Pyrrolopyrazine compounds, their preparations, and their therapeutic use

Abstract

Compounds capable of inhibiting ERK5 are provided. Pharmaceutical compositions and their medical uses are also provided, including for use in treating or preventing conditions such as cancer.

Description

[Technical Field]

[0001] Compounds capable of inhibiting ERK5 are provided. Pharmaceutical compositions and their medical uses are also provided, including for use in treating or preventing conditions such as cancer. [Background technology]

[0002] The mitogen-activated protein kinase (MAPK) cascade is a highly conserved cellular pathway that transmits signals from the cell surface to the nucleus. This pathway plays a crucial role in cell proliferation, differentiation, and migration, and is well known to be involved in cancer development. The proteins in this pathway include extracellular signal-regulated kinase (ERK) proteins, among which ERK5 (expressed from the MAPK7 gene) plays a vital role in cell proliferation, as well as in epithelial development and neural differentiation (see, e.g., Nishimoto et al., EMBO Reports (2006) 7(8):782-786). ERK5 is unique among ERK proteins in that it has a transcriptional activation domain (TAD), a nuclear localization signal, and a large C-terminal domain containing two proline-rich regions (see, e.g., Guo et al., Exp Ther Med. (2020) 19:1997-2007). Autophosphorylation of TAD is required for transcriptional activation (see, for example, Morimoto et al., J Biol Chem. (2007) 282(49):35449-35456).

[0003] ERK5 plays a crucial role in regulating cell proliferation and cell cycle progression, for example, through the direct or indirect phosphorylation of MEF2C, cMYC, SGK1, RSK, FOS, and FRA1 (see, e.g., Paudel et al., Int J Mol Sci. (2021) 22:7594-7614; Terasawa et al., Genes to Cells (2003) 8(3):263-273). The involvement of ERK5 in numerous biological pathways suggests that its activity is associated with many aspects of cancer progression, including tumor angiogenesis, metastasis, inflammation, persistent proliferation, and evasion of growth inhibition. Therefore, it presents an attractive target for modulating disease pathology and treatment under a wide range of conditions. Previous studies have shown that ERK5 inhibition or downregulation is necessary, among other things, to block tumorigenesis in mouse leukemia cells, reduce the proliferation of chronic myeloid leukemia cells, inhibit the proliferation of breast cancer and multiple myeloma cells, suppress colon cancer cell proliferation, and affect the proliferation or survival of renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, and hepatocellular carcinoma cells (see, for example, Stecca et al., Int J Mol Sci. (2019) 20:1426-1446).

[0004] Therefore, ERK5 inhibition represents a promising approach to address a wide range of cancers. Several ERK5 inhibitors have been developed, and some are currently undergoing clinical review. For example, International Publication No. 2019 / 170543 (Bayer AG and Bayer Pharma AG) discloses compounds that are said to be active as ERK5 inhibitors in the μM to nM concentration range. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] Despite recent advances in cancer treatment through the development of targeted chemotherapy and immunotherapy, an efficient treatment solution cannot be provided for all cancer patients. Therefore, there is a need to identify and develop new drugs. The present disclosure aims to address this need by providing novel compounds for use as ERK5 inhibitors and novel compounds for the treatment of ERK5-related diseases and conditions.

Means for Solving the Problems

[0006] Therefore, a first aspect provides a compound of formula (I)

Chem.

[0007] In this embodiment, R 1 teeth, [ka] Selected from, in the formula, R 1 However, as previously defined, R A It is optionally replaced by the appearance of one or two of the following. In the embodiment, each R A The group is independently selected from the group consisting of -F, -OH, methyl, -OCH3, and cyclopropyl.

[0008] In the embodiment, the compound is a compound of formula (IG). [ka] or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , L 1 , and n are as previously defined.

[0009] Another embodiment is a compound of formula (II). [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula, R 1 However, R is selected from -(C1-C6)alkyl, -(C3-C7)cycloalkyl, and 4-10 member heterocycloalkyl. 1 However, RA It is optionally replaced by one or more occurrences of Each R A However, independently selected from halo (e.g., -F), -OH, -(C1-C3)alkyl, -O(C1-C3)alkyl, and -(C3-C6)cycloalkyl, R 2 However, -(C3-C6)cycloalkyl and -(C6-C 10 ) Selected from the aryl, R 2 However, R B It is optionally replaced by one or two occurrences of Each R B However, independently selected from halo, -NH2, -SF5, -(C1-C3)alkyl, -O(C1-C3)alkyl, and -O(C3-C6)cycloalkyl, the appearance of -(C1-C3)alkyl and -O(C1-C3)alkyl is substituted by one or more groups independently selected from halo and -OH. n is either 0 or 1.

[0010] In this embodiment, R 2 R B Substituted by one or two occurrences of -(C6-C 10 ) is an aryl, and each R B However, these are independently selected from halo (e.g., -F), -NH2, -SF5, -OCF3, -O-cyclopropyl, -C(OH)(CF3)2, and -CF2CF3.

[0011] A further embodiment is a compound of formula (III-A). [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula R 1 , L 1 , and n are as defined above, R B1 However, it is either -H or selected from the group consisting of -NH2 and -F. R B2However, it is selected from the group consisting of -OCF3, -SF5, -CF2CF3, -C(OH)(CF3)2, and -O-cyclopropyl.

[0012] Further embodiments include compounds of formula (IV-A) or formula (VA). [ka] Or provide pharmaceutically acceptable salts thereof, in the formula, R 1 , L 1 , and n are as previously defined.

[0013] Further embodiments include compounds of formula (VI), formula (VII), or formula (VIII). [ka] Or provide pharmaceutically acceptable salts thereof, in the formula, R 1 However, this is as defined previously.

[0014] Further aspects include: -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(pentafluoro-λ 6 -Sulfanyl)phenyl]methanone, -[2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(pentafluoro-λ 6 -Sulfanyl)phenyl]methanone, -[4-(cyclopropoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-(1,1,2,2,2-pentafluoroethyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -Cyclohexyl-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]methanone, -[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-fluoro-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetan-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[tetrahydrofuran-3-yl]oxy-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -Trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(4-hydroxycyclohexyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(4-methylpiperazine-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(tetrahydropyran-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(tetrahydropyran-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-(2-morpholino-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-(4,4-difluoro-1-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]methanone, -[2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetane-3-yloxy)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, The present invention provides compounds selected from the group consisting of and pharmaceutically acceptable salts thereof.

[0015] A further embodiment provides a pharmaceutical composition comprising a compound as defined above and at least one pharmaceutically acceptable excipient or carrier.

[0016] Further embodiments provide compounds or pharmaceutical compositions as defined above for use in therapy.

[0017] Further embodiments provide compounds or pharmaceutical compositions as defined above for use in the treatment or prevention of cancer.

[0018] In this embodiment, the cancer is characterized by increased MAPK7 expression and / or increased ERK5 activity.

[0019] In this embodiment, the cancer is selected from leukemia, breast cancer, multiple myeloma, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, melanoma, and hepatocellular carcinoma. [Modes for carrying out the invention]

[0020] Herein, specific embodiments of the present disclosure will be described with reference to the description and examples, but it should be understood that such embodiments are for illustrative purposes only and are merely a few examples of many possible specific embodiments that can represent the application of the principles of the present disclosure. Various changes and modifications will be apparent to those skilled in the art in consideration of the interests of the present disclosure and will be deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[0021] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. Any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, but exemplary methods, apparatus and materials are described herein. All technical and patent publications referenced herein are incorporated herein by reference in their entirety.

[0022] The implementation of this disclosure will utilize conventional techniques, such as chemical synthesis, tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA, which are within the scope of the art of those skilled in the art, unless otherwise specified. For example, Michael R. Green and Joseph Sambrook, Molecular Cloning (4 thed.,Cold Spring Harbor Laboratory Press 2012);the series Ausubel et al.eds.(2007)Current Protocols in Molecular Biology;the series Methods in Enzymology(Academic Press,Inc.,N.Y.);MacPherson et al.(1991)PCR 1:A Practical Approach(IRL Press at Oxford University Press);MacPherson et al.(1995)PCR 2:A Practical Approach;Harlow and Lane eds.(1999)Antibodies,A Laboratory Manual;Freshney(2005)Culture of Animal Cells:A Manual of Basic Technique,5 thedition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Patent No. 4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds. (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); Herzenberg et al. eds (1996) Weir’s Handbook of Experimental Immunology; Manipulating the Mouse Embryo: A Laboratory Manual, 3 rd edition (Cold Spring Harbor Laboratory Press (2002)); See Sohail (ed.) (2004) Gene Silencing by RNA Interference: Technology and Application (CRC Press).

[0023] All numerical specifications (e.g., pH, temperature, time, concentration, molecular weight, including ranges) are approximations that, where appropriate, vary by (+) or (-) in increments of, for example, 0.1 or 1.0. It should be understood that, although not necessarily explicitly stated, the term “approximately” is used before every numerical specification to indicate a conventional level of variability. For example, a numerical specification that is “approximately” given a value may vary by ±10% of that value, or conversely, this variation may be ±5%, ±2%, or ±1% of that value. It should also be understood that, although not necessarily explicitly stated, the reagents described herein are merely illustrative, and their equivalents are known in the art.

[0024] As used herein and in the claims, the singular forms “a,” “an,” and “the” include multiple referents unless otherwise clearly indicated by the context. For example, the term “cell” includes multiple cells (including mixtures thereof). Unless otherwise specified or made clear by the context, the term “or” as used herein is understood to be inclusive. The term “including” is used herein to mean “including, but not limited to,” and is used interchangeably with this phrase.

[0025] Where used herein, the terms “comprising” or “comprises” are intended to mean that compositions and methods include the listed elements without excluding other elements. “Essentially consisting of” when used to define compositions and methods is intended to mean excluding any other elements that are essentially important to the purposes described. Thus, compositions essentially consisting of the elements defined herein will not exclude isolation and purification methods and trace impurities from pharmaceutically acceptable carriers, such as phosphate-buffered saline, preservatives, etc. “Consists of” is intended to mean excluding other components, other components beyond trace elements, and substantial method steps for administering the compositions of this disclosure or process steps for producing the compositions or achieving the intended results. Embodiments defined by each of these transitional terms are within the scope of this disclosure. The use of the term “comprising” herein is intended to encompass and disclose corresponding statements in which the term “comprising” is replaced by “consisting essentially of” or “consisting of.”

[0026] The terms "subject," "individual," or "patient" are used interchangeably herein and refer to vertebrates such as mammals. Mammals include, but are not limited to, rodents, livestock, sports animals, pets, and primates, such as mice, rats, rabbits, monkeys, cattle, sheep, pigs, dogs, cats, horses, and humans. In certain embodiments, the mammal is a human.

[0027] "Administering" is defined herein as a means of providing a drug or a composition containing a drug to a target in a manner that brings the drug into contact with the target body (e.g., internally). Such administration may be by any route, including but not limited to oral, transdermal (e.g., by vagina, rectal, or oral mucosa), injection (e.g., subcutaneous, intravenous, parenteral, intraperitoneal, or intracentral nervous system), or inhalation (e.g., oral or nasal). Administration may also include providing a substance or composition to a portion of the surface of the target body, for example, by topical administration to the skin. Pharmaceutical formulations are, of course, administered in a form appropriate to each route of administration.

[0028] Treating or treating a disease includes: (1) preventing the disease, i.e., preventing the development of clinical symptoms of the disease in patients who are susceptible to the disease but have not yet experienced or manifested symptoms of the disease; (2) inhibiting the disease, i.e., stopping or reducing the onset of the disease or its clinical symptoms; and / or (3) alleviating the disease, i.e., causing regression of the disease or its clinical symptoms.

[0029] The term "affected" refers, when used in conjunction with the term "treatment," to a patient or individual who has been diagnosed with or is susceptible to the disease. A patient may also be referred to as "at risk of developing" the disease due to a family history of the disease or the presence of disease-related genetic mutations. A patient at risk of developing the disease has not yet developed all or some of the characteristic pathological features of the disease.

[0030] An “effective dose” or “therapeutic effective dose” is an amount sufficient to produce a beneficial or desired result. An effective dose may be administered in one or more doses, applications, or dosages. Such delivery depends on many variables, including the duration of use of individual dose units, the bioavailability of the therapeutic agent, and the route of administration. However, the specific dose level of the therapeutic agent of this disclosure for any particular subject depends on various factors, including, for example, the activity of the specific compound used, the subject’s age, weight, overall health, sex, and diet, administration time, excretion rate, drug combination, severity of the specific disorder being treated, and the form of administration. Therapeutic doses can generally be titrated to optimize safety and efficacy. Typically, dose-response relationships from in vitro and / or in vivo studies can first provide useful guidance regarding an appropriate dose for patient administration. Generally, it would be desirable to administer an amount of the compound effective in achieving a serum level corresponding to the concentration found to be effective in vitro. Determining these parameters is well within the scope of the art of the skilled. These considerations, as well as effective formulations and administration procedures, are well known in the art and described in standard texts. As used herein in accordance with this definition, the term “therapeutic dose” is a quantity sufficient to treat (e.g., improve) one or more symptoms associated with a condition. The total daily dose may be administered as a single dose or in divided doses and may, at the physician’s discretion, deviate from the typical range shown herein.

[0031] As used herein, the terms “increase” and “rise” are interchangeable and encompass any measurable increase in biological function and / or biological activity and / or concentration. For example, an increase could be at least about 10%, for example at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, for example at least about 95%, 96%, 97%, 98%, 99%, or 100%. Thus, an increase could be at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 times the amount or function, or activity or concentration of the control or baseline, for example at least about 20, 25, 50, 100, or more.

[0032] As used herein, the terms “increased expression” and / or “increased activity” of a substance such as ERK5 in a sample or cancer or patient typically refer to an increase in the amount of the substance (e.g., MAPK7 gene product or ERK5 protein), but may also mean an increase in the biological activity of the substance (e.g., constitutive activation of phosphorylation and / or decreased recognition of phosphorylation sites of ERK5). For example, the increase may be in amounts of about 5%, e.g., about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, e.g., about 96%, 97%, 98%, 99%, or 100%. Therefore, the increase may be about 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, for example, about 20, 25, 50, 100 times or more, compared to the amount (or activity) of a substance such as ERK5 in a control sample or multiple control samples, for example, individuals or populations without disease or disorder (e.g., cancer), or in internal controls, as determined by techniques known in the art. If the expression and / or activity of ERK5 increases by 1, 2, 3, 4, 5, or more standard deviations compared to the mean (value) or median of ERK5 in the control group of the sample, the baseline group of the sample, or retrospective analysis of patient samples, the subject may also be determined to have "increased expression" or "increased activity" of ERK5. As practiced in the art, such control or baseline expression levels can be determined or measured in advance of measurements in the sample or cancer or subject, or can be obtained from a database of such control samples.

[0033] As used herein, the term “pharmaceutically acceptable excipients” encompasses any of the standard pharmaceutically acceptable excipients, such as those listed in, for example, Remington's Pharmaceutical Sciences (20th ed., Mack Publishing Co., 2000). Such excipients include carriers such as phosphate-buffered saline and water, and emulsions such as oil / water or water / oil emulsions, as well as various types of wetting agents. Pharmaceutical compositions may also include stabilizers, preservatives, adjuvants, fillers, binders, lubricants, and the like.

[0034] As used herein, the term “alkyl” means a saturated linear or branched free radical essentially consisting of carbon atoms and a corresponding number of hydrogen atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like. Other alkyl groups will be readily apparent to those skilled in the art, given the interests of this disclosure. Terms such as “(C1-C3) alkyl” and “(C1-C6) alkyl” have an equivalent meaning, i.e., a saturated linear or branched free radical essentially consisting of 1 to 3 (or 1 to 6) carbon atoms and a corresponding number of hydrogen atoms. The definition of “alkyl” also applies in the context of other groups containing alkyl groups, e.g., “-O(C1-C3) alkyl”. The term “haloalkyl” means an alkyl group substituted with one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, trifluoroethyl, difluoroethyl, pentafluoroethyl, chloromethyl, and the like. One or more carbon atoms in the alkyl group skeleton may be substituted (or bonded) by heteroatoms via multiple bonds (e.g., double bonds). For example, the carbon atoms of an alkyl group may be bonded to oxygen via double bonds (i.e., substituted with oxos to provide carbonyl functionality). The presence of such substituents does not prevent the carbon skeleton of a free radical from being considered an alkyl group.

[0035] As used herein, the term “cyclic group” means a saturated, partially or fully unsaturated, or aromatic group having at least 3 to 10 atoms (i.e., ring atoms) that form a ring. Where a cyclic group is defined as having a certain number of members, terms such as “membered,” “membered,” etc., are used to indicate the number of ring atoms in the cyclic group. For example, a five-membered cyclic group (e.g., a five-membered heterocyclic group) contains five ring atoms. It will be understood that a cyclic group may be part of a larger cyclic system. For example, bicyclo[4.3.0]nonane contains two carboncyclic groups, namely a cyclohexane group and a cyclopentane group, fused to form a carbocyclic system that constitutes the molecule. The term “cyclic group” is intended to encompass both carboncyclic and heterocyclic groups. The term “carboncyclic” refers to a group having at least 3 to 9 carbon atoms that form a ring. The term "heterocyclic" refers to a group having at least 3 to 10 atoms forming a ring, where at least 1 to 9 of the ring atoms are carbon, and the remaining at least 1 to 9 ring atoms (i.e., heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen.

[0036] As used herein with respect to cyclic groups, the terms “spiro” or “spirocyclic” indicate that a first cyclic group in a polycyclic system is bonded to a second cyclic group in the same polycyclic system, and the ring atoms of the first cyclic group and the ring atoms of the second cyclic group have only one common atom, i.e., the first and second cyclic groups share only one common ring atom. For example, the spiro[5.5]undecanyl group contains two cyclohexane rings that share a single carbocyclic atom.

[0037] As used herein with respect to cyclic groups, the term “fusion” means that a first cyclic group in a polycyclic system is bonded to a second cyclic group in the same polycyclic system, and the ring atoms of the first cyclic group and the ring atoms of the second cyclic group have two adjacent atoms in common, i.e., the first and second cyclic groups share two common ring atoms. For example, the bicyclo[4.4.0]decanyl group contains two cyclohexane rings that have two adjacent carbocyclic atoms in common.

[0038] As used herein with respect to cyclic groups, the term “bridged” means that a first cyclic group in a polycyclic system is bonded to a second cyclic group in the same polycyclic system, and the ring atoms of the first cyclic group and the ring atoms of the second cyclic group have more than two adjacent atoms in common, i.e., the first and second cyclic groups share three or more common ring atoms. For example, the bicyclo[3.3.1]nonanyl group contains two cyclohexane rings that have three adjacent carbocyclic atoms in common.

[0039] Within the structural formulas described herein, any ring system (including any spiro, fusion, or bridging ring systems) may be connected to other parts of the molecule via any atom having the appropriate valency. For example, a bicyclic ring may be connected to another part of the molecule via a ring atom (e.g., a second carbon atom or a heteroatom such as N) or a bridgehead (e.g., a third carbon atom). Spiro, fusion, and bridging rings may be fully unsaturated, partially unsaturated, or fully saturated, and one or more of the rings constituting them may have aromatic properties.

[0040] As used herein, the term “cycloalkyl” means a saturated free radical having at least 3 to 9 carbon atoms (i.e., ring atoms) forming a ring. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. It should be understood that cycloalkyl groups can be monocyclic or polycyclic (e.g., fused, cross-linked, or spirocyclic). In the case of polycyclic cycloalkyl groups, there may be further rings, e.g., one or more additional rings, all containing 3 to 7 carbon atoms (i.e., ring atoms). An example of a cycloalkyl group having such additional rings is bicyclo[1.1.1]pentanyl. The term “(C3-C7) cycloalkyl” indicates that the cycloalkyl group contains 3 to 7 carbon atoms in the ring portion of the group, which may be monocyclic or polycyclic (e.g., fused, cross-linked, or spirocyclic), e.g., cyclopropanyl (having 3 ring carbon atoms) or bicyclo[1.1.1]pentanyl (having 5 ring carbon atoms). One or more ring atoms of a cycloalkyl group can be substituted (i.e., bonded) by a heteroatom via a double bond (e.g., an oxo-substituted cycloalkyl group). The presence of such substituents does not prevent the carbon skeleton of the free radical from being considered a cycloalkyl group.

[0041] As used herein, the term “aryl” means an aromatic free radical having at least six carbon atoms (i.e., ring atoms) forming a ring. It will be understood that aryl groups can be monocyclic or polycyclic (e.g., fusion). In the case of polycyclic aryl groups, there are further rings, e.g., one or more further rings, all of which contain at least three carbon atoms (i.e., ring atoms). The further rings may also contain one or more heteroatoms, which may be saturated, unsaturated, or aromatic. Polycyclic aryl groups are typically bonded to the rest of the molecule via an aromatic ring and not typically via a ring containing heteroatoms. In embodiments, polycyclic aryl groups do not contain ring heteroatoms. Examples of aryl groups include the phenyl and naphthalenyl groups, as well as the indenyl and indanyl groups. Other aryl groups include, for example, tetrahydroisoquinolinyl bonded to the rest of the molecule via its phenyl ring. (C6-C 10 The term "aryl" indicates that the aryl group contains 6 to 10 carbon atoms in the ring portion of the group, which can be monocyclic or polycyclic (e.g., fusion), and can be, for example, phenyl (having 6 ring carbon atoms) or indanyl (having 9 ring carbon atoms). In embodiments, (C6-C 10 ) Aryl is phenyl.

[0042] As used herein, the term “heterocycloalkyl” means a saturated free radical having at least 3 to 10 atoms (i.e., ring atoms) forming a ring, where at least 1 to 9 of the ring atoms are carbon, and the remaining at least 1 to 9 ring atoms (i.e., heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. In embodiments, the heterocyclic atoms are independently selected from the group consisting of nitrogen and oxygen. For example, the term “4-10 membered heterocycloalkyl” means a saturated free radical containing 4 to 10 ring atoms, one or more of which are heterocyclic atoms. Heterocycloalkyl rings typically have oxo substituents adjacent to the heteroatoms (e.g., 2-oxopyrrolidinyl), but oxygen atoms do not form part of the ring and are excluded from the number of ring atoms. The presence of such substituents does not prevent the ring (or more rings) of the free radical from being considered a heterocycloalkyl group. Exemplary heterocycloalkyl groups include tetrahydrofuranil, piperidinyl, morpholinil, and piperazinyl. Any ring sulfur atom can optionally support one or more pendant (i.e., acyclic) oxygen atoms, as seen in, for example, sulforanyl groups. In the case of polycyclic heterocyclic groups, there are further rings, e.g., one or more rings, all containing 3 to 7 ring atoms selected from carbon, nitrogen, sulfur, and oxygen. The further rings may be saturated or partially or completely unsaturated (e.g., having aromatic properties). Examples of polycyclic heterocyclic groups include fusion, bridging, and spirocyclic ring systems. If a polycyclic heterocycloalkyl group contains an unsaturated fusion ring, the group typically does not bond to the rest of the molecule via its fusion ring. When a heterocycloalkyl group is described as "X-Y member" (where X and Y are integers), this means that the heterocycloalkyl group contains a total number of ring atoms from X to Y. Thus, for example, a "4-7 member heterocycloalkyl group" contains a total of 4, 5, 6, or 7 ring atoms, such as tetrahydropyranyl (6 ring atoms).

[0043] As used herein, the terms “halo” and “halogen” mean fluorine, chlorine, bromine, or iodine. These terms are used interchangeably and may refer to a halogen-free radical group or such halogen atom. Those skilled in the art will be able to readily confirm their distinction by considering the context in which these terms are used in this disclosure. In embodiments, the halogen is fluorine.

