhibitors based on their potency and specificity for fms-like receptor tyrosine kinase-3 (FLT3) and their associated downstream targets.

[0104] As used herein, the term "CD20 inhibitor" refers to any agent that reduces the activity of CD20.

[0105] As used herein, the term "isocitrate dehydrogenase (IDH) inhibitor" refers to any agent that interferes with the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle.

[0106] As used herein, the term "immunomodulatory anti-neoplastic agent" refers to any agent that enhances anti-tumor immune cell activity.

[0107] As used herein, the term "programmed cell death protein 1 (PD-1) inhibitor" refers to any agent that inhibits or reduces PD-1 activity.

[0108] As used herein, the term "dihydroorotate dehydrogenase (DHODH) inhibitor" refers to any agent that inhibits or reduces dihydroorotate dehydrogenase activity.

[0109] As used herein, unless otherwise specified, the terms "affected" or "affected" (when referring to a disease, disorder or medical condition affected by inhibition or alteration of menin-MLL activity) include a reduction in the frequency and / or severity of one or more symptoms or signs of said hematopoietic disorder and / or include prevention of the onset of one or more symptoms or signs of said hematopoietic disorder or prevention of the onset of a hematopoietic disorder.

[0110] As used herein, the term "hematopoietic disorder" refers to any disorder associated with the production of the cellular components of blood and plasma, including, but not limited to, blood cancers.

[0111] According to one embodiment, the invention provides a combination as described herein.

[0112] According to one embodiment, the present invention provides a combination as described herein for use as a medicament.

[0113] According to one embodiment, the present invention provides a combination as described herein for the manufacture of a medicament.

[0114] According to one embodiment, the present invention provides a combination as described herein for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned herein.

[0115] According to one embodiment, the invention provides a combination as described herein for use in the prevention or treatment, in particular the treatment, of a disease as described herein.

[0116] According to one embodiment, the present invention provides a combination as described herein for use in the prevention or treatment, particularly the treatment, of a hematopoietic disorder, such as but not limited to, a blood cancer, such as but not limited to, lymphoma, myeloma and leukemia.

[0117] According to one embodiment, the invention provides a combination as described herein for use in the prevention or treatment, in particular the treatment, of a hematopoietic disorder.

[0118] According to one embodiment, the hematopoietic disorder is selected from, but is not limited to, lymphoma, myeloma, myelodysplasia, and leukemia.

[0119] According to one embodiment, the hematopoietic disorder is a lymphoma selected from Hodgkin's lymphoma and non-Hodgkin's lymphoma.

[0120] According to one embodiment, the lymphoma is a non-Hodgkin's lymphoma that is Burkitt's lymphoma, anaplastic large cell lymphoma, splenic marginal zone lymphoma, hepatosplenic T-cell lymphoma, or angioimmunoblastic T-cell lymphoma (AILT).

[0121] In one embodiment, the hematopoietic disorder is myeloma. In one embodiment, the hematopoietic disorder is multiple myeloma, Waldenstrom's macroglobulinemia, or plasmacytoma.

[0122] According to one embodiment, the hematopoietic disorder is myelodysplasia, including but not limited to myelodysplastic syndromes (MDS).

[0123] According to one embodiment, the hematopoietic disorder is leukemia.

[0124] In one embodiment, the hematopoietic disorder is a leukemia selected from acute leukemia and chronic leukemia. In one embodiment, the leukemia is an acute leukemia. In one embodiment, the leukemia is a chronic leukemia.

[0125] According to one embodiment, the hematopoietic disorder is myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, or lymphocytic leukemia. According to one embodiment, the hematopoietic disorder is a leukemia selected from, but not limited to, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), acute myeloid leukemia (AML), chronic idiopathic myelofibrosis (MF), chronic myelogenous leukemia (CML), T-cell prolymphocytic leukemia (T-PLL), B-cell prolymphocytic leukemia (B-PLL), chronic neutrophilic leukemia (CNL), hairy cell leukemia (HCL), T-cell large granular lymphocytic leukemia (T-LGL), and aggressive NK cell leukemia. According to one embodiment, the AML is acute megakaryoblastic leukemia (AMKL).

[0126] According to one embodiment, the leukemia is MDS, CLL, SLL, ALL or AML. According to one embodiment, the leukemia is CLL, SLL or AML. According to one embodiment, the leukemia is CLL or SLL. In some embodiments, the CLL or SLL is a CD20 expressing cancer. According to one embodiment, the leukemia is ALL or AML. According to one embodiment, the leukemia is ALL. According to one embodiment, the leukemia is AML. According to one embodiment, the hematopoietic disorder is Waldenstrom's macroglobulinemia.

[0127] According to one embodiment, the hematopoietic disorder is MLL-rearranged leukemia, MLL partial tandem duplication (PTD) leukemia, MLL-amplified leukemia, MLL-positive leukemia, or leukemia exhibiting an elevated HOX / MEIS1 gene expression signature.

[0128] According to one embodiment, the leukemia is MLL-rearranged leukemia and / or nucleophosmin 1 (NPM1) mutant leukemia. According to one embodiment, the hematopoietic disorder is MLL-rearranged leukemia.

[0129] According to one embodiment, the hematopoietic disorder is nucleophosmin 1 (NPM1) mutant leukemia (eg, NPM1c).

[0130] According to one embodiment, the present invention provides a method for treating a hematopoietic disorder, which is myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and optionally at least one other anti-neoplastic agent.

[0131] According to one embodiment, the hematopoietic disorder is myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

[0132] According to one embodiment, the hematopoietic disorder is acute lymphoblastic leukemia (ALL).

[0133] According to one embodiment, the hematopoietic disorder is acute myeloid leukemia (AML).

[0134] According to one embodiment, the hematopoietic disorder is small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL).

[0135] According to one embodiment, the hematopoietic disorder is SLL or CLL, wherein SLL or CLL is a CD20-expressing cancer.

[0136] According to one embodiment, the hematopoietic disorder is myelodysplastic syndrome (MDS).

[0137] According to one embodiment, the hematopoietic disorder is a myeloproliferative neoplasm (MPN).

[0138] According to one embodiment, the hematopoietic disorder is NPM1 mutant leukemia with a FLT3 mutation.

[0139] According to one embodiment, the hematopoietic disorder is FLT3-dependent leukemia.

[0140] According to one embodiment, the hematopoietic disorder is MEF2G-dependent leukemia.

[0141] According to one embodiment, the hematopoietic disorder has one or more MLL1 (KMT2A) gene rearrangements or alterations (eg, duplications or amplifications) and / or NPM1 mutations.

[0142] According to one embodiment, the hematopoietic disorder has (i) one or more MLL1 (KMT2A) gene rearrangements or alterations (e.g., duplications or amplifications) and / or NPM1 mutations in addition to (ii) a FLT3 mutation.

[0143] According to one embodiment, the hematopoietic disorder is an MLL-rearranged leukemia.

[0144] According to one embodiment, the hematopoietic disorder is acute myeloid leukemia (AML).

[0145] According to one embodiment, the hematopoietic disorder is small lymphocytic lymphoma (SLL).

[0146] According to one embodiment, the hematopoietic disorder is chronic lymphocytic leukemia (CLL).

[0147] According to one embodiment, the hematopoietic disorder is acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), MLL-rearranged leukemia, MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, or leukemia exhibiting an elevated HOX / MEIS1 gene expression signature.

[0148] According to one embodiment, the hematopoietic disorder is AML, specifically nucleophosmin (NPM1)-mutated AML (i.e., NPM1 mut AML), more specifically abstract NPM1-mutated AML.

[0149] According to one embodiment, the hematopoietic disorder is an MLL-rearranged leukemia, in particular MLL-rearranged AML or ALL.

[0150] According to one embodiment, the hematopoietic disorder comprises an MLL gene alteration, in particular the hematopoietic disorder is AML or ALL with an MLL gene alteration. In a particular embodiment, the MLL gene alteration is a duplication. In a particular embodiment, the MLL gene alteration is an amplification.

[0151] According to one embodiment, the hematopoietic disorder comprises an NPM1 gene mutation and / or an MLL1 (also known as KMT2A) gene mutation.

[0152] According to one embodiment, the MLL1 gene mutation includes, but is not limited to, MLL1 gene rearrangement, duplication or amplification.

[0153] According to one embodiment, the hematopoietic disorder is mixed lineage leukemia (MLL), MLL-associated leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, MLL-associated leukemia, acute leukemia, chronic leukemia, myelodysplastic syndrome (MDS), or myeloproliferative neoplasms (MPN).

[0154] All embodiments described herein with respect to methods for treating hematopoietic disorders are also applicable for use in treating said hematopoietic disorders.

[0155] All embodiments described herein for use in treating a hematopoietic disorder are also applicable to methods for treating said hematopoietic disorder.

[0156] All embodiments described herein with respect to methods for treating hematopoietic disorders are also applicable for use in the methods for treating hematopoietic disorders.

[0157] All embodiments described herein for use in a method for treating a hematopoietic disorder are also applicable to the method for treating the hematopoietic disorder.

[0158] In one embodiment, the present invention provides a therapeutically effective amount of a menin-MLL inhibitor of formula (I) or a tautomer or stereoisomeric form thereof or a pharma- ceutical acceptable salt or solvate thereof; a therapeutically effective amount of a BCL-2 inhibitor; - Optionally, with a therapeutically effective amount of at least one other anti-neoplastic agent.

[0159] According to one embodiment, the compound of formula (I) has the structure:

[0160] [ka] and tautomeric and stereoisomeric forms thereof, R 1a is -C(=O)-NR xa R xb , Het, or

[0161] [ka] Het represents a 5- or 6-membered monocyclic aromatic ring containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety; The 5- or 6-membered monocyclic aromatic ring is optionally 3~6 Cycloalkyl and C 1~4 substituted with 1 or 2 substituents selected from the group consisting of alkyl; R xa and R xb is hydrogen, C 1~4 Alkyl and C 3~6 cycloalkyl; R 1b represents F or Cl, Y 1 -CR 5a R 5b -, -O-, or -NR 5c - represents R 2 is hydrogen, halo, C 1~4 Alkyl, -OC 1~4Alkyl, and -NR 7a R 7b is selected from the group consisting of U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 5a , R 5b , R 5c , R 7a and R 7b is hydrogen, C 1~4 Alkyl and C 3~6 cycloalkyl; R 3 -C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b , -C 1~6 Alkyl-OH or -C 1~6 Alkyl-NR 11 -C(=O)-OC 1~4 Alkyl-OC(=O)-C 1~4 represents alkyl, where R 3 C in the definition of 1~4 Alkyl or C 1~6 Each of the alkyl moieties, independently of the others, is selected from cyano, halo, -OH, and -OC. 1~4 and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, R 8a and R 8b is hydrogen, C 1~6 Alkyl, -C(=O)-C 1~4 Alkyl, -C(=O)-OC 1~4 Alkyl, -C(=O)-NR 12a R 12b , as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC1~4 Alkyl, -C(=O)-NR 10a R 10b and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; R 9a , R 9b , R 10a , R 10b , R 10c , R 11 , R 12a , and R 12b is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0162] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb , Het, or

[0163] [ka] represents Het represents a 5- or 6-membered monocyclic aromatic ring containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety; The 5- or 6-membered monocyclic aromatic ring is optionally 3~6 Cycloalkyl and C 1~4 substituted with 1 or 2 substituents selected from the group consisting of alkyl; R xa and R xb is hydrogen, C 1~4 Alkyl and C 3~6 cycloalkyl; R 1b represents F or Cl, Y 1-CR 5a R 5b -, -O-, or -NR 5c - represents R 2 is hydrogen, halo, C 1~4 Alkyl, -OC 1~4 Alkyl, and -NR 7a R 7b is selected from the group consisting of U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 5a , R 5b , R 5c , R 7a and R 7b is hydrogen, C 1~4 Alkyl and C 3~6 cycloalkyl; R 3 -C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b , -C 1~6 Alkyl-OH or -C 1~6 Alkyl-NR 11 -C(=O)-OC 1~4 Alkyl-OC(=O)-C 1~4 represents an alkyl group, Here, R 3 C in the definition of 1~4 Alkyl or C 1~6 Each of the alkyl moieties, independently of the others, is cyano, halo, or -OC. 1~4 and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, R 8a and R 8b is hydrogen, C 1~6 Alkyl, -C(=O)-C1~4 Alkyl, -C(=O)-OC 1~4 Alkyl, -C(=O)-NR 12a R 12b , as well as cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, and -C(=O)-NR 10a R 10b C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 1~6 alkyl; R 9a , R 9b , R 10a , R 10b , R 11 , R 12a , and R 12b is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0164] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb , Het, or

[0165] [ka] represents Het represents a 5- or 6-membered monocyclic aromatic ring containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety; The 5- or 6-membered monocyclic aromatic ring is optionally 3~6 Cycloalkyl and C 1~4 substituted with 1 or 2 substituents selected from the group consisting of alkyl; R xa and R xb is hydrogen, C 1~4 Alkyl and C 3~6cycloalkyl; R 1b represents F or Cl, Y 1 -CR 5a R 5b -, -O-, or -NR 5c - represents R 2 is hydrogen, halo, C 1~4 Alkyl, -OC 1~4 Alkyl, and -NR 7a R 7b is selected from the group consisting of U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 5a , R 5b , R 5c , R 7a and R 7b is hydrogen, C 1~4 Alkyl and C 3~6 cycloalkyl; R 3 is C 1~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 1~6 The alkyl portion can be cyano, halo, -OH, or -OC. 1~4 and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, R 8a and R 8b is hydrogen, C 1~6 Alkyl, and -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b , and -NR10c -C(=O)-C 1~4 C, each independently substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl 1~6 alkyl; R 10a , R 10b , R 10c is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0166] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb , Het, or

[0167] [ka] represents Het represents a 5- or 6-membered monocyclic aromatic ring containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety; The 5- or 6-membered monocyclic aromatic ring is optionally 3~6 Cycloalkyl and C 1~4 substituted with 1 or 2 substituents selected from the group consisting of alkyl; R xa and R xb is hydrogen, C 1~4 Alkyl and C 3~6 cycloalkyl; R 1b represents F or Cl, Y 1 -CR 5a R 5b -, -O-, or -NR 5c - represents R 2 is hydrogen, halo, C 1~4 Alkyl, -OC 1~4Alkyl, and -NR 7a R 7b is selected from the group consisting of U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 5a , R 5b , R 5c , R 7a and R 7b is hydrogen, C 1~4 Alkyl and C 3~6 cycloalkyl; R 3 is C 1~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 1~6 The alkyl portion can be cyano, halo, or -OC. 1~4 and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, and -C(=O)-NR 10a R 10b C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 1~6 alkyl; R 10a and R 10b is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0168] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb or Het, Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms, said 6-membered monocyclic aromatic ring being joined to one C 3~6 is substituted with cycloalkyl; R xa and R xb is C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 -C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b , -C 1~6 Alkyl-OH or -C 1~6 Alkyl-NR 11 -C(=O)-OC 1~4 Alkyl-OC(=O)-C 1~4 represents an alkyl group, Here, R 3 C in the definition of 1~4 Alkyl or C 1~6 Each of the alkyl moieties, independently of the others, is -OH, and -OC 1~4 and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, R 8a and R8b is hydrogen, C 1~6 Alkyl, -C(=O)-C 1~4 Alkyl, -C(=O)-OC 1~4 Alkyl, -C(=O)-NR 12a R 12b , as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; R 9a , R 9b , R 10a , R 10b , R 10c , R 11 , R 12a , and R 12b is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0169] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb or Het, Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms, said 6-membered monocyclic aromatic ring being joined to one C 3~6 is substituted with cycloalkyl; R xa and R xb is C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2represents hydrogen, U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 is C 1~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 1~6 The alkyl portion is -OH and -OC 1~4 and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b , and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; R 10a , R 10b , and R 10c is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0170] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb , Rxa and R xb is C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 is C 1~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 1~6 The alkyl portion is -OH and -OC 1~4 and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b , and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; R 10a , R 10b , and R 10c is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0171] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb or Het, Het is one C 3~6 represents pyrimidinyl substituted by cycloalkyl; R xa and R xb is C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 is C 1~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 1~6 The alkyl portion may be optionally substituted with one -OH. R 8a and R 8b is hydrogen, C 1~6 Alkyl and halo, -OC 1~4 Alkyl, and -NR 10c -C(=O)-C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; R 10a , R 10b , and R 10c is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0172] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb or Het, Het is one C 3~6 represents pyrimidinyl substituted by cycloalkyl; R xa and R xb is C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N; n2 is 2, n1, n3 and n4 are 1; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 is C 1~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 1~6 The alkyl portion may be optionally substituted with one -OH. R 8a and R 8b is hydrogen, C 1~6 Alkyl and halo, -OC 1~4 Alkyl, and -NR 10c -C(=O)-C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; R 10a , R 10b , and R10c is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0173] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb , R xa and R xb is C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N; n2 is 2, n1, n3 and n4 are 1; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 is C 1~6 Alkyl-NR 8a R 8b represents R 8a and R 8b is hydrogen, C 1~6 Alkyl and halo, -OC 1~4 Alkyl, and -NR 10c -C(=O)-C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; R 10a , R 10b , and R 10c is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0174] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N; n2 is 2, n1, n3 and n4 are 1; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 is CH 2 -CH 2 -CH 2 -NR 8a R 8b represents R 8a and R 8b is hydrogen, C 1~6 Alkyl and halo, -OC 1~4 Alkyl, and -NR 10c -C(=O)-C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; R 10a , R 10b , and R 10c is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0175] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 is C 1~6 Alkyl-NR 8a R 8b represents R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, and -C(=O)-NR 10a R 10b C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 1~6 alkyl; R 10a and R 10b is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0176] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 is CH 2 -CH 2 -CH 2 -NR 8a R 8b represents R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, and -C(=O)-NR 10a R 10b C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 1~6 alkyl; R 10a and R 10b is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0177] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb represents R xa and R xb is hydrogen or C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 is CH 2 -CH 2 -CH 2 -NR 8a R 8b represents R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, and -C(=O)-NR 10a R 10b C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 1~6 alkyl; R 10a and R 10b is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0178] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb represents R xa and R xb is hydrogen or C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 is CH 2 -CH 2 -CH 2 -NR 8a R 8b represents R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as -OH and -OC 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; and pharma-ceutically acceptable salts and solvates thereof.

