Derivatives of FGFR inhibitors

Abstract

The present disclosure relates to derivatives (e.g., hydroxyl, keto, glucuronide, sulfonate, and deuterated) of fibroblast growth factor receptor (FGFR) inhibitors, including methods for their preparation and intermediates in their preparation, which are useful in the treatment of FGFR-mediated diseases, such as cancer.

Description

[Technical Field]

[0001] This application relates to derivatives of fibroblast growth factor receptor (FGFR) inhibitors (e.g., hydroxyl, keto, glucuronide, sulfonic acid, and deuterated derivatives), including methods for their preparation and intermediates in their preparation, which are useful in the treatment of FGFR-mediated diseases such as cancer. [Background technology]

[0002] Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases that bind to fibroblast growth factor (FGF) ligands. There are four FGFR proteins (FGFR1-4) that can bind to ligands and are involved in regulating many physiological processes, including tissue development, angiogenesis, wound healing, and metabolic regulation. Upon ligand binding, the receptor undergoes dimerization and phosphorylation, leading to stimulation of protein kinase activity and recruitment of numerous intracellular docking proteins. These interactions promote the activation of a range of intracellular signaling pathways crucial for cell growth, proliferation, and survival, including Ras-MAPK, AKT-PI3K, and phospholipase C (reviewed in Eswarakumar et al., Cytokine & Growth Factor Reviews, 2005).

[0003] Abnormal activation of this pathway, resulting from overexpression of FGF ligands or FGFR, or activation of FGFR mutations, can lead to tumor development, progression, and resistance to conventional cancer treatments. In human cancers, genetic changes, including somatic mutations leading to gene amplification, chromosomal translocations, and ligand-independent receptor activation, have been described. Genetic changes can include mutations, fusions, rearrangements (e.g., translocations, deletions, inversions), and gene amplification. Large-scale DNA sequencing of thousands of tumor samples has revealed that components of the FGFR pathway are among the most frequently mutated in human cancers. Many of these activating mutations are identical to germline mutations that cause skeletal dysplasia. Mechanisms leading to abnormal ligand-dependent signaling in human diseases include FGF overexpression and alterations in FGFR splicing that lead to receptors with more indiscriminate ligand-binding ability (reviewed in Knights and Cook Pharmacology & Therapeutics, 2010; Turner and Grose, Nature Reviews Cancer, 2010). Therefore, the development of FGFR-targeting inhibitors may be useful for the clinical treatment of diseases in which FGF or FGFR activity is elevated.

[0004] Cancers involving FGF / FGFR include, but are not limited to, carcinomas (e.g., bladder, breast, cervix, colorectal, endometrium, stomach, head and neck, kidney, liver, lung, ovary, prostate); hematopoietic malignancies (e.g., multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, myeloproliferative neoplasms, and Waldenström macroglobulinemia); and other neoplasms (e.g., glioblastoma, melanoma, and rhabdomyosarcoma). In addition to its role in oncogenic neoplasms, FGFR activation is also involved in skeletal and chondrocyte disorders, including, but not limited to, chondrodysplasia and craniosynostosis syndrome. Specifically, the FGFR4-FGF19 signaling axis is involved in the pathogenesis of many cancers, including hepatocellular carcinoma (Heinzle et al., Cur. Pharm. Des. 2014, 20:2881). Ectopic expression of FGF19 in transgenic mice has been shown to lead to tumorigenesis in the liver, and neutralizing antibodies against FGF19 have been found to inhibit tumor growth in mice. Furthermore, overexpression of FGFR4 has been observed in multiple tumor types, including hepatocellular carcinoma, colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, lung cancer, and thyroid cancer. In addition, activating mutations in FGFR4 have been reported in rhabdomyosarcoma (Taylor et al. JCI 2009, 119:3395).

[0005] FGFR inhibitors are currently being developed for the treatment of cancer. For example, the molecule 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one and other small molecule inhibitors of FGFR are reported in, for example, U.S. Patent Publication Nos. 2012 / 0165305;2014-0045814;2013-0338134;2014 / 0171405;2014 / 0315902;2016 / 0115164;2016 / 0244448;2016 / 0244449;and 2016-0244450.

[0006] Therefore, novel or improved agents that inhibit FGFR remain needed to develop new and more effective medicines for treating cancer and other diseases. The compounds, including derivatives, compositions, and methods of these compounds described herein, are directed toward these needs and other purposes. [Overview of the project]

[0007] This disclosure, in particular, describes derivatives of compound I: [ka] or provide a pharmaceutically acceptable salt thereof.

[0008] This disclosure further relates to a pharmaceutical composition comprising the compounds of this disclosure or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

[0009] The disclosure further relates to a method for inhibiting an FGFR enzyme, comprising contacting the enzyme with a compound of the disclosure or a pharmaceutically acceptable salt thereof.

[0010] The Disclosure further relates to a method for treating a disease associated with abnormal activity or expression of FGFR enzymes, comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0011] This disclosure further relates to compounds of this disclosure for use in treating diseases associated with abnormal activity or expression of FGFR enzymes.

[0012] The Disclosure further relates to a method for treating a disorder mediated by an FGFR enzyme or a variant thereof in a patient in need thereof, the method comprising administering to the patient a compound of the Disclosure or a pharmaceutically acceptable composition thereof.

[0013] The Disclosure further relates to a method for treating a disorder mediated by an FGFR enzyme or a variant thereof in a patient in need thereof, the method comprising administering to the patient a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of the Disclosure or a pharmaceutically acceptable salt thereof, in combination with another therapy or therapeutic agent described herein.

[0014] This disclosure further relates to the use of the compounds of this disclosure in the preparation of pharmaceuticals for therapeutic use. [Brief explanation of the drawing]

[0015] [Figure 1] This graph shows the average cumulative percentage of radioactive doses recovered in urine and feces at specified intervals after a single oral administration of 13 mg (250 μCi) of compound [14C]1 to healthy male subjects. [Figure 2] This graph shows the mean radioactivity (nM equivalent) in blood or plasma and the amount of compound 1 (nM) in plasma after a single oral administration of approximately 13 mg of [14C] compound 1 to healthy male volunteers in a fasted state. [Figure 3] The mass spectrum of the human circulating metabolite of compound 1 is shown. [Figure 4] The mass spectrum of compound 1 metabolite isolated from urine is shown. [Figure 5] The mass spectrum of compound 1 metabolite isolated from feces is shown. [Modes for carrying out the invention]

[0016] This disclosure relates, in particular, to compounds that are derivatives of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (compound 1), as well as to processes and intermediates for preparing these derivatives. The structure of compound 1 is shown below. [ka]

[0017] Compound 1 is described in U.S. Patent No. 9,611,267, which is incorporated herein by reference in its entirety.

[0018] In some embodiments, this compound is a metabolite of compound 1. In some embodiments, this compound is an active metabolite that can modulate the activity of one or more FGFR proteins and may be useful, for example, in the treatment of diseases related to FGFR expression or activity. In some embodiments, the levels of the metabolites described herein are measured and profiled to assist healthcare providers in adjusting the dosage level of compound 1.

[0019] Therefore, this disclosure also relates to compounds of formula I: [ka] Alternatively, provide a pharmaceutically acceptable salt thereof, here: One or more OCH3 groups are optionally replaced with OH groups, and these OH groups are optionally replaced with OX groups. One CH group can be optionally replaced with a CX group. One CH2 group can be optionally replaced with a C=O group. One or more CH2 groups in the morpholine ring can be optionally replaced with C(OH)H groups. The NH group can be optionally replaced with an NX group, and Here, X is a base selected from the following: [ka] However, this compound has one or more groups selected from OH, OX, CX, C=O, and NX.

[0020] The present invention also relates to compounds of formula II: [ka] Alternatively, provide a pharmaceutically acceptable salt thereof, in the formula: One CH group can be optionally replaced with a CX group. One CH2 group can be optionally replaced with a C=O group. This NH group can be optionally replaced with an NX group, and This OH group can be optionally replaced with an OX group; Here, X is a base selected from the following: [ka] That is the case.

[0021] In some embodiments, the present invention relates to compounds of formula II: [ka] Alternatively, provide a pharmaceutically acceptable salt thereof in which one CH group is replaced with a CX group, an NH group is replaced with an NX group, or an OH group is replaced with an OX group; where X is a group selected from the following: [ka] That is the case.

[0022] In some embodiments, one or more OCH3 groups are optionally replaced with OH groups, which are optionally replaced with OX groups. In some embodiments, this OH group is optionally replaced with an OX group. In some embodiments, one CH group is optionally replaced with a CX group. In some embodiments, one CH2 group is optionally replaced with a C=O group. In some embodiments, this NH group is optionally replaced with an NX group. In some embodiments, one or more CH2 groups of the morpholine ring are optionally replaced with C(OH)H groups.

[0023] In some embodiments, one or more OCH3 groups are replaced with OH groups, where these OH groups are replaced with OX groups. In some embodiments, one or more OCH3 groups are replaced with OH groups. In some embodiments, these OH groups are replaced with OX groups. In some embodiments, one CH group is replaced with a CX group. In some embodiments, one CH2 group is replaced with a C=O group. In some embodiments, this NH group is replaced with an NX group. In some embodiments, one or more CH2 groups of the morpholine ring are each replaced with C(OH)H groups.

[0024] In some embodiments, X is [ka] In some embodiments, X is [ka] That is the case.

[0025] The present invention provides a compound that is 3-(2,6-difluoro-3-hydroxy-5-methoxyphenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (compound 2), or a pharmaceutically acceptable salt thereof. The structure of compound 2 is shown below: [ka] .

[0026] The present invention provides a compound that is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-4-hydroxy-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (compound 3), or a pharmaceutically acceptable salt thereof. The structure of compound 3 is shown below: [ka] .

[0027] The present invention provides a compound that is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (compound 4), or a pharmaceutically acceptable salt thereof. The structure of compound 4 is shown below. [ka] .

[0028] In some embodiments, this compound is selected from the following: 3-(2,6-difluoro-3-hydroxy-5-methoxyphenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one; and 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-4-hydroxy-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one, or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, this compound is a compound of formula I: [ka] Alternatively, a pharmaceutically acceptable salt thereof in which one CH2 group of the morpholine ring is replaced with a (C=O) group.

[0030] In some embodiments, this compound is a compound of formula (II): [ka] Alternatively, a pharmaceutically acceptable salt thereof in which one CH group is replaced by a CX group, an NH group is replaced by an NX group, or an OH group is replaced by an OX group; where X is one of the following groups: [ka] .

