ENL / AF9 YEATS and FLT3 inhibitors

Abstract

Disclosed herein are compounds and pharmaceutical compositions containing the compounds that inhibit ENL / AF9 YEATS and FLT3. Methods for suppressing oncogene expression in cells or treating acute leukemia using the compounds and pharmaceutical compositions containing the compounds are also disclosed. The compounds, pharmaceutical compositions, and methods can be used to inhibit key drivers of cancer and cancer stem cell survival.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 404,659, filed September 8, 2022, which is incorporated herein in its entirety.

[0002] FIELD OF THE INVENTION This application relates generally to compounds that inhibit ENL / AF9 YEATS and FLT3, and methods of treatment using such compounds. The compounds and methods are used to treat a variety of different diseases, including blood cancers such as leukemia. [Background technology]

[0003] The epigenome is the ensemble of compounds adjacent to DNA that modify the genome without altering the DNA sequence. It is dynamically regulated by chemical changes in DNA, RNA, and the histones around which DNA is packaged. Mutations in genes encoding epigenetic regulators have been shown to contribute to the pathogenesis of acute myeloid leukemia (AML) (Shih AH, Abdel-Wahab O, Patel JP, et al. "The role of mutations in epigenetic regulators in myeloid malignancies." Nat. Rev. Cancer 2012;12:599-612).

[0004] ENL is a chromatin reader protein with an amino-terminal YEATS domain (named after the first discovered members of the family: Yaf9, ENL, AF9, Taf14, and Sas5) and a disordered carboxy-terminal protein-protein interaction (PPI) interface. YEATS is a family of histone acetyl-lysine readers that act as effectors by making chromatin more accessible to RNA polymerases and transcription factors. reported that a disproportionate number of leukemia proto-oncogenes and dependencies have ENL in their promoters (Erb, MA et al., "Transcription control by the ENL YEATS domain in acute leukemia," Nature 543, 270-274 (2017)). Wan et al. found that ENL binds to acetylated histone H3 and then colocalizes with H3K27 and H3K9ac on the promoters of genes essential for leukemia, and that ENL is required for AML maintenance (Wan L., et al., "ENL links histone acetylation to oncogenic gene expression in acute myeloid leukemia," Nature 2017;543:265-9).

[0005] Given the role of ENL in leukemia proliferation, inhibitors of the ENL YEATS domain are potential targets for the treatment of hematological cancers. For example, Moustakim et al. described small molecule inhibitors of the ENL YEATS domain (Moustakim, M., et al., "Discovery of an MLLT1 / 3 YEATS Domain Chemical Probe," Angew. Chem. Int. Ed. 2018, 57, 16302-16307). Moustakim's inhibitor compounds contain a cyclic nitrogen-containing heterocycle connected via a nitrogen atom to a methylene group attached to a benzimidazole core.

[0006] FLT3 (Fms-like tyrosine kinase 3, FLK2) is a class III receptor tyrosine kinase that is activated by FLT3 ligand (FL) and signals through the PI3K, RAS, and JAK / STAT pathways (Scholl C. et al., Semin. Oncol., 35:336-45 (2008); Meshinchi S. et al., Clin. Cancer Res., 15:4263-9 (2009)). FLT3 is involved in early hematopoiesis, and FLT3-deficient mice have reduced numbers of multiple lymphoid progenitors (Mackarehtschian K, et al., Immunity, 3:147-61 (1995)). Activating mutations in FLT3 are found in approximately 30% of AML patients and represent the most frequent genetic alteration in this disease. Approximately 75% of activating mutations are internal tandem duplications (ITDs), and 25% are point mutations within the activation loop of the kinase domain. The most frequently identified activating point mutation is D835Y (Yamamoto et al., Blood, 97(8):2434-2439 (2001)). However, mutations have also been found at N841I (Jiang, J. et al., Blood, 104(6):1855-1858 (2004)) and Y842C (Kindler et al. al., Blood, 105(1):335-340 (2005)). Additional point mutations have been identified in the juxtamembrane and kinase domains, which have been shown to result in lower transforming potential (Reindel et al., Blood 107(9):3700-3707 (2006)).

[0007] Mouse bone marrow transplanted with a retrovirus expressing FLT3-ITD has been shown to result in the development of a fatal myeloproliferative disorder in mice characterized by leukocytosis composed of mature neutrophils (Kelly et al., Blood 99:310-318 (2002)). This disease does not exhibit the differentiation block seen in human AML, suggesting that the FLT3 mutation confers a growth or survival advantage to the cells.

[0008] Many FLT3 inhibitors have been tested in clinical trials. Although they have shown initial clinical responses in AML, the observed responses are transient, and resistance can develop rapidly (Weisberg, E. et al., Oncogene, 29:5120-34(2010)). The primary resistance mechanism appears to be through the acquisition of secondary mutations in FLT3, which can prevent FLT3 inhibitors from binding to the FLT3 receptor (Weisberg, E. et al., Oncogene, 29:5120-34(2010); Chu, SH et al., Drug Resist. Update, 12:8-16(2009)). Despite the recognition that chemotherapy is poorly tolerated, the combination of FLT3 inhibitors and chemotherapy has been tested in clinical trials. Further possible mechanisms for the lack of sustained response include insufficient target coverage in the bone marrow, where stromal growth factors may provide growth signals in addition to FLT3 activation (Pratz, KW, et al., Blood, 139:3938-46 (2009)), and protection of AML cells (Tam, WF et al., Best Pract. Res. Clin. Haematol., 21:13-20 (2008)).

[0009] There remains a need for improved inhibitors useful in treating hematological cancers. Summary of the Invention

[0010] The present invention relates to compounds, pharmaceutical compositions, and methods for inhibiting YEATS / ENL and FLT3, thereby treating various cancers, particularly hematological cancers such as leukemia. The compounds, pharmaceutical compositions, and methods disclosed herein can be used to inhibit key drivers of cancer and cancer stem cell survival, thereby providing enhanced anti-cancer activity. Specifically, the compounds, pharmaceutical compositions, and methods disclosed herein can be used to inhibit tyrosine kinase activity via FLT3 and the epigenetic driver ENL-YEATS. Thus, cancer cells dependent on one or both of these pathways can be effectively treated without relying too heavily on molecular diagnostics.

[0011] In a first aspect, compounds of Formula I are provided, which, in some embodiments, inhibit both YEATS / ENL and FLT3:

[0012] [ka] During the ceremony, R 1 and R 2 together to form pyrrolidine or piperidine, R 3 is selected from hydrogen and C1-C8 alkyl; R 4 is C1-C8 alkyl, C1-C 10 Haloalkyl, C3-C8 carbocyclic, C1-C 10 Oxaalkyl, -SO2(C 1~6 ) alkyl, -SO2NH(C 0~3 H 1~7 ), -CONH(C 0~3 H 1~7 ), -SO2NH(C 1~6 ) Oxaalkyl, -CN, -CHCN, -CHNH, -NH, -NR 14 (In the formula, R 14 are independently hydrogen, (C 1~6 ) fluoroalkyl, and (C 1~3) oxaalkyl), one or more R selected from —CHOH, benzyloxy, —C(═NH)—NH, oxo, and halogen; 7 an aromatic 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with a group; R 5 is C1-C8 alkyl, C1-C 10 Haloalkyl, C3-C8 carbocyclic, C1-C 10 Oxaalkyl, -SO2(C 1~6 ) alkyl, -SO2NH(C 0~3 H 1~7 ), -CONH(C 0~3 H 1~7 ), -SO2NH(C 1~6 ) Oxaalkyl, -CN, -CHCN, -CHNH, -NH, -NR 14 (In the formula, R 14 are independently hydrogen, (C 1~6 ) fluoroalkyl, and (C 1~3 ) oxaalkyl), one or more R selected from —CHOH, benzyloxy, —C(═NH)—NH, oxo, and halogen; 6 is a 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with a group.

[0013] In a second aspect, compounds of Formula II are provided, which, in some embodiments, inhibit both YEATS / ENL and FLT3:

[0014] [ka] During the ceremony, R 8 is selected from hydrogen and C1-C8 alkyl; R 4 is C1-C8 alkyl, C1-C 10 Haloalkyl, C3-C8 carbocyclic, C1-C 10 Oxaalkyl, -SO2(C 1~6 ) alkyl, -SO2NH(C 0~3 H 1~7 ), -CONH(C 0~3 H 1~7), -SO2NH(C 1~6 ) Oxaalkyl, -CN, -CHCN, -CHNH, -NH, -NR 14 (In the formula, R 14 are independently hydrogen, (C 1~6 ) fluoroalkyl, and (C 1~3 ) oxaalkyl), one or more R selected from —CHOH, benzyloxy, —C(═NH)—NH, oxo, and halogen; 7 an aromatic 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with a group; R 5 is C1-C8 alkyl, C1-C 10 Haloalkyl, C3-C8 carbocyclic, C1-C 10 Oxaalkyl, -SO2(C 1~6 ) alkyl, -SO2NH(C 0~3 H 1~7 ), -CONH(C 0~3 H 1~7 ), -SO2NH(C 1~6 ) Oxaalkyl, -CN, -CHCN, -CHNH, -NH, -NR 14 (In the formula, R 14 are independently hydrogen, (C 1~6 ) fluoroalkyl, and (C 1~3 ) oxaalkyl), one or more R selected from —CHOH, benzyloxy, —C(═NH)—NH, oxo, and halogen; 6 is a 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with a group.

[0015] In a third aspect, the present invention relates to a pharmaceutical composition comprising a compound of Formula I and / or Formula II and one or more pharmaceutically acceptable carriers. The pharmaceutical composition can further comprise one or more therapeutic agents. Exemplary therapeutic agents include Bcl-2 inhibitors, cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitors, DNA methyltransferase inhibitors, histone deacetylase (HDAC) inhibitors, histone demethylase inhibitors, mTOR inhibitors, mutant isocitrate dehydrogenase (IDH1 and IDH2) inhibitors, glucocorticoids, epigenetic modulators, and chemotherapeutic agents.

[0016] In a fourth aspect, the present invention relates to a method for treating acute leukemia, comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutical composition comprising the same to a subject in need thereof. The acute leukemia can be acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). The method can further comprise administering one or more additional therapeutic agents, such as a Bcl-2 inhibitor, a cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitor, a DNA methyltransferase inhibitor, a histone deacetylase (HDAC) inhibitor, a histone demethylase inhibitor, an mTOR inhibitor, a mutant isocitrate dehydrogenase (IDH1 and IDH2) inhibitor, a glucocorticoid, an epigenetic modulator, and a chemotherapeutic agent. In certain embodiments, one or more compounds of the present invention are administered simultaneously or sequentially with another FLT3 inhibitor. In another specific embodiment, one or more compounds of the present invention are administered simultaneously or sequentially with a chemotherapeutic agent. In certain embodiments, the chemotherapeutic agent is a drug for use in the treatment of AML, such as cytarabine, a BCL-2 inhibitor (e.g., venetoclax), or a menin inhibitor. DETAILED DESCRIPTION OF THE INVENTION

[0017] I. Definition As used herein, "acyl" refers to formyl and refers to groups of 1, 2, 3, 4, 5, 6, 7, and 8 carbon atoms in a linear, branched, or cyclic arrangement, saturated, unsaturated, and aromatic, and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue can be replaced by nitrogen, oxygen, or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl, and the like. Lower acyl refers to groups containing 1 to 4 carbons. A double-bonded oxygen, when referred to as a substituent itself, is called "oxo."

[0018] As used herein, the term "alkyl" includes straight or branched chain hydrocarbon structures. Lower alkyl refers to alkyl groups of 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, and the like. Preferred alkyl groups are C 20 The following, for example, C1 to C 10 alkyl, C1-C8 alkyl and C1-C6 alkyl.

[0019] As used herein, "aryl" and "heteroaryl" refer to (i) a phenyl group (or benzene) or a monocyclic 5- or 6-membered heteroaromatic ring containing 1 to 4 heteroatoms selected from O, N, or S, (ii) a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0 to 4 heteroatoms selected from O, N, or S, or (iii) a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0 to 5 heteroatoms selected from O, N, or S. Aromatic 6- to 14-membered carbocyclic rings include, for example, benzene, naphthalene, indane, tetralin, and fluorene, and 5- to 10-membered aromatic heterocyclic rings include, for example, imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole, and pyrazole. As used herein, aryl and heteroaryl refer to residues in which one or more rings are aromatic, but not all are required to be aromatic.

[0020] As used herein, "arylalkyl" refers to a substituent in which an aryl residue is attached to the parent structure via an alkyl. Examples include benzyl, phenethyl, and the like. "Heteroarylalkyl" refers to a substituent in which a heteroaryl residue is attached to the parent structure via an alkyl. In one embodiment, the alkyl group of an arylalkyl or heteroarylalkyl is an alkyl group of 1 to 6 carbons. Examples include, for example, pyridinylmethyl, pyrimidinylethyl, and the like.

[0021] As used herein, "C1-C 20 Hydrocarbons" or "C1-C 20"Hydrocarbyl" (as a substituent) includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl, and combinations thereof. Examples include cyclopropylmethyl, benzyl, phenethyl, cyclohexylmethyl, camphoryl, and naphthylethyl. Hydrocarbon refers to any substituent composed of hydrogen and carbon as the only elemental components. Cycloalkyl is a subset of hydrocarbyl and includes cyclic hydrocarbon groups of 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, and the like.