[0044] As used herein, the term "oxo" refers to a free radical in which an oxygen atom is connected to the atom having this radical via a double bond. For example, when a carbon atom supports an oxo radical, it forms a carbon-oxygen double bond. It will be understood that not all atoms in a given structure can be substituted with an oxo, and this depends on the free valence of the atom being substituted.

[0045] The compounds of this disclosure are described in particular by their structural formulas. These formulas typically represent only one form of the compound (e.g., resonance form, tautomer form, etc.), but it will be understood that certain compounds may exist in multiple such forms. This will be readily apparent to an experienced reader. This disclosure includes all possible tautomers of the compounds characterized by the structural formulas herein, either as single tautomers or as any mixture of tautomers in any ratio. For example, the pyrrolopyrazine moiety (e.g., as shown in formula (I), which may be called 4H-pyrrolo[2,3-b]pyrazine or 4,7-diazaindole) may be represented by any of the following tautomer forms, which are used interchangeably throughout this description: [ka]

[0046] It should be understood that certain compounds may exist in one or more isomeric (e.g., stereoisomeric) forms. This disclosure includes all possible stereoisomers, enantiomers, diastereomers, etc., of the compounds described above and below, as well as their cis and trans forms and conformations. Purification and separation of isomers can be achieved by the methods described below and by techniques known in the art. For example, optical isomers of a compound can be obtained by degrading a racemic mixture of its diastereoisomer salts (e.g., by using optically active acids or bases, or by forming covalent diastereomers). Different processes for the separation of optical isomers include the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatization. Enzymatic separation may also be useful, with or without derivatization, and the optically active compounds of this disclosure can similarly be obtained by chiral synthesis utilizing optically active starting materials. This disclosure includes all possible stereoisomers of the compounds described herein, either as single stereoisomers or in any mixture of such stereoisomers, for example, as (R)- or (S)-isomers, in any proportion.

[0047] The compounds of this disclosure may exist in the form of free acids or bases, or as addition salts having a suitable acid or base. For example, the basic compound of formula (I) may be provided as a pharmaceutically acceptable acid addition salt having an acid such as HCl, TFA, or formic acid (e.g., formic acid). Methods for forming the salts are described below and are known in the art (see, for example, Berge et al., J Pharm Sci. (1977) 66:1-19).

[0048] As used herein, the term “pharmaceutically acceptable” in relation to salts means salts of the compounds of this disclosure that can be administered without causing any substantially undesirable biological effects or consequently harmful interactions with any other components of a pharmaceutical composition in which they may be included.

[0049] A group defined as "optionally substituted" may be either unsubstituted or substituted with one or more substituents, e.g., 1, 2, 3, 4, 5, 6, or more substituents. In embodiments, the substituent has 1 to 4 substituents, e.g., 1, 2, or 3 substituents. In embodiments, the substituent has 1 or 2 substituents. In embodiments, the substituent has 3 substituents.

[0050] Any reference to a list of chemical groups in any definition of a variable herein includes the definition of that variable as any single group or combination of the listed groups. Any enumeration of embodiments relating to a variable or aspect herein includes this embodiment as any single embodiment or in combination with any other embodiment or part thereof.

[0051] The compositions and methods provided herein can be combined with one or more of the other compositions and methods provided herein.

[0052] The following abbreviations and experimentally based formulas are used herein. ABC Ammonium Bicarbonate Acetyl ACN / MeCN Acetonitrile ATP (Adenosine Triphosphate) Boc tert-butyloxycarbonyl CBZ Benzyloxycarbonyl DAD Diode Array Detection DCM Dichloromethane DIPEA Diisopropylethylamine DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) 4EBP1 Eukaryotic translation initiation factor 4E binding protein 1 EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ERK extracellular signal-regulating kinase ethyl acetate (acetate / AcOEt) FRET Förster Resonance Energy Transfer HATU Hexafluorophosphate Azobenzotriazole Tetramethyluronium HOBt Hydroxybenzotriazole HPLC High Performance Liquid Chromatography LC / MS Liquid Chromatography / Mass Spectrometry LiHMDS Lithium Bis(trimethylsilyl)Amide MS Mass Spectrometry NBS N-Bromosuccinimide NCS N-Chlorosuccinimide NIS N-Iodosuccinimide NMR Nuclear Magnetic Resonance Pd / C Palladium Carbon PdCl2(dppf) [1,1’-Bis(diphenylphosphino)ferrocene]Dichloropalladium(II) Pd2(dba)3 Tris(dibenzylideneacetone)Dipalladium(0) PE Petroleum Ether rac Racemic Mixture RPMI Roswell Park Memorial Institute Medium SEM 2-Trimethylsilylethoxymethyl SGC Silica Gel Chromatography TAD Transcription Activation Domain TATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide Tetrafluoroborate TBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethylaminium Tetrafluoroborate TEA Triethylamine TFA Trifluoroacetic Acid THF Tetrahydrofuran UPLC Ultra Performance Liquid Chromatography UV Ultraviolet XPhosPdG4 dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphanium; methanesulfonic acid; N-methyl-2-phenylaniline; palladium

[0053] Compound In a first aspect, the present disclosure provides a compound of formula (I)

Chemical formula

[0054] In the embodiment, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein, R 1 However, R is selected from -(C1-C6)alkyl, -(C3-C7)cycloalkyl, and 4-10 member heterocycloalkyl. 1 However, R A It is optionally replaced by one or more occurrences of Each R A However, independently selected from halo, -OH, -NH2, -(C1-C3)alkyl, -O(C1-C3)alkyl, and -(C3-C6)cycloalkyl, each occurrence of -(C1-C3)alkyl is optionally substituted by one or more groups independently selected from halo and -OH. L 1 However, it is selected from direct bonding, -O-, and -NH-, R 2 However, -(C3-C6)cycloalkyl and -(C6-C 10 ) Selected from the aryl, R 2 However, R B It is optionally replaced by one, two, or three occurrences. Each R B However, independently selected from halo, -NH2, -SF5, -(C1-C3)alkyl, -O(C1-C3)alkyl, and -O(C3-C6)cycloalkyl, the appearance of -(C1-C3)alkyl and -O(C1-C3)alkyl is optionally substituted by one or more halos. R 3 However, it is selected from -H, -CH3, and -OH, Y is either CH or N, n is either 0 or 1.

[0055] In the embodiment, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein, R 1However, R is selected from -(C1-C6)alkyl, -(C3-C7)cycloalkyl, and 4-10 member heterocycloalkyl. 1 However, R A It is optionally replaced by one or more occurrences of Each R A However, these are independently selected from halo, -OH, -(C1-C3)alkyl, -O(C1-C3)alkyl, and -(C3-C6)cycloalkyl, L 1 However, it is selected from direct bonding, -O-, and -NH-, R 2 However, -(C3-C6)cycloalkyl and -(C6-C 10 ) Selected from the aryl, R 2 However, R B It is optionally replaced by one or two occurrences of Each R B However, independently selected from halo, -NH2, -SF5, -(C1-C3)alkyl, -O(C1-C3)alkyl, and -O(C3-C6)cycloalkyl, the appearance of -(C1-C3)alkyl and -O(C1-C3)alkyl is optionally substituted by one or more groups independently selected from halo and -OH. R 3 However, it is -H, Y is CH, n is either 0 or 1.

[0056] In the embodiment, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein, R 1 However, R is selected from -(C1-C6)alkyl, -(C3-C7)cycloalkyl, and 4-10 member heterocycloalkyl. 1 However, R A It is optionally replaced by one or more occurrences of Each R A However, these are independently selected from halo, -OH, -(C1-C3)alkyl, -O(C1-C3)alkyl, and -(C3-C6)cycloalkyl, L 1 However, it is selected from direct bonding, -O-, and -NH-, R2 is selected from -(C3-C6) cycloalkyl and -(C6-C 10 ) aryl, and R 2 is optionally substituted at one or two occurrences of R B , each R is independently selected from halo, -NH2, -SF5, -(C1-C3) alkyl, -O(C1-C3) alkyl, and -O(C3-C6) cycloalkyl, and each occurrence of -(C1-C3) alkyl and -O(C1-C3) alkyl is optionally substituted by one or more halos, B R is -H, 3 Y is CH, and n is 0 or 1. In embodiments, R

[0057] is selected from -(C1-C3) alkyl (e.g., propyl), -(C5-C7) cycloalkyl, and 4-7 member heterocycloalkyl, and R 1 is optionally substituted at one or more occurrences of R 1 as defined herein. In embodiments, R A is selected from -(C1-C3) alkyl (e.g., propyl), -(C5-C6) cycloalkyl, and 4-6 member heterocycloalkyl, and R 1 is optionally substituted at one or more occurrences of R 1 as defined herein. A In embodiments, R

[0058] is selected from -(C1-C3) alkyl, -(C5-C6) cycloalkyl, and 5-6 member heterocycloalkyl, and R 1 is optionally substituted at one or more occurrences of R 1 as defined herein. A In embodiments, R

[0059] is unsubstituted. 1 In other embodiments, R

[0060] 1is replaced by one, two, or three occurrences of R as defined herein. In an embodiment, R A is replaced by one or two occurrences of R 1 is replaced by one occurrence of R A In an embodiment, R 1 is replaced by one occurrence of R A In an embodiment, R 1 is replaced by two occurrences of R A In an embodiment, R 1 is replaced by three occurrences of R A .

[0061] In an embodiment, each R A is independently selected from halo (e.g., -F), -OH, -NH2, -(C1-C3)alkyl, -OCH3, and cyclopropyl, and each occurrence of -(C1-C3)alkyl is optionally replaced by one or more groups independently selected from halo (e.g., -F) and -OH. In an embodiment, each R A is independently selected from -F, -OH, methyl, -OCH3, and cyclopropyl. In an embodiment, R 1 is replaced by one or two occurrences of R A , and each R A is independently selected from -F, -OH, methyl, -OCH3, and cyclopropyl.

[0062] In an embodiment, R 1 is

Chemical formula

[0063] In this embodiment, R 1 teeth, [ka] Selected from, in the formula, R 1 However, as defined herein, R A It is optionally replaced by one or more occurrences of R. In the embodiment, each R A These are independently selected from the group consisting of halo (e.g., -F), -OH, -NH2, -(C1-C3)alkyl (e.g., methyl or ethyl), -O(C1-C3)alkyl (e.g., -OCH3), and -(C3-C6)cycloalkyl (e.g., cyclopropyl), and each (C1-C3)alkyl appearance can be optionally substituted with one or more substituents selected from halo (e.g., -F) and -OH.

[0064] In this embodiment, R 1 teeth, [ka] Selected from, in the formula, R 1 However, as defined herein, R A It is optionally replaced by the appearance of one or two of the following. In the embodiment, each R A The group is independently selected from the group consisting of -F, -OH, methyl, -OCH3, and cyclopropyl.

[0065] In this embodiment, R 1 teeth, [ka] Selected from, in the formula, R 1 However, as defined herein, R A It is optionally replaced by one or more occurrences of R. A The group is selected from methyl, -OCH3, and cyclopropyl.

[0066] In this embodiment, R 1 teeth, [ka] Selected from.

[0067] In this embodiment, R 1 teeth, [ka] Selected from.

[0068] In this embodiment, R 1 R as defined herein A A cyclohexyl that is optionally substituted by the appearance of one or more of the following. In the embodiment, R 1 It is an unsubstituted cyclohexyl.

[0069] In this embodiment, R 1 The heterocycloalkyl group is a 5-6 member heterocycloalkyl group, and the heterocycloalkyl group comprises one or two atoms independently selected from O and N, and the heterocycloalkyl group is R as defined herein. A It is optionally and independently replaced by one or more occurrences of R. In the embodiment, each R A These are independently selected from -CH3, -OCH3, and cyclopropyl.

[0070] In this embodiment, R 1 teeth, [ka] Selected from.

[0071] In this embodiment, R1 teeth, [ka] Selected from.

[0072] In this embodiment, R 2 R as defined herein B It is a -(C3-C6) cycloalkyl that is optionally substituted by the appearance of one, two, or three of the following. In embodiments, R 2 is an unsubstituted-(C3-C6) cycloalkyl. In the embodiment, R 2 It is an unsubstituted cyclohexyl.

[0073] In this embodiment, R 2 R as defined herein B Substituted by one, two, or three occurrences of -(C6-C 10 ) is an arrow. In this embodiment, R 2 R B It is a phenyl substituted with one, two, or three occurrences of R. In embodiments, R 2 R B Substituted by one or two occurrences of -(C6-C 10 ) is an arrow. In this embodiment, R 2 R B It is a phenyl substituted with the appearance of one or two of the following. In embodiments, R 2 R B Substituted by one occurrence of -(C6-C 10 ) is an arrow. In this embodiment, R 2 R B It is a phenyl substituted with one appearance of R. In the embodiment, R 2 R B Substituted by the two occurrences of -(C6-C 10 ) is an arrow. In this embodiment, R 2 R B It is a phenyl compound substituted with the two appearances of the following.

[0074] In this embodiment, R 2 R as defined hereinB A cyclohexyl or phenyl molecule that is optionally substituted with one, two, or three occurrences of R. In embodiments, R 2 is either an unsubstituted cyclohexyl or R 2 R B It is a phenyl substituted with one, two, or three occurrences of R. In embodiments, R 2 R B It is a phenyl compound substituted with one or two occurrences of the following.

[0075] In this embodiment, R 2 is non-substitutable. In other embodiments, R 2 R as defined herein B It is replaced by one or two occurrences of R. In the embodiment, R 2 R B It is replaced by one occurrence of .

[0076] Control mechanism, each R B These are independently selected from halo(e.g., -F), -NH2, -SF5, -CF2CF3, -C(OH)(CF3)2, -OCF3, and -O-cyclopropyl. In embodiments, each R B The following are independently selected from halo (e.g., -F), -NH2, -SF5, -OCF3, -O-cyclopropyl, and -CF2CF3. In embodiments, R 2 It is phenyl, and each R B The following are independently selected from halo (e.g., -F), -NH2, -SF5, -OCF3, -O-cyclopropyl, and -CF2CF3.

[0077] Control mechanism, each R B The following are independently selected from halo (e.g., -F), -NH2, -SF5, -OCF3, -O-cyclopropyl, and -CF2CF3. In embodiments, R 2 R B It is replaced by one or two occurrences, each R B R is independently selected from -F, -NH2, -SF5, -OCF3, -O-cyclopropyl, and -CF2CF3. In embodiments, R 2 RB It is replaced by two or three occurrences, and each R B The following are independently selected from halo (e.g., -F), -NH2, -SF5, and -OCF3. In the embodiment, R 2 R B It is replaced by three occurrences, and each R B The following are selected independently from -F, -NH2, and -OCF3.

[0078] In this embodiment, R B At least one occurrence of is -SF5. In an embodiment, R B One example is -SF5. In the embodiment, R 2 R B It is replaced by one occurrence of R B is -SF5. In this embodiment, R 2 R B It is replaced by two or three occurrences, R B One occurrence of is -SF5, and R B Other occurrences are independently selected from halo (e.g., -F) and -NH2. In embodiments, R 2 R B It is replaced by two occurrences, R B One occurrence of is -SF5, and R B Other occurrences of -F and -NH2 are selected from -F and -NH2.

[0079] In this embodiment, R B At least one occurrence of is a halo. In embodiments, each halo is -F. In embodiments, R B At least one occurrence of is -F. In the embodiment, R 2 R B Phenyl substituted with one, two, or three occurrences of each R B The following are independently selected from halo (e.g., -F), -NH2, -SF5, -OCF3, -O-cyclopropyl, and -CF2CF3. In embodiments, R 2 R B Phenyl is substituted with two or three occurrences of each R BThe following are independently selected from halo (e.g., -F), -NH2, -SF5, -OCF3, -O-cyclopropyl, and -CF2CF3. In embodiments, R 2 R B It is a phenyl substituted with one appearance of R B R is selected from -SF5, -OCF3, -O-cyclopropyl, and -CF2CF3. In the embodiment, R 2 R B Phenyl is substituted with two appearances of each R B The following are independently selected from halo (e.g., -F), -NH2, -SF5, and -OCF3. In the embodiment, R 2 R B Phenyl is substituted with the appearance of three R B The following are selected independently from -F, -NH2, and -OCF3.

[0080] In this embodiment, R 2 R B A phenyl substituted with one, two, or three occurrences of R B At least one occurrence of is -SF5. In an embodiment, R 2 R B A phenyl substituted with one, two, or three occurrences of R B One occurrence of is -SF5. In the embodiment, R 2 R B A phenyl substituted with one or two of the following, R B One occurrence of is -SF5, and R B Other occurrences (if any) are selected from -F and -NH2. In the embodiment, R 2 R B It is a phenyl substituted with two appearances of R B One occurrence of is -SF5, and R B Other occurrences are selected from -F and -NH2. In the embodiment, R 2 R B It is a phenyl substituted with one appearance of R B It is -SF5.

[0081] In this embodiment, R 2 teeth, [ka] Selected from. In this embodiment, R 2 teeth, [ka] Selected from. In this embodiment, R 2 teeth, [ka] Selected from.

[0082] In this embodiment, R 3 R is selected from -H and -(C1-C3)alkyl. In the embodiment, R 3 is selected from -H and -CH3. In the embodiment, R 3 is -CH3. In this embodiment, R 3 It is -H.

[0083] In this embodiment, Y is CH. In this embodiment, Y is N.

[0084] In the embodiment, n is 0. In the embodiment, n is 1. Formula (IA)~(IG)

[0085] In this embodiment, Y is N and n is 1. In this embodiment, the present disclosure relates to a compound of formula (IA). [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 3 , and L 1 However, as defined herein.

[0086] In this embodiment, Y is CH and n is 0. In this embodiment, the present disclosure relates to the compound of formula (IB). [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 3 , and L 1 However, as defined herein.

[0087] In this embodiment, R 2 R B A phenyl substituted with one or two of the following, each R B The following are independently selected from -NH2, -OCF3, and -SF5.

[0088] In this embodiment, Y is CH and n is 1.

[0089] In this embodiment, L 1 This is a direct bond.

[0090] In this embodiment, R 3 It is -H.

[0091] In this embodiment, L 1 The is selected from -O- and -NH-. In this embodiment, the present disclosure relates to compounds of formula (IC) or formula (ID). [ka] Or provide pharmaceutically acceptable salts thereof, in the formula, R 1 , R 2 , R 3 , Y, and n are as defined herein. In the embodiment, L 1 is -O-, that is, the compound is the compound of formula (IC) or a pharmaceutically acceptable salt thereof. In other embodiments, L 1 The compound is -NH-, meaning the compound is the compound of formula (ID), or a pharmaceutically acceptable salt thereof.

[0092] In the embodiment, n is 1. In the embodiment, R 3It is -H.

[0093] In this embodiment, Y is CH and L 1 The is selected from -O- and -NH-. In this embodiment, the present disclosure relates to compounds of formula (IE) or formula (IF). [ka] Or provide pharmaceutically acceptable salts thereof, in the formula, R 1 , R 2 , R 3 , and n are as defined herein. In the embodiment, L 1 is -O-, that is, the compound is the compound of formula (IE) or a pharmaceutically acceptable salt thereof. In other embodiments, L 1 is -NH-, meaning the compound is the compound of formula (IF), or a pharmaceutically acceptable salt thereof.

[0094] In the embodiment, n is 1. In the embodiment, R 3 is -H. In the embodiment, n is 1 and R 3 It is -H.

[0095] In this embodiment, Y is CH, and R 3 is -H. In this aspect, the present disclosure relates to the compound of formula (IG). [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , L 1 , and n are as defined herein.

[0096] In this embodiment, L 1 In other embodiments, L 1 is -NH-. In this embodiment, n is 1. Formula (II)

[0097] In this embodiment, the compound is the compound of formula (II). [ka] Or provide a pharmaceutically acceptable salt thereof. R 1 However, R is selected from -(C1-C6)alkyl, -(C3-C7)cycloalkyl, and 4-10 member heterocycloalkyl. 1 However, R A It is optionally replaced by one or more occurrences of Each R A However, independently selected from halo (e.g., -F), -OH, -(C1-C3)alkyl, -O(C1-C3)alkyl, and -(C3-C6)cycloalkyl, R 2 However, -(C3-C6)cycloalkyl and -(C6-C 10 ) Selected from the aryl, R 2 However, R B It is optionally replaced by one or two occurrences of Each R B However, independently selected from halo, -NH2, -SF5, -(C1-C3)alkyl, -O(C1-C3)alkyl, and -O(C3-C6)cycloalkyl, the appearance of -(C1-C3)alkyl and -O(C1-C3)alkyl is substituted by one or more groups independently selected from halo and -OH. n is either 0 or 1.

[0098] In the embodiment, the compound is a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein, R 1 However, R is selected from -(C1-C6)alkyl, -(C3-C7)cycloalkyl, and 4-10 member heterocycloalkyl. 1 However, R A It is optionally replaced by one or more occurrences of Each R A However, they are independently selected from -(C1-C3)alkyl, -O(C1-C3)alkyl, and -(C3-C6)cycloalkyl, R 2 However, -(C3-C6)cycloalkyl and -(C6-C 10) Selected from the aryl, R 2 However, R B It is optionally replaced by one or two occurrences of Each R B However, independently selected from halo, -NH2, -SF5, -(C1-C3)alkyl, -O(C1-C3)alkyl, and -O(C3-C6)cycloalkyl, each occurrence of -(C1-C3)alkyl and -O(C1-C3)alkyl is substituted by one or more halos. n is either 0 or 1.

[0099] In this embodiment, R 1 The heterocycloalkyl group is a 4-6 membered heterocycloalkyl group, which comprises one or two ring heteroatoms independently selected from O and N, and the heterocycloalkyl group is R as defined herein. A It is optionally and independently replaced by one or more occurrences of R. 1 The heterocycloalkyl group is a 5-6 membered heterocycloalkyl group, and the heterocycloalkyl group comprises one ring heteroatom independently selected from O and N, and the heterocycloalkyl group is R as defined herein. A It is optionally and independently replaced by one or more occurrences of R. In the embodiment, each R A R is independently selected from -F, -OH, methyl, -OCH3, and cyclopropyl. In the embodiment, each R A These are independently selected from -CH3, -OCH3, and cyclopropyl.

[0100] In this embodiment, R 1 teeth, [ka] Selected from, in the formula, R 1 However, R A It is optionally substituted by one or two occurrences of R A Each appearance is independently selected from -F, -OH, methyl, -OCH3, and cyclopropyl.

[0101] In this embodiment, R 1 teeth, [ka] Selected from, in the formula, R 1 However, R A It is optionally replaced by one occurrence of R A However, it is methyl, -OCH3, or cyclopropyl.

[0102] In this embodiment, R 1 teeth, [ka] Selected from.

[0103] In this embodiment, R 1 teeth, [ka] Selected from.

[0104] In the embodiment, n is 0. In the embodiment, n is 1.

[0105] In this embodiment, R 2 R as defined herein B It is a -(C3-C6) cycloalkyl (e.g., cyclohexyl) optionally substituted with one or two occurrences of . In embodiments, R 2 is an unsubstituted-(C3-C6) cycloalkyl. In the embodiment, R 2 It is an unsubstituted cyclohexyl.

[0106] In this embodiment, R 2 R B Substituted by one or two occurrences of -(C6-C 10 ) is an arrow. In this embodiment, R 2 R B It is a phenyl substituted with the appearance of one or two of the following. In embodiments, R 2 R B Substituted by one occurrence of -(C6-C10 ) is an arrow. In this embodiment, R 2 R B It is a phenyl compound substituted with one of the appearances of .

