Combination therapy

Abstract

Novel combinations are disclosed that include a therapeutically effective amount of a menin-MLL inhibitor of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, and a therapeutically effective amount of at least one other therapeutic agent that is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory agent, or a DHODH inhibitor. Also disclosed are methods of treating a subject diagnosed with cancer using such combinations. The compounds are represented by the following formula (I): 1a , R 1b , R 2 , R 3 , R 4 , U, Y 1 , X 1 , X 2 , n1, n2, n3 and n4 are defined herein). [Formula 1] JPEG2024519322000217.jpg33128

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to novel combinations comprising a therapeutically effective amount of a menin mixed lineage leukemia 1 (menin-MLL) inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of at least one other therapeutic agent that is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory agent, or a DHODH inhibitor, as well as methods of treating a subject diagnosed with cancer using such combinations.

[0002] BACKGROUND OF THE INVENTION Cancer is a leading cause of death worldwide. Of the 10 million cancer deaths recorded by GLOBOCAN in 2020, 7.1% were attributable to hematopoietic disorders. Therefore, 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 hematologic malignancy with an incidence rate ranging from 3:100,000 in young adults to over 20:100,000 in older adults. Overall survival (OS) is 40–50% in patients under 60 years of age, but only 5% in those over 60 years of age. The majority of newly diagnosed AML patients 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. Standard treatment for AML patients ineligible for combination chemotherapy is treatment with hypomethylating agents (azacytidine or decitabine) or low-dose cytarabine. Relapsed / refractory AML with FMS-like tyrosine kinase 3 (FLT3) mutations is treated with FLT3 kinase inhibitors (e.g., gilteritinib, midostaurin). Despite these cutting-edge treatments, median OS is only approximately 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 (if used) often fail to eradicate all tumor-propagating cells and fail to select for chemotherapy-resistant leukemia-propagating subclones. Patients refractory to salvage therapy are treated palliatively because current treatment options are extremely 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 a poor prognosis and a high risk of progression to AML. Therefore, 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-, and 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 predicted global incidence of 1-4.75 cases 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 relapse. The 5-year overall survival rate is approximately 30-40% in adult and elderly patients.

[0005] Therefore, new therapies are urgently needed for the treatment of cancer, particularly relapsed / refractory ALL, and more specifically, adult and especially elderly patients.

[0006] (Summary of the Invention) An embodiment of the present invention relates to a novel combination of a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof with at least one other therapeutic agent that is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analogue, a purine analogue, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory agent, or a DHODH inhibitor.

[0007] Embodiments of the present invention relate to the use of a menin-MLL inhibitor as described herein in combination with at least one other therapeutic 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 method include administering to the subject a therapeutically effective amount of a menin-MLL inhibitor described herein and a therapeutically effective amount of at least one other therapeutic agent, wherein the menin-MLL inhibitor is a compound of formula (I), or a pharmaceutically 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 method include administering to the subject a therapeutically effective amount of a menin-MLL inhibitor as described herein and a therapeutically effective amount of at least one other therapeutic agent that is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory agent, or a DHODH inhibitor, 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 pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of azacitidine, or a pharmaceutically acceptable salt or solvate thereof.

[0011] 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 pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of azacitidine, or a pharmaceutically acceptable salt or solvate thereof, wherein the azacitidine, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject prior to, simultaneously with, or after administration of the menin-MLL inhibitor.

[0012] In embodiments, the menin-MLL inhibitor has formula (I):

[0013] [ka] and tautomeric and stereoisomeric forms thereof, wherein 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 optionally selected from the group consisting of C 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 represents 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)-NR9a 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, can be 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 are each independently 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 alkyl, and pharmaceutically 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 salt 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 salt 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 salt 2.0 equivalent hydrate.

[0023] 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 hydrate crystalline form A.

[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 salt 0.5 to 2.0 equivalents 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 salt 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 explanation of the drawings]

[0027] [Figure 1] Figure 10 is the 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 bis-besylate hydrate crystalline form A. [Figure 2] A comparison of tumor volume as a function of time is shown for a control group and treatment groups treated with regimens containing various amounts of Compound A3. [Figure 3] A comparison of percent tumor survival is shown 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 4]A shows a comparison of the percent survival as a function of time for mice bearing established OCI-AML3 tumors after treatment with either vehicle, azacitidine, or Compound A1 monotherapy, or the dual combination of Compound A1 and azacitidine.B shows a comparison of the percent survival as a function of time for mice bearing established MOLM-13 tumors after treatment with either vehicle, azacitidine, or Compound A1 monotherapy, or the dual combination of Compound A1 and azacitidine. [Figure 5] 1 shows a comparison of percent survival as a function of time for mice bearing established MOLM-13 tumors after treatment with either vehicle, gilteritinib, or Compound A1 monotherapy, or the dual combination of Compound A1 and gilteritinib. [Figure 6] A) Contour plot of maxR showing the effect of Compound A4 in combination with gilteritinib on the growth of MOLM-13 cells in vitro.B) Contour plot of maxR showing the effect of Compound A4 in combination with gilteritinib on the growth of MV4-11 cells in vitro. [Figure 7] A is a contour plot of maxR showing the effect of Compound A4 in combination with midostaurin on the proliferation of MOLM-13 cells in vitro.B is a contour plot of maxR showing the effect of Compound A4 in combination with midostaurin on the proliferation of MV4-11 cells in vitro. [Figure 8] A) Contour plot of maxR showing the effect of compound A4 in combination with idarubicin on the proliferation of MOLM-13 cells in vitro.B) Contour plot of maxR showing the effect of compound A4 in combination with idarubicin on the proliferation of OCI-AML3 cells in vitro. [Figure 9A] 1 is a contour plot of maxR showing the effect of Compound A4 in combination with decitabine on the growth of MOLM-13 cells in vitro. [Figure 9B] 1 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 10A] 1 is a contour plot of maxR showing the effect of Compound A3 in combination with the DHODH inhibitor Compound 22 on the growth of MOLM-13 cells in vitro. [Figure 10B] 1 is a contour plot of maxR showing the effect of Compound A3 in combination with the DHODH inhibitor Compound 22 on the growth of OCI-AML3 cells in vitro. [Figure 11A] Figure 1 shows a comparison of percent survival of mice bearing established MOLM-13 tumors as a function of time after treatment with vehicle, monotherapy with either the menin-MLL inhibitor Compound A1 or the DHODH inhibitor Compound 22, or dual therapy with Compound A1 and Compound 22. [Figure 11B] Figure 1 shows a comparison of percent survival of mice bearing established OCI-AML3 tumors as a function of time after treatment with vehicle, monotherapy with either the menin-MLL inhibitor Compound A1 or the DHODH inhibitor Compound 22, or dual therapy with Compound A1 and Compound 22.

[0028] DESCRIPTION OF THE INVENTION 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 1~4 The 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 from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0033] It will be apparent to those skilled in the art that S(=O)2 or SO2 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] -CRR

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

[0037] -NR

[0038] [ka] It will be clear to one skilled in the art that an example of such a group is -NR 5c -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 following 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] Generally, whenever the term "substituted" is used herein, unless otherwise indicated or apparent from the context, "substituted" is used to indicate that one or more hydrogens, particularly 1 to 4 hydrogens, more particularly 1 to 3 hydrogens, preferably 1 or 2 hydrogens, and 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 substitution results in a chemically stable compound, i.e., a compound sufficiently robust to withstand isolation to a useful degree of purity from the reaction mixture (post-reaction isolation, e.g., 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 skilled 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 specified.

[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 according to embodiments where such substitution 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 in which the term "comprising" is limited to "consisting of." Likewise, all embodiments described herein using the term "comprising" are also applicable to embodiments of the invention in which 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 the alleviation or reversal of symptoms of the disease or disorder being treated.

[0054] The term "composition" is intended to encompass a product containing specified ingredients in specified amounts, and any product that results directly or indirectly from combining specified ingredients in 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 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] Above and below, the term "compounds of formula (I)" is meant to include 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. If the compound contains double bonds, the substituents may be in either 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 those 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. It follows that 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 a 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, by vacuum, lyophilization, or 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 pharmaceutically acceptable salts referred to above and hereinafter are meant to include the therapeutically active non-toxic acid and base salt forms which 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 acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, 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] 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, salts with organic bases such as primary, secondary, and tertiary aliphatic amines and aromatic amines, for example, 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, base forms can be converted to the free base forms by treatment with acid.

[0075] The term "prodrug" includes any compound that, following oral or parenteral administration, in particular oral administration, is metabolized to a (more) active form in experimentally detectable amounts and within a given time period (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) injection.

[0076] Prodrugs can be prepared by modifying functional groups present on the compound such that the modification is 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 hydroxy 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, Elesevier, 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 and the like.

[0079] The compounds of the present invention prepared by the processes described below may be synthesized in the form of mixtures of enantiomers, particularly racemic mixtures of enantiomers, which can be separated from one another according to art-known resolution procedures. Methods for separating the enantiomeric forms of the compound of formula (I) and its pharmaceutically acceptable salts and solvates include liquid chromatography using chiral stationary phases. Such 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, if a specific stereoisomer is desired, the compound will be synthesized by stereospecific preparative methods. These methods will advantageously employ enantiomerically pure starting materials.

[0080] As used herein, the term "enantiomerically pure" means that a 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 that are identical to those enumerated herein, but due to 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, at natural abundance or in isotopically enriched form, are contemplated within the scope of the present invention. Exemplary isotopes that can be incorporated into 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, etc. Preferably, the isotope is 2 H, 3 H, 11 C. 13 C, and 18 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, deuterated 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 Substitutions such as with hydroxypropyl methyl ... 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 is useful for helping to localize and identify tumors, stage disease, and determine appropriate 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. The compounds may also be administered 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), in the form of a suppository or pessary, or topically in the form of a lotion, solution, cream, ointment, or dusting powder. For example, the compounds can be added to a cream comprising, consisting of, and / or consisting essentially of an aqueous emulsion of polyethylene glycol or liquid paraffin. The compounds can 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 via the use of a 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, pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent as an active ingredient can be prepared by mixing the compound with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and / or a pharmaceutically 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. In order 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 preservation of the composition. Injectable suspensions or solutions can also be prepared using aqueous carriers together with appropriate additives, such as solubilizers and preservatives.

[0091] According to certain embodiments, a method of using a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent may include a dosage range of about 0.1 mg to about 3000 mg of active ingredient, or any specific amount or range therein, particularly a dosage range of about 1 mg to about 1000 mg, 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 pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic 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 pharmaceutically acceptable salt or solvate thereof in an amount of about 1 mg to about 500 mg. Advantageously, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may be administered in a single daily dose, or the total daily dosage may be administered in 2, 3 and (4x) divided doses daily.

[0093] The optimal dosage of the compound of formula (I) or its pharmaceutically 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 disorders.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 an appropriate therapeutic level and the desired therapeutic effect.Therefore, the dosages above are examples of average cases.Of course, 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 pharmaceutically acceptable salt or solvate thereof can be administered in any of the compositions and administration regimens described above, or by compositions and administration regimens established in the art, whenever the compound of formula (I) or a pharmaceutically 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 therapeutic agent in an amount of about 1 mg to about 500 mg. Advantageously, the therapeutic agent can be administered in a single dose per day, or the total daily dose can be administered in 2, 3, and (4x) divided doses per day.

[0096] The optimal dose of the administered therapeutic agent can be easily determined and varies depending on the specific compound used, the administration form, the strength of the preparation, and the progression of the disease, syndrome, condition, or disorder. In addition, factors related to the specific subject being treated, such as the subject's gender, age, weight, diet, and administration time, may require adjustment of the dose to achieve an appropriate therapeutic level and the desired therapeutic effect. Therefore, the above dosage amounts are examples of average cases. Of course, 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 therapeutic agent can be administered in any of the compositions and administration regimens described above, or using compositions and administration regimens established in the art, whenever the therapeutic agent is administered to a subject in need thereof.

[0098] As used herein, the term "menin-MLL inhibitor" refers to an inhibitor of the protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) (also known in the scientific community as histone-lysine N-methyltransferase 2A (KMT2A) protein (UniProt Accession No. Q03164)), which inhibits or reduces menin-MLL1 activity. The menin-MLL inhibitors described herein are disclosed in International Application No. CN2020 / 137266 (published as WO2021 / 121327 on June 24, 2021), which is incorporated herein by reference in its entirety, and which also discloses corresponding synthetic schemes and analytical characterization.

[0099] As used herein, the term "therapeutic agent" refers to any agent that treats cancer. In the context of this application, in some embodiments, therapeutic agents are limited to those therapeutic agents explicitly listed herein.

[0100] As used herein, the term "hypomethylating agent" refers to an agent that inhibits or reduces DNA methylation.

[0101] As used herein, the term "cytidine deaminase inhibitor" refers to an agent that inhibits or reduces cytidine deaminase activity.

[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 inhibitor" 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 agent" refers to any agent that stimulates or suppresses the immune system (e.g., via cytokine modulation, T cell costimulation, downregulation of co-inhibitory molecules, enhancement of natural killer cell activity, inhibition of regulatory T cells, and repair of disrupted synapse formation on T cells). In certain embodiments, immunomodulatory agents, such as monoclonal antibodies, cytokines, and vaccines, affect specific parts of the immune system. In other embodiments, immunomodulatory agents, such as sterile Mycobacterium bovis (BCG) and levamisole, affect the immune system in a general manner.

[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 present 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 present 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, in particular the treatment, of cancer.

[0117] According to one embodiment, the present invention provides a combination as described herein for use in the prevention or treatment, particularly the treatment, of cancer, including but not limited to solid tumors, sarcomas and hematopoietic disorders.

[0118] According to one embodiment, the cancer is selected from, but is not limited to, breast cancer, colorectal cancer, gastric cancer, glioma, head and neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, and sarcoma.

[0119] According to one embodiment, the sarcoma is selected from, but not limited to, soft tissue sarcoma, glioma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0120] 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, including but not limited to, a blood cancer, including but not limited to, lymphoma, myeloma, and leukemia.

[0121] According to one embodiment, the present invention provides a combination as described herein for use in the prevention or treatment, in particular the treatment, of a hematopoietic disorder.

[0122] According to one embodiment, the hematopoietic disorder is selected from, but not limited to, lymphoma, myeloma, myelodysplasia, and leukemia.

[0123] According to one embodiment, the hematopoietic disorder is a lymphoma selected from Hodgkin's lymphoma and non-Hodgkin's lymphoma.

[0124] 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).

[0125] In one embodiment, the hematopoietic disorder is myeloma. In one embodiment, the hematopoietic disorder is multiple myeloma, Waldenstrom's macroglobulinemia, or plasmacytoma.

[0126] According to one embodiment, the hematopoietic disorder is myelodysplasia, including but not limited to myelodysplastic syndromes (MDS).

[0127] According to one embodiment, the hematopoietic disorder is leukemia.

[0128] In one embodiment, the hematopoietic disorder is a leukemia selected from acute leukemia and chronic leukemia. In one embodiment, the leukemia is acute leukemia. In one embodiment, the leukemia is chronic leukemia.

[0129] In one embodiment, the hematopoietic disorder is myeloid leukemia, myeloid leukemia, lymphoblastic leukemia, or lymphocytic leukemia. In 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. In one embodiment, the AML is acute megakaryoblastic leukemia (AMKL).

[0130] In one embodiment, the leukemia is MDS, CLL, SLL, ALL, or AML. In one embodiment, the leukemia is CLL, SLL, or AML. In one embodiment, the leukemia is CLL or SLL. In some embodiments, the CLL or SLL is a CD20-expressing cancer. In one embodiment, the leukemia is ALL or AML. In one embodiment, the leukemia is ALL. In one embodiment, the leukemia is AML. In one embodiment, the hematopoietic disorder is Waldenstrom's macroglobulinemia.

[0131] 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.

[0132] According to one embodiment, the leukemia is MLL-rearranged leukemia and / or nucleophosmin 1 (NPM1)-mutated leukemia.

[0133] According to one embodiment, the hematopoietic disorder is an MLL-rearranged leukemia.

[0134] According to one embodiment, the hematopoietic disorder is nucleophosmin 1 (NPM1) mutant leukemia (eg, NPM1c).

[0135] According to one embodiment, the present invention provides a method of 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 pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory agent or a DHODH inhibitor.

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

[0137] According to one embodiment, the hematopoietic disorder is acute lymphoblastic leukemia (ALL).

[0138] According to one embodiment, the hematopoietic disorder is acute myeloid leukemia (AML).

[0139] According to one embodiment, the hematopoietic disorder is small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL).

[0140] According to one embodiment, the hematopoietic disorder is SLL or CLL, wherein the SLL or CLL is a CD20-expressing cancer.