[0179] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 is C 1~6 Alkyl-NR 8a R 8b represents R 8a and R 8b is C 1~6 Alkyl and one -OC 1~4 Alkyl-substituted C 1~6 alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0180] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 is CH 2 -CH 2 -CH 2 -NR 8a R 8b represents R 8a and R 8b is C 1~6 Alkyl and one -OC 1~4 Alkyl-substituted C 1~6 alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0181] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb , or Het, Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms, said 6-membered monocyclic aromatic ring optionally containing one C 3~6 is substituted with cycloalkyl; R xa and R xb is C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 is hydrogen, U represents N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3-C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b , -C 1~6 Alkyl-OH or -C 1~6 Alkyl-NR 11 -C(=O)-OC 1~4 Alkyl-OC(=O)-C 1~4 represents an alkyl group, R 8a and R 8b is hydrogen, C 1~6 Alkyl, -C(=O)-C 1~4 Alkyl, -C(=O)-OC 1~4 Alkyl, -C(=O)-NR 12a R 12b , as well as cyano, halo, -S(=O) 2 -C 1~4 Alkyl and -OC 1~4 C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; R 9a , R 9b , R 12a , and R 12b is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0182] According to one embodiment, the compounds of formula (I) are as defined herein, as well as their tautomeric and stereoisomeric forms, R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents an alkyl group, R 1b represents F, Y 1 represents -O-, R 2 is hydrogen, U represents N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N, R 4 represents isopropyl, R 3 -C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b Or -C 1~6 represents alkyl-OH, R 8a and R 8b is hydrogen, C 1~6 Alkyl, -C(=O)-C 1~4 Alkyl, -C(=O)-OC 1~4 Alkyl, -C(=O)-NR 12a R 12b , as well as cyano, halo, -S(=O) 2 -C 1~4 Alkyl and -OC 1~4 C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; R 9a , R 9b , R 12a , and R 12b is hydrogen and C 1~6 each independently selected from the group consisting of alkyl, and pharma-ceutically acceptable salts and solvates thereof.

[0183] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 1b represents F.

[0184] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 2 represents hydrogen.

[0185] In one embodiment, the present invention comprises a compound of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein n1 is 1, n2 is 2, n3 is 1 and n4 is 1.

[0186] In one embodiment, the present invention comprises a compound of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y 1 represents -O-.

[0187] In one embodiment, the present invention comprises a compound of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y 1 represents -O-, and U represents N.

[0188] In one embodiment, the present invention comprises a compound of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y 1 represents -O-, U represents N, R 1b represents F, R 2 represents hydrogen.

[0189] In one embodiment, the present invention comprises compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het is

[0190] [ka] Represents.

[0191] In one embodiment, the present invention comprises compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents a monocyclic 5- or 6-membered aromatic ring containing 1 or 2 nitrogen atoms, wherein the monocyclic 5- or 6-membered aromatic ring is one C 3~6 It is substituted with cycloalkyl.

[0192] In one embodiment, the present invention comprises compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents a monocyclic 5- or 6-membered aromatic ring containing 1 or 2 nitrogen atoms, said monocyclic 5- or 6-membered aromatic ring containing one C 3~6 cycloalkyl-substituted, R 1b represents F.

[0193] In one embodiment, the present invention comprises compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents a monocyclic 6-membered aromatic ring containing 1 or 2 nitrogen atoms, said monocyclic 6-membered aromatic ring containing one C 3~6 It is substituted with cycloalkyl.

[0194] In one embodiment, the present invention comprises compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents a monocyclic 6-membered aromatic ring containing 1 or 2 nitrogen atoms, said monocyclic 6-membered aromatic ring containing one C 3~6 cycloalkyl-substituted, R 1b represents F.

[0195] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 1~6 The alkyl portion can be cyano, halo, or -OC. 1~4 It may be substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl.

[0196] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 1~6 The alkyl portion can be cyano, halo, -OH, or -OC. 1~4 It may be substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl.

[0197] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b Represents.

[0198] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b where R 3C in the definition of 1~6 The alkyl portion can be cyano, halo, or -OC. 1~4 alkyl; R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl.

[0199] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b R 3 C in the definition of 1~6 The alkyl portion can be cyano, halo, -OH, or -OC. 1~4 alkyl; R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl.

[0200] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 1~6 The alkyl portion can be cyano, halo, or -OC. 1~4 alkyl; R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, and -C(=O)-NR 10a R 10b C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 1~6 alkyl.

[0201] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 1~6 The alkyl portion can be cyano, halo, or -OC. 1~4 alkyl; R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10aR 10b and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl.

[0202] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 1~6 The alkyl portion can be cyano, halo, -OH, or -OC. 1~4 alkyl; R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, and -C(=O)-NR 10a R 10b C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 1~6 alkyl.

[0203] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 1~6 The alkyl portion can be cyano, halo, -OH, or -OC. 1~4alkyl; R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl.

[0204] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl portion is cyano, halo and -OC 1~4 It may be substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl.

[0205] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl portion can be cyano, halo, -OH, or -OC. 1~4 It may be substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl.

[0206] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl portion is cyano, halo and -OC 1~4 alkyl; R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl.

[0207] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl portion can be cyano, halo, -OH, or -OC. 1~4 alkyl; R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4Alkyl, -C(=O)-NR 10a R 10b and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl.

[0208] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl portion can be cyano, halo, -OH, or -OC. 1~4 alkyl; R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, and -C(=O)-NR 10a R 10b C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 1~6 alkyl.

[0209] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl portion is cyano, halo and -OC 1~4alkyl; R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, and -C(=O)-NR 10a R 10b C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 1~6 alkyl.

[0210] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b represents R 8a and R 8b is C 1~6 Alkyl, as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, and -C(=O)-NR 10a R 10b C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 1~6 alkyl.

[0211] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl portion can be cyano, halo, -OH, or -OC.1~4 alkyl; R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl.

[0212] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl portion is cyano, halo and -OC 1~4 alkyl; R 8a and R 8b is hydrogen, C 1~6 Alkyl, as well as cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl.

[0213] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b represents R 8a and R 8b is C 1~6 Alkyl, as well as -OH, cyano, halo, -S(=O) 2 -C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl 1~6 alkyl.

[0214] In one embodiment, the present invention comprises a compound of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b R 8a is C 1~6 represents alkyl, R 8b 1 piece -OC 1~4 Alkyl-substituted C 1~6 Represents alkyl.

[0215] In one embodiment, the present invention relates to a method of using a compound of formula (I) and pharma- ceutical acceptable salts and solvates thereof, or any subgroup thereof as described in any of the other embodiments, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b , -C1~6 Alkyl-OH or -C 1~6 Alkyl-NR 11 -C(=O)-OC 1~4 Alkyl-OC(=O)-C 1~4 represents alkyl, where R 3 C in the definition of 1~4 Alkyl moiety or C 1~6 Each of the alkyl moieties, independently of the others, is cyano, halo, or -OC. 1~4 It may be substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl.

[0216] In one embodiment, the present invention comprises compounds of formula (I) and pharma- ceutical acceptable salts and solvates thereof, or any subgroup thereof as described in any of the other embodiments, wherein R 3 -C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b , or -C 1~6 Alkyl-NR 11 -C(=O)-OC 1~4 Alkyl-OC(=O)-C 1~4 represents alkyl, where R 3 C in definition 1~4 Alkyl moiety or C 1~6 Each of the alkyl moieties, independently of the others, is selected from cyano, halo, -OH, and -OC. 1~4 It may be substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl.

[0217] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 is -CH 2 -CH 2 -CH 2 -NR 8a R 8b Represents.

[0218] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 is -CH 2 -CH 2 -CH 2 -NR 8a R 8b R 8a represents methyl, R 8b is -CH 2 -CH 2 -OCH 3 Represents.

[0219] In one embodiment, the present invention comprises compounds of formula (I) and pharma- ceutical acceptable salts and solvates thereof, or any subgroup thereof as described in any of the other embodiments, wherein R 3 C in the definition of 1~6 Alkyl, -C 1~6 Alkyl-NR 8a R 8b is -CH 2 -CH 2 -CH 2 -Limited to.

[0220] In one embodiment, the invention comprises a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, or any subgroup thereof, as described in any of the other embodiments, wherein the compound of formula (I) has formula (Ia) or formula (Ib):

[0221] [ka] Limited to the compounds In the formula, R 1a , R 1b , R 3 , R 4 , R 5a , R 5b , X 1 , X 2, n1, n2, n3, n4 and halo are as defined for the compounds of formula (I) or any subgroup thereof according to any of the other embodiments.

[0222] In one embodiment, the compounds of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, or any subgroup thereof described in any of the other embodiments, is limited to compounds of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof.In one embodiment, the compounds of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, or any subgroup thereof described in any of the other embodiments, is limited to compounds of formula (Ib), or a pharma- ceutically acceptable salt or solvate thereof.

[0223] In one embodiment, the invention comprises a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, or any subgroup thereof, as described in any of the other embodiments, wherein the compound of formula (I) has the formula (Iy):

[0224] [ka] Limited to In the formula, R 3 is as defined for the compounds of formula (I) or any subgroup thereof as described in any of the other embodiments.

[0225] In formula (Iy), n1 is 1, n2 is 2, n3 is 1, and n4 is 1.

[0226] In certain embodiments, the compound of formula (I) is compound A:

[0227] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0228] In certain embodiments, the compound of formula (I) is compound A1:

[0229] [ka] It is.

[0230] In certain embodiments, the compound of formula (I) is compound A2:

[0231] [ka] It is.

[0232] In certain embodiments, the compound of formula (I) is compound A3:

[0233] [ka] It is.

[0234] In certain embodiments, the compound of formula (I) is compound A4-a:

[0235] [ka] or a solvate thereof.

[0236] In certain embodiments, the menin-MLL inhibitor of formula (I) is (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide besylate, or a hydrate thereof.

[0237] In certain embodiments, the menin-MLL inhibitor of formula (I) is (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate, or a solvate thereof.

[0238] In certain embodiments, the menin-MLL inhibitor of formula (I) is (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4 triazin-6-yl)oxy)benzamide bisbesylate (compound A4-b) or a hydrate thereof.

[0239] In certain embodiments, the menin-MLL inhibitor of formula (I) is compound A4, i.e., crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4 triazin-6-yl)oxy)benzamide bisbesylate hydrate hydrate.

[0240] In certain embodiments, the menin-MLL inhibitor of formula (I) is crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4 triazin-6-yl)oxy)benzamide bisbesylate 0.5-2.0 equivalent hydrate.

[0241] In one embodiment, the present invention relates to a subgroup of formula (I) defined in the general reaction scheme:

[0242] In one embodiment, the compound of formula (I) is selected from the group consisting of the exemplified compounds, their tautomers and stereoisomeric forms, and any of the free bases, any pharma- ceutically acceptable salts, and solvates thereof.

[0243] In some embodiments, a pharmaceutical composition is provided that includes a pharma- ceutical acceptable carrier and, as an active ingredient, a therapeutically effective amount of a combination as described in any of the other embodiments.

[0244] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and, optionally, at least one other anti-neoplastic agent.

[0245] According to an embodiment, the menin-MLL inhibitor is a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof.

[0246] According to certain embodiments, the menin-MLL inhibitor is compound A or a pharma- ceutically acceptable salt or solvate thereof.

[0247] According to a particular embodiment, the menin-MLL inhibitor is compound A1.

[0248] According to a particular embodiment, the menin-MLL inhibitor is compound A2.

[0249] According to a particular embodiment, the menin-MLL inhibitor is compound A3.

[0250] According to certain embodiments, the menin-MLL inhibitor is compound A4-a or a solvate thereof.

[0251] According to certain embodiments, the menin-MLL inhibitor is compound A4-b or a hydrate thereof.

[0252] According to a particular embodiment, the menin-MLL inhibitor is compound A4.

[0253] In certain embodiments, menin-MLL inhibitors may have improved metabolic stability properties.

[0254] In certain embodiments, menin-MLL inhibitors may have an extended in vivo half-life (T1 / 2).

[0255] In certain embodiments, menin-MLL inhibitors may have improved oral bioavailability.

[0256] In certain embodiments, menin-MLL inhibitors may reduce tumor growth, for example, tumors harboring MLL (KMT2A) gene rearrangements / alterations and / or NPM1 mutations.

[0257] In certain embodiments, menin-MLL inhibitors may have improved PD properties in vivo over an extended period of time, for example inhibition of target gene expression such as MEIS1 and upregulation of differentiation markers over a period of at least 16 hours.

[0258] In certain embodiments, menin-MLL inhibitors may have an improved safety profile (e.g., reduced hERG inhibition, improved cardiovascular safety).

[0259] In certain embodiments, the menin-MLL inhibitor may be suitable for QD dosing (once daily).

[0260] According to embodiments, the BCL-2 inhibitor is selected from obatoclax, HA14-1, navitoclax, ABT-737, TW-37, AT101, sabutoclax, gambogic acid and venetoclax, or a pharmaceutically acceptable salt or solvate thereof.

[0261] According to certain embodiments, the BCL-2 inhibitor is venetoclax, or a pharma- ceutically acceptable salt or solvate thereof.

[0262] According to embodiments, the at least one other anti-neoplastic agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory anti-neoplastic agent, or a DHODH inhibitor.

[0263] According to embodiments, the at least one other anti-neoplastic agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, or an isocitrate dehydrogenase (IDH) inhibitor.

[0264] According to embodiments, hypomethylating agents include, but are not limited to, azacitidine, decitabine, or a pharma- ceutically acceptable salt or solvate thereof.

[0265] According to embodiments, DNA intercalating agents include, but are not limited to, anthracyclines (eg, daunorubicin, doxorubicin, idarubicin).

[0266] According to an embodiment, the DNA intercalating agent is daunorubicin.

[0267] According to an embodiment, the DNA intercalating agent is doxorubicin.

[0268] According to an embodiment, the DNA intercalating agent is idarubicin.

[0269] According to embodiments, pyrimidine analogs include, but are not limited to, cytarabine (ARA-C).

[0270] According to an embodiment, the purine analog is fludarabine.

[0271] According to embodiments, the kinase inhibitor is an FLT-3 inhibitor, a BTK inhibitor, an ABL inhibitor, an Aurora inhibitor, or a multikinase inhibitor consisting of two or more of these kinase inhibitors.

[0272] According to an embodiment, the kinase inhibitor is a multikinase inhibitor consisting of an FLT-3 inhibitor, an ABL inhibitor, and an Aurora inhibitor. According to an embodiment, such a multikinase inhibitor includes, but is not limited to, KW-2449.

[0273] According to an embodiment, the kinase inhibitor is a tyrosine kinase inhibitor.

[0274] According to an embodiment, the tyrosine kinase inhibitor is an FLT-3 inhibitor or a BTK inhibitor.

[0275] According to embodiments, FLT3 inhibitors include, but are not limited to, sorafenib, sunitinib, midostaurin (PKC412), lestaurtinib (CEP-701), tanzutinib (MLN518), quizartinib (AC220), gilteritinib (ASP2215), and KW-2449.

[0276] According to embodiments, BTK inhibitors include, but are not limited to, ibrutinib.

[0277] According to embodiments, CD20 inhibitors include, but are not limited to, anti-CD20 antibodies (e.g., obinutuzumab (GA101)).

[0278] According to embodiments, IDH inhibitors include, but are not limited to, ivosidenib and enasidenib.

[0279] According to embodiments, isocitrate dehydrogenase-1 inhibitors include, but are not limited to, ivosidenib.

[0280] According to embodiments, isocitrate dehydrogenase-2 inhibitors include, but are not limited to, enadidenib.

[0281] According to embodiments, immunomodulatory anti-neoplastic agents include, but are not limited to, PD-1 inhibitors (e.g., nivolumab, atezolizumab, and pembrolizumab), thalidomide, lenalidomide, pomalidomide, killed Mycobacterium bovis (BCG), and levamisole.

[0282] According to embodiments, PD-1 inhibitors include, but are not limited to, nivolumab, atezolizumab, and pembrolizumab.

[0283] According to embodiments, the DHODH inhibitor may be represented by, but is not limited to, the formula (Z):

[0284] [ka] A compound having the structure: 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; R 2 teeth,

[0285] [ka] where: R a is C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6cycloalkyl; R b is C 1~6 Alkyl, or OH, halo, CN, OC 1~6 Alkyl, OC 1~6 Haloalkyl and OC 3~6 C substituted with a member selected from the group consisting of cycloalkyl 1~6 is alkyl, R 3 H, halo, CH 3 and OCH 3 is selected from the group consisting of R 4 teeth, ●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 Cycloalkyl, -CH 2 -C 3~6 Cycloalkyl, and

[0286] [ka] ●

[0287] [ka] ●

[0288] [ka] and, ●

[0289] [ka] is selected from the group consisting of In the formula, each R c are independently: H; halo; C 1~6 Alkyl; OH, OCH 3 , S.C.H.3 , and OCF 3 C substituted with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Haloalkyl; OH and OCH 3 C substituted with a member selected from the group consisting of 1~6 Haloalkyl;NO 2 ;OH;O-CH 2 CH 2 OH and OC 1~6 alkyl; R d ,H;Halo;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C substituted with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Haloalkyl; OH and OCH 3 C substituted with a member selected from the group consisting of 1~6 Haloalkyl; 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 C substituted with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Haloalkyl, as well as OH and OCH 3 C substituted with a member selected from the group consisting of 1~6 haloalkyl; n is 1 or 2; or a pharma- ceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof; or,

[0290] [ka] or a pharma- ceutically acceptable salt, N-oxide, solvate, or stereoisomer thereof.