[0107] In this embodiment, R 2 R as defined herein B Cyclohexyl or phenyl is optionally substituted with one or two of the following. In embodiments, R 2 is either an unsubstituted cyclohexyl or R 2 R B It is a phenyl compound substituted with one or two of the following.

[0108] In this embodiment, R 2 R as defined herein B It is replaced by one or two occurrences of R. In the embodiment, R 2 R B It is replaced by one occurrence of R. In the embodiment, R 2 This is a non-substitution.

[0109] Control mechanism, each R B R is independently selected from halo(e.g., -F), -NH2, -SF5, -OCF3, -O-cyclopropyl, -CF2CF3, and C(OH)(CF3)2. In embodiments, each R B The following are independently selected from halo (e.g., -F), -NH2, -SF5, -OCF3, -O-cyclopropyl, and -CF2CF3. In embodiments, R 2 R B Substituted by one or two occurrences, each R B The following are independently selected from halo (e.g., -F), -NH2, -SF5, and -OCF3. In the embodiment, R 2 R B It is replaced by one occurrence of R B R is selected from -OCF3, -SF5, -O-cyclopropyl, and -CF2CF3. In the embodiment, R 2 R B It is replaced by two occurrences, and each R BThe following are independently selected from halo (e.g., -F), -NH2, -SF5, and -OCF3.

[0110] In this embodiment, R B At least one occurrence of is a halo. In embodiments, each halo is -F. In embodiments, R B At least one occurrence of is -F.

[0111] In this embodiment, R B At least one occurrence of is -SF5. In an embodiment, R B One example is -SF5. In the embodiment, R 2 R B Substituted by one or two occurrences of R B One occurrence of is -SF5, and R B Other occurrences (if any) are selected from -F and -NH2. In the embodiment, R 2 R B It is replaced by two occurrences, R B One occurrence of is -SF5, and R B Other occurrences are selected from -F and -NH2. In the embodiment, R 2 R B It is replaced by one occurrence of R B It is -SF5. Equations (II-A) and (II-B)

[0112] In one embodiment, n is 1. In another embodiment, n is 0. In this embodiment, the present disclosure relates to a compound of formula (II-A) or formula (II-B). [ka] Or provide pharmaceutically acceptable salts thereof, in the formula, R 1 and R 2 However, as defined herein. In some embodiments, the compound is the compound of formula (II-A) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is the compound of formula (II-B) or a pharmaceutically acceptable salt thereof. Equations (III-A) and (III)

[0113] In this embodiment, the compound is the compound of formula (III-A). [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula R 1 , L 1 , and n are as defined herein, R B1 However, it is either -H or selected from the group consisting of -NH2 and -F. R B2 However, it is selected from the group consisting of -OCF3, -SF5, -CF2CF3, -C(OH)(CF3)2, and -O-cyclopropyl.

[0114] In the embodiment, the compound is the compound of formula (III-A) or a pharmaceutically acceptable salt thereof, where R 1 , L 1 , and n are as defined herein, R B1 However, it is either -H or selected from the group consisting of -NH2 and -F. R B2 However, it is selected from the group consisting of -OCF3, -SF5, -CF2CF3, and -O-cyclopropyl.

[0115] In this embodiment, L 1 In other embodiments, L 1 It is -O-.

[0116] In this embodiment, the compound is the compound of formula (III). [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula R 1 and n are as defined herein, R B1However, it is either -H or selected from the group consisting of -NH2 and -F. R B2 However, it is selected from the group consisting of -OCF3, -SF5, -CF2CF3, -C(OH)(CF3)2, and -O-cyclopropyl.

[0117] In the embodiment, the compound is the compound of formula (III) or a pharmaceutically acceptable salt thereof, where R 1 and n are as defined herein, R B1 However, it is either -H or selected from the group consisting of -NH2 and -F. R B2 However, it is selected from the group consisting of -OCF3, -SF5, -CF2CF3, and -O-cyclopropyl.

[0118] In this embodiment, R B1 is -H. In some embodiments, R B1 is -NH2. In the embodiment, R B1 It is -F.

[0119] In this embodiment, R B2 is -OCF3. In the embodiment, R B2 is -SF5. In this embodiment, R B2 is -CF2CF3. In the embodiment, R B2 It is -O-cyclopropyl.

[0120] In this embodiment, R B1 is -H, and R B2 is -OCF3. In the embodiment, R B1 It is -NH2, and R B2 is -OCF3. In the embodiment, R B1 is -H, and R B2 is -SF5. In this embodiment, R B1 It is -NH2, and R B2 is -SF5. In this embodiment, R B1 is -F, and R B2is -SF5. In this embodiment, R B1 is -H, and R B2 is -O-cyclopropyl. In the embodiment, R B1 is -H, and R B2 It is -CF2CF3. Formulas (IV-A), (IV), (VA), and (V)

[0121] In the embodiment, the compound is a compound of formula (VI-A) or (VA). [ka] Or provide pharmaceutically acceptable salts thereof, in the formula, R 1 , L 1 , and n are as defined herein. In some embodiments, the compound is the compound of formula (IV-A) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is the compound of formula (VA) or a pharmaceutically acceptable salt thereof.

[0122] In this embodiment, L 1 In other embodiments, L 1 It is -O-.

[0123] In the embodiment, the compound is a compound of formula (IV) or (V). [ka] Or provide pharmaceutically acceptable salts thereof, in the formula, R 1 and n are as defined herein. In some embodiments, the compound is the compound of formula (IV) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is the compound of formula (V) or a pharmaceutically acceptable salt thereof. Formulas (VI)~(VIII)

[0124] In the embodiment, the compound is a compound of formula (VI), formula (VII), or (VIII). [ka] or a pharmaceutically acceptable salt thereof, where R 1 However, as defined herein. In some embodiments, the compound is the compound of formula (VI) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is the compound of formula (VII) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is the compound of formula (VIII) or a pharmaceutically acceptable salt thereof.

[0125] In this embodiment, the compound is -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(pentafluoro-λ 6 -Sulfanyl)phenyl]methanone, -[2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(pentafluoro-λ 6 -Sulfanyl)phenyl]methanone, -[4-(cyclopropoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-(1,1,2,2,2-pentafluoroethyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -Cyclohexyl-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]methanone, -[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-fluoro-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetan-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[tetrahydrofuran-3-yl]oxy-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -Trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(4-hydroxycyclohexyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(4-methylpiperazine-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(tetrahydropyran-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(tetrahydropyran-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-(2-morpholino-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-(4,4-difluoro-1-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]methanone, -[2-amino-4-(pentafluoro-λ 6-Sulfanyl)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetane-3-yloxy)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, The group consists of these and their pharmaceutically acceptable salts, which are selected from this group.

[0126] In this embodiment, the compound is -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(pentafluoro-λ 6 -Sulfanyl)phenyl]methanone, -[2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(pentafluoro-λ 6-Sulfanyl)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(pentafluoro-λ 6 -Sulfanyl)phenyl]methanone, -[4-(cyclopropoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-(1,1,2,2,2-pentafluoroethyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -Cyclohexyl-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]methanone, -[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-fluoro-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, The group consists of these and their pharmaceutically acceptable salts, which are selected from this group.

[0127] In embodiments where the compound has an enantiomer form (for example, where the compound has a chiral center, e.g., a chiral carbon atom), the compound exists as a racemic mixture of enantiomers. In embodiments where the compound has a chiral center (e.g., a chiral carbon atom), the compound exists as an (R) isomer. In other embodiments where the compound has a chiral center (e.g., a chiral carbon atom), the compound exists as an (S) isomer. Therefore, in embodiments, the compound is, -(rac)-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -(rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(3S)-tetrahydrofuran-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(3R)-tetrahydrofuran-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -(rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]methanone, -(rac)-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]-[4-(trifluoromethoxy)phenyl]methanone, The group consists of these and their pharmaceutically acceptable salts, which are selected from this group.

[0128] In this embodiment, the compound is -(rac)-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -(rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(3S)-tetrahydrofuran-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(3R)-tetrahydrofuran-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -(rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]methanone, -(rac)-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(3R)-tetrahydrofuran-3-yl]oxy-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(3S)-tetrahydrofuran-3-yl]oxy-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -(rac)-trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(4-hydroxycyclohexyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-[[(3R)-tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-[[(3S)-tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[(3R)-tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[(3S)-tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -(rac)-[4-[2-(tetrahydrofuran-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -(rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(tetrahydrofuran-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -(rac)-[2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]methanone, The group consists of these and their pharmaceutically acceptable salts, which are selected from this group.

[0129] In some embodiments, the compound is selected from the compounds produced in Examples 1 to 44 (i.e., selected from the group consisting of compounds 1 to 44) and their pharmaceutically acceptable salts. In other embodiments, the compound is selected from the compounds that can be obtained by the synthesis method described in any one of Examples 1 to 44 (i.e., the method for synthesizing compounds 1 to 44) and their pharmaceutically acceptable salts.

[0130] In some embodiments, the compound is selected from the compounds produced in Examples 1 to 26 (i.e., selected from the group consisting of compounds 1 to 26) and their pharmaceutically acceptable salts. In other embodiments, the compound is selected from the compounds that can be obtained by the synthesis method described in any one of Examples 1 to 26 (i.e., the method for synthesizing compounds 1 to 26) and their pharmaceutically acceptable salts. In some embodiments, the compound is -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -(rac)-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -(rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(3S)-tetrahydrofuran-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(3R)-tetrahydrofuran-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(pentafluoro-λ 6 -Sulfanyl)phenyl]methanone, -[2-amino-4-(pentafluoro-λ 6-Sulfanyl)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(pentafluoro-λ 6 -Sulfanyl)phenyl]methanone, -[4-(cyclopropoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-(1,1,2,2,2-pentafluoroethyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -Cyclohexyl-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -(rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]methanone, -(rac)-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-fluoro-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, The group consists of these and their pharmaceutically acceptable salts, which are selected from this group. Due to functional activation

[0131] In embodiments, the compounds of the present disclosure are characterized according to their inhibitory activity against ERK5, as measured, for example, according to a cell-based assay or cell-free assay described in the following examples. In embodiments, the compounds have an IC50 of less than about 10 μM against ERK5 (when measured, for example, according to a cell-free assay described below). 50 It has a value. In embodiments, the compound has an IC50 of less than approximately 5 μM against ERK5 (for example, when measured according to the cell-free assay described below). 50 The compound has a value of less than about 2 μM relative to ERK5, e.g., about 1 μM, 0.5 μM, 0.2 μM, 100 nM, or less than 50 nM IC5 (when measured according to the cell-free assay described below, for example). 50 It has a value. In embodiments, when the compound is measured according to the cell-free assay described below, it has an IC50 of less than 10 μM relative to ERK5. 50 The compound has a value of less than about 5 μM relative to ERK5, for example, about 2 μM, about 1 μM, 0.5 μM, 0.2 μM, 100 nM, or less than 50 nM, when measured according to the cell-free assay described below. 50 It has a value. In embodiments, when the compound is measured according to the cell-based assay described below, it has an IC50 of less than approximately 10 μM against ERK5. 50The compound has a value of less than about 5 μM relative to ERK5, for example, about 2 μM, about 1 μM, 0.5 μM, 0.2 μM, 100 nM, or less than 50 nM, when measured according to the cell-based assay described below. 50 It has a value.

[0132] In one embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, and 26. In another embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 26. In another embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 7, 10, 12, 13, 14, 15, 16, 18, and 19. In another embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 10, 12, 13, 14, 16, and 18.

[0133] In one embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 26. In another embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 26. In another embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, and 21. In another embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 7, 10, 11, 12, 13, 14, 15, 16, and 19. In other embodiments, the compound is selected from the compounds of Examples 1, 2, 4, 10, 11, 13, 14, 15, and 16.

[0134] In one embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 28, 29, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44. In another embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 26, 28, 30, 31, 32, 33, 36, 37, 38, 39, and 40. In other embodiments, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 7, 10, 12, 13, 14, 15, 16, 18, 19, 30, 31, 32, 37, and 39.

[0135] In one embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 43, and 44. In another embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, and 39. In other embodiments, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, and 39. In other embodiments, the compound is selected from the compounds of Examples 1, 2, 3, 4, 7, 10, 11, 12, 13, 14, 15, 16, 19, 30, 31, 34, 35, and 37. In other embodiments, the compound is selected from the compounds of Examples 1, 2, 4, 10, 11, 13, 14, 15, 16, 30, 34, and 37. In other embodiments, the compound is selected from the compounds of Examples 1, 2, 4, 10, 11, 13, 14, 15, 16, and 30.

[0136] Pharmaceutical composition This disclosure provides pharmaceutical compositions comprising a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient or carrier.

[0137] In the embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IA) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IB) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IC) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (ID) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IE) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IF) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IG) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (II-A) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (II-B) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (III-A) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IV) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IV-A) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (V) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (VA) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (VI) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (VII) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (VIII) or a pharmaceutically acceptable salt thereof.

[0138] The pharmaceutical compositions of this disclosure can be formulated for administration in solid or liquid form, for example, using conventional carriers or excipients. The compositions can be adapted, for example, using techniques known in the art, for oral administration (e.g., as a solution, suspension, tablet, or capsule), parenteral administration (e.g., as a solution, dispersion, suspension, or emulsion, or as a dry powder for reconstitution), or topical application (e.g., as a cream, ointment, patch, or spray applied to the skin).

[0139] Medical use The compounds disclosed herein act as ERK5 inhibitors and are useful in treating ERK5-related disorders and conditions. In particular, the compounds disclosed herein are useful in the treatment of cancer.

[0140] In this embodiment, the Disclosure provides a method of treatment comprising administering a therapeutically effective amount of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) to a subject in need of treatment. In a related embodiment, the Disclosure provides the use of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product. In a further related embodiment, the Disclosure provides the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in therapy.

[0141] The compounds of this disclosure are useful for treating or preventing diseases or adverse conditions in which ERK5 or its variants or variants are known to play a role; diseases or disorders associated with increased MAPK7 (i.e., ERK5 gene) expression and / or increased ERK5 activity; and diseases or disorders in which inhibition or antagonism of ERK5 activity is beneficial.

[0142] In one aspect, the Disclosure provides a method for treating or preventing a disease or disorder mediated by ERK5, or a disease or disorder involving ERK5, in a subject in need thereof, comprising administering an effective amount of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) to the subject. In a related aspect, the Disclosure provides the use of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product for treating or preventing a disease or disorder mediated by ERK5, or a disease or disorder involving ERK5. In a further related aspect, the Disclosure provides the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in treating or preventing a disease or disorder mediated by ERK5, or a disease or disorder involving ERK5.

[0143] In another aspect, the Disclosure provides a method for treating or preventing an ERK5-related disease or disorder (e.g., cancer) in a subject requiring treatment or prevention of the disease or disorder, comprising administering an effective amount of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) to the subject. In a related aspect, the Disclosure provides the use of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product for treating or preventing an ERK5-related disease or disorder (e.g., cancer). In a further related aspect, the Disclosure provides the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in treating or preventing an ERK5-related disease or disorder (e.g., cancer).

[0144] In another aspect, the Disclosure provides a method for treating or preventing cancer in a subject requiring treatment or prevention of cancer, comprising administering an effective amount of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) to the subject. In a related aspect, the Disclosure provides the use of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product for treating or preventing cancer. In a further related aspect, the Disclosure provides the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in treating or preventing cancer.

[0145] In the embodiments, the compound reduces angiogenesis, reduces or prevents metastasis, reduces inflammation, blocks tumorigenesis (e.g., partially or completely), reduces evasion of growth inhibition, reduces or inhibits the growth of cancerous or precancerous cells, suppresses the proliferation of cancerous or precancerous cells, and / or reduces the survival of cancerous or precancerous cells.

[0146] In one embodiment, cancer is characterized by increased MAPK7 (i.e., ERK5 gene) expression and / or increased ERK5 activity. In another embodiment, cancer has elevated ERK5 activity. In yet another embodiment, cancer overexpresses ERK5. In yet another embodiment, cancer is characterized by MAPK7 genome amplification and / or constitutively active ERK5 signaling.

[0147] In the embodiment, the cancer has genomically amplified ERK5. In the embodiment, the cancer has constitutively active ERK5 signaling.

[0148] In some embodiments, the cancer is a solid tumor (e.g., melanoma, carcinoma, or blastoma). In other embodiments, the cancer is a leukemia (e.g., chronic lymphocytic leukemia, CLL; acute myeloid leukemia, AML; or chronic myeloid leukemia, CML).

[0149] In one embodiment, the cancer is a primary tumor. In another embodiment, the cancer is a secondary tumor (e.g., a metastatic tumor).

[0150] In the embodiment, cancer is selected from breast cancer (e.g., ductal carcinoma or mammary gland carcinoma), liver cancer, kidney cancer (e.g., hepatocellular carcinoma), prostate cancer, colorectal cancer (CRC), lung cancer (e.g., non-small cell lung cancer, NSCLC; lung adenocarcinoma; or lung squamous cell carcinoma), pancreatic cancer (e.g., adenocarcinoma), ovarian cancer, brain cancer (e.g., glioblastoma), cervical cancer (e.g., adenocarcinoma), gastric cancer, skin cancer (e.g., melanoma), bile duct cancer (e.g., cholangiocarcinoma), nervous system cancer (e.g., neuroblastoma), and melanoma.

[0151] In the embodiment, cancer is selected from leukemia (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, or chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenström macroglobulinemia, and multiple myeloma.

[0152] In the embodiment, the cancer is selected from leukemia (e.g., chronic myeloid leukemia), breast cancer, multiple myeloma, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, melanoma, and hepatocellular carcinoma.

[0153] In this embodiment, the cancer is selected from leukemia (e.g., chronic myeloid leukemia), breast cancer, multiple myeloma, colon cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, and hepatocellular carcinoma.

[0154] In another embodiment, the Disclosure provides a method for inhibiting ERK5 activity, comprising contacting ERK5 (e.g., cells containing ERK5) with a compound of the Disclosure (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof). In embodiments, the method is in vitro or ex vivo. In other embodiments, the method is in vivo. In relevant embodiments, the Disclosure provides an in vitro method for inhibiting ERK5 activity in cells, comprising contacting cells with a compound of the Disclosure (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof).

[0155] The compounds of this disclosure (e.g., compounds of formula (I)) and pharmaceutically acceptable salts thereof may be administered as pharmaceutical compositions that may optionally contain one or more pharmaceutically acceptable excipients.

[0156] It will be understood that various aspects of the methods and treatments of the present disclosure can be achieved by administering an effective amount of the compound of the present disclosure (e.g., the compound of formula (I) or a pharmaceutically acceptable salt thereof) to a subject in the form of a pharmaceutical composition which may optionally contain one or more pharmaceutically acceptable excipients, as described herein.

[0157] The compounds of this disclosure may be used alone (for example, as monotherapy) or in combination with one or more cancer therapies.

[0158] As generally described herein, non-limiting embodiments are provided below to further illustrate the present disclosure. [Examples]

[0159] General synthesis scheme The following scheme, Scheme 1A, illustrates an exemplary method for preparing compounds in accordance with the present disclosure and examples. [ka]

[0160] Scheme 1A (wherein R 1 , R 2 , and n can be defined, for example, as described above, R 3 However, it is -H or -CH3, and L 1 According to the formula, compound 1B (where X is directly bonded), 1 However, it could be, for example, I, or Br, and X 2 However, for example, it could be Br or Cl) is NIS or NBS (i.e., X 1 The compound 1A can be obtained in step 1 by halogenation with either I or Br, for example, the reagent is X 1 and X 2The halogens can be selected to be different. Compound 1C can be protected in step 2 by N-alkylation of compound 1B using, for example, a base such as sodium hydride and an alkylating agent such as SEM-Cl. Compound 1E can be obtained in step 3 by Suzuki coupling between compound 1C and compound 1D by heating to reflux in the presence of a base such as sodium carbonate and using a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in a mixture of dioxane and water, for example. Compound 1G can be obtained by heating compound 1E and compound 1F (wherein R is R) by heating to reflux in the solvent using a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in a mixture of dioxane and water, for example. 1 Precursors to R 1 It can be prepared by Suzuki coupling in step 4 between (which is an oxidized or protected analog of) compound 1G. Compound 1G can be reduced to compound 1H in step 5 by hydrogenation with a catalyst such as Pd / C under a hydrogen pressure of about 5 bar (H2) at 40°C. Step 5 can optionally be reduced to R by etherification by hydrogenation with Pd / C and H2 or reduction with LiAlH4 and alkylhalogenation (e.g., as in Example 6). 1 This may further include modification of R to . Compound 1H can then be converted to compound 1I in step 6 by deprotection using TFA or HCl in DCM. Compound 1K can then be prepared in step 7 using carboxylic acid compound 1J from compound 1I using conditions known to those skilled in the art, such as EDC in a solvent such as DMF in the presence of a base such as DIPEA. Step 7 optionally involves R 1 It may further include modifications. For example, R 1 A compound in which the oxo is substituted is reduced, for example, using a hydrogenation reagent, R 1 However, a corresponding compound substituted with -OH may be obtained.

[0161] L 1However, in the preparation of the compounds of this disclosure which are -O-, the conversion of compound 1C to compound 1H' can be carried out according to the following schemes, scheme 1B: [ka]

[0162] Scheme 1B (wherein R 1 , R 3 , X 1 , X 2 , and n can be defined, for example, as described above, L 1 According to the formula (where R is -O-), compound 1M is converted using a base such as tBuOK to compound 1L (where R is R 1 , or R 1 Precursors of, for example, R 1 Compound 1N can then be prepared in step 1 by nucleophilic substitution of compound 1C by a protected analog of (which may be a protected analog of). Compound 1N is then prepared in step 2 by Suzuki coupling between compound 1M and compound 1D' (wherein A is selected from R2 as defined herein, and a precursor to R2 (e.g., having a -NO2 group instead of a -NH2 group) by heating to reflux using a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in a mixture of dioxane and water, and in the presence of a base such as sodium carbonate), or by protecting the carbonyl it is bonded to (e.g., BOC(A is Compound 1N can form -O-tBu, or Cbz (where A is -OBn). Compound 1N can be reduced to compound 1H in step 3 by hydrogenation with a catalyst such as Pd / C under a hydrogen pressure of approximately 5 bar (H2) at 40°C. Step 3 can optionally be reduced by deprotection (e.g., removal of the Boc group using TFA in DCM, or removal of the Cbz group by hydrogenation in step 3), and optionally by reductive amination with an aldehyde such as formaldehyde in the presence of a hydrogenation reagent such as sodium cyanohydride. 1 This may further include modification of R to . Compound 1H' is then converted to the compound of the present disclosure (e.g., L) by following steps 6 and 7 of scheme 1A above.1 However, it can be converted to a compound of formula (I) which is -O-.

[0163] L 1 However, in the preparation of compounds that are -NH-, the conversion of compound 1C to compound 1H' can be carried out according to the following scheme, scheme 1C: [ka]

[0164] Scheme 1C (wherein R 1 , R 3 , X 2 And n can be defined, for example, as described above, L 1 According to the formula (wherein R is -NH-), compound 1O can be prepared in step 1 by Suzuki coupling of compound 1C and compound 1D' (wherein A can be defined as above, for example) by heating to reflux in the presence of a base such as sodium carbonate and using a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in a mixture of dioxane and water. Then, compound 1N' can be prepared in step 2 by Suzuki coupling of compound 1C and compound 1L' (wherein R is R) by heating to reflux in the presence of a base such as tBuONa and using a catalyst such as tris(dibenzylideneacetone)dipalladium and RuPhos in dioxane. 1 , or R 1 Precursors to R 1 It can be prepared by Buchwald coupling with (which may be a protected analog of). Compound 1N' can be reduced to compound 1H' in step 3 by hydrogenation with a catalyst such as Pd / C under a hydrogen pressure of about 5 bar (H2) at 40°C. Step 3 can be optionally reduced by deprotection (e.g., removal of the Boc group using TFA in DCM), and optionally by reductive amination with an aldehyde such as formaldehyde in the presence of a hydrogenation reagent such as sodium cyanohydride. 1This may further include modification of R to . Compound 1H' is then converted to the compound of the present disclosure (e.g., L) by following steps 6 and 7 of scheme 1A above. 1 However, it can be converted to a compound of formula (I) which is -NH-.