[0141] According to one embodiment, the hematopoietic disorder is myelodysplastic syndrome (MDS).

[0142] According to one embodiment, the hematopoietic disorder is a myeloproliferative neoplasm (MPN).

[0143] According to one embodiment, the hematopoietic disorder is NPM1 mutant leukemia with a FLT3 mutation.

[0144] According to one embodiment, the hematopoietic disorder is FLT3-dependent leukemia.

[0145] According to one embodiment, the hematopoietic disorder is MEF2G-dependent leukemia.

[0146] 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.

[0147] 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.

[0148] According to one embodiment, the hematopoietic disorder is an MLL-rearranged leukemia.

[0149] According to one embodiment, the hematopoietic disorder is acute myeloid leukemia (AML).

[0150] According to one embodiment, the hematopoietic disorder is small lymphocytic lymphoma (SLL).

[0151] According to one embodiment, the hematopoietic disorder is chronic lymphocytic leukemia (CLL).

[0152] 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.

[0153] 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.

[0154] According to one embodiment, the hematopoietic disorder is an MLL-rearranged leukemia, in particular, MLL-rearranged AML or ALL.

[0155] According to one embodiment, the hematopoietic disorder comprises an MLL gene alteration, and 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.

[0156] According to one embodiment, the hematopoietic disorder comprises an NPM1 gene mutation and / or an MLL1 (also known as KMT2A) gene mutation.

[0157] According to one embodiment, the MLL1 gene mutation includes, but is not limited to, an MLL1 gene rearrangement, duplication, or amplification.

[0158] 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 neoplasm (MPN).

[0159] All embodiments described herein with respect to methods for treating a disorder are also applicable for use in treating said disorder.

[0160] All embodiments described herein for use in treating a disorder are also applicable to methods for treating that disorder.

[0161] All embodiments described herein with respect to methods for treating disorders are also applicable for use in the methods for treating said disorders.

[0162] All embodiments described herein for use in a method for treating a disorder are also applicable to the method for treating that disorder.

[0163] In one embodiment, the present invention relates to a novel combination comprising a therapeutically effective amount of a menin-MLL inhibitor of formula (I), or a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of at least one other therapeutic agent which is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analogue, a purine analogue, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory agent, or a DHODH inhibitor.

[0164] According to one embodiment, the compound of formula (I) has the structure:

[0165] [ka] and tautomeric and stereoisomeric forms thereof, wherein R 1a is -C(=O)-NR xa R xb , Het, or

[0166] [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 selected from the group consisting of C 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 represents 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, can be 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 are each independently 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 , R10b , R 10c , R 11 , R 12a , and R 12b is hydrogen and C 1~6 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0167] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb , Het, or

[0168] [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 selected from the group consisting of C 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 represents 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 other, 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 are each independently 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, -OC 1~4 Alkyl, and -C(=O)-NR 10a R 10bC 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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0169] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb , Het, or

[0170] [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 selected from the group consisting of C 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 1~4Alkyl, -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 represents 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 moiety can be 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 are each independently 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 -NR 10c -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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0171] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb , Het, or

[0172] [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 selected from the group consisting of C 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 represents 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 are each independently hydrogen, C 1~6 Alkyl, 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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0173] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb or Het, Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms, and the 6-membered monocyclic aromatic ring is 3~6 is substituted with cycloalkyl, Rxa and R xb is C 1~4 represents alkyl, 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 represents 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 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 -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 are each independently 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 R10b 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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0174] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb or Het, Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms, and the 6-membered monocyclic aromatic ring is 3~6 is substituted with cycloalkyl, R xa and R xb is C 1~4 represents alkyl, 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 represents CH, and X 2 represents N, R 4 represents isopropyl, R 3 is C 1~6 Alkyl-NR 8aR 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 are each independently 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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0175] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb , R xa and R xb is C 1~4 represents alkyl, 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; X1 represents 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 are each independently 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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0176] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: 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 1~4represents alkyl, 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 represents 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 are each independently 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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0177] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb or Het, Het is one C 3~6represents pyrimidinyl substituted by cycloalkyl; R xa and R xb is C 1~4 represents alkyl, 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 represents 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 are each independently 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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0178] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1ais -C(=O)-NR xa R xb , R xa and R xb is C 1~4 represents alkyl, 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 represents 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 are each independently 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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0179] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb represents Rxa and R xb is C 1~4 represents alkyl, 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 represents CH, and X 2 represents N, R 4 represents isopropyl, R 3 is CH2-CH2-CH2-NR 8a R 8b represents R 8a and R 8b are each independently 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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0180] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents alkyl, 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 represents 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 are each independently 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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0181] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents alkyl, R 1b represents F, Y1 represents -O-, R 2 represents hydrogen, U represents N; n1, n2, n3, and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N, R 4 represents isopropyl, R 3 is CH2-CH2-CH2-NR 8a R 8b represents R 8a and R 8b are each independently 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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0182] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb represents R xa and R xb is hydrogen or C 1~4 represents alkyl, R 1b represents F, Y 1 represents -O-, R 2represents hydrogen, U represents N; n1, n2, n3, and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N, R 4 represents isopropyl, R 3 is CH2-CH2-CH2-NR 8a R 8b represents R 8a and R 8b are each independently 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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0183] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb represents R xa and R xb is hydrogen or C 1~4 represents alkyl, 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 represents CH, and X 2 represents N, R 4 represents isopropyl, R 3 is CH2-CH2-CH2-NR 8a R 8b represents R 8a and R 8b are each independently 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 pharmaceutically acceptable salts and solvates thereof.

[0184] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents alkyl, 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 represents 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 are each independently 1~6 alkyl and one -OC 1~4 Alkyl-substituted C 1~6 is selected from the group consisting of alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0185] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents alkyl, 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 represents CH, and X 2 represents N, R 4 represents isopropyl, R 3 is CH2-CH2-CH2-NR 8a R 8b represents R 8a and R 8b are each independently 1~6 alkyl and one -OC 1~4 Alkyl-substituted C 1~6 is selected from the group consisting of alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0186] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: 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 alkyl, 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 represents 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 alkyl, R 8a and R 8b are each independently 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-C1~4 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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0187] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents alkyl, 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 represents 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 are each independently hydrogen, C 1~6Alkyl, -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 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0188] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein R 1b represents F.

[0189] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein R 2 represents hydrogen.

[0190] In one embodiment, the invention comprises compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein n1 is 1, n2 is 2, n3 is 1, and n4 is 1.

[0191] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein Y 1 represents -O-.

[0192] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein Y 1 represents -O-, and U represents N.

[0193] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein Y 1 represents -O-, U represents N, and R 1b represents F and R 2 represents hydrogen.

[0194] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein Het is

[0195] [ka] Represents.

[0196] In one embodiment, the present invention comprises compounds of formula (I) as described in any of the other embodiments, and pharmaceutically 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; Here, the monocyclic 5- or 6-membered aromatic ring is one C 3~6 It is substituted with cycloalkyl.

[0197] In one embodiment, the present invention comprises compounds of formula (I) as described in any of the other embodiments, and pharmaceutically 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, and wherein said monocyclic 5- or 6-membered aromatic ring contains one C 3~6 substituted with cycloalkyl, R1b represents F.

[0198] In one embodiment, the present invention comprises compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents a monocyclic 6-membered aromatic ring containing 1 or 2 nitrogen atoms, wherein said monocyclic 6-membered aromatic ring contains one C 3~6 It is substituted with cycloalkyl.

[0199] In one embodiment, the present invention comprises compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents a monocyclic 6-membered aromatic ring containing 1 or 2 nitrogen atoms, wherein said monocyclic 6-membered aromatic ring contains one C 3~6 substituted with cycloalkyl, R 1b represents F.

[0200] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically 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 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.

[0201] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically 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 where R 3 C in the definition of 1~6The alkyl moiety can be 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.

[0202] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically 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 Represents.

[0203] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically 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 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 are each independently 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.

[0204] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein R3 -C 1~6 Alkyl-NR 8a R 8b represents R 3 C in the definition of 1~6 The alkyl moiety can be cyano, halo, -OH, and -OC. 1~4 alkyl; R 8a and R 8b are each independently 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.

[0205] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically 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 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 are each independently hydrogen, C 1~6 Alkyl, 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 1~6alkyl.

[0206] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically 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 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 are each independently hydrogen, C 1~6 Alkyl, 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 compounds of formula (I) and pharmaceutically 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 where R 3 C in the definition of 1~6 The alkyl moiety can be cyano, halo, -OH, and -OC. 1~4 alkyl; R 8a and R 8b are each independently hydrogen, C 1~6Alkyl, 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.

[0208] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically 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 where R 3 C in the definition of 1~6 The alkyl moiety can be cyano, halo, -OH, and -OC. 1~4 alkyl; R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl, 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.

[0209] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6The alkyl portion may 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.

[0210] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl moiety can be 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.

[0211] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl portion may be cyano, halo, or -OC. 1~4 alkyl; R 8a and R 8b are each independently 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.

[0212] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl moiety can be cyano, halo, -OH, and -OC. 1~4 alkyl; R 8a and R 8b are each independently 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.

[0213] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl moiety can be cyano, halo, -OH, and -OC. 1~4 alkyl; R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl, cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC1~4 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.

[0214] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl portion may be cyano, halo, or -OC. 1~4 alkyl; R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl, 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.

[0215] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically 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 represents R 8a and R 8b are each independently 1~6 Alkyl, as well as -OH, cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4Alkyl, 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.

[0216] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl moiety can be cyano, halo, -OH, and -OC. 1~4 alkyl; R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl, 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.

[0217] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as described in any of the other embodiments, wherein R 3 -C 2~6 Alkyl-NR 8a R 8b where R 3 C in the definition of 2~6 The alkyl portion may be cyano, halo, or -OC. 1~4alkyl; R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl, 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.

[0218] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically 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 represents R 8a and R 8b are each independently 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.

[0219] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically 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 represents R 8ais C 1~6 represents alkyl, and R 8b 1 piece of -OC 1~4 Alkyl-substituted C 1~6 Represents alkyl.

[0220] In one embodiment, the present invention relates to a method of using compounds of formula (I) and pharmaceutically 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 , -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 moiety or C 1~6 Each of the alkyl moieties, independently of the other, 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.

[0221] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically 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 C1~6 Each of the alkyl moieties, independently of the others, can be 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.

[0222] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 is -CH2-CH2-CH2-NR 8a R 8b Represents.

[0223] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 is -CH2-CH2-CH2-NR 8a R 8b represents R 8a represents methyl, and R 8b represents -CH2-CH2-OCH3.

[0224] In one embodiment, the present invention comprises compounds of formula (I) and pharmaceutically 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 limited to -CH2-CH2-CH2-.

[0225] In one embodiment, the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or any subgroup thereof, as described in any of the other embodiments, wherein the compound of formula (I) is of formula (Ia) or formula (Ib):

[0226] [ka] Limited to compounds of 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.

[0227] In one embodiment, the compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or any subgroup thereof as described in any of the other embodiments, are limited to compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or any subgroup thereof as described in any of the other embodiments, are limited to compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof.

[0228] In one embodiment, the present invention comprises a compound of formula (I) or a pharmaceutically 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):

[0229] [ka] wherein R 3 is as defined for the compounds of formula (I) or any subgroup thereof as described in any of the other embodiments.

[0230] In formula (Iy), n1 is 1, n2 is 2, n3 is 1, and n4 is 1.

[0231] In certain embodiments, the compound of formula (I) is compound A:

[0232] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0233] In certain embodiments, the compound of formula (I) is compound A1:

[0234] [ka] is.

[0235] In certain embodiments, the compound of formula (I) is compound A2:

[0236] [ka] is.

[0237] In certain embodiments, the compound of formula (I) is compound A3:

[0238] [ka] is.

[0239] In certain embodiments, the compound of formula (I) is compound A4-a:

[0240] [ka] or a solvate thereof.

[0241] 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.

[0242] 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.

[0243] 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 salt (compound A4-b) or a hydrate thereof.

[0244] 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.

[0245] 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 salt 0.5 to 2.0 equivalents hydrate.

[0246] In one embodiment, the present invention relates to a subgroup of formula (I) as defined in the general reaction scheme:

[0247] 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 pharmaceutically acceptable salts, and solvates thereof.

[0248] In some embodiments, a pharmaceutical composition is provided that includes a pharmaceutically acceptable carrier and, as active ingredients, a therapeutically effective amount of a combination as described in any of the other embodiments.

[0249] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, and at least one other therapeutic agent is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory agent, or a DHODH inhibitor.

[0250] According to an embodiment, the menin-MLL inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0251] According to certain embodiments, the menin-MLL inhibitor is Compound A or a pharmaceutically acceptable salt or solvate thereof.

[0252] According to a particular embodiment, the menin-MLL inhibitor is compound A1.

[0253] According to a particular embodiment, the menin-MLL inhibitor is compound A2.

[0254] According to a particular embodiment, the menin-MLL inhibitor is compound A3.

[0255] According to certain embodiments, the menin-MLL inhibitor is compound A4-a or a solvate thereof.

[0256] According to certain embodiments, the menin-MLL inhibitor is compound A4-b or a hydrate thereof.

[0257] According to a particular embodiment, the menin-MLL inhibitor is compound A4.

[0258] In certain embodiments, menin-MLL inhibitors may have improved metabolic stability properties.

[0259] In certain embodiments, menin-MLL inhibitors may have an extended in vivo half-life (T1 / 2).

[0260] In certain embodiments, menin-MLL inhibitors may have improved oral bioavailability.

[0261] In certain embodiments, menin-MLL inhibitors may reduce tumor growth, for example, tumors harboring MLL (KMT2A) gene rearrangements / alterations and / or NPM1 mutations.

[0262] 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.

[0263] In certain embodiments, menin-MLL inhibitors may have an improved safety profile (e.g., reduced hERG inhibition, improved cardiovascular safety).

[0264] In certain embodiments, the menin-MLL inhibitor may be suitable for QD dosing (once daily).

[0265] According to embodiments, the at least one other therapeutic agent is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory agent, or a DHODH inhibitor.

[0266] According to embodiments, hypomethylating agents include, but are not limited to, azacitidine, decitabine, or pharmaceutically acceptable salts or solvates thereof.

[0267] According to embodiments, cytidine deaminase inhibitors include, but are not limited to, cedazuridine or a pharmaceutically acceptable salt or solvate thereof.

[0268] According to embodiments, DNA intercalating agents include, but are not limited to, anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin).

[0269] According to an embodiment, the DNA intercalating agent is daunorubicin.

[0270] According to an embodiment, the DNA intercalating agent is doxorubicin.

[0271] According to an embodiment, the DNA intercalating agent is idarubicin.

[0272] According to embodiments, pyrimidine analogs include, but are not limited to, cytarabine (ARA-C).

[0273] According to an embodiment, the purine analog is fludarabine.

[0274] 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.

[0275] According to embodiments, the kinase inhibitor is a multikinase inhibitor consisting of an FLT-3 inhibitor, an ABL inhibitor, and an Aurora inhibitor, including, but not limited to, KW-2449.

[0276] According to an embodiment, the kinase inhibitor is a tyrosine kinase inhibitor.

[0277] According to an embodiment, the tyrosine kinase inhibitor is an FLT-3 inhibitor or a BTK inhibitor.

[0278] 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.

[0279] According to an embodiment, the FLT3 inhibitor is gliteritinib (ASP2215).

[0280] According to an embodiment, the FLT3 inhibitor is midostaurin (PKC412).

[0281] According to embodiments, BTK inhibitors include, but are not limited to, ibrutinib.

[0282] According to embodiments, CD20 inhibitors include, but are not limited to, anti-CD20 antibodies (e.g., obinutuzumab (GA101)).

[0283] According to embodiments, IDH inhibitors include, but are not limited to, ivosidenib and enazidenib.

[0284] According to embodiments, isocitrate dehydrogenase-1 inhibitors include, but are not limited to, ivosidenib.

[0285] According to embodiments, isocitrate dehydrogenase-2 inhibitors include but are not limited to enazidenib.

[0286] According to embodiments, immunomodulatory agents include, but are not limited to, PD-1 inhibitors (e.g., nivolumab, atezolizumab, and pembrolizumab), thalidomide, lenalidomide, pomalidomide, sterile Mycobacterium bovis (BCG), and levamisole.

[0287] According to embodiments, PD-1 inhibitors include, but are not limited to, nivolumab, atezolizumab, and pembrolizumab.