[0291] According to embodiments, the DHODH inhibitor may be represented by, but is not limited to, the formula (Z):

[0292] [ka] A compound having the structure: 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; R 2 teeth,

[0293] [ka] where: R a is C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl; R b is C 1~6 Alkyl, or OH, halo, CN, OC 1~6 Alkyl, OC 1~6 Haloalkyl and OC 3~6 C substituted with a member selected from the group consisting of cycloalkyl1~6 is alkyl, R 3 H, halo, CH 3 and OCH 3 is selected from the group consisting of R 4 teeth, ●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 Cycloalkyl, -CH 2 -C 3~6 Cycloalkyl, and

[0294] [ka] ●

[0295] [ka] ●

[0296] [ka] and, ●

[0297] [ka] is selected from the group consisting of In the formula, each R c are independently: H; halo; C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C substituted with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Haloalkyl; OH and OCH 3 C substituted with a member selected from the group consisting of 1~6 Haloalkyl;NO 2;OH;O-CH 2 CH 2 OH and OC 1~6 alkyl; R d ,H;Halo;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C substituted with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Haloalkyl; OH and OCH 3 C substituted with a member selected from the group consisting of 1~6 Haloalkyl; 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 C substituted with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Haloalkyl, as well as OH and OCH 3 C substituted with a member selected from the group consisting of 1~6 haloalkyl; n is 1 or 2; or a pharma- ceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0298] In relation to formula (Z), the following definitions apply:

[0299] The term "alkenyl" includes unsaturated aliphatic groups similar in length and possible substitution to alkyl, except that they contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like). The term alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur, or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight-chain or branched-chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C for straight chain). 2~6 , C for branched chain 3~6 ).

[0300] The term "haloalkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain, optionally with a hydrogen being replaced by a halogen. 1~6 The term "haloalkyl" as used herein refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain, optionally with hydrogens replaced with halogens. 1~4 The term "haloalkyl" as used herein refers to a straight- or branched-chain alkyl group having 1 to 4 carbon atoms in the chain, optionally with hydrogens replaced with halogens. Examples of "haloalkyl" groups include trifluoromethyl (CF 3 ), difluoromethyl (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 ), as well as groups that would be considered equivalent to any one of the preceding examples given the ordinary skill in the art and the teachings provided herein.

[0301] The term "haloalkenyl" includes unsaturated aliphatic groups similar in length and optional substitution to the alkyls described above, but containing at least one double bond and, optionally, having hydrogens replaced with halogens, having 1 to 6 carbon atoms in the chain.

[0302] The term "aryl" refers to a monocyclic aromatic carbocycle (a ring structure in which the ring atoms are all carbon) having six atoms per ring. (The carbon atoms in an aryl group are sp2 hybridized.)

[0303] The term "heteroaryl" refers to a monocyclic or fused bicyclic heterocycle (a ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having 3 to 9 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities in the form of appropriately bonded moieties:

[0304] [ka]

[0305] One of ordinary skill in the art will recognize that the above listed or exemplified species are not all inclusive and that additional species may be selected within the scope of these defined terms.

[0306] The term "variable point of attachment" means that a group may be attached at two or more alternative positions within a structure. The bond always replaces a hydrogen atom on one of the ring atoms. In other words, all permutations of the bond, as shown in the diagram below, are represented by a single diagram.

[0307] [ka]

[0308] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), where X is CH.

[0309] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), where X is N.

[0310] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), where Y is CH.

[0311] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), where Y is N.

[0312] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 is C 1~4 Alkyl; OH or OCH 3 C replaced with 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 cyclopropyl substituted with alkyl; or phenyl.

[0313] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 is CH 3 , C.H. 2 CH 3 ,

[0314] [ka] It is.

[0315] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 teeth

[0316] [ka] It is.

[0317] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 2 teeth,

[0318] [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 But, C 1~4 Alkyl, C 1~4 Haloalkyl or C 3~6 It is cycloalkyl.

[0319] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 2 teeth

[0320] [ka] It is.

[0321] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is H.

[0322] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is F.

[0323] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 CH 3 It is.

[0324] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 OCH 3 It is.

[0325] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth

[0326] [ka] It is.

[0327] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth,

[0328] [ka] where: Each R c are independently: H; halo; C 1~4 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C substituted with a member selected from the group consisting of 1~ Alkyl;C 1~4 Haloalkyl; OH and OCH 3 C substituted 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;C 1~4 Haloalkyl; OH or OCH 3 C replaced with 1~4 Haloalkyl; or OC 1~4 Alkyl; CN and OC 1~6alkyl; n is 1 or 2.

[0329] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth,

[0330] [ka] and Each R c H, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, NO 2 , O-CH 2 CH 2 OH and OC 1~4 independently selected from the group consisting of alkyl, R d H, halo, C 1~4 Alkyl, CN, and OC 1~6 is selected from the group consisting of alkyl, n is 1 or 2.

[0331] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth

[0332] [ka] It is.

[0333] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth,

[0334] [ka] It is.

[0335] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4teeth,

[0336] [ka] and In the formula, R c ,H;Halo;C 1~4 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C substituted 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; R d Ha, halo;C 1~4 Alkyl; OH, OCH 3 , S.C.H. 3 , or OCF 3 C replaced with 1~4 Alkyl;C 1~4 Haloalkyl; OH or OCH 3 C replaced with 1~4 Haloalkyl; or OC 1~4 Alkyl; CN and OC 1~6 alkyl.

[0337] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth,

[0338] [ka] where: Each R c H, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 independently selected from the group consisting of alkyl, aryl, and OH; R d Halo, C 1~4 Alkyl and OC 1~4is selected from the group consisting of alkyl, n is 1 or 2.

[0339] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth

[0340] [ka] It is.

[0341] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth

[0342] [ka] It is.

[0343] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth,

[0344] [ka] where: R c ,H;Halo;C 1~4 Alkyl, OH, OCH 3 , S.C.H. 3 , or OCF 3 C replaced with 1~4 Alkyl;C 1~4 Haloalkyl; OH or OCH 3 C replaced with 1~4 Haloalkyl; or OC 1~4 Alkyl; R d Ha, halo;C 1~4 Alkyl; OH, OCH 3 , S.C.H. 3 , or OCF 3 C replaced with 1~4 Alkyl;C 1~4Haloalkyl; or OH or OCH 3 C replaced with 1~4 is haloalkyl, R g is H;C 1~4 Alkyl; OH, OCH 3 , S.C.H. 3 , or OCF 3 C replaced with 1~4 Alkyl;C 1~4 Haloalkyl; or OH or OCH 3 C replaced with 1~4 It is haloalkyl.

[0345] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth,

[0346] [ka] where: R c is H or halo, R d is C 1~4 is alkyl, R g is H.

[0347] In one embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth

[0348] [ka] It is.

[0349] In one embodiment of the invention, the DHODH inhibitor is 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; 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; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-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-phenylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-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)-6-(4-ethyl-3-(hydroxymethyl)-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; 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-triazol-1-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-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)-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-en-2-yl)isoquinolin-2(1H)-yl)benzonitrile; 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-triazol-1-yl)-4-(prop-1-en-2-yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 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-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-isopropylphthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-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-dihydro-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-dihydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl)phthalazin-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-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-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)-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)-6-(4-ethyl-3-(hydroxymethyl)-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-(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-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-en-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-tolyl)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)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-(prop-1-en-2-yl)-1,6-naphthyridin-5(6H)-one; 6-(2-chloro-6-fluorophenyl)-2-(4-ethyl-3-(hydroxymethyl)-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-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl)-8-(1,1,1-trifluoropropan-2-yl)-1,6-naphthyridin-5(6H)-one; (R)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl)-8-(1,1,1-trifluoropropan-2-yl)-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-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-methylphenyl)-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-methylphenyl)-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-methoxyphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chlorophenyl)-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-4-(prop-1-en-2-yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methoxyphenyl)-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; 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-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-(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-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-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-4-isopropyl-2-(o-tolyl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-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-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)phthalazin-1(2H)-one; (S * )-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)phthalazin-1(2H)-one; (R * )-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-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-methylpyridin-3-yl)-4-(prop-1-en-2-yl)isoquinolin-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-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-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-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-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-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-methylphenyl)-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-methylphenyl)-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-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-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-methylphenyl)-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-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-3-methoxyphenyl)-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-methoxy-3,5-dimethylpyridin-4-yl)-4-(prop-1-en-2-yl)isoquinolin-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-methylphenyl)-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-methylphenyl)-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-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-methylphenyl)-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-en-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-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-(o-tolyl)-4-(3,3,3-trifluoroprop-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-methylphenyl)-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-(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-(5-fluoro-2-methoxypyridin-4-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-triazol-1-yl)-7-fluoro-2-(3-fluoro-2-methylphenyl)-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-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; Racemic-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)isoquinolin-1(2H)-one; 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-methoxypyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-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-4-isopropyl-2-(2-(methyl-d 3 )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-methoxypyridin-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-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-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-methylphenyl)-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-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)isoquinolin-1(2H)-one; (R)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-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-(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)-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-triazol-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-isopropylisoquinolin-1(2H)-one; 2-(3-chloro-6-methylpyridin-2-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-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-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-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-((1R,2S)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 2-(1,3-dimethoxypropan-2-yl)-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-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-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-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-(3-methylpyridin-2-yl)isoquinolin-1(2H)-one; Racemic-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-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-(pentan-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-((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-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-(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-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-(hydroxymethyl)-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-(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-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)-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-(oD 3 -tolyl)-1,6-naphthyridin-5(6H)-one; and, optionally, one or more of a pharma- ceutically acceptable salt, isotope, N-oxide, solvate, and stereoisomer thereof.

[0350] In one embodiment of the invention, the DHODH inhibitor is 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; 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; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-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-phenylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-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)-6-(4-ethyl-3-(hydroxymethyl)-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; 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-triazol-1-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-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)-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-en-2-yl)isoquinolin-2(1H)-yl)benzonitrile; 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-triazol-1-yl)-4-(prop-1-en-2-yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 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-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-isopropylphthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-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-dihydro-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-dihydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl)phthalazin-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-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-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)-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)-6-(4-ethyl-3-(hydroxymethyl)-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-(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-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-en-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-tolyl)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)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-(prop-1-en-2-yl)-1,6-naphthyridin-5(6H)-one; 6-(2-chloro-6-fluorophenyl)-2-(4-ethyl-3-(hydroxymethyl)-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-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl)-8-(1,1,1-trifluoropropan-2-yl)-1,6-naphthyridin-5(6H)-one; (R)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl)-8-(1,1,1-trifluoropropan-2-yl)-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-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-methylphenyl)-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-methylphenyl)-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-methoxyphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chlorophenyl)-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-4-(prop-1-en-2-yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methoxyphenyl)-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; 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-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-(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-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-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-4-isopropyl-2-(o-tolyl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-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-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)phthalazin-1(2H)-one; (S * )-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)phthalazin-1(2H)-one; (R * )-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-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-methylpyridin-3-yl)-4-(prop-1-en-2-yl)isoquinolin-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-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-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-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-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-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-methylphenyl)-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-methylphenyl)-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-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-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-methylphenyl)-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-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-3-methoxyphenyl)-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-methoxy-3,5-dimethylpyridin-4-yl)-4-(prop-1-en-2-yl)isoquinolin-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-methylphenyl)-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-methylphenyl)-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-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-methylphenyl)-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-en-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-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-(o-tolyl)-4-(3,3,3-trifluoroprop-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-methylphenyl)-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-(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-(5-fluoro-2-methoxypyridin-4-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-triazol-1-yl)-7-fluoro-2-(3-fluoro-2-methylphenyl)-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-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; Racemic-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)isoquinolin-1(2H)-one; 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-methoxypyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-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-4-isopropyl-2-(2-(methyl-d 3 )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-methoxypyridin-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-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-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-methylphenyl)-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-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)isoquinolin-1(2H)-one; (R)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-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-(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)-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-triazol-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-isopropylisoquinolin-1(2H)-one; 2-(3-chloro-6-methylpyridin-2-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-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-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-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-((1R,2S)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 2-(1,3-dimethoxypropan-2-yl)-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-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-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-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-(3-methylpyridin-2-yl)isoquinolin-1(2H)-one; Racemic-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-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-(pentan-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-((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-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-(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-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-(hydroxymethyl)-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-(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-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)-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-(oD 3 -tolyl)-1,6-naphthyridin-5(6H)-one; and, optionally, one or more of a pharma- ceutically acceptable salt, isotope, N-oxide, solvate, and stereoisomer thereof; or 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)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-chloro-6-fluorophenyl)-7-(4-ethyl-3-(hydroxymethyl)-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)-7-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-6-methoxy-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; or a pharma- ceutically acceptable salt, N-oxide, solvate, or stereoisomer thereof.

[0351] In one embodiment of the invention, the DHODH inhibitor is 2-(2-chloro-6-fluorophenyl)-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-4-isopropyl-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-4-methylpyridin-3-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-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-chloro-6-fluorophenyl)-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)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)-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-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-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-(2-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one; 2-(2-(difluoromethyl)phenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; and, optionally, one or more of a pharma- ceutically acceptable salt, isotope, N-oxide, solvate, and stereoisomer thereof.

[0352] In one embodiment of the invention, the DHODH inhibitor has the formula (Za):

[0353] [ka] A compound of formula (Z) having the formula 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; R 2 teeth,

[0354] [ka] and R 3 H, halo, CH 3 and OCH 3 is selected from the group consisting of R 4 teeth, 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 Cycloalkyl; -CH 2 -C 3~6 Cycloalkyl, and

[0355] [ka] and,

[0356] [ka] is selected from In the formula, R c ,H;Halo;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C substituted with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Haloalkyl; OH and OCH 3 C substituted with a member selected from the group consisting of 1~6 Haloalkyl;NO 2 ;OH;O-CH 2 CH 2 OH and OC 1~6 alkyl; R d ,H;Halo;C 1~6Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C substituted with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Haloalkyl; OH and OCH 3 C substituted with a member selected from the group consisting of 1~6 Haloalkyl; 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 C substituted with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Haloalkyl, as well as OH and OCH 3 C substituted with a member selected from the group consisting of 1~6 haloalkyl; n is 1 or 2; or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

[0357] In one embodiment of the invention, the DHODH inhibitor has the formula (Zb):

[0358] [ka] A compound of formula (Z) having the formula Y is CH or N; R 1 is C 1~6 Alkyl, C 1~6 Haloalkyl and C 2~6 alkenyl, R 2 teeth,

[0359] [ka] and R3 H, halo, and OCH 3 is selected from the group consisting of R 4 teeth,

[0360] [ka] is selected from the group consisting of In the formula, R c ,H;Halo;C 1~6 Alkyl; OH, OCH 3 , S.C.H. 3 , and OCF 3 C substituted with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Haloalkyl; OH and OCH 3 C substituted with a member selected from the group consisting of 1~6 Haloalkyl 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 C substituted with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Haloalkyl; OH and OCH 3 C substituted with a member selected from the group consisting of 1~6 Haloalkyl; 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 C substituted with a member selected from the group consisting of 1~6 Alkyl;C 1~6 Haloalkyl, as well as OH and OCH 3 C substituted with a member selected from the group consisting of 1~6 haloalkyl; n is 1], or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

[0361] Exemplary compounds of formula (Z) useful in the method of the present invention are described below with reference to exemplary synthetic schemes for their general preparation and the following examples. To obtain various compounds herein, those skilled in the art will understand that starting materials can be suitably selected so that the ultimately desired substituents are retained throughout the reaction scheme, with or without appropriate protection, to obtain the desired product. Alternatively, it may be necessary or desirable to use a suitable group in place of the ultimately desired substituent, which is retained throughout the reaction scheme and can be appropriately substituted with the desired substituent. Unless otherwise specified, variables are as defined above with reference to formula (Z). The reaction can be carried out between the melting point and the reflux temperature of the solvent, preferably between 0° C. and the reflux temperature of the solvent. The reaction can be heated using conventional or microwave heating. The reaction can also be carried out in a closed pressure vessel at a temperature higher than the normal reflux temperature of the solvent.

[0362] All abbreviations used in the general schemes and examples of formula (Z) are as defined in Table 1A. Variables are as defined within ranges or as specifically defined in the general schemes.

[0363] [Table 1-1]

[0364] [Table 1-2]

[0365] [Table 1-3]

[0366] Preparation Example Exemplary compounds of formula (Z) useful in the methods of the present invention will now be described by reference to the following exemplary synthetic schemes for their general preparation and the following specific examples.

[0367] Scheme 1

[0368] [ka] According to Scheme 1, 1,2,4-triazol-5(4H)-one compounds of formula (II), where PG is Bn, are prepared in three steps from ethyl 2-(benzyloxy)acetate. In the first step, 2-(benzyloxy)acetohydrazide is prepared by reacting ethyl 2-(benzyloxy)acetate with hydrazine hydrate in a suitable solvent, such as EtOH, at a temperature in the range of 70-85° C. The hydrazide and 1,2,4-triazol-5(4H)-one compounds of formula (II), where PG is Bn, are prepared in a suitable solvent, such as water, at a temperature in the range of 70-85° C. a -NCO(in the formula, R a is C 1~6 with an isocyanate of PG (wherein PG is an alkyl group); to provide the corresponding semicarbazide. Subsequent cyclization of the semicarbazide with a suitable base, such as NaOH, in a suitable solvent, such as water, provides a compound of formula (II), where PG is Bn.

[0369] R a C 1~6 Haloalkyl or C 3~6 The compound of formula (II) is R a C 1~6 Haloalkyl or C 3~6 Cycloalkyl group of formula R a The appropriately substituted --NCO compounds may be prepared as described above.

[0370] Protective group exchange from a compound of formula (II) where PG is Bn to a compound of formula (II) where PG is TBDPS is accomplished in two steps using established methods such as those described in TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis," 3 ed., John Wiley & Sons, 1999. In the first step, deprotection of the benzyl group is accomplished under hydrogenolysis conditions well known to those skilled in the art to provide the alcohol. For example, a palladium catalyst such as Pd / C is used to catalyze the reaction with H 2 Deprotection is achieved in a suitable solvent such as EtOH, MeOH, EtOAc, or mixtures thereof, preferably EtOH, with or without HCl for 4-72 hours under reduced pressure. In the second step, a compound of formula (II) where PG is TBDPS is obtained using a suitable base such as tert-butyldiphenylsilyl chloride, imidazole, dimethylaminopyridine, pyridine, in a solvent such as DMF, DCM, at a temperature ranging from 0° C. to room temperature.

