CN121002026A

CN121002026A - Pyrrolopyrazine compounds, their preparation and therapeutic uses

Info

Publication number: CN121002026A
Application number: CN202480025883.3A
Authority: CN
Inventors: F·斯洛文斯基; 张吉东; A·多梅尔格
Original assignee: Sanofi Aventis France
Current assignee: Sanofi Aventis France
Priority date: 2023-04-19
Filing date: 2024-04-18
Publication date: 2025-11-21
Also published as: WO2024218235A1; EP4698531A1

Abstract

Compounds are provided that can inhibit ERK 5. Also provided are pharmaceutical compositions and medical uses thereof, including use in treating or preventing a condition such as cancer.

Description

Pyrrolopyrazine compounds, their preparation and their therapeutic use

Disclosure of Invention

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 an important role in cell proliferation, differentiation and migration, and is well known to be involved in the development of cancer. Proteins in this pathway include extracellular signal regulated kinase (ERK) proteins, where ERK5 (expressed by the MAPK7 gene) plays an important role in cell proliferation, epithelial development and neural differentiation (see, e.g., nishimoto et al, EMBO Reports (European molecular biology report) (2006) 7 (8): 782-786). ERK5 is unique in ERK proteins, which have a large C-terminal domain that contains a Transcriptional Activation Domain (TAD) as well as a nuclear localization signal and two proline-rich regions (see, e.g., guo et al, exp Ther Med. [ journal of experimental and therapeutic medicine ] (2020) 19:1997-2007). Autophosphorylation of TADs is essential for transcriptional activation (see, e.g., morimoto et al, J Biol Chem. (2007) 282 (49): 35449-35456).

ERK5 plays an important role in controlling cell proliferation and cell cycle progression, for example, via direct or indirect phosphorylation of MEF2C, cMYC, SGK, RSK, FOS, FRA1, and the like (see, e.g., paudel et al, int J Mol Sci [ J.International molecular sciences ] (2021) 22:7594-7614; terasawa et al, genes to Cells [ J.Gene to cell ] (2003) 8 (3): 263-273). ERK5 is involved in a variety of biological pathways meaning that its activity is associated with many aspects of cancer progression, including tumor angiogenesis, metastasis, inflammation, sustained proliferation, and evasion of growth inhibition. Thus, it provides an attractive target for modulating disease pathology and treatment in a wide range of conditions. In previous studies, ERK5 inhibition or down-regulation has been shown to block tumorigenesis in murine leukemia cells, reduce growth of chronic myelogenous leukemia cells, inhibit growth of breast cancer and multiple myeloma cells, inhibit proliferation of colon cancer cells, and must have an effect on renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, and hepatocellular carcinoma cell growth or survival, among others (see, e.g., stecca et al, int J MolSci [ journal of international molecular sciences ] (2019) 20:1426-1446).

Thus ERK5 inhibition represents a promising approach to address a variety of cancers. Several ERK5 inhibitors have been developed, some of which are undergoing clinical examination. For example, WO 2019/170543 (Bayer AG) and Bayer pharmaceutical AG) disclose compounds that are said to be active as ERK5 inhibitors in the μm to nM concentration range.

Although cancer therapy has recently progressed with the development of targeted therapies and immunotherapy, not all cancer patients can get effective therapeutic solutions. Thus, there is a need to identify and develop new drugs. The present disclosure seeks to address this need by providing novel compounds that are useful as inhibitors of ERK5 and for the treatment of ERK5 related diseases and conditions.

Accordingly, in a first aspect, there is provided a compound having formula (I)

Or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from the group consisting of- (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl and 4 to 10 membered heterocycloalkyl, wherein R ¹ is optionally substituted by one or more occurrences of R ^A,

Wherein each R ^A is independently selected from halogen, -OH, oxo, -NH ₂、＝N-OH、-(C₁-C₃) alkyl, -O (C ₁-C₃) alkyl, and- (C ₃-C₆) cycloalkyl, wherein each occurrence of- (C ₁-C₃) alkyl is optionally substituted with one or more groups independently selected from halogen and-OH;

L ¹ is selected from the group consisting of a direct bond, -O-, and-NH-;

R ² is selected from the group consisting of- (C ₃-C₆) cycloalkyl and- (C ₆-C₁₀) aryl, wherein R ² is optionally substituted by one, two or three occurrences of R ^B,

Wherein each R ^B is independently selected from halogen, -NH ₂、-SF₅、-(C₁-C₃) alkyl, -O (C ₁-C₃) alkyl, and-O (C ₃-C₆) cycloalkyl, wherein each occurrence of- (C ₁-C₃) alkyl and-O (C ₁-C₃) alkyl is optionally substituted with one or more groups independently selected from halogen and-OH;

R ³ is selected from the group consisting of-H, (C ₁-C₃) alkyl (e.g., -CH ₃) and-OH;

Y is CH or N, and

N is 0 or 1.

In embodiments, R ¹ is selected from: Wherein R ¹ is optionally substituted with one or two occurrences of R ^A as defined previously herein. In embodiments, each R ^A is independently selected from the group consisting of-F, -OH, methyl, -OCH ₃, and cyclopropyl.

In an embodiment, the compound is a compound having the formula (I-G)

Or a pharmaceutically acceptable salt thereof, wherein R ¹、R²、L¹ and n are as defined previously herein.

In another aspect, compounds having formula (II) are provided

Or a pharmaceutically acceptable salt thereof, wherein:

Wherein each R ^A is independently selected from halogen (e.g., -F), -OH, -C ₁-C₃ alkyl, -O (C ₁-C₃) alkyl, and- (C ₃-C₆) cycloalkyl;

R ² is selected from the group consisting of- (C ₃-C₆) cycloalkyl and- (C ₆-C₁₀) aryl, wherein R ² is optionally substituted by one or two occurrences of R ^B,

Wherein each R ^B is independently selected from halogen, -NH ₂、-SF₅、-(C₁-C₃) alkyl, -O (C ₁-C₃) alkyl, and-O (C ₃-C₆) cycloalkyl, wherein each occurrence of- (C ₁-C₃) alkyl and-O (C ₁-C₃) alkyl is substituted with one or more groups independently selected from halogen and-OH, and

N is 0 or 1.

In embodiments, R ² is- (C ₆-C₁₀) aryl substituted with one or two occurrences of R ^B, wherein each R ^B is independently selected from halogen (e.g., -F), -NH ₂、-SF₅、-OCF₃, -O-cyclopropyl, -C (OH) (CF ₃)₂ and-CF ₂CF₃).

In another aspect, compounds having formula (III-A) are provided

Or a pharmaceutically acceptable salt thereof, wherein R ¹、L¹ and n are as defined previously herein, and wherein:

R ^B1 is-H, or is selected from the group consisting of-NH ₂ and-F, and

R ^B2 is selected from the group consisting of-OCF ₃、-SF₅、-CF₂CF₃、-C(OH)(CF₃)₂ and-O-cyclopropyl.

In another aspect, compounds having formulA (IV-A) or formulA (V-A) are provided

Or a pharmaceutically acceptable salt thereof, wherein R ¹、L¹ and n are as defined previously herein.

In another aspect, compounds having formula (VI), formula (VII) or formula (VIII) are provided

Or a pharmaceutically acceptable salt thereof, wherein R ¹ is as previously defined herein.

Further aspects provide a compound selected from the group consisting of:

- [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone,

- [4- (2-Tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [4- [2- (1-Methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [4- (2-Tetrahydrofuran-3-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [4- [2- (3-Methoxypropyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (3-methoxypropyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- [4- (2-Cyclohexyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- (2-cyclohexyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (1-cyclopropyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- [4- [2- (1-Cyclopropyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- (2-tetrahydrofuran-3-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone,

- [4- [2- (1-Methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] methanone,

- [ 2-Amino-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- [4- (Pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone,

- [ 2-Amino-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone,

- [ 2-Amino-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- [2- (1-cyclopropyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- [4- [2- (1-Cyclopropyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] methanone,

- [4- (Cyclopropyloxy) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone,

- [4- (1, 2-Pentafluoroethyl) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone,

-Cyclohexyl- [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [3- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyrrolidin-1-yl ] methanone,

- [3- (2-Tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyrrolidin-1-yl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [ 2-Fluoro-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-ylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ tetrahydrofuran-3-yl ] oxy-5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

-Trans- [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (4-hydroxycyclohexyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- [4- [2- (4-Methylpiperazin-1-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [4- [2- [ [ Tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- [4- [2- (Tetrahydropyran-4-ylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (tetrahydropyran-4-ylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- [4- (2-Morpholino-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [4- [2- (4, 4-Difluoro-1-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [4- (2-Tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- [2, 2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl ] phenyl ] methanone,

- [ 2-Amino-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [3- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyrrolidin-1-yl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-yloxy) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

And pharmaceutically acceptable salts thereof.

Further aspects provide pharmaceutical compositions comprising a compound as defined herein before and at least one pharmaceutically acceptable excipient or carrier.

Further aspects provide a compound or pharmaceutical composition as defined herein before for use in therapy.

Further aspects provide a compound or pharmaceutical composition as defined herein before for use in the treatment or prevention of cancer.

In embodiments, the cancer is characterized by increased MAPK7 expression and/or increased ERK5 activity.

In embodiments, 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.

Detailed Description

While specific embodiments of the present disclosure will now be described with reference to the specification and examples, it is to be understood that such embodiments are by way of example only and are illustrative of but a few of the many possible specific embodiments that may represent applications of the principles of the present disclosure. Various changes and modifications will be apparent to those skilled in the art having the benefit of this disclosure and are considered to be within the spirit and scope of the disclosure as further defined in the appended claims.

Definition of the definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the exemplary methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety.

The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of chemical synthesis, tissue culture, immunology, molecular biology, microbiology, cell biology, recombinant DNA, etc., which are within the skill of the art. See, e.g., michael R.Green and Joseph Sambrook, molecular Cloning [ molecular cloning ] (4 th edition, cold spring harbor laboratory Press (Cold Spring Harbor Laboratory Press) 2012), ausubel et al, eds (2007) Current Protocols in Molecular Biology [ modern methods of molecular biology ]; methods in Enzymology [ methods of enzymology ] (ACADEMIC PRESS, inc. of New York)); macPherson et al, (1991) PCR 1:A Practical Approach[PCR 1: practical methods ] (IRL Press of oxforum university Press (IRL PRESS AT Oxford University Press)); (MacPherson et al, (1995) PCR 2:A Practical Approach[PCR 2: practical methods ]; harlow and Lane, eds (1999) Antibodies, A Laboratory Manual [ laboratory Manual ]; freshney (2005) Culture of ANIMAL CELLS: A Manual of Basic Technique [ animal cell Culture: basic technology handbook ], 5 th edition; gait editions (1984) Oligonucleotide Synthesis [ oligonucleotide synthesis ]; U.S. Pat. No.4,683,195; hames and Higgins editions (1984) Nucleic Acid Hybridization [ nucleic acid hybridization ]; anderson (1999) Nucleic Acid Hybridization [ nucleic acid hybridization ]; hames and Higgins editions (1984) Transcription and Translation [ transcription and translation ]; immobilized Cells and Enzymes [ immobilized cells and enzymes ] (IRL Press) (1986)); perbal (1984) A PRACTICAL Guide to Molecular Cloning [ molecular cloning Utility guidelines ]; miller and Calos editions (1987) GENE TRANSFER Vectors for MAMMALIAN CELLS [ gene transfer Vectors for mammalian cells ] (Cold spring harbor laboratory (Cold Spring Harbor Laboratory)); makrides editions (2003) GENE TRANSFER AND Expression IN MAMMALIAN CELLS [ gene transfer and Expression in mammalian cells ]; mayer and Walker editions (1987) Immunochemical Methods IN CELL AND Molecular Biology [ immunochemical methods in cells and molecular biology ]; (Dunn (35) (1996) Wel et al, edited (67) Wil laboratory (35)); wel' 1996, et al, edited (67). A Laboratory Manual [ manipulate mouse embryo: laboratory Manual ], 3 rd edition (Cold spring harbor laboratory Press (Cold Spring Harbor Laboratory Press) (2002)); sohail (edit) (2004) GENE SILENCING by RNA INTERFERENCE: technology and Application [ gene silencing by RNA interference: techniques and applications ] (CRC Press).

All numerical labels, such as pH, temperature, time, concentration, molecular weight, etc. (including ranges) are approximations that may be varied (+) or (-) in increments of, for example, 0.1 or 1.0, where appropriate. It should be understood that all numerical designations are preceded by the term "about" which is used to indicate a conventional level of variability, although not always explicitly stated. For example, a numerical designation of "about" a given value may vary by + -10% of the value, alternatively the variation may be + -5%, + -2%, or + -1% of the value. It is also to be understood that the agents described herein are merely exemplary, although not always explicitly described, and that equivalents thereof are known in the art.

As used in the specification and in the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "cell" includes a plurality of cells, including mixtures thereof. As used herein, the term "or" is to be understood as being inclusive unless explicitly stated or apparent from the context. The term "comprising" as used herein means, and is used interchangeably with, the phrase "including, but not limited to.

As used herein, the term "comprising" is intended to mean that the compositions and methods include the recited elements, without excluding other elements. When used to define compositions and methods, "consisting essentially of" shall mean excluding other elements that have any significance for the purpose. Thus, a composition consisting essentially of the elements as defined herein will not exclude trace contaminants from the isolation and purification process as well as pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. "consisting of" shall mean more than one trace element excluding other ingredients and essential method steps for applying the compositions of the present disclosure or process steps for producing the compositions or achieving the desired result. Embodiments defined by each of these transitional terms are within the scope of this disclosure. The term "comprising" as used herein is intended to encompass and disclose the corresponding statement in which the term "comprising" is replaced by "consisting essentially of.

"Subject," "individual," or "patient" are used interchangeably herein and refer to a vertebrate, such as a mammal. Mammals include, but are not limited to, rodents, farm animals, racing animals, pets, and primates, such as mice, rats, rabbits, apes, cattle, sheep, pigs, dogs, cats, horses, and humans. In a particular embodiment, the mammal is a human.

"Administering" is defined herein as the manner in which an agent, or a composition comprising the agent, is provided to a subject in a manner that results in the agent coming into contact with the subject's body (e.g., in vivo). Such administration may be by any route including, but not limited to, oral, transdermal (e.g., via the vaginal, rectal, or oral mucosa), injection (e.g., subcutaneously, intravenously, parenterally, intraperitoneally, or into the central nervous system), or inhalation (e.g., orally or nasally). Administration may also include providing a substance or composition to a portion of a surface of a subject's body, for example by topical application to the skin. Of course, the pharmaceutical formulations are administered in a form suitable for each route of administration.

"Treating" or "treatment" of a disease includes (1) preventing the disease, i.e., causing the clinical symptoms of the disease to not develop in a patient who may be susceptible to the disease but who has not experienced or exhibited symptoms of the disease, (2) inhibiting the disease, i.e., preventing or reducing the development of the disease or its clinical symptoms, and/or (3) alleviating the disease, i.e., causing the disease or its clinical symptoms to subside.

The term "suffering from" in connection with the term "treatment" refers to a patient or individual who has been diagnosed with or is susceptible to a disease. A patient may also be said to be "at risk for" a disease due to a history of the disease in the patient's family lineage or due to the presence of a mutation in a gene associated with the disease. Patients at risk of disease have not developed all or some of the characteristic pathology of the disease.

An "effective amount" or "therapeutically effective amount" is an amount sufficient to achieve a beneficial or desired result. The effective amount may be administered in one or more administrations, applications or dosages. Such delivery depends on many variables including the period of time in which the individual dosage units are used, the bioavailability of the therapeutic agent, the route of administration, and the like. However, it will be appreciated that the particular dosage level of a therapeutic agent of the present disclosure for any particular subject depends on a variety of factors including, for example, the activity of the particular compound employed, the age, weight, general health, sex and diet of the subject, the time of administration, the rate of excretion, drug combination, the severity of the particular disorder being treated and the form of administration. Therapeutic doses can generally be adjusted to optimize safety and efficacy. Typically, the dose-response relationship from in vitro and/or in vivo assays may initially provide useful guidance for the proper dose administered to a patient. In general, it is desirable to administer an amount of a compound effective to achieve serum levels comparable to concentrations found to be effective in vitro. The determination of these parameters is well known to those skilled in the art. These considerations, as well as effective formulations and administration procedures, are well known in the art and described in standard textbooks. Consistent with this definition, the term "therapeutically effective amount" as used herein is an amount sufficient to treat (e.g., ameliorate) one or more symptoms associated with a disorder. The total daily dose may be administered in single or divided doses and may fall outside the typical ranges given herein at the discretion of the physician.

As used herein, the terms "increased" and "enhanced" are used interchangeably and encompass any measurable increase in biological function and/or biological activity and/or concentration. For example, the increase may be at least about 10%, such as at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, such as at least about 95%, 96%, 97%, 98%, 99%, or 100%. Thus, the increase may be at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, such as at least about 20-fold, 25-fold, 50-fold, 100-fold, or more, relative to a control or baseline amount or function, or activity or concentration.

As used herein, the term "increased expression" and/or "increased activity" of a substance (e.g., ERK 5) in a sample or cancer or patient typically refers to an increase in the amount of the substance (e.g., MAPK7 gene product or ERK5 protein), although it may also mean an increase in the biological activity of the substance (e.g., constitutive phosphorylation activation and/or a reduction in differentiation of ERK5 phosphorylation sites). For example, the increase may be an amount 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%. Thus, the increase may be about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, such as about 20-fold, 25-fold, 50-fold, 100-fold, or more, relative to the amount (or activity) of a substance (e.g., ERK 5) in one or more control samples (e.g., an individual or group of individuals not suffering from a disease or disorder (e.g., cancer) or an internal control) as determined by techniques known in the art. A subject may also be determined to have "increased expression" or "increased activity" of ERK5 if the expression and/or activity of ERK5 is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more relative to the mean (mean/average) or median amount of ERK5 in a sample control group or sample baseline group or in a retrospective analysis of patient samples. Such control or baseline expression levels may be predetermined, or measured prior to measuring the sample or cancer or subject, or may be obtained from a database of such control samples, as practiced in the art.

As used herein, the term "pharmaceutically acceptable excipient" encompasses any standard pharmaceutical excipient, for example as described in Remington's Pharmaceutical Sciences [ rest pharmaceutical science ] (20 th edition, mack Publishing Co [ merck publishing company ]. 2000). Such excipients include carriers, such as phosphate buffered saline solutions, water and emulsions (e.g., oil/water or water/oil emulsions), and various types of wetting agents. The pharmaceutical composition may further comprise stabilizers, preservatives, adjuvants, fillers, binders, lubricants and the like.

As used herein, the term "alkyl" means a saturated straight or branched radical consisting essentially 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 apparent to those skilled in the art, given the benefit of this disclosure. The terms "(C ₁-C₃) alkyl", "(C ₁-C₆) alkyl", and the like have equivalent meaning, i.e., saturated straight or branched chain radicals consisting essentially of 1 to 3 (or 1 to 6) carbon atoms and a corresponding number of hydrogen atoms. The definition of "alkyl" also applies to the context of other groups comprising alkyl groups, such as "-O (C ₁-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 backbone of the alkyl group may be substituted with (or bonded to) a heteroatom through multiple bonds (e.g., double bonds), for example, the carbon atoms of the alkyl group may be bonded to oxygen via a double bond (i.e., substituted with an oxo group to provide a carbonyl functionality). The presence of such substituents does not prevent the carbon backbone of the radical from being considered an alkyl group.

As used herein, the term "cyclic group" means a saturated, partially or fully unsaturated or aromatic group having at least 3 to 10 atoms forming a ring (i.e., ring atoms). When a cyclic group is defined as having a certain number of members, the terms "member," "member," and the like are used to denote the number of ring atoms in the cyclic group. For example, a5 membered cyclic group (e.g., a5 membered heterocyclic group) contains 5 ring atoms. It will be appreciated that the cyclic group may be part of a larger cyclic system, for example, bicyclo [4.3.0] nonane includes two carbocyclic groups, a cyclohexane group and a cyclopentane group, which are fused to form the carbocyclic system that makes up the molecule. The term "cyclic group" is intended to encompass both carbocyclic and heterocyclic groups. The term "carbocycle" refers to a group having at least 3 to 9 ring-forming carbon atoms. The term "heterocycle" refers to a group having at least 3 to 10 ring-forming atoms, wherein at least 1 to 9 of the ring atoms are carbon, and the remaining at least 1 to 9 ring atoms (i.e., one or more heterocycle atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen.