[0288] According to embodiments, the DHODH inhibitor may be selected from the group consisting of, but not limited to, the formula (Z):

[0289] [ka] A compound having the structure: X is CH or N; Y is CH or N; R 1 is C 1~6 Alkyl; C substituted with OH or OCH 1~6 Alkyl; C 2~6 Alkenyl; C 1~6 Haloalkyl; C substituted with OH or OCH 1~6 Haloalkyl;C 2~6 Haloalkenyl;N(CH3)2;C 3~6 Cycloalkyl; C 1~6 Alkyl-substituted C 3~6 cycloalkyl; and phenyl, R 2 teeth,

[0290] [ka] where: R a is C 1~6 Alkyl, C 1~6 Haloalkyl, and C 3~6 cycloalkyl; R b is C1~6 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 is selected from the group consisting of H, halo, CH3 and OCH3; R 4 teeth, C 1~6 Alkyl, C substituted with 1 or 2 OCH 1~6 Alkyl, C 3~6 C substituted with cycloalkyl, CH3 or OCH3 3~6 Cycloalkyl, -CH2-C 3~6 cycloalkyl, and

[0291] [ka] ·

[0292] [ka] ·

[0293] [ka] and, ·

[0294] [ka] is selected from the group consisting of In the formula, each R c are independently H; halo; C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~6Haloalkyl; NO2; OH; O-CH2CH2OH, and OC 1~6 alkyl; R d is H; halo; C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~6 Haloalkyl; CN and OC 1~6 is selected from the group consisting of alkyl, R g is H;C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 C substituted with a member selected from the group consisting of haloalkyl, OH, and OCH 1~6 haloalkyl; n is 1 or 2; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof; or,

[0295] [ka] or a pharmaceutically acceptable salt, N-oxide, solvate, or stereoisomer thereof.

[0296] According to embodiments, the DHODH inhibitor may be selected from the group consisting of, but not limited to, the formula (Z):

[0297] [ka] A compound having the structure: X is CH or N; Y is CH or N; R 1 is C 1~6Alkyl; C substituted with OH or OCH 1~6 Alkyl; C 2~6 Alkenyl; C 1~6 Haloalkyl; C substituted with OH or OCH 1~6 Haloalkyl;C 2~6 Haloalkenyl;N(CH3)2;C 3~6 Cycloalkyl; C 1~6 Alkyl-substituted C 3~6 cycloalkyl; and phenyl, R 2 teeth,

[0298] [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 cycloalkyl 1~6 is alkyl, R 3 is selected from the group consisting of H, halo, CH3 and OCH3; R 4 teeth, C 1~6 Alkyl, C substituted with 1 or 2 OCH 1~6 Alkyl, C 3~6 C substituted with cycloalkyl, CH3 or OCH3 3~6 Cycloalkyl, -CH2-C 3~6 cycloalkyl, and

[0299] [ka] ·

[0300] [ka] ·

[0301] [ka] and, ·

[0302] [ka] is selected from the group consisting of In the formula, each R c are independently H; halo; C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~6 Haloalkyl; NO2; OH; O-CH2CH2OH, and OC 1~6 alkyl; R d is H; halo; C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~6 Haloalkyl; CN and OC 1~6 is selected from the group consisting of alkyl, R g is H;C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 C substituted with a member selected from the group consisting of haloalkyl, OH, and OCH 1~6 haloalkyl; n is 1 or 2; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0303] In relation to formula (Z), the following definitions apply:

[0304] The term "alkenyl" includes unsaturated aliphatic groups analogous 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, etc.). The term alkenyl also 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 ).

[0305] 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 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 a hydrogen replaced with a halogen. 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 a hydrogen replaced by a halogen. Examples of "haloalkyl" groups include trifluoromethyl (CF), difluoromethyl (CFH), monofluoromethyl (CHF), pentafluoroethyl (CFCF), tetrafluoroethyl (CHFCF), monofluoroethyl (CHCHF), trifluoroethyl (CHCF), tetrafluorotrifluoromethylethyl (CF(CF)), as well as groups deemed equivalent to any one of the foregoing examples given ordinary skill in the art and the teachings provided herein.

[0306] 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, replacing a hydrogen with a halogen, having 1 to 6 carbon atoms in the chain.

[0307] 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.)

[0308] 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:

[0309] [ka]

[0310] Those skilled in the art will recognize that the above listed or exemplified species are not all inclusive and that additional species within the scope of these defined terms may also be selected.

[0311] 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.

[0312] [ka]

[0313] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein X is CH.

[0314] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein X is N.

[0315] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein Y is CH.

[0316] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein Y is N.

[0317] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 is C 1~4 Alkyl; C substituted with OH or OCH 1~4 Alkyl; C 2~4 Alkenyl; C 1~4 Haloalkyl; C substituted with OH or OCH 1~4 Haloalkyl;C 2~4 Haloalkenyl; N(CH3)2; Cyclopropyl, C 1~4 cyclopropyl substituted with alkyl; or phenyl.

[0318] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 are CH3, CH2CH3.

[0319] [ka]

[0320] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 teeth

[0321] [ka] is.

[0322] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 2 teeth,

[0323] [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.

[0324] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 2 teeth

[0325] [ka] is.

[0326] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is H.

[0327] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is F.

[0328] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is CH3.

[0329] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is OCH3.

[0330] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 is.

[0331] [ka]

[0332] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 4 teeth,

[0333] [ka] wherein: Each R c are independently H; halo; C 1~4 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1- Alkyl; C 1~4 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~4 haloalkyl, and NO2; R d is H; halo; C 1~4 Alkyl; C substituted with OH, OCH3, SCH3, or OCF3 1~4 Alkyl; C 1~4 Haloalkyl; C substituted with OH or OCH 1~4 Haloalkyl; or OC 1~4 Alkyl; CN and OC 1~6 alkyl; n is 1 or 2.

[0334] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 4 teeth,

[0335] [ka] and Each R c are independently H, halo, and C 1~4 Alkyl, C 1~4 Haloalkyl, NO2, O-CH2CH2OH, and OC 1~4 is selected from the group consisting of alkyl, R d H, halo, C 1~4 Alkyl, CN, and OC 1~6 is selected from the group consisting of alkyl, n is 1 or 2.

[0336] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 is.

[0337] [ka]

[0338] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth,

[0339] [ka] is.

[0340] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 4 teeth,

[0341] [ka] and In the formula, R c are independently H; halo; C 1~4 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1- Alkyl; C 1~4haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~4 haloalkyl; R d Ha, halo;C 1~4 Alkyl; C substituted with OH, OCH3, SCH3, or OCF3 1~4 Alkyl; C 1~4 Haloalkyl; C substituted with OH or OCH 1~4 Haloalkyl; or OC 1~4 Alkyl; CN and OC 1~6 alkyl.

[0342] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 4 teeth,

[0343] [ka] where: Each R c are independently H, halo, and C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 selected from the group consisting of alkyl, and OH; R d Ha, Halo, C 1~4 Alkyl and OC 1~4 is selected from the group consisting of alkyl, n is 1 or 2.

[0344] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 is.

[0345] [ka]

[0346] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth

[0347] [ka] is.

[0348] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 4 teeth,

[0349] [ka] where: R c is H; halo; C 1~4 C substituted with alkyl, OH, OCH3, SCH3, or OCF3 1~4 Alkyl; C 1~4 Haloalkyl; C substituted with OH or OCH 1~4 Haloalkyl; or OC 1~4 alkyl; R d Ha, halo;C 1~4 Alkyl; C substituted with OH, OCH3, SCH3, or OCF3 1~4 Alkyl; C 1~4 haloalkyl; or C substituted with OH or OCH 1~4 is haloalkyl, R g is H;C 1~4 Alkyl; C substituted with OH, OCH3, SCH3, or OCF3 1~4 Alkyl; C 1~4 haloalkyl; or C substituted with OH or OCH 1~4 It is haloalkyl.

[0350] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 4 teeth,

[0351] [ka] where: R c is H or halo, R d is C 1~4 is alkyl, R g is H.

[0352] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth

[0353] [ka] is.

[0354] In one embodiment of the present 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-d3)phenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4-methylpyridin-5-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methoxyphenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-6-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-fluoro4-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-(o-D3-tolyl)-1,6-naphthyridin-5(6H)-one; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or 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 pharmaceutically acceptable salt, N-oxide, solvate, or stereoisomer thereof.

[0355] In one embodiment of the present 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; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0356] In one embodiment of the present invention, the DHODH inhibitor is 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, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

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

[0358] [ka] A compound of formula (Z) having the formula: Y is CH or N; R 1 is C 1~6 Alkyl; C substituted with OH or OCH 1~6 Alkyl; C 2~6 Alkenyl; C 1~6 Haloalkyl; C substituted with OH or OCH1~6 Haloalkyl;C 2~6 Haloalkenyl;N(CH3)2;C 3~6 Cycloalkyl; C 1~6 Alkyl-substituted C 3~6 cycloalkyl; and phenyl, R 2 teeth,

[0359] [ka] and R 3 is selected from the group consisting of H, halo, CH3 and OCH3; R 4 teeth, C 1~6 Alkyl; C substituted with 1 or 2 OCH 1~6 Alkyl; C 3~6 Cycloalkyl; C substituted with CH3 or OCH3 3~6 Cycloalkyl; -CH2-C 3~6 cycloalkyl, and

[0360] [ka] and,

[0361] [ka] is selected from In the formula, R c are independently H; halo; C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~6 Haloalkyl; NO2; OH; O-CH2CH2OH, and OC 1~6 alkyl; R d is H; halo; C 1~6alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~6 Haloalkyl; CN and OC 1~6 is selected from the group consisting of alkyl, R g is H;C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 C substituted with a member selected from the group consisting of haloalkyl, OH, and OCH 1~6 haloalkyl; n is 1 or 2; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

[0362] In one embodiment of the present invention, the DHODH inhibitor has the formula (Zb):

[0363] [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,

[0364] [ka] and R 3 is selected from the group consisting of H, halo, and OCH3; R 4 teeth,

[0365] [ka] is selected from the group consisting of In the formula, R c is H; halo; C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~6 haloalkyl, and NO2; R d is H; halo; C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~6 Haloalkyl; CN and OC 1~6 is selected from the group consisting of alkyl, R g is H;C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 C substituted with a member selected from the group consisting of haloalkyl, OH, and OCH 1~6 haloalkyl; n is 1], or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

[0366] Exemplary compounds of formula (Z) useful in the methods of the present invention are described below with reference to exemplary synthetic schemes for their general preparation and the following examples. To obtain the 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 yield the desired product. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that is retained throughout the reaction scheme and can be optionally 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 sealed pressure vessel at a temperature higher than the normal reflux temperature of the solvent.

[0367] 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.

[0368] [Table 1-1]

[0369] [Table 1-2]

[0370] [Table 1-3]

[0371] 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.

[0372] Scheme 1 [ka]

[0373] 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 ranging from 70 to 85°C. The hydrazide and the compound of formula R are then reacted in a suitable solvent such as water. a -NCO(in the formula, R a is C 1~6 Reaction of PG with an isocyanate of PG (where PG is an alkyl) provides the corresponding semicarbazide. Subsequent cyclization of the semicarbazide with a suitable base such as NaOH in a suitable solvent such as water provides a compound of formula (II) where PG is Bn.

[0374] 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 A group of formula R a They can be prepared as described above using appropriately substituted compounds of --NCO.

[0375] Protecting group exchange from a compound of formula (II) where PG is Bn to a compound of formula (II) where PG is TBDPS can be achieved in two steps using established methods, such as those described in T.W. Greene and P.G.Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999. In the first step, deprotection of the benzyl group is achieved under hydrogenolysis conditions well known to those skilled in the art to provide the alcohol. For example, deprotection is achieved using a palladium catalyst, such as Pd / C, under H2 in a suitable solvent, such as EtOH, MeOH, EtOAc, or a mixture thereof, preferably EtOH, with or without HCl for 4 to 72 hours. In the second step, a suitable base, such as tert-butyldiphenylsilyl chloride, imidazole, dimethylaminopyridine, or pyridine, is used in a solvent, such as DMF or DCM, at a temperature ranging from 0°C to room temperature, to provide a compound of formula (II) where PG is TBDPS.

[0376] Scheme 2

[0377] [ka]

[0378] According to Scheme 2, R 3 Compounds of formula (XIV) where H is H are treated with a halogenating reagent such as N-iodosuccinimide (NIS) in an aprotic solvent such as acetonitrile under heating to give halogenated compounds of formula (III) where HAL is iodo. 1 The compound of -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 (wherein, R 1 is an optionally substituted C as defined herein with reference to formula (Z). 2~6Reaction of the compound of formula (IV) with a commercially available or synthetically available boronic acid (or boronic acid ester), such as bis(triphenylphosphine)palladium(II) dichloride, tetrakis(triphenylphosphine)palladium, potassium phosphate, a suitable base, such as CsCO, in a suitable solvent, such as dioxane, water, ethanol, or a mixture thereof, provides a compound of formula (IV). 3 is H, the compound of formula (IV) 4 -B(OH) 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 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 (wherein, R 4 is as defined herein with reference to formula (Z)), a catalyst such as copper(II) acetate, a base such as pyridine, NEt3, in a suitable solvent such as DCM, ACN, dioxane, THF, etc. to provide a compound of formula (V).

[0379] Scheme 3

[0380] [ka]

[0381] According to Scheme 3, a compound of formula (V), 1 is optionally substituted C 2~6 alkenyl, and 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 1~6

[0043] Ullmann-type aromatic amination of a compound of formula (VI) wherein X is CH, X is CH and Y is CH, 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) in the presence of catalyst CuI and a diamine such as trans-1,2-diaminocyclohexane, and a base such as KPO, KCO, CsCO, NaHCO, triethylamine, and the like, in a suitable solvent such as 1,4-dioxane, DMSO, DMF, THF, ACN, and the like, provides a compound of formula (VI) wherein X is CH, X is CH and Y is CH.

[0382] A compound of formula (VI) wherein PG is Bn and R 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

[0383] [ka] ) with diiodomethane and diethyl zinc 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 is a cyclopropyl substituted with CH3.

[0384] Deprotection using established methods such as those described in T.W. Greene and P.G.M. Butts, "Protective Groups in Organic Synthesis", 3rd Edition, John Wiley & Sons, 1999, then provides a compound of formula (Z) where X and Y are CH. For example, a compound of formula (VI) where R 3is 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 (Et3N·3HF).

[0385] 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 can also be achieved using TFA at a temperature of about 80° C.

[0386] 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) is reduced using hydrogenation conditions known to those skilled in the art, for example, reaction with Pd / C or Wilkinson's catalyst [RhCl(PPh3)3] under H2 in a suitable solvent such as MeOH, THF, EtOAc, etc., to give a compound of formula (Z) (wherein R 1 C 2~6 alkyl).

[0387] Scheme 4

[0388] [ka]

[0389] According to Scheme 4, compounds of formula (VII) can be reductively aminated using an unsaturated aldehyde, such as 3-methyl-2-butenal, 3-methylpent-2-enal, and the like, with TiCl and a base such as triethylamine in an aprotic solvent such as dichloromethane (DCM) to give an enamine intermediate, which can then be reduced with a reducing agent such as NaBH to give compounds of formula (VIII), where R 5 is C1~4 alkyl, and R 4 is as defined herein for formula (Z). Coupling of the compound of formula (VIII) with commercially available or synthetically available 4-bromo-2-iodobenzoyl chloride using a base such as triethylamine and 4-dimethylaminopyridine (DMAP) in an anhydrous aprotic solvent such as dichloromethane (DCM) provides 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 provides the intramolecularly cyclized compound of formula (V), where R 1 is optionally substituted C 2~6 alkyl, and 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, and R 3 is H, X is CH2, and HAL is Br).

[0390] Scheme 5

[0391] [ka]

[0392] According to Scheme 5, a commercially available or synthetically available 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 1~6In a preferred method, PG is Bn and R is selected from 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, in the presence of a base such as K3PO4, K2CO3, Cs2CO3, NaHCO3, triethylamine, and the like, in a suitable solvent such as DMSO, DMF, THF, ACN, and the like, to provide a compound of formula (XI). a is C 1~6 The ester of formula (XI) is R 5 C 1~4 If it is an alkyl, it is 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 those skilled in the art to give the acyl chloride of formula (XII). For example, the compound of formula (XIa) is heated in SOCl or treated with oxalyl chloride in DCM.

[0393] Scheme 6

[0394] [ka]

[0395] 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 (VI) 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). Compounds of formula (VI) where X is CH and Y is CH can be prepared by reacting the compound of formula (VI) 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 alkyl, and R 3 The intermediate compound, wherein is H or F, is isolated.

[0396] Scheme 7

[0397] [ka]

[0398] 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 described above, to give 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 reagent 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.