[0022] "Alkoxy" or "alkoxyl" refers to groups of 1 to 8 carbon atoms of a straight, branched, or cyclic configuration and combinations thereof, attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Lower alkoxy refers to groups containing 1 to 4 carbons. For purposes of this application, alkoxy and lower alkoxy include methylenedioxy and ethylenedioxy.

[0023] As used herein, "carbocycle" includes ring systems in which the ring atoms are all carbon but in any oxidation state. Thus, (C3-C8) carbocycle refers to both non-aromatic and aromatic systems, including systems such as cyclopropane, benzene, and cyclohexene. (C8-C 12 ) Carbopolycycle refers to systems such as norbornane, decalin, indane, and naphthalene. Carbocycle refers to monocyclic, bicyclic, and polycyclic rings, unless otherwise limited.

[0024] As used herein, the term "therapeutically effective amount" refers to any amount of a compound of the invention or any other pharmaceutically active agent that results in improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding patient who does not receive such amount of a compound of the invention or other pharmaceutically active agent.

[0025] As used herein, the term "fused bicycle" refers to bicyclic carbocycles and bicyclic heterocycles in which each ring (carbocycle or heterocycle) shares two adjacent atoms with another ring (carbocycle or heterocycle). Each ring of a fused carbocycle can be selected from non-aromatic or aromatic rings. In preferred embodiments, an aromatic ring, such as phenyl, can be fused to another aromatic ring. In other embodiments, an aromatic ring can be fused to a non-aromatic ring, such as cyclohexane, cyclopentane, or cyclohexene. Exemplary fused bicycles include 6,6, 6,5, and 5,6 fused bicycles, where each number indicates the number of atoms in each ring. A fused bicycle can be substituted at any one or more positions where it can have a hydrogen atom. A fused bicycle is attached to the parent structure at the first-numbered ring, e.g., the "6" ring of a fused 6,5 bicycle.

[0026] As used herein, "heterocycle" refers to a cycloalkyl or aryl carbocyclic residue in which one to four carbons are replaced by heteroatoms selected from the group consisting of N, O, and S. The nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Unless otherwise specified, a heterocycle may be non-aromatic or aromatic. Examples of heterocycles within the scope of the present invention include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxane, benzodioxole (commonly referred to as methylenedioxyphenyl when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran, and the like. Note that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic. Non-limiting examples of heteroaromatic rings include furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, triazole, tetrazole, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine, cinnoline, phthalazine, and triazine.Examples of heterocyclyl radicals additionally include piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl, triazolyl, and tetrahydroquinolinyl.

[0027] An oxygen heterocycle is a heterocycle containing at least one oxygen atom in the ring, which may contain additional oxygen atoms and other heteroatoms. A sulfur heterocycle is a heterocycle containing at least one sulfur atom in the ring, which may contain additional sulfur atoms and other heteroatoms. An oxygen heteroaryl is a subset of an oxygen heterocycle, and non-limiting examples include furan and oxazole. A sulfur heteroaryl is a subset of a sulfur heterocycle, and examples include thiophene and thiazine. A nitrogen heterocycle is a heterocycle containing at least one nitrogen atom in the ring, which may contain additional nitrogen atoms and other heteroatoms. Non-limiting examples include piperidine, piperazine, morpholine, pyrrolidine, and thiomorpholine. A nitrogen heteroaryl is a subset of a nitrogen heterocycle, and non-limiting examples include pyridine, pyrrole, and thiazole.

[0028] As used herein, the term "optionally substituted" can be used interchangeably with "unsubstituted or substituted." The term "substituted" refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical. For example, substituted aryl, heterocyclyl, etc. refer to the replacement of one or more hydrogen atoms in each group with a halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxy lower alkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, lower alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl [—C(═O)O-alkyl], carboxamido [—C(═O)NH2], alkylaminocarbonyl [—C(═O)NH-alkyl], cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, dialkylaminoalkyl, dialkylaminoalkylalkoxy, hydroxyl ... (C) refers to aryl or heterocyclyl substituted with oxy, heterocyclylalkoxy, arylalkyl, (cycloalkyl)alkyl, heterocyclyl, heterocyclylalkyl, alkylaminoalkyl, heterocyclylaminoalkyl, heterocyclylalkylaminoalkyl, cycloalkylaminoalkyl, cycloalkylalkylaminoalkyl, arylaminoalkyl, and arylalkylaminoalkyl, mercapto, alkylthio, alkylsulfinyl, benzyl, heterocyclyl, phenoxy, benzyloxy, heteroaryloxy, aminosulfonyl, amidino, guanidino, and ureido. 1~6 Hydrocarbyl, -SO2 alkyl, -SO2 NH2, or -SO2 NH alkyl.

[0029] As used herein, "oxaalkyl" refers to an alkyl residue in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl, and the like. Alkoxy is a subset of oxaalkyl in which the carbon at the point of attachment has been replaced by oxygen. The term oxaalkyl is intended to be as understood in the art (see Naming and Indexing of Chemical Substances for Chemical Abstracts, 196, published by the American Chemical Society, but without the limitation of 127(a)); i.e., the term refers to compounds in which oxygen is bonded to its adjacent atom through a single bond (forming an ether bond), and not a double-bonded oxygen such as found in a carbonyl group. Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Non-limiting examples include ethylaminoethyl and methylthiopropyl.

[0030] As used herein, "solvate" refers to a compound in the solid state in which molecules of a suitable solvent are incorporated into the crystal lattice along with the compound. A suitable solvent for therapeutic administration is physiologically acceptable at the administered dose. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is called a hydrate. Generally, solvates are formed by dissolving a compound in a suitable solvent and isolating the solvate by cooling or using an anti-solvent. The solvate is typically dried or azeotroped under ambient conditions.

[0031] As used herein, the terms "subject" or "subject in need thereof" are used interchangeably herein. These terms refer to a patient diagnosed with an underlying disease to be treated. The subject may currently be experiencing symptoms associated with the disorder or may have experienced symptoms in the past. In addition, a "subject in need thereof" may be a patient at risk of developing a particular disease, or a patient who reports one or more physiological systems of the disease even if the disease has not been diagnosed.

[0032] As used herein, the terms "treatment" and "treating" are used interchangeably. These terms refer to an approach to obtaining beneficial or desired results, including, but not limited to, therapeutic benefit. Therapeutic benefit includes eradication or alleviation of the underlying disease being treated, which also includes eradication or alleviation of one or more symptoms associated with the underlying disease, such that an improvement is observed in the patient, even though the patient may still be afflicted with the underlying disease.

[0033] II. Compounds In one aspect, a compound of formula I is provided:

[0034] [ka] During the ceremony, R 1 and R 2 together to form pyrrolidine or piperidine, R 3 is selected from hydrogen and C1-C8 alkyl; R 4 is C1-C8 alkyl, C1-C 10 Haloalkyl, C3-C8 carbocyclic, C1-C 10 Oxaalkyl, -SO2(C 1~6 ) alkyl, -SO2NH(C 0~3 H 1~7 ), -CONH(C 0~3 H 1~7 ), -SO2NH(C 1~6 ) Oxaalkyl, -CN, -CHCN, -CHNH, -NH, -NR 14 (In the formula, R 14 are independently hydrogen, (C 1~6 ) fluoroalkyl, and (C 1~3 ) oxaalkyl), one or more R selected from —CHOH, benzyloxy, —C(═NH)—NH, oxo, and halogen; 7 an aromatic 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with a group; R5 is C1-C8 alkyl, C1-C 10 Haloalkyl, C3-C8 carbocyclic, C1-C 10 Oxaalkyl, -SO2(C 1~6 ) alkyl, -SO2NH(C 0~3 H 1~7 ), -CONH(C 0~3 H 1~7 ), -SO2NH(C 1~6 ) Oxaalkyl, -CN, -CHCN, -CHNH, -NH, -NR 14 (In the formula, R 14 are independently hydrogen, (C 1~6 ) fluoroalkyl, and (C 1~3 ) oxaalkyl), one or more R selected from —CHOH, benzyloxy, —C(═NH)—NH, oxo, and halogen; 6 is a 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with a group.

[0035] Illustrative R 4 Groups include, but are not limited to, benzene, pyridine, pyrimidine, pyridazine, and pyrazine.

[0036] Illustrative R 5 Groups include, but are not limited to, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazoline, imidazoline, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, 1,2,3-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, isothiazole, thiazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, furan, and thiophene.

[0037] R 4 In certain embodiments, R is a heterocycle. 4The heteroatom in 5 Similarly, R 5 In certain embodiments, R is a heterocycle. 5 The heteroatom in R 4 does not directly bind to

[0038] In a more particular embodiment, a compound of formula Ia' is provided:

[0039] [ka] In the formula, R 3 , R 4 , and R 5 is as defined above for Formula I.

[0040] In one embodiment, R 3 is methyl. In another embodiment, R 4 is benzene optionally substituted as described above. In yet another embodiment, R 4 is pyrimidine optionally substituted as described above. In yet another embodiment, R 5 is pyrazole optionally substituted as described above. In more particular embodiments, R 3 is methyl and R 4 is benzene or pyrimidine optionally substituted as above, and R 5 is a pyrazole optionally substituted as above. The compound has a chiral center ( * ) can have the R or S configuration.

[0041] In another more particular embodiment, there is provided a compound of formula Ia″:

[0042] [ka] In the formula, R 3 , R 4 , and R 5 is as defined above for Formula I.

[0043] In one embodiment, R 3 is methyl. In another embodiment, R 4 is benzene optionally substituted as described above. In yet another embodiment, R 4 is pyrimidine optionally substituted as described above. In yet another embodiment, R 5 is pyrazole optionally substituted as described above. In more particular embodiments, R 3 is methyl and R 4 is benzene or pyrimidine optionally substituted as above, and R 5 is a pyrazole optionally substituted as above. The compound has a chiral center ( * ) can have the R or S configuration.

[0044] In another embodiment, there is provided a compound of formula Ib:

[0045] [ka] In the formula, R 1 , R 2 , R 3 , R 5 , and R 7 is as defined above for formula I, Each X is independently selected from CH and N.

[0046] In a more particular embodiment, a compound of formula Ib' is provided:

[0047] [ka] In the formula, R 3 , R 5 , and R 7 is as defined above for formula I, Each X is independently selected from CH and N.

[0048] In certain embodiments, R 3is methyl. In another particular embodiment, at least one X is N. In yet another particular embodiment, all X are C. In yet another particular embodiment, R 5 is pyrazole optionally substituted as described above. In more particular embodiments, R 3 is methyl, at least one X is N, and R 5 is pyrazole optionally substituted as described above. In another more particular embodiment, R 3 is methyl, all X are C, and R 5 is a pyrazole optionally substituted as above. The compound has a chiral center ( * ) which can be in the R or S configuration.

[0049] In another more particular embodiment, there is provided a compound of formula Ib″:

[0050] [ka] In the formula, R 3 , R 5 , and R 7 is as defined above for formula I, Each X is independently selected from CH and N.

[0051] In certain embodiments, R 3 is methyl. In another particular embodiment, at least one X is N. In yet another particular embodiment, all X are C. In yet another particular embodiment, R 5 is pyrazole optionally substituted as described above. In more particular embodiments, R 3 is methyl, at least one X is N, and R 5 is pyrazole optionally substituted as described above. In another more particular embodiment, R 3 is methyl, all X are C, and R 5 is a pyrazole optionally substituted as above. The compound has a chiral center ( *) which can be in the R or S configuration.

[0052] In another more particular embodiment, there is provided a compound of formula Ic:

[0053] [ka] In the formula, R 1 , R 2 , R 3 , R 4 , and R 6 is as defined above for formula I, each Z is independently selected from CH and N; Y is selected from NH and CH2.

[0054] In a more particular embodiment, a compound of formula Ic' is provided:

[0055] [ka] In the formula, R 3 , R 4 , and R 6 is as defined above for formula I, each Z is independently selected from CH and N; Y is selected from NH and CH2.

[0056] In certain embodiments, R 3 is methyl. In another particular embodiment, at least one Z is N and Y is NH. In another particular embodiment, R 4 is benzene or pyrimidine optionally substituted as described above. In more particular embodiments, R 3 is methyl, at least one Z is N, Y is NH, and R 4 is benzene or pyrimidine optionally substituted as above. The compound has a chiral center ( * ) which can be in the R or S configuration.

[0057] In another more particular embodiment, there is provided a compound of formula Ic″:

[0058] [ka] In the formula, R 3 , R 4 , and R 6 is as defined above for formula I, each Z is independently selected from CH and N; Y is selected from NH and CH2.

[0059] In certain embodiments, R 3 is methyl. In another particular embodiment, at least one Z is N and Y is NH. In another particular embodiment, R 4 is benzene or pyrimidine optionally substituted as described above. In more particular embodiments, R 3 is methyl, at least one X is N, Y is NH, and R 4 is benzene or pyrimidine optionally substituted as above. The compound has a chiral center ( * ) which can be in the R or S configuration.