As used herein, the term "spiro" or "spiro" in relation to a cyclic group means that a first cyclic group in a polycyclic ring system is attached to a second cyclic group in the polycyclic ring system, wherein the ring atoms of the first cyclic group and the second cyclic group have only one common atom, i.e., the first and second cyclic groups share one common ring atom. For example, a spiro [5.5] undecyl group includes two cyclohexane rings that share a single carbon ring atom.

As used herein, the term "fused" in connection with a cyclic group means that a first cyclic group in a polycyclic ring system is attached to a second cyclic group in the polycyclic ring system, wherein the ring atoms of the first cyclic group and 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, a bicyclo [4.4.0] decane group includes two cyclohexane rings having two common adjacent carbon ring atoms.

As used herein, the term "bridged" in connection with a cyclic group means that a first cyclic group in a polycyclic ring system is attached to a second cyclic group in the polycyclic ring system, wherein 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, a bicyclo [3.3.1] nonyl group includes two cyclohexane rings having three common adjacent carbon ring atoms.

In the formulae described herein, any ring system (including any spiro, fused or bridged ring system) can be attached to the rest of the molecule through any atom of suitable valency. For example, a bicyclic ring may be attached to another portion of the molecule through a ring atom (e.g., a secondary carbon atom or a heteroatom such as N) or a bridgehead (e.g., a tertiary carbon atom). The spiro, fused and bridged rings may be fully unsaturated, partially unsaturated or fully saturated, and may have aromatic character in one or more of their constituent rings.

As used herein, the term "cycloalkyl" means a saturated radical having at least 3 to 9 carbon atoms forming a ring (i.e., ring atoms). Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. It is understood that cycloalkyl groups may be monocyclic or polycyclic (e.g., fused, bridged or spiro). In the case of polycyclic cycloalkyl groups, there are additional rings, for example 1 or more additional rings, all of which contain 3 to 7 carbon atoms (i.e., ring atoms). Exemplary cycloalkyl groups having such additional rings include bicyclo [1.1.1] pentyl. The term "(C ₃-C₇) cycloalkyl" means 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, bridged or spiro), such as cyclopropenyl (having 3 ring carbon atoms) or bicyclo [1.1.1] pentyl (having 5 ring carbon atoms). One or more ring atoms of a cycloalkyl group may be substituted by (i.e., bonded to) a heteroatom through a double bond (e.g., cycloalkyl substituted by oxo). The presence of such substituents does not prevent the carbon backbone of the radical from being considered a cycloalkyl group.

As used herein, the term "aryl" means an aromatic radical having at least 6 carbon atoms forming a ring (i.e., ring atoms). It is understood that the aryl groups may be monocyclic or polycyclic (e.g., fused). In the case of polycyclic aryl groups, there are additional rings, for example 1 or more additional rings, all of which contain at least 3 carbon atoms (i.e., ring atoms). These additional rings may also contain one or more heteroatoms, and they may be saturated, unsaturated, or aromatic. Polycyclic aryl groups are typically attached to the remainder of the molecule via an aromatic ring, and are typically not attached via a heteroatom-containing ring. In embodiments, the polycyclic aryl groups do not contain any ring heteroatoms. Examples of aryl groups include phenyl and naphthyl, and indenyl and indanyl groups. Other aryl groups include, for example, tetrahydroisoquinolinyl, which is bound to the remainder of the molecule via its benzene ring. The term "(C ₆-C₁₀) aryl" means that the aryl group contains 6 to 10 carbon atoms in the ring portion of the group, which may be monocyclic or polycyclic (e.g., fused), such as phenyl (having 6 ring carbon atoms) or indanyl (having 9 ring carbon atoms). In an embodiment, (C ₆-C₁₀) aryl is phenyl.

As used herein, the term "heterocycloalkyl" means a saturated radical having at least 3 to 10 ring-forming atoms (i.e., ring atoms), wherein at least 1 to 9 of the ring atoms are carbon, and the remaining at least 1 to 9 ring atoms (i.e., one or more heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. In embodiments, one or more of the heterocyclic atoms are independently selected from the group consisting of nitrogen and oxygen. For example, the term "4 to 10 membered heterocycloalkyl" means a saturated radical containing 4 to 10 ring atoms, one or more of which are heterocyclic atoms. The heterocycloalkyl ring can have an oxo substituent (e.g., 2-oxopyrrolidinyl) typically adjacent to a heteroatom, but the oxygen atom does not form part of the ring and is not included in the number of ring atoms. The presence of such substituents does not interfere with the ring (or rings) of the radical being considered a heterocycloalkyl group. Exemplary heterocycloalkyl groups include tetrahydrofuranyl, piperidinyl, morpholinyl, and piperazinyl. Any of the episulfide atoms can optionally carry one or more pendant (i.e., non-cyclic) oxygen atoms, as found, for example, in sulfolane groups. In the case of polycyclic heterocyclic groups, there are additional rings, for example 1 or more additional rings, which all contain 3 to 7 ring atoms selected from carbon, nitrogen, sulfur and oxygen. These additional rings may be saturated, or partially or fully unsaturated (e.g., having aromatic character). Polycyclic heterocyclic groups include fused, bridged, and spiro systems. When a polycyclic heteroaryl group contains an unsaturated fused ring, the group is typically not bound to the remainder of the molecule via the fused ring. When heterocycloalkyl groups are described as "X to Y members" (where X and Y are integers), this means that the heterocycloalkyl group contains a total of X to Y ring atoms. Thus, for example, a "4-to 7-membered heterocycloalkyl group" contains a total of 4, 5, 6 or 7 ring atoms, for example tetrahydropyranyl (6 ring atoms).

As used herein, the term "halo" means fluorine, chlorine, bromine or iodine. These terms are used interchangeably and may refer to a halogen radical or a halogen atom itself. Given the context in which this term is used in this disclosure, one of ordinary skill in the art will be able to readily determine its identity. In an embodiment, the halogen is fluorine.

As used herein, the term "oxo" means a radical in which an oxygen atom is attached via a double bond to an atom carrying this group. For example, where a carbon atom carries an oxo group, it forms a carbon-oxygen double bond. It is understood that not all atoms within a given structure may be substituted with oxo groups, and that this will depend on the free valency of the atom to be substituted.

The compounds of the present disclosure are described, inter alia, by structural formulas. It is to be understood that these formulae typically show only one form of the compounds (e.g., resonant forms, tautomeric forms, etc.), and that certain compounds may exist in more than one such form. As will be apparent to the skilled reader. The present disclosure includes all possible tautomers of the compounds characterized by the formulae herein, including as a single tautomer or as any mixture of tautomers in any ratio. For example, a pyrrolopyrazine moiety (as shown, for example, in formula (I), and which may be referred to as 4H-pyrrolo [2,3-b ] pyrazine or 4, 7-diazaindole) may be illustrated by any of the following tautomeric forms, which are used interchangeably throughout the present specification:

It will also be appreciated that some of the compounds of the present invention may exist in the form of one or more isomers (e.g., stereoisomers). The present disclosure includes all possible stereoisomers, enantiomers, diastereomers, and the like, as well as cis and trans forms and conformational isomers of the compounds described above and below. Purification and isolation of the isomers may be accomplished by the methods described below, as well as by techniques known in the art. For example, an optical isomer of a compound may be obtained by resolution of a racemic mixture of its diastereomeric salts (e.g., using an optically active acid or base, or by formation of a covalent diastereomer). A different method for separating optical isomers involves the use of chiral chromatography (e.g., HPLC columns using chiral phases) with or without conventional derivatization. Enzymatic separation with or without derivatization is also useful, and optically active compounds of the present disclosure can also be obtained by chiral synthesis using optically active starting materials. The present disclosure includes all possible stereoisomers of the compounds described herein, either as a single stereoisomer, or as any mixture of the stereoisomers in any ratio, such as the (R) -or (S) -isomer.

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

As used herein, the term "pharmaceutically acceptable" when used in combination with salts means salts of the presently disclosed compounds that can be administered without any resulting substantially undesired biological effect or effects or any resulting deleterious interactions with any other component of the pharmaceutical composition in which they may be included.

A group defined as "optionally substituted" may be unsubstituted or substituted with one or more substituents (e.g., 1,2, 3, 4, 5, 6, or more substituents). In embodiments, a substituted group has 1 to 4 substituents, for example 1,2 or 3 substituents. In embodiments, a substituted group has 1 or 2 substituents. In an embodiment, a substituted group has 3 substituents.

Recitation of 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 groups listed. Recitation of embodiments of variables or aspects herein includes embodiments as any single embodiment or in combination with any other embodiment or portion thereof.

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

The following abbreviations and empirical formulas are used herein:

ABC ammonium bicarbonate

Ac acetyl group

ACN/MeCN acetonitrile

Adenosine ATP triphosphate

Boc t-Butoxycarbonyl group

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 regulated kinase

EtOAc/AcOEt ethyl acetate

FRET Forst resonance energy transfer

HATU hexafluorophosphate azabenzenes benzotriazole tetramethyl uronium

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

PdCl ₂ (dppf) [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride

Pd ₂(dba)₃ tris (dibenzylideneacetone) dipalladium (0)

PE Petroleum ether

Rac racemic mixture

RPMI Rockwell park souvenir institute (Roswell Park Memorial Institute) culture medium

SEM 2-trimethylsilylethoxymethyl group

SGC silica gel chromatography

TAD transcriptional activation domains

TATU 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide tetrafluoroborate

TBTU 2- (1H-benzotriazol-1-yl) -1, 3-tetramethylammonium tetrafluoroborate

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

UPLC ultra-high performance liquid chromatography

UV ultraviolet

XPhosPdG4 dicyclohexyl- [2,4, 6-tris (propan-2-yl) phenyl ] phosphonium, methanesulfonic acid, N-methyl-2-phenylaniline, palladium

Compounds of formula (I)

In a first aspect, the present disclosure provides a compound having formula (I)

Or a pharmaceutically acceptable salt thereof, wherein:

L ¹ is selected from the group consisting of a direct bond, -O-, and-NH-;

R ³ is selected from the group consisting of-H, - (C ₁-C₃) alkyl (e.g., -CH ₃) and-OH;

Y is CH or N, and

N is 0 or 1.

In embodiments, the compound is a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein:

Wherein each R ^A is independently selected from halogen, -OH, -NH ₂、-(C₁-C₃) alkyl, -O (C ₁-C₃) alkyl, and- (C ₃-C₆) cycloalkyl, wherein each occurrence of- (C ₁-C₃) alkyl is optionally substituted with one or more groups independently selected from halogen and-OH;

L ¹ is selected from the group consisting of a direct bond, -O-, and-NH-;

Wherein each R ^B is independently selected from halogen, -NH ₂、-SF₅、-(C₁-C₃) alkyl, -O (C ₁-C₃) alkyl, and-O (C ₃-C₆) cycloalkyl, wherein each occurrence of- (C ₁-C₃) alkyl and-O (C ₁-C₃) alkyl is optionally substituted with one or more halogens;

R ³ is selected from the group consisting of-H, -CH ₃, and-OH;

Y is CH or N, and

N is 0 or 1.

Wherein each R ^A is independently selected from halogen, -OH, - (C ₁-C₃) alkyl, -O (C ₁-C₃) alkyl, and- (C ₃-C₆) cycloalkyl;

L ¹ is selected from the group consisting of a direct bond, -O-, and-NH-;

R ³ is-H;

y is CH, and

N is 0 or 1.

L ¹ is selected from the group consisting of a direct bond, -O-, and-NH-;

R ³ is-H;

y is CH, and

N is 0 or 1.

In embodiments, R ¹ is selected from- (C ₁-C₃) alkyl (e.g., propyl), - (C ₅-C₇) cycloalkyl, and 4-to 7-membered heterocycloalkyl, wherein R ¹ is optionally substituted with one or more occurrences of R ^A as defined herein. In embodiments, R ¹ is selected from- (C ₁-C₃) alkyl (e.g., propyl), - (C ₅-C₆) cycloalkyl, and 4-to 6-membered heterocycloalkyl, wherein R ¹ is optionally substituted with one or more occurrences of R ^A as defined herein.

In embodiments, R ¹ is selected from- (C ₁-C₃) alkyl, - (C ₅-C₆) cycloalkyl and 5-to 6-membered heterocycloalkyl, wherein R ¹ is optionally substituted with one or more occurrences of R ^A as defined herein.

In embodiments, R ¹ is unsubstituted.

In other embodiments, R ¹ is substituted with one, two, or three occurrences of R ^A as defined herein. In embodiments, R ¹ is substituted with one or two occurrences of R ^A. In embodiments, R ¹ is substituted with one occurrence of R ^A. In embodiments, R ¹ is substituted with two occurrences of R ^A. In an embodiment, R ¹ is substituted with three occurrences of R ^A.

In embodiments, each R ^A is independently selected from halogen (e.g., -F), -OH, -NH ₂、-(C₁-C₃) alkyl, -OCH ₃, and cyclopropyl, wherein each occurrence of- (C ₁-C₃) alkyl is optionally substituted with one or more groups independently selected from halogen (e.g., -F) and-OH. In embodiments, each R ^A is independently selected from the group consisting of-F, -OH, methyl, -OCH ₃, and cyclopropyl. In embodiments, R ¹ is substituted with one or two occurrences of R ^A, wherein each R ^A is independently selected from-F, -OH, methyl, -OCH ₃, and cyclopropyl.

In embodiments, R ¹ is selected from: Wherein R ¹ is optionally substituted with one or more occurrences of R ^A as defined herein. In embodiments, each R ^A is independently selected from the group consisting of halogen (e.g., -F), -OH, -NH ₂、-(C₁-C₃) alkyl (e.g., methyl or ethyl), -O (C ₁-C₃) alkyl (e.g., -OCH ₃)、-(C₃-C₆) cycloalkyl (e.g., cyclopropyl), wherein each occurrence of (C ₁-C₃) alkyl may be optionally substituted with one or more substituents selected from halogen and-OH.

In embodiments, R ¹ is selected from: Wherein R ¹ is optionally substituted with one or more occurrences of R ^A as defined herein. In embodiments, each R ^A is independently selected from the group consisting of halogen (e.g., -F), -OH, -NH ₂、-(C₁-C₃) alkyl (e.g., methyl or ethyl), -O (C ₁-C₃) alkyl (e.g., -OCH ₃), and- (C ₃-C₆) cycloalkyl (e.g., cyclopropyl), wherein each occurrence of (C ₁-C₃) alkyl may be optionally substituted with one or more substituents selected from halogen (e.g., -F) and-OH.

In embodiments, R ¹ is selected from: Wherein R ¹ is optionally substituted with one or two occurrences of R ^A as defined herein. In embodiments, each R ^A is independently selected from the group consisting of-F, -OH, methyl, -OCH ₃, and cyclopropyl.

In embodiments, R ¹ is selected from: Wherein R ¹ is optionally substituted with one occurrence of R ^A as defined herein. In embodiments, R ^A is selected from the group consisting of methyl, -OCH ₃, and cyclopropyl.

In embodiments, R ¹ is selected from:

in embodiments, R ¹ is selected from:

In embodiments, R ¹ is cyclohexyl optionally substituted with one or more occurrences of R ^A as defined herein. In embodiments, R ¹ is unsubstituted cyclohexyl.

In embodiments, R ¹ is a 5-to 6-membered heterocycloalkyl, wherein the heterocycloalkyl group contains one or two atoms independently selected from O and N, and wherein the heterocycloalkyl group is optionally and independently substituted with one or more occurrences of R ^A as defined herein. In embodiments, each R ^A is independently selected from-CH ₃、-OCH₃ and cyclopropyl.

In embodiments, R ¹ is selected from:

in embodiments, R ¹ is selected from:

In embodiments, R ² is- (C ₃-C₆) cycloalkyl optionally substituted with one, two or three occurrences of R ^B as defined herein. In embodiments, R ² is unsubstituted- (C ₃-C₆) cycloalkyl. In embodiments, R ² is unsubstituted cyclohexyl.

In embodiments, R ² is- (C ₆-C₁₀) aryl substituted with one, two or three occurrences of R ^B as defined herein. In embodiments, R ² is phenyl substituted with one, two, or three occurrences of R ^B. In embodiments, R ² is- (C ₆-C₁₀) aryl substituted with one or two occurrences of R ^B. In embodiments, R ² is phenyl substituted with one or two occurrences of R ^B. In embodiments, R ² is- (C ₆-C₁₀) aryl substituted with one occurrence of R ^B. In an embodiment, R ² is phenyl substituted with one occurrence of R ^B. In an embodiment, R ² is- (C ₆-C₁₀) aryl substituted with two occurrences of R ^B. In an embodiment, R ² is phenyl substituted with two occurrences of R ^B.

In embodiments, R ² is cyclohexyl or phenyl optionally substituted with one, two, or three occurrences of R ^B as defined herein. In embodiments, R ² is unsubstituted cyclohexyl, or R ² is phenyl substituted with one, two, or three occurrences of R ^B. In embodiments, R ² is phenyl substituted with one or two occurrences of R ^B.

In embodiments, R ² is unsubstituted. In other embodiments, R ² is substituted with one or two occurrences of R ^B as defined herein. In embodiments, R ² is substituted with one occurrence of R ^B.

In embodiments, each R ^B is independently selected from halogen (e.g., -F), -NH ₂、-SF₅、-CF₂CF₃、-C(OH)(CF₃)₂、-OCF₃, and-O-cyclopropyl. In embodiments, each R ^B is independently selected from halogen (e.g., -F), -NH ₂、-SF₅、-OCF₃, -O-cyclopropyl, and-CF ₂CF₃. In embodiments, R ² is phenyl, and each R ^B is independently selected from halogen (e.g., -F), -NH ₂、-SF₅、-OCF₃, -O-cyclopropyl, and-CF ₂CF₃.

In embodiments, each R ^B is independently selected from halogen (e.g., -F), -NH ₂、-SF₅、-OCF₃, -O-cyclopropyl, and-CF ₂CF₃. In embodiments, R ² is substituted with one or two occurrences of R ^B, and each R ^B is independently selected from the group consisting of-F, -NH ₂、-SF₅、-OCF₃, -O-cyclopropyl, and-CF ₂CF₃. In embodiments, R ² is substituted with two or three occurrences of R ^B, and each R ^B is independently selected from the group consisting of halogen (e.g., -F), -NH ₂、-SF₅, and-OCF ₃. In embodiments, R ² is substituted with three occurrences of R ^B, and each R ^B is independently selected from-F, -NH ₂, and-OCF ₃.

In an embodiment, at least one occurrence of R ^B is-SF ₅. In an embodiment, one occurrence of R ^B is-SF ₅. In embodiments, R ² is substituted with one occurrence of R ^B, and R ^B is-SF ₅. In embodiments, R ² is substituted with two or three occurrences of R ^B, wherein one occurrence of R ^B is-SF ₅, and the other occurrences of R ^B are independently selected from halogen (e.g., -F) and-NH ₂. In an embodiment, R ² is substituted with two occurrences of R ^B, wherein one occurrence of R ^B is-SF ₅ and the other occurrence of R ^B is selected from-F and-NH ₂.

In an embodiment, at least one occurrence of R ^B is halogen. In an embodiment, each halogen is-F. In an embodiment, at least one occurrence of R ^B is-F. In embodiments, R ² is phenyl substituted with one, two, or three occurrences of R ^B, and each R ^B is independently selected from halogen (e.g., -F), -NH ₂、-SF₅、-OCF₃, -O-cyclopropyl and-CF ₂CF₃. In embodiments, R ² is phenyl substituted with two or three occurrences of R ^B, and each R ^B is independently selected from halogen (e.g., -F), -NH ₂、-SF₅、-OCF₃, -O-cyclopropyl and-CF ₂CF₃. In embodiments, R ² is phenyl substituted with one occurrence of R ^B and R ^B is selected from the group consisting of-SF ₅、-OCF₃, -O-cyclopropyl and-CF ₂CF₃. In embodiments, R ² is phenyl substituted with two occurrences of R ^B, and each R ^B is independently selected from halogen (e.g., -F), -NH ₂、-SF₅、-OCF₃. In embodiments, R ² is phenyl substituted with three occurrences of R ^B, and each R ^B is independently selected from-F, -NH ₂, and-OCF ₃.