[0399] Scheme 8

[0400] [ka]

[0401] 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 a commercially available or synthetically available appropriately substituted alkyl Grignard reagent, such as i-PrMgCl or EtMgBr, in the presence of CdCl in an aprotic solvent, such as THF, followed by the reaction of R 5 C 1~4 Formula R is alkyl 5 -I with an alkylating agent (such as iodomethane or iodoethane) in the presence of a suitably selected base such as, for example, K2CO3, Cs2CO3, in an aprotic solvent such as DMF, DMSO, to give the regioisomeric esters of formula (XVIIa) and (XVIIb) (wherein R 1 is optionally substituted with 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 regioisomers by precipitation, crystallization, or purification by flash chromatography. The compound of formula (V) can be easily separated from the other regioisomers by reaction of a compound of formula (II) (wherein R a is C 1~6and PG is selected from benzyl, 4-methoxybenzyl, or an alkyl or aryl silane such as TBDPS, TBS, TES, or TIPS) with a suitably protected triazolone in the presence of catalyst CuI and a diamine such as trans-1,2-diaminocyclohexane, and a base such as KPO, KCO, CsCO, NaHCO, triethylamine, etc. in a suitable solvent such as 1,4-dioxane, DMSO, DMF, THF, ACN, etc. to give compounds of formula (XVIII) where X is N.

[0402] 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 diethyl zinc 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 is a cyclopropyl substituted with CH3.

[0403] Scheme 9

[0404] [ka]

[0405] According to Scheme 9, a compound of formula (X) 3 is H and R 5 is CH3) in a palladium-catalyzed carbonylation reaction with 1 -CHO(in the formula, R 1 is C 1~6The ketone compound of formula (XIX) can be coupled with a commercially available or synthetically available aldehyde (wherein the alkyl group is an alkyl group) to give the corresponding ketone compound of formula (XIX). (A similar transformation has been reported in Suchand et al., J. Org. Chem. 2016, 81, 6409-6423.) For example, the reaction of methyl 4-bromo-2-iodobenzoate with isobutyraldehyde in the presence of a palladium catalyst such as Pd(OAc)2, Ag2O2, and an oxidizing agent such as aqueous tert-butyl hydroperoxide (TBHP) at a temperature of approximately 120 °C for 10-14 hours gives methyl 4-bromo-2-isobutyrylbenzoate. The ketone compound of formula (XIX) can be coupled with hydrazine R 4 -NHNH2(wherein, 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 of the compound of formula (V) with the aforementioned appropriately protected triazolone (II) gives a compound of formula (VI) where Y is CH and R 1 is C 1~6 alkyl).

[0406] A compound of formula (VI) wherein Y is CH and R 1 is phenyl and X is N, reacts methyl 4-bromo-2-iodobenzoate with 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 (wherein R is phenyl).

[0407] Scheme 10

[0408] [ka]

[0409] According to Scheme 10, 1The compound of -B(OH)2 is 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 (wherein, R 1 is an 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, a suitable base such as CsCO 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 compounds of formula (XVIII) (wherein X is CH or N) can be obtained by cleaving a compound of formula R 4 -B(OH)2 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, and R 3 is H or F, and R 4 is an appropriately substituted phenyl as described herein with reference to formula (Z).

[0410] A compound of formula (XVIII) 1 is N(CH3)2) is prepared from a compound of formula (XVI) where HAL is Br and PG is Bn. The compound of formula (XVI) is reacted with an amine bs, for example, NH(CH3)2, in water at a temperature of about 110°C for 96 hours to give a compound of formula (XVIII) where R 1 is N(CH3)2 and R aC 1~6 A compound of formula (Z) (wherein R 1 is N(CH3)2) is prepared according to the method described above.

[0411] A compound of formula (XVIII) 1 C replaced by OH 1~6 alkyl) can be prepared by the compound of formula (XVIII) 1 C 2~6 In the first step, a compound of formula (XVIII) (wherein R is alkenyl and PG is Bn) is prepared in two steps. 1 but

[0412] [ka] (XVIII) (wherein R is an integer from 1 to 3) 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) (wherein R is an integer from 1 to 3). 1 C replaced by OH 1~6 alkyl).

[0413] Scheme 11

[0414] [ka]

[0415] According to Scheme 11, 4,5-difluorophthalic anhydride can be reacted with a compound of formula R 4 -NHNH2 hydrazine compound (wherein R 4is an appropriately substituted phenyl or heteroaryl, for example, (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), where R 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, or THF, at room temperature for a period of approximately 1.5 hours, affords the ring-expanded compound of formula (XXI). Derivatization of the compound of formula (XXI) with a sulfonate-based leaving group, such as trifluoromethanesulfonyl (triflate), is achieved by reaction with a triflating agent, such as trifluoromethanesulfonic anhydride (TfO), a base, such as triethylamine (TEA), or pyridine, in a suitable solvent, such as DCM, to afford the compound of formula (XXII). Milder triflating agents, such as N-phenylbis(trifluoromethanesulfonimide) (TFNPh), and bases, such as TEA or DIEA, can be used in a suitable solvent, such as DCM.

[0416] Scheme 12

[0417] [ka]

[0418] According to Scheme 12, 1 The compound of formula -B(OH) 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, the 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 (wherein, R 1 is C as defined herein with reference to formula (Z) 2~6 Alkenyl or C 2~6haloalkenyl) with a palladium catalyst such as bis(triphenylphosphine)palladium(II) dichloride or 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, and a suitable base such as potassium phosphate, Cs2CO3K2CO3 in a suitable solvent such as dioxane, water, ethanol, or a mixture thereof to provide 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, compounds of formula (V) (wherein R 1 but

[0419] [ka] (wherein R is a methyl group) is reacted with a compound of formula (V) (wherein R is a methyl group) 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) (wherein R is a methyl group) 1 but

[0420] [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.

[0421] Scheme 13

[0422] [ka]

[0423] According to Scheme 13, N-arylation of compounds of formula (XVIII) can be carried out using 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) (wherein R 1 H, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-substituted C 3~6 (X is cycloalkyl and X is CH or N) is reacted with a commercially available or synthetically available fluoro compound of formula (XXIII) under nucleophilic substitution conditions in the presence of a base such as K2CO3 or Cs2CO3 in an aprotic solvent such as DMF or DMSO at a temperature in the range of 65-100°C to give a compound of formula (XXIV).

[0424] Reduction of compounds of formula (XXIV) is accomplished using zinc or iron and NH4Cl in a mixed solvent of methanol and water to give amino compounds of formula (XXV).

[0425] Compounds of formula (XXV) can be diazotized with NaNO in aqueous acid or other nitrite reagents in organic solvents 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 by treatment with HPO to give compounds of formula (XXVI), where R c and R d is as defined herein for formula (Z).

[0426] Scheme 14

[0427] [ka]

[0428] According to Scheme 14, a compound of formula (X) wherein HAL is F and R5 is H and R 3 is F) with a commercially available or synthetically available compound of formula (XXVII) 1a and R 1b are each independently H or C 1~4 alkyl), for example, 1-bromo-3-methyl-2-butene, in the presence of a base such as KCO or CsCO in a suitable solvent such as DMSO, DMF, THF, ACN, to give an ester compound of formula (XXVIII) (wherein R 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 Ullmann-type aromatic amination with a suitably protected triazolone compound of formula (II) in the presence of a base such as K3PO4, K2CO3, Cs2CO3, NaHCO3, triethylamine, etc., in a suitable solvent such as 1,4-dioxane, DMSO, DMF, THF, ACN, etc., to give compounds 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) may undergo intramolecular cyclization under Heck reaction conditions, such as using a catalyst such as chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (P(tBu3)PdG2), N-cyclohexyl-N-methyl-cyclohexanamine, in a suitable solvent such as toluene, at a temperature of about 15-80°C for about 18-36 hours to give isocoumarin compounds of formula (XXX), where Y is CH and R 1 is isopropyl, and R 3 is H or F, and R a and PG is as defined above).

[0429] Isocoumarin compounds of formula (XXX) 1 but

[0430] [ka] (XIa) and methylbuta-1,2-dien-1-yl acetate. Methylbuta-1,2-dien-1-yl acetate 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 in the presence of a catalyst such as Mg(ClO4)2 in a suitable solvent such as DCM to give 2-methylbut-3-yn-2-yl acetate. 2-Methylbut-3-yn-2-yl acetate is reacted with a catalytic amount of a Lewis acid such as AgBF4, AgClO4, or PtCl2 to give 3-methylbuta-1,2-dien-1-yl acetate. 3-Methylbuta-1,2-dien-1-yl acetate can be prepared by intermolecular cyclization under Heck reaction conditions as described above to give the compound of formula (XIa) (wherein R 5 is H), for example, by using a catalyst such as Catacxium A Pd G2 and Cy2NMe palladium (II), 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 10-16 hours to give an isocoumarin compound of formula (XXX) (wherein Y is CH and R 1 teeth

[0431] [ka] (which is

[0432] A compound of formula (XXX) wherein Y is CH and R 1 in

[0433] [ka] ) can be selectively reduced under hydrogenation conditions using a catalyst such as Wilkinson's catalyst [RhCl(PPh3)3] in a suitable solvent such as THF at room temperature to give isocoumarin compounds of formula (XXX) 1 is isopropyl).

[0434] Scheme 15

[0435] [ka]

[0436] 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, in a suitable solvent, such as toluene, at a temperature ranging from room temperature to the reflux temperature of the solvent, with or without additives, such as benzoic acid, LiCl, and sodium dodecyl sulfate (SDS), 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 to 3-methylpent-2-enal using oxidation conditions well known to those skilled in the art, such as DMP (Dess-Martin periodinane), SO3-pyridine, Swern conditions [(COCl)2, DMSO, Et3N], PCC, etc., in solvents such as EtOAc, DMSO, DCM, etc., at temperatures ranging from about -78°C to room temperature (about 23°C). In a preferred method, 3-methylpent-2-en-1-ol is oxidized with Dess-Martin periodinane in DCM at 25°C for 1-4 hours to give 3-methylpent-2-enal.

[0437] Scheme 16

[0438] [ka]

[0439] According to Scheme 16, isocoumarins of formula (XXX) (wherein Y is CH) can be prepared by reacting commercially or synthetically available isocoumarins of formula R 4 -NH2 amine compounds (wherein R 4 is as defined herein for formula (Z)) and a Lewis acid such as AlMe, AlCl, 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).

[0440] Scheme 17

[0441] [ka]

[0442] Isocoumarin compounds of formula (XXX) can be prepared according to Scheme 17. 4,5-Difluoro-2-iodobenzoic acid chloride can be converted to compounds of formula (X), where HAL is F and R is 0, 1, 2, 3, 4, 5-difluoro-2-iodobenzoic acid chloride, using conditions well known to those skilled in the art, such as oxalyl chloride or thionyl chloride, in the presence of a catalytic amount of DMF in a suitable solvent, such as dichloromethane (DCM), tetrahydrofuran (THF), acetonitrile (ACN), toluene, and other aprotic nonpolar solvents, at temperatures ranging from 0° C. to room temperature. 5 is H and R 3is F) to form 4,5-difluoro-2-iodobenzoic acid chloride. 4,5-Difluoro-2-iodobenzoic acid chloride can be reacted with commercially available or synthetically available 2-methylbut-3-yn-2-ol 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). Using the method described above, a compound of formula (XXXIII) can be reacted with a compound of formula (II) to give a compound of formula (XXXIV). Compounds of formula (XXXIV) can be treated with a catalytic amount of a Lewis acid, such as AgClO4, PtCl2, or the like to give the rearranged compound of formula (XXXV). Compounds of formula (XXXV) (wherein R 3 is H or F) may undergo intramolecular cyclization 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) (wherein Y is CH).

[0443] Scheme 18

[0444] [ka]

[0445] According to Scheme 18, a compound of formula (Xa) wherein HAL is Cl and R 5 is CH(CH3)2 and R 3 is F) are commercially available or synthetically available according to the methods described in Chen et al., U.S. Patent Application Publication No. 2016-0176869. Compounds of formula (Xa) can be converted to nucleophilic compounds of formula (II) (wherein PG is benzyl and R is F), which are commercially available or synthetically available. c is C 1~6In the presence of a suitable base such as K2CO3, Cs2CO3, NaHCO3, triethylamine, or the like, in a suitable solvent such as dimethyl sulfoxide (DMSO), DMF, THF, or ACN, a compound of formula (XXXIX) (wherein R is N) is obtained. 3 is F and R 5 is C 1~4 Reaction of 1-ethoxyethene-2-boronic acid pinacol ester, where Y is N or CH, with a palladium catalyst such as commercially available 1-ethoxyethene-2-boronic acid pinacol ester, bis(triphenylphosphine)palladium(II) dichloride, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, and a suitable base such as CsCO in a suitable solvent such as dioxane, water, ethanol, or a mixture thereof using conventional or microwave heating methods provides a compound of formula (XL), where Y is N or CH.

[0446] Scheme 19

[0447] [ka]

[0448] According to Scheme 19, the compound of formula R 4 -NH2 compounds (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) (wherein Y is CH or N) to give a compound of formula (XLI). The compound of formula (XLI) (wherein Y is CH or N) is treated with acetic acid or trifluoroacetic acid under heating conditions at 50°C to 90°C to give a compound of formula (XLII). The compound of formula (XLII) is halogenated using N-bromosuccinimide in anhydrous dimethylformamide at room temperature to give a compound of formula (XVI) (wherein HAL is Br). The compound of formula R 1-B(OH)2 is 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 an optionally substituted C 2~6 Alkenyl, C 2~6 to obtain a compound of formula (VI), wherein R is haloalkenyl, or aryl as defined herein for formula (Z). 1 is optionally substituted with C 2~6 Alkenyl or C 2~6 haloalkenyl) with Wilkinson's catalyst ((PPh3)3RhCl) under hydrogenation conditions to give a compound of formula (VI), 1 C 2~6 Alkyl or C 2~6 haloalkyl).

[0449] Scheme 20

[0450] [ka]

[0451] According to Scheme 20, 3-methylbutanal can be converted to a compound of formula (XXXIX) (wherein Y is N and R 5 is CH(CH3)2), a ligand such as 1,1'-bis(diphenylphosphino)ferrocene (dppf), and a suitable base such as Cs2CO3 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), where R 1 is isopropyl) to obtain the formula R 4 -NH2 compounds (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), followed by treatment 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), where X is CH, Y is N, and R 1 is isopropyl, and R 3 is F).

[0452] Scheme 21

[0453] [ka]

[0454] According to Scheme 21, a compound of formula (XXXIX) or formula (XI) 3 is F and R 5 C 1~4

[0033] Reaction of vinylboronic acid pinacol ester (wherein Y is an alkyl group) with a palladium catalyst such as commercially available vinylboronic acid pinacol ester, bis(triphenylphosphine)palladium(II) dichloride, or 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, and a suitable base such as CsCO in a suitable solvent such as dioxane, water, ethanol, or a mixture thereof, provides a compound of formula (XLIII) (wherein Y is N or CH). The vinyl group in 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. Compounds of formula (XLIV) can be reacted with a commercially available or synthetically available suitably substituted alkyl Grignard reagent (e.g., 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, to afford ketone compounds of formula (XLV).

[0455] 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) (wherein 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 a mixture thereof. Acidic hydrolysis using conditions such as treatment with aqueous HCl at room temperature then affords a compound of formula (XLV) (wherein X is N, Y is N or CH, and R is an alkyl group). 1 is methyl).

[0456] Commercially available or synthetically available hydrazine R 4 -NHNH2(wherein, R 4 is as defined herein for formula (Z)), for example, 2-chloro-6-fluorophenylhydrazine, o-tolylhydrazine, 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 a mixture thereof to give a compound of formula (VI) (wherein X is N, Y is CH or N, and R 4 is as defined herein with reference to formula (Z).

[0457] Scheme 22

[0458] [ka]

[0459] According to Scheme 22, methyl 2-bromo-4,5-difluorobenzoate is reacted with a suitably protected triazolone compound of formula (II) in the presence of a base such as KPO, KCO, CsCO, NaHCO, triethylamine, etc., in a suitable solvent such as 1,4-dioxane, DMSO, DMF, THF, ACN, etc., to provide a compound of formula (XLVI). In a preferred method, PG is Bn and R a is C 1~6 The alkyl group (as previously described in Scheme 14) is reacted with 3-methylbutanal of the compound of formula (XLVI) using a palladium catalyst such as allylpalladium(II) chloride dimer, a ligand such as 1,1'-bis(diphenylphosphino)ferrocene (dppf), and a suitable base such as CsCO in the absence of a water scavenger such as molecular sieves (4A) in a suitable solvent such as dioxane to give a compound of formula (XLVII). 4 -NH2 compounds (wherein R 4 is as defined herein for formula (Z)) with trimethylaluminum in a suitable solvent such as dichloromethane, dichloroethane, toluene, or a mixture thereof, and the resulting solution is combined with a compound of formula (XLVII), followed by treatment with acetic acid at a heating temperature of 80-100° C. for a period of time ranging from 5 to 24 hours to give a compound of formula (VI), where X is CH, Y is CH, and R 1 is isopropyl, and R 3 In some cases, compounds of formula R, such as o-toluidine, are obtained. 4 -NH2 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 give a compound of formula (VI) 1 , R 3 is defined above).