[0031] In some embodiments, the compound is the compound of formula (II): [ka] Alternatively, a pharmaceutically acceptable salt thereof in which one CH group is replaced by a CX group, an NH group is replaced by an NX group, or an OH group is replaced by an OX group; where X is one of the following groups: [ka] .

[0032] In some embodiments, the compound is a compound of formula I. [ka] Alternatively, a pharmaceutically acceptable salt thereof in which the two CH2 groups of the morpholine ring are each replaced by a C(OH)H group.

[0033] In some embodiments, the compound is the compound of formula I: [ka] Alternatively, a pharmaceutically acceptable salt thereof in which each OCH3 group is replaced by an OH group; and one CH2 group of the morpholine ring is replaced by a (C=O) group.

[0034] In some embodiments, this compound is the compound of formula II: [ka] Alternatively, a pharmaceutically acceptable salt thereof, in which one CH2 group of the morpholine ring is replaced by a (C=O) group.

[0035] Furthermore, the Specified also provides compounds that are 3-(2,6-difluoro-3-hydroxy-5-methoxyphenyl)-1-ethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-8-carboxylic acid (compound 5), or pharmaceutically acceptable salts thereof.

[0036] The structure of compound 5 is shown below: [ka] .

[0037] This specification also provides compounds that are 3-(2,6-difluoro-3,5-bis(methoxy-d3)phenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (compound 6), or pharmaceutically acceptable salts thereof. The structure of compound 6 is shown below: [ka] .

[0038] Each of the embodiments described above assumes that appropriate valence rules are being followed.

[0039] The specific compounds described herein are metabolites of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (compound 1). This metabolite was isolated from human blood / serum, urine, and fecal samples collected from pharmacokinetic and toxicological studies of compound 1. The metabolites of the present invention may also be FGFR inhibitors and may have advantageous properties (PK, PD, toxicity, etc.) compared to the parent compound (compound 1). For example, the metabolite of this disclosure (e.g., compound 2) may be a better substrate for Pgp transport compared to compound 1. Therefore, the metabolite of this disclosure (e.g., compound 2) may be a more suitable candidate for intravenous administration or hepatic arterial infusion for the treatment of the diseases and disorders disclosed herein (e.g., cholangiocarcinoma).

[0040] In some embodiments, the compounds of the present invention are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial isolation may include, for example, a composition in which the compounds of the present invention are concentrated. Substantially isolated may include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of metabolites.

[0041] This specification also provides compositions comprising the compound or a pharmaceutically acceptable salt thereof, comprising at least about 50% by weight of the compound or salt. In some embodiments, the composition comprises at least about 60% by weight of the compound or salt. In some embodiments, the composition comprises at least about 70% by weight of the compound or salt. In some embodiments, the composition comprises at least about 80% by weight of the compound or salt. In some embodiments, the composition comprises at least about 90% by weight of the compound or salt.

[0042] Preparation process of compound 2 This application further provides a process for preparing compound 2, which may be suitable for scale-up.

[0043] In this specification, compound 2 having the following formula: [ka] A process for preparing the salt thereof is provided, which is given by the following formula: [ka] or a compound F4 having a salt thereof, wherein P 1 This involves deprotecting compound F4, which is an amino protecting group. In some embodiments, P 1 is a sulfonamide group. In some embodiments, P 1 It is -SO2N(CH3)2.

[0044] In some embodiments, deprotection of compound F4 involves reacting compound F4 with A1, where A1 is an acid. In some embodiments, A1 is hydrochloric acid. In some embodiments, A1 is aqueous hydrochloric acid. In some embodiments, deprotection is carried out at 70–90°C (e.g., 80°C). In some embodiments, this deprotection is carried out in the presence of S1, where S1 is a polar aprotic solvent. In some embodiments, S1 is 1,4-dioxane. In some embodiments, deprotection of compound F4 involves using about 1 to about 50 molar equivalents of a deprotecting agent relative to compound F4, about 10 to about 30 molar equivalents of a deprotecting agent relative to compound F4, or about 20 molar equivalents of a deprotecting agent relative to compound F4.

[0045] Compound F4 or its salt is compound F3 having the following formula: [ka] Alternatively, the salt may be produced by a process comprising reacting morpholine in the presence of RA1, where RA1 is a reducing agent. In some embodiments, RA1 is sodium triacetoxyborohydride. In some embodiments, the reaction of compound F3 with RA1 is carried out in the presence of an acid, A2. In some embodiments, A2 is an organic acid. In some embodiments, A2 is acetic acid. In some embodiments, the reaction of compound F3 with RA1 is carried out in the presence of a solvent, S2. In some embodiments, S2 is a polar aprotic solvent. In some embodiments, S2 is methylene chloride.

[0046] Compound F3 or its salt is compound F2 having the following formula: [ka] Alternatively, it can be produced by a process comprising reacting a salt thereof with DMF in the presence of a base B1. In some embodiments, B1 is lithium diisopropylamide ("LDA"). In some embodiments, the reaction of compound F2 with DMF in the presence of B1 is carried out in the presence of S3, where S3 is a polar aprotic solvent. In some embodiments, S3 is tetrahydrofuran. The reaction of compound F2 with DMF in the presence of B1 may be carried out at a temperature between about -100°C and about -50°C (e.g., about -64°C).

[0047] Compound F2 or its salt is compound F1 having the following formula: [ka] or its salt, P 1 It can be produced by a process that includes reacting it with an amino protective agent containing

[0048] In some embodiments, the aminoprotectant is P 1-X, where X is a halogen. In some embodiments, the amino protective agent is Me2NSO2Cl. The reaction between compound F1 and the amino protective agent may be carried out in the presence of B2, where B2 is a base. In some embodiments, B2 is a metal hydroxide base. In some embodiments, B2 is NaOH.

[0049] The reaction between compound F1 and the amino protective agent may be carried out in the presence of tetrabutylammonium hydrogen sulfate. In some embodiments, the reaction between compound F1 and the amino protective agent is carried out in the presence of S4, where S4 is a polar aprotic solvent. In some embodiments, S4 is tetrahydrofuran. In some embodiments, the reaction between compound F1 and the amino protective agent is carried out at a temperature of about 0°C to about 50°C (e.g., about 0°C to about 30°C).

[0050] In this specification, compound 2 having the following formula: [ka] or a process for preparing the salt thereof: a) Compound F1 having the following formula: [ka] And, P 1 A compound F2 having the following formula is obtained by reacting it with an amino protective agent containing: [ka] or to provide a salt thereof, wherein P 1 It is an amino protecting group; b) Compound F2 is reacted with DMF in the presence of B1, which is a base, to form compound F3 having the following formula: [ka] To provide a salt thereof; c) Reacting compound F3 with morpholine in the presence of RA1 as a reducing agent to provide a compound F4 having the following formula:

Chemical formula

[0051] Process for preparing compound 6 The present disclosure relates to a process for preparing compound 6 having the following formula:

Chemical formula

Chemical formula

[0052] The deprotection of compound F5 may include treating compound F5 with B3, where B3 is a base. In some embodiments, B3 is a metal hydroxide base. In some embodiments, B3 is NaOH. In some embodiments, B3 is aqueous NaOH. In some embodiments, the deprotection of compound F5 is carried out in the presence of S5, where S5 is 1,4-dioxane. In some embodiments, the reaction of compound F5 with B3 includes using about 1 to about 10 molar equivalents of B3 relative to compound F5, about 2 to about 8 molar equivalents of B3 relative to compound F5, or about 4 molar equivalents of B3 relative to compound F5.

[0053] Compound F5 is a compound F6 having the following formula:

Chemical formula

[0054] The reaction between compound F6 and CD3I may be carried out in the presence of a polar aprotic solvent, S6. In some embodiments, S6 is DMF. The reaction between compound F6 and CD3I may involve using about 1 to about 5 molar equivalents of CD3I, about 1 to about 3 molar equivalents of CD3I, or about 2 molar equivalents of CD3I relative to compound F6. The reaction between compound F6 and CD3I may involve using about 1 to about 10 molar equivalents of B4, about 2 to about 8 molar equivalents of B4, or about 4 to about 5 molar equivalents of B4 relative to compound F6.

[0055] Compound F6 is compound F7 having the following formula: [ka] It can be prepared by a process that includes reacting it with a Lewis acid, A3. In some embodiments, A3 is BBr3.

[0056] The reaction between compound F7 and A3 may be carried out in the presence of a polar aprotic solvent, S7. In some embodiments, S7 is methylene chloride. The reaction between compound F7 and A3 may be carried out at temperatures ranging from about -100°C to about 30°C (e.g., from about -100°C to room temperature). The reaction between compound F7 and A3 may involve using about 1 to about 20 molar equivalents of A3 relative to compound F7, about 5 to about 15 molar equivalents of A3 relative to compound F7, or about 8 to about 12 molar equivalents of A3 relative to compound F7.

[0057] This specification refers to compound 6 having the following formula: [ka] or a process for preparing the salt thereof: a) Compound F7 having the following formula: [ka] Then, react with the Lewis acid A3, and here P 2 is an amino protecting group, and compound F6 has the following formula: [ka] To provide a salt thereof; b) Compound F6 is reacted with CD3I in the presence of the base B4 to form compound F5 having the following formula: [ka] To provide a salt thereof; c) A process is provided which includes deprotecting compound F5 to provide compound 6 or a salt thereof.

[0058] The processes described herein may be monitored according to any suitable method known in the art. For example, the formation of the product may be monitored by spectroscopic means, e.g., nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C) can be monitored by infrared spectroscopy, spectrophotometric methods (e.g., UV-Vis light), or mass spectrometry; or by chromatography, e.g., high-performance liquid chromatography (HPLC) or thin-layer chromatography. The compounds obtained by the reaction can be purified by any suitable method known in the art. For example, chromatography (intermediate pressure), HPLC, or preparative thin-layer chromatography on a suitable adsorbent (e.g., silica gel, alumina, etc.); distillation; sublimation, titration, or recrystallization. The purity of the compound is generally determined by physical methods such as measuring the melting point (for solids), obtaining an NMR spectrum, or performing HPLC separation. A compound can be said to be purified if the melting point decreases, undesirable signals in the NMR spectrum decrease, or exogenous peaks in the HPLC trace are removed. In some embodiments, the compound is substantially purified.

[0059] The preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Greene's Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons: New York, 2006, which is incorporated herein by reference in its entirety. As used herein, “amino protecting group” refers to any protecting group for protecting an amine. Examples of amino protecting groups include phenylsulfonyl, benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-trifluoromethylphenylsulfonyl)ethoxycarbonyl (Tsc), t-butoxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpenta-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2 Examples include, but are not limited to, 2-trichloroethoxycarbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N',N'-dimethylhydrazinyl, methoxymethyl, t-butoxymethyl (Bum), benzyloxymethyl (BOM), or 2-tetrahydropyranyl (THP), tri(C1-4 alkyl)silyl (e.g., tri(isopropyl)silyl), 1,1-diethoxymethyl, or N-pivaloyloxymethyl (POM).