[0165] In schemes 1B and 1C, group A in compound 1D' corresponds to R in step 3 of scheme 1B or 1C. 1 The optional modification of R can be selected so as to be performed without modifying A. For example, if A is -O-tBu, R may contain an amine having a Cbz protecting group that can be modified, for example as described above, without affecting the protecting group containing A.

[0166] Alternatively, group A in compound 1D' may be converted in step 3 of scheme 1B or 1C, for example, to R 2 By converting (A is R 2 The group may also be modified by removing the protecting group to provide compound 1I, as described in scheme 1A above, or by being a precursor to R. 2 Compounds of the present disclosure containing the -NH2 group can be obtained by reduction of -NO2, for example, by hydrogenation with H2 and Pd / C in step 3 of scheme 1B or 1C above; in this scenario, step 3 of scheme 1B or 1C is compound 1H, i.e., A is the group R as defined herein. 2 This provides compound 1H', which is -OBn (i.e., forming a Cbz protecting group on the nitrogen atom of the heterocyclic group), then the hydrogenation in step 3 of scheme 1B or 1C may also remove the Cbz group and provide compound 1I as described in scheme 1A above. Compound 1I is then converted to the compounds of the present disclosure (e.g., L) by following step 7 of scheme 1A above. 1 However, it can be converted to a compound of formula (I) which is -O- or -NH-. These and other suitable protection / deprotection strategies will be readily apparent to those skilled in the art in light of this disclosure.

[0167] If not commercially available, compound 1D' can be prepared, for example, by the following scheme, scheme 1D. [ka]

[0168] According to scheme 1D (wherein n may be defined, for example, as described above), compound 1D can be deprotected, for example, using TFA in DCM to obtain compound 1P. Compound 1D' (wherein A may be defined, for example, as described above) can then be prepared from compound 1P and compound 1Q using amide coupling conditions such as HATU in DMF. If not commercially available, compound 1Q can be obtained from the corresponding nitrile compound, for example, using H2SO4 and AcOH in water. Other methods for preparing carboxylic acids such as compound 1Q will be apparent to those skilled in the art in consideration of this disclosure.

[0169] L 1 However, in the preparation of the -O- compound, the conversion of compound 1E to compound 1H' can be carried out according to the following scheme, scheme 1E: [ka]

[0170] Scheme 1E(R 1 , X 2 , and n can be defined, for example, as described above, L 1 However, it is -O- and R 3 According to the formula, compound 1G' is heated to reflux using a catalyst such as XPhosPdG4 in dioxane and in the presence of a base such as tBuONa, thereby enabling the palladium coupling reaction between compound 1E and compound 1L in step 1 (wherein R is R 1 , or R 1 Precursors to R 1Compound 1G can be obtained by (possibly a protected analogue of) compound 1G can be reduced to compound 1H in step 2 by hydrogenation using a catalyst such as Pd / C under a hydrogen pressure of 1 to 5 bar (H2) at room temperature to 40°C. Step 2 can be optionally reduced by, for example, deprotection (e.g., removal of the Cbz group by hydrogenation in step 2), and optionally by reductive amination using an aldehyde such as formaldehyde in the presence of a hydrogenation reagent such as sodium cyanohydride. 1 Further modifications of R to it may be included.

[0171] R 1 However, it is a heterocycloalkyl group linked to the rest of the molecule via a heteroatom (e.g., a nitrogen atom), L 1 However, in the preparation of compounds with direct bonding, the conversion of compound 1E to compound 1H can be carried out according to the following scheme, scheme 1F: [ka]

[0172] Scheme 1F(R 1 , X 2 , and n can be defined, for example, as described above, L 1 However, it is a direct bond, R 3 According to the formula, compound 1S is subjected to a palladium coupling reaction in step 1 between compound 1E and compound 1R (wherein ring E is R), by heating to reflux using a catalyst such as XPhosPdG4 in dioxane and in the presence of a base such as tBuONa. 1 , or R 1 Precursors to R 1 It can be obtained by (which may be a protected analogue of). Compound 1S can be reduced to compound 1H in step 2, for example, by hydrogenation using a catalyst such as Pd / C under a hydrogen pressure of 1 to 5 bar (H2) at room temperature to 40°C.

[0173] Compounds of the present disclosure in which Y is N may be synthesized by the methods shown above, for example, using modified versions of schemes 1A, 1B, or 1C. The following scheme 2A shows how such compounds may be prepared by scheme 1A. [ka]

[0174] Scheme 2A (wherein R 1 and R 2 However, it can be defined as above, for example, R 3 However, it is -H or -CH3, and L 1 According to the formula, compound 1B (where X is directly bonded), 1 However, it could be, for example, Br or Cl, and X 2 However, for example, it could be I, or Br) is NBS or NCS (i.e., X 1 The compound 1A can be obtained in step 1 by halogenation with either Br or Cl, for example, the reagent is X 1 and X 2 The halogens can be selected to be different. Compound 1C can be protected in step 2 by N-alkylation of compound 1B using a base such as sodium hydride and an alkylating agent such as SEM-Cl. Compound 2A can be protected in step 3 by heating to reflux of the solvent using a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in a mixture of dioxane and water, and in the presence of a base such as sodium carbonate, so as to compound 1C (wherein X is used in the formula). 2 However, it may be I or Br) and compound 1F (wherein R is R 1 or R 1 Precursors to R 1Compound 2H can be obtained by Suzuki coupling between (an oxidized or protected analog of) compound 2A and compound 2D in step 4 by heating at 140°C using a catalyst such as CUI in DMSO and in the presence of a base such as proline and potassium carbonate. Step 4 is optionally performed by, for example, if R has a double bond 1 If it is a precursor of R, then R 1 Step 4 may further include a step of conversion, and step 4 may further include reduction by hydrogenation with a catalyst such as Pd / C under a hydrogen pressure (H2) of about 5 bar at 40°C. For example, deprotection of compound 2H in step 5 using TFA or HCl in DCM can yield compound 2I. Compound 2K can then be prepared in step 6 using carboxylic acid compound 1J from compound 2I using conditions known to those skilled in the art, such as EDC in a solvent such as DMF in the presence of a base such as DIPEA. 1 Corresponding compounds in which are -O- or -NH- can be obtained, for example, by making similar modifications to schemes 1B and 1C above. For example, compound 1M can be used in place of compound 2A in the scheme above (L 1 (A compound in which is -O- can be obtained), or a product can be obtained by reacting compound 1C with compound 2D (not compound 1D) in step 3 of scheme 1A, and then proceeding through a process similar to scheme 1C (L 1 (A compound with -NH- is obtained).

[0175] R 3 Compounds in which the hyphen is -OH may be accessible, for example, by following the synthesis procedure described in U.S. Patent Application Publication No. 2005 / 0288299A1. 3 The intermediate in which is -OH can be protected for some of the above synthesis steps, for example, by etherification. 1 However, compounds that are directly bonded to the pyrrolopyrazine core via a tertiary carbon atom (for example, R 1However, the bicyclo[1.1.1]pentanyl group) is, for example, a heteroaryl halide such as compound 1E, which is, for example, in the form of a redox-active ester, as described in Polites et al., Org. Lett. (2021) 23(12):4828-4833. 1 This can be obtained by a modified version of Scheme 1A that directly reacts with R. 1 However, compounds that are directly bonded to a pyrrolopyrazine core via a tertiary carbon atom having one oxygen substituent (e.g., R A However, if it is -OH or -O(C1-C3)alkyl, it can be obtained, for example, by alkylating the carbonyl group directly bonded to the pyrrolopyrazine core at that position using an alkylating agent such as MEI in the presence of a base such as NaH, or by further alkylating the -OH group obtained using an alkylating agent such as MEI in the presence of a base such as NaH.

[0176] Experimental Techniques At 400MHz and 500MHz 1 ¹H NMR spectra were obtained using Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometers, respectively, and the chemical shift (δ(ppm)) in the solvent dimethyl sulfoxide-d6 (DMSO-d6) was referenced at 2.5 ppm at the cited temperature. The coupling constant (J) is given in Hertz units.

[0177] Liquid chromatography / mass spectroscopy (LC / MS) was performed using a UPLC Acquity Waters instrument, a Sedere light scattering detector, and a SQD Waters mass spectrometer. UV (210-400 nm) was detected using a DAD. A flash Acquity UPLC CSH C18 (1.7 μm, dimensions 2.1 × 30 mm) was used, with H2O + 0.1% HCO2H / CH3CN + 0.1% HCO2H as the mobile phase.

[0178] All synthesis reactions were carried out under an inert atmosphere unless otherwise specified. In the following examples, if the source of the starting product is not specified, it should be understood that the product is a known compound (e.g., a compound commercially available from suppliers such as Sigma-Aldrich).

[0179] Examples 1-44 - Compounds Table 1 below lists the compounds synthesized in the following synthesis examples.

[0180] [Table 1]

[0181] [Table 2]

[0182] [Table 3]

[0183] [Table 4]

[0184] [Table 5]

[0185] [Table 6]

[0186] [Table 7]

[0187] [Table 8]

[0188] [Table 9]

[0189] Example 1: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka]

[0190] Step 1: 2-Bromo-7-iodine-5H-pyrrolo[2,3-b]pyrazine [ka] A mixture of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (5.00 g, 0.25.2 mmol) and N-iodosuccinimide (6.82 g, 30.3 mmol) in N,N-dimethylformamide (40 mL) was stirred at room temperature for 16 hours. The mixture was then diluted with brine (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with saturated sodium chloride aqueous solution (100 mL x 2), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine (8.17 g, 24.2 mmol, yield: 96%) as a yellow solid. LC / MS (m / z, M+H): Calculated value 324.9, Measured value 324.9

[0191] Step 2: 2-[(2-bromo-7-iodo-pyrrolo[2,3-b]pyridine-5-yl)methoxy]ethyl-trimethyl-silane [ka] A mixture of 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine (8.17 g, 24.1 mmol) in N,N-dimethylformamide (60 mL) was mixed with a 60% dispersion of sodium hydride in oil (1.45 g, 15.1 mmol) at 0°C. After the addition, the mixture was stirred at room temperature for 1 hour. Then, 2-(chloromethoxy)ethyl-trimethyl-silane (4.82 g, 28.9 mmol) was slowly added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with brine (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over Na2SO4, concentrated under vacuum, and the resulting residue was purified by silica gel flash chromatography (0-5% ethyl acetate in petroleum ether) to obtain 2-[(2-bromo-7-iodo-pyrrolo[2,3-b]pyrazine-5-yl)methoxy]ethyl-trimethyl-silane (9.05 g, 19.9 mmol, yield: 83%) as a yellow solid. LC / MS (m / z, M+H): Calculated value 455.2, measured value 455.9

[0192] Step 3: tert-butyl4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] A mixture of 2-[(2-bromo-7-iodopyrrolo[2,3-b]pyrazine-5-yl)methoxy]ethyl-trimethyl-silane (9.05 g, 0.0199 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (6.16 g, 19.9 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.729 g, 0.996 mmol), and disodium carbonate (6.34 g, 59.8 mmol) in 1,4-dioxane (200 mL) and water (40 mL) was stirred at 80°C for 3 hours under an N2 atmosphere. The mixture was then diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (0-6% ethyl acetate in petroleum ether) to obtain tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (4.62 g, 9.07 mmol, yield: 45%) as a yellow solid. LC / MS (m / z, M-tBu+H): Calculated value 453.1, measured value 453.0

[0193] Step 4: tert-butyl4-[2-(1-methyl-3,6-dihydro-2H-pyridine-4-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] A mixture of tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.5 g, 2.94 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (0.657 g, 2.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.108 g, 0.147 mmol), and sodium carbonate (0.936 g, 8.83 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was stirred at 80°C for 3 hours under an N2 atmosphere. Next, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with brine (40 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography (0-15% ethyl acetate in petroleum ether) to obtain tert-butyl 4-[2-(1-methyl-3,6-dihydro-2H-pyridine-4-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.20 g, 2.28 mmol, yield: 77%). LC / MS (m / z, M+H): 526

[0194] Step 5: tert-butyl4-[2-(1-methyl-4-piperidyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-[2-(1-methyl-3,6-dihydro-2H-pyridine-4-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.20 g, 2.28 mmol) and 5% Pd / C (1 g) in ethyl acetate (40 mL) was stirred at room temperature under an H2 atmosphere for 3 hours. The mixture was then filtered and concentrated under vacuum to obtain tert-butyl 4-[2-(1-methyl-4-piperidyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (1.10 g, crude). LC / MS (m / z, M+H): Calculated value 530.3, Measured value 530.3

[0195] Step 6: 2-(1-methyl-4-piperidyl)-7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine [ka] A mixture of tert-butyl 4-[2-(1-methyl-4-piperidyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (1.10 g, 2.08 mmol) in trifluoroacetic acid (4 mL) and dichloromethane (4 mL) was stirred at room temperature for 2 hours. The mixture was then concentrated. The resulting residue was dissolved in methanol (30 mL) and 30% aqueous ammonia solution (5 mL) was added. The resulting mixture was stirred at room temperature for 4 hours. The mixture was then concentrated, and the resulting residue was purified by reverse-phase chromatography (0-40% acetonitrile (0.5%) in aqueous trifluoroacetic acid) to obtain 2-(1-methyl-4-piperidyl)-7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine (0.400 g, 1.34 mol, yield: 64%). LC / MS (m / z, M+H): Calculated value 300.2, Measured value 300.2

[0196] Step 7: tert-butyl N-[2-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate [ka] A mixture of 2-(1-methyl-4-piperidyl)-7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine (0.200 g, 0.651 mmol), 2-(tert-butoxycarbonylamino)-4-(trifluoromethoxy)benzoic acid (0.209 g, 0.651 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.313 g, 0.976 mmol), and N-ethyl-N-isopropyl-propan-2-amine (0.252 g, 0.195 mmol) in N,N-dimethylformamide (8 mL) was stirred at room temperature for 3 hours. The mixture was then diluted with brine (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to obtain tert-butyl N-[2-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (0.120 g, 0.199 mmol, yield: 31%). LC / MS (m / z, M+H): calculated value 603.3, measured value 603.3.

[0197] Step 8: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] To a solution of tert-butyl N-[2-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (0.120 g, 0.199 mmol) in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction product was then concentrated, and the residue was purified by preparative HPLC to obtain [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone (0.031 g, 0.062 mmol, yield: 31%) as a white solid. LC / MS (m / z, M+H): Calculated value 503.2, Measured value 503.4. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.76-1.96(m,6H),2.00-2.12(m,4H),2.22(s,3H),2.70-2.81(m,1H),2.88(br d,J=12Hz,2H),3.05-3.25(m,3H),4.09(br d,J=13Hz,2H),5.31(s,2H),6.47(br dd,J=8,1Hz,1H),6.67(br d,J=1Hz,1H),7.13(d,J=8Hz,1H),7.48(s,1H),8.09(s,1H),11.06-11.48(m,1H)

[0198] Example 2: [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone [ka]

[0199] Step 1: tert-butyl4-[2-(3,6-dihydro-2H-pyran-4-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] A mixture of tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.5 g, 2.94 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.618 g, 2.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.108 g, 0.147 mmol), and sodium carbonate (0.936 g, 8.83 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was stirred at 80°C for 3 hours under an N2 atmosphere. Next, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with brine (40 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography (0-15% ethyl acetate in petroleum ether) to obtain tert-butyl 4-[2-(3,6-dihydro-2H-pyran-4-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.10 g, 2.15 mmol, yield: 73%). LC / MS (m / z, M+H): Calculated value 513.3, Measured value 513.3

[0200] Step 2: tert-butyl4-[2-tetrahydropyran-4-yl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-[2-(3,6-dihydro-2H-pyran-4-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.10 g, 2.15 mmol) and 5% Pd / C (1 g) in ethyl acetate (40 mL) was stirred at room temperature under an H2 atmosphere for 3 hours. The mixture was filtered and concentrated to obtain tert-butyl 4-[2-tetrahydropyran-4-yl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (1.10 g, crude). LC / MS (m / z, M+H): Calculated value 517.3, Measured value 517.3

[0201] Step 3: 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine [ka] A mixture of tert-butyl 4-[2-tetrahydropyran-4-yl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (1.00 g, 1.94 mmol) in trifluoroacetic acid (4 mL) and dichloromethane (1 mL) was stirred at room temperature for 2 hours. The mixture was then concentrated. The resulting residue was dissolved in methanol (30 mL), 30% aqueous ammonia (5 mL) was added, and the resulting mixture was stirred at room temperature for 4 hours. The mixture was concentrated, and the resulting residue was purified by reverse-phase chromatography (0-40% acetonitrile in 0.5% aqueous trifluoroacetic acid) to obtain 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine (0.400 g, 1.40 mmol, yield: 72%). LC / MS (m / z, M+H): Calculated value 287.2, Measured value 287.2

[0202] Step 4: tert-butyl N-[2-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate [ka] A mixture of 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine (0.200 g, 0.70 mmol), 2-(tert-butoxycarbonylamino)-4-(trifluoromethoxy)benzoic acid (0.224 g, 0.70 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.336 g, 1.05 mmol), and N,N-diisopropylethylamine (0.271 g, 2.10 mmol) in N,N-dimethylformamide (8 mL) was stirred at room temperature for 3 hours. The mixture was diluted with brine (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The obtained residue was purified by preparative HPLC to obtain tert-butyl N-[2-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]piperidine-7-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (0.247 g, 4.19 mmol, yield: 60%). LC / MS (m / z, M+H): Calculated value 590.2, Measured value 590.2

[0203] Step 5: [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone [ka] To a solution of tert-butyl N-[2-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (0.411 g, 0.70 mmol) in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction product was then concentrated, and the crude residue was purified by preparative HPLC to obtain [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone (0.0627 g, 0.128 mmol, yield: 18%) as a white solid. LC / MS (m / z, M+H): Calculated value 490.2, Measured value 490.2 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.66-1.99(m,6H),2.03-2.20(m,2H),2.99-3.31(m,4H),3.50(ddd,J=11.4,11.4,2.9Hz,2H),3.90-4.03(m,2H),4.09(br d,J=13.3Hz,2H),5.31(s,2H),6.47(br d,J=8.2Hz,1H),6.66-6.70(m,1H),7.12(d,J=8.4Hz,1H),7.50(s,1H),8.11(s,1H),11.18-11.38(m,1H)

[0204] Example 3: [4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka] A mixture of 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine (0.200 g, 0.70 mmol), 4-(trifluoromethoxy)benzoic acid (0.144 g, 0.70 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.336 g, 1.05 mmol), and N-ethyl-N-isopropyl-propan-2-amine (0.271 g, 2.10 mmol) in N,N-dimethylformamide (4 mL) was stirred at room temperature for 3 hours. The mixture was then diluted with brine (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The obtained residue was purified by preparative HPLC to obtain [4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (0.0501 g, 0.106 mmol, yield: 15%). LC / MS (m / z, M+H): Calculated value 475.2, Measured value 475.3. 1 H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.78-1.98(m,6H),2.10(br dd,J=13,3Hz,2H),3.02-3.29(m,4H),3.51(td,J=11,3Hz,2H),3.93-4.01(m,2H),4.08(br d,J=12Hz,2H),7.36(br d,J=9Hz,2H),7.49(d,J=2Hz,1H),7.53(d,J=9Hz,2H),8.11(s,1H),11.16(br s,1H)

[0205] Example 4: [4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka] A mixture of 2-(1-methyl-4-piperidyl)-7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine (0.200 g, 0.67 mmol), 4-(trifluoromethoxy)benzoic acid (0.138 g, 0.67 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.322 g, 1.00 mmol), and N-ethyl-N-isopropyl-propan-2-amine (0.259 g, 2.00 mmol) in N,N-dimethylformamide (4 mL) was stirred at room temperature for 3 hours. The mixture was diluted with brine (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over Na2SO4, concentrated under vacuum, and the resulting residue was purified by preparative HPLC to obtain [4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methane (0.0210 g, 0.043 mmol, yield: 6.5%). LC / MS (m / z, M+H): Calculated value 488.2, Measured value 488.2. 1 H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.79-1.97(m,6H),2.02-2.15(m,4H),2.22(s,3H),2.69-3.00(m Partially hidden,3H),3.09-3.31(m,3H),4.04-4.14(m,2H),7.36(br d,J=8Hz,2H),7.47(s,1H),7.53(d,J=8Hz,2H),8.08(s,1H),10.47-11.73(m,1H)

[0206] Example 5: (rac)-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka]

[0207] Step 1: tert-butyl4-[2-(2,5-dihydrofuran-3-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] A mixture of tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (100 mg, 0.20 mmol), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.0404 g, 0.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0144 g, 0.02 mmol), and sodium carbonate (0.0624 g, 0.59 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 80°C for 4 hours under an N2 atmosphere. Next, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with brine (40 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by SGC (elution with 0-15% ethyl acetate in petroleum ether) to obtain tert-butyl 4-[2-(2,5-dihydrofuran-3-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (805 mg, 82%) as a white solid. LC / MS (m / z, M+H): Calculated value 499.3, measured value 499.2

[0208] Step 2: (rac)-tert-butyl4-[2-tetrahydrofuran-3-yl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-[2-(2,5-dihydrofuran-3-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (800 mg, 1.50 mmol) in ethyl acetate (10 mL), Pd / C (20% by weight, 160 mg) was added. The mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was then purified by silica gel chromatography (15% ethyl acetate in petroleum ether) to obtain (rac)-tert-butyl 4-[2-tetrahydrofuran-3-yl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (0.670 mg, 0.88 mmol, yield: 55%). LC / MS (m / z, M+H): Calculated value 503.3, Measured value 503.0

[0209] Step 3: (rac)-7-(4-piperidyl)-2-tetrahydrofuran-3-yl-pyrrolo[2,3-b]pyrazine-5-yl]methanol [ka] A solution of (rac)-tert-butyl 4-[2-tetrahydrofuran-3-yl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (620 mg, 0.82 mmol) in dichloromethane (6 mL) was mixed with trifluoroacetic acid (6 mL) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to obtain a yellow oil (510 mg, 0.82 mmol, crude), which was used in the next step without further purification. LC / MS (m / z, M+30): Calculated value 303.2, Measured value 303.3

[0210] Step 4: (rac)-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka] To a solution of (rac)-7-(4-piperidyl)-2-tetrahydrofuran-3-yl-pyrrolo[2,3-b]pyrazine-5-yl]methanol (510 mg, 0.82 mmol) and 4-(trifluoromethoxy)benzoic acid (343 mg, 1.66 mmol) in N,N-dimethylformamide (5 mL), 1-hydroxybenzotriazole hydrate (255 mg, 1.66 mmol), N'-(ethylcarbonimidoyl)-N,N-dimethylpropane-1,3-diamine hydrochloride (319 mg, 1.66 mmol), and N-ethyl-N-isopropyl-propane-2-amine (537 mg, 4.16 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined and concentrated to obtain crude oil. The crude product was dissolved in a mixed solution of methanol (10 mL) and 30% aqueous ammonia (15 mL). After stirring for 1 hour, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain crude oil. This was purified by silica gel chromatography (3% methanol in dichloromethane) to obtain (rac)-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (288 mg, yield: 75%) as a colorless solid. LC / MS (m / z, M+H): Calculated value 461.2, measured value 461.0. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.78-1.93(m,2H),2.03-2.13(m,2H),2.16-2.37(m,2H),3.06-3.27(m,3H),3.68(quin,J=8Hz,1H),3.76-3.90(m,2H),3.97(td ,J=8,5Hz,1H),4.01-4.20(m,1H),4.11(t,J=8Hz,2H),7.38(d,J=8Hz,2H),7.50-7.59(m,3H),8.13(s,1H),11.00-11.68(m,1H)