[0460] Scheme 23

[0461] [ka]

[0462] According to Scheme 23, a compound of formula (XXXIX) 5 C 1~4 alkyl, Y is N, and R 3 (wherein 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 or toluene. Deprotection using TBAF in a suitable solvent such as THF at room temperature gives a compound of formula (XLVIII). Compounds of formula (XLIX) can be obtained using a gold catalyst, preferably AuCl3, in a suitable solvent mixture such as MeCN. A similar transformation via AuCl3-catalyzed cyclization has been described by Marchal, E. et al. in Tetrahedron 2007, 63, 9979-9990. Compounds of formula R 4 -NH2 compounds (wherein R 4 is as defined herein for formula (Z)) with trimethylaluminum in a suitable solvent such as dichloromethane, dichloroethane, toluene, or a mixture thereof, and the resulting solution is combined with a compound of formula (XLIX), followed by treatment with acetic acid at a heating temperature of 80-100°C for a period ranging from 5 to 24 hours to provide a compound of formula (L). NBS is used in a suitable solvent (preferably DMF) at room temperature, 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, a base such as CsCO or NaCO, in a solvent mixture of 1,4-dioxane and water at a temperature of 100°C to provide a compound of formula (VI) (wherein X is CH, Y is N, and R 3 is F and R 1 , R a and PG are defined as above).

[0463] Scheme 24

[0464] [ka]

[0465] According to Scheme 24, compounds of formula (VI) (wherein PG is Bn) are deprotected using conditions well known to those skilled in the art, preferably in neat TFA in a sealed tube at a temperature of about 60-90°C, or with BCl3 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 give compounds of formula (Z).

[0466] In a similar manner, a compound of formula (XVIII) (wherein R 1 is I, PG is TBDPS, and X is N), and in situ TBDPS deprotection is achieved using conditions well known to those skilled in the art or conditions previously described to provide compounds of formula (Z).

[0467] A compound of formula (Z) 3 is F) in an aromatic nucleophilic substitution reaction to give a compound of formula (Z), 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) (wherein Y is CH and R 3 is OCH3).

[0468] The compound of formula (Z) may be converted to its corresponding salt using methods known to those skilled in the art. For example, the amine of formula (Z) may be treated with trifluoroacetic acid, HCl, or citric acid in a solvent such as EtO, CHCl, THF, MeOH, chloroform, or isopropanol to obtain the corresponding salt form. Alternatively, reverse-phase HPLC purification conditions may result in the trifluoroacetate or formate salt. Crystalline forms of the pharmaceutically acceptable salts of the compound of formula (Z) may be obtained in crystalline form by recrystallization from a polar solvent (including a mixture of polar solvents and an aqueous mixture of polar solvents) or a nonpolar solvent (including a mixture of nonpolar solvents).

[0469] When the compounds according to the present invention have at least one chiral center, they may consequently exist as enantiomers. When the compounds have two or more chiral centers, they may additionally exist as diastereomers. It is understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0470] 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, as appropriate, using conventional methods, such as chromatography or crystallization.

[0471] The following specific examples further illustrate the compounds of formula (Z) and various preferred embodiments. [Example]

[0472] 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.

[0473] Unless otherwise noted, reaction mixtures were magnetically stirred under a nitrogen atmosphere at room temperature (rt). Solutions were generally dried over a drying agent such as NaSO or MgSO. Mixtures, solutions, and extracts were typically concentrated under reduced pressure on a rotary evaporator.

[0474] Normal phase silica gel chromatography (FCC) was performed on silica gel (SiO2) using prepacked cartridges.

[0475] 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 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 to 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. 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 to 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. 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 minutes, followed by a 2 minute hold at 100% ACN; or Method E. Gilson GX-281 semi-preparative HPLC equipped with a Phenomenex Gemini C18 (10 μm, 150 × 25 mm) or a Waters XBridge C18 column (5 μm, 150 × 30 mm), with a mobile phase of 5–99% ACN in water (10 mM NH4HCO3) over 10 min, followed by a 2 min hold at 100% ACN, at a flow rate of 25 mL / min.

[0476] 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. The ABPR was set at 100 bar, CO2 was maintained 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.

[0477] Unless otherwise noted, mass spectra (MS) were obtained on a SHIMADZU LCMS-2020 MSD or an Agilent 1200\G6110A MSD using electrospray ionization (ESI) in positive mode. Calculated masses correspond to exact masses.

[0478] 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 for compounds containing exchangeable protons, the protons may or may not be visible in the NMR spectrum, depending on the choice of solvent used to perform the NMR spectrum and the concentration of the compound in solution.

[0479] 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).

[0480] R * or S * Compounds designated as are enantiomerically pure compounds for which the absolute configuration has not been determined.

[0481] Intermediate 1: 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one.

[0482] [ka]

[0483] Step A. 2-(Benzyloxy)acetohydrazide. To a solution of ethyl 2-(benzyloxy)acetate (55 g, 283.17 mmol) in EtOH (500 mL) was added NHNH·H0 (28.3 g, 566 mmol, 27.5 mL). 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.

[0484] Step B. 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one. To a solution of 2-(benzyloxy)acetohydrazide (52 g, 288 mmol) in HO (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. To the mixture was added HO (20 mL) and a solution of NaOH (57.7 g, 1.44 mol) in water (120 mL). 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, adjusting the pH to 6. The solid was filtered and dried under reduced pressure to give the title compound as a white solid (61 g, 91% yield). 1 H NMR(400MHz,CDCl3)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.

[0485] Intermediate 2: 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one.

[0486] [ka]

[0487] 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 maintained under hydrogen and stirred at room temperature for 6 hours. 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 (4.3 g, 88% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)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.

[0488] 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, 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 H 27 Calculated mass of N3O2Si: 381.2; observed m / z: 382.2 [M+H] + . 1H NMR(400MHz,CDCl3)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.

[0489] 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.

[0490] [ka]

[0491] 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, dried over Na2SO4, filtered, and concentrated. 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(400MHz,CDCl3)δ 7.77(dd,J=10.2,7.9Hz,1H),7.63(dd,J=10.2,7.9Hz,1H),1.62(s,9H)ppm; 19 F NMR (376MHz, CDCl3) δ-131.55--131.13(m,1F),-136.97--136.65(m,1F)ppm.

[0492] 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. A mixture of 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 CsCO (6.1 g, 18.7 mmol) in anhydrous DMF (30 mL) 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 combined filtrate was 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 Calculated mass of FIN3O4: 553.1; observed m / z: 554.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.16(d,J=7.1Hz,1H),7.62(d,J=10.8Hz,1H),7.29-7.45(m,5H),4.61(s,2H) ),4.50(s,2H),3.84(q,J=7.2Hz,2H),1.63(s,9H),1.35(t,J=7.2Hz,3H)ppm; 19 F NMR(376MHz, CDCl3)δ-119.09(dd,J=10.6,7.0Hz,1F)ppm.

[0493] 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 in vacuo. The resulting residue was triturated with petroleum ether at room temperature for 30 minutes. The mixture was filtered and the solid was rinsed with petroleum ether. The precipitate was collected and dried in vacuo to give the title compound as a white solid (4.1 g, yield: 91%). ESI (MS): C 19 H 17 Calculated mass of FIN3O4: 497.0; measured m / z: 498.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.16(d,J=7.3Hz,1H),7.78(d,J=11.0Hz,1H),7.28-7.43(m,5H),4.60(s,2H),4.57(s,2H),3.74(q,J=7.2Hz,2H),1.23(t,J=7.2Hz,3H)ppm; 19 F NMR(376MHz,DMSO-d6)δ-119.91(s,1F)ppm.

[0494] 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. To a mixture of 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 CyNMe (867 mg, 4.4 mmol) in DMF (7 mL) was added Catacxium A Pd G (74.2 mg, 0.11 mmol) under nitrogen. The reaction mixture was stirred under nitrogen at 90 °C overnight. 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 dried over NaSO, 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): C 24 H 22 Calculated mass for FN3O4, 435.2; m / z 436.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.15(d,J=10.5Hz,1H),7.86(d,J=6.8Hz,1H),7.30-7.45(m,5H),7.19(s,1H),5.37-5.39(m,1H),5 .18(s,1H),4.62(s,2H),4.53(s,2H),3.87(q,J=7.1Hz,2H),2.11(s,3H),1.37(t,J=7.2Hz,3H)ppm.

[0495] 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.

[0496] [ka]

[0497] Method I: Step A. 3-Methylbut-2-en-1-yl 4,5-difluoro-2-iodobenzoate. To a mixture of 4,5-difluoro-2-iodobenzoic acid (1.4 g, 4.9 mmol) and CsCO (4.8 g, 14.8 mmol) in anhydrous DMF (20 mL) 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 extracted with DCM and EtOAc. The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography (SiO, gradient elution: 10–20% EtOAc in heptane) to give the desired product as a colorless oil (1.6 g, 92% yield). 1 H NMR(400MHz,CDCl3)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.

[0498] 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. To 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 CsCO (2.9 g, 9.1 mmol). 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 dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography (SiO, gradient elution: 20-50% EtOAc in heptane) to give the title compound as a white solid (2.4 g, 93% yield). LCMS (ES-API): C24 H 25 Calculated mass of FIN3O4: 565.1; observed m / z: 566.2 [M+H] + . 1 H NMR(400MHz,CDCl3)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.

[0499] 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. To 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 (tBuP)PdG (351 mg, 0.69 mmol, 0.1 equiv.) and N-cyclohexyl-N-methyl-cyclohexanamine (1.60 mL, 7.54 mmol, 1.1 equiv.). The reaction mixture was degassed with nitrogen three times and then heated at 80 °C under a nitrogen atmosphere for 18 h. LCMS analysis indicated that approximately 18% of the starting material remained. The mixture was cooled to 15 °C, and additional N-cyclohexyl-N-methyl-cyclohexanamine (0.72 mL, 3.43 mmol, 0.5 equiv.) and tBu3PPdG2 (176 mg, 0.34 mmol, 0.05 equiv.) were 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, then diluted with HO (200 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to give the title compound as a yellow oil (1.1 g, 35%). ESI (MS): C 24 H 24 Calculated mass of FN3O4: 437.2; observed m / z: 438.5 [M+H] + . 1 H NMR(400MHz,CDCl3)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.

[0500] Method II: To 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 added Wilkinson's catalyst [RhCl(PPh3)3] (3.8 g, 4.1 mmol) at room temperature. The mixture was degassed and purged with hydrogen gas. The reaction mixture was stirred under a hydrogen atmosphere (15 Psi) at room temperature for 12 hours. 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, 77% yield). ESI (MS): C 24 H 24 Calculated mass of FN3O4: 437.2; observed m / z: 438.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.10(d,J=10.5Hz,1H),8.01(d,J=7.0Hz,1H),7.46(s,1H),7.26-7.42(m,5H),4.61(s,2H) ),4.59(s,2H),3.77(q,J=7.3Hz,2H),3.08(dt,J=13.4,6.8Hz,1H),1.22-1.28(m,9H)ppm; 19 F NMR(376MHz,DMSO-d6)δ-118.29(brs,1F)ppm.

[0501] 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.

[0502] [ka]

[0503] 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, dried over Na2SO4, filtered, and concentrated. 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(400MHz,CDCl3)δ 7.77(dd,J=10.2,7.9Hz,1H),7.63(dd,J=10.2,7.9Hz,1H),1.62(s,9H)ppm; 19 F NMR (376MHz, CDCl3) δ-131.55--131.13(m,1F),-136.97--136.65(m,1F)ppm.

[0504] 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. A mixture of 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 CsCO (6.1 g, 18.7 mmol) in anhydrous DMF (30 mL) 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 combined filtrate was 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 25Calculated mass of FIN3O4: 553.1; observed m / z: 554.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.16(d,J=7.1Hz,1H),7.62(d,J=10.8Hz,1H),7.29-7.45(m,5H),4.61(s,2H) ),4.50(s,2H),3.84(q,J=7.2Hz,2H),1.63(s,9H),1.35(t,J=7.2Hz,3H)ppm; 19 F NMR(376MHz, CDCl3)δ-119.09(dd,J=10.6,7.0Hz,1F)ppm.

[0505] 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 in vacuo. The resulting residue was triturated with petroleum ether at room temperature for 30 minutes. The mixture was filtered and the solid was rinsed with petroleum ether. The precipitate was collected and dried in vacuo to give the title compound as a white solid (4.1 g, yield: 91%). ESI (MS): C 19 H 17 Calculated mass of FIN3O4: 497.0; measured m / z: 498.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.16(d,J=7.3Hz,1H),7.78(d,J=11.0Hz,1H),7.28-7.43(m,5H),4.60(s,2H),4.57(s,2H),3.74(q,J=7.2Hz,2H),1.23(t,J=7.2Hz,3H)ppm; 19 F NMR(376MHz,DMSO-d6)δ-119.91(s,1F)ppm.

[0506] 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. 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 SOCl2 (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.

[0507] Intermediate 6: 2-chloro-6-fluoro-N-(3-methylpent-2-en-1-yl)aniline.

[0508] [ka]

[0509] 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(400MHz,CDCl3)δ 5.58-5.69(m,1H),4.13(qd,J=7.1,4.9Hz,2H),2.62(q,J=7.5Hz,1H),2.09- 2.20(m,3H),1.86(d,J=1.2Hz,1H),1.24-1.28(m,3H),1.01-1.09(m,3H)ppm.

[0510] Step B. 3-Methylpent-2-en-1-ol. To a 1 M solution of DIBAL-H (118 mL, 118 mmol) in toluene (1 M) at −78°C under nitrogen, a solution of ethyl 3-methylpent-2-enoate (20 g, crude) in toluene (40 mL) was added dropwise. The reaction mixture was stirred at −78°C for 2 h. The mixture was warmed to room temperature and slowly poured into saturated aqueous 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, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica column chromatography (elution: 0 to 100% DCM in petroleum ether, then 0 to 30% EtOAc in DCM) to give the title compound as a colorless liquid (7 g, 57% yield for two steps). 1 H NMR(400MHz, CDCl3)δ 5.35-5.46(m,1H),4.11-4.21(m,2H),2.02-2.13(m,2H),1.67-1.76(m,3H),0.98-1.06(m,3H)ppm.

[0511] 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 washed with saturated aqueous NaHCO3. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure at 0-2 °C. The crude product was purified by silica column chromatography (eluent: DCM) to give the title compound as a colorless liquid (1.5 g, yield: 77%). 1H NMR(400MHz,CDCl3)δ 9.91-10.04(m,1H),5.78-5.90(m,1H),2.58(q,J=7.6Hz,1H),2.23(d,J=7.3Hz,1H), 2.16(s,2H),1.96(d,J=1.1Hz,1H),1.16(t,J=7.6Hz,1H),1.09(t,J=7.4Hz,2H)ppm.

[0512] Step DN-(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 the dropwise addition of a 1 M solution of TiCl (5 mL, 5 mmol) in DCM. The resulting mixture was stirred at 0 °C for 1 h, then warmed to room temperature and stirred for 4 h. The mixture was poured into saturated aqueous NH Cl. The mixture became cloudy and was filtered through a pad of Celite®. The pad was washed with EtOAc. The combined filtrate was diluted with DCM and water. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated. The residual product 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%).

[0513] Step E. 2-Chloro-6-fluoro-N-(3-methylpent-2-en-1-yl)aniline. To 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 NaBH (218 mg, 5.8 mmol), and after 1 h, another batch of NaBH (218 mg, 5.8 mmol) was added. A total of 1.1 g, 29 mmol of NaBH was added. The reaction mixture was stirred overnight at room temperature. The mixture was concentrated, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by CombiFlash column chromatography on silica gel (eluent: 0–5% DCM in petroleum ether) to give the title compound as a yellow oil (430 mg, 33% yield). 1 H NMR(400MHz,CDCl3)δ 6.95-7.02(m,1H),6.84(ddd,J=12.2,8.3,1.3Hz,1H),6.52-6.63(m,1H),5.17-5.28(m,1H), 3.85(d,J=5.6Hz,2H),3.73(s,1H),1.91-2.07(m,2H),1.58-1.68(m,3H),0.89-0.96(m,3H).

[0514] Intermediate 7: 5-chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine.