[0060] The reactions of the processes described herein may be carried out at appropriate temperatures that can be readily determined by those skilled in the art. The reaction temperature will depend, for example, on the melting and boiling points of the reagents and solvents (if any), the thermodynamics of the reaction (e.g., violently exothermic reactions may need to be carried out at lower temperatures), and the kinetics of the reaction (e.g., high activation energy barriers may require higher temperatures).

[0061] In some embodiments, the concentration of a solution as described herein refers to a solution whose volume is reduced by evaporating the solvent, by heating the solution, by applying a reduced pressure to the solution, or by any combination thereof.

[0062] The reactions of the processes described herein may be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially inactive with the starting materials (reactants), intermediates, or products at the temperature in which the reaction is carried out, which may range from the freezing temperature to the boiling temperature of the solvent. A given reaction may be carried out in one solvent or a mixture of two or more solvents. Depending on the specific reaction step, a solvent suitable for a particular reaction step may be selected. In some embodiments, the reaction may be carried out in the absence of a solvent, for example, when at least one of the reagents is a liquid or a gas.

[0063] Suitable solvents include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane (methylene chloride), tetrachloride, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, α,α,α-trifluorotoluene, 1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, and mixtures thereof.

[0064] Suitable ether solvents include dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, tetrahydrofuran (THF), diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether (diglym), diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, tert-butyl methyl ether, and mixtures thereof.

[0065] Suitable protic solvents include, but are not limited to, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, tert-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.

[0066] Suitable aprotic solvents include, but are not limited to, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.

[0067] Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-xylene, o-xylene, or p-xylene, octane, indan, nonane, or naphthalene.

[0068] The reactions of the processes described herein may be carried out in air or under an inert atmosphere. Typically, reactions involving reagents or products that are substantially reactive with air may be carried out using air-sensitive synthesis techniques well known to those skilled in the art.

[0069] The terms “ambient temperature” and “room temperature,” as used herein, are understood in the art and generally refer to a temperature, for example, the temperature of the room in which the reaction takes place, e.g., a reaction temperature close to a temperature of about 20°C to about 30°C. The term “high temperature,” as used herein, is understood in the art and generally refers to a temperature above room temperature, e.g., 30°C, e.g., a reaction temperature.

[0070] The compound F2 provided herein: [ka] or a salt thereof, in the formula, P 1 This is an amino protecting group.

[0071] In some embodiments, compound F2 has the following structure: [ka] or a salt thereof.

[0072] The compound F3 is provided herein: [ka] or a salt thereof, in the formula, P 1 This is an amino protecting group.

[0073] In some embodiments, compound F3 has the following structure: [ka] or a salt thereof.

[0074] The compound F4 is provided herein: [ka] or a salt thereof, in the formula, P 1 This is an amino protecting group.

[0075] In some embodiments, compound F4 has the following structure: [ka] or a salt thereof.

[0076] The compound F5 is provided herein: [ka] or a salt thereof, in the formula, P 2 This is an amino protecting group.

[0077] In some embodiments, compound F5 has the following structure: [ka] or a salt thereof.

[0078] The compound F6 is provided herein: [ka] or a salt thereof, in the formula, P 2 This is an amino protecting group.

[0079] In some embodiments, compound F6 has the following structure: [ka] or a salt thereof.

[0080] The compounds of this disclosure also include tautomers. Tautomers are obtained by the exchange of adjacent double and single bonds and the simultaneous transfer of protons. Examples of tautomers include prototropic tautomers, which are protonated states of isomers having the same empirical formula and total charge. Exemplary prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomers may be in equilibrium or may be sterically fixed into a single form by appropriate substitution.

[0081] The compounds of this disclosure also include all isotopes of atoms that occur in intermediate or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of this disclosure may be replaced or substituted with isotopes of atoms of natural or unnatural abundance. In some embodiments, the compound contains at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of this disclosure may be replaced or substituted with deuterium. In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopic-labeled compounds can be used in a variety of studies, including NMR spectroscopy, metabolic experiments, and / or assays.

[0082] Substitution with heavier isotopes, such as deuterium, may result in certain therapeutic benefits, such as increased half-life in vivo or reduced required doses, which may be preferable in some cases due to greater metabolic stability. (A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312).

[0083] When used herein, the term “compound” means all stereoisomers, geometric isomers, tautomers, and isotopes of the illustrated structure. The term also means any method of preparation, whether synthetic, biological (e.g., metabolic or enzymatic transformation), or a combination thereof.

[0084] How to use The compounds described herein may inhibit the activity of FGFR enzymes. For example, the compounds of this disclosure may be used to inhibit the activity of FGFR enzymes in cells, individuals, or patients where enzyme inhibition is required, by administering an inhibitory dose of the compound to cells, individuals, or patients.

[0085] As FGFR inhibitors, the compounds of this disclosure are useful for treating a variety of diseases associated with abnormal expression or activity of FGFR enzymes or FGFR ligands. Compounds that inhibit FGFR may be useful in providing a means of preventing tumor growth or inducing apoptosis, particularly by inhibiting angiogenesis. Therefore, it is expected that the compounds of this disclosure will prove useful in treating or preventing proliferative disorders such as cancer. In particular, tumors with activating mutants of receptor tyrosine kinases or upregulation of receptor tyrosine kinases may be especially sensitive to inhibitors.

[0086] In certain embodiments, the Disclosure provides a method for treating FGFR-mediated disorders in a patient in need thereof, the method comprising the step of administering to the patient a compound of the Disclosure or a pharmaceutically acceptable composition thereof.

[0087] For example, the compounds of this disclosure are useful in the treatment of cancer. Examples of cancer include bladder cancer, breast cancer (e.g., hormone receptor R positive, triple negative), cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, gastric cancer (e.g., gastrointestinal stromal tumor), head and neck cancer (e.g., larynx, hypopharynx, nasopharynx, oropharynx, lip, mouth cancer, head and neck squamous cell carcinoma), kidney cancer (e.g., renal cell carcinoma, urothelial carcinoma, sarcoma, Wilms' tumor), liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma, hepatic angiosarcoma, hepatoblastoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer, and Examples include non-small cell lung cancer, small cell and non-small cell lung cancer, bronchial cancer, bronchial adenoma, pleuroblastoma, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), gastric cancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer (e.g., pheochromocytoma, Merkel cell carcinoma, neuroendocrine carcinoma), skin cancer (e.g., squamous cell carcinoma, Kaposi's sarcoma, Merkel cell carcinoma), and brain tumors (e.g., astrocytoma, medulloblastoma, ependymoma, neuroexocrine tumor, pineal gland tumor).

[0088] Further examples of cancer include hematopoietic malignancies, such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myeloid leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma, myeloproliferative neoplasms (e.g., 8p11 myeloproliferative syndrome, polycythemia, essential thrombocythemia, and primary myelofibrosis), myelodysplastic syndromes, chronic eosinophilic leukemia, Waldenström macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-associated lymphoma, and Burkitt's disease.

[0089] In certain embodiments, what is provided herein is a method for treating a myeloid / lymphoid neoplasm in a patient in need thereof. In certain embodiments, the myeloid / lymphoid neoplasm is 8p11 myeloproliferative syndrome. As used herein, the term “8p11 myeloproliferative syndrome” (EMS) means a myeloid / lymphoid neoplasm associated with eosinophilia and abnormalities of FGFR1, or a myeloid / lymphoid neoplasm (MLN) with FGFR1 rearrangement. 8p11 myeloproliferative syndrome is outlined in Jackson, Courtney C., et al. Human Pathology, 2010, 41, 461-476. Characterization of EMS is the presence of translocations involving the FGFR1 gene at the chromosome 8p11 locus, with at least 10 additional translocations and 1 insertion identified in EMS, each disrupting FGFR1 and creating novel fusion genes with various partners. See Jackson, Courtney C., et al., Human Pathology, 2010, 41, 461-476.

[0090] In some embodiments, myeloid / lymphoid neoplasms are characterized by FGF / FGFR gene alterations. Gene alterations may include mutations, fusions, rearrangements (e.g., translocations, deletions, inversions), and gene amplifications. In certain embodiments, myeloid / lymphoid neoplasms exhibit FGFR1 fusions. FGFR1 fusions may be translocations, stromal deletions, or chromosomal inversions. In some embodiments, FGFR1 fusions are FGFR1 translocations. In certain embodiments, myeloid / lymphoid neoplasms exhibit 8p11 translocations. In certain embodiments, 8p11 translocations are associated with FGFR1 activation. In some embodiments, myeloid / lymphoid neoplasms exhibit FGF / FGFR alterations other than FGFR1 translocations. In certain embodiments, the patient has failed at least one prior treatment for myeloid / lymphoid neoplasm (e.g., 8p11 myeloproliferative syndrome). In some embodiments, the prior treatment is surgery or radiotherapy. In some embodiments, the patient has a history of hepatitis. In some embodiments, the hepatitis is chronic hepatitis B or hepatitis C. In some embodiments, the patient has no history of hepatitis.

[0091] In certain embodiments, what is provided herein is a method for treating cancer, comprising administering a therapeutically effective amount of the compound disclosed herein to a patient in need thereof. In certain embodiments, cancer is selected from bladder cancer, breast cancer, cervical cancer, small intestine cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, brain cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma, Waldenström macroglobulinemia, myeloproliferative neoplasm, chronic myeloid lymphoma, acute lymphoblastic lymphoma, T-lymphoblastic lymphoma, hairy cell lymphoma, Burkitt lymphoma, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma.

[0092] In certain embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma, squamous cell carcinoma, adenocarcinoma).

[0093] In certain embodiments, liver cancer is cholangiocarcinoma (e.g., intrahepatic, hilar or perihilar, distal extrahepatic). As used herein, cholangiocarcinoma is the same as cholangiocarcinoma or bile duct cancer. In certain embodiments, bile duct cancer is advanced or metastatic bile duct cancer. In certain embodiments, bile duct cancer is surgically unresectable. In certain embodiments, bile duct cancer is intrahepatic. In certain embodiments, bile duct cancer is extrahepatic. In certain embodiments, bile duct cancer exhibits an FGFR2 tyrosine kinase fusion that defines a particular molecular subtype, as described in Arai, Yasuhito, et al. Hepatology, 2014, 59, 1427-1434. In some embodiments, bile duct cancer is characterized by an FGF / FGFR gene-modified tumor. In some embodiments, this tumor exhibits an FGFR2 fusion. The FGFR2 fusion may be a translocation, stromal deletion, or chromosomal inversion. In some embodiments, FGFR2 fusion is an FGFR2 translocation. FGFR2 translocations may be selected from a group including, but not limited to, FGFR2-BICC1, FGFR2-AHCYL1, FGFR2-MACF1, and FGFR2 intron 17 rearrangements. In some embodiments, the tumor exhibits FGF / FGFR changes other than FGFR2 translocations. In some embodiments, cholangiocarcinoma does not exhibit FGF / FGFR gene-modified tumors.