[0211] Example 6: [4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka]

[0212] Step 1: tert-butyl4-[2-[(E)-3-ethoxy-3-oxopropa-1-enyl]-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] A mixture of ethyl(E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propa-2-enoate (1.33 g, 5.89 mmol), tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (3.00 g, 5.89 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.129 g, 0.18 mmol), and sodium carbonate (1.87 g, 17.7 mmol) in 1,4-dioxane (30 mL) and water (6 mL) was stirred at 80°C for 3 hours under an algonautifying atmosphere. The reaction mixture was diluted with brine (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over Na2SO4, concentrated, and the resulting residue was purified by silica gel flash chromatography (0-20% ethyl acetate in petroleum ether) to obtain tert-butyl4-[2-[(E)-3-ethoxy-3-oxoprop-1-enyl]-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.6 g, 83%) as a yellow solid. LC / MS (m / z, M-tBu): Calculated value 473.3, Measured value 473.3

[0213] Step 2: tert-butyl4-[2-(3-ethoxy-3-oxopropyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-[2-[(E)-3-ethoxy-3-oxopropa-1-enyl]-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.60 g, 4.92 mmol) and 10% Pd / C (10.0%, 1.30 g) in ethyl acetate (50 mL) was stirred at room temperature under an H2 atmosphere for 48 hours. Next, the reaction mixture was filtered and concentrated, and the resulting residue was purified by silica gel flash chromatography (0-15% ethyl acetate in petroleum ether) to obtain tert-butyl 4-[2-(3-ethoxy-3-oxopropyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (2.3 g, 88%) as a yellow solid. LC / MS (m / z, M+H): Calculated value 533.3, measured value 533.0

[0214] Step 3: tert-butyl4-[2-(3-hydroxypropyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] To a mixture of tert-butyl 4-[2-(3-ethoxy-3-oxopropyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (2.30 g, 0.00432 mol) in tetrahydrofuran (30 mL), 1N LiAlH4 (1.00 mol / L, 5.18 mL, 0.00518 mol) in tetrahydrofuran was slowly added at 0°C. After the addition, the mixture was stirred at 0°C for 1 hour. The reaction mixture was then quenched with Na2SO4.10H2O (5 g) and filtered. The mixture was concentrated with the added solvent. The obtained residue was purified by silica gel flash chromatography (0-25% ethyl acetate in petroleum ether) to obtain tert-butyl 4-[2-(3-hydroxypropyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (1.8 g, 85%) as a yellow solid. LC / MS (m / z, M+H): Calculated value 491.3, Measured value 491.0

[0215] Step 4: tert-butyl4-[2-(3-methoxypropyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-[2-(3-hydroxypropyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (1.80 g, 3.67 mmol) in tetrahydrofuran (30 mL) was mixed with sodium hydride (60%, 0.220 g, 5.50 mmol) at 0°C. After the addition, the mixture was stirred for 1 hour. Then, iodomethane (0.625 g, 4.40 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 72 hours. The reaction mixture was then diluted with brine (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated. The obtained residue was purified by silica gel flash chromatography (0-10% ethyl acetate in petroleum ether) to obtain tert-butyl 4-[2-(3-methoxypropyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (700 mg, 38%) as a yellow solid. LC / MS (m / z, M+H): Calculated value 505.3, measured value 505.2

[0216] Step 5: 2-(3-methoxypropyl)-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol [ka] A mixture of tert-butyl 4-[2-(3-methoxypropyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (0.200 g, 0.4 mmol) in trifluoroacetic acid (2 mL) and dichloromethane (4 mL) was stirred at room temperature for 1 hour. The reaction mixture was then concentrated. The resulting residue was dissolved in methanol (30 mL), and 30% aqueous ammonium hydroxide solution (5 mL) was added. The resulting mixture was stirred at room temperature for 4 hours. The mixture was concentrated to obtain [2-(3-methoxypropyl)-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol (0.100 g, crude). LC / MS (m / z, M+H): Calculated value 305.2, measured value 305.3

[0217] Step 6: 2-(3-methoxypropyl)-7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine [ka] A mixture of [2-(3-methoxypropyl)-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol (0.140 g, 0.51 mmol), 4-(trifluoromethoxy)benzoic acid (0.105 g, 0.51 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (0.146 g, 0.765 mmol), 1-hydroxybenzotriazole (0.207 g, 1.53 mmol), and N-ethyl-N-isopropyl-propan-2-amine (0.330 g, 2.55 mmol) in N,N-dimethylformamide (4 mL) was stirred at room temperature for 3 hours. The reaction mixture was then diluted with brine (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over Na₂SO₄, and concentrated to obtain crude oil. This crude product was dissolved in a mixed solution of methanol (10 mL) and 30% aqueous ammonia (15 mL). After stirring for 1 hour, the resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were diluted with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain crude oil. This was purified by preparative HPLC to obtain [4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (0.118 g, 0.255 mmol, yield: 50%) as a white solid. LC / MS (m / z, M+H): Calculated value 463.2, Measured value 463.3. 1 H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.78-1.90(m,2H),1.92-2.03(m,2H),2.09(br dd,J=13,3Hz,2H),2.85-2.93(m Partially hidden, 2H), 3.08-3.23 (m, 3H), 3.24 (s, 3H), 3.41 (t, J=7Hz, 2H), 4.08 (br d,J=13Hz,2H),7.36(d,J=9Hz,2H),7.47(s,1H),7.53(d,J=9Hz,2H),8.05(s,1H),10.93-11.42(m,1H)

[0218] Example 7: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] A mixture of [2-(3-methoxypropyl)-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol (0.080 g, 0.292 mmol), 2-amino-4-(trifluoromethoxy)benzoic acid (0.0645 g, 0.292 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (0.0835 g, 0.44 mmol), 1-hydroxybenzotriazole (0.197 g, 1.46 mmol), and N-ethyl-N-isopropyl-propan-2-amine (0.188 g, 1.46 mmol) in N,N-dimethylformamide (4 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with brine (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over Na₂SO₄, and concentrated to obtain crude oil. This crude product was dissolved in a mixed solution of methanol (10 mL) and 30% aqueous ammonia (15 mL). After stirring for 1 hour, the resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain crude oil. This was purified by preparative HPLC to obtain [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone (36 mg, yield: 26%) as a white solid. LC / MS (m / z, M+H): Calculated value 478.2, Measured value 478.2. 1H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.75-1.90(m,2H),1.92-2.03(m,2H),2.09(br dd,J=13,3Hz,2H),2.82-2.89(m,2H),3.06-3.24(m,3H),3.24(s,3H),3.40(t,J=7Hz,2H),4.08(br d,J=13Hz,2H),5.31(s,2H),6.35-6.52(m,1H),6.67(br d,J=1Hz,1H),7.12(d,J=8Hz,1H),7.48(s,1H),8.05(s,1H),10.84-11.77(m,1H)

[0219] Example 8: [4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka]

[0220] Step 1: tert-butyl4-[2-(cyclohexen-1-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] A mixture of tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.70 g, 0.00334 mmol), 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.694 g, 3.34 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.244 g, 0.334 mmol), and sodium carbonate (1.06 g, 10.0 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was stirred at 80°C for 3 hours under an N2 atmosphere. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography (0-10% ethyl acetate in petroleum ether) to obtain tert-butyl 4-[2-(cyclohexen-1-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.22 g, 2.4 mmol, yield: 71%) as oil. LC / MS (m / z, M+H): Calculated value 511.3, measured value 511.1

[0221] Step 2: tert-butyl4-[2-cyclohexyl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-[2-(cyclohexen-1-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.22 g, 2.4 mmol) in ethyl acetate (20 mL), Pd / C (20 wt%, 244 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (10% ethyl acetate in petroleum ether) to obtain tert-butyl 4-[2-cyclohexyl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (1.15 g, 2.23 mmol, yield: 94%). LC / MS (m / z, M+H): Calculated value 515.3, Measured value 515.2

[0222] Step 3: 2-Cyclohexyl-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol [ka] A solution of tert-butyl 4-[2-cyclohexyl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (600 mg, 1.17 mmol) in dichloromethane (5 mL) was mixed with trifluoroacetic acid (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to obtain a yellow oil (430 mg, crude), which was used in the next step without further purification. LC / MS (m / z, M+H): Calculated value 315.2, measured value 315.1

[0223] Step 4: [4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka] To a solution of [2-cyclohexyl-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol (430 mg, 1.32 mmol) and 4-(trifluoromethoxy)benzoic acid (343 mg, 1.66 mmol) in N,N-dimethylformamide (5 mL), 1-hydroxybenzotriazole hydrate (255 mg, 1.66 mmol), N'-(ethylcarbonimidoyl)-N,N-dimethylpropane-1,3-diamine hydrochloride (319 mg, 1.66 mmol), and N-ethyl-N-isopropyl-propane-2-amine (537 mg, 4.16 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined and concentrated to obtain crude oil. The crude product was dissolved in a mixed solution of methanol (10 mL) and purified aqueous ammonia (15 mL). After stirring for 1 hour, the resulting solution was treated with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain crude oil. This was purified by silica gel chromatography (3% methanol in dichloromethane) to obtain [4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (750 mg, 2.77 mmol, yield 53%) as a white solid. LC / MS (m / z, M+H): Calculated value 473.2, Measured value 473.3. 1 H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.31(tt,J=12,3Hz,1H),1.44(qt,J=12,3Hz,2H),1.62(qd,J=12,3Hz,2H),1.69-1.77(m,1H),1.79-1.89(m,4H),1.89-1.99(m,2H),2.09(br dd,J=13,3Hz,2H),2.75-2.91(m Partially hidden,1H),3.09-3.31(m,3H),4.02-4.15(m,2H),7.36(d,J=9Hz,2H),7.46(s,1H),7.53(d,J=9Hz,2H),8.07(s,1H),11.13(br s,1H)

[0224] Example 9: [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone [ka]

[0225] Step 1: [2-Cyclohexyl-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol [ka] A solution of tert-butyl 4-[2-cyclohexyl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (550 mg, 1.07 mmol) in dichloromethane (5 mL) was mixed with trifluoroacetic acid (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to obtain yellow oil [2-cyclohexyl-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol (0.390 g, 1.07 mmol, yield: 100%), which was used in the next step without further purification. LC / MS (m / z, M+H): Calculated value 315.2, measured value 315.1

[0226] Step 2: [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone [ka] To a solution of [2-cyclohexyl-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol (384 mg, 1.07 mmol) and 2-amino-4-(trifluoromethoxy)benzoic acid (150 mg, 0.68 mmol) in N,N-dimethylformamide (5 mL), 1-hydroxybenzotriazole hydrate (0.328 g, 2.14 mmol), N'-(ethylcarbonimidoyl)-N,N-dimethylpropane-1,3-diamine hydrochloride (0.411 g, 2.14 mmol) and N-ethyl-N-isopropyl-propane-2-amine (0.692 g, 5.36 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined and concentrated to obtain crude oil. The crude product was dissolved in a mixed solution of methanol (10 mL) and 30% aqueous ammonia (15 mL). After stirring for 1 hour, the resulting solution was treated with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain crude oil. This was purified by silica gel chromatography (3% methanol in dichloromethane) and preparative HPLC to obtain [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone (100.8 mg, 0.205 mmol, yield: 19%) as a white solid. LC / MS (m / z, M+H): Calculated value 488.2, Measured value 488.1. 1H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.31(tt,J=12,3Hz,1H),1.43(qt,J=12,3Hz,2H),1.62(qd,J=12,3Hz,2H),1.68-1.76(m,1H),1.77-1.99(m,6H),2.09(br dd,J=13,3Hz,2H),2.71-2.85(m partially hidden,1H),3.05-3.32(m,3H),4.08(br d,J=13Hz,2H),5.24(br s,2H),6.40-6.53(m,1H),6.68(br d,J=1Hz,1H),7.12(d,J=8Hz,1H),7.45(s,1H),8.07(s,1H),10.79-11.49(m,1H)

[0227] Example 10: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka]

[0228] Step 1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine [ka] A solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.00 g, 16.2 mmol) in dichloromethane (20 mL) and trifluoroacetic acid (10 mL) was stirred at room temperature for 2 hours. The resulting solution was then concentrated under vacuum to obtain the crude product 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (4.00 g, 16.2 mmol, yield: 100%), which was used in the next step without further purification. LC / MS (m / z, M+H): Calculated value 210.2, Measured value 210.1

[0229] Step 2: 1-Cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine [ka] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (4.00 g, 16.2 mmol), (1-ethoxycyclopropoxy)-trimethyl-silane (4.25 g, 24.4 mmol), and acetic acid (1.86 mL, 32.5 mmol) in methanol (40 mL) was stirred at room temperature for 0.5 hours. Then, sodium borohydride (3.06 g, 48.7 mmol) was partially added, and the resulting mixture was heated to 60°C and stirred for 12 hours. After cooling to room temperature, the reaction mixture was concentrated, and the resulting residue was purified by reverse-phase chromatography using a gradient of acetonitrile (5-60%) in water (containing NH4HCO3) to obtain (1-cyclopropyl-3,6-dihydro-2H-pyridine-4-yl)boronic acid (P1, 2.00 g, 9.96 mmol, yield: 61%) as a white powder, and 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (P2, 0.760 g, 2.66 mmol, yield: 16%) as a pale yellow powder. LC / MS, P1 (m / z, M+H): calculated value 168.1, measured value 168.1, P2 (m / z, M+H): calculated value 250.2, measured value 250.2

[0230] Step 3: tert-butyl4-[2-(1-cyclopropyl-3,6-dihydro-2H-pyridine-4-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] A mixture of tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.00 g, 0.00297 mmol), (1-cyclopropyl-3,6-dihydro-2H-pyridine-4-yl)boronic acid (0.596 g, 2.97 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.217 g, 0.297 mmol), and sodium carbonate (0.943 g, 8.90 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was stirred at 80°C for 16 hours under an N2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography (0-20% ethyl acetate in petroleum ether) to obtain tert-butyl 4-[2-(1-cyclopropyl-3,6-dihydro-2H-pyridine-4-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (0.920 g, 1.28 mmol yield: 43%) as a yellow oil. LC / MS (m / z, M+H): Calculated value 552.3, Measured value 552.3

[0231] Step 4: tert-butyl4-[2-(1-cyclopropyl-4-piperidyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-[2-(1-cyclopropyl-3,6-dihydro-2H-pyridine-4-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (300 mg, 0.544 mmol) in ethyl acetate (10 mL), Pd / C (20% by weight, 60 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 24 hours. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-[2-(1-cyclopropyl-4-piperidyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (0.334 g, 0.542 mmol, yield: 100%), which was used in the next step without further purification. LC / MS (m / z, M+H): Calculated value 556.4, Measured value 556.3

[0232] Step 5: [2-(1-cyclopropyl-4-piperidyl)-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol [ka] To a solution of tert-butyl 4-[2-(1-cyclopropyl-4-piperidyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (167 mg, 0.271 mmol) in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to obtain 2-(1-cyclopropyl-4-piperidyl)-7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine (98 mg, 0.266 mmol, yield: 98%) as a yellow oil, which was used in the next step without further purification. LC / MS (m / z, M+H): Calculated value 356.2, Measured value 356.2

[0233] Step 6: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] To a solution of [2-(1-cyclopropyl-4-piperidyl)-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol (96.0 mg, 0.266 mmol) and 2-amino-4-(trifluoromethoxy)benzoic acid (58.8 mg, 0.266 mmol) in N,N-dimethylformamide (5 mL), 1-hydroxybenzotriazole hydrate (0.0815 g, 0.532 mmol), N'-(ethylcarbonimidoyl)-N,N-dimethylpropane-1,3-diamine hydrochloride (0.102 g, 0.532 mmol) and N-ethyl-N-isopropyl-propane-2-amine (0.172 g, 1.33 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. Next, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layers were combined and concentrated to obtain crude oil. The crude product was dissolved in a mixed solution of methanol (5 mL) and 30% aqueous ammonia (5 mL). After stirring for 1 hour, the resulting solution was treated with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain crude oil, which was purified by preparative HPLC to obtain [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyro[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone (0.0118 g, 0.022 mmol, yield: 8.2%). LC / MS (m / z, M+H): Calculated value 529.2, Measured value 529.3. 1H NMR(400MHz,DMSO-d6,100℃)δ ppm 0.28-0.51(m,4H),1.59-1.70(m,1H),1.71-1.93(m,6H),2.07(br dd,J=13,3Hz,2H),2.32(td,J=11,4Hz,2H),2.76-2.87(m,1H),3.00-3.29(m,5H),4.08(br d,J=13Hz,2H),5.30(s,2H),6.46(br dd,J=8,1Hz,1H),6.67(br d,J=1Hz,1H),7.12(d,J=8Hz,1H),7.48(d,J=2Hz,1H),8.08(s,1H),11.23(br s,1H)

[0234] Example 11: [4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka] To a solution of [2-(1-cyclopropyl-4-piperidyl)-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol (97.0 mg, 0.27 mmol) and 4-(trifluoromethoxy)benzoic acid (55.4 mg, 0.27 mmol) in N,N-dimethylformamide (5 mL), 1-hydroxybenzotriazole hydrate (0.0823 g, 0.54 mmol), N-(3-(dimethylamino)propyl)propionimidamide (0.0846 g, 0.54 mmol), and N-ethyl-N-isopropyl-propane-2-amine (0.174 g, 1.34 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layers were combined and concentrated to obtain crude oil. The crude product was dissolved in a mixed solution of methanol (5 mL) and 30% aqueous ammonia (5 mL). After stirring for 1 hour, the resulting solution was treated with water and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with water and brine, dried over anhydrous sodium 2SO4, filtered, and concentrated to obtain crude oil. This was purified by preparative HPLC to obtain [4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (0.0136%, 0.026 mmol, yield: 10%). LC / MS (m / z, M+H): Calculated value 514.2, Measured value 514.3. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 0.28-0.51(m,4H),1.60-1.70(m,1H),1.73-1.93(m,6H),2.08(br dd,J=13,2Hz,2H),2.33(td,J=11,3Hz,2H),2.76-2.88(m,1H),3.06(br d,J=12Hz,2H),3.09-3.29(m,3H),3.92-4.29(m,2H),7.37(br d,J=9Hz,2H),7.49(br s,1H),7.54(d,J=9Hz,2H),8.09(s,1H),11.24(br s,1H)

[0235] Example 12: (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone [ka] To a solution of (rac)-7-(4-piperidyl)-2-tetrahydrofuran-3-yl-pyrrolo[2,3-b]pyrazine-5-yl]methanol (300 mg, 0.83 mmol) and 2-amino-4-(trifluoromethoxy)benzoic acid (150 mg, 0.68 mmol) in N,N-dimethylformamide (5 mL), 1-hydroxybenzotriazole hydrate (255 mg, 1.66 mmol), N'-(ethylcarbonimidoyl)-N,N-dimethylpropane-1,3-diamine hydrochloride (319 mg, 1.66 mmol), and N-ethyl-N-isopropyl-propane-2-amine (537 mg, 4.16 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined and concentrated to obtain crude oil. The crude product was dissolved in a mixed solution of methanol (10 mL) and 30% aqueous ammonia (15 mL). After stirring for 1 hour, the resulting solution was treated with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain crude oil. This was purified by silica gel chromatography (3% methanol in dichloromethane) and preparative HPLC to obtain (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone (81.6 mg, 0.172 mmol, yield: 21%) as a white solid. LC / MS (m / z, M+H): Calculated value 476.2, Measured value 476.1. 1H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.78-1.93(m,2H),2.08(br dd,J=13,3Hz,2H),2.16-2.39(m,2H),3.07-3.27(m,3H),3.68(quin,J=8Hz ,1H),3.79-3.88(m,2H),3.96(td,J=8,5Hz,1H),4.04-4.14(m,3H),5.24(br s,2H),6.42-6.55(m,1H),6.68(br d,J=1Hz,1H),7.11(d,J=8Hz,1H),7.49(s,1H),8.12(s,1H),11.18(br s,1H)

[0236] Examples 13 and 14: [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, isomers 1 and 2 [ka] Chiral separation of (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone (61 mg, 0.13 mmol) using a chiralpak IF column (5 μm, 250 × 30 mm) that eluted with 30% EtOH + 0.1% TEA in n-heptane (flow rate 40 mL / min, UV detection at 240 nm) yielded a first eluted isomer of 29 mg (47%) (Example 13, isomer 1) and a second eluted isomer of 33 mg (54%) (Example 14, isomer 2) as white solids.