[0371] Scheme 2

[0372] [ka] According to Scheme 2, R 3 Compounds of formula (XIV), where H is H, are treated with a halogenating agent such as N-iodosuccinimide (NIS) in an aprotic solvent such as acetonitrile under heating conditions to give halogenated compounds of formula (III), where HAL is iodo. 1 -B(OH) 2 is reacted with a compound of formula (III) under Suzuki coupling conditions well known to those skilled in the art to provide a compound of formula (IV). For example, a compound of formula (III) in which HAL is an iodide can be reacted with R 1 -B(OH) 2 (In the formula, R 1 is an optionally substituted C as defined herein with reference to formula (Z). 2~6A commercially available or synthetically available boronic acid (or boronic acid ester) such as boronic acid ester (which is an alkenyl or aryl group), a palladium catalyst such as bis(triphenylphosphine)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium, potassium phosphate, Cs 2 CO 3 in a suitable solvent such as dioxane, water, ethanol, or a mixture thereof to give a compound of formula (IV). 3 is H, 4 -B(OH) 2 with a compound of formula (V) under copper(II) mediated Chan-Lam coupling conditions known to those skilled in the art to give a compound of formula (V) (wherein HAL is a bromide, X is CH, and R 3 is H). For example, a compound of formula (IV) can be prepared by reacting a compound of formula R 4 -B(OH) 2 (In the formula, R 4 is as defined herein with reference to formula (Z), a catalyst such as copper(II) acetate, pyridine, NEt 3 in a suitable solvent such as DCM, ACN, dioxane, THF to provide a compound of formula (V).

[0373] Scheme 3

[0374] [ka] According to Scheme 3, a compound of formula (V), 1 is an optionally substituted C 2~6 alkenyl, R 3 is H and R 4 is an appropriately substituted phenyl as described herein with reference to formula (Z) and HAL is Br) with a commercially available or synthetically available nucleophilic compound of formula (II) a is C 1~6PG is selected from benzyl, 4-methoxybenzyl, or an alkyl or aryl silane such as TBDPS, TBS, TES, or TIPS, with the catalyst CuI and a diamine such as trans-1,2-diaminocyclohexane, and a base such as K 3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , in the presence of triethylamine or the like in a suitable solvent such as 1,4-dioxane, DMSO, DMF, THF, ACN, etc., to give a compound of formula (VI) (wherein X is CH and Y is CH).

[0375] A compound of formula (VI) 1 C 2~6 alkenyl) under Simmons-Smith cyclopropanation reaction conditions known to those skilled in the art to give a compound of formula (VI), 1 C 1~6 Alkyl-substituted C 3~6 For example, a compound of formula (VI) (wherein R 1 but

[0376] [ka] ) with diiodomethane and diethylzinc in a suitable solvent such as toluene at a temperature ranging from 0° C. to room temperature for 3 to 26 hours to give a compound of formula (VI) (R 1 CH 3 substituted cyclopropyl).

[0377] Subsequent deprotection using established methods such as those described in TW Greene and PG M Huts, "Protective Groups in Organic Synthesis", 3rd Edition, John Wiley & Sons, 1999, gives compounds of formula (Z) where X and Y are CH. For example, compounds of formula (VI) where R 3 is H and PG is TBDPS) is deprotected using conditions known to those skilled in the art, preferably with TBAF in a suitable solvent such as THF. In a preferred method, PG is TBDPS and R a is C 1~6 Alternatively, removal of the TBDPS protecting group can be achieved using triethylamine trihydrofluoride (Et 3 This is achieved using N 3HF).

[0378] Removal of the Bn protecting group is accomplished in the presence of hydrogen gas in the presence of a catalyst such as palladium on carbon (Pd / C). Removal of the Bn protecting group is also accomplished using TFA at a temperature of about 80° C.

[0379] A compound of formula (Z) wherein X is CH, Y is CH, and R 2 , R 3 , R 4 are each defined as described herein for formula (Z); R 1 C 2~6 alkenyl) can be hydrogenated using hydrogenation conditions known to those skilled in the art, e.g., 2 Under Pd / C or Wilkinson catalyst [RhCl(PPh 3 ) 3 ] in a suitable solvent such as MeOH, THF, EtOAc to give a compound of formula (Z), 1 C 2~6 alkyl).

[0380] Scheme 4

[0381] [ka] According to Scheme 4, the compound of formula (VII) can be reacted with an α,β-unsaturated aldehyde, such as 3-methyl-2-butenal, 3-methylpent-2-enal, etc., with -TiCl 4 and triethylamine in an aprotic solvent such as dichloromethane (DCM) to give the enamine intermediate, followed by NaBH 4 to obtain a compound of formula (VIII) (wherein R 5 is C 1~4 is alkyl, R 4 is as defined herein for formula (Z). Coupling of the compound of formula (VIII) with 4-bromo-2-iodobenzoyl chloride, which is commercially available or available by synthesis, using a base such as triethylamine and 4-dimethylaminopyridine (DMAP) in an anhydrous aprotic solvent such as dichloromethane (DCM) gives the compound of formula (IX). Treatment of the compound of formula (IX) with palladium(II) acetate, tetrabutylammonium bromide and potassium acetate under heated Heck reaction conditions gives the intramolecularly cyclized compound of formula (V), where R 1 is optionally substituted C 2~6 is alkyl, R 3 is H, X is CH and HAL is Br), and an intramolecular cyclization compound of formula (Va) 1 is optionally substituted C 2~6 alkenyl, R 3 is H and X is CH 2 and HAL is Br).

[0382] Scheme 5

[0383] [ka] According to Scheme 5, a compound of formula (X) (wherein HAL is F and R 3 is F and R 5 is H or C 1~4 alkyl) with a commercially available or synthetically available nucleophilic compound of formula (II),a is C 1~6 alkyl, e.g., a suitably protected triazolone, where PG is selected from benzyl, 4-methoxybenzyl, or an alkyl or aryl silane such as TBDPS, TBS, TES, or TIPS), and K 3 PO 4 , 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 DMSO, DMF, THF, ACN, etc., to obtain a compound of formula (XI). In a preferred method, 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 ester, it can be hydrolyzed to its corresponding acid under acidic or basic conditions. For example, the tert-butyl ester (R 5 is tert-Bu) with TFA or hydrolysis with a base such as NaOH in aqueous solvent gives compounds of formula (XIa) 5 is H). The compound of formula (XIa) is chlorinated using conditions known to one skilled in the art to provide the acyl chloride of formula (XII). For example, the compound of formula (XIa) can be chlorinated with SOCl 2 Heat in or treat with oxalyl chloride in DCM.

[0384] Scheme 6

[0385] [ka] According to Scheme 6, a compound of formula (XII), 3 is H or F, PG is Bn, and R a C 1~6 alkyl) to a compound of formula (VIII), 5 C 1~4Compounds of formula (VI) where X is CH and Y is CH can be prepared by reacting the compound of formula (VII) where R is an alkyl group with a base such as a mixture of triethylamine (TEA) and 4-dimethylaminopyridine (DMAP) in an anhydrous aprotic solvent such as dichloromethane (DCM) to give compounds of formula (XIII). 1 is optionally substituted as described herein for formula (Z), 1~6 (alkyl) is reacted with palladium(II) acetate, tetrabutylammonium bromide, and potassium acetate under heated Heck reaction conditions to give a mixture of intramolecularly cyclized compounds which are then separated to give R 1 C 2~6 is alkyl, R 3 The intermediate compound, wherein is H or F, is isolated.

[0386] Scheme 7

[0387] [ka] According to Scheme 7, a compound of formula (XIV) (R 3 is H or F, with a compound of formula (II), for example a suitably protected triazolone, where PG is selected from benzyl, 4-methoxybenzyl, or an alkyl or aryl silane such as TBDPS, TBS, TES, or TIPS, according to the methods previously described, to obtain a compound of formula (XV). In a preferred method, PG is Bn and R a is C 1~6 Compounds of formula (XV) are treated with a halogenating agent such as N-iodosuccinimide (NIS) in an aprotic solvent such as acetonitrile under heating to give halogenated compounds of formula (XVI) where Y is CH and HAL is iodide.

[0388] Scheme 8

[0389] [ka] According to Scheme 8, compounds of formula (XVIIa) and (XVIIb) are prepared in two steps from 5-bromoisobenzofuran-1,3-dione. 5-Bromoisobenzofuran-1,3-dione is reacted with an appropriately substituted alkyl Grignard reagent, such as i-PrMgCl, EtMgBr, or other commercially available or synthetically available alkyl Grignard reagent, and CdCl 2 in an aprotic solvent such as THF, followed by reaction with R 5 C 1~4 Formula R is alkyl 5 -I alkylating agents (such as iodomethane or iodoethane), e.g., K 2 CO 3 , Cs 2 CO 3 in the presence of a suitably selected base such as DMF, DMSO, or the like, to give the regioisomeric esters of formula (XVIIa) and (XVIIb), 1 is optionally substituted C 1~6 Similarly, aryl Grignard reagents can be used to give compounds of formula (XVIIa) and (VXIIb), where R 1 is an appropriately substituted phenyl). The regioisomers of formula (XVIIa) and (XVIIb) are not separated but are used directly and converted to the corresponding phthalazinone (mixture). For example, a mixture of formula (XVIIa) and formula (XVIIb) is treated with excess hydrazine in a suitable solvent such as ethanol or methanol at a temperature ranging from room temperature to 90° C. for 6 to 20 hours. The desired phthalazinone compound of formula (V) can be easily separated from the other regioisomer by purification by precipitation, crystallization, or flash chromatography. The reaction of a compound of formula (V) with a compound of formula (II) (wherein R a is C 1~6 and PG is selected from benzyl, 4-methoxybenzyl, or an alkyl or aryl silane such as TBDPS, TBS, TES, or TIPS) with the catalyst CuI and a diamine, such as trans-1,2-diaminocyclohexane, and a base, such as K3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 Ullmann-type aromatic amination reaction in the presence of, for example, triethylamine in a suitable solvent such as 1,4-dioxane, DMSO, DMF, THF, ACN, etc., provides a compound of formula (XVIII) (wherein X is N).

[0390] A compound of formula (XVIII) 1 C 2~6 alkenyl) under Simmons-Smith cyclopropanation reaction conditions known to those skilled in the art to give a compound of formula (XVIII), 1 C 1~6 Alkyl-substituted C 3~6 For example, a compound of formula (XVIII) (wherein R 1 C 2~6 alkenyl) with diiodomethane and diethylzinc in a suitable solvent such as toluene at a temperature ranging from 0° C. to room temperature for 24 to 26 hours to give a compound of formula (XVIII), 1 CH 3 substituted cyclopropyl).

[0391] Scheme 9

[0392] [ka] According to Scheme 9, a compound of formula (X) 3 is H and R 5 CH 3 in a palladium catalyzed carbonylation reaction with 1 -CHO(in the formula, R 1 is C 1~6(XIX) to give the corresponding ketone compound (XIX). (A similar transformation is reported in Suchand et al., J. Org. Chem. 2016, 81, 6409-6423). For example, methyl 4-bromo-2-iodobenzoate and isobutyraldehyde can be reacted with Pd(OAc) 2 Palladium catalysts such as Ag 2 The ketone compound of formula (XIX) was reacted with hydrazine R at a temperature of about 120° C. for 10 to 14 hours to obtain methyl 4-bromo-2-isobutyrylbenzoate. 4 -NHNH 2 (In the formula, R 4 is an appropriately substituted aryl, for example 2-chloro-6-fluorophenylhydrazine, to give a compound of formula (V) where X is N. Ullmann-type aromatic amination reaction of the compound of formula (V) with the appropriately protected triazolone (II) as described above gives a compound of formula (VI) where Y is CH and R 1 is C 1~6 alkyl).

[0393] A compound of formula (VI) 1 is phenyl and X is N, reacts with methyl 4-bromo-2-iodobenzoate in a compound of formula R 1 -CHO(in the formula, R 1 can be prepared in a similar manner using the methods described above by coupling with commercially available or synthetically available aldehydes of formula (I) (wherein R is phenyl).

[0394] Scheme 10

[0395] [ka] According to Scheme 10, 1 -B(OH) 2is reacted with a compound of formula (XVI) under Suzuki coupling conditions well known to those skilled in the art to give a compound of formula (XVIII) where X is CH. For example, a compound of formula (XVI) where Y is CH and HAL is iodide can be reacted with a commercially available or synthetically available boronic acid (or boronic ester), such as R 1 -B(OH) 2 (In the formula, R 1 is optionally substituted C as defined herein with reference to formula (Z). 2~6 Alkenyl, C 3~6 cycloalkyl or aryl), a palladium catalyst such as bis(triphenylphosphine)palladium(II) dichloride, potassium phosphate, Cs 2 CO 3 in a suitable solvent such as dioxane, water, ethanol, or a mixture thereof to give a compound of formula (XVIII) where X is CH. During the above coupling reaction, loss of iodide during the reaction conditions can lead to the formation of a compound of formula (XVIII) where X is CH and R 1 It has been found that a compound of formula (XVIII) (wherein X is CH or N) is obtained by condensing the compound of formula R 4 -B(OH) 2 with a compound of formula (VI), under copper(II) mediated Chan-Lam coupling conditions known to those skilled in the art, or as described above, to give a compound of formula (VI), 1 is optionally substituted C 2~6 alkenyl, R 3 is H or F, and R 4 is an appropriately substituted phenyl as described herein with reference to formula (Z).

[0396] A compound of formula (XVIII) 1 N(CH 3 ) 2 The compound of formula (XVI) is prepared from a compound of formula (XVI) where HAL is Br and PG is Bn. 3 )2 and reacting them in water at a temperature of about 110° C. for 96 hours to give a compound of formula (XVIII), 1 N(CH 3 ) 2 and R a C 1~6 A compound of formula (Z) (wherein R 1 N(CH 3 ) 2 ) is prepared according to the method described above.

[0397] A compound of formula (XVIII) 1 C replaced by OH 1~6 is a compound of formula (XVIII), 1 C 2~6 In the first step, a compound of formula (XVIII) (wherein R is an alkenyl group and PG is Bn) is prepared in two steps. 1 but

[0398] [ka] For example, NaIO 4 , and K 2 OsO 4 .2H 2 O or OsO 4 Under oxidizing conditions such as THF / H 2 In a second step, the ketone intermediate compound is reacted with a Grignard reagent, such as methylmagnesium bromide, in a suitable solvent, such as diethyl ether, at a temperature ranging from 0° C. to room temperature for 3-30 hours to give a compound of formula (XVIII), where R 1 C replaced by OH 1~6 alkyl).

[0399] Scheme 11

[0400] [ka] According to Scheme 11, 4,5-difluorophthalic anhydride is reacted with a compound of formula R 4 -NHNH 2 A hydrazine compound of the formula 4 is an appropriately substituted phenyl or heteroaryl, such as (2-chloro-6-fluorophenyl)hydrazine hydrochloride, in acetic acid at a temperature of about 125° C. for about 1.5 hours to give a compound of formula (XX), 3 is F). Reconstitution of the compound of formula (XX) under basic conditions, such as sodium ethoxide or sodium methoxide, in a suitable solvent, such as ethanol, methanol, at room temperature for a period of about 1.5 hours, gives the ring-expanded compound of formula (XXI). Derivatization of the compound of formula (XXI) with a sulfonate-based leaving group, such as trifluoromethanesulfonyl (triflate), can be achieved by reaction with trifluoromethanesulfonic anhydride (Tf) in a suitable solvent, such as DCM. 2 This can be achieved by reacting the compound with a triflate agent such as N-phenylbis(trifluoromethanesulfonimide) (TF 2 A milder triflating agent such as NPh) and a base such as TEA, DIEA in a suitable solvent such as DCM can be used.

[0401] Scheme 12

[0402] [ka] According to Scheme 12, 1 -B(OH) 2 is reacted with a compound of formula (XXII) under Suzuki coupling conditions as described above to give a compound of formula (V) where X is N. For example, a compound of formula (XXII) can be reacted with a commercially available or synthetically available boronic acid (or boronic ester), such as R 1 -B(OH) 2 (In the formula, R 1 is as defined herein with reference to formula (Z); 2~6Alkenyl or C 2~6 haloalkenyl), a palladium catalyst such as bis(triphenylphosphine)palladium(II) dichloride or 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, and potassium phosphate, Cs 2 CO 3 K 2 CO 3 in a suitable solvent such as dioxane, water, ethanol, or a mixture thereof to obtain a compound of formula (V). 1 C 2~6 Alkyl or C 2~6 haloalkyl) can be prepared by the compound of formula (V), 1 C 2~6 Alkenyl or C 2~6 For example, a compound of formula (V) (wherein R 1 but

[0403] [ka] (wherein R is an integer from 1 to 20) is reacted under hydrogenation conditions using a catalyst such as Pd / C in a suitable solvent such as EtOAc under an atmosphere of hydrogen gas (20-45 psi) at room temperature for 4-24 hours to give a compound of formula (V), 1 but

[0404] [ka] Reaction of a compound of formula (V) with a suitably protected triazolone of formula (II) using the conditions described above gives a mixture of compounds of formula (VI) and (VIa), which can be separated before or after deprotection of the protecting groups.

[0405] Scheme 13

[0406] [ka] According to Scheme 13, the N-arylation of compounds of formula (XVIII) can be carried out by the addition of appropriately substituted commercially or synthetically available fluoro compounds of formula (XXIII), where R c and R d is achieved by reaction of a compound of formula (XVIII), where R 1 H, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-substituted C 3~6 cycloalkyl, and X is CH or N, under nucleophilic substitution reaction conditions with a commercially available or synthetically available fluoro compound of formula (XXIII) and K 2 CO 3 , Cs 2 CO 3 In the presence of a base such as , in an aprotic solvent such as DMF or DMSO, at a temperature in the range of 65 to 100°C, a compound of formula (XXIV) is obtained.

[0407] The reduction of the compound of formula (XXIV) can be carried out with zinc or iron and NH 4 Cl is achieved in a mixed solvent of methanol and water to give the amino compound of formula (XXV).