[0060] In another embodiment, there is provided a compound of formula Id:

[0061] [ka] In the formula, R 1 , R 2 , R 3 , R 6 , and R 7 is as defined above for formula I, each X is independently selected from CH and N; each Z is independently selected from CH and N; Y is selected from CH2 and NH.

[0062] In another particular embodiment, a compound of formula Id' is provided:

[0063] [ka] In the formula, R 3 , R 6 , and R 7 is as defined above for formula I, each X is independently selected from CH and N; each Z is independently selected from CH and N; Y is selected from CH2 and NH.

[0064] In certain embodiments, R 3 is methyl. In another particular embodiment, at least one Z is N and Y is NH. In another particular embodiment, R 3 is methyl, at least one X is N, at least one Z is N, and Y is NH. In another particular embodiment, R 3 is methyl, all X are C, at least one Z is N, and Y is NH. The compound has a chiral center ( * ) which can be in the R or S configuration.

[0065] In another particular embodiment, a compound of formula Id″ is provided:

[0066] [ka] In the formula, R 3 , R 6 , and R 7 is as defined above for formula I, each X is independently selected from CH and N; each Z is independently selected from CH and N; Y is selected from CH and NH.

[0067] In certain embodiments, R 3is methyl. In another particular embodiment, at least one Z is N and Y is NH. In another particular embodiment, R 3 is methyl, at least one X is N, at least one Z is N, and Y is NH. In another particular embodiment, R 3 is methyl, all X are C, at least one Z is N, and Y is NH. The compound has a chiral center ( * ) which can be in the R or S configuration.

[0068] As noted above, the compounds described herein may have chiral centers ( * ) and can be in the R or S configuration. In one embodiment, the compound has the R configuration, for example, formula Ia' is:

[0069] [ka]

[0070] In another embodiment, the compound has the S configuration, for example, formula Ia″:

[0071] [ka]

[0072] In another aspect, compounds of formula II are provided:

[0073] [ka] During the ceremony, R 8 is selected from hydrogen and C1-C8 alkyl; R 4 is C1-C8 alkyl, C1-C 10 Haloalkyl, C3-C8 carbocyclic, C1-C 10 Oxaalkyl, -SO2(C 1~6 ) alkyl, -SO2NH(C 0~3 H 1~7 ), -CONH(C0~3 H 1~7 ), -SO2NH(C 1~6 ) Oxaalkyl, -CN, -CHCN, -CHNH, -NH, -NR 14 (In the formula, R 14 are independently hydrogen, (C 1~6 ) fluoroalkyl, and (C 1~3 ) oxaalkyl), one or more R selected from —CHOH, benzyloxy, —C(═NH)—NH, oxo, and halogen; 7 an aromatic 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with a group; R 5 is C1-C8 alkyl, C1-C 10 Haloalkyl, C3-C8 carbocyclic, C1-C 10 Oxaalkyl, -SO2(C 1~6 ) alkyl, -SO2NH(C 0~3 H 1~7 ), -CONH(C 0~3 H 1~7 ), -SO2NH(C 1~6 ) Oxaalkyl, -CN, -CHCN, -CHNH, -NH, -NR 14 (In the formula, R 14 are independently hydrogen, (C 1~6 ) fluoroalkyl, and (C 1~3 ) oxaalkyl), one or more R selected from —CHOH, benzyloxy, —C(═NH)—NH, oxo, and halogen; 6 is a 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with a group.

[0074] Illustrative R 4 Groups include, but are not limited to, benzene, pyridine, pyrimidine, pyridazine, and pyrazine.

[0075] Illustrative R 5Groups include, but are not limited to, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazoline, imidazoline, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, 1,2,3-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, isothiazole, thiazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, furan, and thiophene.

[0076] R 4 In certain embodiments, R is a heterocycle. 4 The heteroatom in 5 Similarly, R 5 In certain embodiments, R is a heterocycle. 5 The heteroatom in R 4 does not directly bind to

[0077] In one embodiment, a compound of formula IIa is provided:

[0078] [ka] In the formula, R 5 , R 7 , and R 8 is as defined above for formula II, Each X is independently selected from CH and N.

[0079] In one embodiment, R 8 is methyl. In another embodiment, at least one X is N. In yet another embodiment, all X are C. In yet another embodiment, R 5 is pyrazole optionally substituted as described above. In more particular embodiments, R 8 is methyl, at least one X is N, and R5 is pyrazole optionally substituted as described above. In another more particular embodiment, R 8 is methyl, all X are C, and R 5 is pyrazole optionally substituted as above.

[0080] In another particular embodiment, compounds of formula IIb are provided:

[0081] [ka] In the formula, R 4 , R 6 , and R 8 is as defined above for formula II, each Z is independently selected from CH and N; Y is selected from NH and CH2.

[0082] In one embodiment, R 8 is methyl. In another embodiment, at least one Z is N. In yet another embodiment, R 4 is benzene or pyrimidine optionally substituted as described above. In certain embodiments, R 8 is methyl, at least one Z is N, Y is NH, and R 4 is benzene or pyrimidine optionally substituted as above.

[0083] In another embodiment, a compound of formula IIc is provided:

[0084] [ka] In the formula, R 6 , R 7 , and R 8 is as defined above for formula II, each X is independently selected from CH and N; each Z is independently selected from CH and N; Y is selected from CH2 and NH.

[0085] In one embodiment, R 8 is methyl. In another embodiment, at least one Z is N and Y is NH. In certain embodiments, R 8 is methyl, at least one X is N, at least one Z is N, and Y is NH. In another particular embodiment, R 8 is methyl, all X are C, at least one Z is N, and Y is NH. The compound has a chiral center ( * ) which can be in the R or S configuration.

[0086] In another embodiment, the compound of the present invention is selected from the group consisting of:

[0087] [ka]

[0088] As used herein, "compound," unless expressly limited further, is intended to include salts of that compound. Thus, for example, reference to "a compound of Formula I," as depicted above, includes salts of:

[0089] [ka] wherein X is an optional counterion. In certain embodiments, the term "compound of Formula I" refers to the compound or a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, including inorganic acids and bases and organic acids and bases. When the compound of the present invention is basic, as is usually the case, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid (besylate), benzoic acid, boric acid, butyric acid, camphoric acid, camphorsulfonic acid, carbonic acid, citric acid, ethanedisulfonic acid, ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydrobromic acid, and salts thereof. Acids that are suitable for pharmaceutically acceptable salts include hydroxybenzoates, ...

[0090] Compounds having R stereochemistry generally exhibit greater activity than the corresponding S enantiomers. In other embodiments, the compounds have an S stereochemical configuration at the chiral center.

[0091] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen with deuterium or tritium, or 13 C or 14Compounds having the present structure except for the replacement of a carbon by a C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0092] III. Pharmaceutical Compositions The present invention also provides pharmaceutical compositions comprising at least one compound described herein, including pharmaceutically acceptable salts and solvates thereof.

[0093] The pharmaceutical composition comprises at least one compound described herein and one or more pharmaceutically acceptable excipients.Exemplary excipients include, but are not limited to, one or more binders, bulking agents, buffers, stabilizers, surfactants, wetting agents, lubricants, diluents, disintegrants, viscosity enhancing or viscosity reducing agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, coloring agents, sweeteners, flavoring agents, flavoring agents, diluents, abrasives, polymer matrix systems, plasticizers, and other known additives for providing the appearance of a drug or for assisting in the manufacture of a medicament or pharmaceutical product comprising the composition of the present invention. Examples of carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C., Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.

[0094] Non-limiting examples of excipients include corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., Nos. 2208, 2906, 2910), hydroxypropyl cellulose, titanium dioxide, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, silicic acid, sorbitol, starch, alginate, etc. Perfumed starch, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polacrilin, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clay, other algins, other celluloses, gums, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, syloid silica gel (WR Grace, Baltimore, MD) Co. AEROSIL 200), coagulated aerosol of synthetic silica (sold by Degussa Co. of Plano, Texas), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Massachusetts), colorants, and mixtures thereof.

[0095] The pharmaceutical composition may optionally contain one or more additional therapeutic agents.

[0096] Additional therapeutic agents include Bcl-2 inhibitors, cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitors, DNA methyltransferase inhibitors, histone deacetylase (HDAC) inhibitors, histone demethylase inhibitors, mTOR inhibitors, mutant isocitrate dehydrogenase (IDH1 and IDH2) inhibitors, glucocorticoids, epigenetic modulators, and chemotherapeutic agents.

[0097] The standard of care for AML and ALL is currently chemotherapy with chemotherapeutic agents, including, but not limited to, daunorubicin, cytarabine, methotrexate, mitoxantrone, methotrexate, mafosamide, and vincristine.

[0098] Targeted therapeutic agents, such as those discussed below, can be used alone or in combination with chemotherapeutic agents.

[0099] Exemplary Bcl-2 inhibitors include, but are not limited to, oblimersen, navitoclax, and venetoclax.

[0100] Exemplary cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitors include, but are not limited to, palbociclib, ribociclib, and abemaciclib.

[0101] Epigenetic modulators include, but are not limited to, menin-histone methyltransferase MLL (i.e., menin-MLL) inhibitors, FLT3 inhibitors, P-TEFb inhibitors, histone methyltransferase inhibitors (e.g., DOT1L and EZH2 inhibitors), bromodomain and extra-terminal domain (BET) inhibitors, and dihydroorotate dehydrogenase (DHODH) inhibitors.

[0102] Exemplary FLT3 inhibitors include, but are not limited to, sorafenib, lestaurtinib, sunitinib, tanzutinib, quizartinib, midostaurin, gilteritinib, crenolanib, cabozantinib, and ponatinib.

[0103] Epigenetic modulators, such as the combination of menin-MLL inhibitors and FLT3 inhibitors, are also contemplated, as these have shown enhanced apoptosis induction in AML models.

[0104] In one embodiment, the additional therapeutic agents comprise a combination of at least one Bcl-2 inhibitor and at least one FLT3 inhibitor.

[0105] Exemplary DNA methyltransferase inhibitors include, but are not limited to, azacitidine and decitabine.

[0106] Exemplary HDAC inhibitors include, but are not limited to, panobinostat and vorinostat.

[0107] Exemplary mTOR inhibitors include, but are not limited to, everolimus.

[0108] Exemplary glucocorticoids include, but are not limited to, dexamethasone and prednisolone.

[0109] Exemplary mutant isocitrate dehydrogenase inhibitors include, but are not limited to, ivosidenib (IDH1) and enasidenib (IDH2).

[0110] In one embodiment, the additional therapeutic agents comprise a combination of at least one isocitrate dehydrogenase inhibitor and at least one CDK4 / 6 inhibitor.

[0111] IV.How to use The present invention also relates to methods of using at least one compound described herein or a pharmaceutical composition described herein to inhibit oncogene expression in a cell. In one embodiment, the method of inhibiting oncogene expression in a cell comprises exposing the cell to at least one compound described herein. The present invention also relates to methods of using at least one compound described herein or a pharmaceutical composition described herein to treat acute leukemia. In one embodiment, the method of treating acute leukemia comprises administering a therapeutically effective amount of at least one compound described herein to a subject in need thereof.

[0112] Acute leukemia is a rapidly progressing form of leukemia characterized by the replacement of normal bone marrow by clonal blast cells resulting from malignant transformation of hematopoietic cells. Acute leukemia includes acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). ALL often involves the CNS, while acute monoblastic leukemia involves the gums, and AML involves localized collections (granulocytic sarcoma or chloroma) in any location.

[0113] In one embodiment, the acute leukemia is ALL. ALL is the most common malignant tumor in children, with a peak incidence between 3 and 5 years of age. ALL also occurs in adolescents, with a second, lower peak in adults. Typical treatment emphasizes early introduction of an intensive multidrug regimen that may include prednisone, vincristine, anthracycline, or asparaginase. Other drugs and combinations include cytarabine and etoposide, and cyclophosphamide. Relapse usually occurs in the bone marrow, but can also occur in the CNS or testes, alone or simultaneously with bone marrow remission. While a second remission can be induced in many children, subsequent remissions tend to be short-lived.

[0114] In another embodiment, the acute leukemia is AML. The incidence of AML increases with age, making it the more common acute leukemia in adults. AML may be associated with chemotherapy or radiation (secondary AML). Remission induction rates are lower than for ALL, and long-term disease-free survival reportedly occurs in only 20-40% of patients. Treatment differs most from ALL in that AML responds to fewer drugs. The basic induction regimen includes cytarabine in combination with daunorubicin or idarubicin. Some regimens include 6-thioguanine, etoposide, vincristine, and prednisone. Clinical aspects of AML are reviewed by CA Chiffer and RM Stone in Cancer Medicine, Ed. David W. Kufe et al., 6th Edition, BC Decker, 2003.