In embodiments, R ² is phenyl substituted with one, two, or three occurrences of R ^B, and at least one occurrence of R ^B is-SF ₅. In embodiments, R ² is phenyl substituted with one, two, or three occurrences of R ^B, and one occurrence of R ^B is-SF ₅. In embodiments, R ² is phenyl substituted with one or two occurrences of R ^B, wherein one occurrence of R ^B is-SF ₅, and the other occurrence of R ^B (if present) is selected from-F and-NH ₂. In an embodiment, R ² is phenyl substituted with two occurrences of R ^B, wherein one occurrence of R ^B is-SF ₅ and the other occurrence of R ^B is selected from-F and-NH ₂. In an embodiment, R ² is phenyl substituted with one occurrence of R ^B, and R ^B is-SF ₅.

In embodiments, R ² is selected from In embodiments, R ² is selected from: in embodiments, R ² is selected from

In embodiments, R ³ is selected from the group consisting of-H and- (C ₁-C₃) alkyl. In embodiments, R ³ is selected from the group consisting of-H and-CH ₃. In an embodiment, R ³ is-CH ₃. In an embodiment, R ³ is-H.

In an embodiment, Y is CH. In an embodiment, Y is N.

In an embodiment, n is 0. In an embodiment, n is 1.

In an embodiment, Y is N, and N is 1. In this regard, the present disclosure provides compounds having the formula (I-A)

Or a pharmaceutically acceptable salt thereof, wherein R ¹、R²、R³ and L ¹ are as defined herein.

In an embodiment, Y is CH and n is 0. In this regard, the present disclosure provides compounds having the formula (I-B)

In embodiments, R ² is phenyl substituted with one or two occurrences of R ^B, wherein each R ^B is independently selected from-NH ₂、-OCF₃ and-SF ₅.

In an embodiment, Y is CH and n is 1.

In an embodiment, L ¹ is a direct bond.

In an embodiment, R ³ is-H.

In embodiments, L ¹ is selected from the group consisting of-O-and-NH-. In this regard, the present disclosure provides compounds having formula (I-C) or formula (I-D)

Or a pharmaceutically acceptable salt thereof, wherein R ¹、R²、R³, Y, and n are as defined herein. In embodiments, L ¹ is-O-, i.e., the compound is a compound having the formula (I-C) or a pharmaceutically acceptable salt thereof. In other embodiments, L ¹ is-NH-, i.e., the compound is a compound having formula (I-D) or a pharmaceutically acceptable salt thereof.

In an embodiment, n is 1. In an embodiment, R ³ is-H.

In embodiments, Y is CH and L ¹ is selected from the group consisting of-O-and-NH-. In this regard, the present disclosure provides compounds having formula (I-E) or formula (I-F)

Or a pharmaceutically acceptable salt thereof, wherein R ¹、R²、R³ and n are as defined herein. In embodiments, L ¹ is-O-, i.e., the compound is a compound having the formula (I-E) or a pharmaceutically acceptable salt thereof. In other embodiments, L ¹ is-NH-, i.e., the compound is a compound having formula (I-F) or a pharmaceutically acceptable salt thereof.

In an embodiment, n is 1. In an embodiment, R ³ is-H. In an embodiment, n is 1 and R ³ is-H.

In an embodiment, Y is CH and R ³ is-H. In this regard, the present disclosure provides compounds having the formula (I-G)

Or a pharmaceutically acceptable salt thereof, wherein R ¹、R²、L¹ and n are as defined herein.

In an embodiment, L ¹ is-O-. In other embodiments, L ¹ is-NH-. In an embodiment, n is 1.

In an embodiment, the compound is a compound having formula (II)

Or a pharmaceutically acceptable salt thereof, wherein:

N is 0 or 1.

In embodiments, the compound is a compound having formula (II) or a pharmaceutically acceptable salt thereof, wherein:

Wherein each R ^A is independently selected from the group consisting of- (C ₁-C₃) alkyl, -O (C ₁-C₃) alkyl and- (C ₃-C₆) cycloalkyl;

Wherein each R ^B is independently selected from the group consisting of halogen, -NH ₂、-SF₅、-(C₁-C₃) alkyl, -O (C ₁-C₃) alkyl, and-O (C ₃-C₆) cycloalkyl, wherein each occurrence of- (C ₁-C₃) alkyl and-O (C ₁-C₃) alkyl is substituted with one or more halogens, and

N is 0 or 1.

In embodiments, R ¹ is 4-to 6-membered heterocycloalkyl, wherein the heterocycloalkyl group contains one or two ring heteroatoms independently selected from O and N, and wherein the heterocycloalkyl group is optionally and independently substituted with one or more occurrences of R ^A as defined herein. In embodiments, R ¹ is a 5-to 6-membered heterocycloalkyl, wherein the heterocycloalkyl group contains one ring heteroatom selected from O and N, and wherein the heterocycloalkyl group is optionally and independently substituted with one or more occurrences of R ^A as defined herein. In embodiments, each R ^A is independently selected from the group consisting of-F, -OH, methyl, -OCH ₃, and cyclopropyl. In embodiments, each R ^A is independently selected from-CH ₃、-OCH₃ and cyclopropyl.

In embodiments, R ¹ is selected from: Wherein R ¹ is optionally substituted with one or two occurrences of R ^A, wherein each occurrence of R ^A is independently selected from the group consisting of-F, -OH, methyl, -OCH ₃, and cyclopropyl.

In embodiments, R ¹ is selected from: Wherein R ¹ is optionally substituted with one occurrence of R ^A, wherein R ^A is methyl, -OCH ₃, or cyclopropyl.

In embodiments, R ¹ is selected from:

in embodiments, R ¹ is selected from:

In an embodiment, n is 0. In an embodiment, n is 1.

In embodiments, R ² is- (C ₃-C₆) cycloalkyl (e.g., cyclohexyl) optionally substituted with one or both occurrences of R ^B as defined herein. In embodiments, R ² is unsubstituted- (C ₃-C₆) cycloalkyl. In embodiments, R ² is unsubstituted cyclohexyl.

In embodiments, R ² is- (C ₆-C₁₀) aryl substituted with one or two occurrences of R ^B. In embodiments, R ² is phenyl substituted with one or two occurrences of R ^B. In embodiments, R ² is- (C ₆-C₁₀) aryl substituted with one occurrence of R ^B. In an embodiment, R ² is phenyl substituted with one occurrence of R ^B.

In embodiments, R ² is cyclohexyl or phenyl optionally substituted with one or two occurrences of R ^B as defined herein. In embodiments, R ² is unsubstituted cyclohexyl, or R ² is phenyl substituted with one or two occurrences of R ^B.

In embodiments, R ² is substituted with one or two occurrences of R ^B as defined herein. In embodiments, R ² is substituted with one occurrence of R ^B. In embodiments, R ² is unsubstituted.

In embodiments, each R ^B is independently selected from halogen (e.g., -F), -NH ₂、-SF₅、-OCF₃, -O-cyclopropyl, -CF ₂CF₃, and-C (OH) (CF ₃)₂). In embodiments, each R ^B is independently selected from halogen (e.g., -F), -NH ₂、-SF₅、-OCF₃, -O-cyclopropyl, and-CF ₂CF₃. In embodiments, R ² is substituted with one or two occurrences of R ^B, and each R ^B is independently selected from the group consisting of halogen (e.g., -F), -NH ₂、-SF₅, and-OCF ₃. in embodiments, R ² is substituted with one occurrence of R ^B and R ^B is selected from the group consisting of-OCF ₃、-SF₅, -O-cyclopropyl and-CF ₂CF₃. In embodiments, R ² is substituted with two occurrences of R ^B, and each R ^B is independently selected from the group consisting of halogen (e.g., -F), -NH ₂、-SF₅, and-OCF ₃.

In an embodiment, at least one occurrence of R ^B is halogen. In an embodiment, each halogen is-F. In an embodiment, at least one occurrence of R ^B is-F.

In an embodiment, at least one occurrence of R ^B is-SF ₅. In an embodiment, one occurrence of R ^B is-SF ₅. In embodiments, R ² is substituted with one or two occurrences of R ^B, wherein one occurrence of R ^B is-SF ₅ and the other occurrence of R ^B (if present) is selected from-F and-NH ₂. In embodiments, R ² is substituted with two occurrences of R ^B, one occurrence of R ^B is-SF ₅, and the other occurrence of R ^B is selected from-F and-NH ₂. In embodiments, R ² is substituted with one occurrence of R ^B, and R ^B is-SF ₅.

In an embodiment, n is 1. In other embodiments, n is 0. In this regard, the present disclosure provides compounds having formula (II-A) or formula (II-B)

Or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are as defined herein. In embodiments, the compound is a compound having the formula (II-A) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is a compound having formula (II-B) or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound is a compound having the formula (III-A)

Or a pharmaceutically acceptable salt thereof, wherein R ¹、L¹ and n are as defined herein, and wherein:

R ^B1 is-H, or is selected from the group consisting of-NH ₂ and-F, and

In embodiments, the compound is a compound having the formula (III-a), or a pharmaceutically acceptable salt thereof, wherein R ¹、L¹ and n are as defined herein, and wherein:

R ^B1 is-H, or is selected from the group consisting of-NH ₂ and-F, and

R ^B2 is selected from the group consisting of-OCF ₃、-SF₅、-CF₂CF₃ and-O-cyclopropyl.

In an embodiment, L ¹ is-NH-. In other embodiments, L ¹ is-O-.

In an embodiment, the compound is a compound having formula (III)

Or a pharmaceutically acceptable salt thereof, wherein R ¹ and n are as defined herein, and wherein:

R ^B1 is-H, or is selected from the group consisting of-NH ₂ and-F, and

In embodiments, the compound is a compound having formula (III) or a pharmaceutically acceptable salt thereof, wherein R ¹ and n are as defined herein, and wherein:

R ^B1 is-H, or is selected from the group consisting of-NH ₂ and-F, and

In an embodiment, R ^B1 is-H. In an embodiment, R ^B1 is —nh ₂. In an embodiment, R ^B1 is-F.

In an embodiment, R ^B2 is-OCF ₃. In an embodiment, R ^B2 is-SF ₅. In an embodiment, R ^B2 is-CF ₂CF₃. In an embodiment, R ^B2 is-O-cyclopropyl.

In embodiments, R ^B1 is-H and R ^B2 is-OCF ₃. In an embodiment, R ^B1 is-NH ₂ and R ^B2 is-OCF ₃. In embodiments, R ^B1 is-H and R ^B2 is-SF ₅. In an embodiment, R ^B1 is-NH ₂ and R ^B2 is-SF ₅. In embodiments, R ^B1 is-F and R ^B2 is-SF ₅. In embodiments, R ^B1 is-H and R ^B2 is-O-cyclopropyl. In embodiments, R ^B1 is-H and R ^B2 is-CF ₂CF₃.

In embodiments, the compound is A compound having formulA (IV-A) or formulA (V-A)

Or a pharmaceutically acceptable salt thereof, wherein R ¹、L¹ and n are as defined herein. In embodiments, the compound is A compound having formulA (IV-A) or A pharmaceutically acceptable salt thereof. In other embodiments, the compound is A compound having formulA (V-A) or A pharmaceutically acceptable salt thereof.

In an embodiment, L ¹ is-NH-. In other embodiments, L ¹ is-O-.

In embodiments, the compound is a compound having formula (IV) or formula (V)

Or a pharmaceutically acceptable salt thereof, wherein R ¹ and n are as defined herein. In embodiments, the compound is a compound having formula (IV) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is a compound having formula (V) or a pharmaceutically acceptable salt thereof.

In embodiments, the compound is a compound having formula (VI), formula (VII), or formula (VIII)

Or a pharmaceutically acceptable salt thereof, wherein R ¹ is as defined herein. In embodiments, the compound is a compound having formula (VI) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is a compound having formula (VII) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is a compound having formula (VIII) or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound is selected from the group consisting of:

And pharmaceutically acceptable salts thereof.

In an embodiment, the compound is selected from the group consisting of:

And pharmaceutically acceptable salts thereof.

In embodiments in which the compound has an enantiomeric form (e.g., in which the compound has a chiral center, such as a chiral carbon atom), the compound exists as a racemic mixture of enantiomers. In embodiments in which the compound has a chiral center (e.g., a chiral carbon atom), the compound exists as an (R) isomer. In other embodiments in which the compound has a chiral center (e.g., a chiral carbon atom), the compound exists as the (S) isomer. Thus, in an embodiment, the compound is selected from the group consisting of:

- (rac) - [4- (2-tetrahydrofuran-3-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- (Rac) - [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- (2-tetrahydrofuran-3-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ (3S) -tetrahydrofuran-3-yl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ (3R) -tetrahydrofuran-3-yl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- (Rac) - [ 2-amino-4- (trifluoromethoxy) phenyl ] - [3- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyrrolidin-1-yl ] methanone,

- (Rac) - [3- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyrrolidin-1-yl ] - [4- (trifluoromethoxy) phenyl ] methanone,

And pharmaceutically acceptable salts thereof.

In an embodiment, the compound is selected from the group consisting of:

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ (3R) -tetrahydrofuran-3-yl ] oxy-5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ (3S) -tetrahydrofuran-3-yl ] oxy-5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- (Rac) -trans- [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (4-hydroxycyclohexyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- [4- [2- [ [ (3R) -tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [4- [2- [ [ (3S) -tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ [ (3R) -tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- [ 2-Amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ [ (3S) -tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- (Rac) - [4- [2- (tetrahydrofuran-3-ylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone,

- (Rac) - [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (tetrahydrofuran-3-ylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone,

- (Rac) - [ 2-amino-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [3- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyrrolidin-1-yl ] methanone,

And pharmaceutically acceptable salts thereof.

In an embodiment, the compound is selected from the compounds produced in examples 1-44 (i.e., selected from the group consisting of compounds 1-44) and pharmaceutically acceptable salts thereof. In other embodiments, the compound is selected from the group consisting of compounds obtainable by the synthetic methods described in any one of examples 1 to 44 (i.e., methods for synthesizing compounds 1-44) and pharmaceutically acceptable salts thereof.

In an embodiment, the compound is selected from the compounds produced in examples 1-26 (i.e., selected from the group consisting of compounds 1-26) and pharmaceutically acceptable salts thereof. In other embodiments, the compound is selected from the group consisting of compounds obtainable by the synthetic methods described in any one of examples 1 to 26 (i.e., methods for synthesizing compounds 1-26) and pharmaceutically acceptable salts thereof. In an embodiment, the compound is selected from the group consisting of:

And pharmaceutically acceptable salts thereof.

In embodiments, compounds of the present disclosure are characterized in terms of their inhibitory activity on ERK5, e.g., as measured according to a cell-based assay or a cell-free assay described in the examples below. In an embodiment, the compound has an IC ₅₀ value of less than about 10 μm for ERK5 (e.g., when measured according to the cell-free assay described below). In an embodiment, the compound has an IC ₅₀ value of less than about 5 μm for ERK5 (e.g., when measured according to the cell-free assay described below). In embodiments, the compound has an IC ₅₀ value for ERK5 of less than about 2 μm, e.g., less than about 1 μm, 0.5 μm, 0.2 μm, 100nM, or 50nM (e.g., when measured according to the cell-free assay described below). In an embodiment, the compound has an IC ₅₀ value of less than about 10 μm for ERK5 when measured according to the cell-free assay described below. In embodiments, the compound has an IC ₅₀ value for ERK5 of less than about 5 μm, e.g., less than about 2 μm, 1 μm, 0.5 μm, 0.2 μm, 100nM, or 50nM, when measured according to the cell-free assay described below. In an embodiment, the compound has an IC ₅₀ value of less than about 10 μm for ERK5 when measured according to the cell-based assay described below. In embodiments, the compound has an IC ₅₀ value for ERK5 of less than about 5 μm, e.g., less than about 2 μm, 1 μm, 0.5 μm, 0.2 μm, 100nM, or 50nM, when measured according to the cell-based assay described below.

In embodiments, 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 other embodiments, 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 other embodiments, the compound is selected from the group consisting of the compounds of examples 1,2, 3,4, 5, 7, 10, 12, 13, 14, 15, 16, 18, and 19. In other embodiments, the compound is selected from the group consisting of the compounds of examples 1,2, 3, 10, 12, 13, 14, 16, and 18.

In embodiments, 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 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, 17, 18, 19, 20, 21, and 26. 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, and 21. In other embodiments, 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 group consisting of the compounds of examples 1,2,4, 10, 11, 13, 14, 15, and 16. In other embodiments, the compound is selected from the compounds of examples 1,2, 10, and 16.

In an 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 other embodiments, 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. In other embodiments, the compound is selected from the group consisting of the compounds of examples 1, 2, 3, 10, 12, 13, 14, 16, 18, 30, and 39.

In an 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 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, 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 group consisting of the compounds of examples 1, 2, 4, 10, 11, 13, 14, 15, 16, and 30.

Pharmaceutical composition

The present disclosure provides pharmaceutical compositions comprising a compound described herein (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient or carrier.

In embodiments, the pharmaceutical composition comprises a compound having formula (I) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (I-a) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (I-B) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (I-C), or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (I-D) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (I-E) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (I-F) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (I-G) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (II) or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutical composition comprises a compound having formula (II-a) or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutical composition comprises a compound having formula (II-B) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (III) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (III-a) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (IV) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises A compound having formulA (IV-A) or A pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (V) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises A compound having formulA (V-A) or A pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (VI) or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutical composition comprises a compound having formula (VII) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound having formula (VIII) or a pharmaceutically acceptable salt thereof.

The pharmaceutical compositions of the present disclosure may be formulated for administration in solid or liquid form, for example using conventional carriers or excipients. The composition may be suitable for, for example, 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 administration using techniques known in the art (e.g., as a cream, ointment, patch or spray to be applied to the skin).

Medical use

The compounds of the present disclosure act as inhibitors of ERK5, which confers them utility in the treatment of ERK5 related disorders and conditions. In particular, the compounds of the present disclosure are useful for treating cancer.

Viewed from this aspect, the disclosure provides a method of treatment comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, the present disclosure provides the use of a compound of the present disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament. In further related aspects, the disclosure provides compounds of the disclosure (e.g., compounds having formula (I) or a pharmaceutically acceptable salt thereof) for use in therapy.

The compounds of the present disclosure are useful for the treatment or prevention of diseases or disorders in which ERK5 or variants or mutants thereof are known to function, 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.

In one aspect, the present disclosure provides a method of treating or preventing an ERK5 mediated disease or disorder or a disease or disorder involving ERK5 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, the present disclosure provides the use of a compound of the present disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment or prevention of a disease or disorder mediated by ERK5 or a disease or disorder involving ERK 5. In further related aspects, the disclosure provides compounds of the disclosure (e.g., a compound having 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 ERK 5.

In another aspect, the disclosure provides a method of treating or preventing a disease or disorder associated with ERK5 (e.g., cancer) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, the present disclosure provides the use of a compound of the present disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating or preventing a disease or disorder associated with ERK5 (e.g., cancer). In further related aspects, the disclosure provides compounds of the disclosure (e.g., compounds having formula (I) or a pharmaceutically acceptable salt thereof) for use in treating or preventing diseases or disorders associated with ERK5 (e.g., cancer).

In another aspect, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, the present disclosure provides the use of a compound of the present disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating or preventing cancer. In further related aspects, the disclosure provides compounds of the disclosure (e.g., compounds having formula (I) or a pharmaceutically acceptable salt thereof) for use in treating or preventing cancer.

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

In embodiments, the cancer is characterized by increased MAPK7 (i.e., ERK5 gene) expression and/or increased ERK5 activity. In embodiments, the cancer has increased ERK5 activity. In embodiments, the cancer overexpresses ERK5. In embodiments, the cancer is characterized by MAPK7 genomic amplification and/or constitutively active ERK5 signaling. In embodiments, the cancer has genome amplified ERK5. In embodiments, the cancer has constitutively active ERK5 signaling.