[0408] The compound of formula (XXV) is reacted with NaNO 2 in an acidic aqueous solution or other nitrite reagent in an organic solvent such as EtOH at a temperature of 0 °C, followed by reduction of the diazo group with zinc at temperatures ranging from 0 to 85 °C, or 3 PO 2 to give a compound of formula (XXVI), c and R d is as defined herein for formula (Z).

[0409] Scheme 14

[0410] [ka] According to Scheme 14, a compound of formula (X) 5 is H and R 3 is F) with a compound of formula (XXVII), which is commercially available or available by synthesis, 1a and R 1b are each independently H or C 1~4 alkyl), for example, 1-bromo-3-methyl-2-butene and K 2 CO 3 , Cs 2 CO 3 in a suitable solvent such as DMSO, DMF, THF, ACN, etc., to give an ester compound of formula (XXVIII), 3 is F and HAL is F. 1a and R 1b is C 1~4 Haloalkyl or C 3~6 The esters of formula (XXVIII) can be prepared in a similar manner by reacting an ester of formula (XXVIII) with a suitably protected triazolone compound of formula (II) and K 3 PO 4 , 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 1,4-dioxane, DMSO, DMF, THF, ACN, etc., is subjected to an Ullmann-type aromatic amination reaction to obtain a compound of formula (XXIX). 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), in a suitable solvent such as toluene, 3 )PdG 2), N-cyclohexyl-N-methyl-cyclohexanamine, or a similar catalyst, at a temperature of about 15-80° C. for about 18-36 hours to obtain isocoumarin compounds of formula (XXX), 1 is isopropyl, R 3 is H or F, and R a and PG is as defined above.

[0411] An isocoumarin compound of formula (XXX), 1 but

[0412] [ka] (XIa) is prepared from the compound of formula (XIa) and methylbuta-1,2-dien-1-yl acetate, which is commercially available or can be prepared in two steps from 2-methyl-3-butyn-2-ol. Acetic anhydride is reacted with 2-methyl-3-butyn-2-ol and Mg(ClO 4 ) 2 In the presence of a catalyst such as 2-methylbut-3-yn-2-yl acetate, the reaction is carried out in a suitable solvent such as DCM to give 2-methylbut-3-yn-2-yl acetate. 4 , AgClO 4 , PtCl 2 to give 3-methylbuta-1,2-dien-1-yl acetate, which can be converted to a compound of formula (XIa), where R 5 is H). For example, Catacxium A Pd G2 and Cy 2 isocoumarin compound of formula (XXX), wherein Y is CH and R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 1 teeth

[0413] [ka] ) is obtained.

[0414] A compound of formula (XXX) where Y is CH and R 1 teeth

[0415] [ka] The Wilkinson catalyst [RhCl(PPh 3 ) 3 ] in a suitable solvent such as THF at room temperature to give isocoumarin compounds of formula (XXX), 1 is isopropyl).

[0416] Scheme 15

[0417] [ka] According to Scheme 15, 2-butanone is converted to ethyl 3-methylpent-2-enoate using Wittig reaction conditions well known to those skilled in the art. For example, 2-butanone is reacted with a triphenylphosphonium ylide, such as (carbethoxymethylene)triphenylphosphorane, with or without additives, such as benzoic acid, LiCl, and sodium dodecyl sulfate (SDS), in a suitable solvent, such as toluene, at a temperature ranging from room temperature to the reflux temperature of the solvent for 12 to 24 hours. Ethyl 3-methylpent-2-enoate is reduced to 3-methylpent-2-en-1-ol using a suitable reducing agent, such as DIBAL-H, in a suitable solvent, such as toluene, at a temperature ranging from -78°C to room temperature. 3-Methylpent-2-en-1-ol can be oxidized under oxidation conditions well known to those skilled in the art, for example, with DMP (Dess-Martin periodinane), SO in a solvent such as EtOAc, DMSO, or DCM at a temperature ranging from about -78°C to room temperature (about 23°C). 3 -Pyridine, Swern conditions [(COCl)2 , DMSO, Et 3 N], PCC, etc. to give 3-methylpent-2-enal. In a preferred method, 3-methylpent-2-en-1-ol is oxidized to 3-methylpent-2-enal with Dess-Martin periodinane in DCM at 25 °C for 1-4 h.

[0418] Scheme 16

[0419] [ka] According to Scheme 16, isocoumarins of formula (XXX) where Y is CH can be prepared by reacting commercially available or synthetically available isocoumarins of formula R 4 -NH 2 (wherein R 4 is as defined herein for formula (Z), and AlMe 3 , AlCl 3 in a suitable aprotic solvent such as DCM, toluene, to give a compound of formula (XXXI), 1 , R 3 , R 4 and R a is defined as described herein with reference to formula (Z).

[0420] Scheme 17

[0421] [ka] Isocoumarin compounds of formula (XXX) can be prepared according to Scheme 17. 4,5-Difluoro-2-iodobenzoyl chloride can be converted to compounds of formula (X), where HAL is F and R is 1, 2, 3, 4, 5-difluoro-2-iodobenzoyl chloride, using conditions well known to those skilled in the art, such as oxalyl chloride or thionyl chloride, in the presence of catalytic amount of DMF in a suitable solvent, such as aprotic non-polar solvents, such as dichloromethane (DCM), tetrahydrofuran (THF), acetonitrile (ACN), toluene, etc., at temperatures ranging from 0°C to room temperature. 5 is H and R3 is F) to form 4,5-difluoro-2-iodobenzoic acid chloride. 4,5-difluoro-2-iodobenzoic acid chloride can be reacted with 2-methylbut-3-yn-2-ol, available commercially or by synthesis, in the presence of a base such as triethylamine and DMAP in a suitable solvent such as DCM to give an ester compound of formula (XXXIII). Compounds of formula (XXXIII) can be reacted with compounds of formula (II) to give compounds of formula (XXXIV) using the methods described above. Compounds of formula (XXXIV) can be reacted with a catalytic amount of a Lewis acid, e.g., AgClO 4 , PtCl 2 or the like to give the rearranged compound of formula (XXXV). 3 is H or F) can be intramolecularly cyclized under Heck reaction conditions, such as using a catalyst such as palladium(II) acetate, a phase transfer reagent such as tetrabutylammonium bromide, and a base such as potassium acetate, in a suitable solvent such as DMF, at a temperature of 70-90° C. for 1-3 hours to provide isocoumarin compounds of formula (XXX), where Y is CH.

[0422] Scheme 18

[0423] [ka] According to Scheme 18, a compound of formula (Xa) (wherein HAL is Cl and R 5 CH(CH 3 ) 2 and R 3 Compounds of formula (Xa) can be prepared by reacting a commercially available or synthetically available nucleophilic compound of formula (II), where PG is benzyl and R is F, with a commercially available or synthetically available nucleophilic compound of formula (II), where PG is benzyl and R is F. c is C 1~6 alkyl) and K 2 CO 3 , Cs 2 CO 3, NaHCO 3 in the presence of a suitable base such as triethylamine in a suitable solvent such as dimethylsulfoxide (DMSO), DMF, THF, ACN, etc. to obtain a compound of formula (XXXIX) where Y is N. 3 is F and R 5 is C 1~4 The alkyl group is reacted with commercially available 1-ethoxyethene-2-boronic acid pinacol ester, palladium catalysts such as bis(triphenylphosphine)palladium(II) dichloride, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, and Cs 2 CO 3 with an appropriate base, such as, in a suitable solvent, such as dioxane, water, ethanol, or mixtures thereof, using conventional or microwave heating methods to provide a compound of formula (XL), where Y is N or CH.

[0424] Scheme 19

[0425] [ka] According to Scheme 19, a compound of formula R 4 -NH 2 (wherein R 4 is as defined herein with reference to formula (Z)) is reacted with trimethylaluminum in a suitable solvent such as dichloromethane, toluene, or a mixture thereof, and the resulting solution is combined with a compound of formula (XL) where Y is CH or N to obtain a compound of formula (XLI). The compound of formula (XLI) where Y is CH or N is treated with acetic acid or trifluoroacetic acid under heating conditions at 50° C. to 90° C. to obtain a compound of formula (XLII). The compound of formula (XLII) is halogenated using N-bromosuccinimide in anhydrous dimethylformamide at room temperature to obtain a compound of formula (XVI) where HAL is Br. The compound of formula R 1 -B(OH) 2is reacted with a compound of formula (XVI) under Suzuki coupling conditions known to those skilled in the art or as previously described to give a compound of formula (VI), 1 is optionally substituted C 2~6 Alkenyl, C 2~6 is haloalkenyl, or aryl as defined herein for formula (Z). 1 is optionally substituted C 2~6 Alkenyl or C 2~6 haloalkenyl) is reacted with Wilkinson's catalyst ((PPh 3 ) 3 RhCl) to give a compound of formula (VI), 1 C 2~6 Alkyl or C 2~6 haloalkyl).

[0426] Scheme 20

[0427] [ka] According to Scheme 20, 3-methylbutanal can be converted to a compound of formula (XXXIX), where Y is N and R 5 CH(CH 3 ) 2 ), 1,1'-bis(diphenylphosphino)ferrocene (dppf), and Cs 2 CO 3 with a suitable base such as, for example, 1,2-dichlorophenyl ether, in the presence of a water scavenger such as molecular sieves (4A) in a suitable solvent such as dioxane to give a compound of formula (XXX), 1 is isopropyl). 4 -NH 2 (wherein R 4is as defined herein for formula (Z)) with trimethylaluminum in a suitable solvent such as dichloromethane, toluene, or a mixture thereof, and the resulting solution is combined with a compound of formula (XXX) and subsequently treated with acetic acid at a heating temperature of 80-100° C. for a period of time ranging from 5 to 24 hours to obtain a compound of formula (VI), 1 is isopropyl, R 3 is F).

[0428] Scheme 21

[0429] [ka] According to Scheme 21, a compound of formula (XXXIX) or (XI) 3 is F and R 5 C 1~4 The alkyl boronic acid (which is an alkyl group) is reacted with commercially available vinyl boronic acid pinacol ester, a palladium catalyst such as bis(triphenylphosphine)palladium(II) dichloride or 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, and Cs 2 CO 3 In a suitable solvent such as dioxane, water, ethanol, or mixtures thereof, a compound of formula (XLIII) (wherein Y is N or CH) is obtained. The vinyl group in the compound of formula (XLIII) is selectively converted to an aldehyde group of formula (XLIV) using, for example, potassium osmate(VI) dihydrate / sodium periodate or ozonolysis. Reaction of the compound of formula (XLIV) with a suitably substituted alkyl Grignard reagent, either commercially available or available by synthesis (such as i-PrMgCl), in an aprotic solvent such as THF, followed by subsequent treatment with an oxidation reagent such as the Dess-Martin reagent or Swern oxidation conditions, provides a ketone compound of formula (XLV).

[0430] Compounds of formula (XLV) are prepared in two steps from compounds of formula (XXXIX). 3 is F and R 5 C 1~4 The compound of formula (XLV), where X is N, Y is N or CH, and R is an alkyl group, is reacted with commercially available tributyl(1-ethoxyvinyl)tin and a palladium catalyst, such as bis(triphenylphosphine)palladium(II) dichloride, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, in a suitable solvent, such as dioxane, water, ethanol, or mixtures thereof. Compounds of formula (XLV), where X is N, Y is N or CH, and R is an alkyl group, are then ... 1 is methyl).

[0431] Hydrazine R, available commercially or synthetically 4 -NHNH 2 (In the formula, R 4 is as defined herein for formula (Z)), for example, 2-chloro-6-fluorophenylhydrazine, o-tolylhydrazine, is condensed with a compound of formula (XLV) in the presence of a base such as potassium carbonate under heating conditions such as at 70-120° C. in a suitable solvent such as toluene or mixtures thereof to give a compound of formula (VI) 4 is as defined herein with reference to formula (Z).

[0432] Scheme 22

[0433] [ka] According to Scheme 22, methyl 2-bromo-4,5-difluorobenzoate is reacted with a suitably protected triazolone compound of formula (II) and K 3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3In the presence of a base such as triethylamine in a suitable solvent such as 1,4-dioxane, DMSO, DMF, THF, ACN, etc., a compound of formula (XLVI) is obtained. In a preferred method, PG is Bn and R a is C 1~6 The 3-methylbutanal can be converted to a compound of formula (XLVI) by the addition of a ligand such as 1,1'-bis(diphenylphosphino)ferrocene (dppf) and Cs using a palladium catalyst such as dimeric allylpalladium(II) chloride. 2 CO 3 with a suitable base such as, for example, dioxane in the absence of a water scavenger such as molecular sieves (4A) to give a compound of formula (XLVII). 4 -NH 2 (wherein R 4 is as defined herein for formula (Z)) with trimethylaluminum in a suitable solvent such as dichloromethane, dichloroethane, toluene, or mixtures thereof, and the resulting solution is combined with a compound of formula (XLVII) and subsequently treated with acetic acid at a heating temperature of 80-100° C. for a period of time ranging from 5 to 24 hours to obtain a compound of formula (VI), 1 is isopropyl, R 3 In some cases, compounds of the formula R, such as o-toluidine, are obtained. 4 -NH 2 is directly condensed with a compound of formula (XLVII) in acetic acid at a heating temperature of 80-100° C. for a time period ranging from 10 to 24 hours to obtain a compound of formula (VI), 1 , R 3 is defined above).

[0434] Scheme 23

[0435] [ka] According to Scheme 23, a compound of formula (XXXIX), 5C 1~4 alkyl, Y is N, and R 3 is F) is subjected to Sonogashira coupling reaction using a silyl protected alkyne such as trimethylsilylacetylene, a palladium catalyst such as palladium(II) bis(triphenylphosphine) dichloride, a copper catalyst such as copper iodide, and a suitable base such as triethylamine in a suitable solvent such as ACN, toluene, etc. Deprotection reaction is carried out using TBAF in a suitable solvent such as THF at room temperature to give a compound of formula (XLVIII). Compounds of formula (XLIX) can be prepared by the reaction of a gold catalyst, preferably AuCl, in a suitable solvent mixture such as MeCN. 3 It is obtained using AuCl 3 A similar transformation by catalytic cyclization is described by Marchal, E. et al. in Tetrahedron 2007, 63, 9979-9990. 4 -NH 2 (wherein R 4 (wherein Z is as defined herein for formula (Z)) is reacted with trimethylaluminum in a suitable solvent such as dichloromethane, dichloroethane, toluene, or mixtures thereof, and the resulting solution is combined with a compound of formula (XLIX) and subsequently treated with acetic acid at a heating temperature of 80-100° C. for a period ranging from 5-24 hours to obtain a compound of formula (L). NBS is used at room temperature in a suitable solvent, preferably DMF, followed by cross-coupling using conditions well known to those skilled in the art, preferably using a palladium catalyst such as palladium(II) bis(triphenylphosphine) dichloride, Cs 2 CO 3 , Na 2 CO 3 in a solvent mixture of 1,4-dioxane and water at a temperature of 100° C. to give a compound of formula (VI), 3 is F and R 1 , R a and PG is defined as above).

[0436] Scheme 24

[0437] [ka] According to Scheme 24, a compound of formula (VI) (wherein PG is Bn) can be reacted with a tetrahydrofuran (TFA) at a temperature of about 60-90° C. or BCl in neat TFA in a sealed tube using conditions well known to those skilled in the art. 3 in a suitable solvent such as DCM at a temperature of about -78°C or by treatment with hydrogen gas in the presence of a catalyst such as palladium on carbon (Pd / C) to provide a compound of formula (Z).

[0438] In a similar manner, a compound of formula (XVIII) 1 N-arylation of (I, PG is TBDPS, and X is N) and in situ TBDPS deprotection is accomplished using conditions well known to one of skill in the art or conditions previously described to provide compounds of formula (Z).

[0439] A compound of formula (Z) 3 is F) in an aromatic nucleophilic substitution reaction to give a compound of formula (Z), 3 OCH 3 For example, a compound of formula (Z) (wherein R 3 is F) with a suitable base such as NaOH in a suitable solvent such as MeOH to give a compound of formula (Z) 3 OCH 3 ) is obtained.

[0440] Compounds of formula (Z) may be converted to their corresponding salts using methods known to those skilled in the art. For example, an amine of formula (Z) can be converted to its corresponding salt by reaction with Et 2 O, C.H. 2 Cl 2The crystalline forms of the pharmaceutically acceptable salts of the compound of formula (Z) can be obtained by treatment with trifluoroacetic acid, HCl, or citric acid in a solvent such as THF, MeOH, chloroform, or isopropanol to give the corresponding salt forms. Alternatively, reverse phase HPLC purification conditions result in the trifluoroacetate or formate salts. Crystalline forms of the pharmaceutically acceptable salts of the compound of formula (Z) can be obtained in crystalline form by recrystallization from polar solvents (including mixtures of polar solvents and aqueous mixtures of polar solvents) or non-polar solvents (including mixtures of non-polar solvents).

[0441] When the compounds according to the present invention have at least one chiral center, they can therefore exist as enantiomers. When the compounds have two or more chiral centers, they can additionally exist as diastereomers. It is understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0442] The compounds prepared according to the above schemes can be obtained in a single form, such as a single enantiomer, by form-specific synthesis or by resolution. Alternatively, the compounds prepared according to the above schemes can be obtained as a mixture of various forms, such as a racemic (1:1) mixture or a non-racemic (non-1:1) mixture. When racemic and non-racemic mixtures of enantiomers are obtained, single enantiomers can be isolated using conventional isolation methods known to those skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization to diastereomeric adducts, biotransformation, or enzymatic conversion. When regioisomeric or diastereomeric mixtures are obtained, single isomers can be separated using conventional methods, such as chromatography or crystallization, as appropriate.

[0443] The following specific examples further illustrate the compounds of formula (Z) and various preferred embodiments. EXAMPLES

[0444] In obtaining the compounds of formula (Z) and the corresponding analytical data described in the Examples below, the following experimental and analytical protocols were followed, unless otherwise indicated.

[0445] Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. When solutions are "dried", they are generally 2 SO 4 or MgSO 4 The mixtures, solutions, and extracts were "concentrated" by evaporation, typically under reduced pressure on a rotary evaporator.

[0446] Normal phase silica gel chromatography (FCC) uses prepacked cartridges to separate silica gel (SiO 2 ) was conducted.