[0115] The French, American, and British (FAB) classification was developed to diagnose and classify acute myeloid leukemia. A diagnosis of acute myeloid leukemia requires that myeloblasts constitute 30% or more of the bone marrow cells or circulating leukocytes (or 20% based on the most recent World Health Organization (WHO) classification system). The hematological characteristics of the disease define the various subtypes described below. The FAB nomenclature (M1-M7) classifies acute myeloid leukemia subtypes according to the normal bone marrow element to which the blasts most closely resemble. The following list includes both the FAB classification as well as additional classes recognized by the WHO. Minimally differentiated acute myeloid leukemia (M0) Acute myeloid leukemia without maturation (M1) Acute myeloid leukemia with maturation (M2) Acute myeloid leukemia with maturation harboring t(8;21) Acute promyelocytic leukemia (M3) Hypergranular type microgranular type Acute myelomonocytic leukemia (M4) Acute myelomonocytic leukemia with bone marrow eosinophilia (M4E0) Acute monocytic leukemia (M5) Acute monoblastic leukemia (M5a) Acute monocytic leukemia with maturation (M5b) Erythroid / myeloid erythroleukemia (M6a) Pure erythroid malignancies (M6b) Acute megakaryoblastic leukemia (M7) t(1;22)-associated acute megakaryoblastic leukemia acute basophilic leukemia Acute myelofibrosis (acute myelodysplasia with myelofibrosis) Acute leukemia and transient myeloproliferative disorders in Down syndrome Hypocellular acute myeloid leukemia Myeloid sarcoma

[0116] In one embodiment, the method of treating the above-listed subtypes of AML comprises administering to a subject in need thereof a therapeutically effective amount of at least one compound described herein.

[0117] At least one compound used in the methods of the present invention may be provided in the form of a pharmaceutical composition as described herein above.

[0118] Routes of administration include enteral routes, such as oral, and parenteral routes, such as intravenous, intraarterial, intramuscular, intranasal, rectal, intraperitoneal, subcutaneous and topical routes.

[0119] For parenteral administration, the active compound can be mixed with a suitable carrier or diluent, such as water, oil (especially vegetable oil), ethanol, saline, aqueous dextrose (glucose) and related sugar solutions, glycerol, or glycols, such as propylene glycol or polyethylene glycol. Solutions for parenteral administration preferably contain a water-soluble salt of the active agent. Stabilizers, antioxidants, and preservatives can also be added. Suitable antioxidants include sulfites, ascorbic acid, citric acid and its salts, and sodium EDTA. Suitable preservatives include benzalkonium chloride, methyl or propyl paraben, and chlorbutanol. Compositions for parenteral administration can take the form of aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions.

[0120] For oral administration, the active compound can be combined with one or more solid inactive ingredients to prepare tablets, capsules, pills, powders, granules or other suitable oral dosage forms. For example, the active compound can be combined with at least one excipient, such as a filler, binder, humectant, disintegrant, dissolution retardant, absorption accelerator, wetting agent, absorbent or lubricant.

[0121] The particular dosage of the active compounds employed in the compositions and methods of the present invention to achieve therapeutic benefit will, of course, be determined by the particular circumstances of each individual patient, including the patient's size, weight, age, and sex, the nature and stage of the disease, the aggressiveness of the disease, and the route of administration.

[0122] For the compounds described herein, preferred daily doses range, for example, from about 1 to about 10,000 mg, more preferably from about 5 to about 5,000 mg, even more preferably from about 10 to about 3,000 mg, and most preferably from about 50 to about 1,000 mg. In certain embodiments, preferred daily doses range from about 50 mg to about 4,000 mg, about 100 mg to about 3,000 mg, about 500 to about 2,000 mg, or about 750 mg to about 1,500 mg. In other embodiments, preferred daily doses range from 2,000 mg to about 10,000 mg, about 3,000 mg to about 9,000 mg, about 4,000 mg to about 8,000 mg, or about 4,500 mg to about 7,500 mg.

[0123] Doses may be administered 1 to 4 times daily, for example, once daily, as needed to provide therapeutic benefit. In certain embodiments, therapeutic compounds of the present invention are administered intravenously either as a single dose or as part of a planned dosing regimen that may be spread over several days, weeks, or months. Compounds of the present invention may also be administered by regular injections as needed to provide therapeutic benefit.

[0124] The methods described herein can further include administering an additional therapeutic agent, such as a Bcl-2 inhibitor, a cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitor, a DNA methyltransferase inhibitor, a histone deacetylase (HDAC) inhibitor, a histone demethylase inhibitor, an mTOR inhibitor, a mutant isocitrate dehydrogenase (IDH1 and IDH2) inhibitor, a glucocorticoid, an epigenetic modulator, and a chemotherapeutic agent. The additional therapeutic agent can be administered simultaneously or sequentially with the compound described herein. In some embodiments, the administration of the compound described herein and the additional therapeutic agent can result in a synergistic effect. [Example]

[0125] The following compounds have been prepared, isolated, and characterized using the methods disclosed herein and represent a partial scope of the invention and are not meant to limit the scope of the invention.

[0126] The compounds of the present invention were prepared by methods well known in the art of synthetic organic chemistry. During the synthetic sequence, it may be necessary or desirable to protect sensitive or reactive groups on any of the molecules concerned. This was achieved by conventional protecting groups, such as those described in T.W. Greene and P.G.M.Wuts Greene's Protective Groups in Organic Synthesis, Fourth edition, John Wiley and Sons, 2006. The protecting groups were removed at a convenient subsequent stage using methods well known in the art.

[0127] All reactions were carried out under a dry atmosphere of nitrogen unless otherwise noted. Reaction temperatures indicated refer to the reaction bath; room temperature (rt) is indicated as 25 °C. Commercial-grade reagents and anhydrous solvents were used as received from the suppliers, and no attempt was made to further purify or dry these components. Removal of solvents under reduced pressure was achieved with a Buchi rotary evaporator at approximately 28 mmHg pressure using a Teflon-coupled KNf vacuum pump. Flash column chromatography was performed using a Teledyne Isco CombiFlash Companion unit equipped with a RediSep Rf silica gel column. Proton NMR spectra were acquired on a 300 MHz and 400 MHz Bruker nuclear magnetic resonance spectrometer. Chemical shifts (δ) are reported in parts per million (ppm), and coupling constant (J) values ​​are provided in Hz. The following spectral pattern designations are used: s, singlet; d, doublet; t, triplet; q, quartet; dd, complex doublet; m, multiplet; and brs, broad singlet. Tetramethylsilane was used as an internal standard. Mass spectrometric analysis was performed using positive and negative mode electron spray ionization (ESI) on an Agilent 1200 system. High-pressure liquid chromatography (HPLC) purity analysis was performed using a Varian Pro Star HPLC system with binary solvent systems A and B using gradient elution [A, HO containing 0.0284% NHOAc and 0.0116% acetic acid; B, CHCN] and a flow rate of 1 mL / min, with a PDA scan for UV detection.

[0128] [Table 1]

[0129] Intermediate 1: (R)-2-(1-methylpyrrolidin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-6-amine

[0130] [ka]

[0131] A 20 L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2-chloro-5-iodopyridin-4-amine (490.0 g, 1.90 mol, 1.00 equiv.), TEA (974 g, 9.60 mol, 5.00 equiv.), and DCM (12.30 L). Then, a solution of MsCl (882 g, 7.70 mol, 4.00 equiv.) in DCM (7.4 L) was added dropwise with stirring at 0-5 °C. The resulting solution was stirred at 0-10 °C for 6 h. The pH of the solution was adjusted to 7-8 with NaHCO3 (1 mol / L). The resulting solution was extracted with 3 × 5 L of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. This gave 935 g (94.6%) of N-(2-chloro-5-iodopyridin-4-yl)-N-methanesulfonyl methanesulfonamide as a yellow oil. LC-MS: (ES, m / z): [M+1] + =411.

[0132] [ka]

[0133] A 10 L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with N-(2-chloro-5-iodopyridin-4-yl)-N-methanesulfonyl methanesulfonamide (935.0 g, 2.28 mol, 1.00 equiv.), THF (4.70 L), HO (4.70 L), and NaOH (455 g, 11.4 mol, 5.00 equiv.). The resulting solution was stirred at room temperature for 16 h. The resulting mixture was concentrated. The pH of the solution was adjusted to 3-4 with citric acid (1 mol / L). The solid was collected by filtration. This yielded 438 g (57.9%) of N-(2-chloro-5-iodopyridin-4-yl)methanesulfonamide as a white solid. LC-MS(ES,m / z):[M+1] + =333.

[0134] [ka]

[0135] A 10 L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (530.00 g, 2.6 mol, 1.00 equiv.), DCM (5.30 L), and DMP (1340 g, 3.16 mol, 1.20 equiv.). The resulting solution was stirred at room temperature for 6 hours. The resulting solution was diluted with 5.3 L of HO. The resulting solution was extracted with 3 × 10 L of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 × 5 L of NaSO (aq.) and 3 × 5 L of NaHCO (aq.). The resulting mixture was washed with 3 × 10 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. This afforded 415 g (79.09%) of tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate as a yellow oil. LC-MS: (ES, m / z): [M+1] + =200.

[0136] [ka]

[0137] A 10 L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with K2CO3 (348 g, 2.5 mol, 1.20 equiv.), methanol (4.15 L), tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate (415.00 g, 2.09 mol, 1.00 equiv.), and dimethyl (1-diazo-2-oxopropyl)phosphonate (600 g, 3.1 mol, 1.50 equiv.). The reaction mixture was stirred at room temperature for 16 hours and diluted with 4 L of HO. The resulting solution was extracted with 3 x 4 L of petroleum ether, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. This afforded 297 g (73.03%) of tert-butyl (2R)-2-ethynylpyrrolidine-1-carboxylate as a yellow oil. LC-MS: (ES, m / z): [M+1] + =196.

[0138] [ka]

[0139] A 10 L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with N-(2-chloro-5-iodopyridin-4-yl)methanesulfonamide (438.00 g, 1.32 mol, 1.00 equiv.), TEA (533 g, 5.27 mol, 4.00 equiv.), dimethylformamide (4.40 L), tert-butyl (2R)-2-ethynylpyrrolidine-1-carboxylate (283 g, 1.45 mol, 1.10 equiv.), Pd(PPh)Cl (46 g, 0.066 mol, 0.05 equiv.), and CuI (25 g, 0.13 mol, 0.10 equiv.). The reaction mixture was stirred at 55 °C for 6 h and diluted with 4.4 L of HO. The resulting solution was extracted with 3 × 4.4 L of ethyl acetate, and the combined organic layers were washed with 3 × 4.4 L of brine, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:5). This afforded 363 g (68.9%) of tert-butyl (2R)-2-[6-chloro-1-methanesulfonylpyrrolo[3,2-c]pyridin-2-yl]pyrrolidine-1-carboxylate as a white solid. LC-MS: (ES, m / z): [M+1] + =400.

[0140] [ka]

[0141] A 10 L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with tert-butyl (2R)-2-[6-chloro-1-methanesulfonylpyrrolo[3,2-c]pyridin-2-yl]pyrrolidine-1-carboxylate (363.00 g, 0.91 mol, 1.00 equiv.), MeOH (2.50 L), HO (1.10 L), and NaOH (109 g, 2.72 mol, 3.00 equiv.). The reaction mixture was stirred at room temperature for 16 hours and concentrated. The solid was collected by filtration. This afforded 259 g (88.67%) of tert-butyl (2R)-2-[6-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyrrolidine-1-carboxylate as a white solid. LC-MS: (ES, m / z): [M+1] + =322.

[0142] [ka]

[0143] A 5 L four-neck round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with tert-butyl (2R)-2-[6-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyrrolidine-1-carboxylate (259.0 g, 0.80 mol, 1.00 equiv.), CsCO (787 g, 2.4 mol, 3.00 equiv.), and DMF (2.60 L). SEMCl (161 g, 0.97 mol, 1.20 equiv.) was then added dropwise with stirring at 0–5°C. The reaction mixture was stirred at room temperature for 6 h. The resulting solution was diluted with 2.6 L of HO and extracted with 3 × 2.6 L of ethyl acetate. The organic layers were combined and washed with 3 × 2 L of brine. The organic layers were dried over anhydrous sodium sulfate and concentrated. The solid was collected by filtration. This gave 248 g (68.2%) of tert-butyl (2R)-2-(6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-2-yl)pyrrolidine-1-carboxylate as a white solid. LC-MS: (ES, m / z): [M+1] + =452.

[0144] [ka]

[0145] A 10 L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with tert-butyl (2R)-2-(6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-2-yl)pyrrolidine-1-carboxylate (248.00 g, 0.55 mol, 1.00 equiv.), MeOH (2.40 L), and HCl (1.5 M) in MeOH (1.20 L). The reaction mixture was stirred at room temperature for 12 h and concentrated. The resulting solution was diluted with 2.5 L of HO. The pH of the solution was adjusted to 7-8 with NaHCO (1 mol / L) and extracted with 3 × 2.5 L of dichloromethane. The organic layers were then combined and concentrated. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:2). This gave 177 g (91.7%) of (2R)-2-(6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-2-yl)pyrrolidine as a white solid. LC-MS(ES,m / z):[M+1] + =352.