In embodiments, the cancer is a solid tumor (e.g., melanoma, carcinoma, or blastoma). In other embodiments, the cancer is leukemia (e.g., chronic lymphocytic leukemia, CLL, acute myelogenous leukemia, AML, or chronic myelogenous leukemia, CML).

In embodiments, the cancer is a primary tumor. In other embodiments, the cancer is a secondary tumor (e.g., a metastatic tumor).

In embodiments, the cancer is selected from breast cancer (e.g., ductal breast cancer or breast adenocarcinoma), 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), stomach cancer, skin cancer (e.g., melanoma), cholangiocarcinoma (e.g., cholangiocarcinoma), nervous system cancer (e.g., neuroblastoma), and melanoma.

In embodiments, the cancer is selected from leukemia (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelogenous leukemia, or chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., hodgkin's or non-hodgkin's disease), megaloblastic, and multiple myeloma.

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

In embodiments, the cancer is selected from leukemia (e.g., chronic myelogenous leukemia), breast cancer, multiple myeloma, colon cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, and hepatocellular carcinoma.

In another aspect, the disclosure provides methods of inhibiting ERK5 activity comprising contacting ERK5 (e.g., a cell comprising ERK 5) with a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof). In embodiments, the method is an in vitro or ex vivo method. In other embodiments, the method is an in vivo method. In a related aspect, the present disclosure provides an in vitro method of inhibiting ERK5 activity in a cell, the method comprising contacting the cell with a compound of the present disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof).

The compounds of the present disclosure (e.g., compounds having formula (I)) and pharmaceutically acceptable salts thereof may be administered as pharmaceutical compositions, which may optionally include one or more pharmaceutically acceptable excipients.

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

The compounds of the present disclosure may be used alone (e.g., as monotherapy) or in combination with one or more cancer therapies.

Having generally described the disclosure herein, the following non-limiting examples are provided to further illustrate the disclosure.

Examples

General synthetic scheme

The following scheme (scheme 1A) illustrates an exemplary manner of preparing compounds according to the disclosure and examples:

According to scheme 1A (where R ¹、R² and n can be defined, for example, as described above; R ³ is-H or-CH ₃; and L ¹ is a direct bond), compound 1B (where X ¹ can be, for example, I or Br; and X ² can be, for example, br or Cl) can be obtained in step 1 by halogenation of compound 1A with, for example, NIS or NBS (i.e., X ¹ = I or Br), the reagents can be selected such that X ¹ and X ² are different halogens. Compound 1C may be protected by N-alkylation of compound 1B in step 2 using, for example, a base (e.g., sodium hydride) and an alkylating agent (e.g., SEM-Cl). Compound 1E can be obtained by suzuki coupling between compound 1C and compound 1D in step 3, for example, in a mixture of dioxane and water and in the presence of a base such as sodium carbonate, using a catalyst such as [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride, by heating to reflux. Compound 1G can be prepared by suzuki coupling between compound 1E and compound 1F (where R is a precursor of R ¹, e.g., oxidation of R ¹ or a protected analog) in step 4, e.g., in a mixture of dioxane and water and in the presence of a base (e.g., sodium carbonate) using a catalyst such as [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride, by heating to solvent reflux. For example, compound 1G can be reduced to compound 1H in step 5 by hydrogenation with a catalyst (e.g., pd/C) at 40 ℃ under a hydrogen pressure (H ₂) of about 5 bar. Step 5 may optionally further comprise modifying R to R ¹, for example by hydrogenation with Pd/C and H ₂, or by reduction with LiAlH ₄ and etherification with an alkyl halide (e.g. as in example 6). 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 from compound 1I in step 7 using carboxylic acid compound 1J, using conditions known to those skilled in the art, such as EDC, in a solvent like DMF in the presence of a base (such as DIPEA). Step 7 may optionally further comprise modification of R ¹. For example, compounds in which R ¹ is substituted with oxo may be reduced, for example using a hydride reagent, to give the corresponding compounds in which R ¹ is substituted with-OH.

In the preparation of the presently disclosed compounds wherein L ¹ is-O-, the conversion of compound 1C to compound 1H' can be accomplished according to the following scheme, scheme 1B:

According to scheme 1B (where R ¹、R³、X¹、X² and n may be, for example, as defined above; and L ¹ is-O-) compound 1M may be prepared in step 1 by nucleophilic substitution of compound 1C with compound 1L (where R may be R ¹, or a precursor of R ¹, e.g., a protected analog of R ¹) using a base such as tBuOK. Compound 1N can then be prepared in step 2 by suzuki coupling between compound 1M and compound 1D '(wherein a is selected from the precursors of R ²、R² as defined herein (e.g. having a-NO ₂ group instead of a-NH ₂ group), or together with the carbonyl group to which it is attached, forming a protecting group (e.g. Boc (wherein a is-O-tBu) or Cbz (wherein a is-OBn)), e.g. in a mixture of dioxane and water and in the presence of a base such as sodium carbonate, using a catalyst such as [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride by heating to reflux. For example, compound 1N can be reduced to compound 1H in step 3 by hydrogenation with a catalyst (e.g., pd/C) at 40 ℃ under a hydrogen pressure (H ₂) of about 5 bar. Step 3 may optionally further comprise modification of R to R ¹, for example by deprotection (e.g. removal of the Boc group, e.g. using TFA in DCM, or removal of the Cbz group by hydrogenation of step 3), and optionally further functionalization, e.g. reductive amination with an aldehyde (e.g. formaldehyde) in the presence of a hydride reagent (e.g. sodium cyanoborohydride). Then, by following steps 6 and 7 of scheme 1A above, compound 1H' can be converted to a compound of the disclosure (e.g., a compound having formula (I) wherein L ¹ is-O-).

In the preparation of compounds wherein L ¹ is-NH-, the conversion of compound 1C to compound 1H' can be achieved according to the following scheme, scheme 1C:

According to scheme 1C (where R ¹、R³、X² and n may be defined, for example, as described above; and L ¹ is-NH-) compound 1O may be prepared in step 1 by Suzuki coupling between compound 1C and compound 1D '(where A may be defined, for example, as described above), for example, in a mixture of dioxane and water and in the presence of a base such as sodium carbonate using a catalyst such as [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride, by heating to reflux. Compound 1N 'can then be prepared in step 2 by a buhelde coupling between compound 1O and compound 1L' (where R can be R ¹, or a precursor of R ¹, e.g., a protected analog of R ¹), e.g., in dioxane and in the presence of a base such as tBuONa, using a catalyst such as tris (dibenzylideneacetone) dipalladium and RuPhos, by heating to reflux. For example, compound 1N 'can be reduced to compound 1H' in step 3 by hydrogenation with a catalyst (e.g., pd/C) at 40 ℃ under a hydrogen pressure (H ₂) of about 5 bar. Step 3 may optionally further comprise modification of R to R ¹, for example by deprotection (e.g. removal of the Boc group, e.g. using TFA in DCM), and optionally further functionalization, e.g. reductive amination with an aldehyde (e.g. formaldehyde) in the presence of a hydride reagent (e.g. sodium cyanoborohydride). Then, by following steps 6 and 7 of scheme 1A above, compound 1H' can be converted to a compound of the disclosure (e.g., a compound having formula (I) wherein L ¹ is-NH-).

In schemes 1B and 1C, group a in compound 1D' can be selected such that the optional modification of R to R ¹ in step 3 of schemes 1B or 1C can be performed without modification of a. For example, when A is-O-tBu, R may contain an amine having a Cbz protecting group that may be modified, e.g., as described above, without affecting the protecting group containing A.

Alternatively, the group a in compound 1D' may be selected such that one or more transformations in step 3 of scheme 1B or 1C also modify the group, for example by converting a to R ² (where a is a precursor to R ²), or by removing a protecting group, to give compound 1I as described in scheme 1A above. For example, compounds of the present disclosure wherein R ² contains a-NH ₂ group can be obtained by reduction of-NO ₂, e.g., by hydrogenation with H ₂ and Pd/C, as in step 3 of schemes 1B or 1C as described above, in which case step 3 of schemes 1B or 1C provides compound 1H, i.e., compound 1H', wherein a is a group R ² as defined herein. In another example, when a is-OBn (i.e., a Cbz protecting group is formed on the nitrogen atom of the heterocyclic group), 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. Then, by following step 7 of scheme 1A above, compound 1I may be converted to a compound of the disclosure (e.g., a compound having formula (I), wherein L ¹ is-O-or-NH-). These and other suitable protection/deprotection strategies will be apparent to those skilled in the art in view of this disclosure.

If not commercially available, compound 1D' may be prepared, for example, by the following scheme, scheme 1D.

According to scheme 1D (where n may be defined, for example, as described above), compound 1D may be deprotected, for example using TFA in DCM, to give compound 1P. Compound 1D' (where a may be defined, for example, as described above) may then be prepared from compound 1P and compound 1Q using amide coupling conditions (e.g., HATU in DMF). If not commercially available, compound 1Q may be obtained from the corresponding nitrile compound, for example, using, for example, H ₂SO₄ and AcOH in water. Other methods for preparing carboxylic acids such as compound 1Q will be apparent to those skilled in the art in view of this disclosure.

In the preparation of compounds wherein L ¹ is-O-, the conversion of compound 1E to compound 1H can be achieved according to the following scheme, scheme 1E:

according to scheme 1E (where R ¹、X² and n may be defined, for example, as described above; L ¹ is-O-; and R ³ is-H or- (C ₁-C₃) alkyl), compound 1G' may be obtained in step 1 by a palladium coupling reaction between compound 1E and compound 1L (where R may be R ¹, or a precursor of R ¹, such as a protected analog of R ¹), for example, in dioxane and in the presence of a base (such as tBuona) using a catalyst such as XPhosPdG, by heating to reflux. For example, compound 1G' can be reduced in step 2 to compound 1H by hydrogenation with a catalyst (e.g., pd/C) at a hydrogen pressure (H ₂) of 1 to 5 bar at room temperature to 40 ℃. Step 2 may optionally further comprise modification of R to R ¹, for example by deprotection (e.g. removal of the Cbz group, e.g. by hydrogenation of step 2), and optionally further functionalization, e.g. reductive amination with an aldehyde (e.g. formaldehyde) in the presence of a hydride reagent (e.g. sodium cyanoborohydride).

In the preparation of compounds in which R ¹ is a heterocycloalkyl group attached to the rest of the molecule via a heteroatom (e.g., nitrogen atom), and L ¹ is a direct bond, the conversion of compound 1E to compound 1H can be achieved according to scheme 1F:

According to scheme 1F (where R ¹、X² and n may be defined, for example, as described above; L ¹ is a direct bond; and R ³ is-H or- (C ₁-C₃) alkyl), compound 1S may be obtained in step 1 by a palladium coupling reaction between compound 1E and compound 1R (where ring E is R ¹, or a precursor of R ¹, e.g., a protected analog of R ¹), for example, in dioxane and in the presence of a base (e.g., tBuona) using a catalyst such as XPhosPdG, by heating to reflux. For example, compound 1S can be reduced in step 2 to compound 1H by hydrogenation with a catalyst (e.g., pd/C) at a hydrogen pressure (H ₂) of 1 to 5 bar at room temperature to 40 ℃.

Compounds of the present disclosure wherein Y is N can be synthesized by methods similar to those shown above, for example using modified forms of schemes 1A, 1B or 1C. Scheme 2A below depicts how such compounds can be prepared by analogy to scheme 1A.

According to scheme 2A (where R ¹ and R ² may be defined, for example, as described above; R ³ is-H or-CH ₃; and L ¹ is a direct bond), compound 1B (where X ¹ may be, for example, br or Cl; and X ² may be, for example, I or Br) may be obtained in step 1 by halogenation of compound 1A with, for example, NBS or NCS (i.e., X ¹ = Br or Cl; the reagents may be selected such that X ¹ and X ² are different halogens. Compound 1C may be protected by N-alkylation of compound 1B in step 2 using, for example, a base (e.g., sodium hydride) and an alkylating agent (e.g., SEM-Cl). Compound 2A can be obtained in step 3 by suzuki coupling between compound 1C (where X ² can be e.g. I or Br) and compound 1F (where R is R ¹ or a precursor of R ¹, e.g. an oxidized or protected analogue of R ¹), e.g. in a mixture of dioxane and water and in the presence of a base such as sodium carbonate using a catalyst such as [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride, by heating to solvent reflux. compound 2H can be obtained in step 4 by a coupling reaction between compound 2A and compound 2D, for example, using a catalyst such as CuI in DMSO and in the presence of proline and a base (such as potassium carbonate) by heating at 140 ℃. Step 4 may optionally further comprise the step of converting R to R ¹, for example, if R is a precursor of R ¹ having a double bond, step 4 may further comprise reduction by hydrogenation, for example using a catalyst such as Pd/C at a hydrogen pressure (H ₂) of about 5bar at 40 ℃. For example, deprotection of compound 2H using TFA or HCl in DCM in step 5 can provide compound 2I. Compound 2K can then be prepared from compound 2I in step 6 using carboxylic acid compound 1J, using conditions known to those skilled in the art, such as EDC, in a solvent like DMF in the presence of a base (such as DIPEA). The corresponding compounds in which L ¹ is-O-or-NH-can be obtained, for example, by analogous modifications to schemes 1B and 1C described above. For example, compound 1M may be used instead of compound 2A in the above scheme (to give a compound in which L ¹ is-O), or compound 1C may be reacted with compound 2D (instead of compound 1D) in step 3 of scheme 1A to give a product, which may then be obtained by a method similar to scheme 1C (to give a compound in which L ¹ is-NH-.

Compounds in which R ³ is-OH can be obtained, for example, following the synthetic procedure described in, for example, U.S. Pat. No. 2005/0288299 A1. For some of the synthetic steps described above, the intermediate in which R ³ is-OH may be protected, for example by etherification. Compounds in which R ¹ is directly bonded to the pyrrolopyrazine core via a tertiary carbon atom (e.g., where R ¹ is a bicyclo [1.1.1] pentyl group) can be obtained, for example, by a modified form of scheme 1A, in which a heteroaryl halide (e.g., like compound 1E) is reacted directly with R ¹ in the form of a redox-active ester, e.g., as described in Polites et al, org.Lett. [ organic chemistry communication ] (2021) 23 (12): 4828-4833. Compounds in which R ¹ is directly bonded to the pyrrolopyrazine core via a tertiary carbon atom having one oxygen substituent (e.g., wherein R ^A is-OH or-O (C ₁-C₃) alkyl) may be obtained, for example, by alkylating the carbonyl group directly bonded to the pyrrolopyrazine core at that position using, for example, an alkyllithium or an alkyl grignard reagent (as by the procedure described in WO 2021/195781), optionally further alkylating the resulting-OH group with an alkylating agent (e.g., meI) in the presence of a base (e.g., naH).

Experimental techniques

¹ H NMR spectra at 400 and 500MHz were carried out on Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometers, respectively, with a chemical shift (delta in ppm) in the solvent dimethyl sulfoxide-d ₆(DMSO-d₆) referenced to 2.5ppm at the temperatures cited. The coupling constant (J) is given in hertz.

Liquid chromatography/mass spectrometry (LC/MS) was obtained using UV detection DAD 210< 400nm and column Acquity UPLC CSH C, 18.7 μm, size 2.1x30 mm, mobile phase H ₂O+0.1％ HCO₂H/CH₃CN+0.1％ HCO₂ H on UPLC Acquity Waters instrument, light scattering detector Sedere and SQD WATERS mass spectrometer.

Unless otherwise indicated, all synthesis reactions were carried out under an inert atmosphere. In the examples below, when the source of the starting product is not specified, it is understood that the product is a known compound (e.g., a compound commercially available from a vendor such as Sigma Aldrich).

Examples 1 to 44 Compounds

The compounds synthesized in the following synthesis examples are listed in table 1 below.

Table 1:

EXAMPLE 1 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

Step 1 2-bromo-7-iodo-5H-pyrrolo [2,3-b ] pyrazine

A mixture of 2-bromo-5H-pyrrolo [2,3-b ] pyrazine (5.00 g,025.2 mmol), 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×3). The organic layers were combined, washed with saturated aqueous sodium chloride (100 mL. Times.2), dried over Na ₂SO₄, filtered and concentrated in vacuo to give 2-bromo-7-iodo-5H-pyrrolo [2,3-b ] pyrazine as a yellow solid (8.17 g,24.2mmol, yield: 96%). LC/MS (M/z, M+H) calculated 324.9, found 324.9

Step 2- [ (2-bromo-7-iodo-pyrrolo [2,3-b ] pyrazin-5-yl) methoxy ] ethyl-trimethyl-silane

Sodium hydride (60% dispersion in oil) (1.45 g,15.1 mmol) was added to 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) at 0 ℃. 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×3). The organic layers were combined and washed with brine (100 ml×2), dried over Na ₂SO₄, concentrated in vacuo, and the resulting residue was purified by silica gel flash chromatography (0-5% ethyl acetate in petroleum ether) to give 2- [ (2-bromo-7-iodo-pyrrolo [2,3-b ] pyrazin-5-yl) methoxy ] ethyl-trimethyl-silane (9.05 g,19.9mmol, yield: 83%) as a yellow solid. LC/MS (M/z, M+H) calculated 455.2, found 455.9

Step 3 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

A mixture of 2- [ (2-bromo-7-iodo-pyrrolo [2,3-b ] pyrazin-5-yl) methoxy ] ethyl-trimethyl-silane (9.05 g,0.0199 mol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (6.16 g,19.9 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (0.729 g,0.996 mmol), sodium bicarbonate (6.34 g,59.8 mmol) in 1, 4-dioxane (200 mL) and water (40 mL) was stirred under an atmosphere of N ₂ at 80℃for 3 hours. The mixture was then diluted with water (200 mL) and extracted with ethyl acetate (100 ml×3). The organic layers were combined, washed with brine (100 ml×2), dried over Na ₂SO₄, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (0-6% ethyl acetate in petroleum ether) to give 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.62 g,9.07mmol, yield: 45%) as a yellow solid. LC/MS (M/z, M-tBu+H) calculated 453.1, found 453.0

Step 4- [2- (1-methyl-3, 6-dihydro-2H-pyridin-4-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

A mixture of 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.5 g,2.94 mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine (0.657 g,2.94 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (0.108 g,0.147 mmol), sodium carbonate (0.936 g,8.83 mmol) in1, 4-dioxane (15 mL) and water (3 mL) was stirred under an atmosphere of N ₂ at 80℃for 3 hours. The mixture was then diluted with water (40 mL) and extracted with ethyl acetate (40 ml×3). The organic layers were combined, washed with brine (40 ml×2), dried over Na ₂SO₄, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (0-15% ethyl acetate in petroleum ether) to give tert-butyl 4- [2- (1-methyl-3, 6-dihydro-2H-pyridin-4-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylate (1.20 g,2.28mmol, yield: 77%). LC/MS (M/z, M+H): 526

Step 5 4- [2- (1-methyl-4-piperidinyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

A mixture of 4- [2- (1-methyl-3, 6-dihydro-2H-pyridin-4-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.20 g,2.28 mmol), 5% Pd/C (1 g) in ethyl acetate (40 mL) was stirred at room temperature at 1H ₂ atm for 3 hours. The mixture was then filtered and concentrated in vacuo to give 4- [2- (1-methyl-4-piperidinyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester (1.10 g, crude). LC/MS (M/z, M+H) calculated 530.3, found 530.3

Step 6 2- (1-methyl-4-piperidinyl) -7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazines

A mixture of tert-butyl 4- [2- (1-methyl-4-piperidinyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-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 in aqueous trifluoroacetic acid (0.5%) to give 2- (1-methyl-4-piperidinyl) -7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazine (0.400 g,1.34mol, yield: 64%). LC/MS (M/z, M+H) calculated 300.2, found 300.2

Step 7N- [2- [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carbonyl ] -5- (trifluoromethoxy) phenyl ] carbamic acid tert-butyl ester