[0515] [ka]

[0516] Step A. 5-Chloro-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole. To a solution of 3-methyl-4-nitropyrazole (2 g, 15.7 mmol) in EtOAc (20 mL) were added DHP (2 g, 23.6 mmol) and TsOH.HO (150 mg, 0.79 mmol) at room temperature. The mixture was stirred at room temperature overnight. EtN (0.4 mL) was added, and the mixture was washed with brine. The organic layer was then separated, dried over anhydrous NaSO, filtered, and concentrated. The residue was dissolved in THF (45 mL), and the temperature was lowered 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 warmed to room temperature and stirred overnight. The mixture was poured into saturated aqueous NHCl and extracted with EtOAc. The organic phase was separated, washed with brine, dried over anhydrous NaSO, filtered, 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 white solid (1.8 g, yield: 58%). 1 H NMR(400MHz,CDCl3)δ 5.52(dd,J=10.0,2.7Hz,1H),4.07-4.15(m,1H),3.70(td,J=11.3,2.8Hz,1H),2.57(s,3H),2.37-2.47(m,1H) ),2.11-2.19(m,1H),1.86-1.90(m,1H),1.72-1.75(m,1H),1.64(d,J=2.0Hz,1H),1.53(d,J=6.6Hz,1H)ppm.

[0517] Step B. 5-Chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine. To a mixture of 5-chloro-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (100 mg, 0.4 mmol) in MeOH / THF / HO (v / v / v, 1 / 1 / 1, 3 mL) was added iron powder (114 mg, 2.0 mmol) and NH4Cl (109 mg, 2.0 mmol). 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 washed with saturated aqueous NaHCO3. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica column chromatography (gradient elution: 0 to 50% EtOAc in petroleum ether) to give the title compound as a yellow oil (70 mg, yield: 79%). ESI(MS):C9H 14 Calculated mass for ClNO, 215.1; observed m / z, 216.1 [M+H] + .

[0518] Intermediate 8: 3-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)-2-chloroaniline.

[0519] [ka]

[0520] Step A. tert-butyl(2-(2-chloro-3-nitrophenoxy)ethoxy)diphenylsilane. To a mixture of 2-chloro-3-nitrophenol (200 mg, 1.2 mmol), 2-((tert-butyldiphenylsilyl)oxy)ethan-1-ol (554 mg, 1.8 mmol), and PPh3 (453 mg, 1.7 mmol) in THF (10 mL) at 0 °C under nitrogen, DEAD (281 mg, 161 mmol) was added. The mixture was warmed to room temperature and stirred at room temperature for 12 h. Saturated aqueous NH4Cl 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, 46% yield). 1 H NMR(400MHz,CDCl3)δ 7.72(dd,J=7.8,1.5Hz,4H),7.35-7.49(m,7H),7.30(t,J=8.2Hz,1H),7.12(dd ,J=8.3,1.2Hz,1H),4.20-4.25(m,2H),4.06(t,J=4.9Hz,2H),1.06(s,9H)ppm.

[0521] Step B. 3-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)-2-chloroaniline. To a mixture of tert-butyl(2-(2-chloro-3-nitrophenoxy)ethoxy)diphenylsilane (220 mg, 0.5 mmol), NH4Cl (258 mg, 4.8 mmol) in THF (3 mL), MeOH (3 mL), and HO (3 mL) 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, dried over Na2SO4, 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, 92% yield). ESI (MS): C 24 H 28Calculated mass of ClNO2Si: 425.2; observed m / z: 426.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.75(dd,J=7.9,1.6Hz,4H),7.35-7.48(m,6H),6.97(t,J=8.1Hz,1H),6.42(dd,J=8.2,1.1Hz,1H),6 .33(dd,J=8.2,1.1Hz,1H),4.13-4.17(m,2H),4.07-4.13(m,2H),4.01-4.06(m,2H),1.06(s,9H)ppm.

[0522] 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.

[0523] [ka]

[0524] Step A. tert-Butyl 2-bromo-4-fluoro-5-methylbenzoate. To a solution of 2-bromo-4-fluoro-5-methylbenzoic acid (1 g, 4.3 mmol) in THF (10 mL) was added (Boc)O (1.9 g, 8.6 mmol), followed by DMAP (262 mg, 2.1 mmol). The reaction mixture turned orange and was stirred overnight at 50 °C under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The organic layer was separated, dried over NaSO, 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 (400MHz, CDCl3) δ 7.57(d,J=8.1Hz,1H),7.24(d,J=4.6Hz,1H),2.22(d,J=1.5Hz,3H),1.58(s,9H)ppm.

[0525] 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. A mixture of 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 CsCO (1.7 g, 5.2 mmol) in DMF (8 mL) was stirred at 90 °C for 16 h. The reaction was quenched by the addition of saturated aqueous NHCl. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by Combiflash chromatography (SiO, eluent: 0-22% EtOAc in petroleum ether) to give the title compound as a colorless gum (1 g, yield: 71%). ESI (MS): C 24 H 28 Calculated mass for BrN3O4: 501.1; observed m / z: 502.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.64(d,J=6.1Hz,2H),7.33-7.43(m,5H),4.61(s,2H),4.50(s,2H),3.85(q,J=7.3Hz,2H),2.31(s,3H),1.62(s,9H),1.36(t,J=7.2Hz,3H)ppm.

[0526] 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 hours. 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 minutes. The mixture was filtered, and the precipitate was rinsed with petroleum ether. The solid was collected and dried in vacuo to give the title compound as a white solid (360 mg, yield: 86%). ESI (MS): C 20 H 20 Calculated mass for BrN3O4: 445.1; observed m / z: 446.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.77(s,1H),7.70(s,1H),7.29-7.41(m,5H),4.59(s,2H),4.56(s,2H),3.74(q,J=7.0Hz,2H),2.24(s,3H),1.23(t,J=7.2Hz,3H)ppm.

[0527] 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-methylbuta-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) was added Pd(OAc) (141 mg, 0.63 mmol) 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 dried over Na SO , 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): C 25 H 25 Calculated mass of N3O4: 431.2; observed m / z: 432.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.28(s,1H),7.59(s,1H),7.31-7.46(m,5H),7.17(s,1H),5.30-5.37(m,1H),5.15(s,1H),4.63 (s,2H),4.52(s,2H),3.87(q,J=7.1Hz,2H),2.46(s,3H),2.10(s,3H),1.38(t,J=7.2Hz,3H)ppm.

[0528] 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.

[0529] [ka]

[0530] Step A. 2,6-Dichloro-5-fluoronicotinoyl chloride. To a solution of 2,6-dichloro-5-fluoronicotinic acid (20 g, 95 mmol) in THF (200 mL) at 0° C. was added (COCl) (12.7 g, 10.0 mmol) and DMF (69.6 mg, 0.952 mmol) 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.

[0531] 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 phases were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 10:1) to give the title compound (21 g, 86.82% yield). MS (ESI): mass calculated for C9H8Cl2FNO2, 250.1; observed m / z, 252.0 [M+H]+. 1 H NMR (400MHz, CDCl3) δ 7.97-7.95(d,J=7.2Hz,1H),5.32-5.25(m,1H),1.58-1.39(m,6H)ppm.

[0532] 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. To a mixture of isopropyl 2,6-dichloro-5-fluoronicotinate (4 g, 15.87 mmol) in DMSO (40 mL) was added 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (3.89 g, 16.66 mmol) and K2CO3 (3.29 g, 23.80 mmol). The mixture was stirred at 80 °C for 3 h. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 1:1) to give the title compound (5.7 g, 79.86% yield). MS(ESI):C 21 H 22 Calculated mass for ClFN4O4, 448.1; observed m / z, 449.2 [M+H]+. 1 H NMR(400MHz,CDCl3)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.

[0533] 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.

[0534] [ka]

[0535] 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. To a flask containing 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 KCO (100.0 g, 724 mmol), anhydrous DMF (1000 mL) was added. The reaction mixture was heated at 50° C. under nitrogen for 16 hours, 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 minutes. Water (1000 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. 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 minutes, and then water (500 mL) was added. The mixture was stirred for 2 hours. The precipitate was collected by filtration and dried to give the title compound (180 g, yield: 90%). 1 H NMR(300MHz,CDCl3)δ 7.95(d,J=6.7Hz,1H),7.73(d,J=10.7Hz,1H),7.44-7.27(m,5H),4.60(s,2H) ),4.50(s,2H),3.95(s,3H),3.84(q,J=7.2Hz,2H),1.34(t,J=7.2Hz,3H)ppm.

[0536] 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. To a mixture of 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] (1.38 g, 3.77 mmol), and CsCO (42.6 g, 130 mmol) in dimethylacetamide (300 mL) was slowly added 3-methylbutanal (41.4 mL, 386 mmol). The reaction mixture was heated at 80 °C under nitrogen for 22 h. The mixture was filtered and quenched with aqueous NH4Cl until the pH reached 7–8. The mixture was extracted with ethyl acetate (2000 mL x 2). The combined organic extracts were concentrated. The residue was purified by column chromatography (SiO2, gradient elution: 1-33% ethyl acetate in petroleum ether) to give the title compound as an oil (61.7 g, yield: 56%). 1 H NMR(300MHz,CDCl3)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 ppm.

[0537] Intermediate 12: 3-methylbuta-1,2-dien-1-yl acetate.

[0538] [ka]

[0539] Step A. 2-Methylbut-3-yn-2-yl acetate. To a mixture of acetic anhydride (38 g, 371 mmol) and Mg(ClO) (796 mg, 3.6 mmol) at 0° C., 2-methyl-3-butyn-2-ol (30 g, 357 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 10 minutes, then warmed to room temperature and stirred overnight. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO and saturated aqueous NaCO. The organic layer was separated, dried over NaSO, filtered, and concentrated at 0° C. The residue was purified by silica column chromatography (elution: DCM) to give the title compound as a pale yellow oil (35.8 g, yield: 80%). 1 H NMR (400MHz, CDCl3) δ 2.54 (s, 1H), 2.03 (s, 3H), 1.67 (s, 6H) ppm.

[0540] Step B. 3-Methylbut-1,2-dien-1-yl acetate. To a solution of 2-methylbut-3-yn-2-yl acetate (2.5 g, 20 mmol) in DCM (20 mL) was added AgBF (117 mg, 0.6 mmol) under nitrogen. 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 dried over NaSO, filtered, and concentrated. 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, 26% yield). 1 H NMR(400MHz, CDCl3) δ 7.20(dt,J=4.1,2.0Hz,1H),2.11(s,3H),1.81(d,J=2.0Hz,6H)ppm.

[0541] 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).

[0542] [ka]

[0543] 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 the pH was adjusted to 7-8 with aqueous NaHCO3. The mixture was extracted with ethyl acetate (160 mL x 2). The combined organic extracts were concentrated. The residue was purified by flash chromatography (SiO2, 0-20% ethyl acetate in DCM) to give the title compound as an oil (32.5 g, 50% yield). MS (ESI): C 31 H 31 Calculated mass of FN4O3: 526.2; observed m / z: 527.4 [M+H] + . 1 H NMR(300MHz,CDCl3)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.

[0544] 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 a 1 M solution of BCl3 (290 mL, 290 mL) in DCM at −78° C. under nitrogen. The reaction mixture was stirred at 15° C. for 0.5 h. The reaction was quenched to −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 (2×110 mL). The combined organic extracts were washed with brine (30 mL x 2), dried over anhydrous NaSO, 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 Calculated mass of FN4O3: 436.2; observed m / z: 437.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.33(d,J=11.2,1H),8.08(d,J=6.8,1H),7.39-7.33(m,3H),7.28(s,1H),6.85(s,1H),4.69(br s,2H),3.94(q,J=7.11Hz,2H),3.27(td,J=13.66,6.82Hz,1H),2.32(br s,1H),2.17(s,3H),1.45(t,J=7.11Hz,3H),1.32(dd,J=6.82,1.83Hz,6H)ppm.

[0545] It is noted that the compounds of formula (Z) described herein are described in International Application No. IB2020 / 053601 (published on October 22, 2020 as WO 2020 / 212897), which is incorporated by reference herein in its entirety for all purposes.

[0546] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, and at least one other therapeutic agent is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory agent, or a DHODH inhibitor.

[0547] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent, wherein the at least one other therapeutic agent is a hypomethylating agent.

[0548] According to embodiments, the hypomethylating agent is azacitidine, decitabine, or a pharmaceutically acceptable salt or solvate thereof.

[0549] According to certain embodiments, the hypomethylating agent is azacitidine, or a pharmaceutically acceptable salt or solvate thereof.

[0550] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is azacitidine or a pharmaceutically acceptable salt or solvate thereof.

[0551] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is azacitidine, or a pharmaceutically acceptable salt or solvate thereof.

[0552] In some embodiments, combination therapies are provided that include a combination therapy comprising Compound A1, wherein at least one other therapeutic agent is azacitidine or a pharmaceutically acceptable salt or solvate thereof.

[0553] In some embodiments, combination therapies are provided that include a combination therapy comprising Compound A2, wherein at least one other therapeutic agent is azacitidine or a pharmaceutically acceptable salt or solvate thereof.

[0554] In some embodiments, combination therapies are provided that include a combination therapy comprising Compound A3, wherein at least one other therapeutic agent is azacitidine or a pharmaceutically acceptable salt or solvate thereof.

[0555] In some embodiments, a combination therapy is provided that includes a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is azacitidine or a pharmaceutically acceptable salt or solvate thereof.

[0556] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof, wherein at least one other therapeutic agent is azacitidine or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0557] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is azacitidine or a pharmaceutically acceptable salt or solvate thereof.

[0558] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is azacitidine or a pharmaceutically acceptable salt or solvate thereof.

[0559] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, and azacitidine, or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0560] In some embodiments, a combination therapy comprising Compound A1 and azacitidine, or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0561] In some embodiments, a combination therapy comprising Compound A2 and azacitidine, or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0562] In some embodiments, a combination therapy comprising Compound A3 and azacitidine, or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0563] In some embodiments, a combination therapy comprising compound A4-a, or a solvate thereof, and azacitidine, or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0564] In some embodiments, a combination therapy comprising compound A4-b, or a hydrate thereof, and azacitidine, or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0565] In some embodiments, a combination therapy comprising Compound A4 and azacitidine, or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0566] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is decitabine or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0567] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is decitabine, or a pharmaceutically acceptable salt or solvate thereof.

[0568] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is decitabine or a pharmaceutically acceptable salt or solvate thereof.

[0569] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is decitabine or a pharmaceutically acceptable salt or solvate thereof.

[0570] In some embodiments, a combination therapy comprising compound A3 is provided, wherein at least one other therapeutic agent is decitabine or a pharmaceutically acceptable salt or solvate thereof.

[0571] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is decitabine or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0572] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof, wherein at least one other therapeutic agent is decitabine or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0573] In some embodiments, a combination therapy comprising compound A4 is provided, wherein at least one other therapeutic agent is decitabine or a pharmaceutically acceptable salt or solvate thereof.

[0574] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is a DNA intercalator.

[0575] According to an embodiment, the DNA intercalating agent is an anthracycline.

[0576] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is an anthracycline.

[0577] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is an anthracycline is provided.

[0578] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is an anthracycline.

[0579] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is an anthracycline.

[0580] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is an anthracycline.

[0581] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is an anthracycline, is provided.

[0582] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is an anthracycline.

[0583] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is an anthracycline.

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

[0585] According to an embodiment, the pyrimidine analog is cytarabine.

[0586] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is cytarabine.

[0587] In some embodiments, a combination therapy comprising Compound A or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is cytarabine, is provided.

[0588] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is cytarabine.

[0589] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is cytarabine.

[0590] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is cytarabine.

[0591] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is cytarabine, is provided.

[0592] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is cytarabine.

[0593] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is cytarabine.

[0594] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent, wherein the at least one other therapeutic agent is a purine analog.

[0595] According to an embodiment, the purine analog is fludarabine.

[0596] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is fludarabine.

[0597] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is fludarabine is provided.

[0598] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is fludarabine.

[0599] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is fludarabine.

[0600] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is fludarabine.

[0601] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is fludarabine, is provided.

[0602] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is fludarabine.

[0603] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is fludarabine.

[0604] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent, wherein the at least one other therapeutic agent is an IDH inhibitor.

[0605] In some embodiments, the IDH inhibitor is an isocitrate dehydrogenase-1 inhibitor (e.g., ivosidenib).

[0606] According to an embodiment, the IDH inhibitor is ivosidenib.

[0607] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is ivosidenib.

[0608] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is ivosidenib is provided.

[0609] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is ivosidenib.

[0610] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is ivosidenib.

[0611] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is ivosidenib.

[0612] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is ivosidenib, is provided.

[0613] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is ivosidenib.

[0614] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is ivosidenib.

[0615] In some embodiments, the IDH is an isocitrate dehydrogenase-2 inhibitor (e.g., enadidenib).

[0616] According to an embodiment, the IDH inhibitor is enazidenib.