[0146] [ka]

[0147] A 10 L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with (2R)-2-(6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-2-yl)pyrrolidine (177.00 g, 0.5 mol, 1.00 equiv.), DCM (3.50 L), MeOH (1.77 L), paraformaldehyde (453 g, 5 mol, 10.00 equiv.), and NaBH(OAc)3 (640 g, 3 mol, 6.00 equiv.). The reaction mixture was stirred at room temperature for 12 h. The pH value of the solution was adjusted to 8-9 with NaHCO3 (1 mol / L), and the solid was filtered off. The filtrate was extracted with 3 × 1.7 L of dichloromethane, and the organic layers were combined and concentrated. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:3), which gave 129 g (70.1%) of (2R)-2-(6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-2-yl)-1-methylpyrrolidine as a yellow oil. LC-MS: (ES, m / z): [M+1] + =366.

[0148] [ka]

[0149] A 5 L four-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with (2R)-2-(6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-2-yl)-1-methylpyrrolidine (129.00 g, 0.35 mol, 1.00 equiv.), toluene (2.60 L), BINAP (22 g, 0.035 mol, 0.10 equiv.), t-BuONa (101 g, 1.06 mol, 3.00 equiv.), Pd(dba) (16 g, 0.017 mol, 0.05 equiv.), and diphenylmethanimine (192 g, 1.06 mol, 3.00 equiv.). The reaction mixture was stirred at 110 °C for 16 h and then diluted with 2.6 L of EA. The organic layer was collected, washed with 3 × 1 L of brine, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column eluted with THF / PE (1:3). This afforded 131 g (72.8%) of N-[2-[(2R)-1-methylpyrrolidin-2-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl]-1,1-diphenylmethanimine as a yellow oil.

[0150] [ka]

[0151] A 10 L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with N-[2-[(2R)-1-methylpyrrolidin-2-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl]-1,1-diphenylmethanimine (131.00 g, 0.26 mol, 1.00 equiv.), THF (6.50 L), HO (1.10 L), and HCl (0.5 M) (88 g, 1.28 mol, 5.00 equiv.). The resulting solution was stirred at room temperature for 12 h. The resulting solution was diluted with 2.6 L of HO. The resulting solution was extracted with 3 × 1 L of dichloromethane, and the aqueous layers were combined. The pH of the solution was adjusted to 8–9 with NaHCO (1 mol / L). The resulting solution was extracted with 3 × 2 L of dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column using THF / PE (1:1). This afforded 53.1 g (59.7%) of 2-[(2R)-1-methylpyrrolidin-2-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine as a brown oil. LC-MS: (ES, m / z): [M+1] + =347. 1 H-NMR: (300MHz, CD3OD , ppm):δ 8.18(d,J=1.0Hz,1H),6.68(d,J=1.0Hz,1H),6.46(s,1H),5.61-5.48(m,2H),3.61-3.49(m,3H),3.23(t, J=7.9Hz,1H),2.46-2.35(m,2H),2.33(s,3H),2.02-1.84(m,3H),0.90(dd,J=8.8,7.4Hz,2H),0.0(s,9H) SFC: Chiralpack IC-3 50 x 3.0 mm, 3 μm; IPA-Hex = 1:1 (20 mM NH3); RT 1.27 (>98% enantiomeric excess)

[0152] Intermediate 2: (R)-2-(1-methylpiperidin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-6-amine

[0153] [ka]

[0154] A 50 mL three-necked round-bottom flask was charged with tert-butyl (2R)-2-(hydroxymethyl)piperidine-1-carboxylate (5.00 g, 23.22 mmol, 1.00 equiv.), DMP (19.70 g, 46.45 mmol, 2.00 equiv.), and DCM (20.00 mL). The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by the addition of NaSO (aq.). The resulting solution was extracted with 2 × 50 mL of dichloromethane, and the organic layers were combined and concentrated. This afforded 4.0 g (80.8%) of tert-butyl (2R)-2-formylpiperidine-1-carboxylate as a brown oil.

[0155] [ka]

[0156] A 50 mL three-necked round-bottom flask was charged with tert-butyl (2R)-2-formylpiperidine-1-carboxylate (4.00 g, 18.755 mmol, 1.00 equiv.), KCO (3.11 g, 22.506 mmol, 1.20 equiv.), and MeOH (12.00 mL). A solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (5.40 g, 0.028 mmol, 1.50 equiv.) in MeOH (6 mL) was then added dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 6 h. The resulting solution was extracted with 2 × 50 mL of petroleum ether, and the organic layers were combined and concentrated. This afforded 2 g (51%) of tert-butyl (2R)-2-ethynylpiperidine-1-carboxylate as a yellow oil. GC-MS: (ES, m / z): [M-81] = 128.

[0157] [ka]

[0158] A 50 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with N-(2-chloro-5-iodopyridin-4-yl)methanesulfonamide (700.0 mg, 2.1 mmol, 1.00 equiv.), tert-butyl (2R)-2-ethynylpiperidine-1-carboxylate (881.11 mg, 4.210 mmol, 2.00 equiv.), CuI (40.09 mg, 0.211 mmol, 0.10 equiv.), TEA (852.02 mg, 8.420 mmol, 4.00 equiv.), DMF (10.00 mL), and Pd(PPh3)2Cl2 (295.5 mg, 0.421 mmol, 0.20 equiv.). The resulting solution was stirred at 55 °C for 2 h. The solids were filtered off, and the resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:10), which gave 540 mg (62%) of tert-butyl (2R)-2-[6-chloro-1-methanesulfonylpyrrolo[3,2-c]pyridin-2-yl]piperidine-1-carboxylate as a brown solid. LC-MS: (ES, m / z): [M+H] = 414

[0159] [ka]

[0160] A 50 mL round-bottom flask was charged with tert-butyl (2R)-2-[6-chloro-1-methanesulfonylpyrrolo[3,2-c]pyridin-2-yl]piperidine-1-carboxylate (430.00 mg) in ethyl acetate (10.00 mL) and HCl (gas). The resulting solution was stirred at room temperature for 6 hours. The resulting mixture was concentrated. This afforded 380 mg of (2R)-2-[6-chloro-1-methanesulfonylpyrrolo[3,2-c]pyridin-2-yl]piperidine hydrochloride as a brown solid. LC-MS:(ES,m / z):[M+H-HCl]=314.

[0161] [ka]

[0162] A 100 mL three-necked round-bottom flask was charged with (2R)-2-[6-chloro-1-methanesulfonylpyrrolo[3,2-c]pyridin-2-yl]piperidine hydrochloride (380.0 mg, 1.089 mmol, 1.00 equiv), DCM (20.00 mL), MeOH (10.00 mL), paraformaldehyde (488.63 mg, 5.43 mmol, 5.00 equiv), and NaBH(OAc)3 (2299.37 mg, 10.85 mmol, 10.00 equiv). The resulting solution was stirred at room temperature for 12 hours. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2 × 30 mL of dichloromethane, and the organic layers were combined and concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:1). This gave 201 mg (56.5%) of (2R)-2-[6-chloro-1-methanesulfonylpyrrolo[3,2-c]pyridin-2-yl]-1-methylpiperidine as a white solid. LC-MS: (ES, m / z): [M+H] = 328.

[0163] [ka]

[0164] A 50 mL round-bottom flask was charged with (2R)-2-[6-chloro-1-methanesulfonylpyrrolo[3,2-c]pyridin-2-yl]-1-methylpiperidine (185.00 mg, 0.564 mmol, 1.00 equiv), NaOH (67.71 mg, 0.000 mmol, 3.00 equiv), HO (1.00 mL), and MeOH (5.00 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting solution was extracted with 2 × 20 mL of ethyl acetate, and the organic layers were combined and concentrated. This afforded 120 mg (85.2%) of (2R)-2-[6-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl]-1-methylpiperidine as a brown solid. LC-MS: (ES, m / z): [M+H]=250.

[0165] [ka]

[0166] A 50 mL three-necked round-bottom flask was charged with (2R)-2-[6-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl]-1-methylpiperidine (120.0 mg, 0.480 mmol, 1.00 equiv.), CsCO (469.7 mg, 1.44 mmol, 3.00 equiv.), DMF (5.00 mL), and SEM-Cl (120.16 mg, 0.720 mmol, 1.50 equiv.). The resulting solution was stirred at room temperature for 2 h. The solids were filtered, and the resulting solution was extracted with 2 × 20 mL of ethyl acetate. The organic layers were combined and concentrated. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:2). This gave 85 mg (46.6%) of (2R)-2-(6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-2-yl)-1-methylpiperidine as a light brown oil. LC-MS: (ES, m / z): [M+H] = 380.

[0167] [ka]

[0168] In an 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen, add 2-(6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-octahydropyrrolo[3,2-c]pyridin-2-yl)-1-methylpiperidine (80.00 mg, 0.206 mmol, 1.00 equiv.), diphenylmethanimine (112.09 mg, 0.618 mmol, 3.00 equiv.), t-BuONa (59.43 mg, 0.618 mmol, 3.00 equiv.), toluene (3.00 mL), Pd(dba) 3.CHCl3 (23.71 mg, 0.041 mmol, 0.20 equiv.) and BINAP (51.35 mg, 0.082 mmol, 0.40 equiv.) were added. The resulting solution was stirred at 100 °C for 5 h. The resulting mixture was concentrated. This afforded 100 mg (crude) of N-[2-[(2R)-1-methylpiperidin-2-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl]-1,1-diphenylmethanimine as a brown oil. LC-MS: (ES, m / z): [M+H] = 525.

[0169] [ka]

[0170] A 50 mL round-bottom flask was charged with N-[2-[(2R)-1-methylpiperidin-2-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl]-1,1-diphenylmethanimine (100.00 mg, 0.191 mmol, 1.00 equiv), THF (5.00 mL), and HCl (5.00 mL). The resulting solution was stirred at room temperature for 16 hours and extracted with 2 × 20 mL of ethyl acetate. The organic layers were then combined and concentrated. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:1). This gave 44 mg (34% over two steps) of 2-[(2R)-1-methylpiperidin-2-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine as a brown solid. The product was further purified by SFC using the following conditions: Column: Lux 5 μm Amylose-1, 5 × 25 cm, 10 μm; Mobile phase A: CO, Mobile phase B: IPA (0.5% 2M NH-MeOH); Flow rate: 160 mL / min; Gradient: Isocratic 40% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 4.47; RT2 (min): 5.89; Sample solvent: ACN; Injection volume: 2 mL; and the major enantiomer recovered to give material: >98% enantiomeric excess. LC-MS: (ES, m / z): [M+H] = 361 1 H-NMR (300MHz, methanol-d4, ppm):δ 8.23-8.17(m,1H),6.68(s,1H),6.47(s,1H),3.56(t,J=8.2Hz,2H),3.08(d,J=11.9Hz,1H),2.24(d,J=14.1Hz,1H), 2.15(s,3H),1.97-1.68(m,5H),1.48(d,J=10.5Hz,1H),1.17(d,J=6.2Hz,3H),0.91(t,J=8.1Hz,2H),-0.22(s,9H).

[0171] Acid 1: 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid

[0172] [ka]

[0173] A 40 mL vial purged and maintained with an inert atmosphere of nitrogen was charged with methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (1.00 g, 3.801 mmol, 1.00 equiv.), dioxane (20.00 mL), 4-bromo-1-(oxan-2-yl)pyrazole (0.97 g, 4.181 mmol, 1.1 equiv.), Pd(dppf)Cl (0.28 g, 0.380 mmol, 0.1 equiv.), and KPO (2.42 g, 11.403 mmol, 3 equiv.). The reaction mixture was stirred under a nitrogen atmosphere in an oil bath at 100 °C for 5 h and concentrated in vacuo. The residue was diluted with 30 mL of HO and extracted with 3 × 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:1). This afforded 800 mg (73.3%) of methyl 5-[1-(oxan-2-yl)pyrazol-4-yl]pyridine-2-carboxylate as a yellow solid. LC-MS: (ES, m / z): [M+H]+ =288

[0174] [ka]

[0175] A 50 mL round-bottom flask was charged with methyl 5-[1-(oxan-2-yl)pyrazol-4-yl]pyridine-2-carboxylate (800 mg, 2.784 mmol, 1.00 equiv.), CHOH (16 mL), HO (5 mL), and sodium hydroxide (330 mg, 8.251 mmol, 2.96 equiv.). The resulting solution was stirred at room temperature for 16 hours and concentrated under vacuum. The residue was diluted with 30 mL of HO and extracted with 2 × 20 mL of ethyl acetate, and then the aqueous layers were combined. The pH of the solution was adjusted to 3 with HCl (3 mol / L). The resulting solid was collected by filtration to give 600 mg (78.85%) of 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid as a pale yellow solid. LC-MS: (ES, m / z): [M+H] + =274

[0176] Acid 2: 4-[5-(methoxymethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl]benzoic acid

[0177] [ka]

[0178] A solution of methyl 4-bromo-2H-pyrazole-3-carboxylate (3.0 g, 14.633 mmol, 1 equiv) in DMF (30 mL) was treated with NaH (900 mg, 37.503 mmol, 2.56 equiv) under a nitrogen atmosphere at 0 °C for 10 min, followed by the dropwise addition of [2-(chloromethoxy)ethyl]trimethylsilane (3.7 g, 22.193 mmol, 1.52 equiv) at 0 °C. The mixture was stirred at room temperature for 4 h. The reaction was quenched by adding water (20 mL) at 0 °C. The resulting mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with NaCl (aq) (50 mL × 3), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE=3 / 1 to give methyl 4-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (3.5 g, 64.20%) as a yellow solid. LC-MS(ES,m / z):[M+1] + =335.1,337.1