[0447] Preparative reversed-phase high performance liquid chromatography (RP HPLC) was performed in one of the following ways. Method A. Gilson GX-281 semi-preparative HPLC with a Phenomenex Synergi C18 (10 μm, 150×25 mm) or Boston Green ODS C18 (5 μm, 150×30 mm) and a mobile phase of 5-99% ACN in water (with 0.225% FA) at a flow rate of 25 mL / min over 10 min, followed by a 2 min hold at 100% ACN; or Method B. Gilson GX-281 semi-preparative HPLC (Phenomenex Synergi C18 (10 μm, 150×25 mm), or Boston Green ODS C18 (5 μm, 150×30 mm) and a mobile phase of 5-99% ACN in water (0.1% TFA) held for 10 min, then 100% ACN for 2 min at a flow rate of 25 mL / min. or Method C. Gilson GX-281 semi-preparative HPLC (Phenomenex Synergi C18 (10 μm, 150×25 mm), or Boston Green ODS C18 (5 μm, 150×30 mm) and a mobile phase of 5-99% ACN in water (0.05% HCl) held for 10 min, then 100% ACN for 2 min at a flow rate of 25 mL / min. or Method D. Gilson GX-281 semi-preparative HPLC with a Phenomenex Gemini C18 (10 μm, 150×25 mm), AD (10 μm, 250 mm×30 mm), or Waters XBridge C18 column (5 μm, 150×30 mm), a mobile phase of 0-99% ACN in water (with 0.05% ammonium hydroxide v / v) at a flow rate of 25 mL / min over 10 min, followed by a 2 min hold at 100% ACN; or Method E. A Gilson GX-281 semi-preparative HPLC equipped with a Phenomenex Gemini C18 (10 μm, 150 × 25 mm) or Waters XBridge C18 column (5 μm, 150 × 30 mm) was run at a flow rate of 25 mL / min using a mobile phase of 5–99% ACN in water (10 mM NH 4 HCO 3 ), followed by a 2 min hold in 100% ACN.

[0448] Preparative supercritical fluid high performance liquid chromatography (SFC) was performed on either a Thar 80 Prep-SFC system or a Waters 80Q Prep-SFC system from Waters. The ABPR was set at 100 bar to maintain CO2 at SF conditions, and the flow rate ranged from 50 g / min to 70 g / min, depending on the compound properties. The column temperature was ambient.

[0449] Mass spectra (MS) were obtained on a SHIMADZU LCMS-2020 MSD or an Agilent 1200\G6110A MSD using electrospray ionization (ESI) in positive mode unless otherwise noted. Calculated masses (calcd.) correspond to exact masses.

[0450] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker AVIII 400 spectrometer. Multiplicity definitions are as follows: s=singlet, d=doublet, t=triplet, q=quartet, dd=double doublet, ddd=double doublet doublet, td=triple doublet, dt=double triplet, spt=septet, quin=quintet, m=multiplet, br=broad line. It will be understood that in compounds that contain exchangeable protons, the protons may or may not be visible in the NMR spectrum, depending on the choice of solvent used to perform the NMR spectrum and the concentration of the compounds in solution.

[0451] Chemical names were generated using ChemDraw Ultra 12.0, ChemDraw Ultra 14.0 (CambridgeSoft Corp., Cambridge, MA) or ACD / Name Version 10.01 (Advanced Chemistry). * Or S * Compounds designated as are enantiomerically pure compounds for which the absolute configuration has not been determined.

[0452] Intermediate 1: 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one.

[0453] [ka]

[0454] Step A. 2-(Benzyloxy)acetohydrazide. To a solution of ethyl 2-(benzyloxy)acetate (55 g, 283.17 mmol) in EtOH (500 mL), NH2 NH 2 H 2 O (28.3 g, 566 mmol, 27.5 mL) was added. The reaction 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) as a colorless oil, which was used directly in the next step without further purification.

[0455] Step B. 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. H 2 To a solution of 2-(benzyloxy)acetohydrazide (52 g, 288 mmol) in 2H2O (500 mL) was added isocyanatoethane (25.1 g, 346 mmol, 27.9 mL) dropwise at 0° C. After the addition was complete, the mixture was stirred at 25° C. for 12 h. The mixture was then rinsed with H2O. 2 O (20 mL) and a solution of NaOH (57.7 g, 1.44 mol) in water (120 mL) were added. The mixture was stirred at 95° C. for 12 h. The reaction mixture was cooled to room temperature and then quenched with HCl (12 M) at 0° C. and the pH was adjusted to 6. The solid was filtered and dried under vacuum to give the title compound as a white solid (61 g, 91% yield). 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.

[0456] Intermediate 2: 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one.

[0457] [ka]

[0458] Step A. 4-Ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. To a solution of 5-[(benzyloxy)methyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (8 g, 34.3 mmol, 1.0 equiv.) in methanol (200 mL) was added Pd / C (2 g). The resulting mixture was kept under hydrogen and stirred at room temperature for 6 h. The resulting mixture was then filtered and the filtrate was concentrated to give the crude product 4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one as a white solid (4.3 g, 88% yield). 1 H NMR (400MHz, DMSO-d 6 )δ 11.52(s,1H),5.55(t,J=5.50Hz,1H),4.32(d,J=5.50Hz,2H),3.64(q,J=6.97Hz,2H),1.18(t,J=6.97Hz,3H)ppm.

[0459] Step B. 5-(((tert-Butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. To a solution of 4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (3 g, 21 mmol, 1.0 equiv.) in DCM (30 mL) was added tert-butylchlorodiphenylsilane (6.5 mL, 25 mmol, 1.2 equiv.) and pyridine (1.86 mL, 23 mmol, 1.1 equiv.). The resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (100 mL). The resulting mixture was extracted with DCM (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (SiO 2 , 50-80% ethyl acetate / petroleum ether) to give 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one as a white solid (4.9 g, 61% yield). LCMS (ES-API): C 21 H27 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),4.54(s,2H),3.84(q,J=7.34Hz,2H),1.33(t,J=7.34Hz,3H),1.07(s,9H)ppm.

[0460] 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.

[0461] [ka]

[0462] 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) and then di-tert-butyl dicarbonate (4.6 g, 21 mmol) was added, followed by DMAP (645 mg, 5.3 mmol). The reaction mixture was stirred under nitrogen at 50° C. overnight and then cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was diluted with EtOAc and washed with brine. The organic layer was separated and washed with Na 2 SO 4 The residue was purified by silica column chromatography (gradient elution: 0-5% EtOAc in petroleum ether) 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,9 H)ppm;19 F NMR (376 MHz, CDCl 3 )δ-131.55--131.13(m,1 F),-136.97--136.65(m,1 F)ppm.

[0463] 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. In anhydrous DMF (30 mL) was added tert-butyl 4,5-difluoro-2-iodobenzoate (3.2 g, 9.4 mmol), 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 1, 2.6 g, 11.2 mmol), and Cs 2 CO 3 (6.1 g, 18.7 mmol) was stirred at 75° C. under nitrogen for 1 h and then cooled to room temperature. The mixture was filtered through a pad of Celite® and the pad was washed with EtOAc. The filtrates were combined, washed with brine and concentrated. The residue was purified by silica column chromatography (gradient elution: 0-40% EtOAc in petroleum ether) to give the title compound as a colorless amorphous solid (5 g, yield: 96%). ESI (MS): C 23 H 25 FIN 3 O 4 Calculated mass, 553.1; measured m / z, 554.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ 8.16(d,J=7.1Hz,1 H),7.62(d,J=10.8Hz,1 H),7.29-7.45(m,5 H),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 (376 MHz, CDCl 3 )δ-119.09(dd,J=10.6,7.0Hz,1 F)ppm.

[0464] Step C. 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4 triazol-1-yl)-5-fluoro-2-iodobenzoic acid. To a solution of tert-butyl 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4 triazol-1-yl)-5-fluoro-2-iodobenzoate (5 g, 9 mmol) in DCM (50 mL) was added TFA (10 mL) slowly. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. 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 in vacuum to give the title compound as a white solid (4.1 g, yield: 91%). ESI (MS): C 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=7.2Hz,2 H),1.23(t,J=7.2Hz,3 H)ppm; 19 F NMR (376MHz, DMSO-d 6 )δ-119.91(s,1 F)ppm.

[0465] 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. In DMF (7 mL) was added 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 To a mixture of NMe (867 mg, 4.4 mmol) was added Catacxium A Pd G2 (74.2 mg, 0.11 mmol) under nitrogen. The reaction mixture was stirred at 90° C. overnight under nitrogen. The mixture was then cooled to room temperature, diluted with EtOAc, and washed with brine. The organic layer was separated and the aqueous layer was combined and extracted with EtOAc. The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: 0-80% EtOAc in petroleum ether) to give the title compound as a yellow solid (240 mg, yield: 25%). ESI (MS): 24 H 22 FN 3 O 4 Calculated mass, 435.2; m / z 436.2 [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,2 H),2.11(s,3 H),1.37(t,J=7.2Hz,3 H)ppm.

[0466] Intermediate 4: 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.

[0467] [ka]

[0468] Method I: Step A. 3-Methylbut-2-en-1-yl 4,5-difluoro-2-iodobenzoate. In anhydrous DMF (20 mL) was added 4,5-difluoro-2-iodobenzoic acid (1.4 g, 4.9 mmol) and Cs 2 CO 3 To a mixture of 1-bromo-3-methyl-2-butene (4.8 g, 14.8 mmol) was added 1-bromo-3-methyl-2-butene (1.5 g, 9.9 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with water and the mixture was extracted with DCM and EtOAc. The combined organic extracts were washed with Na 2 SO 4 The residue was purified by flash chromatography (SiO 2 , gradient elution: 10-20% EtOAc in heptane) 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,3H),1.78(s,3H)ppm.

[0469] Step B. 3-Methylbut-2-en-1-yl 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-iodobenzoate. A mixture of 3-methylbut-2-en-1-yl 4,5-difluoro-2-iodobenzoate (1.6 g, 4.5 mmol), 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 1, 2.1 g, 9.1 mmol) in anhydrous DMF (25 mL) was added to the solution of Cs 2 CO 3(2.9 g, 9.1 mmol) was added. The reaction mixture was heated at 85° C. under nitrogen for 1 h and then cooled to room temperature. The mixture was diluted with water and the mixture was extracted with DCM and EtOAc. The combined organic extracts were washed with Na 2 SO 4 The residue was purified by flash chromatography (SiO 2 , gradient elution: 20-50% EtOAc in heptane) 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, 565.1; measured m / z, 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),4.84(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.

[0470] 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. A mixture of 3-methylbut-2-en-1-yl 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-iodobenzoate (4 g, 6.86 mmol, 1 equiv.) in toluene (200 mL) was added (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) were added. The reaction mixture was degassed with nitrogen three times and then heated at 80° C. under nitrogen atmosphere for 18 h. LCMS analysis indicated that approximately 18% of the starting material remained. The mixture was cooled to 15° C. and further N-cyclohexyl-N-methyl-cyclohexanamine (0.72 mL, 3.43 mmol, 0.5 equiv) and tBu were added. 3 PPdG 2 (176 mg, 0.34 mmol, 0.05 equiv) was added. The reaction mixture was degassed with nitrogen and then heated at 80° C. under a nitrogen atmosphere for 16 h. The mixture was concentrated under reduced pressure and then diluted with H 2 The mixture was diluted with 200 mL of 2H2O and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (100 mL x 2) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure. 2 The residue was purified with ethyl acetate / petroleum ether (5 / 1 to 3 / 1) to give the title compound as a yellow oil (1.1 g, 35%). ESI(MS):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=6.6Hz,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,2 H),3.88(dd,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.

[0471] Method II: A mixture of 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 (Intermediate 3, 5.9 g, 13.5 mmol) in THF (100 mL) 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 h. The mixture was concentrated. The residue was purified by silica column chromatography (elution: 0-25% EtOAc in petroleum ether) 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,1 H),8.01(d,J=7.0Hz,1 H),7.46(s,1 H),7.26-7.42(m,5 H),4.61(s,2 H),4.59(s,2 H),3.77(q,J=7.3Hz,2 H),3.08(dt,J=13.4,6.8Hz,1 H),1.22-1.28(m,9 H)ppm; 19 F NMR (376MHz, DMSO-d 6 )δ-118.29(br s,1 F)ppm.

[0472] Intermediate 5: 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-isobenzoyl chloride.

[0473] [ka]

[0474] 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) and then di-tert-butyl dicarbonate (4.6 g, 21 mmol) was added, followed by DMAP (645 mg, 5.3 mmol). The reaction mixture was stirred under nitrogen at 50° C. overnight and then cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was diluted with EtOAc and washed with brine. The organic layer was separated and washed with Na 2 SO 4 The residue was purified by silica column chromatography (gradient elution: 0-5% EtOAc in petroleum ether) 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,9 H)ppm; 19 F NMR (376 MHz, CDCl 3 )δ-131.55--131.13(m,1 F),-136.97--136.65(m,1 F)ppm.

[0475] 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. In anhydrous DMF (30 mL) was added tert-butyl 4,5-difluoro-2-iodobenzoate (3.2 g, 9.4 mmol), 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 1, 2.6 g, 11.2 mmol), and Cs 2 CO 3(6.1 g, 18.7 mmol) was stirred at 75° C. under nitrogen for 1 h and then cooled to room temperature. The mixture was filtered through a pad of Celite® and the pad was washed with EtOAc. The filtrates were combined, washed with brine and concentrated. The residue was purified by silica column chromatography (gradient elution: 0-40% EtOAc in petroleum ether) to give the title compound as a colorless amorphous solid (5 g, yield: 96%). ESI (MS): C 23 H 25 FIN 3 O 4 Calculated mass, 553.1; measured m / z, 554.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ 8.16(d,J=7.1Hz,1 H),7.62(d,J=10.8Hz,1 H),7.29-7.45(m,5 H),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 (376 MHz, CDCl 3 )δ-119.09(dd,J=10.6,7.0Hz,1 F)ppm.

[0476] Step C. 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4 triazol-1-yl)-5-fluoro-2-iodobenzoic acid. To a solution of tert-butyl 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4 triazol-1-yl)-5-fluoro-2-iodobenzoate (5 g, 9 mmol) in DCM (50 mL) was added TFA (10 mL) slowly. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. 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 in vacuum to give the title compound as a white solid (4.1 g, yield: 91%). ESI (MS): C 19 H17 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=7.2Hz,2 H),1.23(t,J=7.2Hz,3 H)ppm; 19 F NMR (376MHz, DMSO-d 6 )δ-119.91(s,1 F)ppm.

[0477] Step D. 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-iodobenzoyl chloride. SOCl 2 A solution of 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) in 14 mL was heated at reflux for 15 min. The reaction mixture was cooled to room temperature and concentrated. Anhydrous toluene was added to the residue and the mixture was evaporated to give the crude product as a yellow gum (3.6 g), which was used directly in the next step without further purification.

[0478] Intermediate 6: 2-Chloro-6-fluoro-N-(3-methylpent-2-en-1-yl)aniline.

[0479] [ka]

[0480] Step A. Ethyl 3-methylpent-2-enoate. To a solution of 2-butanone (52 g, 717.6 mmol) and (carbethoxymethylene)triphenylphosphorane (50 g, 143.5 mmol) in toluene (65 mL) was added benzoic acid (3.5 g, 28.7 mmol). The reaction mixture was heated to reflux for 16 h. The mixture was diluted with petroleum ether and filtered through a short pad of silica gel. The silica gel was washed with hexane. The filtrate was concentrated under reduced pressure at 0-2 °C. The residue was purified by silica column chromatography (elution: 0-10% EtOAc in petroleum ether) to give the title compound as a colorless liquid (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,1 H),2.09-2.20(m,3 H),1.86(d,J=1.2Hz,1 H),1.24-1.28(m,3 H),1.01-1.09(m,3 H)ppm.

[0481] Step B. 3-Methylpent-2-en-1-ol. To a solution of DIBAL-H (118 mL, 118 mmol) in toluene (1M) at -78°C under nitrogen was added dropwise a solution of ethyl 3-methylpent-2-enoate (20 g, crude) in toluene (40 mL). The reaction mixture was stirred at -78°C for 2 h. The mixture was warmed to room temperature and slowly poured into a saturated aqueous solution of potassium sodium tartrate at 0°C. The mixture was stirred for 2 h and filtered through a short pad of Celite®. The pad was washed with DCM / EtOAc (v / v, 3 / 1) and the filtrate was extracted with DCM. The organic extract was separated and diluted with Na 2 SO 4 The residue was purified by silica column chromatography (elution: 0-100% DCM in petroleum ether, then 0-30% EtOAc in DCM) to give the title compound as a colorless liquid (7 g, 2 steps 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),0.98-1.06(m,3 H)ppm.

[0482] Step C. 3-Methylpent-2-enal. To a solution of 3-methylpent-2-en-1-ol (2 g, 20.0 mmol) in DCM (20 mL) was added Dess-Martin periodinane (10 g, 24.0 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a short pad of Celite®. The pad was washed with DCM. The combined filtrate was diluted with saturated NaHCO 3 The organic layer was separated and washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure at 0-2° C. The crude product was purified by silica column chromatography (elution: DCM) to give the title compound as a colorless liquid (1.5 g, yield: 77%). 1 H NMR (400 MHz, CDCl 3 )δ 9.91-10.04(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=7.4Hz,2 H)ppm.

[0483] Step D N-(2-chloro-6-fluorophenyl)-3-methylpent-2-en-1-imine. To a mixture of 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) at 0 °C under nitrogen, triethylamine (4.6 mL, 33 mmol) was added, followed by TiCl 4 (5 mL, 5 mmol) in DCM (1M) was added dropwise. The resulting mixture was stirred at 0° C. for 1 h, then warmed to room temperature and stirred for 4 h. The mixture was diluted with saturated NH 4The mixture became cloudy and was filtered through a pad of Celite®. The pad was washed with EtOAc. The combined filtrates were diluted with DCM and water. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (gradient elution: 0-5% DCM in petroleum ether) to give the title compound as a pale yellow oil (1.3 g, yield: 70%).