A mixture of 2- (1-methyl-4-piperidinyl) -7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazine (0.200 g,0.195 mmol), 2- (tert-butoxycarbonylamino) -4- (trifluoromethoxy) benzoic acid (0.209 g,0.195 mmol), 2- (1H-benzotriazol-1-yl) -1, 3-tetramethylurea tetrafluoroborate (0.313 g,0.976 mmol), 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×3). The organic layers were combined, washed with brine (20 ml×2), dried over Na ₂SO₄, filtered and concentrated. The residue was purified by preparative HPLC to give tert-butyl N- [2- [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carbonyl ] -5- (trifluoromethoxy) phenyl ] carbamate (0.120 g,0.199mmol, yield: 31%). LC/MS (M/z, M+H) calculated 603.3, found 603.3

Step 8 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

To a solution of tert-butyl N- [2- [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carbonyl ] -5- (trifluoromethoxy) phenyl ] carbamate (0.120 g, 0.199mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was then concentrated, and the residue was purified by preparative HPLC to give [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone (0.031 g,0.062mmol, yield: 31%) as a white solid. LC/MS (M/z, M+H) calculated 503.2, found 503.4;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 2 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone

Step 1 4- [2- (3, 6-dihydro-2H-pyran-4-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

A mixture of 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.5 g,2.94 mmol), 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (0.618 g,2.94 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (0.108 g,0.147 mmol), sodium carbonate (0.936 g,8.83 mmol) in 1, 4-dioxane (15 mL) and water (3 mL) was stirred under an atmosphere at 80℃for 3 hours under an atmosphere of N ₂. The mixture was then diluted with water (40 mL) and extracted with ethyl acetate (40 ml×3). The organic layers were combined, washed with brine (40 ml×2), dried over Na ₂SO₄, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (0-15% ethyl acetate in petroleum ether) to give 4- [2- (3, 6-dihydro-2H-pyran-4-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.10 g,2.15mmol, yield: 73%). LC/MS (M/z, M+H) calculated 513.3, found 513.3

Step 2 4- [ 2-tetrahydropyran-4-yl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

A mixture of 4- [2- (3, 6-dihydro-2H-pyran-4-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.10 g,2.15 mmol), 5% Pd/C (1 g) in ethyl acetate (40 mL) was stirred at room temperature at 1H ₂ atm for 3 hours. The mixture was filtered and concentrated to give tert-butyl 4- [ 2-tetrahydropyran-4-yl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (1.10 g, crude). LC/MS (M/z, M+H) calculated 517.3, found 517.3

Step 3 7- (4-piperidinyl) -2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazines

A mixture of tert-butyl 4- [ 2-tetrahydropyran-4-yl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-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 solution (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 aqueous trifluoroacetic acid (0.5%) to give 7- (4-piperidinyl) -2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazine (0.400 g,1.40mmol, yield: 72%). LC/MS (M/z, M+H) calculated 287.2, found 287.2

Step 4N- [2- [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) piperidine-1-carbonyl ] -5- (trifluoromethoxy) phenyl ] carbamic acid tert-butyl ester

A mixture of 7- (4-piperidinyl) -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-benzotriazol-1-yl) -1, 3-tetramethylurea tetrafluoroborate (0.336 g,1.05 mmol), N-diisopropylethylamine (0.271g, 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×3). The organic layers were combined, washed with brine (20 ml×2), dried over Na ₂SO₄, filtered and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give tert-butyl N- [2- [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) piperidine-1-carbonyl ] -5- (trifluoromethoxy) phenyl ] carbamate (0.247 g,4.19mmol, yield: 60%). LC/MS (M/z, M+H) calculated 590.2, found 590.2

Step 5 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone

To a solution of tert-butyl N- [2- [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) piperidine-1-carbonyl ] -5- (trifluoromethoxy) phenyl ] carbamate (0.411 g,0.70 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was then concentrated, and the crude residue was then purified by preparative HPLC to give [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone (0.0627 g,0.128mmol, yield: 18%) as a white solid. LC/MS (M/z, M+H) calculated 490.2, found 490.2;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 3 [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

A mixture of 7- (4-piperidinyl) -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-benzotriazol-1-yl) -1, 3-tetramethylurea tetrafluoroborate (0.336 g,1.05 mmol), N-ethyl-N-isopropyl-propan-2-amine (0.271g, 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×3). The organic layers were combined, washed with brine (20 ml×2), dried over Na ₂SO₄, filtered and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone (0.0501 g,0.106mmol, yield: 15%). LC/MS (M/z, M+H) calculated 475.2, found 475.3;¹H NMR(400MHz,DMSO-d6,120℃)δppm 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)

EXAMPLE 4 [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

A mixture of 2- (1-methyl-4-piperidinyl) -7- (4-piperidinyl) -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, 3-tetramethylurea tetrafluoroborate (0.322 g,1.00 mmol), N-ethyl-N-isopropyl-propan-2-amine (0.319 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×3). The organic layers were combined, washed with brine (20 ml×2), dried over Na ₂SO₄, concentrated in vacuo, and the resulting residue was purified by preparative HPLC to give [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone (0.0210 g,0.043mmol, yield: 6.5%). LC/MS (M/z, M+H) calculated 488.2, found 488.2;¹H NMR(400MHz,DMSO-d6,120℃)δppm 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)

EXAMPLE 5 (rac) - [4- (2-tetrahydrofuran-3-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

Step 1 4- [2- (2, 5-Dihydrofuran-3-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

A mixture of 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (100 mg,0.20 mmol), 2- (2, 5-dihydrofuran-3-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (0.0404 g,0.21 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (0.0144 g,0.02 mmol), sodium carbonate (0.0624 g,0.59 mmol) in 1, 4-dioxane (2 mL) and water (0.5 mL) was stirred under an atmosphere of N ₂ at 80℃for 4 hours. The mixture was then diluted with water (40 mL) and extracted with ethyl acetate (40 ml×3). The organic layers were combined, washed with brine (40 ml×2), dried over Na ₂SO₄, filtered and concentrated in vacuo. The resulting residue was purified by SGC (eluting with 0-15% ethyl acetate in petroleum ether) to give 4- [2- (2, 5-dihydrofuran-3-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (805 mg, 82%) as a white solid. LC/MS (M/z, M+H) calculated 499.3, found 499.2

Step 2 (rac) -4- [ 2-tetrahydrofuran-3-yl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4- [2- (2, 5-dihydrofuran-3-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (800 mg,1.50 mmol) in ethyl acetate (10 mL) was added Pd/C (20 wt%, 160 mg). The mixture was stirred at room temperature under 1 atmosphere of hydrogen 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 give tert-butyl (rac) -4- [ 2-tetrahydrofuran3-yl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (0.640 mg,0.88mmol, yield: 55%). LC/MS (M/z, M+H) calculated 503.3, found 503.0

Step 3 (rac) -7- (4-piperidinyl) -2-tetrahydrofuran-3-yl-pyrrolo [2,3-b ] pyrazin-5-yl ] methanol

To a solution of (rac) -4- [ 2-tetrahydrofuran-3-yl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester (620 mg,0.82 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (6 mL) at 0 ℃. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to give a yellow oil (510 mg,0.82mmol, crude) which was used in the next step without further purification. LC/MS (M/z, M+30) calculated 303.2, found 303.3

Step 4 (rac) - [4- (2-tetrahydrofuran-3-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

To a solution of (rac) -7- (4-piperidinyl) -2-tetrahydrofuran-3-yl-pyrrolo [2,3-b ] pyrazin-5-yl ] methanol (510 mg,0.82 mmol) and 4- (trifluoromethoxy) benzoic acid (343 mg,1.66 mmol) in N, N-dimethylformamide (5 mL) was added 1-hydroxybenzotriazole hydrate (255 mg,1.66 mmol), N' - (ethylcarboimino) -N, N-dimethylpropane-1, 3-diamine hydrochloride (319 mg,1.66 mmol) and N-ethyl-N-isopropyl-propan-2-amine (537 mg,4.16 mmol). 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 give a 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, brine, dried over anhydrous Na ₂SO₄, filtered and concentrated to give a crude oil which was purified by silica gel chromatography (3% methanol in dichloromethane) to give (rac) - [4- (2-tetrahydrofuran-3-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone as a colorless solid (288 mg, yield: 75%). LC/MS (M/z, M+H) calculated 461.2, found 461.0;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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( five peaks ,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)

EXAMPLE 6 [4- [2- (3-methoxypropyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

Step 1 4- [2- [ (E) -3-ethoxy-3-oxo-prop-1-enyl ] -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

A mixture of ethyl (E) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) prop-2-enoate (1.33 g,5.89 mmol), tert-butyl 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-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), sodium carbonate (1.87 g,17.7 mmol) in 1, 4-dioxane (30 mL) and water (6 mL) was stirred under argon atmosphere at 80℃for 3 hours. The reaction mixture was diluted with brine (30 mL) and extracted with ethyl acetate (20 ml×3). The organic layers were combined, washed with brine (20 ml×2), dried over Na ₂SO₄, concentrated, and the resulting residue was purified by silica gel flash chromatography (0-20% ethyl acetate in petroleum ether) to give 4- [2- [ (E) -3-ethoxy-3-oxo-prop-1-enyl ] -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.6 g, 83%) as a yellow solid. LC/MS (M/z, M-tBu) calculated 473.3, found 473.3

Step 2 4- [2- (3-ethoxy-3-oxo-propyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

A mixture of 4- [2- [ (E) -3-ethoxy-3-oxo-prop-1-enyl ] -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.60 g,4.92 mmol), 10% Pd/C (10.0%, 1.30 g) in ethyl acetate (50 mL) was stirred at 1H ₂ atm for 48 hours at room temperature. The reaction mixture was then filtered, concentrated, and the resulting residue was purified by silica gel flash chromatography (0-15% ethyl acetate in petroleum ether) to give 4- [2- (3-ethoxy-3-oxo-propyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester (2.3 g, 88%) as a yellow solid. LC/MS (M/z, M+H) calculated clcd 533.3.3, found 533.0

Step 3 4- [2- (3-hydroxypropyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

To a mixture of tert-butyl 4- [2- (3-ethoxy-3-oxo-propyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (2.30 g,0.00432 mol) in tetrahydrofuran (30 mL) was slowly added 1N LiAlH ₄ (1.00 mol/L,5.18mL,0.00518 mol) in tetrahydrofuran at 0 ℃. After the addition, the mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was then quenched with Na ₂SO₄.10H₂ O (5 g) and filtered. The solvents were combined and concentrated. The resulting residue was purified by flash chromatography on silica gel (0-25% ethyl acetate in petroleum ether) to give tert-butyl 4- [2- (3-hydroxypropyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (1.8 g, 85%) LC/MS (M/z, m+h) as a yellow solid, calculated 491.3, found 491.0

Step 4- [2- (3-methoxypropyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

To a mixture of tert-butyl 4- [2- (3-hydroxypropyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (1.80 g,3.67 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (60%, 0.220g,5.50 mmol) at 0 ℃. After the addition, the mixture was stirred for 1 hour. Then, methyl iodide (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×3). The organic layers were combined, washed with brine (30 ml×2), dried over Na ₂SO₄, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (0-10% ethyl acetate in petroleum ether) to give tert-butyl 4- [2- (3-methoxypropyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (700 mg, 38%) as a yellow solid. LC/MS (M/z, M+H) calculated 505.3, found 505.2

Step 5 2- (3-methoxypropyl) -7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-5-yl ] methanol

A mixture of 4- [2- (3-methoxypropyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester (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 in solution (5 mL) was added. The resulting mixture was stirred at room temperature for 4 hours. The mixture was concentrated to give [2- (3-methoxypropyl) -7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-5-yl ] methanol (0.100 g, crude). LC/MS (M/z, M+H) calculated 305.2, found 305.3

Step 6 2- (3-methoxypropyl) -7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazine

A mixture of [2- (3-methoxypropyl) -7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-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), 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×3). The organic layers were combined, washed with brine (20 ml×2), dried over Na ₂SO₄, and concentrated to give a 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 (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was diluted with water, brine, dried over anhydrous Na ₂SO₄, filtered, concentrated to give a crude oil which was purified by preparative HPLC to give [4- [2- (3-methoxypropyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone (0.118 g,0.255mmol, yield: 50%) as a white solid. LC/MS (M/z, M+H) calculated 463.2, found 463.3;¹H NMR(400MHz,DMSO-d6,120℃)δppm 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)

EXAMPLE 7 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (3-methoxypropyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

A mixture of [2- (3-methoxypropyl) -7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-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 (0.197g, 1.46 mmol), 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×3). The organic layers were combined, washed with brine (20 ml×2), dried over Na ₂SO₄, and concentrated to give a 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 (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was washed with water, brine, dried over anhydrous Na ₂SO₄, filtered and concentrated to give a crude oil which was purified by preparative HPLC to give [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (3-methoxypropyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone as a white solid (36 mg, yield: 26%). LC/MS (M/z, M+H) calculated 478.2, found 478.2;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 8 [4- (2-cyclohexyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

Step 1 4- [2- (cyclohexen-1-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

A mixture of 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.70 g,0.00334 mol), 2- (cyclohexen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (0.694 g,3.34 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (0.244 g, 0.336 mmol), sodium bicarbonate (1.06 g,10.0 mmol) in 1, 4-dioxane (20 mL) and water (5 mL) was stirred under an atmosphere of N ₂ at 80℃for 3 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 ml×3). The organic layers were combined and washed with brine (100 mL), dried over Na ₂SO₄, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (0-10% ethyl acetate in petroleum ether) to give 4- [2- (cyclohexen-1-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.22 g,2.4mmol, yield: 71%) as an oil. LC/MS (M/z, M+H) calculated 511.3, found 511.1

Step 2 4- [ 2-cyclohexyl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4- [2- (cyclohexen-1-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.22 g,2.4 mmol) in ethyl acetate (20 mL) was added Pd/C (20 wt%, 244 mg). The mixture was stirred at room temperature under 1 atmosphere of hydrogen 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 give tert-butyl 4- [ 2-cyclohexyl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (1.15 g,2.23mmol, yield: 94%). LC/MS (M/z, M+H) calculated 515.3, found 515.2

Step 3 2-cyclohexyl-7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-5-yl ] methanol

To a solution of tert-butyl 4- [ 2-cyclohexyl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (600 mg,1.17 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) at 0 ℃. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to give a yellow oil (430 mg, crude) which was used in the next step without further purification. LC/MS (M/z, M+H) calculated 315.2, found 315.1

Step 4 [4- (2-cyclohexyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

To a solution of [ 2-cyclohexyl-7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-5-yl ] methanol (430 mg,1.32 mmol) and 4- (trifluoromethoxy) benzoic acid (803 mg,1.66 mmol) in N, N-dimethylformamide (5 mL) was added 1-hydroxybenzotriazole hydrate (255 mg,1.66 mmol), N' - (ethylcarboximino) -N, N-dimethylpropane-1, 3-diamine hydrochloride (319 mg,1.66 mmol) and N-ethyl-N-isopropyl-propan-2-amine (537 mg,04.16 mmol). 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 give a crude oil. The crude product was dissolved in a mixed solution of methanol (10 mL) and purified 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, brine, dried over anhydrous Na ₂SO₄, filtered and concentrated to give a crude oil which was purified by silica gel chromatography (3% methanol in dichloromethane) to give [4- (2-cyclohexyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone as a white solid (750 mg,2.77mmol,53% yield). LC/MS (M/z, M+H) calculated 473.2, found 473.3;¹H NMR(400MHz,DMSO-d6,120℃)δppm 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)

EXAMPLE 9 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- (2-cyclohexyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone

Step 1 [ 2-cyclohexyl-7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-5-yl ] methanol

To a solution of tert-butyl 4- [ 2-cyclohexyl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (550 mg,1.07 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) at 0 ℃. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to give [ 2-cyclohexyl-7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-5-yl ] methanol (0.390 g,1.07mmol, yield: 100%) as a yellow oil, which was used in the next step without further purification. LC/MS (M/z, M+H) calculated 315.2, found 315.1

Step 2, [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- (2-cyclohexyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone

To a solution of [ 2-cyclohexyl-7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-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) was added 1-hydroxybenzotriazole, hydrate (0.328 g,2.14 mmol), N' - (ethylcarboimino) -N, N-dimethylpropane-1, 3-diamine hydrochloride (0.411 g,2.14 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.692 g,5.36 mmol). 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 give a 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 Na ₂SO₄, filtered and concentrated to give a crude oil which was purified by silica gel chromatography (3% methanol in dichloromethane) and preparative HPLC to give [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- (2-cyclohexyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone (100.8 mg,0.205mmol, yield: 19%) as a white solid. LC/MS (M/z, M+H) calculated 488.2, found 488.1;¹H NMR(400MHz,DMSO-d6,120℃)δppm 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)

EXAMPLE 10 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (1-cyclopropyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

Step 14- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine

A solution of 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (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 in vacuo to give the crude product 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine (4.00 g,16.2mmol, yield: 100%) which was used in the next step without further purification. LC/MS (M/z, M+H) calculated 210.2, found 210.1

Step 2 1-cyclopropyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -3, 6-dihydro-2H-pyridine

A mixture of 4- (4, 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 h. Sodium cyanoborohydride (3.06 g,48.7 mmol) was then added in portions and the resulting mixture was warmed to 60 ℃ 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 NH ₄HCO₃) to give (1-cyclopropyl-3, 6-dihydro-2H-pyridin-4-yl) boronic acid (P1; 2.00g,9.96mmol, yield: 61%) and 1-cyclopropyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine (P2; 0.760g,2.66mmol, yield: 16%) as a white powder. LC/MS, P1 (M/z, M+H) calculated 168.1, found 168.1, P2 (M/z, M+H) calculated 250.2, found 250.2

Step 3 4- [2- (1-cyclopropyl-3, 6-dihydro-2H-pyridin-4-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

A mixture of 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.00 g,0.00297 mol), (1-cyclopropyl-3, 6-dihydro-2H-pyridin-4-yl) boronic acid (0.596 g,2.97 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (0.217g, 0.297 mmol), sodium carbonate (0.943 g,8.90 mmol) in 1, 4-dioxane (40 mL) and water (10 mL) was stirred under an atmosphere of N ₂ at 80℃for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 ml×3). The organic layers were combined, washed with brine (50 ml×2), dried over Na ₂SO₄, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (0-20% ethyl acetate in petroleum ether) to give 4- [2- (1-cyclopropyl-3, 6-dihydro-2H-pyridin-4-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.920 g,1.28mmol, yield: 43%) as a yellow oil. LC/MS (M/z, M+H) calculated 552.3, found 552.3

Step 4- [2- (1-cyclopropyl-4-piperidinyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4- [2- (1-cyclopropyl-3, 6-dihydro-2H-pyridin-4-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (300 mg,0.544 mmol) in ethyl acetate (10 mL) was added Pd/C (20 wt%, 60 mg). The mixture was stirred at room temperature under 1 atmosphere of hydrogen for 24 hours. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 4- [2- (1-cyclopropyl-4-piperidinyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (0.334 g, 0.552 mmol, yield: 100%) which was used in the next step without further purification. LC/MS (M/z, M+H) calculated 556.4, found 556.3

Step 5 [2- (1-cyclopropyl-4-piperidinyl) -7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-5-yl ] methanol

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

Step 6 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (1-cyclopropyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

To a solution of [2- (1-cyclopropyl-4-piperidinyl) -7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-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) was added 1-hydroxybenzotriazole hydrate (0.0815 g, 0.284 mmol), N' - (ethylcarboimino) -N, N-dimethylpropane-1, 3-diamine hydrochloride (0.102 g,0.532 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.172 g,1.33 mmol). 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 give a 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, brine, dried over anhydrous Na ₂SO₄, filtered and concentrated to give a crude oil which was purified by preparative HPLC to give [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (1-cyclopropyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone (0.0118 g,0.022mmol, yield: 8.2%). LC/MS (M/z, M+H) calculated 529.2, found 529.3;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 11 [4- [2- (1-cyclopropyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

To a solution of [2- (1-cyclopropyl-4-piperidinyl) -7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-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) was added 1-hydroxybenzotriazole, hydrate (0.0823 g,0.54 mmol), N- (3- (dimethylamino) propyl) propionamidine (0.0846 g,0.54 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.174 g,1.34 mmol). 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 give a 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×3). The organic layers were combined, washed with water, brine, dried over anhydrous Na ₂SO₄, filtered and concentrated to give a crude oil which was purified by preparative HPLC to give [4- [2- (1-cyclopropyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone (0.01336 g,0.026mmol, yield: 10%). LC/MS (M/z, M+H) calculated 514.2, found 514.3;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 12 (rac) - [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- (2-tetrahydrofuran-3-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone

To a solution of (rac) -7- (4-piperidinyl) -2-tetrahydrofuran-3-yl-pyrrolo [2,3-b ] pyrazin-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) was added 1-hydroxybenzotriazole hydrate (255 mg,1.66 mmol), N' - (ethylcarboximino) -N, N-dimethylpropane-1, 3-diamine hydrochloride (319 mg,1.66 mmol) and N-ethyl-N-isopropyl-propan-2-amine (537 mg,4.16 mmol). 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 give a 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, brine, dried over anhydrous Na ₂SO₄, filtered and concentrated to give a crude oil which was purified by silica gel chromatography (3% methanol in dichloromethane) to give (rac) - [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- (2-tetrahydrofuran-3-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone as a white solid (81.6 mg,0.172mmol, yield: 21%). LC/MS (M/z, M+H) calculated 476.2, found 476.1;¹H NMR(400MHz,DMSO-d6,120℃)δppm 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)

Examples 13 and 14 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- (2-tetrahydrofurane-3-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone, isomers 1 and 2

Chiral separation of (rac) - [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- (2-tetrahydrofuran-3-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone (61 mg,0.13 mmol) was performed using a CHIRALPAK IF column (5 μm,250x30 mm), eluting with 30% EtOH in n-heptane+0.1% TEA (flow rate 40mL/min, UV detection at 240 nm) to give 29mg (47%) of the first eluting isomer (example 13, isomer 1) and 33mg (54%) of the second eluting isomer (example 14, isomer 2) as a white solid.