[0179] [ka]

[0180] To a solution of LiAlH4 (400 mg, 10.540 mmol, 2.94 equiv.) in THF (10 mL, 123.428 mmol, 34.48 equiv.) under a nitrogen atmosphere was added methyl 4-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (1.2 g, 3.579 mmol, 1 equiv.) in THF dropwise at −78°C. The mixture was stirred at −78°C to 0°C for 4 h. The reaction was quenched at −30°C by the addition of water / NaOH, filtered, and the filter cake was washed with EA. The filtrate was extracted with EA (20 mL × 3). The combined organic layers were washed with NaCl (aq.), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE=1 / 2 to give (4-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-yl)methanol (270 mg, 22%) as a yellow oil. LC-MS(ES,m / z):[M+1] + =306.9,308.9

[0181] [ka]

[0182] To a solution of (4-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-yl)methanol (250 mg, 0.814 mmol, 1 equiv) in THF was added sodium hydride (60% in oil, NaH (25 mg, 1.042 mmol, 1.28 equiv) mg) at 0 °C. The mixture was stirred at 0 °C for 15 min. CHCl (200 mg, 1.409 mmol, 1.73 equiv) was added, and the mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with DCM (3 × 25 mL). The residue was purified by silica gel column chromatography eluting with EA / PE = 1 / 4 to give 4-bromo-5-(methoxymethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole (200 mg, 68.86%) as a yellow oil. LC-MS(ES,m / z):[M+1] +=321.2,323.2

[0183] [ka]

[0184] To a solution of 4-bromo-5-(methoxymethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole (200 mg, 0.622 mmol, 1 equiv.) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (250 mg, 0.954 mmol, 1.53 equiv.) in dioxane (8 mL, 94.432 mmol, 151.70 equiv.) and water (0.8 mL, 44.407 mmol, 71.34 equiv.) was added KCO (250 mg, 1.809 mmol, 2.91 equiv.) and Pd(dppf)Cl (20 mg, 0.027 mmol, 0.04 equiv.). After stirring at 80 °C under a nitrogen atmosphere for 6 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC / silica gel column chromatography eluting with EA / PE=1 / 3 to give methyl 4-[5-(methoxymethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl]benzoate (150 mg, 57.6%) as a yellow solid. LC-MS(ES,m / z):[M+1] + =377.2

[0185] [ka]

[0186] To a solution of methyl 4-[5-(methoxymethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl]benzoate (150 mg, 0.398 mmol, 1 equiv) in THF (8 mL, 98.742 mmol, 247.86 equiv) and water (1 mL, 55.509 mmol, 139.34 equiv), LiOH (100 mg, 4.175 mmol, 10.48 equiv) was added. The mixture was stirred at room temperature for 16 h and acidified to pH 5 with oxalic acid. The resulting mixture was extracted with EA (20 mL × 3). The combined organic layers were washed with NaCl (aq), dried over anhydrous NaSO, and the filtrate was concentrated under reduced pressure to give 4-[5-(methoxymethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl]benzoic acid (100 mg, 58.86%) as a yellow solid. LC-MS(ES,m / z):[M+1] + =363.2

[0187] Example 1: N-(2-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-5-(1H-pyrazol-4-yl)picolinamide (Sample 1)

[0188] [ka]

[0189] To a solution of 6-chloro-2-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridine (550 mg, 1.346 mmol, 1.00 equiv.) and trimethyl-1,3,5,2,4,6-trioxatriborinane (1.69 g, 13.460 mmol, 10 equiv.) in DMF (2 mL) was added KCO (557.91 mg, 4.038 mmol, 3 equiv.) and Pd(dppf)Cl.CHCl (109.62 mg, 0.135 mmol, 0.1 equiv.). After stirring at 80 °C under a nitrogen atmosphere for 60 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give 6-chloro-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridine (296 mg, 74.10%) as a yellow solid.

[0190] [ka]

[0191] To a solution of 6-chloro-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridine (290 mg, 0.977 mmol, 1.00 equiv.) and diphenylmethanimine (531.13 mg, 2.931 mmol, 3 equiv.) in toluene (2 mL) and BINAP (121.65 mg, 0.195 mmol, 0.2 equiv.), t-BuONa (281.64 mg, 2.931 mmol, 3 equiv.) and Pd(dba)CHCl (101.11 mg, 0.098 mmol, 0.10 equiv.) were added. After stirring at 100 °C under a nitrogen atmosphere for 16 h, the resulting mixture was cooled and concentrated under reduced pressure. The reaction was diluted with water at room temperature. The resulting mixture was extracted with CHCl (2 × 50 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give N-(2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl)-1,1-diphenylmethanimine (300 mg, 41.72%) as a brown oil. The crude product / resulting mixture was used directly in the next step without further purification. LC-MS: (ES, m / z): [M+H] = 442

[0192] [ka]

[0193] To a stirred solution of N-(2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl)-1,1-diphenylmethanimine (300 mg, 0.408 mmol, 1.00 equiv, 60%) in THF (5 mL) was added HCl 1.0 M (2.45 mL, 2.448 mmol, 6 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for 16 h and extracted with THF (2 × 30 mL). The aqueous layer was basified to pH 7 with saturated NaHCO (aq) and extracted with CHCl (2 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. The filtrate was concentrated under reduced pressure. This gave 2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-amine (180 mg, crude) as a brown solid. LC-MS: (ES, m / z): [M+H] = 278

[0194] [ka]

[0195] To a stirred solution of 2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-amine (60 mg, 0.216 mmol, 1.00 equiv.) and 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid (acid 1, 59.10 mg, 0.216 mmol, 1.0 equiv.) in pyridine (1 mL) was added EDCI (82.92 mg, 0.432 mmol, 2.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give N-(2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl)-5-[1-(oxan-2-yl)pyrazol-4-yl]pyridine-2-carboxamide (120 mg, crude) as a brown solid. LC-MS: (ES, m / z): [M+H] = 533

[0196] [ka]

[0197] To a stirred solution of N-(2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl)-5-[1-(oxan-2-yl)pyrazol-4-yl]pyridine-2-carboxamide (120 mg, crude) in DCM (1 mL) was added CF3COOH (0.80 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 16 h and concentrated in vacuo. The residue was basified to pH 7 with NH4OH (aq). The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% NH3HO) and ACN (41% phase B, up to 54% in 7 min); detector, UV 254 nm) to give N-{2-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl}-5-(1H-pyrazol-4-yl)pyridine-2-carboxamide (17.8 mg) as a pale yellow solid. LC-MS: (ES, m / z): [M+H] = 319 H-NMR (400 MHz, DMSO-d 6, ppm)δ 13.22(s,1H),11.39(s,1H),10.26(s,1H),9.05(d,J=0.8Hz,1H),8.46(s ,1H),8.35-8.18(m,4H),8.18(d,J=8.0Hz,1H),6.24(s,1H),2.40(s,3H).

[0198] Example 2: (R)—N-(2-(1-methylpyrrolidin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-5-(1H-pyrazol-4-yl)picolinamide (Sample 2)

[0199] [ka]

[0200] An 8 mL vial purged and maintained with an inert atmosphere of nitrogen was charged with 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid (acid 1, 80 mg, 0.293 mmol, 1.00 equiv.), pyridine (4 mL), EDCI (84.17 mg, 0.440 mmol, 1.5 equiv.), and 2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-amine (Intermediate 1, 101.44 mg, 0.293 mmol, 1 equiv.). The resulting solution was stirred at room temperature for 16 h and concentrated in vacuo. The residue was diluted with 20 mL of HO and extracted with 3 × 10 mL of ethyl acetate, then the organic layers were combined and washed with 2 × 10 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give 130 mg (73.79%) of N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}-5-[1-(oxan-2-yl)pyrazol-4-yl]pyridine-2-carboxamide as a brown oil. LC-MS: (ES, m / z): [M+H] + =602

[0201] [ka]

[0202] A 50 mL round-bottom flask was charged with N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}-5-[1-(oxan-2-yl)pyrazol-4-yl]pyridine-2-carboxamide (130 mg, 0.216 mmol, 1.00 equiv.), DCM (4.00 mL), and CF3COOH (4.00 mL). The resulting solution was stirred at room temperature for 16 hours and concentrated in vacuo. The resulting solution was diluted with 4 mL of DMF. The pH of the mixture was adjusted to 8 with NH3 / HO. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% NH H O) and ACN (15% Phase B, up to 31% in 7 min); detector, UV 254 nm. This afforded 22.2 mg (26.53%) of N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1H-pyrrolo[3,2-c]pyridin-6-yl}-5-(1H-pyrazol-4-yl)pyridine-2-carboxamide as a yellow solid. LC-MS: (ES, m / z): [M+H] + =388 1 H-NMR: (300 MHz, methanol-d 4, ppm)δ 8.99(s,1H),8.51(d,J=0.9Hz,1H),8.38(s,1H),8.23(m,4H),6.52(s,1H),3. 43(t,J=7.8Hz,1H),3.24-3.19(m,1H),2.41-2.27(m,5H),1.89-2.07(m,3H).

[0203] Example 3: (S)—N-(2-(1-methylpyrrolidin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-5-(1H-pyrazol-4-yl)picolinamide (Sample 3)

[0204] [ka]

[0205] To an 8 mL vial were added 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid (acid 1, 60 mg, 0.220 mmol, 1.00 equiv.), pyridine (4 mL), 2-[(2S)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-amine (prepared according to Intermediate 1 using tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate in Step 3, 76.08 mg, 0.220 mmol, 1 equiv.), and EDCI (63.13 mg, 0.330 mmol, 1.5 equiv.) at room temperature. The resulting solution was stirred at room temperature for 16 hours and concentrated in vacuo. The reaction mixture was diluted with 20 mL of HO and extracted with 3 × 10 mL of ethyl acetate. The organic layers were combined and then washed with 2 × 10 mL of brine. The solution was dried over anhydrous sodium sulfate and concentrated in vacuo. This afforded N-{2-[(2S)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}-5-[1-(oxan-2-yl)pyrazol-4-yl]pyridine-2-carboxamide (80 mg, crude) as a brown oil. LC-MS: (ES, m / z): [M+H] + =602

[0206] [ka]

[0207] A 50 mL round-bottom flask was charged with N-{2-[(2S)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}-5-[1-(oxan-2-yl)pyrazol-4-yl]pyridine-2-carboxamide (80 mg), DCM (4 mL), and CF3COOH (4 mL). The resulting solution was stirred at room temperature for 16 hours and concentrated in vacuo. The residue was diluted with 4 mL of DMF. The pH of the solution was adjusted to 8 with NH3 / HO. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% NH H O) and ACN (15% Phase B, up to 31% in 7 min); detector, UV 254 nm, to afford N-{2-[(2S)-1-methylpyrrolidin-2-yl]-1H-pyrrolo[3,2-c]pyridin-6-yl}-5-(1H-pyrazol-4-yl)pyridine-2-carboxamide (7.8 mg, 15.14%) as a pale yellow solid. LC-MS: (ES, m / z): [M+H] + =388 1 H-NMR: (300 MHz, methanol-d 4, ppm)δ 8.98(s,1H),8.49(s,1H),8.38(s,1H),8.25-8.20(m,4H),6.51(s,1H),3.43(t,J=7.8Hz,1H ),3.28-3.16(m,1H),2.43-2.34(m,1H),2.29(s,3H),2.30-2.21(m,1H),2.09-1.94(m,3H).