[0484] Step E. 2-Chloro-6-fluoro-N-(3-methylpent-2-en-1-yl)aniline. A solution of N-(2-chloro-6-fluorophenyl)-3-methylpent-2-en-1-imine (1.3 g, 5.76 mmol) in MeOH (20 mL) was added to NaBH 4 (218 mg, 5.8 mmol) was added and after 1 h another batch of NaBH 4 (218 mg, 5.8 mmol) was added. 4 (1.1 g, 29 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated, then diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine and added Na 2 SO 4 The residue was purified by Combi-Flash column chromatography on silica gel (eluent: 0-5% DCM in petroleum ether) to give the title compound as a yellow oil (430 mg, yield: 33%). 1 H NMR (400 MHz, CDCl 3 )δ 6.95-7.02(m,1 H),6.84(ddd,J=12.2,8.3,1.3Hz,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).

[0485] Intermediate 7: 5-Chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine.

[0486] [ka]

[0487] Step A. 5-Chloro-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole. A solution of 3-methyl-4-nitropyrazole (2 g, 15.7 mmol) in EtOAc (20 mL) was treated with DHP (2 g, 23.6 mmol) and TsOH.H 2 Et O (150 mg, 0.79 mmol) was added at room temperature. The mixture was stirred at room temperature overnight. 3 N (0.4 mL) was added and the mixture was washed with brine. The organic layer was then separated and washed with anhydrous Na 2 SO 4 The mixture was dried over 100° C., filtered and concentrated. The residue was dissolved in THF (45 mL) and the temperature was reduced to −78° C. A solution of LiHMDS (10.6 mL, 13.8 mmol) in THF (1 M) was added to the mixture under nitrogen. After 45 min at −78° C., a solution of hexachloroethane (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 The mixture was poured into aqueous Cl and extracted with EtOAc. The organic phase was separated, washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica column chromatography (gradient elution: 0-40% EtOAc in petroleum ether) 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,1 H),4.07-4.15(m,1 H),3.70(td,J=11.3,2.8Hz,1 H),2.57(s,3 H),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,1 H)ppm.

[0488] Step B. 5-Chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine. MeOH / THF / H 2 A mixture of 5-chloro-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (100 mg, 0.4 mmol) in 2H2O (v / v / v, 1 / 1 / 1, 3 mL) was added to 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 filtered through a pad of Celite®. 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 combined organic extracts were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: 0-50% EtOAc in petroleum ether) to give the title compound as a yellow oil (70 mg, yield: 79%). ESI (MS): 9 H 14 ClN 3 Calculated mass of O, 215.1; measured m / z, 216.1 [M+H] + .

[0489] Intermediate 8: 3-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)-2-chloroaniline.

[0490] [ka]

[0491] Step A. tert-Butyl(2-(2-chloro-3-nitrophenoxy)ethoxy)diphenylsilane. In THF (10 mL), 2-chloro-3-nitrophenol (200 mg, 1.2 mmol), 2-((tert-butyldiphenylsilyl)oxy)ethan-1-ol (554 mg, 1.8 mmol) and PPh 3 (453 mg, 1.7 mmol) 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. Saturated NH 4 Aqueous Cl was added and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: 0-10% EtOAc in petroleum ether) to give the title compound as a yellow oil (240 mg, yield: 46%). 1 H NMR (400 MHz, CDCl 3 )δ 7.72(dd,J=7.8,1.5Hz,4 H),7.35-7.49(m,7 H),7.30(t,J=8.2Hz,1 H),7.12(dd,J=8.3,1.2Hz,1 H),4.20-4.25(m,2 H),4.06(t,J=4.9Hz,2 H),1.06(s,9 H)ppm.

[0492] Step B. 3-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)-2-chloroaniline. In a solution of THF (3 mL), MeOH (3 mL) and HO (3 mL), tert-butyl(2-(2-chloro-3-nitrophenoxy)ethoxy)diphenylsilane (220 mg, 0.5 mmol), NH 4To the mixture of Cl (258 mg, 4.8 mmol) was added iron powder (269 mg, 4.8 mmol). The reaction mixture was stirred at 70° C. for 2 h. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through a pad of Celite®. The Celite® was washed with EtOAc. The combined filtrate was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: 0-11% EtOAc in petroleum ether) to give the title compound as a yellow solid (192 mg, yield: 92%). ESI (MS): 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,4 H),7.35-7.48(m,6 H),6.97(t,J=8.1Hz,1 H),6.42(dd,J=8.2,1.1Hz,1 H),6.33(dd,J=8.2,1.1Hz,1 H),4.13-4.17(m,2 H),4.07-4.13(m,2 H),4.01-4.06(m,2 H),1.06(s,9 H)ppm.

[0493] 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.

[0494] [ka]

[0495] Step A. tert-Butyl 2-bromo-4-fluoro-5-methylbenzoate. A solution of 2-bromo-4-fluoro-5-methylbenzoic acid (1 g, 4.3 mmol) in THF (10 mL) was added to the reaction mixture (Boc) 2O (1.9 g, 8.6 mmol) was added, followed by DMAP (262 mg, 2.1 mmol). The reaction mixture turned orange and was stirred under nitrogen at 50° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The organic layer was separated and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica column chromatography (elution: 0-3% EtOAc in petroleum ether) to give the title compound as a colorless oil (900 mg, yield: 72%). 1 H NMR (400 MHz, CDCl 3 )δ 7.57(d,J=8.1Hz,1 H),7.24(d,J=4.6Hz,1 H),2.22(d,J=1.5Hz,3 H),1.58(s,9 H)ppm. 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.

[0496] In DMF (8 mL) was added tert-butyl 2-bromo-4-fluoro-5-methylbenzoate (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) was stirred at 90 °C for 16 h. 4 The reaction was quenched by adding aqueous Cl. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine and added Na 2 SO 4 The residue was purified by CombiFlash chromatography (SiO 2 , eluent: 0-22% EtOAc in petroleum ether) to give the title compound as a colorless gum (1 g, yield: 71%). ESI (MS): 24 H 28 BrN 3 O 4Calculated 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,9 H),1.36(t,J=7.2Hz,3 H)ppm.

[0497] Step C. 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4 triazol-1-yl)-2-bromo-5-methylbenzoic acid. To a mixture of tert-butyl 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4 triazol-1-yl)-2-bromo-5-methylbenzoate (500 mg, 0.90 mmol) in DCM (5 mL) 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 min. The mixture was filtered and the precipitate was rinsed with petroleum ether. The solid was collected and dried in vacuum to give the title compound as a white solid (360 mg, yield: 86%). ESI (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),2.24(s,3 H),1.23(t,J=7.2Hz,3 H)ppm.

[0498] 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. To a mixture of 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-bromo-5-methylbenzoic acid (560 mg, 1.26 mmol), 3-methylbut-1,2-dien-1-yl acetate (Intermediate 12, 1.58 g, 12.5 mmol), AcOK (369 mg, 3.76 mmol) and TBAB (809 mg, 2.51 mmol) in DMF (3.9 mL), Pd(OAc) 2 (141 mg, 0.63 mmol) was added under nitrogen. The reaction mixture was stirred under nitrogen at 90° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were combined and washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: 0-70% EtOAc in petroleum ether) to give the title compound as a yellow solid (410 mg, yield: 73%). ESI (MS): 25 H 25 N 3 O 4 Calculated mass, 431.2; measured m / z, 432.1 [M+H] + . 1 H NMR (400 MHz, CDCl 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,2 H),2.46(s,3 H),2.10(s,3 H),1.38(t,J=7.2Hz,3 H)ppm.

[0499] Intermediate 10: Isopropyl 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-chloro-5-fluoronicotinate.

[0500] [ka]

[0501] Step A. 2,6-Dichloro-5-fluoronicotinoyl chloride. A solution of 2,6-dichloro-5-fluoronicotinic acid (20 g, 95 mmol) in THF (200 mL) was added at 0 °C and (COCl) 2 (12.7 g, 10.0 mmol) and DMF (69.6 mg, 0.952 mmol) were added dropwise. The mixture was stirred at 0° C. for 30 min, then warmed to 25° C. and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give the desired product (21.7 g, crude) as a colorless oil, which was used without further purification.

[0502] Step B. Isopropyl 2,6-dichloro-5-fluoronicotinate. To a mixture of propan-2-ol (8.56 g, 142 mmol, 10.9 mL) and pyridine (9.02 g, 114 mmol) in THF (200 mL) was added a solution of 2,6-dichloro-5-fluoronicotinoyl chloride (21.7 g, 96.0 mmol) in THF (50 mL) at 0° C. 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 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated. The residue was purified by column chromatography (SiO 2 The mixture was purified with petroleum ether / ethyl acetate (1 / 1 to 10:1) to give the title compound (21 g, 86.82% yield). MS (ESI): 9 H 8 Cl 2 FNO 2 Calculated mass, 250.1; observed m / z, 252.0 [M+H]+.1 H 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.

[0503] Step C. Isopropyl 6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4 triazol-1-yl)-2-chloro-5-fluoronicotinate. A mixture of isopropyl 2,6-dichloro-5-fluoronicotinate (4 g, 15.87 mmol) in DMSO (40 mL) was treated with 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (3.89 g, 16.66 mmol) and K 2 CO 3 (3.29 g, 23.80 mmol) was added. The mixture was stirred at 80° C. for 3 h. LCMS showed that the starting material was consumed and the desired material was detected. The mixture was diluted with H 2 The mixture was diluted with 200 mL of 2H2O (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL) and 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 The mixture was purified with petroleum ether / ethyl acetate (1 / 0 to 1:1) to give the title compound (5.7 g, 79.86% yield). MS (ESI): 21 H 22 ClFN 4 O 4 Calculated mass, 448.1; observed m / z, 449.2 [M+H]+. 1 H NMR (400 MHz, CDCl 3 )δ 8.10(d,J=8.8Hz,1H),7.43-7.31(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.

[0504] Intermediate 11: 5-((benzyloxy)methyl)-4-ethyl-2-(7-fluoro-3-hydroxy-4-isopropyl-1-oxoisochroman-6-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

[0505] [ka]

[0506] Step A. Methyl 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4 triazol-1-yl)-2-bromo-5-fluorobenzoate. Methyl 2-bromo-4,5-difluorobenzoate (100.0 g, 398 mmol), 5-((benzyloxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 1, 113.5 g, 508 mmol) and K 2 CO 3 To a flask containing 5-((benzyloxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (100.0 g, 724 mmol) was added anhydrous DMF (1000 mL). The reaction mixture was heated at 50° C. under nitrogen for 16 h, after which additional 5-((benzyloxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (11 g, 51 mmol) was added. The reaction mixture continued to stir at 50° C. The mixture was cooled to room temperature and stirred for 10 min. Water (1000 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. The precipitate was collected by filtration and dried to give the crude product (190 g). The product was stirred in DMF (500 mL) for 30 min, after which water (500 mL) was added. The mixture was stirred for 2 h. The precipitate was collected by filtration and dried to give the title compound (180 g, yield: 90%). 1 H NMR (300 MHz, CDCl 3)δ 7.95(d,J=6.7Hz,1H),7.73(d,J=10.7Hz,1H),7.44-7.27(m,5 H),4.60(s,2 H),4.50(s,2 H),3.95(s,3H),3.84(q,J=7.2Hz,2 H),1.34(t,J=7.2Hz,3 H)ppm.

[0507] Step B. 5-((benzyloxy)methyl)-4-ethyl-2-(7-fluoro-3-hydroxy-4-isopropyl-1-oxoisochroman-6-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one. In dimethylacetamide (300 mL), methyl 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4 triazol-1-yl)-2-bromo-5-fluorobenzoate (30 g, 65.9 mmol), Xantphos (4.02 g, 6.6 mmol), [Pd(allyl)Cl] 2 (1.38g, 3.77mmol), Cs 2 CO 3 To a mixture of 3-methylbutanal (41.4 mL, 386 mmol) and 3-methylbutanal (42.6 g, 130 mmol) was slowly added. The reaction mixture was heated at 80 °C under nitrogen for 22 h. The mixture was filtered and diluted with NH 4 The mixture was quenched with aqueous Cl. 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% ethyl acetate in petroleum ether) to afford 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,1H),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,1H),1.92(spt,J=6.8Hz,1H),1.35(t,J=7.2Hz,3H),1.05(d,J=6.8Hz,3H),0.93(d,J=6.8Hz,3H)ppm.

[0508] Intermediate 12: 3-Methylbuta-1,2-dien-1-yl acetate.

[0509] [ka]

[0510] Step A. 2-Methylbut-3-yn-2-yl acetate. Acetic anhydride (38 g, 371 mmol) at 0 °C was dissolved in Mg(ClO 4 ) 2 (796 mg, 3.6 mmol) was added dropwise to 2-methyl-3-butyn-2-ol (30 g, 357 mmol). The reaction mixture was stirred at 0° C. for 10 min, then warmed to room temperature and stirred overnight. The reaction mixture was diluted with DCM and then saturated NaHCO 3 Aqueous and saturated Na 2 CO 3 The organic layer was separated and washed with Na 2 SO 4 It was dried at 40° C., filtered and concentrated at 0° C. The residue was purified by silica column chromatography (eluent: DCM) to give the title compound as a pale yellow oil (35.8 g, 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.

[0511] Step B. 3-Methylbut-1,2-dien-1-yl acetate. A solution of 2-methylbut-3-yn-2-yl acetate (2.5 g, 20 mmol) in DCM (20 mL) was added to AgBF under nitrogen. 4 (117 mg, 0.6 mmol) was added. The resulting colorless solution was stirred at 35° C. under nitrogen for 2 h until the mixture became a black solution. The mixture was washed with aqueous ammonia (10%). The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with Na 2 SO 4 The residue was purified by silica column chromatography (gradient elution: 0-3% EtOAc in petroleum ether) to give the title compound as a yellow oil (650 mg, 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,6 H)ppm.

[0512] Example 22 of International Application No. IB2020 / 053601 (published as WO 2020 / 212897 on October 22, 2020) discloses 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 (compound 22).

[0513] [ka]

[0514] Step A. 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. To a mixture of 5-((benzyloxy)methyl)-4-ethyl-2-(7-fluoro-3-hydroxy-4-isopropyl-1-oxoisochroman-6-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 11, 56 g, 123 mmol) in AcOH (160 mL) was added o-toluidine (14.8 g, 138 mmol). The reaction mixture was heated at 80° C. for 16 h. The mixture was concentrated and then diluted with NaHCO 3 The pH was adjusted to 7-8 with 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) to give the title compound as an oil (32.5 g, yield: 50%). MS (ESI): 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,9H),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.

[0515] Step B. 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. To a stirred solution of 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 mL) was added 10 mL of BCl under nitrogen at -78 °C. 3 (290 mL, 290 mL) in DCM (1M) was added. The reaction mixture was stirred at 15° C. for 0.5 h. The reaction was quenched at −20° C. with MeOH (100 mL) at −78° C. The mixture was partitioned between water and DCM. The organic layer was separated and the aqueous layer was extracted with DCM (110 mL×2). The combined organic extracts were washed with brine (30 mL×2) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product (27.5 g). The product was triturated with methyl ethyl ketone (82 mL) and heptane (290 mL) to give the pure product (17.5 g). This was recrystallized with ethanol and water to give the title compound 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,2 H),3.27(td,J=13.66,6.82Hz,1 H),2.32(br s,1 H),2.17(s,3 H),1.45(t,J=7.11Hz,3 H),1.32(dd,J=6.82,1.83Hz,6 H)ppm.

[0516] It is noted that the compounds of formula (Z) described herein are described in International Application No. IB2020 / 053601 (published as WO 2020 / 212897 on October 22, 2020), the entirety of which is incorporated by reference herein for all purposes.

[0517] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent.

[0518] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is a hypomethylating agent.

[0519] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is a hypomethylating agent.

[0520] According to embodiments, the hypomethylating agent is azacitidine, decitabine, or a pharma- ceutically acceptable salt or solvate thereof.

[0521] In certain embodiments, the hypomethylating agent is azacitidine, or a pharma- ceutically acceptable salt or solvate thereof.

[0522] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof and a BCL-2 inhibitor.

[0523] In some embodiments, there is provided a combination therapy consisting of a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof and a BCL-2 inhibitor.

[0524] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof and venetoclax or a pharma- ceutical acceptable salt or solvate thereof.

[0525] In some embodiments, a combination therapy comprising compound A, or a pharma- ceutically acceptable salt or solvate thereof, and venetoclax, or a pharma- ceutically acceptable salt or solvate thereof, is provided.

[0526] In some embodiments, a combination therapy comprising compound A1 and venetoclax or a pharma- ceutical acceptable salt or solvate thereof is provided.

[0527] In some embodiments, a combination therapy comprising compound A2 and venetoclax, or a pharma- ceutically acceptable salt or solvate thereof, is provided.

[0528] In some embodiments, a combination therapy comprising compound A3 and venetoclax, or a pharma- ceutically acceptable salt or solvate thereof, is provided.

[0529] In some embodiments, a combination therapy comprising compound A4-a, or a solvate thereof, and venetoclax, or a pharma- ceutical acceptable salt or solvate thereof, is provided.

[0530] In some embodiments, a combination therapy comprising compound A4-b, or a hydrate thereof, and venetoclax, or a pharma- ceutical acceptable salt or solvate thereof, is provided.

[0531] In some embodiments, a combination therapy comprising compound A4 and venetoclax, or a pharma- ceutically acceptable salt or solvate thereof, is provided.

[0532] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is azacitidine or a pharma- ceutical acceptable salt or solvate thereof.

[0533] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is azacitidine or a pharma- ceutical acceptable salt or solvate thereof.

[0534] In some embodiments, a combination therapy is provided comprising compound A or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is azacitidine or a pharma- ceutical acceptable salt or solvate thereof.

[0535] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is azacitidine or a pharma- ceutical acceptable salt or solvate thereof.

[0536] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is azacitidine or a pharma- ceutically acceptable salt or solvate thereof.

[0537] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is azacitidine or a pharma- ceutical acceptable salt or solvate thereof.

[0538] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is azacitidine or a pharma- ceutically acceptable salt or solvate thereof.

[0539] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is azacitidine or a pharma- ceutically acceptable salt or solvate thereof.

[0540] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is azacitidine or a pharma- ceutically acceptable salt or solvate thereof.