[0237] Isomer 1 (Embodiment 13): LC / MS (m / z, M+H): 476, 1H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.77-1.89(m,2H),2.03-2.12(m,2H),2.17-2.33(m,2H),3.08-3.24(m,3H),3.68(q uin,J=7.8Hz,1H),3.78-3.89(m,2H),3.93-4.00(m,1H),4.04-4.15(m,3H),5.30(br s,2H),6.47(br d,J=8.3Hz,1H),6.68(br s,1H),7.11(d,J=8.3Hz,1H),7.51(s,1H),8.12(s,1H),11.21-11.45(m,1H)

[0238] Heterogeneous body 2 (actual form 14): LC / MS (m / z, M+H): 476 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.76-1.91(m,2H),2.03-2.14(m,2H),2.17-2.38(m,2H),3.08-3.27(m,3H),3.68(quin, J=8Hz,1H),3.78-3.90(m,2H),3.92-4.1(m,1H),4.04-4.16(m,3H),5.30(s,2H),6.47(br d,J=8.3,1H),6.68(br s,1H),7.12(d,J=8.3Hz,1H),7.51(br s,1H),8.12(s,1H),11.27-11.36(m,1H)

[0239] Example 15: [4-[2-(1-メチル-4-ピペリジル)-5H-ピロロ[2, 3-b]ピラジン-7-イル]-1-ピペリジル]-[4-(ペンタフルオロ-λ 6 -スルファニル)フェニル]メタノン

change

[0240] Example 16: [2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] At room temperature, under an argon atmosphere, a solution of 2-(1-methyl-4-piperidyl)-7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine (120 mg, 0.4 mmol) in DMF (2 mL) was prepared by adding triethylamine (280 μL, 2 mmol) and 2-amino-4-(pentafluoro-λ). 6 (-sulfanyl)benzoic acid, hydrochloride (126 mg, 0.42 mmol) and TBTU (154 mg, 0.48 mmol) were added. The reaction mixture was then stirred at room temperature for 0.5 hours, then diluted with AcOEt, and transferred to a separation funnel containing a saturated aqueous solution of NaCl. The entire mixture was extracted three times with AcOEt. The combined organic layer was dried over MgSO4, filtered, and concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel (12 g) eluted with DCM / MeOH / NH4OH (90 / 10 / 1) to obtain 30 mg (yield 14%) of [2-amino-4-(pentafluoro-λ]. 6 -Sulfanyl)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone was obtained as a white solid. LC / MS (m / z, M+H): Calculated value 545.6, Measured value 545.2. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.82-1.98(m,6H),2.04-2.15(m,4H),2.25(s,3H),2.74-2.83(m,1H),2. 88-2.93(partially hidden,m,3H),3.12-3.28(m,3H),4.04-4.15(m,2H),5.44(br s,2H),7.03(dd,J=8.5,2.3Hz,1H),7.24(d,J=8.5Hz,1H),7.29(d,J=2.3Hz,1H),7.51(s,1H),8.12(s,1H),11.23-11.30(m,1H)

[0241] Example 17: [4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] At room temperature, under an argon atmosphere, 4-(pentafluoro-λ) in DMF (1 mL) 6 To a solution of -sulfanyl)benzoic acid (36 mg, 0.14 mmol), TBTU (54 mg, 0.17 mmol) and N,N-diisopropylethylamine (40 μL, 0.23 mmol) were added. Then, at 0°C, a solution of 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine (40 mg, 0.14 mmol) in DMF (1.5 mL) was added to the resulting mixture. The reaction mixture was then stirred for 10 minutes, then diluted with AcOEt, and transferred to a separatory funnel containing water. The whole mixture was extracted three times with AcOEt. The combined organic layer was dried over MgSO4, filtered, and concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel (12 g) eluted with DCM / MeOH (90 / 10) to obtain 55 mg (yield 79%) of [4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone was obtained as a white solid. LC / MS (m / z, M+H): Calculated value 517.2, Measured value 517.1. 1 H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.78-1.98(m,6H),2.10(br dd,J=13,3Hz,2H),3.02-3.29(m,4H),3.51(td,J=11,3Hz,2H),3.93-4.01(m,2H),4.08(br d,J=12Hz,2H),7.36(br d,J=9Hz,2H),7.49(d,J=2Hz,1H),7.53(d,J=9Hz,2H),8.11(s,1H),11.16(br s,1H)

[0242] Example 18: [2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] Example 18 was carried out according to the procedure described in Example 17, using 2-amino-4-(pentafluoro-λ 6 Prepared using [2-amino-4-(pentafluoro-λ], 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine (50 mg, 0.17 mmol), TBTU (67 mg, 0.21 mmol), N,N-diisopropylethylamine (0.11 mL, 0.61 mmol), and 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine (50 mg, 0.17 mmol), yielding 63 mg (68%) of [2-amino-4-(pentafluoro-λ]. 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone was obtained as a white solid. LC / MS (m / z, M+H): Calculated value 532.5, Measured value 532.0. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.77-1.95(m,6H),2.10(br dd,J=12.9,2.8Hz,2H),3.03-3.26(m,4H),3.50(ddd,J=11.3,11.3,2.9Hz,2H),3.94-4.14(m,4H),5.42(br s,2H),6.99(dd,J=8.4,2.3Hz,1H),7.21(d,J=8.4Hz,1H),7.27(d,J=2.3Hz,1H),7.50(s,1H),8.11(s,1H),11.23-11.34(m,1H)

[0243] Example 19: [2-amino-4-(pentafluoro-λ 6 -Sulfanyl)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] Example 19 was carried out according to the procedure described in Example 17, using 2-amino-4-(pentafluoro-λ 6Prepared using [2-amino-4-(pentafluoro-λ], 2-(1-cyclopropyl-4-piperidyl)-7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine, dihydrochloride (45 mg, 0.11 mmol), [2-amino-4-(pentafluoro-λ], 2-(1-cyclopropyl-4-piperidyl)-7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine, dihydrochloride (45 mg, 0.11 mmol), to obtain 34 mg (53% yield) of [2-amino-4-(pentafluoro-λ]. 6 -Sulfanyl)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone was obtained as a white solid. LC / MS (m / z, M+H): Calculated value 571.6, Measured value 571.1. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 0.29-0.36(m,2H),0.37-0.45(m,2H),1.62-1.69(m,1H),1.72-1.92(m,6H),2.04-2.14(m,2H),2.28-2.37(m,2H),2.76- 2.86(m,1H),3.01-3.09(m,2H),3.09-3.24(m,3H),3.99-4.12(m,2H),5.41(s,2H),6.98(dd,J=8.5,2.2Hz,1H),7.20(br d,J=8.5Hz,1H),7.26(d,J=2.2Hz,1H),7.48(s,1H),8.08(s,1H),11.23(m,1H)

[0244] Example 20: [4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(pentafluoro-λ 6 -Sulfanyl)phenyl]methanone [ka] Example 20 was carried out according to the procedure described in Example 17, with respect to 4-(pentafluoro-λ 6Prepared using [4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(pentafluoro-λ]-1-piperidyl]-[4-(pentafluoro-λ]-1-piperidyl]-[4-(pentafluoro-λ]-1-piperidyl]-[4-(pentafluoro-λ]-1-piperidyl]-[4-(pentafluoro-λ]-1-piperidyl]-[4-(pentafluoro-λ]-1-piperidyl]-1-piperidyl]-1-piperidyl]-1-piperidyl]-1-piperidyl]-1-piperidyl]-1-piperidyl]-1-piperidyl]-1-(pentafluoro-λ) 6 -Sulfanyl)phenyl]methanone was obtained as a white solid. LC / MS (m / z, M+H): Calculated value 556.6, Measured value 556.1. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 0.27-0.36(m,2H),0.37-0.48(m,2H),1.61-1.72(m,1H),1.73-1.94(m,6H ),2.03-2.16(m,2H),2.26-2.39(m,2H),2.76-2.87(m,1H),3.01-3.10(br d,m,2H),3.10-3.29(m,3H),3.87-4.29(m,2H),7.49(s,1H),7.62(br d,J=8.5Hz,2H),7.92(d,J=8.5Hz,2H),8.09(s,1H),11.24(m,1H)

[0245] Example 21: [4-(cyclopropoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] Example 21 was prepared according to the procedure described in Example 17 using 4-(cyclopropoxy)benzoic acid (35 mg, 0.20 mmol), TBTU (54 mg, 0.17 mmol), 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine hydrochloride (40 mg, 0.12 mmol), and N,N-diisopropylethylamine (65 μL, 0.37 mmol) to obtain 36 mg (65% yield) of [4-(cyclopropoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): Calculated value 447.5, Measured value 447.2. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 0.62-0.84(m,4H),1.76-1.95(m,6H),2.03-2.13(m,2H),3.02-3.27(m,4H),3.45-3.50(ddd,J=11.3,11.3,2.8Hz,2H),3.83-3.91(m,1 H),3.95-4.01(m,2H),4.10-4.20(m,2H),7.07(d,J=8.6Hz,2H),7.37(d,J=8.6Hz,2H),7.51(d,J=2.8Hz,1H),8.11(s,1H),11.26(m,1H)

[0246] Example 22: [4-(1,1,2,2,2-pentafluoroethyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] Example 22 was prepared according to the procedure described in Example 17 using 4-(1,1,2,2,2-pentafluoroethyl)benzoic acid (31 mg, 0.13 mmol), TBTU (47 mg, 0.15 mmol), 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine hydrochloride (42 mg, 0.13 mmol), and N,N-diisopropylethylamine (87 μL, 0.50 mmol) to obtain 40 mg (61% yield) of [4-(1,1,2,2,2-pentafluoroethyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): Calculated value 509.5, Measured value 509.2. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.76-1.95(m,6H),2.03-2.17(m,2H),3.02-3.28(m,4H),3.50(ddd,J=11.4,11.4,2.9Hz,2H),3.87-4 .27(m,4H),7.51(d,J=2.8Hz,1H),7.65(d,J=8.1Hz,2H),7.75(d,J=8.1Hz,2H),8.12(s,1H),11.28(br s,1H)

[0247] Example 23: Cyclohexyl-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone [ka] Example 23 was prepared according to the procedure described in Example 17 using cyclohexanecarboxylic acid (19 mg, 0.15 mmol), TBTU (46 mg, 0.14 mmol), DIPEA (68 μL, 0.39 mmol), 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine, and hydrochloride (42 mg, 0.13 mmol) to obtain 30 mg (58% yield) of cyclohexyl-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): Calculated value 397.5, Measured value 397.3. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.13-1.47(m,4H),1.60-1.97(m,12H),2.07(br d,J=12.7Hz,2H),2.55-2.67(m,1H),2.96-3.21(Partially hidden m,4H),3.50(ddd,J=11.3,2.9Hz,2H),3.93-4.01(m,2H),4.17-4.30(m,2H),7.48(s,1H),8.11(s,1H),10.75-12.14(m,1H)

[0248] Example 24: (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrrolidine-1-yl]methanone [ka]

[0249] Step 1: tert-butyl3-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-2,5-dihydropyrrole-1-carboxylate [ka] To a solution of 2-[(2-bromo-7-iodopyrrolo[2,3-b]pyrazine-5-yl)methoxy]ethyl-trimethyl-silane (13 g, 28.6 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (9.29 mg, 31.5 mmol) in a dioxane / water (130 mL / 26 mL) mixture, Pd(dppf)Cl2 (622 mg) and Na2CO3 (9.1 g, 85.8 mmol) were sequentially added. The reaction mixture was then refluxed under a nitrogen atmosphere for 5 hours. After 5 hours, the reaction mixture was cooled to room temperature, diluted with brine (200 mL), and extracted with Â(3 × 150 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated to obtain crude oil. The crude product was purified by silica gel chromatography (ÂTED / PE 25 / 75) to obtain 8.3 g (58% yield) of tert-butyl 3-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-2,5-dihydropyrrole-1-carboxylate as a yellow solid. LC / MS (m / z, M+H): Calculated value 496.5, measured value 496.1

[0250] Step 2: tert-butyl3-[2-(3,6-dihydro-2H-pyran-4-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-2,5-dihydropyrrole-1-carboxylate [ka] To a solution of tert-butyl 3-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-2,5-dihydropyrrole-1-carboxylate (8.4 g, 17 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.9 g, 18.6 mmol), Pd(dppf)Cl2 (370 mg) and Na2CO3 (5.4 g, 51 mmol) were sequentially added. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 5 hours. After 5 hours, the reaction mixture was diluted with brine (150 mL) and extracted with Â(3 × 150 mL). The combined organic layers were washed with brine (2 × 150 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated to obtain crude oil. The crude product was purified by silica gel chromatography (siRNA / PE 25 / 75) to obtain 6 g (82% yield) of tert-butyl 3-[2-(3,6-dihydro-2H-pyran-4-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-2,5-dihydropyrrole-1-carboxylate as a yellow solid. LC / MS (m / z, M+H): Calculated value 499.7, measured value 499.1

[0251] Step 3: tert-butyl3-[2-tetrahydropyran-4-yl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]pyrroridine-1-carboxylate [ka] To a solution of tert-butyl 3-[2-(3,6-dihydro-2H-pyran-4-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-2,5-dihydropyrrole-1-carboxylate (6 g, 12 mmol) in ethyl acetate (120 mL), Pd (20 wt%, 6 g) on ​​carbon was added. The mixture was stirred under a hydrogen atmosphere (1 atmosphere) at room temperature for 48 hours. The reaction mixture was then filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 5 g (yield 83%) of crude tert-butyl 3-[2-tetrahydropyran-4-yl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]pyrrolidine-1-carboxylate as a white solid. LC / MS (m / z, M+H): Calculated value 503.7, Measured value 503.2

[0252] Step 4: (7-Pyrrolidine-3-yl-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyrazine-5-yl)methanol, 2,2,2-trifluoroacetic acid [ka] To a solution of tert-butyl 3-[2-tetrahydropyran-4-yl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]pyrrolidine-1-carboxylate (1.6 g, 3.18 mol) in DCM (10 mL), TFA (5 mL) was added at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was then concentrated to obtain 0.96 g (99% yield) of crude (7-pyrrolidine-3-yl-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyrazine-5-yl)methanol, 2,2,2-trifluoroacetic acid as a pale yellow oil. LC / MS (m / z, M+H-TFA): Calculated value 303.4, Measured value 303.1

[0253] Step 5: (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]methanone [ka] To a solution of (7-pyrroridine-3-yl-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyrazine-5-yl)methanol, 2,2,2-trifluoroacetic acid (445 mg, 1.07 mmol), and 2-amino-4-(trifluoromethoxy)benzoic acid (150 mg, 0.68 mmol) in N,N-dimethylformamide (5 mL), 1-hydroxybenzotriazole hydrate (328 mg, 2.14 mmol), N'-(ethylcarbonimidoyl)-N,N-dimethylpropane-1,3-diamine hydrochloride (411 mg, 2.14 mmol), and DIPEA (692 mg, 5.4 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water (50 mL) and extracted with ethylpropyl alcohol (3 × 50 mL). The combined organic layer was concentrated to obtain crude oil. The crude product was dissolved in a mixed solution of methanol (10 mL) and 30% NH4OH aqueous solution (15 mL). After stirring for 1 hour, the resulting solution was treated with water (50 mL) and extracted with siRNA (3 × 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain crude oil. This was purified by silica gel chromatography (3% methanol in dichloromethane) and preparative HPLC to obtain 101 mg (19% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl] as a colorless solid. LC / MS (m / z, M+H): Calculated value 476.5, Measured value 476.3. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.73-1.93(m,4H),2.22-2.32(m,1H),2.33-2.43(m,1H),3.00-3.12(m,2H), 3.48(ddd,J=11.2,2.9Hz,2H),3.56-3.80(m,4H),3.91-4.04(m,3H),7.35(br d,J=8.4Hz,2H),7.58(s,1H),7.64(br d,J=8.6Hz,2H),8.13(s,1H),11.23-11.52(m,1H)

[0254] Example 25: (rac)-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrrolidine-1-yl]-[4-(trifluoromethoxy)phenyl]methanone [ka] Example 25 was prepared using the procedure used in step 5 of Example 24, with (7-pyrrolidine-3-yl-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyrazine-5-yl)methanol, 2,2,2-trifluoroacetic acid (0.48 g, 1.15 mmol), and 4-(trifluoromethoxy)benzoic acid (0.36 g, 1.74 mmol) in N,N-dimethylformamide (10 mL) to produce 1-hydroxybenzotriazole, hydrate ( (rac)-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]-[4-(trifluoromethoxy)phenyl]methanone] was added (0.32 g, 2.4 mmol), N'-(ethylcarbonyl)-N,N-dimethylpropane-1,3-diamine hydrochloride (0.46 g, 2.4 mmol) and DIPEA (3.1 g, 24 mmol) to obtain 290 mg (55% yield) of (rac)-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrrolidine-1-yl]-[4-(trifluoromethoxy)phenyl]methanone as a colorless solid. LC / MS (m / z, M+H): Calculated value 461.4, Measured value 461.2. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.73-1.93(m,4H),2.22-2.32(m,1H),2.33-2.43(m,1H),3.00-3.12(m,2H), 3.48(ddd,J=11.2,2.9Hz,2H),3.56-3.80(m,4H),3.91-4.04(m,3H),7.35(br d,J=8.4Hz,2H),7.58(s,1H),7.64(br d,J=8.6Hz,2H),8.13(s,1H),11.23-11.52(m,1H)

[0255] Example 26: [2-fluoro-4-(pentafluoro-λ 6-Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] Example 26 was carried out according to the procedure described in Example 17, using 2-fluoro-4-(pentafluoro-λ 6 Prepared using -sulfanyl)benzoic acid (91 mg, 0.34 mmol), TBTU (121 mg, 0.38 mmol), N,N-diisopropylethylamine (170 μL, 0.97 mmol), and 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine hydrochloride (97 mg, 0.30 mmol), yielding 75 mg (46% yield) of [2-fluoro-4-(pentafluoro-λ]. 6 -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone was obtained as a white solid. LC / MS (m / z, M+H): Calculated value 535.5, Measured value 535.2. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.77-1.95(m,6H),2.04-2.22(m,2H),2.88-3.59(m,2H),3.03-3.12(m,1H),3.18-3.27(m,1H), 3.50(ddd,J=11.4,11,4,2.8Hz,2H),3.92-4.02(m,2H),3.93-4.75(m,2H),7.50(s,1H),7.67(br t,J=7.8.Hz,1H),7.80(dd,J=8.6,2.2Hz,1H),7.87(dd,J=9.6,2.2Hz,1H),8.12(s,1H),11.25-11.34(m,1H)

[0256] Example 27: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetan-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka]

[0257] Step 1: tert-butyl4-[2-(oxetane-3-ylamino)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.00 g, 1.96 mmol, prepared in step 3 of Example 1) and oxetane-3-amine (717 mg, 9.81 mmol) in 1,4-dioxane (10 mL), sodium 2-methylpropane-2-oleate (566 mg, 5.89 mmol) was added at room temperature, and the resulting reaction mixture was aerated with argon for 10 minutes. Then, XPhosPdG4 (237 mg, 0.28 mmol) was added under a nitrogen atmosphere, and the resulting reaction mixture was microwaved at 100°C for 1 hour. After 1 hour, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (2 × 100 mL), and the combined organic layer was dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by flash chromatography using elution with 20% ethyl acetate in hexane to obtain 550 mg (52% yield) of tert-butyl 4-[2-(oxetane-3-ylamino)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate as a yellow viscous solid. LC / MS (m / z, M+H): Calculated value 502.3, measured value 502.1.

[0258] Step 2: tert-butyl4-[2-(oxetane-3-ylamino)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[2-(oxetane-3-ylamino)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (550 mg, 1.1 mmol) in methanol (5 mL), 10% Pd / C (583 mg, 5.5 mmol) was added at room temperature, and the resulting mixture was hydrogenated under an H2 atmosphere for 12 hours. After 12 hours, the reaction mixture was filtered through Celite, the resulting filtrate was dried over sodium sulfate, and concentrated under vacuum to obtain 500 mg (88% yield) of tert-butyl 4-[2-(oxetane-3-ylamino)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate as a yellow liquid. LC / MS (m / z, M+H): Calculated value 504.3, measured value 504.1.

[0259] Step 3: [2-(oxetane-3-ylamino)-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol, 2,2,2-trifluoroacetic acid [ka] A stirred solution of tert-butyl 4-[2-(oxetane-3-ylamino)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (500 mg, 0.99 mmol) in dichloromethane (5 mL) was cooled to 0°C, and then trifluoroacetic acid (226 mg, 1.99 mmol) was added. The resulting reaction mixture was stirred at room temperature for 3 hours. After 3 hours, the reaction mixture was concentrated under vacuum, the resulting residue was triturated, and washed with n-hexane (2 × 25 mL) to obtain 417 mg (100% yield) of [2-(oxetane-3-ylamino)-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol and 2,2,2-trifluoroacetic acid as a yellow solid. LC / MS (m / z, M+H-TFA): Calculated value 304.2, measured value 304.5.

[0260] Step 4: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetan-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] To a stirred solution of [2-(oxetane-3-ylamino)-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol, 2,2,2-trifluoroacetic acid (280 mg, 0.67 mmol), and 2-amino-4-(trifluoromethoxy)benzoic acid (102 mg, 0.46 mmol) in N,N-dimethylformamide (5 mL), benzotriazole-1-yloxy(tripyrrolidine-1-yl)phosphonium, hexafluorophosphate (720 mg, 1.38 mmol), and N,N-diethylethaneamine (280 mg, 2.77 mmol) were added at 0°C, and the resulting reaction mixture was stirred at room temperature for 2 hours. After 2 hours, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2 × 50 mL), and the combined organic layer was dried over sodium sulfate and concentrated under vacuum. The obtained residue was purified by preparative HPLC (conditions: mobile phase: A = 10 mM ABC in water, B = ACN, column: Gemini NX (250 mm x 21.2 mm), 5.0 μm, flow rate: 18 mL / min). The pure fraction was lyophilized to obtain 15 mg (yield 3.4%) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetan-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone as an off-white solid. LC / MS (m / z, M+H): calculated value 477.2, measured value 477.1. 1 1H NMR (400MHz, DMSO-d 6 )δ ppm 7.39(s,1H)7.13(d,J=8.36Hz,1H)6.65(s,1H)6.48(br d,J=8.36Hz,1H)5.58(s,2H)4.89(br s,1H)4.48(br s,1H)4.13-4.29(m,2H)3.39-3.61(m,3H)2.99(br s,3H)1.84(br s,2H)1.57(br d,J=12.91Hz,2H).

[0261] Example 28: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(3R)-tetrahydrofuran-3-yl]oxy-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka]

[0262] Step 1: tert-butyl4-[2-[(3R)-tetrahydrofuran-3-yl]oxy-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.00 g, 1.96 mmol, prepared in step 3 of Example 1) and (3R)-tetrahydrofuran-3-ol (865 mg, 9.81 mmol) in 1,4-dioxane (3 mL), sodium 2-methylpropane-2-oleate (566 mg, 5.89 mmol) was added at room temperature, and the resulting reaction mixture was aerated with nitrogen for 10 minutes. Then, XPhosPdG4 (169 mg, 0.2 mmol) was added under a nitrogen atmosphere, and the resulting mixture was microwaved at 100°C for 1 hour. After 1 hour, the reaction mixture was quenched with water (30 mL), extracted with RINKAN (2 × 100 mL), and the combined organic layer was dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by flash chromatography using elution with 12% ethyl acetate in hexane to obtain 250 mg (23% yield) of tert-butyl4-[2-[(3R)-tetrahydrofuran-3-yl]oxy-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate as a yellow solid. LC / MS (m / z, M+H): Calculated value 517.3, Measured value 517.3.

[0263] Step 2: tert-butyl4-[2-[(3R)-tetrahydrofuran-3-yl]oxy-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[2-[(3R)-tetrahydrofuran-3-yl]oxy-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (250 mg, 0.48 mmol) in methanol (2 mL), 10% Pd / C (302 mg, 2.84 mmol) was added at room temperature, and the resulting mixture was hydrogenated under an H2 atmosphere for 12 hours. After 12 hours, the reaction mixture was filtered through Celite, then washed with MeOH (2 × 5 mL), and the resulting filtrate was dried over sodium sulfate and concentrated under vacuum to obtain 180 mg (72% yield) of tert-butyl 4-[2-[(3R)-tetrahydrofuran-3-yl]oxy-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate. LC / MS (m / z, M+H): Calculated value 519.3, Measured value 519.3.

[0264] Step 3: [7-(4-piperidyl)-2-[(3R)-tetrahydrofuran-3-yl]oxy-pyrrolo[2,3-b]pyrazine-5-yl]methanol, 2,2,2-trifluoroacetic acid [ka] To a stirred solution of tert-butyl 4-[2-[(3R)-tetrahydrofuran-3-yl]oxy-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (180 mg, 0.35 mmol) in dichloromethane (5.0 mL), trifluoroacetic acid (2 mL) was added at 0°C, and the resulting reaction mixture was stirred at room temperature for 3 hours. After 3 hours, the reaction mixture was concentrated under vacuum. The crude material was triturated and washed with n-hexane (2 × 10 mL) to obtain 150 mg (100% yield) of [7-(4-piperidyl)-2-[(3R)-tetrahydrofuran-3-yl]oxy-pyrrolo[2,3-b]pyrazine-5-yl]methanol and 2,2,2-trifluoroacetic acid as a yellow solid. LC / MS (m / z, M+H-TFA): Calculated value 319.2, measured value 319.0.