[0094] Other cancers treatable with the compounds of this disclosure include tumors of the eye, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, leiomyosarcoma, urothelial carcinoma (e.g., ureter, urethra, bladder, urachus), and osteosarcoma.

[0095] The compounds disclosed herein may also be useful in inhibiting tumor metastasis.

[0096] In some embodiments, the compounds of the present disclosure may be used to treat Alzheimer's disease, HIV, or tuberculosis.

[0097] In addition to oncogenic neoplasms, the compounds of this disclosure may be useful in the treatment of skeletal and chondrocyte disorders, including but not limited to achondroplasia, hypochondrosis, dwarfism, thanatophoric dysplasia (TD) (clinical forms TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Behle-Stevenson gyriform scalp syndrome, Pfeiffer syndrome, and craniosynostosis syndrome.

[0098] The compounds provided herein may also be useful in the treatment of fibrotic diseases, such as when the symptoms or impairments of the disease are characterized by fibrosis. Examples of fibrotic diseases include cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and wound healing.

[0099] In some embodiments, the compounds provided herein can be used to treat hypophosphatemic disorders such as X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, or tumor-induced osteomalacia.

[0100] In some embodiments, provided herein are methods for increasing a patient's survival or progression-free survival, comprising administering a compound provided herein to the patient. In some embodiments, the patient has cancer. In some embodiments, the patient has a disease or disorder described herein. In some embodiments, the patient has cholangiocarcinoma. In some embodiments, provided herein are methods for increasing a patient's survival or progression-free survival, wherein the cholangiocarcinoma is characterized by FGFR2 fusion, comprising administering a compound provided herein to the patient. As used herein, progression-free survival refers to the length of time during and after treatment of a solid tumor in which the patient lives with the disease but does not worsen. Progression-free survival refers to the time from the first administration of the compound to death or disease progression, whichever comes first. Disease progression can be defined by RECIST v.1.1 (Solid Tumor Response Assessment Criteria) as assessed by an independent Central Institutional Review Board. In some embodiments, administration of the compound results in progression-free survival of approximately 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 9 months, 12 months, 16 months, or more than 24 months. In some embodiments, administration of the compound results in progression-free survival of at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 9 months, or 12 months; and less than 24 months, 16 months, 12 months, 9 months, 8 months, 6 months, 5 months, 4 months, 3 months, or less than 2 months. In some embodiments, administration of the compound results in an increase in progression-free survival of at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months.

[0101] As used herein, the term “cell” means a cell that is in vitro, ex vivo, or in vivo. In some embodiments, ex vivo cells may be part of a tissue sample excised from an organism such as a mammal. In some embodiments, in vitro cells may be cells in a cell culture. In some embodiments, in vivo cells are cells residing in an organism such as a mammal.

[0102] As used herein, the term “contact” refers to bringing together the indicated parts in an in vitro or in vivo setting. For example, “contact” an FGFR enzyme with a compound described herein (e.g., Compound 1) includes administering the compound described herein to an individual or patient, such as a human, who has FGFR, and introducing the compound described herein (e.g., Compound 1) into a sample, for example, a cell preparation or purified preparation containing an FGFR enzyme.

[0103] As used herein, the terms “individual” or “patient” are interchangeable and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans.

[0104] As used herein, the term “therapeutically effective amount” means the amount of an active compound or pharmaceutical product that elicits a desired biological or pharmacokinetic response in a tissue, system, animal, individual, or human, eliciting, for example, any solid form thereof or a salt thereof disclosed herein. The appropriate “effective” amount in any individual case can be determined using techniques known to those skilled in the art.

[0105] As used herein, the term “pharmaceutically acceptable” means those compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, within the bounds of safe medical judgment, and corresponding to a reasonable benefit-to-risk ratio.

[0106] As used herein, the phrase “pharmaceutically acceptable carrier or excipient” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers include those that are generally safe and non-toxic, not biologically or otherwise undesirable, and are acceptable for veterinary and human pharmaceutical applications. In one embodiment, each component is “pharmaceutically acceptable” as defined herein. For example, Remington:The Science and Practice of Pharmacy,21st ed.;Lippincott Williams & Wilkins:Philadelphia,Pa.,2005;Handbook of Pharmaceutical Excipients,6th ed.;Rowe et al.,Eds.;The Pharmaceutical Press and the American Pharmaceutical Association:2009;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0107] As used herein, the terms “to treat” or “to cure” mean to inhibit a disease, for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or total symptoms of a disease, condition, or disorder (i.e., halting the further development of the pathology and / or total symptoms), or to improve a disease, for example, improving a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or total symptoms of a disease, condition, or disorder (i.e., reversing the pathology and / or total symptoms), for example, reducing the severity of the disease.

[0108] For clarity, it is understood that certain features of the Disclosure described in the context of separate embodiments may also be combined and provided in a single embodiment (whereas these embodiments are intended to be combined as if described in a multiple dependency). Conversely, various features of the Disclosure described in a single embodiment for the sake of brevity may be provided separately or as any suitable partial combination.

[0109] Combination therapy One or more additional pharmaceuticals or treatments, such as antiviral agents, chemotherapeutic agents or other anticancer agents, immunoenhancing agents, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapies (e.g., IL-2, GM-CSF, etc.), and / or tyrosine kinase inhibitors, may be used in combination with the compounds described herein for the treatment of FGFR-related diseases, disorders, or conditions, or the diseases or conditions described herein. These agents may be used in combination with the compounds in a single dosage form, or they may be administered simultaneously or sequentially in separate dosage forms.

[0110] The compounds described herein may be used in combination with one or more other kinase inhibitors for the treatment of diseases such as cancer, which are affected by multiple signaling pathways. For example, combinations may include one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FL K-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. Furthermore, the solid forms of the FGFR inhibitors described herein may be combined with inhibitors of kinases associated with the PIK3 / Akt / mTOR signaling pathway, such as PI3K, Akt (including Akt1, Akt2, and Akt3), and mTOR kinases.

[0111] In some embodiments, the compounds described herein may be used in combination with one or more inhibitors of enzymes or protein receptors such as HPK1, SBLB, TUT4, A2A / A2B, CD47, CDK2, STING, ALK2, LIN28, ADAR1, MAT2a, RIOK1, HDAC8, WDR5, SMARCA2, and DCLK1 for the treatment of diseases and disorders. Exemplary diseases and disorders include cancer, infections, inflammation, and neurodegenerative disorders.

[0112] In some embodiments, the compounds described herein may be used in combination with therapeutic agents that target epigenetic regulators. Examples of epigenetic regulators include bromodomain inhibitors, histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, and DNA methyltransferases. An example of a histone deacetylase inhibitor is vorinostat.

[0113] For the treatment of cancer and other proliferative disorders, the compounds described herein include JAK kinase inhibitors (ruxolitinib, additional JAK1 / 2 and JAK1-selective, baricitinib or INCB39110), Pim kinase inhibitors (e.g., LGH447, INCB053914, and SGI-1776), PI3 kinase inhibitors, e.g., PI3K-δ selective and broad-spectrum PI3K inhibitors (e.g., INCB50465 and INCB54707), PI3K-γ inhibitors, e.g., PI3K-γ selective inhibitors, MEK inhibitors, CSF1R inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinase inhibitors (Tyro-3, Axl, and Mer; e.g., INCB81776), angiogenesis inhibitors, interleukin receptor inhibitors, cyclin-dependent kinase inhibitors, and BRAF inhibitors. It may be used in combination with BTK inhibitors such as mTOR inhibitors, proteasome inhibitors (bortezomib, carfilzomib), HDAC inhibitors (panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo and specific terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, e.g., OTX015, CPI-0610, INCB54329 or INCB57643), LSD1 inhibitors (e.g., GSK2979552, INCB59872 and INCB60003), arginase inhibitors (e.g., INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat, NLG919 or BMS-986205), PARP inhibitors (e.g., olaparib or rucaparib), and ibrutinib. Furthermore, to treat cancer and other proliferative disorders, the compounds described herein may be used in combination with targeted therapies such as, for example, c-MET inhibitors (e.g., capmatinib), anti-CD19 antibodies (e.g., tafacitamab), ALK2 inhibitors (e.g., INCB00928); or combinations thereof.

[0114] For the treatment of cancer and other proliferative disorders, the compounds described herein may be used in combination with chemotherapeutic agents, nuclear receptor agonists or antagonists, or other antiproliferative agents. The compounds described herein may also be used in combination with medical therapies such as surgery or radiotherapy, e.g., gamma radiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, close-range radiotherapy, and systemic radioactive isotopes.

[0115] Examples of appropriate chemotherapeutic agents include avalerix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amidox, amsacrin, anastrozole, aphydicolone, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide, bleomycin, bortezombie, bortezomib, brivanib, buparlisib, intravenous busulfan, oral busulfan, carsterone, and camptosar L, capecitabine, carboplatin, carmustine, cedilanib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin difutitox, deoxycoformycin, dexrazoxane, zidox, docetaxel, doxorubicin, droloxafin, dromostanolone propionate, Eculizumab, Enazalutamide, Epidophyllotoxin, Epirubicin, Epothiron, Erlotinib, Estramustine, Etoposide Phosphate, Etoposide, Exemestane, Fentanyl Citrate, Filgrastim, Furoxuridine, Fludarabine, Fluorouracil, Flutamide, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab Ozogamicin, Goserelin Acetate, Histrelin Acetate, Ibritumomab Tiuxetan, Idarubicin, Idelalisib, Ifosfamide, Imatinib Mesylate, Interferon Alpha 2a, Irinoteca N, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisol, ronafarnib, lomustine, mechloretamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitaramycin, mitomycin C, mitotane, mitoxantrone, nandrolone fenpropionate, nevelben, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab,Panobinostat, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pyraralisib, pipobromane, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib, reloxafine, levlimide, rituximab, rucaparib, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, Examples include tegafur, temozolomide, teniposide, testactone, tezacitabine, thalidomide, thioguanine, thiotepa, tipifarnib, topotecan, toremifene, tocitumomab, trastuzumab, tretinoin, triapine, trimidox, triptorelin, uracil mustard, barrubicin, vandetanib, vinblastine, vincristine, vindesine, vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

[0116] In some embodiments, the compounds described herein may be used in combination with immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3 (e.g., INCAGN2385), TIM3 (e.g., INCB2390), VISTA, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulating checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40 (e.g., INCAGN1949), GITR (e.g., INCAGN1876), and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

[0117] In some embodiments, the inhibitor of the immune checkpoint molecule is a small molecule PD-L1 inhibitor. In some embodiments, the small molecule PD-L1 inhibitor has an IC50 of less than 1 μM, less than 100 nM, less than 10 nM, or less than 1 nM in the PD-L1 assay described in U.S. Patent Application Publications 20170107216, 20170145025, 20170174671, 20170174679, 20170320875, 20170342060, 20170362253, and 20180016260, each of which is incorporated by reference as a whole for all purposes.