Isomer 1 (example 13)_：LC/MS(m/z,M+H)：476;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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(quin,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)

Isomer 2 (example 14)_：LC/MS(m/z,M+H)：476;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 15 [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] methanone

To a solution of 2- (1-methyl-4-piperidinyl) -7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazine (60 mg,0.2 mmol) in DMF (1 mL) was added triethylamine (140 μl,1 mmol), 4- (pentafluorothioyl) benzoic acid (51 mg,0.2 mmol) and TATU (77 mg,0.24 mmol) at room temperature under an argon atmosphere. The reaction mixture was then stirred at room temperature for 0.5 hours, then diluted with AcOEt and transferred to a separatory funnel containing saturated aqueous NaCl. The whole was extracted three times with AcOEt. The combined organic layers were dried over MgSO ₄, filtered and concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel (12 g), eluting with DCM/MeOH (90/10) to give 15mg (14% yield) of [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] methanone as a white solid. LC/MS (M/z, M+H) calculated 530.6, found 530.2, ¹ H NMR (400 MHz, DMSO-d6,100 ℃) delta ppm 1.78-2.26 (M, 12H), 2.31 (s, 3H), 2.77-2.86 (partially hidden) ,m,1H),3.10-3.29(m,3H),3.89-4.26(m,2H),7.51(d,J＝2.6Hz,1H),7.63(br d,J＝8.5Hz,2H),7.93(d,J＝8.8Hz,2H),8.10(s,1H),11.30(m,1H)

EXAMPLE 16 [ 2-amino-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

To a solution of 2- (1-methyl-4-piperidinyl) -7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazine (120 mg,0.4 mmol) in DMF (2 mL) was added triethylamine (280 μl,2 mmol), 2-amino-4- (pentafluoro- λ ⁶ -sulfanyl) benzoic acid, hydrochloride (126 mg,0.42 mmol) and TBTU (154 mg,0.48 mmol) at room temperature under an argon atmosphere. The reaction mixture was then stirred at room temperature for 0.5 hours, then diluted with AcOEt and transferred to a separatory funnel containing saturated aqueous NaCl. The whole was extracted three times with AcOEt. The combined organic layers were dried over MgSO ₄, filtered and concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel (12 g), eluting with DCM/MeOH/NH ₄ OH (90/10/1) to give 30mg (14% yield) of [ 2-amino-4- (pentafluoro- λ ⁶ -sulfanyl) phenyl ] - [4- [2- (1-methyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone as a white solid. LC/MS (M/z, M+H) calculated 545.6, found 545.2;¹HNMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 17 [4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone

To a solution of 4- (pentafluoro-lambda ⁶ -sulfanyl) benzoic acid (36 mg,0.14 mmol) in DMF (1 mL) was added TBTU (54 mg,0.17 mmol), N-diisopropylethylamine (40. Mu.L, 0.23 mmol) at room temperature under an argon atmosphere. Then, to the resulting mixture was added a solution of 7- (4-piperidinyl) -2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazine (40 mg,0.14 mmol) in DMF (1.5 mL) at 0 ℃. The reaction mixture was then stirred for 10 minutes, then diluted with AcOEt and transferred to a separatory funnel containing water. The whole was extracted three times with AcOEt. The combined organic layers were dried over MgSO ₄, filtered and concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel (12 g), eluting with DCM/MeOH (90/10) to give 55mg (79% yield) of [4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone as a white solid. LC/MS (M/z, M+H) calculated 517.2, found 517.1;¹H NMR(400MHz,DMSO-d6,120℃)δppm 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)

EXAMPLE 18 [ 2-amino-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone

Example 18 was prepared following the procedure described in example 17 using 2-amino-4- (pentafluoro-lambda ⁶ -sulfanyl) benzoic acid (46 mg,0.17mmol,100 mass%), TBTU (67 mg,0.21 mmol), N-diisopropylethylamine (0.11 ml,0.61 mmol) and 7- (4-piperidinyl) -2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazine (50 mg,0.17 mmol) to give 63mg (68% yield) of [ 2-amino-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone as a white solid. LC/MS (M/z, M+H) calculated 532.5, found 532.0;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 19 [ 2-amino-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- [2- (1-cyclopropyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

Example 19 was prepared following the procedure described in example 17 using 2-amino-4- (pentafluoro-lambda ⁶ -sulfanyl) benzoic acid (50 mg,0.19 mmol), TBTU (70 mg,0.22 mmol), N-diisopropylethylamine (40 μl,0.23 mmol), 2- (1-cyclopropyl-4-piperidinyl) -7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazine, dihydrochloride (45 mg,0.11 mmol) to give 34mg (53% yield) of [ 2-amino-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- [2- (1-cyclopropyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone as a white solid. LC/MS (M/z, M+H) calculated 571.6, found 571.1;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 20 [4- [2- (1-cyclopropyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] methanone

Example 20 was prepared following the procedure described in example 17 using 4- (pentafluoro-lambda ⁶ -sulfanyl) benzoic acid (32 mg,0.13 mmol), TBTU (46 mg,0,14 mmol), N-diisopropylethylamine (60 μl,0.34 mmol), 2- (1-cyclopropyl-4-piperidinyl) -7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazine, dihydrochloride (35 mg,0.09 mmol) to give 29mg (60% yield) of [4- [2- (1-cyclopropyl-4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] methanone as a white solid. LC/MS (M/z, M+H) calculated 556.6, found 556.1;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 21 [4- (cyclopropyloxy) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone

Example 21 was prepared following the procedure described in example 17 using 4- (cyclopropyloxy) benzoic acid (35 mg,0.20 mmol), TBTU (54 mg,0.17 mmol), 7- (4-piperidinyl) -2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazine, hydrochloride (40 mg,0.12 mmol), N-diisopropylethylamine (65 μl,0.37 mmol) to give 36mg (65% yield) of [4- (cyclopropyloxy) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone as a white solid. LC/MS (M/z, M+H) calculated 447.5, found 447.2;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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,1H),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)

EXAMPLE 22 [4- (1, 2-pentafluoroethyl) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone

Example 22 was prepared following the procedure described in example 17 using 4- (1, 2-pentafluoroethyl) benzoic acid (31 mg,0.13 mmol), TBTU (47 mg,0.15 mmol), 7- (4-piperidinyl) -2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazine; hydrochloride (42 mg,0.13 mmol), N-diisopropylethylamine (87 μl,0.50 mmol) to give 40mg (61% yield) of [4- (1, 2-pentafluoroethyl) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone as a white solid. LC/MS (M/z, M+H) calculated 509.5, found 509.2;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 23 cyclohexyl- [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone

Example 23 was prepared following the procedure described for example 17 using cyclohexane carboxylic acid (19 mg,0.15 mmol), TBTU (46 mg,0.14 mmol), DIPEA (68 μl,0.39 mmol), 7- (4-piperidinyl) -2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazine, hydrochloride (42 mg,0.13 mmol) to give 30mg (58% yield) of cyclohexyl- [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone as a white solid. LC/MS (M/z, M+H) calculated 397.5, found 397.3;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 24 (rac) - [ 2-amino-4- (trifluoromethoxy) phenyl ] - [3- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyrrolidin-1-yl ] methanone

Step 1 3- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester

To a solution of 2- [ (2-bromo-7-iodo-pyrrolo [2,3-b ] pyrazin-5-yl) methoxy ] ethyl-trimethyl-silane (13 g,28.6 mmol) and 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester (9.29 mg,31.5 mmol) in a mixture of dioxane/water (130 mL/26 mL) was added sequentially Pd (dppf) Cl ₂ (622 mg) and Na ₂CO₃ (9.1 g,85.8 mmol). The reaction mixture was refluxed under nitrogen atmosphere for 5 hours. After five hours, the reaction mixture was cooled to room temperature, diluted with brine (200 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na ₂SO₄, filtered and concentrated to give a crude oil. The crude product was purified by silica gel chromatography (EtOAc/PE 25/75) to give 8.3g (58% yield) of 3- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester as a yellow solid. LC/MS (M/z, M+H) calculated 496.5, found 496.1

Step 2 3- [2- (3, 6-dihydro-2H-pyran-4-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester

To a solution of 3- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester (8.4 g,17 mmol) and 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (3.9 g,18.6 mmol) in a mixture of dioxane/water (100 mL/20 mL) was added Pd (dppf) Cl ₂ (370 mg) and Na ₂CO₃ (5.4 g,51 mmol) in sequence. The reaction mixture was stirred at 80 ℃ under nitrogen atmosphere for 5 hours. After 5 hours, the reaction mixture was diluted with brine (150 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (2×150 mL), dried over anhydrous Na ₂SO₄, filtered and concentrated to give a crude oil. The crude product was purified by silica gel chromatography (EtOAc/PE 25/75) to give 6g (82% yield) of tert-butyl 3- [2- (3, 6-dihydro-2H-pyran-4-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -2, 5-dihydropyrrole-1-carboxylate as a yellow solid. LC/MS (M/z, M+H) calculated 499.7, found 499.1

Step 3 tert-butyl 3- [ 2-tetrahydropyran-4-yl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] pyrrolidine-1-carboxylate

To a solution of 3- [2- (3, 6-dihydro-2H-pyran-4-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester (6 g,12 mmol) in ethyl acetate (120 mL) was added palladium on carbon (20 wt%, 6 g). The mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 48 hours. The reaction mixture was then filtered through celite, and the filtrate was concentrated under reduced pressure to give 5g (83% yield) of crude 3- [ 2-tetrahydropyran-4-yl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid. LC/MS (M/z, M+H) calculated 503.7, found 503.2

Step4 (7-pyrrolidin-3-yl-2-tetrahydropyran-4-yl-pyrrolo [2,3-b ] pyrazin-5-yl) methanol; 2, 2-trifluoro acetic acid

To a solution of tert-butyl 3- [ 2-tetrahydropyran-4-yl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] pyrrolidine-1-carboxylate (1.6 g,3.18 mol) in DCM (10 mL) was added TFA (5 mL) at 0 ℃. The resulting mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was then concentrated to give 0.96g (99% yield) of crude (7-pyrrolidin-3-yl-2-tetrahydropyran-4-yl-pyrrolo [2,3-b ] pyrazin-5-yl) methanol, 2-trifluoroacetic acid as a pale yellow oil. LC/MS (M/z, M+H-TFA) calculated 303.4, found 303.1

Step 5 (rac) - [ 2-amino-4- (trifluoromethoxy) phenyl ] - [3- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyrrolidin-1-yl ] methanone

To a solution of (7-pyrrolidin-3-yl-2-tetrahydropyran-4-yl-pyrrolo [2,3-b ] pyrazin-5-yl) methanol, 2-trifluoro acetic acid (445 mg,1.07 mmol) and 2-amino-4- (trifluoromethoxy) benzoic acid (150 mg,0.68 mmol) in N, N-dimethylformamide (5 mL) was added 1-hydroxybenzotriazole, hydrate (328 mg,2.14 mmol), N' - (ethylcarboimino) -N, N-dimethylpropane-1, 3-diamine hydrochloride (411 mg,2.14 mmol) and DIPEA (692 mg,5.4 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were concentrated to give a crude oil. The crude product was dissolved in a mixed solution of methanol (10 mL) and 30% aqueous NH ₄ OH (15 mL). After stirring for 1 hour, the resulting solution was treated with water (50 mL) and extracted with EtOAc (3X 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered and concentrated to give a crude oil which was purified by silica gel chromatography (3% methanol in dichloromethane) and preparative HPLC to give 101mg (19% yield) of [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- (2-cyclohexyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] as a colourless solid. LC/MS (M/z, M+H) calculated 476.5, found 476.3;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 25 (rac) - [3- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyrrolidin-1-yl ] - [4- (trifluoromethoxy) phenyl ] methanone

Example 25 was prepared following the procedure used in step 5 of example 24 using (7-pyrrolidin-3-yl-2-tetrahydropyran-4-yl-pyrrolo [2,3-b ] pyrazin-5-yl) methanol in N, N-dimethylformamide (10 mL), 2-trifluoroacetic acid (0.48 g,1.15 mmol) and 4- (trifluoromethoxy) benzoic acid (0.36 g,1.74 mmol) with the addition of 1-hydroxybenzotriazole, hydrate (0.32 g,2.4 mmol), N' - (ethylcarboimino) -N, N-dimethylpropane-1, 3-diamine hydrochloride (0.46 g,2.4 mmol) and DIPEA (3.1 g,24 mmol) to give 290mg (55% yield) of (rac) - [3- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyrrolidin-1-yl ] - [ trifluoromethoxy ] phenyl ] methanone as a colorless solid. LC/MS (M/z, M+H) calculated 461.4, found 461.2;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 26 [ 2-fluoro-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone

Example 26 was prepared following the procedure described in example 17 using 2-fluoro-4- (pentafluoro-lambda ⁶ -sulfanyl) benzoic acid (91 mg,0.34 mmol), TBTU (121 mg,0.38 mmol), N-diisopropylethylamine (170 μl,0.97 mmol), 7- (4-piperidinyl) -2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazine, hydrochloride (97 mg,0.30 mmol) to give 75mg (46% yield) of [ 2-fluoro-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] methanone as a white solid. LC/MS (M/z, M+H) calculated 535.5, found 535.2;¹H NMR(400MHz,DMSO-d6,100℃)δppm 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)

EXAMPLE 27 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-ylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

Step 1 4- [2- (oxetan-3-ylamino) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To a stirred solution of 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.00 g,1.96mmol, prepared in step 3 of example 1) and oxetan-3-amine (719 mg,9.81 mmol) in 1, 4-dioxane (10 mL) was added sodium 2-methylpropan-2-alkoxide (566 mg,5.89 mmol) at room temperature, and the resulting reaction mixture was bubbled with argon for 10 min. Then XPhosPdG4 (237 mg,0.28 mmol) was added under nitrogen atmosphere and the resulting reaction mixture was subjected to microwave irradiation at 100 ℃ for 1 hour. After 1 hour, the reaction mixture was diluted with water (30 mL), extracted with EtOAc (2 x 100 mL), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with 20% ethyl acetate in hexane to give 550mg (52% yield) of tert-butyl 4- [2- (oxetan-3-ylamino) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylate as a yellow viscous solid. LC/MS (M/z, M+H) calculated 502.3, found 502.1.

Step2 4- [2- (oxetan-3-ylamino) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 4- [2- (oxetan-3-ylamino) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (550 mg,1.1 mmol) in methanol (5 mL) at room temperature was added 10% Pd/C (803 mg,5.5 mmol), and the resulting mixture was hydrogenated at 1H ₂ atm for 12 hours. Then, after 12 hours, the reaction mixture was filtered through celite, and the resulting filtrate was dried over sodium sulfate and concentrated in vacuo to give 500mg (88% yield) of 4- [2- (oxetan-3-ylamino) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester as a yellow liquid. LC/MS (M/z, M+H) calculated 504.3, found 504.1.

Step 3[ 2- (Oxetan-3-ylamino) -7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-5-yl ] methanol, 2-trifluoroacetate

A stirred solution of tert-butyl 4- [2- (oxetan-3-ylamino) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (500 mg,0.99 mmol) in dichloromethane (5 mL) was cooled to 0℃and then trifluoroacetic acid (226 mg,1.99 mmol) was added and the resulting reaction mixture was stirred at room temperature for 3 hours. After 3 hours, the reaction mixture was concentrated in vacuo and the resulting residue was triturated and washed in n-hexane (2×25 ml) to give 417mg (100% yield) of [2- (oxetan-3-ylamino) -7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-5-yl ] methanol, 2-trifluoroacetic acid as a yellow solid. LC/MS (M/z, M+H-TFA) calculated 304.2, found 304.5.

Step 4, [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-ylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

To a stirred solution of [2- (oxetan-3-ylamino) -7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-5-yl ] methanol, 2-trifluoro acetic acid (280 mg,0.67 mmol) and 2-amino-4- (trifluoromethoxy) benzoic acid (102 mg,0.46 mmol) in N, N-dimethylformamide (5 mL) was added benzotriazol-1-yloxy (tripyrrolidin-1-yl) phosphorus; hexafluorophosphate (720 mg,1.38 mmol) and N, N-diethyl ethylamine (280 mg,2.77 mmol), 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 x 50 mL), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting 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) and the pure fractions were lyophilized to give 15mg (3.4% yield) of [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-ylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone as an off-white solid. LC/MS (M/z, M+H) calculated 477.2, found 477.1.¹HNMR(400MHz,DMSO-d⁶)δppm 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).

EXAMPLE 28 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ (3R) -tetrahydrofuran-3-yl ] oxy-5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

Step 14- [2- [ (3R) -tetrahydrofuran-3-yl ] oxy-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To a stirred solution of 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.00 g,1.96mmol, prepared in step 3 of example 1) and (3R) -tetrahydrofuran-3-ol (865 mg,9.81 mmol) in 1, 4-dioxane (3 mL) was added sodium 2-methylpropan-2-alkoxide (566 mg,5.89 mmol) at room temperature, and the resulting reaction mixture was bubbled with nitrogen for 10 min. Then XPhosPdG4 (169 mg,0.2 mmol) was added under nitrogen atmosphere and the resulting mixture was subjected to microwave irradiation at 100 ℃ for 1 hour. After 1 hour, the reaction mixture was quenched with water (30 mL), extracted with EtOAc (2 x 100 mL), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with 12% ethyl acetate in hexane to give 250mg (23% yield) of tert-butyl 4- [2- [ (3R) -tetrahydrofuranyl-3-yl ] oxy-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylate as a yellow solid. LC/MS (M/z, M+H) calculated 517.3, found 517.3.

Step 2 4- [2- [ (3R) -tetrahydrofuran-3-yl ] oxy-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 4- [2- [ (3R) -tetrahydrofuran-3-yl ] oxy-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (250 mg,0.48 mmol) in methanol (2 mL) at room temperature was added 10% Pd/C (302 mg,2.84 mmol), and the resulting mixture was hydrogenated at 1H ₂ atm for 12 hours. After 12 hours, the reaction mixture was filtered through celite, then washed with MeOH (2 x5 ml), and the resulting filtrate was dried over sodium sulfate and concentrated in vacuo to give 180mg (72% yield) of 4- [2- [ (3R) -tetrahydrofuranl-3-yl ] oxy-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester. LC/MS (M/z, M+H) calculated 519.3, found 519.3.