[0265] Step 4: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(3R)-tetrahydrofuran-3-yl]oxy-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] To a stirred solution of 2-amino-4-(trifluoromethoxy)benzoic acid (115 mg, 0.52 mmol) in N,N-dimethylformamide (5 mL), 3-(ethylminomethyllenamino)-N,N-dimethyl-propan-1-amine hydrochloride (150 mg, 0.78 mmol) and 1-hydroxybenzotriazole (84 mg, 0.62 mol), cooled to 0°C, were added. N,N-diethylethaneamine (158 mg, 1.56 mmol) was added at 0°C, followed by [7-(4-piperidyl)-2-[(3R)-tetrahydrofuran-3-yl]oxypyrrolo[2,3-b]pyrazine-5-yl]methanol (150 mg, 0.47 mmol) after 10 minutes. The reaction mixture was then stirred at room temperature for 16 hours. After 16 hours, the reaction mixture was concentrated under vacuum. The obtained residue was purified by preparative HPLC (preparative conditions: mobile phase: A = 10 mM ABC in water, B = ACN, column: Gemini NX (250 mm x 21.2 mm), 5.0 μm, flow rate: 18 mL / min, gradient programmer (time (min) % B): 0 min 30%, 2 min 40%, 8 min 70%), and the pure fraction was concentrated to obtain 6 mg (yield 2.5%) of [[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(3S)-tetrahydrofuran-3-yl]oxy-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): calculated value 492.2, measured value 492.2. 1H NMR(400MHz,DMSO-d6)δ ppm 11.49-11.75(m,1H)7.72-7.92(m,1H)7.42-7.61(m,1H)7.03-7.16(m,1H)6.57-6.72(m,1H)6.37-6.57(m,1H) )5.49-5.68(m,2H)3.72-4.11(m,5H)3.00-3.20(m,3H)2.14-2.31(m,1H)1.98-2.14(m,3H)1.62-1.98(m,3H).

[0266] Example 29: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(3S)-tetrahydrofuran-3-yl]oxy-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] Example 29 was prepared according to the protocol described in steps 1-4 of Example 28, using (3S)-tetrahydrofuran-3-ol (259 mg, 0.29 mmol) in step 1 to obtain 16 mg (7% yield in step 4) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(3R)-tetrahydrofuran-3-yl]oxy-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): Calculated value 492.2, measured value 492.3. 1 H NMR(400MHz,DMSO-d6)δ ppm:11.61(d,J=2.4Hz,1H).83(s,1H)7.47-7.53(m,1H)7.08-7.14(m,1H)6.63-6.69(m,1H)6.43-6.53(m,1H)5.54-5.64(m,2H) )5.44-5.53(m,1H)3.95-4.05(m,1H)3.73-3.92(m,4H)3.00-3.18(m,3H)2.21-2.37(m,2H)1.95-2.11(m,3H)1.69-1.88(m,2H).

[0267] Example 30: trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(4-hydroxycyclohexyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka]

[0268] Step 1: tert-butyl4-[2-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.50 g, 2.94 mmol, prepared in step 3 of Example 1) and 2-(1,4-dioxapiro[4.5]deca-7-en-8-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (784 mg, 2.94 mmol) in 1,4-dioxane (30 mL) and water (8 mL), K2CO3 (1.22 g, 8.83 mmol) was added, and the resulting mixture was aerated with nitrogen for 15 minutes. Then, PdCl2 (dppf).DCM (215 mg, 0.26 mmol) was added at room temperature, and the reaction mixture was stirred at 90°C for 4 hours. After 4 hours, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2 × 100 mL), and the combined organic layer was dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by flash chromatography using elution with 40% ethyl acetate in hexane to obtain 1.5 g (90% yield) of tert-butyl 4-[2-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate as a yellow, gum-like liquid. LC / MS (m / z, M+H): Calculated value 569.3, measured value 569.2.

[0269] Step 2: tert-butyl4-[2-(1,4-dioxaspiro[4.5]decane-8-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[2-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.50 g, 2.64 mmol) in methanol (20 mL), 10% Pd / C (2.81 g, 26.4 mmol) was added under an inert atmosphere, and the reaction mixture was then stirred at room temperature under an H2 atmosphere for 4 hours. After 4 hours, the reaction mixture was filtered through Celite, the resulting filtrate was dried over sodium sulfate, and concentrated under vacuum to obtain 1.2 g (79% yield) of tert-butyl 4-[2-(1,4-dioxaspiro[4.5]decane-8-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate as a yellow solid. LC / MS (m / z, M+H): Calculated value 573.3, measured value 573.3.

[0270] Step 3: 4-[7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl]cyclohexanone, 2,2,2-trifluoroacetic acid [ka] To a stirred solution of tert-butyl 4-[2-(1,4-dioxaspiro[4.5]decane-8-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (1.50 g, 2.62 mmol) in dichloromethane (20 mL), 2,2,2-trifluoroacetic acid (2.99 g, 26.2 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After 16 hours, the reaction mixture was concentrated under vacuum, triturated, and washed with n-hexane (2 × 25 mL) to obtain 900 mg (83% yield) of 4-[7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl]cyclohexanone and 2,2,2-trifluoroacetic acid as an off-white solid. LC / MS (m / z, MH-TFA): Calculated value 297.2, measured value 297.2.

[0271] Step 4: 4-[7-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-5H-pyrrolo[2,3-b]pyrazine-2-yl]cyclohexanone [ka] To a stirred solution of 2-amino-4-(trifluoromethoxy)benzoic acid (500 mg, 2.26 mmol), 4-[7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl]cyclohexanone and 2,2,2-trifluoroacetic acid (675 mg, 1.64 mol) in N,N-dimethylformamide (10 mL), 3-(ethyliminomethyllenamino)-N,N-dimethyl-propan-1-amine hydrochloride (650 mg, 3.39 mmol), 1-hydroxybenzotriazole hydrate (519 mg, 3.39 mmol), and N,N-diethylethaneamine (686 g, 6.78 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 4 hours. After 4 hours, the reaction mixture was concentrated under reduced pressure, diluted with ice water (30 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 500 mg (44% yield) of 4-[7-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-5H-pyrrolo[2,3-b]pyrazine-2-yl]cyclohexanone as an off-white solid. LC / MS (m / z, M+H): Calculated value 502.2, measured value 502.2.

[0272] Step 5: trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(4-hydroxycyclohexyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] To a stirred solution of 4-[7-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-5H-pyrrolo[2,3-b]pyrazine-2-yl]cyclohexanone (500 g, 0.99 mmol) in methanol (10 mL), NaBH4 (189 mg, 4.99 mol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After 1 hour, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ice water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain 15 mg (yield 3%) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(4-hydroxycyclohexyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone as an off-white solid. LC / MS (m / z, M+H): Calculated value 504.2, measured value 504.2. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.50-11.66(m,1H)7.48-7.63(m,1H)7.09-7.18(m,1H)6.63-6.72(m,1H)6.44-6.57(m,1H)5.46-5.64(m,2H) )4.40-4.63(m,1H)3.42-3.55(m,2H)3.01-3.20(m,3H)1.83-2.14(m,6H)1.51-1.77(m,4H)1.27-1.42(m,3H).

[0273] Example 31: [4-[2-(4-methylpiperazin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, formic acid [ka]

[0274] Step 1: tert-butyl4-[2-(4-methylpiperazin-1-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1 g, 1.96 mmol, prepared in step 3 of Example 1) in 1,4-dioxane (10 mL), 1-methylpiperazine (393 mg, 3.93 mmol) and sodium 2-methylpropane-2-oleate (566 mg, 5.89 mmol) were added at room temperature, and the resulting mixture was aerated with nitrogen for 10 minutes. Then, XPhosPdG4 (169 mg, 0.2 mmol) was added under an N2 atmosphere, and the resulting mixture was microwaved at 100°C for 1 hour. After 1 hour, the reaction mixture was diluted with water (30 mL), extracted with siRNA (2 × 100 mL), and the combined organic layer was dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by flash chromatography using elution with 40% ethyl acetate in hexane to obtain 500 mg (48% yield) of tert-butyl 4-[2-(4-methylpiperazin-1-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate as a yellow solid. LC / MS (m / z, M+H): Calculated value 529.3, measured value 529.2.

[0275] Step 2: tert-butyl4-[2-(4-methylpiperazine-1-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[2-(4-methylpiperazin-1-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (500 mg, 0.95 mmol) in ethanol (20 mL), 10% Pd / C (302 mg, 2.84 mmol) was added at room temperature, and the resulting reaction mixture was hydrogenated under an H2 atmosphere for 12 hours. After 12 hours, the reaction mixture was filtered through Celite, the resulting filtrate was dried over sodium sulfate, and concentrated under vacuum to obtain 350 mg (70% yield) of tert-butyl 4-[2-(4-methylpiperazin-1-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate as a yellow liquid. LC / MS (m / z, M+H): Calculated value 531.3, measured value 531.2.

[0276] Step 3: [2-(4-methylpiperazin-1-yl)-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol, dihydrochloride [ka] To a stirred solution of tert-butyl 4-[2-(4-methylpiperazin-1-yl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (320 mg, 0.6 mmol) in dichloromethane (10 mL), 4 M HCl (3 mL, 0.056 mmol) in dioxane was added at 0°C, and the resulting reaction mixture was stirred at room temperature for 4 hours. After 4 hours, the reaction mixture was concentrated under vacuum, the resulting residue was triturated, and washed with n-hexane (2 × 25 mL) to obtain 350 mg of crude [2-(4-methylpiperazin-1-yl)-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol, dihydrochloride (0.350 g) as a yellow solid. This solid was then carried out to the next step without further purification.

[0277] Step 4: 2-(4-methylpiperazin-1-yl)-7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine [ka] To a stirred solution of [2-(4-methylpiperazin-1-yl)-7-(4-piperidyl)pyrrolo[2,3-b]pyrazine-5-yl]methanol and dihydrochloride (350 mg crude from step 3) in methanol, an aqueous solution of NH3 (25% w / v, 3 mL, 0.056 mmol) was added at 0°C, and the resulting reaction mixture was stirred at room temperature for 4 hours. After 4 hours, the reaction mixture was concentrated under vacuum. The resulting residue was purified by preparative HPLC to obtain 100 mg (55% yield) of 2-(4-methylpiperazin-1-yl)-7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine as a pale yellow solid. LC / MS (m / z, M+H): Calculated value 301.2, measured value 301.1.

[0278] Step 5: [4-[2-(4-methylpiperazine-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, formic acid [ka] To a stirred solution of 4-(pentafluoromethoxy)benzoic acid (70 mg, 0.34 mol) in N,N-dimethylformamide (10 mL), [benzotriazole-1-yloxy(dimethylamino)methylene]-dimethyl-ammonium, tetrafluoroborate (164 mg, 0.51 mmol) and N,N-diethylethaneamine (103 mg, 1.02 mmol) were added, and the resulting reaction mixture was stirred for 15 minutes. Then, 2-(4-methylpiperazin-1-yl)-7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine (92 mg, 0.31 mmol) was added at 0°C, and the resulting reaction mixture was stirred at room temperature for 4 hours. After 4 hours, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2 × 50 mL), and the combined organic layers were dried over sodium sulfate and concentrated under vacuum. The obtained residue was purified by preparative HPLC (preparative conditions: mobile phase: A = 0.1% HCOOH in water, B = ACN, column: X SELECT (250 mm x 20 mm), 5 μm flow rate: 15 mL / min). The pure fraction was lyophilized to obtain 12 mg (yield 7%) of [4-[2-(4-methylpiperazin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone and formic acid as off-white solids. LC / MS (m / z, M+H-HCOOH): calculated value 489.2, measured value 489.1. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.18-11.42(m,1H)7.86-8.07(m,1H)7.49-7.64(m,2H)7.26-7.55(m,5H)4.47-4.63(m,1H)3.53-3.67(m,1H)3.42-3.53(m, 5H)3.05-3.16(m,1H)2.67(s,1H)2.43-2.47(m,4H)2.30-2.35(m,1H)1.94-2.15(m,3H)1.68-1.83(m,2H)1.37-1.55(m,2H).

[0279] Examples 36, 32 and 33: (rac)-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, and [4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-yl]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, isomers 1 and 2 [ka]

[0280] Step 1: (rac)-tert-butyl4-[2-[[tetrahydrofuran-3-yl]amino]-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] To a solution of tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (950 mg, 1.86 mmol, prepared in step 3 of Example 1) and tetrahydrofuran-3-amine hydrochloride (461 mg, 3.73 mmol) in dioxane (9 mL), t-BuONa (717 mg, 7.46 mmol) was added, and the resulting mixture was aerated with argon for 5 minutes. Then, Pd2(dba)3 (171 mg, 0.19 mmol) and RuPhos (104 mg, 0.22 mmol) were added, and the resulting mixture was microwaved at 100°C for 1 hour. The entire mixture was then diluted with ethyl acetate and washed with water and brine. The combined aqueous layer was extracted with ethyl acetate, the combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel (SiO280g) eluted with DCM / ethyl acetate 7 / 3 to obtain 548 mg (yield 57%) of (rac)-tert-butyl4-[2-[[tetrahydrofuran-3-yl]amino]-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate as an orange solid. LC / MS (m / z, M+H): Calculated value 516.3, measured value 516.5.

[0281] Step 2: (rac)-tert-butyl4-[2-[[tetrahydrofuran-3-yl]amino]-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] To a solution of (rac)-tert-butyl4-[2-[[tetrahydrofuran-3-yl]amino]-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (577 mg, 1.12 mmol) in EtOH (10 mL), ammonium formate (1.41 g, 22.4 mmol) and Pd / C 10% (50% wet) (110 mg) were added, and the entire mixture was stirred at 80°C for 1 hour. After 1 hour, the mixture was cooled to room temperature, filtered, washed with EtOH, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with a 1N solution of NaOH, dried over sodium sulfate, filtered, and concentrated to obtain 561 mg (96% yield) of (rac)-tert-butyl 4-[2-[tetrahydrofuran-3-yl]amino]-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate as a brown solid. LC / MS (m / z, M+H): Calculated value 518.3, measured value 518.6.

[0282] Step 3: (rac)-tert-butyl4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate [ka] To a solution of (rac)-tert-butyl4-[2-[[tetrahydrofuran-3-yl]amino]-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (557 mg, 1.07 mmol) in THF (2 mL), ethylenediamine (0.72 mL, 10.76 mmol) and a 1 M solution of tetrabutylammonium fluoride in THF (8.6 mL, 8.6 mmol) were added, and the resulting reaction mixture was stirred under reflux for 12 hours. After 12 hours, the reaction mixture was cooled to room temperature, concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography on silica gel (SiO2 24g) eluted with ethyl acetate / heptane 8 / 2 to obtain 373 mg (89% yield) of (rac)-tert-butyl 4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate as a brown solid. LC / MS (m / z, M+H): Calculated value 388.2, measured value 388.4.

[0283] Step 4: (rac)-7-(4-piperidyl)-N-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-2-amine, trihydrochloride [ka] To a solution of (rac)-tert-butyl4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (370 mg, 0.95 mmol) in MeOH (6 mL), a solution of 4N HCl in dioxane (2.38 mL, 9.55 mmol) was added, and the resulting mixture was stirred at room temperature for 1.5 hours. The resulting mixture was then concentrated to dryness to obtain 367 mg (96% yield) of (rac)-7-(4-piperidyl)-N-tetrahydrofuran-3-yl-5H-pyrolo[2,3-b]pyrazine-2-amine trihydrochloride as a yellow solid, which was then carried to the next step without purification.

[0284] Step 5 (Example 36): (rac)-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka] To a solution of (rac)-7-(4-piperidyl)-N-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-2-amine and trihydrochloride (182 mg, 0.46 mmol) in DMF (3 mL), DIPEA (237 mg, 1.83 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 5 minutes. Then, 4-(trifluoromethoxy)benzoic acid (94 mg, 0.46 mmol) and TBTU (162 mg, 0.5 mmol) were added sequentially, and the resulting mixture was stirred at room temperature for a further 2.5 hours. The mixture was then diluted with ethyl acetate, washed with saturated aqueous solution of NaHCO3 and water, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was tritulated in MeCN, filtered, washed with MeCN, and dried under reduced pressure. Next, the resulting light brown solid was purified by flash chromatography (SiO2 12g) on ​​silica gel eluted with DCM / MeOH / NH4OH 95 / 5 / 0.5 to obtain 163 mg (75% yield) of (rac)-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone as a light brown solid. LC / MS (m / z, M+): Calculated value 475.2, measured value 475.0. 1H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.82-1.94(m,3H)2.06(br d,J=12.7Hz,2H)2.20-2.29(m,1H)3.05-3.19(m,3H)3.57(dd,J=8.8,4.5Hz,1H)3.72-3.79(m ,1H)3.84-3.91(m,1H)4.00(dd,J=8.8,6.1Hz,1H)4.03-4.19(m,2H)4.34-4.42(m,1H)6.24(br d,J=6.0Hz,1H)7.21(br s,1H)7.39(br d,J=8.4Hz,2H)7.54(br d,J=8.4Hz,2H)7.63(s,1H)10.78(br s,1H)

[0285] Step 6 (Examples 32 and 33): [4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, isomers 1 and 2 [ka] Chiral separation of (rac)-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (151 mg, 0.32 mmol) was performed using a Chiralcel OZ column (30 μm, 350 x 80 mm) eluting (heptane 70 / EtOH 30) + 0.1% TEA (flow rate 400 mL / min, UV detection at 230 nm), yielding 67 mg (yield 44%) of [4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, isomer 1. LC / MS (m / z, M+H): Calculated value 476.2, Measured value 476.4. 1H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.82-1.94(m,3H)2.05(br d,J=12.7Hz,2H)2.20-2.29(m,1H)3.05-3.19(m,3H)3.57(dd,J=8.8,4.5Hz,1H)3.72-3.79(m ,1H)3.83-3.91(m,1H)4.00(dd,J=8.8,6.1Hz,1H)4.03-4.19(m,2H)4.34-4.42(m,1H)6.24(br d,J=6.0Hz,1H)7.21(d,J=2.9Hz,1H)7.39(br d,J=8.4Hz,2H)7.54(br d,J=8.4Hz,2H)7.63(s,1H)10.78(br s,1H) and 63 mg (42% yield) of [4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, isomer 2. LC / MS (m / z,M+H): Calculated value 476.2, Measured value 476.4. 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.82-1.94(m,3H)2.05(br d,J=12.7Hz,2H)2.20-2.29(m,1H)3.05-3.19(m,3H)3.57(dd,J=8.8,4.5Hz,1H)3.72-3.79(m ,1H)3.84-3.91(m,1H)4.00(dd,J=8.8,6.1Hz,1H)4.04-4.19(m,2H)4.34-4.42(m,1H)6.24(br d,J=6.0Hz,1H)7.21(d,J=2.9Hz,1H)7.39(br d,J=8.4Hz,2H)7.54(br d,J=8.4Hz,2H)7.63(s,1H)10.78(br s,1H).

[0286] Examples 37, 34 and 35: (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, and [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, isomers 1 and 2 [ka]

[0287] Step 1 (Example 37): (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] Step 1 was carried out according to the protocol described in Step 5 of Examples 32 and 33, using (rac)-7-(4-piperidyl)-N-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-2-amine, trihydrochloride (182 mg, 0.46 mmol) and 2-amino-4-(trifluoromethoxy)benzoic acid (101 mg, 0.46 mmol) to obtain 189 mg (84% yield) of (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone as a light brown solid. LC / MS (m / z, M+H): Calculated value 491.2, measured value 491.4. 1H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.81-1.92(m,3H)2.05(br d,J=12.7Hz,2H)2.20-2.29(m,1H)3.03-3.17(m,3H)3.57(dd,J=8.8,4.5Hz ,1H)3.72-3.78(m,1H)3.83-3.90(m,1H)4.00(dd,J=8.8,6.1Hz,1H)4.09(br d,J=12.7Hz,2H)4.34-4.41(m,1H)5.32(br s,2H)6.23(br d,J=6.0Hz,1H)6.49(br d,J=8.4Hz,1H)6.69(br s,1H)7.13(d,J=8.4Hz,1H)7.20(br s,1H)7.63(s,1H)10.77(br s,1H).

[0288] Step 2 (Examples 34 and 35): [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, isomers 1 and 2 [ka] Chiral separation of (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone (175 mg, 0.36 mmol) was performed using a Chiralcel OZ column (5 μm, 30 x 250 mm) eluting (heptane 55 / EtOH 45) + 0.1% TEA (flow rate 45 mL / min, UV detection at 254 nm), yielding 78 mg (yield 44%) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, isomer 1. LC / MS (m / z, M+H): Calculated value 491.2, Measured value 491.4 1H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.81-1.92(m,3H)2.05(br d,J=12.7Hz,2H)2.20-2.30(m,1H)3.03-3.17(m,3H)3.57(dd,J=8.8,4.5Hz ,1H)3.72-3.79(m,1H)3.83-3.90(m,1H)3.99(dd,J=8.8,6.1Hz,1H)4.09(br d,J=12.7Hz,2H)4.33-4.42(m,1H)5.31(br s,2H)6.22(br d,J=6.0Hz,1H)6.49(br d,J=8.4Hz,1H)6.69(br s,1H)7.12(d,J=8.4Hz,1H)7.20(br s,1H)7.63(s,1H)10.76(br s,1H); and 84 mg (yield 48%) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, isomer 2. LC / MS (m / z,M+H):calc.491.2, measured value 491.4, 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.81-1.92(m,3H)2.05(br d,J=12.7Hz,2H)2.20-2.30(m,1H)3.03-3.17(m,3H)3.57(dd,J=8.8,4.5Hz ,1H)3.72-3.78(m,1H)3.83-3.90(m,1H)3.99(dd,J=8.8,6.1Hz,1H)4.09(br d,J=12.7Hz,2H)4.33-4.41(m,1H)5.31(br s,2H)6.22(br d,J=6.0Hz,1H)6.49(br d,J=8.4Hz,1H)6.69(br s,1H)7.12(d,J=8.4Hz,1H)7.20(br s,1H)7.63(s,1H)10.76(br s,1H).

[0289] Example 38: [4-[2-(tetrahydropyran-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka] Example 38 was prepared using the same method as in steps 1-5 of Examples 36, 32, and 33 to obtain 105 mg (79% yield in step 5) of [4-[2-(tetrahydropyran-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone as a light brown solid. LC / MS (m / z, M+H): Calculated value 490.2, measured value 490.3. 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.47-1.58(m,2H),1.82-1.95(m,2H),1.95-2.08(m,4H),3.04-3.18(m,3H),3.44(td,J=2.4 and 11.1Hz,2H),3.85-3.97(m,3H),4.01-4.17(m,2H),5.94(br d,J=7.0Hz,1H),7.20(s,1H),7.40(d,J=8.0Hz,2H),7.54(d,=8.0Hz,2H),7.62(s,1H),10.74(br s,1H)

[0290] Example 39: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(tetrahydropyran-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] Example 39 was carried out according to the protocol described in step 5 of Examples 36, 32, and 33, using 7-(4-piperidyl)-N-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-2-amine, trihydrochloride (111 mg, 0.27 mmol), and 2-amino-4-(trifluoromethoxy)benzoic acid (60 mg, 0.27 mmol) to obtain 106 mg (78% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(tetrahydropyran-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone as a light brown solid. LC / MS (m / z, M+H): Calculated value 505.2, measured value 505.3. 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.47-1.58(m,2H),1.81-1.93(m,2H),1.96-2.09(m,4H),3.03-3.18(m,3H),3.45(td,J=2.4 and 11.1Hz,2H),3.85-3.96(m,3H),4.08(br d,J=12.7Hz,2H),5.33(br s,2H),5.93(br d,J=7.0Hz,1H),6.49(br d,J=8.4Hz,1H),6.70(br s,1H),7.13(d,J=8.4Hz,1H),7.19(br s,1H),7.62(s,1H),10.73(br s,1H)

[0291] Example 40: [4-(2-morpholino-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka]

[0292] Step 1: tert-butyl4-[2-morpholino-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] In a 10-20 mL microwave vial, a solution of morpholine (51 mg, 0.59 mmol), tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (250 mg, 0.49 mmol, prepared in step 3 of Example 1), and RuPhos (18 mg, 0.04 mmol) in THF (1 mL) was aerated with argon for 10 minutes, then Pd(OAc)2 (4 mg, 0.02 mmol) was added, followed by the addition of 1.18 mL of a 1 M solution of LiHMDS in THF (1.18 mmol). The resulting mixture was then microwaved at 100°C for 1 hour. After 1 hour, the reaction mixture was cooled to room temperature and diluted with AcOEt and water. The aqueous layer was extracted three times with AcOEt, and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography on silica gel (SiO2 24 g) eluted with DCM / AcOEt 100 / 0~90 / 10 to obtain 140 mg (55% yield) of tert-butyl 4-[2-morpholino-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate as a brown solid. LC / MS (m / z, M+H): Calculated value 516.3, measured value 516.4.