[0617] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is enazidenib.

[0618] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is enazidenib.

[0619] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is enazidenib.

[0620] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is enazidenib.

[0621] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is enazidenib.

[0622] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is enazidenib, is provided.

[0623] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is enazidenib.

[0624] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is enazidenib.

[0625] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent is provided, wherein the at least one other therapeutic agent is an immunomodulatory agent.

[0626] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent, wherein the at least one other therapeutic agent is a PD-1 inhibitor.

[0627] According to embodiments, the immunomodulatory agent is nivolumab, atezolizumab, pembrolizumab, thalidomide, lenalidomide, pomalidomide, killed Mycobacterium bovis (BCG), or levamisole.

[0628] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is nivolumab.

[0629] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is nivolumab.

[0630] In some embodiments, a combination therapy comprising compound A1 is provided, wherein at least one other therapeutic agent is nivolumab.

[0631] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is nivolumab.

[0632] In some embodiments, a combination therapy comprising compound A3 is provided, wherein at least one other therapeutic agent is nivolumab.

[0633] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is nivolumab, is provided.

[0634] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is nivolumab.

[0635] In some embodiments, a combination therapy comprising compound A4 is provided, wherein at least one other therapeutic agent is nivolumab.

[0636] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is atezolizumab.

[0637] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is atezolizumab is provided.

[0638] In some embodiments, a combination therapy comprising compound A1 is provided, wherein at least one other therapeutic agent is atezolizumab.

[0639] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is atezolizumab.

[0640] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is atezolizumab.

[0641] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is atezolizumab, is provided.

[0642] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is atezolizumab.

[0643] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is atezolizumab.

[0644] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is pembrolizumab.

[0645] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is pembrolizumab.

[0646] In some embodiments, a combination therapy comprising compound A1 is provided, wherein at least one other therapeutic agent is pembrolizumab.

[0647] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is pembrolizumab.

[0648] In some embodiments, a combination therapy comprising compound A3 is provided, wherein at least one other therapeutic agent is pembrolizumab.

[0649] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof is provided, wherein at least one other therapeutic agent is pembrolizumab.

[0650] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is pembrolizumab.

[0651] In some embodiments, a combination therapy comprising compound A4 is provided, wherein at least one other therapeutic agent is pembrolizumab.

[0652] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is thalidomide.

[0653] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is thalidomide is provided.

[0654] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is thalidomide.

[0655] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is thalidomide.

[0656] In some embodiments, a combination therapy comprising compound A3 is provided, wherein at least one other therapeutic agent is thalidomide.

[0657] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is thalidomide, is provided.

[0658] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is thalidomide.

[0659] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is thalidomide.

[0660] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is lenalidomide.

[0661] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is lenalidomide is provided.

[0662] In some embodiments, a combination therapy comprising compound A1 is provided, wherein at least one other therapeutic agent is lenalidomide.

[0663] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is lenalidomide.

[0664] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is lenalidomide.

[0665] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is lenalidomide, is provided.

[0666] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is lenalidomide.

[0667] In some embodiments, a combination therapy comprising compound A4 is provided, wherein at least one other therapeutic agent is lenalidomide.

[0668] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is pomalidomide.

[0669] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is pomalidomide is provided.

[0670] In some embodiments, a combination therapy comprising compound A1 is provided, wherein at least one other therapeutic agent is pomalidomide.

[0671] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is pomalidomide.

[0672] In some embodiments, a combination therapy comprising compound A3 is provided, wherein at least one other therapeutic agent is pomalidomide.

[0673] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is pomalidomide, is provided.

[0674] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is pomalidomide.

[0675] In some embodiments, a combination therapy comprising compound A4 is provided, wherein at least one other therapeutic agent is pomalidomide.

[0676] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is BCG.

[0677] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is BCG.

[0678] In some embodiments, a combination therapy comprising compound A1 is provided, wherein at least one other therapeutic agent is BCG.

[0679] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is BCG.

[0680] In some embodiments, a combination therapy comprising compound A3 is provided, wherein at least one other therapeutic agent is BCG.

[0681] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof is provided, wherein at least one other therapeutic agent is BCG.

[0682] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is BCG.

[0683] In some embodiments, a combination therapy comprising compound A4 is provided, wherein at least one other therapeutic agent is BCG.

[0684] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is levamisole.

[0685] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is levamisole.

[0686] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is levamisole.

[0687] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is levamisole.

[0688] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is levamisole.

[0689] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof is provided, wherein at least one other therapeutic agent is levamisole.

[0690] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is levamisole.

[0691] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is levamisole.

[0692] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent, wherein the at least one other therapeutic agent is a DHODH inhibitor.

[0693] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent, wherein the at least one other therapeutic agent is a DHODH inhibitor compound described herein.

[0694] According to an embodiment, the DHODH inhibitor is a compound of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof:

[0695] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and at least one other therapeutic agent is a DHODH inhibitor of formula (Z) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0696] In some embodiments, a combination therapy is provided comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, and at least one other therapeutic agent is a DHODH inhibitor of Formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0697] In some embodiments, a combination therapy is provided that includes compound A1, and at least one other therapeutic agent is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0698] In some embodiments, a combination therapy is provided that includes compound A2, wherein at least one other therapeutic agent is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0699] In some embodiments, a combination therapy is provided that includes compound A3, wherein at least one other therapeutic agent is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0700] In some embodiments, a combination therapy is provided comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0701] In some embodiments, a combination therapy is provided comprising compound A4-b or a hydrate thereof, wherein at least one other therapeutic agent is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0702] In some embodiments, a combination therapy is provided that includes compound A4, wherein at least one other therapeutic agent is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0703] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is a DHODH inhibitor that is compound 22 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof (e.g., 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).

[0704] In some embodiments, a combination therapy is provided comprising Compound A or a pharmaceutically acceptable salt or solvate thereof, and at least one other therapeutic agent is a DHODH inhibitor (e.g., 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), which is Compound 22 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

[0705] In some embodiments, a combination therapy is provided that includes compound A1, and at least one other therapeutic agent is a DHODH inhibitor (e.g., 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), which is compound 22 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

[0706] In some embodiments, a combination therapy is provided that includes compound A2, and at least one other therapeutic agent is a DHODH inhibitor (e.g., 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), which is compound 22 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

[0707] In some embodiments, a combination therapy is provided that includes compound A3, and at least one other therapeutic agent is a DHODH inhibitor (e.g., 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), which is compound 22 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

[0708] In some embodiments, a combination therapy is provided that includes compound A4-a or a solvate thereof, and at least one other therapeutic agent is a DHODH inhibitor that is compound 22 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof (e.g., 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).

[0709] In some embodiments, a combination therapy is provided that includes compound A4-b or a hydrate thereof, and at least one other therapeutic agent is a DHODH inhibitor (e.g., 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), which is compound 22 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

[0710] In some embodiments, a combination therapy is provided that includes compound A4, and at least one other therapeutic agent is a DHODH inhibitor (e.g., 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), which is compound 22 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

[0711] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent, wherein the at least one other therapeutic agent is a kinase inhibitor.

[0712] According to an embodiment, the kinase inhibitor is a serine and / or tyrosine kinase inhibitor.

[0713] According to embodiments, the kinase inhibitor is an inhibitor of FLT3 and / or BTK.

[0714] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent is provided, wherein the at least one other therapeutic agent is a FLT3 inhibitor.

[0715] According to embodiments, the FLT3 inhibitor is sorafenib, sunitinib, midostaurin (PKC412), lestaurtinib (CEP-701), tanzutinib (MLN518), quizartinib (AC220), gilteritinib (ASP2215), or KW-2449.

[0716] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is sorafenib.

[0717] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is sorafenib is provided.

[0718] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is sorafenib.

[0719] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is sorafenib.

[0720] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is sorafenib.

[0721] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is sorafenib, is provided.

[0722] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is sorafenib.

[0723] In some embodiments, a combination therapy comprising compound A4 is provided, wherein at least one other therapeutic agent is sorafenib.

[0724] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is sunitinib.

[0725] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is sunitinib is provided.

[0726] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is sunitinib.

[0727] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is sunitinib.

[0728] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is sunitinib.

[0729] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is sunitinib, is provided.

[0730] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is sunitinib.

[0731] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is sunitinib.

[0732] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is midostaurin.

[0733] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is midostaurin is provided.

[0734] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is midostaurin.

[0735] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is midostaurin.

[0736] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is midostaurin.

[0737] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is midostaurin, is provided.

[0738] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is midostaurin.

[0739] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is midostaurin.

[0740] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is lestaurtinib.

[0741] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is lestaurtinib is provided.

[0742] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is lestaurtinib.

[0743] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is lestaurtinib.

[0744] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is lestaurtinib.

[0745] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is lestaurtinib, is provided.

[0746] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is lestaurtinib.

[0747] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is lestaurtinib.

[0748] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is tandutinib.

[0749] In some embodiments, a combination therapy comprising Compound A or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is tandutinib, is provided.

[0750] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is tandutinib.

[0751] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is tandutinib.

[0752] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is tandutinib.

[0753] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is tandutinib, is provided.

[0754] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is tandutinib.

[0755] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is tandutinib.

[0756] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is AC220.

[0757] In some embodiments, a combination therapy comprising Compound A or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is AC220, is provided.

[0758] In some embodiments, a combination therapy is provided that includes Compound A1, and at least one other therapeutic agent is AC220.

[0759] In some embodiments, a combination therapy is provided that includes Compound A2, wherein at least one other therapeutic agent is AC220.

[0760] In some embodiments, a combination therapy is provided that includes compound A3, wherein at least one other therapeutic agent is AC220.

[0761] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof is provided, wherein at least one other therapeutic agent is AC220.

[0762] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is AC220.

[0763] In some embodiments, a combination therapy is provided that includes compound A4, wherein at least one other therapeutic agent is AC220.

[0764] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is ASP2215.

[0765] In some embodiments, a combination therapy comprising Compound A or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is ASP2215, is provided.

[0766] In some embodiments, a combination therapy comprising compound A1 is provided, wherein at least one other therapeutic agent is ASP2215.

[0767] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is ASP2215.

[0768] In some embodiments, a combination therapy is provided that includes compound A3, wherein at least one other therapeutic agent is ASP2215.

[0769] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof is provided, wherein at least one other therapeutic agent is ASP2215.

[0770] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is ASP2215.

[0771] In some embodiments, a combination therapy comprising compound A4 is provided, wherein at least one other therapeutic agent is ASP2215.

[0772] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is KW-2449. In some embodiments, a combination therapy is provided comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is KW-2449.

[0773] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is KW-2449.

[0774] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is KW-2449.

[0775] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is KW-2449.

[0776] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof is provided, wherein at least one other therapeutic agent is KW-2449.

[0777] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is KW-2449.

[0778] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is KW-2449.

[0779] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent is provided, wherein the at least one other therapeutic agent is a BTK inhibitor.

[0780] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is a BTK inhibitor.

[0781] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is a BTK inhibitor.

[0782] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is a BTK inhibitor.

[0783] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is a BTK inhibitor.

[0784] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof is provided, wherein at least one other therapeutic agent is a BTK inhibitor.

[0785] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is a BTK inhibitor.

[0786] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is a BTK inhibitor.

[0787] According to an embodiment, the BTK inhibitor is ibrutinib.

[0788] In some embodiments, there is provided a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is ibrutinib.

[0789] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is ibrutinib is provided.

[0790] In some embodiments, a combination therapy comprising Compound A1 is provided, wherein at least one other therapeutic agent is ibrutinib.

[0791] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is ibrutinib.

[0792] In some embodiments, a combination therapy comprising Compound A3 is provided, wherein at least one other therapeutic agent is ibrutinib.

[0793] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is ibrutinib, is provided.

[0794] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is ibrutinib.

[0795] In some embodiments, a combination therapy comprising Compound A4 is provided, wherein at least one other therapeutic agent is ibrutinib.

[0796] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent, wherein the at least one other therapeutic agent is a CD20 inhibitor.

[0797] According to an embodiment, the CD20 inhibitor is an anti-CD20 antibody, in particular obinutuzumab (GA101).

[0798] In some embodiments, a combination therapy comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is a CD20 inhibitor.

[0799] In some embodiments, a combination therapy comprising compound A1 is provided, wherein at least one other therapeutic agent is a CD20 inhibitor.

[0800] In some embodiments, a combination therapy comprising Compound A2 is provided, wherein at least one other therapeutic agent is a CD20 inhibitor.

[0801] In some embodiments, a combination therapy comprising compound A3 is provided, wherein at least one other therapeutic agent is a CD20 inhibitor.

[0802] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof is provided, wherein at least one other therapeutic agent is a CD20 inhibitor.

[0803] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is a CD20 inhibitor.

[0804] In some embodiments, a combination therapy comprising compound A4 is provided, wherein at least one other therapeutic agent is a CD20 inhibitor.

[0805] In some embodiments, a combination therapy comprising a menin-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein at least one other therapeutic agent is GA101.

[0806] In some embodiments, a combination therapy comprising Compound A or a pharmaceutically acceptable salt or solvate thereof, wherein at least one other therapeutic agent is GA101, is provided.

[0807] In some embodiments, a combination therapy is provided that includes compound A1, and at least one other therapeutic agent is GA101.

[0808] In some embodiments, a combination therapy is provided that includes compound A2, and at least one other therapeutic agent is GA101.

[0809] In some embodiments, a combination therapy is provided that includes compound A3, wherein at least one other therapeutic agent is GA101.

[0810] In some embodiments, a combination therapy comprising compound A4-a or a solvate thereof, wherein at least one other therapeutic agent is GA101, is provided.

[0811] In some embodiments, a combination therapy comprising compound A4-b or a hydrate thereof is provided, wherein at least one other therapeutic agent is GA101.

[0812] In some embodiments, a combination therapy is provided that includes compound A4, wherein at least one other therapeutic agent is GA101.

[0813] All possible combinations of the above embodiments are considered to fall within the scope of the present invention.

[0814] In some embodiments, methods are provided for treating a subject diagnosed with a hematopoietic disorder. The present invention relates to novel methods, for example, comprising administering to a subject a therapeutically effective amount of a menin-MLL inhibitor described herein and a therapeutically effective amount of at least one other therapeutic agent.

[0815] An additional embodiment of the present invention relates to the methods described herein, wherein a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is orally administered to the subject.

[0816] Additional embodiments of the present invention relate to the methods described herein, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to the subject at a dose of about 1 mg / kg to about 50 mg / kg.

[0817] An additional embodiment of the present invention relates to the methods described herein, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to the subject at a dose of about 2.5 mg / kg to about 25 mg / kg.

[0818] An additional embodiment of the present invention relates to the methods described herein, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to the subject at a dose of about 7.5 mg / kg to about 12.5 mg / kg.

[0819] An additional embodiment of the present invention relates to the methods described herein, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to the subject at a dose of about 8 mg / kg to about 10 mg / kg.

[0820] An additional embodiment of the present invention relates to the methods described herein, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to the subject at a dose of from about 0.1 mg to about 5 mg.

[0821] Additional embodiments of the present invention relate to methods described herein, wherein at least one therapeutic agent is administered orally to the subject.

[0822] Additional embodiments of the present invention relate to the methods described herein, wherein the at least one other therapeutic agent is orally administered to the subject at a dose of from about 1 mg to about 500 mg.

[0823] Additional embodiments of the present invention relate to methods described herein, wherein at least one other therapeutic agent is administered to the subject intravenously or subcutaneously.

[0824] An additional embodiment of the invention is one in which the at least one other therapeutic agent is administered in an amount of about 10 mg / m 2 ~about 250mg / m 2 is administered intravenously or subcutaneously to the subject at a dose of

[0825] An additional embodiment of the invention is one in which the at least one other therapeutic agent is administered in a dose of about 50 mg / m 2 ~about 150mg / m 2 is administered intravenously or subcutaneously to the subject at a dose of

[0826] An additional embodiment of the invention is one in which the at least one other therapeutic agent is administered at a dose of about 60 mg / m 2 ~about 100mg / m 2 is administered intravenously or subcutaneously to the subject at a dose of

[0827] An additional embodiment of the invention is one in which the at least one other therapeutic agent is administered in a dose of about 75 mg / m 2 is administered intravenously or subcutaneously to the subject at a dose of

[0828] Additional embodiments of the invention include a method for treating a subject diagnosed with cancer (e.g., wherein the cancer is a leukemia, such as myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL), or chronic lymphocytic leukemia (CLL)), comprising: a therapeutically effective amount of a menin-MLL inhibitor of formula (I), or a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof; administering to a subject a therapeutically effective amount of a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof, For example, methods include administering to a subject a menin-MLL inhibitor and a DHODH inhibitor according to their administration schedule for a period of time, for example, (i) simultaneously or sequentially in any order on the same day within a period of time (e.g., a 21-day period, or a 28-day period, or a 3-month period, or a 6-month period, or a 1-year period, etc.), and / or (ii) on different days within a period of time.