[0118] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-1 inhibitor, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012 (retifan limab), nivolumab, pembrolizumab (also known as MK-3475), pizilizumab, SHR-1210, PDR001, ipilumimab, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD1 antibody is nivolumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012 (retifan limab). In some embodiments, the anti-PD1 antibody is SHR-1210. Other anticancer drugs (multiple options are possible) include antibody therapies such as 4-1BB (e.g., urelumab, utomirumab).

[0119] In some embodiments, the compounds of this disclosure may be used in combination with INCB086550.

[0120] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-L1 inhibitor, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

[0121] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0122] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, for example, an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

[0123] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, for example, an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0124] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.

[0125] In some embodiments, the inhibitor of the immune checkpoint molecule is an OX40 agonist, such as an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383.

[0126] In some embodiments, the inhibitor of the immune checkpoint molecule is a CD20 inhibitor, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0127] The compounds of this disclosure may be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or the TGFβ receptor.

[0128] In some embodiments, the compounds of the present disclosure may be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitors are inhibitors of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196.

[0129] In some embodiments, the compounds described herein may be used in combination with one or more agents for the treatment of diseases such as cancer. In some embodiments, the agents are alkylating agents, proteasome inhibitors, corticosteroids, or immunomodulators. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulator is lenalidomide (LEN) or pomalidomide (POM).

[0130] Suitable antiviral agents intended for use in combination with the compounds of this disclosure may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral agents.

[0131] Examples of appropriate non-reactive antibiotics (NRTIs) include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stabudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emtricitabine [(-)-FTC]; beta-L-FD4 (also known as beta-L-D4C, and called beta-L-2',3'-dicreoxy-5-fluorocytidene); DAPD, ((-)-beta-D-2,6,-diaminopurine dioxolane); and rhodenosine (FddA). Typical appropriate NNRTIs include nevirapine (BI-RG-587); delavirazine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Typical appropriate protease inhibitors include saquinavir (Ro Examples include 31-8959); ritonavir (ABT-538); indinavir (MK-639); nerufnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafusid, and Yissum project number 11607.

[0132] Suitable agents for use in combination with the compounds described herein for the treatment of cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapies, or radiotherapy. The compounds described herein may be effective in combination with antihormone agents for the treatment of breast cancer and other tumors. Suitable examples include anti-estrogen agents, including but not limited to tamoxifen and toremifene; aromatase inhibitors, including but not limited to letrozole, anastrozole, and exemestane; adrenocorticosteroids (e.g., prednisone); progestins (e.g., megastrol acetate); and estrogen receptor antagonists (e.g., fulvestrant). Suitable antihormone agents used for the treatment of prostate cancer and other cancers may also be used in combination with the compounds described herein. These include, but are not limited to, antiandrogens including flutamide, bicalutamide, and nilutamide; luteinizing hormone-releasing hormone (LHRH) analogs including leuprolide, goserelin, triptorelin, and histrelin; LHRH antagonists (e.g., degarelix); androgen receptor blockers (e.g., enzalutamide); and agents that inhibit androgen production (e.g., abiraterone).

[0133] The compounds described herein may be used in combination with, or sequentially with, other agents against membrane receptor kinases, particularly for patients who have developed primary or acquired resistance to targeted therapy. These therapeutic agents include inhibitors or antibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3, as well as cancer-related fusion protein kinases such as Bcr-Abl and EML4-Alk. Inhibitors against EGFR include, but are not limited to, gefitinib and erlotinib, and inhibitors against EGFR / Her2 include, dacomitinib, afatinib, rapitinib, and neratinib. Antibodies against EGFR include, but are not limited to, cetuximab, panitumumab, and nesitumumab. Inhibitors of c-Met may be used in combination with FGFR inhibitors. These include onaltumuzumab, tivantinib, and INC-280. Drugs for Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib, while drugs for Alk (or EML4-ALK) include crizotinib.

[0134] Angiogenesis inhibitors, in combination with FGFR inhibitors, may be effective in some tumors. These include antibodies against VEGF or VEGFR, or kinase inhibitors of VEGFR. Examples of antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. Examples of VEGFR kinase and other anti-angiogenic inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0135] Activation of intracellular signaling pathways frequently occurs in cancer, and drugs targeting components of these pathways are combined with receptor targeting agents to enhance efficacy and reduce resistance. Examples of drugs that can be combined with the compounds described herein include inhibitors of the PI3K-AKT-mTOR pathway, the Raf-MAPK pathway, the JAK-STAT pathway, and inhibitors of protein chaperones and cell cycle progression.

[0136] Examples of PI3 kinase inhibitors include, but are not limited to, topiralilisib, idelalisib, and buparlisib. mTOR inhibitors such as rapamycin, sirolimus, temsirolimus, and everolimus may be used in combination with FGFR inhibitors. Other preferred examples, but are not limited to, vemurafenib and dabrafenib (Raf inhibitors), as well as trametinib, selumetinib, and GDC-0973 (MEK inhibitors). One or more JAK inhibitors (e.g., ruxolitinib, baricitinib, tofacitinib), Hsp90 inhibitors (e.g., tanespimycin), cyclin-dependent kinase inhibitors (e.g., palbociclib), HDAC inhibitors (e.g., panobinostat), PARP inhibitors (e.g., olaparib), and proteasome inhibitors (e.g., bortezomib, carfilzomib) may be combined with the compounds described herein. In some embodiments, the JAK inhibitors are more selective for JAK1 than for JAK2 and JAK3.

[0137] Other suitable agents for use in combination with the compounds described herein include platinum-based doublets used for lung cancer and other solid tumors (cisplatin or carboplatin + gemcitabine; cisplatin or carboplatin + docetaxel; cisplatin or carboplatin + paclitaxel; cisplatin or carboplatin + pemetrexed), or combinations of chemotherapy such as gemcitabine + paclitaxel conjugate particles (Abraxane®).

[0138] Suitable chemotherapeutic agents or other anticancer agents include, for example, alkylating agents (including, but not limited to, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosourea, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (cytoxane®), ifosfamide, melphalan, chlorambucil, pipobromane, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0139] Other suitable agents for use in combination with the compounds described herein include steroids, specifically 17-alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, and medroxyprogesterone acetate.

[0140] Other suitable agents for use in combination with the compounds described herein include, optionally, dacarbazine (DTIC) with other chemotherapeutic agents such as carmustine (BCNU) and cisplatin; the “Dartmouth regimen” consisting of DTIC, BCNU, cisplatin, and tamoxifen; a combination of cisplatin, vinblastine, and DTIC; or temozolomide. The compounds described herein may also be combined with immunotherapeutic agents containing cytokines such as interferon alpha, interleukin-2, and tumor necrosis factor (TNF).

[0141] Suitable chemotherapeutic agents or other anticancer agents include, for example, antimetabolites (including, but not limited to, folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, phloxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0142] Appropriate chemotherapeutic agents or other anticancer agents include certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TAXOL®), mitramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferon (especially IFN-α), etoposide, and teniposide.

[0143] Other cytotoxic agents include navelben, CPT-11, anastrozole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosfamide, and droloxafine.

[0144] Further appropriate are cytotoxic agents such as epidophyllotoxin; antitumor enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum-coordinated complexes such as cisplatin and carboplatin; biological reaction modifiers; growth inhibitors; antihormone drugs; leucovorin; tegafur; and hematopoietic growth factors.

[0145] Other anticancer drugs (multiple options are possible) include antibody therapies such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4, 4-1BB, PD-L1, and PD-1 antibodies, or antibodies against cytokines (IL-10, TGF-β, etc.).

[0146] Other anticancer agents include those that inhibit the migration of immune cells, such as antagonists to chemokine receptors like CCR2 and CCR4.

[0147] Other anticancer agents include immune system enhancers such as adjuvants or adoptive T-cell transplants.

[0148] Examples of anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. In some embodiments, examples of tumor vaccines include proteins derived from viruses involved in human cancer, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's sarcoma herpesvirus (KHSV). Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as gp100, MAGE antigens, Trp-2, MART1, and / or peptides of tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0149] The compounds of the present disclosure can be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0150] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard literature. For example, many administrations of chemotherapeutic agents are described in the "Physicians’ Desk Reference" (PDR, e.g., the 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if fully set forth.

[0151] As provided throughout, additional compounds, inhibitors, agents, etc. may be combined with the present compounds in a single or continuous dosage form, or they may be administered simultaneously or sequentially as separate dosage forms.

[0152] Pharmaceutical Preparations and Dosage Forms In some embodiments, the compounds of the present disclosure or their pharmaceutical compositions are suitable for oral administration. In some embodiments, the compounds of the present disclosure or their pharmaceutical compositions are suitable for intravenous administration. In some embodiments, the compounds of the present disclosure or their pharmaceutical compositions are suitable for arterial administration. In some embodiments, the arterial administration is hepatic artery infusion.

[0153] When used as a pharmaceutical, the compounds described herein may be administered in the form of a pharmaceutical composition, which refers to a combination of one or more of the compounds described herein and at least one pharmaceutically acceptable carrier. The pharmaceutical composition of this disclosure may contain 20% by weight of the compound or a salt thereof. The pharmaceutical composition of this disclosure may contain 30% by weight of the compound or a salt thereof. The pharmaceutical composition of this disclosure may contain 40% by weight of the compound or a salt thereof. The pharmaceutical composition of this disclosure may contain 50% by weight of the compound or a salt thereof. The pharmaceutical composition of this disclosure may contain 60% by weight of the compound or a salt thereof. The pharmaceutical composition of this disclosure may contain 70% by weight of the compound or a salt thereof. The pharmaceutical composition of this disclosure may contain 80% by weight of the compound or a salt thereof. The pharmaceutical composition of this disclosure may contain 90% by weight of the compound or a salt thereof. The pharmaceutical composition of this disclosure may contain 95% by weight of the compound or a salt thereof. The pharmaceutical composition of this disclosure may contain 99% by weight of the compound or a salt thereof.