[0208] Example 4: (R)-2-fluoro-N-(2-(1-methylpyrrolidin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1H-pyrazol-4-yl)benzamide (Sample 4)

[0209] [ka]

[0210] Into an 8 mL vial purged and maintained with an inert atmosphere of nitrogen was added 2-fluoro-4-[1-(oxan-2-yl)pyrazol-4-yl]benzoic acid (benzoic acid, 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-, methyl ester and -bromo-1-(oxan-2-yl)pyrazole, 100 mg, 0.344 mmol, A mixture of 2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-amine (Intermediate 1, 95.50 mg, 0.275 mmol, 0.8 equiv.) and EDCI (198.11 mg, 1.032 mmol, 3 equiv.) was added to a flask containing 20 mL of HO and 3 mL of ethyl acetate. The resulting solution was stirred at room temperature for 16 hours and concentrated in vacuo. The resulting solution was diluted with 20 mL of HO and extracted with 3 × 10 mL of ethyl acetate, and the organic layers were then combined. The solution was washed with 2 × 10 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This gave 2-fluoro-N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}-4-(1H-pyrazol-4-yl)benzamide (100 mg, crude) as a brown oil. LC-MS: (ES, m / z): [M+H] + =535

[0211] [ka]

[0212] A 50 mL round-bottom flask was charged with 2-fluoro-N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}-4-(1H-pyrazol-4-yl)benzamide (100 mg, crude), DCM (4.00 mL), and CF3COOH (4.00 mL). The resulting solution was stirred at room temperature for 20 hours and concentrated in vacuo. The residue was diluted with 4 mL of DMF, and the pH of the solution was adjusted to 8 with NH3HO. The crude product (60 mg) was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% NH H O) and ACN (15% Phase B, up to 31% in 7 min); detector, UV 254 nm, to give 2-fluoro-N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1H-pyrrolo[3,2-c]pyridin-6-yl}-4-(1H-pyrazol-4-yl)benzamide (19.4 mg) as a white solid. LC-MS: (ES, m / z): [M+H] + =405 1 H-NMR: (300 MHz, methanol-d 4, ppm)δ 8.49(d,J=0.9Hz,1H),8.29(s,1H),8.21-8.05(m,2H),7.97(t,J=8.1Hz,1H),7.65-7.51(m,2H ),6.51(s,1H),3.43(t,J=7.9Hz,1H),3.25-3.20(m,1H),2.43-2.24(m,5H),2.07-1.94(m,3H). F-NMR: (282MHz, methanol-d 4, ppm)δ-114.965

[0213] Example 5: (R)—N-(2-(1-methylpyrrolidin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1H-pyrazol-4-yl)benzamide (Sample 5)

[0214] [ka]

[0215] To a stirred solution of 4-[1-(oxan-2-yl)pyrazol-4-yl]benzoic acid (prepared according to WO 2021 / 127166, Acid AG, 50 mg, 0.184 mmol, 1.00 equiv.) and 2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-amine (Intermediate 1, 63.63 mg, 0.184 mmol, 1.0 equiv.) in pyridine (2 mL), EDCI (70.40 mg, 0.368 mmol, 2.0 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature for 16 hours and concentrated in vacuo. This gave N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}-4-[1-(oxan-2-yl)pyrazol-4-yl]benzamide (100 mg, crude) as a brown oil. LC-MS: (ES, m / z): [M+H] = 601

[0216] [ka]

[0217] To a stirred solution / mixture of N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}-4-[1-(oxan-2-yl)pyrazol-4-yl]benzamide (100 mg, crude) in DCM was added CF3COOH (2 mL, 26.926 mmol, 161.78 equiv) at room temperature. The resulting mixture was stirred at room temperature for 20 hours. The resulting mixture was concentrated in vacuo. The residue was basified to pH 8 with NH4OH (aq). The crude product was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 19 × 150 mm, 5 μm; mobile phase, water (0.05% NH H O) and ACN (18% ACN, up to 35% in 8 min); detector, UV 254 nm) to give N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1H-pyrrolo[3,2-c]pyridin-6-yl}-4-(1H-pyrazol-4-yl)benzamide (30.6 mg, 43.1% over two steps) as a pale yellow solid. LC-MS: (ES, m / z): [M+H] = 387 H-NMR:(400MHz,CD3OD-d4,ppm):δ 8.51(s,1H),8.19(s,1H),8.09(s,2H),8.01(d,J=8.0Hz,2H),7.77(d,J=8.0Hz,2H),6.51(s,1H),3.45(t, J=8.0Hz,1H),3.27-3.22(m,1H),2.42(q,J=8.8Hz,1H),2.31(s,3H),2.32-2.24(m,1H),2.09-1.89(m,3H).

[0218] Example 6: (R)—N-(2-(1-methylpiperidin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1H-pyrazol-4-yl)benzamide (Sample 6)

[0219] [ka]

[0220] To an 8 mL vial, 4-[1-(oxan-2-yl)pyrazol-4-yl]benzoic acid (prepared according to WO 2021 / 127166, Acid AG, 50 mg, 0.184 mmol, 1 equiv.) and EDCI (42.24 mg, 0.221 mmol, 1.2 equiv.) in pyridine (5 mL) were added at room temperature. The resulting mixture was stirred for 10 minutes. To the above mixture, 2-[(2R)-1-methylpiperidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-amine (Intermediate 2, 66.21 mg, 0.184 mmol, 1 equiv.) was added. The resulting mixture was stirred for an additional 16 h, and the crude product was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase: 0.05% NH3.HO in water, MeCN 5% to 60% gradient over 10 min; detector: UV 220 nm) to afford N-{2-[(2R)-1-methylpiperidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}-4-[1-(oxan-2-yl)pyrazol-4-yl]benzamide (79 mg, 69.97%) as a white solid. LC-MS(ES,m / z):[M+1] + =615.3

[0221] [ka]

[0222] To an 8 mL vial was added N-{2-[(2R)-1-methylpiperidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}-4-[1-(oxan-2-yl)pyrazol-4-yl]benzamide (79 mg, 0.128 mmol, 1 equiv.) in DCM (5 mL), and trifluoroacetic acid (1 mL) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 1 h and concentrated under reduced pressure. The residue was dissolved in DMF (1 mL) and adjusted to pH 10 with NH3.HO. The crude product (50 mg) was purified by preparative HPLC under the following conditions: 0.1% NH3.HO in water and MeCN (20%, up to 60% in 8 min) to give N-{2-[(2R)-1-methylpiperidin-2-yl]-1H-pyrrolo[3,2-c]pyridin-6-yl}-4-(1H-pyrazol-4-yl)benzamide (10.3 mg, 20.02%) as a white solid. LC-MS(ES,m / z):[M+1] + =401 1 H-NMR: 1 H NMR(400MHz, methanol-d4)δ 8.55(s,1H),8.21(s,1H),8.17(m,2H),8.04(d,J=8.4Hz,2H),7.79(d,J=8.3Hz,2H),6.52(s,1H),3.18(m, 1H),3.09(s,1H),2.25-2.18(s,1H),2.12(s,3H),2.03-1.83(m,3H),1.79-1.56(m,2H),1.49-1.38(m,1H).

[0223] Example 7: (R)—N-(2-(1-methylpiperidin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-5-(1H-pyrazol-4-yl)picolinamide (Sample 7)

[0224] [ka]

[0225] To an 8 mL vial, 5-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid (acid 1, 50 mg, 0.183 mmol, 1 equivalent) and EDCI (42.09 mg, 0.220 mmol, 1.2 equivalents) in pyridine (1 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 10 minutes. To the above mixture, 2-[(2R)-1-methylpiperidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-amine (intermediate 2, 65.97 mg, 0.183 mmol, 1 equivalent) was added. The resulting mixture was stirred at room temperature for an additional 16 hours. The crude product was purified by reverse-phase flash chromatography (C18 silica gel column; mobile phase: 0.05% NH3HO in water, MeCN gradient from 5% to 60% over 10 min; detector: UV 220 nm) to afford N-{2-[(2R)-1-methylpiperidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}-5-[1-(oxan-2-yl)pyrazol-4-yl]pyridine-2-carboxamide (100 mg, 88.75%) as a white solid.

[0226] [ka]

[0227] To an 8 mL vial was added N-{2-[(2R)-1-methylpiperidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}-5-[1-(oxan-2-yl)pyrazol-4-yl]pyridine-2-carboxamide (100 mg, 0.162 mmol, 1 equiv.) in DCM (10 mL) and trifluoroacetic acid (3 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 1 h and concentrated under reduced pressure. The residue was diluted with DMF (1 mL), adjusted to pH 10 with NH.HO, and the crude product (50 mg) was purified by preparative HPLC using the following conditions: 0.1% NH.HO in water and MeCN (20%, up to 60% in 8 min) to give N-{2-[(2R)-1-methylpiperidin-2-yl]-1H-pyrrolo[3,2-c]pyridin-6-yl}-5-(1H-pyrazol-4-yl)pyridine-2-carboxamide (14.3 mg, 21.94%) as a white solid. LC-MS(ES,m / z):[M+1] + =402.2 1 H-NMR 1 H NMR(400MHz, methanol-d4)δ 9.02(s,1H),8.54(s,1H),8.30(s,1H),8.21-8.16(m,3H),8.10(m,1H),6.57(s,1H),3.18(m,1H),3. 03(m,1H),2.37(m,1H),2.23-2.18(s,3H),1.96-1.92(m,3H),1.72-1.84(m,2H),1.60-1.53(m,1H).

[0228] Example 8: (R)-4-(5-(methoxymethyl)-1H-pyrazol-4-yl)-N-(2-(1-methylpyrrolidin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (Sample 8)

[0229] [ka]

[0230] A mixture of 4-[5-(methoxymethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl]benzoic acid (acid 2, 50 mg, 0.138 mmol, 1 equiv.) and 2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-amine (intermediate 1, 75 mg, 0.216 mmol, 1.57 equiv.) and EDCI (50 mg, 0.261 mmol, 1.89 equiv.) in pyridine (3 mL, 0.038 mmol, 0.27 equiv.) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give 4-[5-(methoxymethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl]-N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}benzamide (60 mg), which was used directly in the next step. LC-MS(ES,m / z):[M+1] + =691.3

[0231] [ka]

[0232] To a solution of 4-[5-(methoxymethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl]-N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}benzamide (60 mg, 0.087 mmol) in DCM (6 mL) was added trifluoroacetic acid (2 mL, 0.009 mmol, 0.10 equiv) at room temperature. The resulting mixture was stirred for 1 h and concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm, 10 nm; mobile phase, water (0.1% NH3HO) and ACN (28% ACN, up to 63% in 9 min); total flow rate, 20 mL / min; detector, UV 220 nm. This afforded (R)-4-(5-(methoxymethyl)-1H-pyrazol-4-yl)-N-(2-(1-methylpyrrolidin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (28.6 mg, 75.1%) as a white solid. LC-MS(ES,m / z):[M+1]+=431.3 1H NMR(400MHz,DMSO-d6)δ 8.50(d,J=1.1Hz,1H),8.18(s,1H),8.02(m,3H),7.72(m,2H),6.50(s,1H),4.58(s,2H),3. 41(m,4H),3.21(t,J=7.5Hz,1H),2.38(m,1H),2.28(m,4H),2.02(m,2H),1.95-1.86(m,1H).

[0233] Example 9: (R)-4-(5-fluoro-1H-pyrazol-4-yl)-N-(2-(1-methylpyrrolidin-2-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (Sample 9)

[0234] [ka]

[0235] A 40 mL vial was charged with 4-bromo-3-fluoro-2H-pyrazole (100 mg, 0.606 mmol, 1 equiv.), [2-(chloromethoxy)ethyl]trimethylsilane (151.60 mg, 0.909 mmol, 1.5 equiv.), NaH (29.09 mg, 1.212 mmol, 2.0 equiv.), and THF (1 mL). The resulting solution was stirred at 25 °C for 4 h. The reaction was monitored by LCMS. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, water (0.1% FA) and ACN (5.0% ACN up to 45.0% in 7 min); total flow rate, 20 mL / min; detector, UV 220 nm. The collected fractions were combined and concentrated under vacuum. This gave 4-bromo-5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole (110 mg, 37.49%) as a pale yellow oil.

[0236] [ka]

[0237] An 8 mL vial was charged with 4-bromo-5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole (100 mg, 0.339 mmol, 1 equiv.), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (115.42 mg, 0.441 mmol, 1.3 equiv.), Pd(dppf)Cl (12.39 mg, 0.017 mmol, 0.05 equiv.), KCO (117.03 mg, 0.848 mmol, 2.5 equiv.), dioxane (1 mL), and HO (0.1 mL). The resulting solution was stirred at 105 °C for 16 h. The reaction was cooled, diluted with water, and extracted with EA. The organic layer was washed with brine, dried over NaSO, and concentrated in vacuo. The residue was applied to a silica gel column and eluted with ethyl acetate / hexane (1 / 5). The collected fractions were combined and concentrated in vacuo to give methyl 4-(5-fluoro-1-{[(trimethylsilyl)methoxy]methyl}pyrazol-4-yl)benzoate (71 mg, 60.2%) as an off-white solid.

[0238] [ka]

[0239] Methyl 4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)benzoate (70 mg, 0.200 mmol, 1 equiv.), 2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-amine (Intermediate 1, 69.22 mg, 0.200 mmol, 1.0 equiv.), and THF (1 mL) were added to an 8 mL vial and stirred. LiHMDS (200.53 mg, 1.200 mmol, 6.0 equiv.) was added dropwise in an ice-water bath and then stirred for 5 minutes. The reaction was warmed to room temperature and stirred for 2 hours. The reaction was then quenched by the addition of 50 mL of NH4Cl (aq.) and extracted with EA. The resulting mixture was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}benzamide (90 mg, 67.8%) as a brown oil. LC-MS(ES,m / z):[M+1] + =665

[0240] [ka]

[0241] An 8 mL vial was charged with 4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-c]pyridin-6-yl}benzamide (70 mg, 0.105 mmol, 1 equiv.), ethylenediamine (126.53 mg, 2.100 mmol, 20 equiv.), TBAF (412.85 mg, 1.575 mmol, 15 equiv.), and DMF (1 mL). The resulting solution was stirred at 70° C. for 8 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (Preparative HPLC-013) under the following conditions: column, SunFire Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase, water (0.1% FA) and ACN (5.0% ACN to 45.0% in 7 min); total flow rate, 20 mL / min; detector, UV 220 nm. Lyophilization afforded 4-(3-fluoro-2H-pyrazol-4-yl)-N-{2-[(2R)-1-methylpyrrolidin-2-yl]-1H-pyrrolo[3,2-c]pyridin-6-yl}benzamide (18.5 mg, 42.5%) as a white solid. LC-MS(ES,m / z):[M+1] + =405 H-NMR(400MHz,DMSO-d6)δ 12.73(s,1H),11.38(s,1H),10.44(s,1H),8.51(s,1H),8.33(t,J=2.0Hz,1H),8.21(d,J=1.0Hz,1H),8.14-8.07(m,2H) ,7.73-7.67(m,2H),6.40(s,1H),3.29(s,1H),3.15(t,J=8.0Hz,1H),2.36-2.22(m,1H),2.18(s,4H),1.93-1.80(m,3H).