[0541] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is azacitidine or a pharma- ceutical acceptable salt or solvate thereof.

[0542] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and azacitidine or a pharma- ceutical acceptable salt or solvate thereof.

[0543] In some embodiments, a combination therapy is provided comprising compound A or a pharma- ceutically acceptable salt or solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and azacitidine or a pharma- ceutically acceptable salt or solvate thereof.

[0544] In some embodiments, a combination therapy is provided that includes compound A1, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and azacitidine or a pharma- ceutically acceptable salt or solvate thereof.

[0545] In some embodiments, a combination therapy is provided that includes compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and azacitidine or a pharma- ceutically acceptable salt or solvate thereof.

[0546] In some embodiments, a combination therapy is provided that includes compound A3, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and azacitidine or a pharma- ceutically acceptable salt or solvate thereof.

[0547] In some embodiments, a combination therapy is provided that includes compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and azacitidine or a pharma- ceutically acceptable salt or solvate thereof.

[0548] In some embodiments, a combination therapy is provided that includes compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and azacitidine or a pharma- ceutically acceptable salt or solvate thereof.

[0549] In some embodiments, a combination therapy is provided that includes compound A4, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and azacitidine or a pharma- ceutically acceptable salt or solvate thereof.

[0550] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is decitabine or a pharma- ceutical acceptable salt or solvate thereof.

[0551] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is decitabine or a pharma- ceutical acceptable salt or solvate thereof.

[0552] In some embodiments, a combination therapy is provided comprising compound A or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is decitabine or a pharma- ceutical acceptable salt or solvate thereof.

[0553] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is decitabine or a pharma- ceutically acceptable salt or solvate thereof.

[0554] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is decitabine or a pharma- ceutically acceptable salt or solvate thereof.

[0555] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is decitabine or a pharma- ceutically acceptable salt or solvate thereof.

[0556] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is decitabine or a pharma-ceutically acceptable salt or solvate thereof.

[0557] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is decitabine or a pharma- ceutically acceptable salt or solvate thereof.

[0558] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is decitabine or a pharma- ceutically acceptable salt or solvate thereof.

[0559] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is a DNA intercalating agent.

[0560] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is a DNA intercalating agent.

[0561] According to an embodiment, the DNA intercalating agent is an anthracycline.

[0562] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is an anthracycline.

[0563] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is an anthracycline.

[0564] In some embodiments, a combination therapy is provided comprising compound A, or a pharma- ceutical acceptable salt or solvate thereof, venetoclax, or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is an anthracycline.

[0565] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is an anthracycline.

[0566] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is an anthracycline.

[0567] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is an anthracycline.

[0568] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is an anthracycline.

[0569] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is an anthracycline.

[0570] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is an anthracycline.

[0571] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is a pyrimidine analog.

[0572] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is a pyrimidine analog.

[0573] According to an embodiment, the pyrimidine analog is cytarabine.

[0574] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is cytarabine.

[0575] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is cytarabine.

[0576] In some embodiments, a combination therapy is provided comprising compound A or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is cytarabine.

[0577] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is cytarabine.

[0578] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is cytarabine.

[0579] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is cytarabine.

[0580] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is cytarabine.

[0581] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is cytarabine.

[0582] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is cytarabine.

[0583] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is a purine analog.

[0584] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is a purine analog.

[0585] According to an embodiment, the purine analog is fludarabine.

[0586] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is fludarabine.

[0587] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is fludarabine.

[0588] In some embodiments, a combination therapy is provided comprising compound A or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is fludarabine.

[0589] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is fludarabine.

[0590] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is fludarabine.

[0591] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is fludarabine.

[0592] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is fludarabine.

[0593] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is fludarabine.

[0594] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is fludarabine.

[0595] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is an IDH inhibitor.

[0596] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is an isocitrate dehydrogenase-1 inhibitor (e.g., ivosidenib).

[0597] According to an embodiment, the IDH inhibitor is ivosidenib.

[0598] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is ivosidenib.

[0599] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is ivosidenib.

[0600] In some embodiments, a combination therapy is provided comprising compound A, or a pharma- ceutical acceptable salt or solvate thereof, venetoclax, or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is ivosidenib.

[0601] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is ivosidenib.

[0602] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is ivosidenib.

[0603] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is ivosidenib.

[0604] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is ivosidenib.

[0605] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is ivosidenib.

[0606] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is ivosidenib.

[0607] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is an isocitrate dehydrogenase-2 inhibitor (e.g., enadidenib).

[0608] According to an embodiment, the IDH inhibitor is enazidenib.

[0609] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is enadidenib.

[0610] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is enadidenib.

[0611] In some embodiments, a combination therapy is provided comprising compound A, or a pharma- ceutical acceptable salt or solvate thereof, venetoclax, or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is enadidenib.

[0612] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is enadidenib.

[0613] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is enadidenib.

[0614] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is enazidenib.

[0615] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is enazidenib.

[0616] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is enazidenib.

[0617] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is enadidenib.

[0618] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is an immunomodulatory anti-neoplastic agent.

[0619] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is an immunomodulatory anti-neoplastic agent that is a PD-1 inhibitor.

[0620] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is an immunomodulatory anti-neoplastic agent.

[0621] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is an immunomodulatory antineoplastic agent that is a PD-1 inhibitor.

[0622] According to embodiments, the immunomodulatory anti-neoplastic agent is nivolumab, atezolizumab, pembrolizumab, thalidomide, lenalidomide, pomalidomide, killed Mycobacterium bovis (BCG) or levamisole.

[0623] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is nivolumab.

[0624] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is nivolumab.

[0625] In some embodiments, a combination therapy is provided comprising compound A, or a pharma- ceutical acceptable salt or solvate thereof, venetoclax, or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is nivolumab.

[0626] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is nivolumab.

[0627] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is nivolumab.

[0628] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is nivolumab.

[0629] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is nivolumab.

[0630] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is nivolumab.

[0631] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is nivolumab.

[0632] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is atezolizumab.

[0633] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is atezolizumab.

[0634] In some embodiments, a combination therapy is provided comprising compound A, or a pharma- ceutical acceptable salt or solvate thereof, venetoclax, or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is atezolizumab.

[0635] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is atezolizumab.

[0636] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is atezolizumab.

[0637] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is atezolizumab.

[0638] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is atezolizumab.

[0639] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is atezolizumab.

[0640] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is atezolizumab.

[0641] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is pembrolizumab.

[0642] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is pembrolizumab.

[0643] In some embodiments, a combination therapy is provided comprising compound A, or a pharma- ceutical acceptable salt or solvate thereof, venetoclax, or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pembrolizumab.

[0644] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pembrolizumab.

[0645] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pembrolizumab.

[0646] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pembrolizumab.

[0647] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pembrolizumab.

[0648] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pembrolizumab.

[0649] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pembrolizumab.

[0650] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is thalidomide.

[0651] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is thalidomide.

[0652] In some embodiments, a combination therapy is provided comprising compound A or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is thalidomide.

[0653] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is thalidomide.

[0654] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is thalidomide.

[0655] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is thalidomide.

[0656] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is thalidomide.

[0657] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is thalidomide.

[0658] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is thalidomide.

[0659] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is lenalidomide.

[0660] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is lenalidomide.

[0661] In some embodiments, a combination therapy is provided comprising compound A, or a pharma- ceutical acceptable salt or solvate thereof, venetoclax, or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is lenalidomide.

[0662] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is lenalidomide.

[0663] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is lenalidomide.

[0664] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is lenalidomide.

[0665] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is lenalidomide.

[0666] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is lenalidomide.

[0667] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is lenalidomide.

[0668] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is pomalidomide.

[0669] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is pomalidomide.

[0670] In some embodiments, a combination therapy is provided comprising compound A or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pomalidomide.

[0671] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pomalidomide.

[0672] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pomalidomide.

[0673] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pomalidomide.

[0674] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pomalidomide.

[0675] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pomalidomide.

[0676] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is pomalidomide.

[0677] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is BCG.

[0678] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is BCG.

[0679] In some embodiments, a combination therapy is provided comprising compound A or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is BCG.

[0680] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is BCG.

[0681] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is BCG.

[0682] In some embodiments, a combination therapy is provided comprising compound A3, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is BCG.

[0683] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is BCG.

[0684] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is BCG.

[0685] In some embodiments, a combination therapy is provided comprising compound A4, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is BCG.

[0686] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is levamisole.

[0687] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is levamisole.

[0688] In some embodiments, a combination therapy is provided comprising compound A or a pharma- ceutical acceptable salt or solvate thereof, venetoclax or a pharma- ceutical acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is levamisole.

[0689] In some embodiments, a combination therapy is provided comprising compound A1, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is levamisole.

[0690] In some embodiments, a combination therapy is provided comprising compound A2, venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent, wherein the at least one other antineoplastic agent is levamisole.

[0691] In some embodiments, a combination therapy is provided comprising compound A...

Claims

1. Menin mixed lineage leukemia 1 (MLL) inhibitor compound A: 【Chemistry 3】 or a pharma- ceutical composition comprising a pharma- ceutical acceptable salt or solvate thereof, The menin-MLL inhibitor is used in a therapeutically effective amount, The pharmaceutical composition comprises: a therapeutically effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor; and Optionally, the pharmaceutical composition is used in combination with a therapeutically effective amount of at least one other anti-neoplastic agent.

2. A pharmaceutical composition comprising a B-cell lymphoma 2 (BCL-2) inhibitor, The BCL-2 inhibitor is used in a therapeutically effective amount, The pharmaceutical composition comprises: A therapeutically effective amount of the menin mixed lineage leukemia 1 (MLL) inhibitor compound A: 【Chemistry 3】 or a pharma- ceutically acceptable salt or solvate thereof, and Optionally, the pharmaceutical composition is used in combination with a therapeutically effective amount of at least one other anti-neoplastic agent.

3. A pharmaceutical composition for use in the treatment or prevention of a hematopoietic disorder, the pharmaceutical composition comprising a menin mixed lineage leukemia 1 (MLL) inhibitor compound A: 【Chemistry 3】 or a pharma- ceutically acceptable salt or solvate thereof, The menin-MLL inhibitor is used in a therapeutically effective amount, The pharmaceutical composition comprises: a therapeutically effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor; and Optionally, a pharmaceutical composition used in combination with a therapeutically effective amount of at least one other anti-neoplastic agent.

4. A pharmaceutical composition for use in the treatment or prevention of a hematopoietic disorder, the pharmaceutical composition comprising a B-cell lymphoma 2 (BCL-2) inhibitor; The BCL-2 inhibitor is used in a therapeutically effective amount, The pharmaceutical composition comprises: A therapeutically effective amount of menin mixed lineage leukemia 1 (MLL) inhibitor compound A: 【Chemistry 3】 or a pharma- ceutically acceptable salt or solvate thereof, and Optionally, the pharmaceutical composition is used in combination with a therapeutically effective amount of at least one other anti-neoplastic agent.

5. Menin mixed lineage leukemia 1 (MLL) inhibitor compound A: 【Chemistry 3】 or a pharma- ceutical composition for use in treating a subject having a hematopoietic disorder, comprising: a therapeutically effective amount of Compound A or a pharma- ceutically acceptable salt or solvate thereof; a therapeutically effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor; and Optionally, a therapeutically effective amount of at least one other anti-neoplastic agent. A pharmaceutical composition comprising the use of

6. A pharmaceutical composition comprising a B-cell lymphoma 2 (BCL-2) inhibitor for use in treating a subject having a hematopoietic disorder, said use comprising: A therapeutically effective amount of menin mixed lineage leukemia 1 (MLL) inhibitor compound A: 【Chemistry 3】 or a pharma- ceutically acceptable salt or solvate thereof, a therapeutically effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor; and Optionally, a therapeutically effective amount of at least one other anti-neoplastic agent. A pharmaceutical composition comprising the use of 7. The pharmaceutical composition of claim 1, wherein the menin-MLL inhibitor is a solvate.

8. The pharmaceutical composition of claim 1, wherein the menin-MLL inhibitor is a pharma- ceutically acceptable salt.

9. The pharmaceutical composition of claim 1, wherein the menin-MLL inhibitor is a solvate of a pharma- ceutically acceptable salt.

10. The menin-MLL inhibitor, 【Chemistry 100】 The pharmaceutical composition according to any one of claims 1 to 6, 11. The menin-MLL inhibitor, 【Chemistry 4】 The pharmaceutical composition according to any one of claims 1 to 6, which is a solvate thereof.

12. The pharmaceutical composition of claim 11, wherein the menin-MLL inhibitor is (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bisbesylate or a hydrate thereof.

13. The pharmaceutical composition of claim 12, wherein the menin-MLL inhibitor is a hydrate of the bisbesylate salt.

14. The pharmaceutical composition of any one of claims 1 to 6, wherein the BCL-2 inhibitor is venetoclax, or a pharma- ceutical acceptable salt or solvate thereof.

15. The pharmaceutical composition of any one of claims 1 to 6 used in combination with at least one other antineoplastic agent which is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analogue, a purine analogue, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase inhibitor, an immunomodulatory antineoplastic agent or a dihydroorotate dehydrogenase inhibitor.

16. 16. The pharmaceutical composition of claim 15, wherein the at least one other anti-neoplastic agent is a hypomethylating agent.

17. 17. The pharmaceutical composition of claim 16, wherein the hypomethylating agent is azacitidine, or a pharma- ceutically acceptable salt or solvate thereof.

18. The pharmaceutical composition of claim 15, wherein the BCL-2 inhibitor is venetoclax or a pharma- ceutical acceptable salt or solvate thereof.

19. The pharmaceutical composition of claim 15, wherein the BCL-2 inhibitor is venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and the at least one other antineoplastic agent is azacitidine, or a pharma- ceutically acceptable salt or solvate thereof.

20. The pharmaceutical composition of claim 15, wherein the at least one other anti-neoplastic agent is a kinase inhibitor, and the kinase inhibitor is an FLT-3 inhibitor.

21. The pharmaceutical composition of claim 15, wherein the at least one other anti-neoplastic agent is a hypomethylating agent or a kinase inhibitor, and the kinase inhibitor is an FLT-3 inhibitor.

22. The pharmaceutical composition of claim 21, wherein the FLT-3 inhibitor is gilteritinib.

23. 22. The pharmaceutical composition of claim 21, wherein the hypomethylating agent is azacitidine, or a pharma- ceutically acceptable salt or solvate thereof.

24. The pharmaceutical composition of claim 15, wherein the at least one other anti-neoplastic agent is a pyrimidine analog.

25. The pharmaceutical composition of claim 24, wherein the pyrimidine analog is cytarabine.

26. The pharmaceutical composition of claim 15, wherein the at least one other anti-neoplastic agent is a DNA intercalating agent.

27. The pharmaceutical composition of claim 26, wherein the DNA intercalating agent is an anthracycline.

28. The pharmaceutical composition of claim 27, wherein the anthracycline is daunorubicin, doxorubicin, or idarubicin.

29. The pharmaceutical composition of any one of claims 1 to 6, wherein the menin-MLL inhibitor, the BCL-2 inhibitor, and optionally at least one other anti-neoplastic agent are administered sequentially or simultaneously in either the same pharmaceutical composition or in different pharmaceutical compositions.

30. The pharmaceutical composition of any one of claims 1 to 6, wherein the menin-MLL inhibitor, the BCL-2 inhibitor, and optionally, at least one other anti-neoplastic agent are administered in separate dosage forms.

31. A pharmaceutical composition according to any one of claims 1 to 2 for use as a medicament.

32. A pharmaceutical composition described in any one of claims 1 to 2 for use in the treatment or prevention of cancer.

33. 10. The pharmaceutical composition of claim 1 for use in the treatment or prevention of hematopoietic disorders.

34. The pharmaceutical composition of claim 2 for use in the treatment or prevention of hematopoietic disorders.

35. The pharmaceutical composition according to any one of claims 3 to 6, 33 and 34, wherein the hematopoietic disorder is nucleophosmin 1 (NPM1) mutant leukemia or KMT2A rearranged leukemia.

36. The pharmaceutical composition according to any one of claims 3 to 6, 33 and 34, wherein the hematopoietic disorder is acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

37. The pharmaceutical composition described in any one of claims 3 to 6, 33 and 34, wherein the hematopoietic disorder is AML having a KMT2A gene alteration or an NPM1 mutation.

38. The pharmaceutical composition described in any one of claims 3 to 6, 33 and 34, wherein the hematopoietic disorder is ALL having a KMT2A gene alteration or an NPM1 mutation.

39. The pharmaceutical composition of any one of claims 3 to 6, 33 and 34, wherein the hematopoietic disorder is AML with a KMT2A gene rearrangement.

40. The pharmaceutical composition described in any one of claims 3 to 6, 33 and 34, wherein the hematopoietic disorder is AML with an NPM1 mutation.

41. The pharmaceutical composition of claim 15, wherein the menin-MLL inhibitor is a hydrate of the bisbesylate salt, the BCL-2 inhibitor is venetoclax or a pharma- ceutically acceptable salt or solvate thereof, and the at least one other antineoplastic agent is azacitidine or a pharma- ceutically acceptable salt or solvate thereof.

42. The pharmaceutical composition of claim 41, for use in treating a hematopoietic disorder, wherein the hematopoietic disorder is nucleophosmin 1 (NPM1) mutant leukemia or KMT2A rearrangement leukemia.

43. The pharmaceutical composition of claim 41, for use in treating a hematopoietic disorder, wherein the hematopoietic disorder is acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

44. The pharmaceutical composition described in claim 41, for use in treating a hematopoietic disorder, wherein the hematopoietic disorder is AML having a KMT2A gene alteration or an NPM1 mutation.

45. The pharmaceutical composition described in claim 41, for use in treating a hematopoietic disorder, wherein the hematopoietic disorder is ALL having a KMT2A gene alteration or an NPM1 mutation.

46. ​​The pharmaceutical composition of claim 41, for use in treating a hematopoietic disorder, wherein the hematopoietic disorder is AML with a KMT2A gene rearrangement.

47. The pharmaceutical composition of claim 41, for use in treating a hematopoietic disorder, wherein the hematopoietic disorder is AML having an NPM1 mutation.

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