[0154] These compositions may be prepared in a manner well known in the pharmaceutical field and may be administered by various routes depending on whether a topical or systemic treatment is desired and the area to be treated. Administration may be topical (including transmucosal, intranasal, intravaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powder or aerosol, including by a sprayer; intratracheal, intranasal, epithelial, and transdermal), ocular, oral, or parenteral. Methods of ocular delivery may include topical administration (ophthalmic instillation), subconjunctival, periorbital, or intravitreal injection, or introduction by a balloon catheter or ocular implant surgically placed in the conjunctival sac. Parenteral administration may include intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous bases, powder bases, or oily bases, thickeners, etc., may be essential or desirable.

[0155] This disclosure also includes pharmaceutical compositions containing the compounds of this disclosure as active ingredients in combination with one or more pharmaceutically acceptable carriers. When preparing the compositions described herein, the active ingredient is typically mixed with an excipient, diluted by the excipient, or encapsulated in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. Where the excipient functions as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid media), for example, ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaging powders containing up to 10% by weight of the active compound.

[0156] When preparing a formulation, the active compound may be ground to provide an appropriate particle size before being combined with other components. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by grinding to result in a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0157] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may further contain lubricants, wetting agents, emulsifiers and suspending agents such as talc, magnesium stearate, and mineral oil, preservatives such as methyl benzoate and propyl hydroxybenzoate, sweeteners, and flavorings. The compositions described herein may be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient using procedures known in the art.

[0158] The composition may be formulated in unit dosage forms, each dose containing approximately 5 to approximately 100 mg, more typically approximately 10 to approximately 30 mg, of the active ingredient. The term "unit dosage form" refers to a physically distinct unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect in relation to a suitable pharmaceutically acceptable excipient.

[0159] Since active compounds can be effective across a wide range of doses, they are generally administered in pharmacologically effective amounts. However, it should be understood that the actual amount of compound administered is usually determined by the physician, taking into account relevant circumstances including the symptoms being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight, and response, and the severity of the patient's symptoms.

[0160] To prepare solid compositions such as tablets, the main active ingredient is mixed with pharmaceutically acceptable excipients to form a solid pre-formulation composition containing a homogeneous mixture of the compounds of the present disclosure. When these pre-formulation compositions are referred to as homogeneous, the active ingredient is typically uniformly dispersed throughout the composition, thereby allowing the composition to be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid pre-formulation is then subdivided into, for example, the aforementioned unit dosage forms containing about 0.1 to about 500 mg of the active ingredient of the present disclosure.

[0161] The tablets or pills of this disclosure may be coated or otherwise formulated to provide a dosage form that offers the benefit of long-term action. For example, the tablets or pills may contain internal and external dose components, the latter in the form of an envelope over the former. The two components may be separated by an enteric coating that resists disintegration in the stomach and allows the internal component to pass intact into the duodenum or delays its release. A variety of substances, including numerous polymer acids, as well as mixtures of polymer acids with substances such as shellac, cetyl alcohol, and cellulose acetate, can be used as such enteric coatings or coatings.

[0162] Liquid forms in which the compounds of this disclosure, or compositions described herein, may be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0163] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous solvents or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered by oral or nasal respiratory pathways for topical or systemic effects. Compositions may be sprayed using an inert gas. The sprayed solution may be inhaled directly from a spraying device, or the spraying device may be attached to a facial mask tent or intermittent positive airway pressure (CPAP) device. Compositions in solution, suspension, or powder form may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0164] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration (such as prevention or treatment), the patient's condition, and the method of administration. For therapeutic use, the composition may be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially prevent the symptoms and complications of the disease. The effective dose depends on the patient's medical condition and the severity of the disease, as well as the physician's judgment based on factors such as the patient's age, weight, and overall health.

[0165] The compositions administered to the patient may be in the form of the pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or aseptically filtered. Aqueous solutions may be packaged for immediate use or lyophilized, and the lyophilized preparations may be combined with a sterile aqueous carrier before administration. The pH of the compound preparations will typically be 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be understood that formulations of pharmaceutical salts can be obtained by using certain aforementioned excipients, carriers, or stabilizers.

[0166] The therapeutic doses of the compounds described herein may vary depending, for example, the specific use of the treatment, the method of administration of the compound, the patient's health and condition, and the judgment of the prescribing physician. The ratio or concentration of the compounds described herein in a pharmaceutical composition may vary depending on many factors, including the dose, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds described herein can be provided for parenteral administration in aqueous physiological buffer solutions containing about 0.1 to about 10% w / v of the compound. Some typical dose ranges are about 1 μg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dose range is about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. The dose may depend on variables such as the type and progression of the disease or disorder, the overall health status of the particular patient, the relative bioefficacy of the selected compound, the formulation of the excipients, and the route of administration. The effective dose may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0167] The compounds of this disclosure may also be formulated in combination with one or more further active ingredients, which may include any pharmaceutical product such as antiviral agents, vaccines, antibodies, immunostimulants, immunosuppressants, and anti-inflammatory agents. [Examples]

[0168] The experimental procedure for the compounds of the present invention is provided below. Partial LC-MS purification of the prepared compounds was performed using Waters mass fractionation systems. The basic instrument setup, protocols, and control software for operating these systems are described in detail in the literature. For example, see "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds were typically subjected to analytical liquid chromatography-mass spectrometry (LCMS) for purity analysis under the following conditions: Instrument: Agilent 1100 series, LC / MSD; Column: Waters Sunfire® C 18 5 μm, 2.1 × 50 mm; buffer: mobile phase A: 0.025% TFA in water, and mobile phase B: acetonitrile; flow rate 2.0 mL / min, gradient of B from 2% to 80% over 3 minutes.

[0169] Furthermore, some of the prepared compounds were separated on a preparative scale by reversed-phase high-performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) with the MS detector shown in the examples. Typical preparative reversed-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows: Purification at pH=2: Waters Sunfire (trademark) C 185 μm, 19 x 100 mm column, eluted with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile, flow rate was 30 mL / min, and the separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874 - 883 (2004)]. Typically, the flow rate used for a 30 x 100 mm column was 60 mL / min.

[0170] Purification at pH = 10: Waters XBridge C 18 5 μm, 19 × 100 mm column, eluted with mobile phase A: 0.15% NH4OH in water and mobile phase B: acetonitrile, flow rate was 30 mL / min, and the separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874 - 883 (2004)]. Typically, the flow rate used for a 30 x 100 mm column was 60 mL / min.

[0171] Example 1 Synthesis of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one (Compound 1)

Chemical Structure

[0172] Step 1: Synthesis of 4-((4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-yl)methyl)morpholine In a 1 L flask, 4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (50.0 g, 137 mmol) (see, e.g., Example 2) and tetrahydrofuran (THF, 266 g, 300 mL) were added under N2 conditions. To this mixture at -70°C, 2.0 M lithium diisopropylamide (77.4 g, 95 mL, 190 mmol, 1.4 equivalents) in THF / heptane / ethylbenzene was added. The mixture was stirred at -70°C for 1 hour. To this mixture, N-formylmorpholine (29.7 g, 258 mmol, 1.9 equivalents) in THF (22.2 g, 25 mL) was added dropwise. The reaction was carried out 30 minutes after addition. LC / MS showed that the desired product, 4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde, was cleanly formed. The reaction mixture was quenched with acetic acid (16.4 g, 15.6 mL, 274 mmol, 2.0 equivalents) to remove the dry ice cooling. Morpholine (33.7 g, 33.5 mL, 387 mmol, 2.83 equivalents) was added to this mixture, followed by the addition of acetic acid (74.0 g, 70 mL, 1231 mmol, 9.0 equivalents) at 0°C (the internal temperature was raised from 0°C to 18°C), and the mixture was stirred overnight. Sodium triacetoxyborohydride (52.50 g, 247.7 mmol, 1.8 equivalents) was added, and the temperature of the reaction mixture was raised from 20°C to 32°C. The mixture was stirred at room temperature for 30 minutes. HPLC and LC / MS indicated that the reaction was complete. After adding water (100 g, 100 mL), 2.0 M sodium carbonate (Na2CO3) in water (236 g, 200 mL, 400 mmol, 2.9 equivalents) was slowly added (off-gas!). The mixture was stirred for approximately 30 minutes. The organic layer was separated, and water (250 g, 250 mL) and heptane (308 g, 450 mL) were added. The resulting slurry was stirred for 1 hour, and the solid was recovered by filtration.The moist cake was washed twice with heptane (75.00 mL x 2, 51.3 g x 2), and then dried overnight in an oven at 50°C to obtain the desired product, 4-((4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-yl)methyl)morpholine as a light brown solid (52.00 g, 81.8% yield):C. 21 H 23 ClN2O5S[M+H] + LCMS calculated value for this value: 464.00; measured value: 464.0; 1 H NMR(400MHz,DMSO-d6)δ 8.48(s,1H),8.38(m,2H),7.72(m,1H),7.64(m,2H),6.83(s,1H),6.13( s,1H),4.12(m,2H),4.00(m,2H),3.92(s,2H),3.55(m,4H),2.47(m,4H).

[0173] Step 2: Synthesis of 4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde A 2 L reactor equipped with a thermocouple, a dropping funnel, and a mechanical stirrer was filled with 4-((4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-yl)methyl)morpholine (20.00 g, 43.1 mmol) and dichloromethane (265 g, 200 mL) at room temperature. The resulting mixture was stirred at room temperature (internal temperature was 19.5 °C) to obtain a solution. To the obtained solution, aqueous hydrochloric acid (0.5 M, 240 g, 200.0 ml, 100 mmol, 2.32 equivalents) was added at room temperature for 7 minutes. After stirring at room temperature for more than 23 hours, the two-layer reaction mixture turned into a thick, colorless suspension. Once HPLC indicated the completion of the reaction, the slurry was cooled to 0–5°C, and aqueous sodium hydroxide solution (1N, 104g, 100mL, 100 mmol, and 2.32 equivalents) was added over approximately 10 minutes to adjust the pH of the reaction mixture to 10–11. n-heptane (164g, 240mL) was added, and the reaction mixture and the mixture were stirred at room temperature for 1 hour. The solid was collected by filtration, and the moist cake was washed with water (2 × 40mL) and heptane (2 × 40mL). It was then dried under vacuum in a 50°C oven to obtain the desired product, 4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde, as a light brown solid (16.9g, 93% yield). 19 H 19 ClN3O4S[M+H] + Calculated LCMS value for this value: 420.00; Measured value: 420.0; 1 H NMR(400MHz,DMSO-d6)δ 10.33(s,1H),8.76(s,1H),8.42(m,2H),7.74(m,1H),7.65(m,2H),6.98(s,1H),3.96(m,2H),3.564(m,4H),2.51(m,4H).