[0242] Example 10: FRET assay: The compounds of the present invention were tested in a TR-FRET ENL screening assay. TR-FRET (time-resolved fluorescence energy transfer) can be used to quantify ENL YEATS domain binding to crotonylated histone peptides (H3K9cr, aa1-20). Streptavidin-Europium (Eu) chelate binds to the biotinylated peptide, while Anti-6xHIS ULight™ binds to 6xHIS-ENL. When the Eu chelate is excited at 320 nm, fluorescence resonance energy transfer (FRET) occurs when Eu and ULight are brought into close proximity by ENL binding to the acyl-peptide. ULight emission (FRET) is measured at 665 nm and normalized to Eu emission at 615 nm to reduce well-to-well variability.

[0243] FRET assay protocol The compounds of the present invention were dissolved in DMSO at a concentration of 3 mM and subsequently diluted in assay buffer (50 mM HEPES pH 7.0, 150 mM NaCl, 0.05% BSA, 0.2% Pluronic F-127) so that the assay contained 1% DMSO. In a white 384-shallow-well microplate (Proxiplate-384 Plus, PerkinElmer, 6008280), 150 nL of compound or vehicle (1% DMSO in assay buffer) for the high control (HC) wells was combined with 5 μL of 30 nM ENL protein (6xHIS ENL YEATS Domain, EpiCypher, 15-0069) and incubated for 15 minutes at room temperature. 5 μL of assay buffer was added to the low control (LC) wells instead of ENL protein. Next, 5 μL of 15 nM H3K9cr peptide (H3 aa1-20, biotinylated; EpiCypher, 12-0099) in assay buffer was added and incubated for 30 min at room temperature. Finally, 5 μL of a mixture of 45 nM anti-6HIS ULight (PerkinElmer, TRF0105) and 1.5 nM streptavidin-europium chelate (PerkinElmer, AD0060) was added and incubated for another 30 min at room temperature. The TR-FRET signal (665 nm signal / 615 nm signal × 10,000) was measured using a PerkinElmer 2104 EnVision (xenon flash lamp excitation, 320 nm ± 37.5 nm excitation filter, 407 nm cutoff dichroic mirror, 615 nm ± 4.25 nm (europium) and 665 nm ± 3.75 nm (ULight) emission filters). Compound concentration-response curves were performed in duplicate over the concentration range of 0.15 nM to 30 μM. The response at each compound concentration was converted to percent inhibition of the vehicle control response (HC-LC). The relationship between percent inhibition and compound concentration was analyzed using a four-parameter logistic equation to estimate the lower and upper asymptote, the compound concentration producing 50% inhibition (IC50 value), and the slope at the midpoint.

[0244] [Table 2]

[0245] Example 11: Cellular assay A cell-based assay was used to evaluate the ability of test compounds to reduce cell viability in both MV4:11 (MLL-AF4 MLL) and K562 cells cultured in Iscove's modified Dulbecco's medium (Gibco, 12440061) containing 10% FBS. The assay was performed over 12 days, with cells split on days 4 and 8. Compound concentration-response curves were performed in duplicate over a concentration range of 0.15 nM to 30 μM. On day 0, 300 nL of compound or vehicle was directly seeded into 96-well cell culture plates (Corning, 3599) at 5,000 cells / well in a volume of 100 μL. Blank wells contained cell culture medium. Plates were incubated at 37°C and 5% CO for 4 days. Cells were split on days 4 and 8 and incubated for an additional 4 days, during which time aliquots of cells were taken for CTG readings. For cell splitting, 270 nL of compound or DMSO was added to a new 96-well cell culture plate, to which 90 μL of medium and 10 μL of cells from the original assay plate (after mixing) or 100 μL of medium (blank wells) were added. This was repeated on day 8.

[0246] Cell viability was assessed using the CellTiter-Glo® Homogeneous Luminescent Assay Kit (Promega, G9243) according to the manufacturer's instructions. This quantifies ATP, which indicates the presence of metabolically active cells. On days 4, 8, and 12, 20 μl of the remaining cell suspension was aspirated into a 384-well plate (Corning 3570) and an equal volume of CellTiter-Glo reagent was added. The plate was incubated at room temperature for 10 minutes, after which the luminescent signal was recorded using an EnVision plate reader (PE, 2104). The resulting data were analyzed as follows: Inhibition (%) = 100% × (Lum ビヒクル -Lum 試料 ) / (Lumビヒクル -Lum ブランク ) where vehicle is cells treated with 0.3% DMSO and blank is culture medium. IC 50 Measurements were calculated by fitting the curve using XLfit (v5.3.1.3): Y = bottom + (top - bottom) / (1 + 10^((LogIC50-X) x Hill slope)).

[0247] [Table 3]

[0248] Example 12: FLT3 activity

[0249] [Table 4]

[0250] [Table 5]

[0251] Starting from a 10 mM stock solution, each test compound was serially diluted to 10 concentrations by 3-fold dilutions using a TECAN EVO 200. 60 nL of each stock was transferred to a 384 plate using an Echo 550.

[0252] Solution 1 was prepared as per the table above and used to dilute FLT3, ATP, and FL2 stocks to 0.9379 nM (1.33x), 400 μM (4x), and 6 μM (4x), respectively. 15 μL of 25°C FLT3 solution was added to each well, shaken for 1 minute, and pre-incubated with test compound and control for 30 minutes. 5 μL of the ATP and FL-peptide 2 solutions prepared above were added to each well, and the plate was shaken for 10 seconds, then spun briefly at 1000 rpm, and then incubated at room temperature for 90 minutes. The plate was read on a Caliper EZ reader, and IC was calculated using XLfit. 50The value was calculated (following formula): Inhibition % = 100% × (Lum HC -Lum 試料 ) / (Lum HC -Lum LC ) Lum 試料 : Test compound signal Lum LC :Low control signal Lum HC :High control signal

[0253] [Table 6] † Not measured

Claims

1. A compound of formula I, 【Chemical 1】 During the ceremony, R １ and R ２ together to form pyrrolidine or piperidine, R ３ is hydrogen and C １ ~C ８ alkyl, R ４ But C １ ~C ８ Alkyl, C １ ~C １０ Haloalkyl, C ３ ~C ８ carbocycle, C １ ~C １０ Oxaalkyl, —SO ２ (C １～６ ) alkyl, —SO ２ NH (C ０～３ H １～７ ), -CONH(C ０～３ H １～７ ), -SO ２ NH (C １～６ ) Oxaalkyl, —CN, —CH ２ CN, -CH ２ NH ２ , -NH ２ , -NR １４ (In the formula, R １４ are independently hydrogen, (C １～６ ) fluoroalkyl, and (C １～３ ) oxaalkyl), —CH ２ OH, benzyloxy, —C(═NH)—NH ２ , oxo, and one or more R selected from halogen ７ an aromatic 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with a group; R ５ But C １ ~C ８ Alkyl, C １ ~C １０ Haloalkyl, C ３ ~C ８ carbocycle, C １ ~C １０ Oxaalkyl, —SO ２ (C １～６ ) alkyl, —SO ２ NH (C ０～３ H １～７ ), -CONH(C ０～３ H １～７ ), -SO ２ NH (C １～６ ) Oxaalkyl, —CN, —CH ２ CN, -CH ２ NH ２ , -NH ２ , -NR １４ (In the formula, R １４ are independently hydrogen, (C １～６ ) fluoroalkyl, and (C １～３ ) oxaalkyl), —CH ２ OH, benzyloxy, —C(═NH)—NH ２ , oxo, and one or more R selected from halogen ６ A compound of formula I which is a 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with a group.

2. The compound belongs to formula Ia', 【Chemistry 2】 In the formula, R ３ , R ４ , and R ５ 2. The compound of claim 1, wherein: is as defined above for formula I.

3. The compound belongs to formula Ia″, 【Chemistry 3】 In the formula, R ３ , R ４ , and R ５ 2. The compound of claim 1, wherein: is as defined above for formula I.

4. R ４ is R as defined above for formula I ７ is selected from the group consisting of benzene, pyridine, pyrimidine, pyridazine, and pyrazine, optionally substituted with a group; R ５ is R as defined above for formula I ６ 4. The compound of claim 2 or 3, wherein the compound is selected from the group consisting of pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazoline, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, 1,2,3-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, isothiazole, thiazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, furan, and thiophene, optionally substituted with a group.

5. R ３ 5. The compound of claim 2, 3, or 4, wherein is methyl.

6. A compound of formula II, 【Chemistry 4】 During the ceremony, R ８ is hydrogen and C １ ~C ８ alkyl, R ４ But C １ ~C ８ Alkyl, C １ ~C １０ Haloalkyl, C ３ ~C ８ carbocycle, C １ ~C １０ Oxaalkyl, —SO ２ (C １～６ ) alkyl, —SO ２ NH (C ０～３ H １～７ ), -CONH(C ０～３ H １～７ ), -SO ２ NH (C １～６ ) Oxaalkyl, —CN, —CH ２ CN, -CH ２ NH ２ , -NH ２ , -NR １４ (In the formula, R １４ are independently hydrogen, (C １～６ ) fluoroalkyl, and (C １～３ ) oxaalkyl), —CH ２ OH, benzyloxy, —C(═NH)—NH ２ , oxo, and one or more R selected from halogen ７ an aromatic 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with a group; R ５ But C １ ~C ８ Alkyl, C １ ~C １０ Haloalkyl, C ３ ~C ８ carbocycle, C １ ~C １０ Oxaalkyl, —SO ２ (C １～６ ) alkyl, —SO ２ NH (C ０～３ H １～７ ), -CONH(C ０～３ H １～７ ), -SO ２ NH (C １～６ ) Oxaalkyl, —CN, —CH ２ CN, -CH ２ NH ２ , -NH ２ , -NR １４ (In the formula, R １４ are independently hydrogen, (C １～６ ) fluoroalkyl, and (C １～３ ) oxaalkyl), —CH ２ OH, benzyloxy, —C(═NH)—NH ２ , oxo, and one or more R selected from halogen ６ A compound of formula II, which is a 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with a group.

7. R ４ is R as defined above for formula I ７ is selected from the group consisting of benzene, pyridine, pyrimidine, pyridazine, and pyrazine, optionally substituted with a group; R ５ is R as defined above for formula I ６ 7. The compound of claim 6, wherein the compound is selected from the group consisting of pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazoline, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, 1,2,3-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, isothiazole, thiazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, furan, and thiophene, optionally substituted with a group.

8. R ８ The compound according to claim 6 or 7, wherein is methyl.

9. 10. The compound of claim 1 or 6, selected from the group consisting of: 【Chemistry 5】

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and one or more pharmaceutically acceptable carriers.

11. 11. The pharmaceutical composition of claim 10, further comprising one or more therapeutic agents.

12. 12. The pharmaceutical composition of claim 11, wherein the one or more therapeutic agents are selected from the group consisting of a Bcl-2 inhibitor, a cyclin-dependent kinase 4 and 6 (CDK4 / 6 inhibitor), a DNA methyltransferase inhibitor, a histone deacetylase (HDAC) inhibitor, an mTOR inhibitor, a mutant isocitrate dehydrogenase (IDH1 and IDH2) inhibitor, a glucocorticoid, an epigenetic modulator, and a chemotherapeutic agent.

13. A method for treating acute leukemia, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claims 10 to 12 to a subject in need thereof.

14. 14. The method of claim 13, wherein the acute leukemia is acute lymphoblastic leukemia (ALL).

15. 14. The method of claim 13, wherein the acute leukemia is acute myeloid leukemia (AML).

16. The AML may be classified into the following types: minimally differentiated acute myeloid leukemia (M0), acute myeloid leukemia without maturation (M1), acute myeloid leukemia with maturation (M2), acute myeloid leukemia with maturation having t(8;21), acute promyelocytic leukemia (M3) (hypergranular type, microgranular type, etc.) 16. The method of claim 15, wherein the leukemia is a subtype selected from the group consisting of acute myelomonocytic leukemia (M4), acute myelomonocytic leukemia with bone marrow eosinophilia (M4E0), acute monocytic leukemia (M5), acute monoblastic leukemia (M5a), acute monocytic leukemia with maturation (M5b), erythroid / myeloid erythroleukemia (M6a), pure erythroid malignancies (M6b), acute megakaryoblastic leukemia (M7), acute megakaryoblastic leukemia associated with t(1;22), acute basophilic leukemia, acute myelofibrosis (acute myelodysplasia with myelofibrosis), acute leukemia and transient myeloproliferative disorder in Down's syndrome, hypocellular acute myeloid leukemia, and myeloid sarcoma.

17. 14. The method of claim 13, wherein the at least one compound is administered orally.

18. 14. The method of claim 13, wherein the at least one compound is administered 1 to 4 times per day.

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