[0829] Additional embodiments of the invention include a method for treating a subject diagnosed with cancer (e.g., wherein the cancer is a leukemia, such as myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL), or chronic lymphocytic leukemia (CLL)), comprising: a therapeutically effective amount of a menin-MLL inhibitor that is Compound A or a pharmaceutically acceptable salt or solvate thereof (e.g., Compound A1, or Compound A2, or Compound A3, or Compound A4-a, or a solvate thereof, or Compound A4-b, or a hydrate thereof, or Compound A4), and administering to a subject a therapeutically effective amount of a DHODH inhibitor, Compound 22, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof (e.g., 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); For example, methods include administering to a subject a menin-MLL inhibitor and a DHODH inhibitor according to their administration schedule for a period of time, for example, (i) simultaneously or sequentially in any order on the same day within a period of time (e.g., a 21-day period, or a 28-day period, or a 3-month period, or a 6-month period, or a 1-year period, etc.), and / or (ii) on different days within a period of time.

[0830] An additional embodiment of the present invention relates to the methods described herein, wherein a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to the subject daily.

[0831] Additional embodiments of the present invention relate to the methods described herein, wherein a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to the subject daily for at least seven days.

[0832] Additional embodiments of the present invention relate to methods described herein, wherein at least one other therapeutic agent is administered to the subject daily.

[0833] Additional embodiments of the present invention relate to methods described herein, wherein at least one other therapeutic agent is administered to the subject daily for at least seven days.

[0834] Additional embodiments of the present invention relate to methods described herein, wherein at least one other therapeutic agent is administered to the subject daily.

[0835] Additional embodiments of the present invention relate to the methods described herein, wherein at least one other therapeutic agent is administered to the subject daily for at least 21 days.

[0836] Optimal dosages of any of the therapeutic compounds described herein to be administered can be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the progression of the disease, syndrome, condition, or disorder. In addition, factors related to the particular subject being treated, such as the subject's sex, age, weight, diet, and time of administration, will necessitate adjustment of the dosage to achieve appropriate therapeutic levels and the desired therapeutic effect.

[0837] The above dosages are therefore exemplary of the average case, and there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

[0838] The therapeutic compounds described herein can be administered in any of the compositions and administration regimens described above, or by compositions and administration regimens established in the art, whenever the therapeutic compounds described herein are administered to a subject in need thereof.

[0839] The therapeutic compounds described herein can be administered to a subject simultaneously or sequentially. When administered sequentially, the menin-MLL inhibitor of Formula (I) may be administered first. When administered simultaneously, the combination can be administered either in the same pharmaceutical composition or in different pharmaceutical compositions. For example, the menin-MLL inhibitor of Formula (I) can be administered before, simultaneously with, or after the administration of at least one other therapeutic agent. Similarly, at least one other therapeutic agent can be administered before, simultaneously with, or after the administration of another therapeutic agent. Adjunctive therapy, i.e., therapy in which one or two agents are used as primary therapy and other agents are used to adjuvant the primary therapy, is also an embodiment of the present invention.

[0840] One embodiment of the present invention relates to a therapeutically effective amount of a menin-MLL inhibitor comprising a compound of Formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof as described in any of the embodiments, for use in combination with a therapeutically effective amount of at least one other therapeutic agent, wherein the at least one other therapeutic agent is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase inhibitor, an immunomodulatory agent, or a dihydroorotate dehydrogenase inhibitor. In certain embodiments, the aforementioned therapeutically effective amounts are administered in separate dosage forms when used in treating a subject diagnosed with a hematopoietic disorder.

[0841] One embodiment of the present invention relates to a medicament comprising a menin-MLL inhibitor of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof according to any of the embodiments, wherein at least one other therapeutic agent is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analogue, a purine analogue, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase inhibitor, an immunomodulatory agent, or a dihydroorotate dehydrogenase inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment of a subject diagnosed with a hematopoietic disorder.

[0842] The following examples are provided to illustrate some of the concepts described within this disclosure and are to be considered as providing an embodiment, but should not be considered as limiting the more general embodiments described herein.

[0843] Example General synthetic scheme Azacitidine Azacitidine is commercially available.

[0844] Compounds of formula (I) In this section, and in all other sections, unless the context indicates otherwise, reference to formula (I) also includes all other subgroups and embodiments thereof defined herein.

[0845] The general preparation of some representative examples of compounds of formula (I) is described below, and in certain examples they are usually prepared from starting materials that are either commercially available or prepared by standard synthetic processes commonly used by those skilled in the art of organic chemistry. The following schemes are merely illustrative of examples of the present invention and are not intended to limit the present invention in any way.

[0846] Alternatively, compounds of formula (I) may also be prepared by analogous reaction protocols as described in the general schemes below, in combination with standard synthetic processes commonly used by those skilled in the art.

[0847] Those skilled in the art will understand that in the reactions depicted in the schemes, although this is not always explicitly shown, it may be necessary to protect reactive functional groups (e.g., hydroxy, amino, or carboxy groups) if these are desired in the final product to prevent their undesired participation in the reaction. Generally, conventional protecting groups (PG) can be used in accordance with standard procedures. The protecting groups can be removed at a later convenient stage using methods well known in the art.

[0848] Those skilled in the art will appreciate that in the reactions depicted in the schemes, it may be advisable or necessary to carry out the reactions under an inert atmosphere, such as, for example, under an atmosphere of N2 gas.

[0849] It will be apparent to those skilled in the art that it may be necessary to cool the reaction mixture before proceeding with the reaction (e.g., referring to a series of operations required to isolate and purify the products of a chemical reaction, such as quenching, column chromatography, extraction, etc.).

[0850] Those skilled in the art will appreciate that heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions, microwave heating may be used instead of conventional heating to reduce the overall reaction time.

[0851] Those skilled in the art will appreciate that the alternative series of chemical reactions shown in the following schemes may also lead to the desired compounds of formula (I).

[0852] Those skilled in the art will understand that the intermediates and final compounds shown in the following schemes can be further functionalized according to methods well known by those skilled in the art. The intermediates and compounds described herein can be isolated in free form or as a salt or solvate thereof. The intermediates and compounds described herein can be synthesized in the form of mixtures of tautomeric and stereoisomeric forms, which can be separated from one another according to art-known resolution procedures.

[0853] All abbreviations used in the general schemes relating to formula (I) are as defined in Table 1B in the Examples part below. Variables are as defined within ranges or as specifically defined in the general schemes.

[0854] Part A) Schemes 1a, 1b, 1c, 2a, 2b and 3

[0855] [ka]

[0856] In Schemes 1a, 1b and 1c, the following reaction conditions apply: Step 1: In the presence of a suitable base (such as TMEDA) and a suitable organometallic reagent (such as isopropylmagnesium bromide) at a suitable temperature (such as -70°C), in a suitable solvent (such as THF), Step 2: In the presence of a suitable oxidizing reagent (e.g., DMP) in a suitable solvent (e.g., DCM) at a suitable temperature (e.g., 0°C to room temperature), Step 3: In the presence of a suitable organometallic reagent (e.g., isopropylmagnesium bromide) in a suitable solvent (e.g., THF) at a suitable temperature (e.g., −20° C. to room temperature), Step 4: In the presence of a suitable base (such as NaOH) at a suitable temperature (such as 80° C.), in a suitable solvent (such as THF and HO), Step 5: In the presence of a suitable amide condensation reagent (such as EDCI and HOBt) in the presence of a suitable base (such as NMM) in a suitable solvent (such as DCM) at a suitable temperature (such as RT), Step 6: In the presence of a suitable organometallic reagent (e.g., isopropyllithium) in a suitable solvent (e.g., THF) at a suitable temperature (e.g., −70° C.), Step 7: At a suitable temperature (such as 90° C.), in the presence of a suitable organometallic catalyst (such as Pd(dppf)Cl), in the presence of a suitable base (such as NaCO), in a suitable solvent (such as 1,4-dioxane and HO), Step 8: In the presence of a suitable Lewis acid (e.g., BBr3) in a suitable solvent (e.g., DCM) at a suitable temperature (e.g., 0°C to room temperature), Step 9: In the presence of a suitable base (e.g., TEA, DBU, or K2CO3) in a suitable solvent (e.g., DCM, THF, or DMF) at a suitable temperature (e.g., −78° C. to 40° C., particularly 0° C. to room temperature),

[0857] [ka]

[0858] [ka]

[0859] In Schemes 2a and 2b, the following reaction conditions apply: Step 9: See Scheme 1, Step 9. Step 10: At a suitable temperature (e.g., room temperature), in the presence of a suitable catalyst (e.g., Pd / C), in the presence of a suitab...

Claims

1. A pharmaceutical composition comprising: Menin mixed lineage leukemia 1 (MLL) inhibitor compound A: 【Chemistry 1】 or a pharma- ceutically acceptable salt or solvate thereof; The menin-MLL inhibitor is used in a therapeutically effective amount, The pharmaceutical composition is used in combination with a therapeutically effective amount of at least one other therapeutic agent, The pharmaceutical composition, wherein the at least one other therapeutic agent is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase inhibitor, an immunomodulatory agent, or a dihydroorotate dehydrogenase inhibitor.

2. A pharmaceutical composition comprising: comprising at least one therapeutic agent; the at least one therapeutic agent is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase inhibitor, an immunomodulatory agent, or a dihydroorotate dehydrogenase inhibitor; The at least one therapeutic agent is used in a therapeutically effective amount, The pharmaceutical composition comprises a therapeutically effective amount of a menin mixed lineage leukemia 1 (MLL) inhibitor compound A: 【Chemistry 2】 or a pharma- ceutical composition for use in combination with the compound or a pharma- ceutical acceptable salt or solvate thereof.

3. A pharmaceutical composition for use in the treatment or prevention of a hematopoietic disorder, comprising: The pharmaceutical composition comprises 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 is used in combination with a therapeutically effective amount of at least one other therapeutic agent, The pharmaceutical composition, wherein the at least one other therapeutic agent is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase inhibitor, an immunomodulatory agent, or a dihydroorotate dehydrogenase inhibitor.

4. A pharmaceutical composition for use in the treatment or prevention of a hematopoietic disorder, comprising: The pharmaceutical composition comprises at least one therapeutic agent; the at least one therapeutic agent is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase inhibitor, an immunomodulatory agent, or a dihydroorotate dehydrogenase inhibitor; The at least one therapeutic agent is used in a therapeutically effective amount, The pharmaceutical composition comprises a therapeutically effective amount of a menin mixed lineage leukemia 1 (MLL) inhibitor compound A: 【Chemistry 4】 or a pharma- ceutical composition for use in combination with the compound or a pharma- ceutical acceptable salt or solvate thereof.

5. For use in treating a subject having a hematopoietic disorder. Menin mixed lineage leukemia 1 (MLL) inhibitor compound A: 【Chemistry 5】 or a pharma- ceutical composition comprising a pharma- ceutical acceptable salt or solvate thereof, The use includes: a therapeutically effective amount of Compound A or a pharma- ceutically acceptable salt or solvate thereof; and a therapeutically effective amount of at least one other therapeutic agent that is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulator, or a DHODH inhibitor; A pharmaceutical composition comprising the use of

6. For use in treating a subject having a hematopoietic disorder.

1. A pharmaceutical composition comprising at least one therapeutic agent, the at least one other therapeutic agent is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory agent, or a DHODH inhibitor; The use includes: A therapeutically effective amount of the menin mixed lineage leukemia 1 (MLL) inhibitor compound A: 【Chemistry 6】 or a pharma- ceutically acceptable salt or solvate thereof; and a therapeutically effective amount of at least one other therapeutic agent that is a hypomethylating agent, a cytidine deaminase inhibitor, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulator, or a DHODH inhibitor; 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 of claim 1, 【Chemistry 7】 The pharmaceutical composition according to any one of claims 1 to 6, 11. The menin-MLL inhibitor of claim 10, 【Chemistry 8】 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 according to any one of claims 1 to 6, wherein the at least one therapeutic agent is a hypomethylating agent.

15. 15. The pharmaceutical composition of claim 14, wherein the hypomethylating agent is azacitidine, or a pharma- ceutically acceptable salt or solvate thereof.

16. The pharmaceutical composition of any one of claims 1 to 6, wherein the at least one other therapeutic agent is a kinase inhibitor, and the kinase inhibitor is an FLT-3 inhibitor.

17. The pharmaceutical composition of any one of claims 1 to 6, wherein the at least one therapeutic agent is a kinase inhibitor, a DNA intercalating agent or a pyrimidine analog, and the kinase inhibitor is an FLT-3 inhibitor.

18. The pharmaceutical composition of claim 16, wherein the FLT-3 inhibitor is gliteritinib.

19. The pharmaceutical composition of claim 17, wherein the FLT-3 inhibitor is gliteritinib.

20. The pharmaceutical composition of any one of claims 1 to 6, wherein at least one of the therapeutic agents is a pyrimidine analog.

21. The pharmaceutical composition of any one of claims 1 to 6, wherein the at least one therapeutic agent is a pyrimidine analog or a DNA intercalating agent.

22. The pharmaceutical composition of any one of claims 1 to 6, wherein the at least one therapeutic agent is a pyrimidine analog, a DNA intercalating agent or a purine analog.

23. The pharmaceutical composition of claim 17, wherein the pyrimidine analog is cytarabine.

24. The pharmaceutical composition of claim 21, wherein the pyrimidine analog is cytarabine.

25. The pharmaceutical composition of any one of claims 1 to 6, wherein at least one of the therapeutic agents is a DNA intercalating agent.

26. The pharmaceutical composition of claim 17, wherein the DNA intercalating agent is an anthracycline.

27. The pharmaceutical composition of claim 26, wherein the anthracycline is daunorubicin or idarubicin.

28. The pharmaceutical composition of claim 22, wherein the DNA intercalating agent is daunorubicin or idarubicin.

29. The pharmaceutical composition of claim 26, wherein the anthracycline is doxorubicin.

30. The pharmaceutical composition of claim 22, wherein the purine analog is fludarabine.

31. The pharmaceutical composition of any one of claims 1 to 6, wherein the menin mixed lineage leukemia 1 (MLL) inhibitor and the at least one other therapeutic agent are administered sequentially or simultaneously, either in the same pharmaceutical composition or in different pharmaceutical compositions.

32. The pharmaceutical composition of any one of claims 1 to 6, wherein the menin mixed lineage leukemia 1 (MLL) inhibitor and the at least one other therapeutic agent are administered in separate dosage forms.

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

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

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

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

37. The pharmaceutical composition described in any one of claims 3 to 6, 35 and 36, wherein the hematopoietic disorder is nucleophosmin 1 (NPM1) mutant leukemia or KMT2A rearrangement leukemia.

38. The pharmaceutical composition described in any one of claims 3 to 6, 35 and 36, wherein the hematopoietic disorder is acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

39. The pharmaceutical composition described in any one of claims 3 to 6, 35 and 36, wherein the hematopoietic disorder is AML having a KMT2A gene alteration or an NPM1 mutation.

40. The pharmaceutical composition described in any one of claims 3 to 6, 35 and 36, wherein the hematopoietic disorder is ALL with a KMT2A gene alteration or an NPM1 mutation.

41. The pharmaceutical composition described in any one of claims 3 to 6, 35 and 36, wherein the hematopoietic disorder is AML with a KMT2A gene rearrangement.

42. The pharmaceutical composition described in any one of claims 3 to 6, 35 and 36, wherein the hematopoietic disorder is AML with an NPM1 mutation.

43. The menin-MLL inhibitor is a hydrate of the bisbesylate 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; 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the at least one therapeutic agent is a DNA intercalating agent that is daunorubicin or idarubicin; or a pyrimidine analog that is cytarabine.

44. The pharmaceutical composition of claim 43 for use in treating a hematopoietic disorder, wherein the hematopoietic disorder is nucleophosmin 1 (NPM1) mutant leukemia or KMT2A rearranged leukemia.

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

46. ​​The pharmaceutical composition of claim 43 for use in treating a hematopoietic disorder, wherein the hematopoietic disorder is AML having a KMT2A gene alteration or an NPM1 mutation.

47. The pharmaceutical composition of claim 43 for use in treating a hematopoietic disorder, wherein the hematopoietic disorder is ALL having a KMT2A gene alteration or an NPM1 mutation.

48. The pharmaceutical composition of claim 43 for use in treating a hematopoietic disorder, wherein the hematopoietic disorder is AML with a KMT2A gene rearrangement.

49. The pharmaceutical composition of claim 43 for use in treating a hematopoietic disorder, wherein the hematopoietic disorder is AML having an NPM1 mutation.

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