[0174] Step 3: Synthesis of N-((4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline A 2 L reactor equipped with a thermocouple, nitrogen inlet, and mechanical stirrer was packed with N,N-dimethylformamide (450 mL, 425 g), 4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (30.0 g, 71.45 mmol), and 2,6-difluoro-3,5-dimethoxyaniline (14.2 g, 75.0 mmol). To this suspension (internal temperature 20°C), chlorotrimethylsilane (19.4 g, 22.7 mL, 179 mmol) was added dropwise at room temperature (internal temperature 20-23°C) for 10 minutes. Five minutes after the addition of chlorotrimethylsilane, the suspension turned into a solution. The solution was stirred at room temperature for 1.5 hours, and then cooled to 0-5°C in an ice bath. While maintaining the temperature at 0-5°C, borane-THF complex (1.0 M, 71.4 mL, 71.4 mmol, 64.2 g, 1.0 equivalent) in THF was added dropwise through an addition funnel over 30 minutes. After addition, the mixture was stirred for 4 hours. Water (150 g, 150 mL) was added for 20 minutes under ice bath cooling, and then, while maintaining the temperature below 10°C, ammonium hydroxide solution (28% NH3, 15.3 g, 17 ml, 252 mmol, 3.53 equivalents) was slowly added to a pH of 9-10. Further water (250 mL, 250 g) was added through an addition funnel. The slurry was stirred for 30 minutes, and the solid was collected by filtration. The moist cake was washed with water (90 g x 2, 90 ml x 2) and heptane (61.6 g x 2, 90 ml x 2). The product was dried overnight by vacuum to obtain the desired product N-((4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline (41.6 g, 96% yield):C 27 H 28 ClF2N4O5S[M+H] + Calculated value LCMS: 593.10; Measured value: 593.1; 1 H NMR(400MHz,DMSO-d6)δ 8.36(m,2H),8.28(s,1H),7.72(m,1H),7.63(m,2H),6.78(s,1H),6.29(m,1H), 5.82(m,1H),4.58(m,2H),3.91(s,2H),3.76(s,6H),3.56(m,4H),2.47(m,4H).

[0175] Step 4: Synthesis of 1-((4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)methyl)-1-(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea A 2 L three-necked round-bottom flask equipped with a thermocouple, nitrogen bubbler inlet, and magnetic stirrer was filled with N-((4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline (67.0 g, 113 mmol) and acetonitrile (670 ml, 527 g). The suspension was cooled to 0-5°C. Ethyl isocyanate (17.7 mL, 15.9 g, 224 mmol, 1.98 equivalents) was added to the mixture over 30 seconds. After filling, the temperature remained unchanged at 0.7°C. Methanesulfonic acid (16.1 mL, 23.9 g, 248 mmol, 2.2 equivalents) was added dropwise over 35 minutes while maintaining the temperature below 2°C. The mixture was heated to room temperature and stirred overnight. After 24 hours, the product was 93.7%, unreacted SM was 0.73%, and the main impurity (bisisocyanate adduct) was 1.3%. The mixture was cooled in an ice bath and quenched with sodium hydroxide (NaOH) solution (1.0 M, 235 mL, 244 g, 235 mmol, 2.08 equivalents) for 20 minutes, then quenched again with saturated sodium bicarbonate (NaHCO3) aqueous solution (1.07 M, 85 mL, 91 g, 0.091 mol, 0.80 equivalents) for 10 minutes. Water (550 mL, 550 g) was added, and the liquid became a single phase. The mixture was stirred for 2 hours, the solid was collected by filtration, and washed with water (165 mL, 165 g) to obtain 1-((4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)methyl)-1-(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea (70.3 g, 93.7% yield).

[0176] Crude 1-((4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea (68.5 g, 103 mmol) was added to acetonitrile (616 mL, 485 g). The mixture was heated to 60-65°C to obtain a pale amber suspension. The solid was filtered off with Celite, and the Celite was washed with acetonitrile (68.5 mL, 53.8 g). Water (685 g, 685 ml) was added to the pale yellow filtrate to form a slurry. The slurry was stirred overnight at room temperature and filtered. The solid was added to water (685 mL, 685 g) and stirred at 60°C for 2 hours. The solid was filtered and re-slurried overnight with heptane (685 mL, 469 g). The product was dried under vacuum in an oven at 50°C for 48 hours to obtain 1-((4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)methyl)-1-(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea as a colorless solid (62.2 g, 90.8% yield, 99.9% purity (by HPLC area %)). KF was 0.028%. Acetonitrile ( 1 (by 1H NMR) is approximately 1.56%, DCM ( 1 The concentration (by 1H NMR) was 2.0%:C 30 H 33 ClF2N5O6S[M+H] + LCMS calculated value for this: EM: 664.17; measured value: 664.2; 1 H NMR(400MHz,DMSO-d6)δ 8.33(m,2H),8.31(s,1H),7.72(m,1H),7.64(m,1H),6.96(m,2H),6.73(s,1H),6.43(m,1H), 4.87(s,2H),3.90(s,2H),3.77(s,6H),3.54(m,4H),3.03(m,2H),2.46(m,4H),0.95(m,3H).

[0177] Step 5: Synthesis of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one A 2000 ml flask equipped with a thermocouple, nitrogen inlet, and mechanical stirring bar was packed with dried 1-((4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)methyl)-1-(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea (30.0 g, 45.2 mmol, KF=0.11%) and tetrahydrofuran (1200 mL, 1063 g). This suspension was then packed at room temperature with 1.0 M lithium hexamethyl disilazide in THF (62.3 mL, 55.5 g, 62.3 mmol, 1.38 equivalents). After the addition of the base, the mixture dissolved. The reaction mixture was stirred for 2 hours, and HPLC showed no detection of the starting materials. To this mixture, 1.0 M hydrochloric acid (18.1 mL, approximately 18.1 g, 18.1 mmol, 0.4 equivalents) was added. The solution was concentrated to 600 mL, and water (1200 mL, 1200 g) was added. After adding water, a slurry was formed. The slurry was stirred at room temperature for 30 minutes, and the solid was collected by filtration. The moist cake was washed twice with water (60 mL x 2, 60 g x 2) and dried overnight at 50°C to obtain 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one as a light brown solid (26.58 g, 93.7% yield as is): 1 ¹H NMR revealed THF 0.32% and KF 5.26%, with a post-adjustment yield of 88.5%. 30 H 32 F2N5O6S[M+H] + LCMS calculated value: EM: 628.20; measured value: 628.2; 1H NMR(400MHz,DMSO-d6)δ 8.41(m,2H),8.07(s,1H),7.70(m,1H),7.63(m,2H),7.05(m,1H),6.89(s,1H),4.76( s, 2H), 4.09 (m, 2H), 3.93 (s, 2H), 3.89 (s, 6H), 3.60 (m, 4H), 2.50 (m, 4H), 1.28 (m, 3H).

[0178] Step 6: Synthesis of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one In a 500 mL flask equipped with a nitrogen inlet, condenser, thermocouple, and heating mantle, a stirred suspension of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholinomethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (10.0 g, 15.93 mmol) in 1,4-dioxane (100 ml, 103 g) was added to a 1 M sodium hydroxide aqueous solution (63.7 ml, 66.3 g, 63.7 mmol). The reaction mixture was heated at 75 °C for 18 hours. LC-MS indicated that the reaction was complete. Water (100 mL, 100 g) was added to obtain a concentrated suspension. This slurry was stirred at room temperature for 1 hour and then filtered. The cake was washed with water (3 × 10 mL, 3 × 10 g) and heptane (2 × 10 mL, 2 × 6.84 g). The cake was dried overnight by vacuum through a filtered cake, and then dried overnight in an oven at 50°C under vacuum to obtain 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (6.8 g, 87.6% yield):C 24 H 28 F2N5O4[M+H] + LCMS calculated value for this: 488.20; measured value: 488.2.

[0179] Example 2. Synthesis of 4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine [ka]

[0180] Step 1: Synthesis of 1H-pyrrolo[2,3-b]pyridine-7-oxide m-chloroperoxybenzoic acid (105.5 kg, 612 mol, 1.2 equivalents) was added over 5 hours to a solution of 1H-pyrrolo[2,3-b]pyridine (60 kg, 507.6 mol) in dichloromethane (600 L) while stirring at 0-10°C. After the addition was complete, the mixture was stirred at 0-10°C for 3 hours. The resulting solid was collected by filtration, washed with heptane, and dried to obtain 1H-pyrrolo[2,3-b]pyridine 7-oxide. The mother liquor was concentrated, the residue was treated with dichloromethane:heptane (2:3), filtered, and excess material was collected. Crude 1H-pyrrolo-2,3-b]pyridine-7-oxide was obtained (72 kg, purity 96%) and used in the next step without purification.

[0181] Step 2: Synthesis of 4-chloro-1H-pyrrolo[2,3-b]pyridine Crude 1H-pyrrolo[2,3-b]pyridine-7-oxide (72 kg, 253 mol) was dissolved in DMF (360 L) and heated at 50°C. A solution of methanesulfonyl chloride (85.2 kg, 746 mol, 3.0 equivalents) was added dropwise to the solution while maintaining the temperature below 70°C. After stirring at 90°C for 2 hours, the reaction solution was cooled to room temperature and added to 720 kg of ice / water. The mixture was neutralized with 6.0 M NaOH at 0°C. The resulting precipitate was collected by filtration and washed with water. The solid was mixed with 72 L of water, 48 L of ethanol, and 29 L of 30% NaOH and stirred at room temperature for 1-2 hours. Water (144 L) was added, and the mixture was treated with 37% HCl to adjust the pH to approximately 1. The product was recovered by filtration and dried to obtain 4-chloro-1H-pyrrolo[2,3-b]pyridine (26 kg of crude, 97% purity, used without purification): 1HNMR (400MHz, CDCl3) δ 11.30 (s, 1H), 8.25 (m, 1H), 7.44 (m, 1H), 7.16 (m, 1H), 6.65 (m, 1H).