Step 3 [7- (4-piperidinyl) -2- [ (3R) -tetrahydrofuran-3-yl ] oxy-pyrrolo [2,3-b ] pyrazin-5-yl ] methanol, 2-trifluoroacetate

To a stirred solution of 4- [2- [ (3R) -tetrahydrofuran-3-yl ] oxy-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester (180 mg,0.35 mmol) in dichloromethane (5.0 mL) at 0 ℃ was added trifluoroacetic acid (2 mL), 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 x 10 ml) to give 150mg (100% yield) of [7- (4-piperidinyl) -2- [ (3R) -tetrahydrofuran-3-yl ] oxy-pyrrolo [2,3-b ] pyrazin-5-yl ] methanol, 2-trifluoroacetic acid as a yellow solid. LC/MS (M/z, M+H-TFA) calculated 319.2, found 319.0.

Step 4 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ (3R) -tetrahydrofurane-3-yl ] oxy-5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

To a stirred solution of 2-amino-4- (trifluoromethoxy) benzoic acid (115 mg,0.52 mmol) in N, N-dimethylformamide (5 mL) was added 3- (ethyliminomethylamino) -N, N-dimethyl-propan-1-amine, hydrochloride (150 mg,0.78 mmol) and 1-hydroxybenzotriazole (84 mg,0.62 mmol), cooled to 0 ℃, N-diethylamine (158 mg,1.56 mmol) was added at 0 ℃, followed by [7- (4-piperidinyl) -2- [ (3R) -tetrahydrofuran-3-yl ] oxy-pyrrolo [2,3-b ] pyrazin-5-yl ] methanol (150 mg,0.47 mmol) after 10 minutes. Then, the reaction mixture was stirred at room temperature for 16 hours. After 16 hours, the reaction mixture was concentrated under vacuum. The resulting residue was purified by preparative HPLC (preparation 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: 18mL/min; gradient programmer (min)% B): 0min 30%, 2min 40%, 8min 70%) and the pure fractions concentrated to give 6mg (2.5% yield) of [ [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ (3S) -tetrahydrofuran-3-yl ] oxy-5H-pyrrolo [2,3-B ] pyrazin-7-yl ] -1-piperidinyl ] methanone as a white solid. LC/MS (M/z, M+H) calculated 492.2, found 492.2.¹H NMR(400MHz,DMSO-d₆)δppm 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).

EXAMPLE 29 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ (3S) -tetrahydrofuran-3-yl ] oxy-5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

Example 29 was prepared following the protocol described in steps 1-4 of example 28 using (3S) -tetrahydrofuran-3-ol (319 mg,0.29 mmol) in step 1 to give 16mg (7% yield in step 4) of [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ (3S) -tetrahydrofuran-3-yl ] oxy-5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone as a white solid. LC/MS (M/z, M+H) calculated 492.2, found 492.3.¹H NMR(400MHz,DMSO-d₆)δppm: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)。

Example 30 trans- [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (4-hydroxycyclohexyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

Step 1 4- [2- (1, 4-Dioxaspiro [4.5] dec-7-en-8-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To a stirred solution of 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.50 g,2.94mmol, prepared in step 3 of example 1) and 2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -4, 5-tetramethyl-1, 3, 2-dioxapentaborane (784 mg,2.94 mmol) in 1, 4-dioxane (30 mL) and water (8 mL) was added K ₂CO₃ (1.22 g,8.83 mmol), and the resulting mixture was bubbled with nitrogen for 15min. Then PdCl ₂ (dppf). DCM (215 mg,0.26 mmol) was added at room temperature, and the reaction mixture was stirred at 90 ℃ for 4 hours. After 4 hours, the reaction mixture was diluted with water (100 mL), extracted with EtOAc (2 x 100 mL), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with 40% ethyl acetate in hexane to give 1.5g (90% yield) of tert-butyl 4- [2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylate as a yellow gummy liquid. LC/MS (M/z, M+H) calculated 569.3, found 569.2.

Step 24- [2- (1, 4-Dioxaspiro [4.5] dec-8-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 4- [2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.50 g,2.64 mmol) in methanol (20 mL) under an inert atmosphere was added 10% Pd/C (2.81 g,26.4 mmol), and the reaction mixture was then stirred at room temperature for 4 hours under 1H ₂ atmosphere. After 4 hours, the reaction mixture was filtered through celite, and the resulting filtrate was dried over sodium sulfate and concentrated in vacuo to give 1.2g (79% yield) of tert-butyl 4- [2- (1, 4-dioxaspiro [4.5] dec-8-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate as a yellow solid. LC/MS (M/z, M+H) calculated 573.3, found 573.3.

Step3 4- [7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] cyclohexanone, 2-trifluoroacetate

To a stirred solution of tert-butyl 4- [2- (1, 4-dioxaspiro [4.5] dec-8-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (1.50 g,2.62 mmol) in dichloromethane (20 mL) was added 2, 2-trifluoroacetic acid (2.99 g,26.2 mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 16 hours. After 16 hours, the reaction mixture was concentrated in vacuo, triturated and washed with n-hexane (2×25 ml) to give 900mg (83% yield) of 4- [7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] cyclohexanone as an off-white solid, 2-trifluoroacetic acid. LC/MS (M/z, M-H-TFA) calculated 297.2, found 297.2.

Step 4- [7- [1- [ 2-amino-4- (trifluoromethoxy) benzoyl ] -4-piperidinyl ] -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] cyclohexanone

To a stirred solution of 2-amino-4- (trifluoromethoxy) benzoic acid (500 mg,2.26 mmol) and 4- [7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] cyclohexanone, 2-trifluoroacetic acid (675mg, 1.64 mmol) in N, N-dimethylformamide (10 mL) was added 3- (ethyliminomethyleneamino) -N, N-dimethyl-propan-1-amine; hydrochloride (650 mg,3.39 mmol), 1-hydroxybenzotriazole; hydrate (719 mg,3.39 mmol) and N, N-diethylamine (686 g,6.78 mmol) at 0 ℃. 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 Na ₂SO₄, filtered and concentrated under reduced pressure to give 500mg (44% yield) of 4- [7- [1- [ 2-amino-4- (trifluoromethoxy) benzoyl ] -4-piperidinyl ] -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] cyclohexanone as an off-white solid. LC/MS (M/z, M+H) calculated 502.2, found 502.2.

Step 5 trans- [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (4-hydroxycyclohexyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

To a stirred solution of 4- [7- [1- [ 2-amino-4- (trifluoromethoxy) benzoyl ] -4-piperidinyl ] -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] cyclohexanone (500 g,0.99 mmol) in methanol (10 mL) was added NaBH ₄ (189 mg,4.99 mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 1 hour. After one 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 Na ₂SO₄, filtered and concentrated to give 15mg (3% yield) of [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (4-hydroxycyclohexyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone as an off-white solid. LC/MS (M/z, M+H) calculated 504.2, found 504.2.¹H NMR(400MHz,DMSO-d₆)δppm 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).

EXAMPLE 31[ 4- [2- (4-methylpiperazin-1-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone, formic acid

Step 1 4- [2- (4-methylpiperazin-1-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To a stirred solution of 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1 g,1.96mmol, prepared in step 3 of example 1) in 1, 4-dioxane (10 mL) was added 1-methylpiperazine (393 mg,3.93 mmol) and sodium 2-methylpropan-2-alkoxide (566 mg,5.89 mmol) at room temperature, and the resulting mixture was bubbled with nitrogen for 10 min. Then, XPhosPdG (169 mg,0.2 mmol) was added under an atmosphere of N ₂, and the resulting mixture was subjected to microwave at 100℃for 1 hour. After one hour, the reaction mixture was diluted with water (30 mL), extracted with EtOAc (2 x 100 mL), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with 40% ethyl acetate in hexane to give 500mg (48% yield) of tert-butyl 4- [2- (4-methylpiperazin-1-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylate as a yellow solid. LC/MS (M/z, M+H) calculated 529.3, found 529.2.

Step 2 4- [2- (4-methylpiperazin-1-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 4- [2- (4-methylpiperazin-1-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (500 mg,0.95 mmol) in ethanol (20 mL) at room temperature was added 10% Pd/C (302 mg,2.84 mmol), and the resulting reaction mixture was hydrogenated at one H ₂ atmosphere for 12 hours. After 12 hours, the reaction mixture was filtered through celite, and the resulting filtrate was dried over sodium sulfate and concentrated in vacuo to give 350mg (70% yield) of 4- [2- (4-methylpiperazin-1-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester as a yellow liquid. LC/MS (M/z, M+H) calculated 531.3, found 531.2.

Step 3 [2- (4-methylpiperazin-1-yl) -7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-5-yl ] methanol, dihydrochloride

To a stirred solution of tert-butyl 4- [2- (4-methylpiperazin-1-yl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (320 mg,0.6 mmol) in dichloromethane (10 mL) was added 4M HCl in dioxane (3 mL,0.056 mmol) at 0 ℃ and the resulting reaction mixture was stirred at room temperature for 4 hours. After 4 hours, the reaction mixture was concentrated in vacuo and the resulting residue was triturated and washed with n-hexane (2×25 mL) to give 350mg of crude [2- (4-methylpiperazin-1-yl) -7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-5-yl ] methanol, dihydrochloride (0.350 g) as a yellow solid, which was used in the next step without further purification.

Step 4 2- (4-methylpiperazin-1-yl) -7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazines

To a stirred solution of [2- (4-methylpiperazin-1-yl) -7- (4-piperidinyl) pyrrolo [2,3-b ] pyrazin-5-yl ] methanol, dihydrochloride (crude 350mg of step 3) in methanol was added aqueous NH ₃ solution (25% w/v,3ml,0.056 mmol) at 0 ℃, 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 give 100mg (55% yield) of 2- (4-methylpiperazin-1-yl) -7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazine as a pale yellow solid. LC/MS (M/z, M+H) calculated 301.2, found 301.1.

Step 5 [4- [2- (4-methylpiperazin-1-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone, formic acid

To a stirred solution of 4- (trifluoromethoxy) benzoic acid (70 mg,0.34 mmol) in N, N-dimethylformamide (10 mL) was added [ benzotriazol-1-yloxy (dimethylamino) methylene ] -dimethyl-ammonium, tetrafluoroborate (164 mg,0.51 mmol) and N, N-diethylamine (103 mg,1.02 mmol), and the resulting reaction mixture was stirred for 15 minutes. Then, 2- (4-methylpiperazin-1-yl) -7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazine (92 mg,0.31 mmol) was added at 0 ℃, 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 in vacuo. The resulting residue was purified by preparative HPLC (preparation conditions: mobile phase: a=0.1% HCOOH in water, b=acn, column: X SELECT (250 mm X20 mm), 5 μm, flow: 15 mL/min) and the pure fractions were lyophilized to give 12mg (7% yield) of [4- [2- (4-methylpiperazin-1-yl) -5H-pyrrolo [2,3-B ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone, formic acid as an off-white solid. LC/MS (M/z, M+H-HCOOH) calculated 489.2, found 489.1.¹H NMR(400MHz,DMSO-d₆)δppm 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).

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

Step 1 (rac) -4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To a solution of 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (950 mg,1.86mmol, prepared in step 3 of example 1) and tetrahydrofuran-3-amine, hydrochloride (463mg, 3.73 mmol) in dioxane (9 mL) was added t-BuONa (7197 mg,7.46 mmol), and the resulting mixture was bubbled with argon for 5 min. Then, pd ₂(dba)₃ (171 mg,0.19 mmol) and RuPhos (104 mg,0.22 mmol) were added, and the resulting mixture was subjected to microwave irradiation at 100 ℃ for 1 hour. The whole mixture was then diluted with ethyl acetate, washed with water and brine. The combined aqueous layers were extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (SiO ₂ g), eluting with DCM/ethyl acetate 7/3 to give 548mg (57% yield) of (rac) -4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as an orange solid. LC/MS (M/z, M+H) calculated 516.3, found 516.5.

Step 2 (rac) -4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

To a solution of (rac) -4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (577 mg,1.12 mmol) in EtOH (10 mL) was added ammonium formate (1.41 g,22.4 mmol) and Pd/C10% (50% wet) (110 mg), and the whole mixture was stirred at 80 ℃ for one hour. After one 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 give 561mg (96% yield) of (rac) -4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester as a brown solid. LC/MS (M/z, M+H) calculated 518.3, found 518.6.

Step 3 (rac) -4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl (rac) -4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylate (557 mg,1.07 mmol) in THF (2 mL) was added a 1M solution of ethylenediamine (0.72 mL,10.76 mmol) and tetrabutylammonium fluoride in THF (8.6 mL,8.6 mmol), and the resulting reaction mixture was stirred at 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 in vacuo. The resulting residue was purified by flash chromatography on silica gel (SiO ₂ g), eluting with ethyl acetate/heptane 8/2, to give 373mg (89% yield) of (rac) -4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester as a brown solid. LC/MS (M/z, M+H) calculated 388.2, found 388.4.

Step 4 (rac) -7- (4-piperidinyl) -N-tetrahydrofuran-3-yl-5H-pyrrolo [2,3-b ] pyrazin-2-amine, tri-hydrochloride

To a solution of (rac) -4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester (370 mg,0.95 mmol) in MeOH (6 mL) was added a 4N solution of HCl in dioxane (2.38 mL,9.55 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours. The resulting mixture was then concentrated to dryness to give 367mg (96% yield) of (rac) -7- (4-piperidinyl) -N-tetrahydrofuran-3-yl-5H-pyrrolo [2,3-b ] pyrazin-2-amine, tri-hydrochloride as a yellow solid, which was used in the next step without purification.

Step 5 (example 36) [4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

To a solution of (rac) -7- (4-piperidinyl) -N-tetrahydrofuran-3-yl-5H-pyrrolo [2,3-b ] pyrazin-2-amine; tri-hydrochloride (182 mg,0.46 mmol) in DMF (3 mL) was added DIPEA (237 mg,1.83 mmol) and the resulting reaction mixture was stirred at room temperature for 5 min. Then, 4- (trifluoromethoxy) benzoic acid (94 mg,0.46 mmol) followed by TBTU (162 mg,0.5 mmol) and the resulting mixture stirred at room temperature for an additional 2.5 hours then diluted with ethyl acetate, washed with saturated aqueous NaHCO ₃, water, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was triturated in MeCN, filtered, washed with MeCN and dried in vacuo. The pale brown solid thus obtained was then purified by flash chromatography on silica gel (SiO ₂ g), eluting with DCM/MeOH/NH ₄ OH 95/5/0.5 to give 163mg (75% yield) of (rac) - [4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone as a pale brown solid. LC/MS (M/z, M+), calculated 475.2, found 475.0.¹H NMR(400MHz,DMSO-d₆,100℃)δppm 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)

Step 6 (examples 32 and 33) [4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone, isomers 1 and 2

Chiral separation of (rac) - [4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone (151 mg,0.32 mmol) was performed using a CHIRALCEL OZ column (30 μm,350x80 mm), eluting with (heptane 70/EtOH 30) +0.1% TEA (flow rate 400mL/min, UV detection at 230 nm) to give 67mg (44% yield) [4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone, isomer 1.LC/MS (M/z, M+H) calculated 476.2, found 476.4,¹H NMR(400MHz,DMSO-d₆,100℃)δppm 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 63mg (42% yield) [4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone, isomer 2.LC/MS (M/z, M+H) calculated 476.2, found 476.4,¹H NMR(400MHz,DMSO-d₆,100℃)δppm 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).

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

Step 1 (example 37) [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

Step 1 was performed following the protocol described in step 5 of examples 32 and 33, using (rac) -7- (4-piperidinyl) -N-tetrahydrofuranyl-3-yl-5H-pyrrolo [2,3-b ] pyrazin-2-amine, tri-hydrochloride (182 mg,0.46 mmol) and 2-amino-4- (trifluoromethoxy) benzoic acid (101 mg,0.46 mmol) to give 189mg (84% yield) of (rac) - [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone as a pale brown solid. LC/MS (M/z, M+H) calculated 491.2, found 491.4.¹H NMR(400MHz,DMSO-d₆,100℃)δppm 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).

Step 2 (examples 34 and 35) [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone, isomers 1 and 2

Chiral separation was performed using CHIRALCEL OZ column (5 μm,30x250 mm) on (rac) - [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone (175 mg,0.36 mmol), eluting with (heptane 55/EtOH 45) +0.1% tea (flow rate 45mL/min, UV detection at 254 nm) to give 78mg (44% yield) [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone, isomer 1.LC/MS (M/z, M+H) calculated 491.2, found 491.4,¹H NMR(400MHz,DMSO-d₆,100℃)δppm 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 84mg (48% yield) [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- [ [ tetrahydrofuran-3-yl ] amino ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone, isomer 2.LC/MS (M/z, M+H) calculated 491.2, found 491.4,¹H NMR(400MHz,DMSO-d₆,100℃)δppm 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).

EXAMPLE 38 [4- [2- (tetrahydropyran-4-ylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

Example 38 was prepared using a method analogous to that of steps 1 to 5 of examples 36, 32 and 33, to give 105mg (79% yield in step 5) of [4- [2- (tetrahydropyran-4-ylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone as a pale brown solid. LC/MS (M/z, M+H) calculated 490.2, found 490.3.¹H 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)

EXAMPLE 39 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (tetrahydropyran-4-ylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

Example 39 was prepared following the procedure described in step 5 of examples 36, 32 and 33 using 7- (4-piperidinyl) -N-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-2-amine, tri-hydrochloride (111 mg,0.27 mmol) and 2-amino-4- (trifluoromethoxy) benzoic acid (60 mg,0.27 mmol) to give 106mg (78% yield) of [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (tetrahydropyran-4-ylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone as a pale brown solid. LC/MS (M/z, M+H) calculated 505.2, found 505.3.¹H NMR(400MHz,DMSO-d₆,100℃)dppm 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)

EXAMPLE 40 [4- (2-morpholino-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

Step 14- [ 2-morpholino-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

In a 10-20mL microwave vial, a solution of morpholine (51 mg,0.59 mmol), 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (250 mg,0.49mmol, prepared in step 3 of example 1), ruPhos (18 mg,0.04 mmol) in THF (1 mL) was bubbled with argon for 10 minutes, and then Pd (OAc) ₂ (4 mg,0.02 mmol) was added followed by 1.18mL of a 1M solution of LiHMDS (1.18 mmol) in THF. The resulting mixture was then microwaved at 100 ℃ for one hour. After one 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 then the combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was then purified by flash chromatography on silica gel (SiO ₂ g), eluting with DCM/AcOEt (from 100/0 to 90/10) to give 140mg (55% yield) of tert-butyl 4- [ 2-morpholino-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylate as a brown solid. LC/MS (M/z, M+H) calculated 516.3, found 516.4.

Step 2-5 [4- (2-morpholino-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

Steps 2 to 5 of example 40 follow the protocol described in steps 2 to 5 of examples 36, 32 and 33. Use of 4- [7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] morpholine, hydrochloride (50 mg,0.15 mmol) and 4- (trifluoromethoxy) benzoic acid (32 mg,0.15 mmol) in step 5 gives 30mg (41% yield) of [4- (2-morpholino-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone as a solid. LC/MS (M/z, M+H) calculated 476.2, found 476.1.¹H 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)

EXAMPLE 41 [4- [2- (4, 4-difluoro-1-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

Step 1 4- [2- (4, 4-difluoro-1-piperidinyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

Step 1 of example 41 was performed following the protocol described in step 1 of example 40, using 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (300 mg,0.59 mmol) and 4, 4-difluoropiperidine (85 mg,0.71 mmol) to give 196mg (60% yield) of 4- [2- (4, 4-difluoro-1-piperidinyl) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a brown solid. LC/MS (M/z, M+H) calculated 550.3, found 550.3.