[0293] Steps 2-5: [4-(2-morpholino-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka] Steps 2-5 of Example 40 were carried out according to the protocols described in steps 2-5 of Examples 36, 32, and 33. In step 5, 30 mg (4-(trifluoromethoxy)phenyl]methanone was obtained as a solid by using 4-[7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl]morpholine hydrochloride (50 mg, 0.15 mmol) and 4-(trifluoromethoxy)benzoic acid (32 mg, 0.15 mmol). LC / MS (m / z, M+H): Calculated value 476.2, measured value 476.1. 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.74-1.86(m,2H),2.07(br d,J=12.7Hz,2H),3.06-3.18(m,3H),3.41-3.48(m,4H),3.72-3.79(m,4H),3.96-4.16(m,2H),7.34(d,J=2.9Hz,1H),7.37(br d,J=8.4Hz,2H),7.51(br d,J=8.4Hz,2H),7.91(s,1H),10.97(br s,1H)

[0294] Example 41: [4-[2-(4,4-difluoro-1-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka]

[0295] Step 1: tert-butyl4-[2-(4,4-difluoro-1-piperidyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] Step 1 of Example 41 was carried out according to the protocol described in Step 1 of Example 40, using tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (300 mg, 0.59 mmol) and 4,4-difluoropiperidine (85 mg, 0.71 mmol) to obtain 196 mg (60% yield) of tert-butyl 4-[2-(4,4-difluoro-1-piperidyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate as a brown solid. LC / MS (m / z, M+H): Calculated value 550.3, Measured value 550.3.

[0296] Steps 2-5: [4-[2-(4,4-difluoro-1-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone [ka] Steps 2-5 of Example 41 were carried out according to the protocols described in steps 2-5 of Examples 36, 32, and 33. In step 5, 35 mg (55% yield) of [4-[2-(4,4-difluoro-1-piperidyl)-7-(4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine hydrochloride (45 mg, 0.12 mmol) and 4-(trifluoromethoxy)benzoic acid (26 mg, 0.12 mmol) of [4-[2-(4,4-difluoro-1-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone was obtained as a light brown solid. LC / MS (m / z, M+H): Calculated value 510.2, measured value 510.1. 1H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.78-1.89(m,2H)2.01-2.13(m,6H)3.09-3.20(m,3H)3.65-3.74(m,4H)4.00-4.19(m,2H)7.37(d,J=2.5Hz,1H)7.40(br d,J=8.4Hz,2H)7.54(br d,J=8.4Hz,2H)8.03(s,1H)11.02(br s,1H)

[0297] Example 42: [4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]methanone [ka]

[0298] Step 1: tert-butyl 4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)piperidine-1-carboxylate [ka] Step 1 of Example 42 was carried out using tert-butyl 4-[2-tetrahydropyran-4-yl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]piperidine-1-carboxylate (189 mg, 0.36 mmol, prepared in Step 2 of Example 2) according to the protocol described in Step 3 of Examples 36, 32, and 33, to obtain 128 mg (90% yield) of tert-butyl 4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)piperidine-1-carboxylate as a solid. LC / MS (m / z, M+H): Calculated value 387.3, measured value 387.3.

[0299] Step 2: 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine, dihydrochloride [ka] A solution of tert-butyl 4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)piperidine-1-carboxylate (117 mg, 0.3 mmol) in HCl (5N, 4 mL, 20 mmol) in dioxane was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to dryness to obtain 109 mg (100% yield) of 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine dihydrochloride as a yellow solid. LC / MS (m / z, M+H-2HCl): Calculated value 287.2, measured value 287.1.

[0300] Step 3: [4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]methanone [ka] Step 3 of Example 42 was carried out according to the protocol described in Step 5 of Examples 36, 32, and 33, using 7-(4-piperidyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine, dihydrochloride (50 mg, 0.14 mmol) and 4-(2-hydroxyhexafluoroisopropyl)benzoic acid (45 mg, 0.15 mmol) to obtain 67 mg (78% yield) of [4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]methanone as a solid. LC / MS (m / z, M+H): Calculated value 557.2, measured value 557.1. 1H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.79-1.95(m,6H)2.09(br d,J=12.7Hz,2H)3.03-3.26(m,4H)3.50(td,J=11.4,2.9Hz,2H)3.95-4.01(m,2H)4.02-4.25(m,2H)7.52(s,1H)7.54(br d,J=8.4Hz,2H)7.76(br d,J=8.4Hz,2H)8.12(s,1H)8.26-8.77(m,1H)11.29(br s,1H)

[0301] Example 43: (rac)-[2-amino-4-(pentafluoro-λ 6 [-sulfanyl)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-129-pyrroridine-1-yl]methanone [ka] Example 43 was prepared according to the protocol described in steps 3-5 of Examples 36, 32, and 33. In step 5, (rac)-7-pyrrolin-3-yl-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine, dihydrochloride (120 mg, 0.35 mmol) and 2-amino-4-(pentafluoro-λ) were added. 6 Using (rac)-[2-amino-4-(pentafluoro-λ)-benzoic acid (100 mg, 0.38 mmol), 53 mg (yield 29%) was prepared. 6 [-sulfanyl)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrrolidine-1-yl]methanone was obtained as a white foam. LC / MS (m / z, M+H): Calculated value 518.2, measured value 518.2. 1H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.78-1.93(m,4H)2.22-2.31(m,1H)2.34-2.43(m,1H)3.03-3.13(m,1H) 3.51(td,J=11.1,3.1Hz,2H)3.56-3.76(m,4H)3.93-4.03(m,3H)5.60(br s,2H)6.97(dd,J=8.4,2.3Hz,1H)7.26(d,J=2.3Hz,1H)7.30(br d,J=8.4Hz,1H)7.60(d,J=2.5Hz,1H)8.15(s,1H)11.38(br s,1H).

[0302] Example 44: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetane-3-yloxy)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka]

[0303] Step 1: tert-butyl4-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.5 g, 2.94 mmol) in THF (15 mL), tetrabutylammonium fluoride trihydrate (10 mL, 8.83 mmol) was added at 0°C, and the reaction mixture was stirred at 70°C for 6 hours. After 6 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography using ethyl acetate in 0-70% hexane to obtain 750 mg (yield 67%) of tert-butyl 4-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylate as a yellow solid. LC / MS (m / z, MH): Calculated value 377.0, measured value 377.1.

[0304] Step 2: 2-Bromo-7-(1,2,3,6-tetrahydropyridine-4-yl)-5H-pyrrolo[2,3-b]pyrazine, hydrochloride [ka] To a stirred solution of tert-butyl 4-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (0.750 g, 1.98 mmol) in 1,4-dioxane (10 mL), a 4 M solution of HCl in dioxane (4 mL, 9.89 mol) was added at 0°C, and the resulting mixture was stirred at room temperature for 3 hours. After 3 hours, the reaction mixture was concentrated under reduced pressure, and the resulting residue was triturated with n-hexane (2 × 20 mL) to obtain 600 mg (97% yield) of 2-bromo-7-(1,2,3,6-tetrahydropyridine-4-yl)-5H-pyrrolo[2,3-b]pyrazine hydrochloride (0.600 g) as a brown solid. LC / MS (m / z, M+H-HCl): Calculated value 279.0, measured value 278.9.

[0305] Step 3: [4-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-yl)-3,6-dihydro-2H-pyridine-1-yl]-[2-nitro-4-(trifluoromethoxy)phenyl]methanone [ka] To a stirred solution of 2-nitro-4-(trifluoromethoxy)benzoic acid (400 mg, 1.59 mmol) and 2-bromo-7-(1,2,3,6-tetrahydropyridine-4-yl)-5H-pyrrolo[2,3-b]pyrazine hydrochloride (489 mg, 1.55 mmol) in DMF (10 mL), N,N-diethylethaneamine (484 mg, 4.78 mmol) was added, and the resulting mixture was stirred for 15 minutes. Then, [benzotriazole-1-yloxy(dimethylamino)methylene]-dimethylammonium tetrafluoroborate (767 mg, 2.39 mmol) was added at 0°C, and the resulting mixture was stirred at room temperature for 2 hours. Then, it was diluted with water (20 mL) and extracted with siRNA (2 × 10 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by flash chromatography using ethyl acetate in 0-70% hexane to obtain 500 mg (63% yield) of [4-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-yl)-3,6-dihydro-2H-pyridine-1-yl]-[2-nitro-4-(trifluoromethoxy)phenyl]methanone as a yellow solid. LC / MS (m / z, M+H): Calculated value 512.0, measured value 512.0.

[0306] Step 4: [4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-yl]-[2-nitro-4-(trifluoromethoxy)phenyl]methanone [ka] To a stirred solution of [4-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-yl)-3,6-dihydro-2H-pyridine-1-yl]-[2-nitro-4-(trifluoromethoxy)phenyl]methanone (500 mg, 0.98 mmol) in N,N-dimethylformamide (10 mL), sodium hydride (60% dispersion in oil, 59 mg, 1.46 mmol) was added in portions at 0°C, and the resulting mixture was stirred for 20 minutes. Then, 2-(chloromethoxy)ethyl-trimethyl-silane (195 mg, 1.17 mmol) was added at 0°C, and the resulting mixture was stirred at room temperature for 3 hours. After 3 hours, the reaction mixture was dissolved in water (2 The mixture was diluted with 0 mL and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by flash chromatography using ethyl acetate in 0–70% hexane to obtain 500 mg (80% yield) of [4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-yl]-[2-nitro-4-(trifluoromethoxy)phenyl]methanone as a yellow, gum-like solid. LC / MS (m / z, M+H): Calculated value 642.1, measured value 642.1.

[0307] Step 5: [2-Nitro-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetane-3-yloxy)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-yl]methanone [ka] To a stirred solution of [4-[2-bromo-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-yl]-[2-nitro-4-(trifluoromethoxy)phenyl]methanone (450 mg, 0.70 mmol) in 1,4-dioxane (20 mL), oxetane-3-ol (259 mg, 3.50 mmol) and sodium 2-methylpropane-2-oleate (202 mg, 2.1 mmol) were added at room temperature. The resulting mixture was stirred for 15 minutes, and then XPhosPdG4 (60 mg, 0.07 mmol) was added under an N2 atmosphere. The resulting reaction mixture was microwaved at 100°C for 1 hour. After 1 hour, the reaction mixture was filtered and dried under reduced pressure. The obtained residue was purified by flash chromatography using elution with ethyl acetate in 0-60% hexane to obtain 250 mg (56% yield) of [2-nitro-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetane-3-yloxy)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-yl]methanone as a yellow liquid. LC / MS (m / z, M+H): Calculated value 636.2, measured value 636.3.

[0308] Step 6: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetane-3-yloxy)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] To a stirred solution of [2-nitro-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetane-3-yloxy)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-3,6-dihydro-2H-pyridine-1-yl]methanone (250 mg, 0.39 mmol) in ethanol (10 mL), 10% palladium carbon (126 mg, 1.18 mmol) was added at room temperature, and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. After 6 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by flash chromatography using elution with ethyl acetate in 0-80% hexane to obtain 110 mg (46% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetane-3-yloxy)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone as a gum-like liquid. LC / MS (m / z, M+H): Calculated value 608.2, measured value 608.3.

[0309] Step 7: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetane-3-yloxy)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone [ka] To a stirred solution of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetane-3-yloxy)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone (100 mg, 0.165 mmol) in THF (5 mL), tetrabutylammonium fluoride trihydrate (0.5 mL, 0.132 mmol) was added at 0°C, and the resulting mixture was stirred at 70°C for 4 hours. After 4 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC (mobile phase: A = 0.1% HCOOH in water, B = ACN, column: Gemini NX (250mm x 21.2mm), flow rate: 18 mL / min) to obtain 16 mg (20% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetan-3-yloxy)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone as an off-white solid. LC / MS (m / z, M+H): calculated value 478.2, measured value 478.1. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.63-11.73(m,1H)7.87-7.95(m,1H)7.48-7.56(m,1H)7.08-7.16(m,1H)6.64-6.70(m,1H)6.45-6.52(m,1H) )5.53-5.67(m,4H)4.88-4.99(m,2H)4.53-4.65(m,2H)3.00-3.20(m,2H)1.95-2.07(m,2H)1.70-1.85(m,2H).

[0310] Example 45 - ERK5 inhibitory activity of the compound Two assays were performed to evaluate the ERK5 inhibitory activity of the compound in the example, as well as cell-based and cell-free biochemical assays. The assay results are shown in Table 2 below. When repeated measurements were performed, the reported values ​​are mean values.

[0311] Inhibition of cellular ERK5 activity Renal cancer cell line SN12C was transduced by lentivirus pGreenFire1 MEF2 EF1 Neo (see TR030VA-N) from SBI using a standard infection protocol. pGreenFire1 MEF2 EF1 Neo enables the expression of the luciferase gene under the control of a minimal promoter with an MEF2 transcriptional response element. Cells containing the reporter construct were selected by genethecin treatment. The selected cells were then transposed with the piggyback-based plasmid pCM4007, enabling the expression of constitutively activated MEK5DD under the control of the doxycycline-regulating promoter, TREG3. Metastatic cells were selected by puromycin treatment. MEK5DD was expressed after doxycycline treatment (1 μg / ml). MEK5DD activates ERK5, which phosphorylates the MEF2C protein. The activated MEF2C protein can then bind to its transcriptional response element. Luciferase is then expressed. 50,000 cells were inoculated into 142.5 μl of RPMI medium containing 10% fetal bovine serum, 1% glutamine, and 1 μg / ml doxycycline in a 96-well plate (96F nuncleon ref137101 thermofisher). After 24 hours, 0.1% of the compound was added to 7.5 μl of culture medium (containing 2% DMSO) to obtain the desired concentration (0.3–10000 nM). Luciferase activity was measured using Kit Bright Glo Luminescent Cell Assay Cat E2610 (Promega) according to the manufacturer's protocol. Luminescence was determined using Tecan SPARK with a reading of 0.2 seconds / well. IC was extracted using XLFIT5 in Microsoft Excel using Method 205. 50 The value was calculated. IC 50 The value represents the concentration of the compound that inhibits measurable luminescence signals by 50% compared to DMSO-treated control cells.

[0312] ERK5 inhibition cell-free assay Assays were performed to measure the ability of each compound to inhibit ERK5 enzyme activity. The potency of the compounds was evaluated by time-resolved Forster resonance energy transfer (FRET system). The activation catalytic domain of the protein ERK5 (CarnaBiosciences#04-146) was mixed with various concentrations of the compounds at 4 nM and incubated at room temperature for 30 minutes. A mixture of 1 mM ATP and 1 μM biotinylated synthetic peptide was added (Biosyntan GmbH). This synthetic peptide represents amino acids 30-52 of eukaryotic translation initiation factor 4E-binding protein 1 (see, for example, the sequence of accession number NP_004086.1) biotinylated at the N-terminus. After 30 minutes at 37°C, peptide phosphorylation by ERK5 was measured by adding a FRET reagent consisting of 12.5 μg / ml streptavidin-XL665, 1 nM anti-P-4EBP1 antibody, and 300 ng / ml anti-rabbit K antibody. After 90 minutes at room temperature, the fluorescence signal was read using a BMG Labtech (Exc° 340nm, Em1 620nm, Em2 665nm) Pherastar FSX multimod detector. 50 The value represents the concentration of the compound that inhibits the measurable fluorescence signal by 50% compared to a control with DMSO alone.

[0313] [Table 10]

[0314] The data in Table 2 show that the synthesized compounds are active in the micromolar or nanomolar concentration range in cell-based and cell-free systems. All of the synthesized compounds showed an IC50 of less than 10 μM in at least one of the cell-based and cell-free assays. 50 It has a value.

[0315] While this disclosure has been described in conjunction with the embodiments described above, it should be understood that the above description and examples are intended to illustrate, and not limit, the scope of this disclosure. Other aspects, advantages, and variations within the scope of this disclosure will be apparent to those skilled in the art in which this disclosure relates.

[0316] In addition, if a feature or aspect is described in terms of the Markush group, a person skilled in the art will recognize that such feature or aspect is also described in terms of any individual member or subgroup of a member of the Markush group.

[0317] All publications, patent applications, patents, and other references referred to herein are expressly incorporated by reference to the same extent as each would be incorporated individually by reference. In case of any conflict, this specification, including its definitions, shall prevail.

Claims

1. A compound of formula (I), 【Chemistry 1】 During the ceremony, R １ However, -(C １ -C ６ ) alkyl, -(C ３ -C ７ ) Selected from cycloalkyl and 4-10 member heterocycloalkyl, R １ However, R Ａ It is optionally replaced by one or more occurrences of Each R Ａ is independently halo, -OH, oxo, -NH ２ , =N-OH, -(C １ -C ３ ), alkyl, -O(C １ -C ３ ), alkyl, and -(C ３ -C ６ ), cycloalkyl, each occurrence of -(C １ -C ３ ), alkyl is optionally substituted by one or more groups independently selected from halo and -OH, L １ However, it is selected from direct bonding, -O-, and -NH-, R ２ However, -(C ３ -C ６ ) Cycloalkyl and -(C ６ -C １０ ) Selected from the aryl, R ２ However, R Ｂ It is optionally substituted by one, two, or three occurrences. Each R Ｂ However, it became independent, Hello, -NH ２ , -SF ５ , - (C １ -C ３ ) alkyl, -O(C １ -C ３ ) alkyl, and -O(C ３ -C ６ ) Selected from cycloalkyl, -(C １ -C ３ ) Alkyl and -O(C １ -C ３ Each alkyl group is optionally substituted by one or more groups independently selected from the halo and -OH groups. R ３ However, -H, (C １ -C ３ ) Alkyl (e.g., -CH ３ ), and -OH are selected, Y is CH or N, n is 0 or 1. A compound, or a pharmaceutically acceptable salt thereof.

2. R １ but, 【Chemistry 2】 Selected from, in the formula, R １ However, as defined in claim 1, R Ａ The compound according to claim 1, which is optionally substituted by the appearance of one or two of the following.

3. Each R Ａ However, independently, -F, -OH, methyl, -OCH ３ The compound according to claim 2, selected from the group consisting of , and cyclopropyl.

4. The aforementioned compound is a compound of formula (I-G), 【Transformation 3】 In the formula, R １ , R ２ , L １ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein n is as defined in any one of claims 1 to 3.

5. A compound of formula (II), 【Chemistry 4】 During the ceremony, R １ However, -(C １ -C ６ ) alkyl, -(C ３ -C ７ ) Selected from cycloalkyl and 4-10 member heterocycloalkyl, R １ However, R Ａ It is optionally replaced by one or more occurrences of Each R Ａ However, independently, halos (e.g., -F), -OH, -(C) １ -C ３ ) alkyl, -O(C １ -C ３ ) alkyl, and -(C ３ -C ６ ) Selected from cycloalkyl, R ２ However, -(C ３ -C ６ ) Cycloalkyl and -(C ６ -C １０ ) Selected from the aryl, R ２ However, R Ｂ It is optionally substituted by one or two occurrences of, Each R Ｂ However, it became independent, Hello, -NH ２ , -SF ５ , - (C １ -C ３ ) alkyl, -O(C １ -C ３ ) alkyl, and -O(C ３ -C ６ ) Selected from cycloalkyl, -(C １ -C ３ ) Alkyl and -O(C １ -C ３ Each alkyl group is substituted by one or more groups independently selected from the halo and -OH groups. n is 0 or 1. A compound, or a pharmaceutically acceptable salt thereof.

6. R ２ is replaced by one or two occurrences of R Ｂ -(C ６ -C １０ )aryl, and each R Ｂ is independently halo (e.g., -F), -NH ２ , -SF ５ , -OCF ３ , -O-cyclopropyl, -C(OH)(CF ３ ) ２ , and -CF ２ CF ３ selected from, the compound according to claim 5.

7. A compound of formula (III-A), 【Transformation 5】 where R １ , L １ , and n are as defined in any one of claims 1 to 3, R Ｂ１ However, it is either -H or -NH ２ It is selected from the group consisting of , and -F, R Ｂ２ However, -OCF ３ , -SF ５ , -CF ２ CF ３ , -C(OH)(CF ３ ) ２ Selected from the group consisting of , and -O-cyclopropyl, A compound, or a pharmaceutically acceptable salt thereof.

8. A compound having the formula (IV-A) or (V-A), 【Transformation 6】 In the formula, R １ , L １ A compound, or a pharmaceutically acceptable salt thereof, wherein n is as defined in any one of claims 1 to 3.

9. A compound having formula (VI), formula (VII), or formula (VIII), 【Transformation 7】 In the formula, R １ However, as defined in any one of claims 1 to 3, Compounds, or pharmaceutically acceptable salts thereof.

10. -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(pentafluoro-λ ６ -Sulfanyl)phenyl]methanone, -[2-amino-4-(pentafluoro-λ) ６ -Sulfanyl)phenyl]-[4-[2-(1-methyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-(pentafluoro-λ) ６ -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(pentafluoro-λ) ６ -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(pentafluoro-λ) ６ -Sulfanyl)phenyl]-[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(1-cyclopropyl-4-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(pentafluoro-λ ６ -Sulfanyl)phenyl]methanone, -[4-(cyclopropoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[4-(1,1,2,2,2-pentafluoroethyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -Cyclohexyl-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrroridine-1-yl]methanone, -[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrrolidine-1-yl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-fluoro-4-(pentafluoro-λ] ６ -Sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetan-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[tetrahydrofuran-3-yl]oxy-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -Trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(4-hydroxycyclohexyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(4-methylpiperazine-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-[2-(tetrahydropyran-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(tetrahydropyran-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, -[4-(2-morpholino-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-[2-(4,4-difluoro-1-piperidyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone, -[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)-1-piperidyl]-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]methanone, -[2-amino-4-(pentafluoro-λ) ６ -Sulfanyl)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazine-7-yl)pyrrolidine-1-yl]methanone, -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetane-3-yloxy)-5H-pyrrolo[2,3-b]pyrazine-7-yl]-1-piperidyl]methanone, Compounds selected from the group consisting of and pharmaceutically acceptable salts thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and at least one pharmaceutically acceptable excipient or carrier.

12. A compound according to any one of claims 1 to 10, or a pharmaceutical composition according to claim 11, for use in therapeutic purposes.

13. A compound according to any one of claims 1 to 10, or a pharmaceutical composition according to claim 11, for use in the treatment or prevention of cancer.

14. The compound or pharmaceutical composition for use according to claim 13, wherein the cancer is characterized by increased MAPK7 expression and / or increased ERK5 activity.

15. The compound or pharmaceutical composition for use according to claim 13 or 14, wherein the cancer is selected from leukemia, breast cancer, multiple myeloma, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, melanoma, and hepatocellular carcinoma.

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