Step 2-5 [4- [2- (4, 4-difluoro-1-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone

Steps 2 to 5 of example 41 follow the protocol described in steps 2 to 5 of examples 36, 32 and 33. Use of 2- (4, 4-difluoro-1-piperidinyl) -7- (4-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazine, hydrochloride (45 mg,0.12 mmol) and 4- (trifluoromethoxy) benzoic acid (26 mg,0.12 mmol) in step 5 gave 35mg (55% yield) of [4- [2- (4, 4-difluoro-1-piperidinyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] - [4- (trifluoromethoxy) phenyl ] methanone as a pale brown solid. LC/MS (M/z, M+H) calculated 510.2, found 510.1.¹H NMR(400MHz,DMSO-d₆,100℃)δppm 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)

EXAMPLE 42 [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- [2, 2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl ] phenyl ] methanone

Step 1 4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) piperidine-1-carboxylic acid tert-butyl ester

Step 1 of example 42 was performed following the protocol described in step 3 of examples 36, 32 and 33, using 4- [ 2-tetrahydropyran-4-yl-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] piperidine-1-carboxylic acid tert-butyl ester (189 mg,0.36mmol, prepared in step 2 of example 2) to give 128mg (90% yield) of 4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) piperidine-1-carboxylic acid tert-butyl ester as a solid. LC/MS (M/z, M+H) calculated 387.3, found 387.3.

Step 2 7- (4-piperidinyl) -2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazine, dihydrochloride

A solution of tert-butyl 4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) piperidine-1-carboxylate (117 mg,0.3 mmol) in HCl in dioxane (5N, 4mL,20 mmol) was stirred at room temperature for one hour. The reaction mixture was then concentrated to dryness to give 109mg (100% yield) of 7- (4-piperidinyl) -2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazine as a yellow solid. LC/MS (M/z, M+H-2 HCl) calculated 287.2, found 287.1.

Step 3 [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- [2, 2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl ] phenyl ] methanone

Step 3 of example 42 was performed following the protocol described in step 5 of examples 36, 32 and 33, using 7- (4-piperidinyl) -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 give 67mg (78% yield) of [4- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1-piperidinyl ] - [4- [2, 2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl ] phenyl ] methanone as a solid. LC/MS (M/z, M+H) calculated 557.2, found 557.1.¹H NMR(400MHz,DMSO-d₆,100℃)δppm 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)

EXAMPLE 43 (rac) - [ 2-amino-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [3- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -129-pyrrolidin-1-yl ] methanone

Example 43 was prepared following the protocol described in steps 3 to 5 of examples 36, 32 and 33. Using (rac) -7-pyrrolidin-3-yl-2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazine, dihydrochloride (120 mg,0.35 mmol) and 2-amino-4- (pentafluoro-lambda ⁶ -sulfanyl) benzoic acid (100 mg,0.38 mmol) in step 5 gave 53mg (29% yield) of (rac) - [ 2-amino-4- (pentafluoro-lambda ⁶ -sulfanyl) phenyl ] - [3- (2-tetrahydropyran-4-yl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyrrolidin-1-yl ] methanone as a white foam. LC/MS (M/z, M+H) calculated 518.2, found 518.2.¹H NMR(400MHz,DMSO-d₆,100℃)δppm 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).

EXAMPLE 44 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-yloxy) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

Step 1 4- (2-bromo-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To a stirred solution of 4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.5 g,2.94 mmol) in THF (15 mL) at 0 ℃ was added tetrabutylammonium fluoride, trihydrate (10 mL,8.83 mmol), and the reaction mixture was then stirred at 70 ℃ for 6 hours. After 6 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography using 0-70% ethyl acetate in hexane to give 750mg (67% yield) of tert-butyl 4- (2-bromo-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate as a yellow solid. LC/MS (M/z, M-H) calculated 377.0, found 377.1.

Step 2-bromo-7- (1, 2,3, 6-tetrahydropyridin-4-yl) -5H-pyrrolo [2,3-b ] pyrazine, hydrochloride

To a stirred solution of tert-butyl 4- (2-bromo-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate (0.750 g,1.98 mmol) in 1, 4-dioxane (10 mL) was added a 4M solution of HCl in dioxane (4 mL,9.89 mmol) at 0 ℃, and the resulting mixture was then 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 give 600mg (97% yield) of 2-bromo-7- (1, 2,3, 6-tetrahydropyridin-4-yl) -5H-pyrrolo [2,3-b ] pyrazine as a brown solid, hydrochloride (0.600 g). LC/MS (M/z, M+H-HCl) calculated 279.0, found 278.9.

Step 3 [4- (2-bromo-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -3, 6-dihydro-2H-pyridin-1-yl ] - [ 2-nitro-4- (trifluoromethoxy) phenyl ] methanone

To a stirred solution of 2-nitro-4- (trifluoromethoxy) benzoic acid (400 mg,1.59 mmol) and 2-bromo-7- (1, 2,3, 6-tetrahydropyridin-4-yl) -5H-pyrrolo [2,3-b ] pyrazine, hydrochloride (4819 mg,1.55 mmol) in DMF (10 mL) was added N, N-diethylamine (284 mg,4.78 mmol), and the resulting mixture was stirred for 15 min, then [ benzotriazol-1-yloxy (dimethylamino) methylene ] -dimethyl-ammonium was added at 0 ℃, [ tetrafluoroborate (767 mg,2.39 mmol), and the resulting mixture was stirred at room temperature for 2 hours, then diluted with water (20 mL) and extracted with EtOAc (2X 10 mL). The combined organic layers were dried over Na ₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by flash chromatography using 0-70% ethyl acetate in hexane to give 500mg (63% yield) of [4- (2-bromo-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -3, 6-dihydro-2H-pyridin-1-yl ] - [ 2-nitro-4- (trifluoromethoxy) phenyl ] methanone as a yellow solid. LC/MS (M/z, M+H) calculated 512.0, found 512.0.

Step 4 [4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridin-1-yl ] - [ 2-nitro-4- (trifluoromethoxy) phenyl ] methanone

To a stirred solution of [4- (2-bromo-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -3, 6-dihydro-2H-pyridin-1-yl ] - [ 2-nitro-4- (trifluoromethoxy) phenyl ] methanone (500 mg,0.98 mmol) in N, N-dimethylformamide (10 mL) was added sodium hydride (60% dispersion in oil, 59mg,1.46 mmol) in portions at 0 ℃ and the resulting mixture was stirred for 20min, then 2- (chloromethoxy) ethyl-trimethyl-silane (195 mg,1.17 mmol) was added at 0 ℃ and the resulting mixture was stirred at room temperature for 3 hours. After 3 hours, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na ₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by flash chromatography using 0-70% ethyl acetate in hexane to give 500mg (80% yield) of [4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridin-1-yl ] - [ 2-nitro-4- (trifluoromethoxy) phenyl ] methanone as a yellow gummy solid. LC/MS (M/z, M+H) calculated 642.1, found 642.1.

Step 5 [ 2-nitro-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-yloxy) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridin-1-yl ] methanone

To a stirred solution of [4- [ 2-bromo-5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridin-1-yl ] - [ 2-nitro-4- (trifluoromethoxy) phenyl ] methanone (450 mg,0.70 mmol) in 1, 4-dioxane (20 mL) was added oxetan-3-ol (319 mg,3.50 mmol) and sodium 2-methylpropan-2-alkoxide (202 mg,2.1 mmol) at room temperature, and the resulting mixture was stirred for 15 minutes, then XPhosPdG (60 mg,0.07 mmol) was added under an atmosphere of N ₂, and the resulting reaction mixture was microwaved at 100 ℃ for 1 hour. After one hour, the reaction mixture was filtered and dried under reduced pressure. The resulting residue was purified by flash chromatography eluting with 0-60% etoac in hexanes to give 250mg (56% yield) of [ 2-nitro-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-yloxy) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridin-1-yl ] methanone as a yellow liquid. LC/MS (M/z, M+H) calculated 636.2, found 636.3.

Step 6 [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-yloxy) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

To a stirred solution of [ 2-nitro-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-yloxy) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -3, 6-dihydro-2H-pyridin-1-yl ] methanone (250 mg,0.39 mmol) in ethanol (10 mL) was added 10% palladium on carbon (126 mg,1.18 mmol) at room temperature, and the resulting mixture was stirred at room temperature under one hydrogen atmosphere for 6 hours. After 6 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with 0-80% EtOAc in hexanes to give 110mg (46% yield) of [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-yloxy) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone as a gummy liquid. LC/MS (M/z, M+H) calculated 608.2, found 608.3.

Step 7, [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-yloxy) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone

Tetrabutylammonium fluoride (100 mg,0.165 mmol) was added to a stirred solution of [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-yloxy) -5- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl ] -1-piperidinyl ] methanone (100 mg,0.165 mmol) in THF (5 mL), the trihydrate (0.5 mL,0.132 mmol), and the resulting mixture was stirred at 70 ℃ for 4 hours. After 4 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC on a mobile phase a=0.1% HCOOH in water, b=acn, column GeminiNX (250 mm x 21.2 mm), flow rate: 18mL/min to give 16mg (20% yield) of [ 2-amino-4- (trifluoromethoxy) phenyl ] - [4- [2- (oxetan-3-yloxy) -5H-pyrrolo [2,3-B ] pyrazin-7-yl ] -1-piperidinyl ] methanone as an off-white solid. LC/MS (M/z, M+H) calculated 478.2, found 478.1. ¹H NMR(400MHz,DMSO-d₆ ) Delta 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).

ERK5 inhibitory Activity of Compounds of example 45

Two assays were performed to evaluate ERK5 inhibitory activity of example compounds, cell-based assays and cell-free biochemical assays. The measurement results are shown in table 2 below. In the case of repeated measurements, the reported values are average values.

Inhibition of cellular ERK5 activity

The renal cancer cell line SN12C was transduced by lentivirus PGREENFIRE1 MEF2 EF1 Neo (reference TR030 VA-N) from SBI using standard infection protocols. PGREENFIRE1 MEF2 EF1 Neo allows expression of the luciferase gene under the control of a minimal promoter with MEF2 transcriptional response elements. Cells carrying the reporter construct were selected by geneticin treatment. The selected cells were then transposed by piggyback-based plasmid pCM4007, allowing the constitutively activated MEK5DD to be expressed under the control of the TREG3 promoter (doxycycline regulated promoter). The transposable cells were selected by puromycin treatment. After doxycycline treatment (1. Mu.g/ml), MEK5DD was expressed. MEK5DD activates ERK5, phosphorylating MEF2C proteins. The activated MEF2C protein can bind to its transcriptional response element. Luciferase is then expressed. In a 96-well plate (96F nuncleon ref137101, siemens (thermofisher)), 50,000 cells were seeded in 142.5. Mu.l of RPMI medium containing 10% fetal bovine serum, 1% glutamine and 1. Mu.g/ml doxycycline. After 24 hours, the compound was added to 7.5 μl of medium (with 2% DMSO to give a final concentration of 0.1%) to obtain the desired concentration (0.3-10000 nM). Luciferase activity was determined using Kit Bright Glo Luminescent CELLASSAY CAT E2610 (Promega) according to the manufacturer's protocol. Luminescence was measured using TECAN SPARK using a 0.2 second reading/well. IC ₅₀ values were calculated using method 205 using XLFIT in Microsoft Excel. IC ₅₀ values represent compound concentrations that inhibited the measurable luminescence signal by 50% compared to DMSO-treated control cells.

Cell-free assay for ERK5 inhibition

Assays were performed to measure the ability of each compound to inhibit ERK5 enzyme activity. Compound efficacy was assessed by time resolved forster resonance energy transfer (FRET system). The activated catalytic domain of protein ERK5 (CarnaBiosciences # 04-146) was mixed with different concentrations of compound at 4nM and incubated for 30 min at room temperature. A mixture of 1mM ATP and 1. Mu.M biotin synthetic peptide (Biosyntan Co., ltd.) was added. The synthetic peptide represents amino acids 30-52 of eukaryotic translation initiation factor 4E binding protein 1 biotinylated at the N-terminus (see, e.g., sequence accession No. NP-004086.1). After 30 minutes at 37 ℃, peptide phosphorylation of ERK5 was measured by adding FRET reagent consisting of 12.5 μg/ml streptavidin-XL 665, 1nM anti-P-4 EBP1 antibody and 300ng/ml anti-rabbit K antibody. After 90 minutes at room temperature, the fluorescent signal was read on a PHERASTAR FSX multi-modality detector (Exc ° 340nm,Em1 620nm,Em2 665nm) from BMG Labtech. IC ₅₀ values represent compound concentrations that inhibited the measurable luminescence signal by 50% compared to DMSO alone control.

TABLE 2 results of cell-based and cell-free assays

"-" Indicates that these values were not measured

The data in table 2 shows that the synthesized compounds are active in the micromolar or nanomolar concentration range in cell-based and/or cell-free systems. All synthesized compounds have an IC ₅₀ value of less than 10 μm in at least one of a cell-based assay and a cell-free assay.

*****

It should be understood that while the disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages, and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Further, when features or aspects are described in terms of a Markush group, those skilled in the art will recognize that such features or aspects are also described in terms of any individual member or subgroup of members of the Markush group.

All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each was individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

Claims

1. A compound having formula (I)

Or its pharmaceutically acceptable salt, wherein:

^R1 is selected from -( _C1 - _C6 )alkyl, -( _C3 - _C7 )cycloalkyl, and 4- to 10-membered heterocyclic alkyl, wherein ^R1 is optionally substituted by one or more of the appearing ^RA .

Each ^RA is independently selected from halogen, -OH, oxo, _-NH2 , =N-OH, -( _C1 - _C3 )alkyl, -O( _C1 - _C3 )alkyl and -( _C3 - _C6 )cycloalkyl, wherein each -( _C1 - _C3 )alkyl group is optionally substituted by one or more groups independently selected from halogen and -OH;

^L1 is selected from direct bond, -O-, and -NH-;

^R2 is selected from -( _C3 - _C6 )cycloalkyl and -( _C6 - _C10 )aryl, wherein ^R2 is optionally substituted by one, two or three ^RBs .

Each ^RB is independently selected from halogens, _-NH2 , _-SF5 , -( _C1 - _C3 )alkyl, -O( _C1 - _C3 )alkyl and -O(C3- _C6 )cycloalkyl, wherein each -( _C1 - _C3 ₎ alkyl and -O( _C1 - _C3 )alkyl group is optionally substituted by one or more groups independently selected from halogens and -OH;

^R3 is selected from -H, ( _C1 - _C3 )alkyl (e.g., _-CH3 ), and -OH;

Y is CH or N; and

n is 0 or 1.

2. The compound of claim 1, wherein ^R1 is selected from:

^R1 may optionally be replaced by one or two ^RAs as defined in claim 1.

3. The compound of claim 2, wherein each ^RA is independently selected from the group consisting of -F, -OH, methyl, _-OCH3 and cyclopropyl.

4. The compound according to any one of claims 1-3, wherein the compound is a compound having formula (I-G).

Or a pharmaceutically acceptable salt thereof, wherein ^R1 , ^R2 , ^L1 and n are as defined in any one of claims 1-3.

5. A compound having formula (II)

Or its pharmaceutically acceptable salt, wherein:

Each ^RA is independently selected from halogens (e.g., -F), -OH, -( _C1 - _C3 )alkyl, -O( _C1 - _C3 )alkyl, and -( _C3 - _C6 )cycloalkyl;

^R2 is selected from -( _C3 - _C6 )cycloalkyl and -( _C6 - _C10 )aryl, wherein ^R2 is optionally substituted by one or both of the R2 ^groups .

Each ^RB is independently selected from halogens, _-NH₂ , _-SF₅ , -( _C₁ - _C₃ )alkyl, -O( _C₁ - _C₃ )alkyl, and -O(C₃- _C₆ )cycloalkyl, wherein each -( _C₁ _- _C₃ )alkyl and -O( _C₁ - _C₃ )alkyl group is substituted by one or more groups independently selected from halogens and -OH; and

n is 0 or 1.

6. The compound of claim 5, wherein ^R2 is a -( _C6 - _C10 ) aryl group substituted by one or two ^RBs , wherein each ^RB is independently selected from halogens (e.g., -F), _-NH2 , _-SF5 , _-OCF3 , -O-cyclopropyl, -C(OH)( _CF3 ) ₂ and _-CF2CF3 _.

7. A compound having the formula (III-A)

Or a pharmaceutically acceptable salt thereof, wherein ^R1 , ^L1 and n are as defined in any one of claims 1-3, and wherein:

^RB1 is -H, or can be chosen from the group consisting of _-NH2 and -F; and

^RB2 is selected from the group consisting of _-OCF3 , _-SF5 , _-CF2CF3 , _-C (OH)( _CF3 ) ₂ and -O-cyclopropyl.

8. A compound having formula (IV-A) or formula (V-A)

Or a pharmaceutically acceptable salt thereof, wherein ^R1 , ^L1 and n are as defined in any one of claims 1-3.

9. A compound having formula (VI), formula (VII) or formula (VIII)

Or a pharmaceutically acceptable salt thereof, wherein R ¹ is as defined in any one of claims 1-3.

10. A compound selected from the group consisting of:

-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-methyl-4-piperidinyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl] methyl ketone,

-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1-piperidinyl] methyl ketone,

-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone,

-[4-[2-(1-methyl-4-piperidinyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone,

-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone,

-[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone,

-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxypropyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl] methyl ketone,

-[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone,

-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine]

[-7-yl)-1-piperidinyl]methyl ketone,

-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(1-cyclopropyl-4-piperidinyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl] methyl ketone,

-[4-[2-(1-cyclopropyl-4-piperidinyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone,

-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1-piperidinyl] methyl ketone,

-[4-[2-(1-methyl-4-piperidinyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl]-[4-(pentafluoro- ^λ6 -thioalkyl)phenyl]methyl ketone,

-[2-amino-4-(pentafluoro- ^λ6 -thioalkyl)phenyl]-[4-[2-(1-methyl-4-piperidinyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl] methyl ketone,

-[4-(pentafluoro- ^λ6 -thioalkyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1-piperidinyl] methyl ketone,

-[2-amino-4-(pentafluoro- ^λ6 -thioalkyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1-piperidinyl] methyl ketone,

-[2-amino-4-(pentafluoro- ^λ6 -thioalkyl)phenyl]-[4-[2-(1-cyclopropyl-4-piperidinyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl] methyl ketone,

-[4-[2-(1-cyclopropyl-4-piperidinyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl]-[4-(pentafluoro- ^λ6 -thioalkyl)phenyl]methyl ketone,

-[4-(cyclopropoxy)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1-piperidinyl] methyl ketone,

-[4-(1,1,2,2,2-pentafluoroethyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1-piperidinyl] methyl ketone,

-cyclohexyl-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1-piperidinyl] methyl ketone,

-[2-amino-4-(trifluoromethoxy)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)pyrrolidin-1-yl] methyl ketone,

-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)pyrrolidin-1-yl]-[4-(trifluoromethoxy)phenyl] ketone,

-[2-fluoro-4-(pentafluoro- ^λ6 -thioalkyl)phenyl]-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1-piperidinyl] methyl ketone,

-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetane-3-ylamino)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl] methyl ketone

-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[tetrahydrofuran-3-yl]oxy-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl] methyl ketone,

-trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(4-hydroxycyclohexyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl] methyl ketone,

-[4-[2-(4-methylpiperazin-1-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone,

-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone,

-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[[tetrahydrofuran-3-yl]amino]-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl] methyl ketone

-[4-[2-(tetrahydropyran-4-ylamino)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone,

-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(tetrahydropyran-4-ylamino)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl] methyl ketone,

-[4-(2-morpholino-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone,

-[4-[2-(4,4-difluoro-1-piperidinyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone,

-[4-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-1-piperidinyl]-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl] ketone,

-[2-amino-4-(pentafluoro- ^λ6 -thioalkyl)phenyl]-[3-(2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)pyrrolidin-1-yl] methyl ketone,

-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(oxetane-3-yloxy)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-1-piperidinyl] methyl ketone

And its pharmaceutically acceptable salts.

11. A pharmaceutical composition comprising a compound as described in any one of claims 1-10 and at least one pharmaceutically acceptable excipient or carrier.

12. The compound of any one of claims 1-10 or the pharmaceutical composition of claim 11, for use in a therapeutic manner.

13. The compound of any one of claims 1-10 or the pharmaceutical composition of claim 11, for use in the treatment or prevention of cancer.

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

15. The compound or pharmaceutical composition for use as described in claim 13 or claim 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.