[0182] Step 3: Synthesis of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine A solution of crude 4-chloro-1H-pyrrolo[2,3-b]pyridine (24 kg, 155.2 mol) in THF (216 L) was stirred at 0°C, and NaH (60%, 7.56 kg, 188.6 mol, 1.3 equivalents) was added in small amounts under N2. After the addition, the mixture was stirred at room temperature for 1 hour. Triisopropylsilyl chloride (39.6 kg, 188.6 mol, 1.3 equivalents) was added dropwise while maintaining the temperature below 25°C. After stirring for 20 hours, the mixture was quenched with 144 L of water and extracted with 144 L of heptane. The aqueous layer was back-extracted with 72 L of methyl t-butyl ether. The combined organic layers were dried over anhydrous MgSO4 and concentrated under vacuum to obtain the crude product 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine in liquid form. This substance was used without purification, but its water content was controlled to less than 0.1%.

[0183] Step 4: Synthesis of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde Crude 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (50 kg, approximately 138 mol) and anhydrous THF (150 kg) were packed into a 1000 L cryogenic reactor. The mixture was cooled to -75°C and stirred under N2, while maintaining the internal temperature below -60°C. S-BuLi (1.3 M, 230 L, 300 mol, 2.2 equivalents in cyclohexane) was added dropwise over 6.0 hours. The mixture was stirred for a further 2 hours at -75°C. N,N-dimethylformamide (30.4 kg, 416.1 mol, 3.0 equivalents) was added dropwise over approximately 3.0 hours, while controlling the internal temperature to below -65°C.

[0184] After stirring at -65 to -75°C for 2 hours, the mixture was quenched by dropwise adding a 20% HCl solution in isopropyl alcohol (115 kg, 635 mol, 4.5 equivalents). The mixture was then stirred overnight at room temperature (20-25°C). The pH was adjusted to 7-8 by packing with saturated NaHCO3. The formed precipitate was collected by filtration. The filtered cake was washed with 76 L of water to obtain 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (14 kg, 58% yield): 1 H NMR (400MHz, DMSO-d6) δ 12.54 (s, 1H), 10.35 (s, 1H), 8.67 (s, 1H), 7.74 (m, 1H), 6.72 (m, 1H).

[0185] Step 5: Synthesis of 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde A 500 L reactor was packed with N,N-dimethylformamide (108 L) and 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (10.8 kg, 59.8 mol) and cooled to 0-5°C. Cesium carbonate (39 kg, 120 mol) was added to the resulting concentrated slurry at 0-5°C. The slurry was stirred at 0°C for approximately 20 minutes, transforming the mixture into a pale amber slurry. Benzesulfonyl chloride (11.6 kg, 65.8 mol, 1.1 equivalents) was added dropwise through a dropping funnel to the pale slurry below 10°C. The resulting slurry was stirred below 10°C for 1 hour, and HPLC indicated that the reaction was complete. Long-term stirring overnight at room temperature had little effect on the reaction mixture profile. Water (160 L) was added to this mixture, and the slurry was stirred for 1 hour. The solid was recovered by filtration (slow). The filtered cake was washed with water and dried in an oven under vacuum to obtain 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde as a light brown solid (17.8 kg, 93% yield):C 14 H 10 ClN2O3S[M+H] + LCMS calculated value: 321.00; measured value: 320.9; 1HNMR (400MHz, DMSO-d6) δ: 10.34 (s, 1H), 8.78 (s, 1H), 8.18 (m, 3H), 7.77 (m, 1H), 7.66 (m, 2H), 7.05 (m, 1H).

[0186] Step 6: Synthesis of 4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine A 1000 L reactor was packed with toluene (270 L), 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (27 kg, 84.2 mmol), p-toluenesulfonic acid monohydrate (217 g, 1.26 mol, 0.015 equivalents), and 1,2-ethanediol (73.7 kg, 1187 mol, 14.1 equivalents). The mixture was stirred and heated under reflux for 9 hours to remove water (some ethylene glycol was also removed as the reaction progressed) (LCMS indicated that the reaction was complete). After stirring overnight at room temperature, the mixture was diluted with ethyl acetate (135 L) and washed with saturated NaHCO3 solution. The layer was separated, and the organic layer was washed with 10% NaCl aqueous solution and concentrated. Heptane (108 L) was added to form a slurry. The solid was recovered by filtration. The solid was dissolved in dichloromethane (10⁸ L) and filtered to remove mechanical impurities. The filtrate was concentrated and then dissolved in 67.5 L (2.5V) hot ethyl acetate and stirred for 2 hours. Once a solid had formed, the mixture was cooled. The solid was recovered by filtration to obtain 4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine as an off-white solid (22 kg, 70% yield):C 16 H 14 ClN2O4S[M+H] + Calculated LCMS value: 365.03; Measured value: 365.1; 1 H NMR(400MHz,DMSO-d6)δ 8.51(s,1H),8.13(m,2H),8.07(m,1H),7.73(m,1H),7.63(m,2H),6.90(m,1H),6.13(s,1H),4.12(m,2H),3.98(m,2H).

[0187] Example 3. Alternative synthesis of 4-chloro-2-(morpholine-4-ylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde [ka]

[0188] Step 1: Synthesis of 5-bromo-4-chloropyridine-2-amine To a slurry of 2-amino-4-chloropyridine (100 g, 777.8 mmol, 1.0 equivalent) in acetonitrile (500 mL, 5 rel. vol.) at 15-20°C, N-bromosuccinimide (131.5 g, 738.9 mmol, 0.95 equivalent) was gradually added over 2 hours while maintaining the temperature at 15-20°C. The reaction mixture was stirred for 30 minutes, and the conversion was checked by HPLC. Depending on the conversion rate, an additional 0-5 mol% of N-bromosuccinimide was added, and the mixture was stirred for a further 15 minutes. After the HPLC indicated completion of the conversion, the reaction mixture was heated, and acetonitrile (300 mL) was removed by distillation at atmospheric pressure. Water (250 mL) was added, and the temperature was adjusted to 50-55°C to form a slurry. The resulting slurry was stirred for 30 minutes, and water (350 mL) was added over 1 hour. The slurry was cooled to 20-25°C, stirred for 1 hour, and the solid was recovered by filtration. The wet cake was washed with a mixture of water (75 mL) and acetonitrile (25 mL) to obtain the wet product 5-bromo-4-chloropyridine-2-amine (191 g, HPLC area % purity 92.1%). The wet product was dissolved in acetic acid (500 mL, 5 rel. vol. of 2-amino-4-chloropyridine, 55-70°C), and this solution was used directly in the next step.

[0189] Step 2: Synthesis of 5-bromo-4-chloro-3-iodopyridine-2-amine A solution of 5-bromo-4-chloropyridine-2-amine in acetic acid (191 g of 5-bromo-4-chloropyridine-2-amine in 500 mL of acetic acid) was removed by vacuum distillation at 40-60°C to remove the solvent. Next, sulfuric acid (39.7 g, 96 w / w, 388.9 mmol, 0.5 equivalents) and iodine (76.2 g, 300.3 mmol, 0.386 equivalents) were added, and the temperature was adjusted to 77-83°C. At this temperature, a solution of periodic acid (50 w / w, 54.89 g, 120.4 mmol, 0.155 equivalents) was added over 2-3 hours. The reaction mixture was stirred at 77-83°C for 2-3 hours, and the conversion was checked by HPLC (SM < 1.0% - a / a). The reaction mixture was quenched at 75-85°C by adding 4.53 g (0.05 equivalents) of solid ammonium sulfite until the KI / starch test was negative. Typically, two parts (0.1 equivalents) of ammonium sulfite were required. The end of the quench can also be indicated by the absence of purple iodine. Next, the reaction mixture was diluted with water (200 mL, 2.0 rel. vol., room temperature) and the temperature was lowered to approximately 50°C. The product precipitated. At 45-60°C, the pH was adjusted to 3.0-3.5 using ammonia (25 (w / w)%, approximately 63.6 g, 0.93 mol, 1.2 equivalents were required in water). Neutralization was highly exothermic. After stirring the slurry at 45-50°C for 30 minutes, the solid was recovered by filtration. The filtration cake was washed with approximately 600 mL of water, and then with 2-propanol (200 mL). The moist product was dried in a vacuum cabinet at 60°C to obtain 5-bromo-4-chloro-3-iodopyridine-2-amine as a yellow to beige solid (213.5 g, 82.3% yield): C5H4BrClIN2[M+H] + LCMS calculated value for this: 332.82; measured value: 332.8; 1 H NMR (400MHz, DMSO-d6) δ 8.09 (s, 1H), 6.60 (s, 2H).

[0190] Step 3: Synthesis of 5-bromo-4-chloro-3-(3-morpholinopropa-1-in-1-yl)pyridine-2-amine 5-Bromo-4-chloro-3-iodopyridine-2-amine (50 g, 150 mmol, 1.0 equivalent), 4-(propan-2-inyl)morpholine (22.5 g, 180 mmol, 1.20 equivalents), diisopropylamine (18.2 g, 180 mmol, 1.2 equivalents), and 150 mL of toluene were packed into the reactor. The solution was carefully degassed by applying three vacuum argon cycles. Next, CuI (0.29 g, 1.5 mmol, 1 mol%) and Pd(PPh3)4 were added, and the flask was purged again with argon. The mixture was stirred overnight (17 hours) at 50°C. Water (50 mL, 1 volume) was added all at once, and the mixture was cooled to 20-25°C. The crude product was filtered and sequentially washed with 10% ammonia (50 ml, 1.0 volume), water (50 ml, 1 volume), toluene (25 ml, 0.5 volume), and 2-isopropanol (50 ml, 1.0 volume). After drying under vacuum at 50°C, 5-bromo-4-chloro-3-(3-morpholinopropa-1-in-1-yl)pyridine-2-amine was obtained as a light brown solid (41.6 g, 87% yield):C 12 H 14 BrClIN5O[M+H] + LCMS calculated value for this value: 329.99; measured value: 330.0; 1 H NMR (400MHz, DMSO-d6) δ 8.13 (s, 1H), 6.69 (s, 2H), 3.64 (s, 2H), 3.61 (m, 4H), 2.54 (m, 4H).

[0191] Step 4: Synthesis of 4-((5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine-2-yl)methyl)morpholine A solution of KOtBu (18.1 g, 1.4 equivalents, 112.21 mmol) in tetrahydrofuran (114 ml, 3 volumes) was heated to 30-35°C, and 5-bromo-4-chloro-3-(3-morpholinopropa-1-in-1-yl)pyridine-2-amine (38 g, 114.9 mmol, 1.0 equivalent) was gradually added over 1.0 hour at 30-35°C. After stirring for 2 hours, the reaction mixture was quenched with a solution of acetic acid (10.4 g, 172.4 mmol, 1.5 equivalents) in water (76 mL, 2 volumes), and 76 mL of THF (76 mL) was removed by distillation. Next, the solution was heated under reflux, MeOH (38 mL, 1 volume) was added, and the resulting suspension was cooled to 23°C over 1 hour. After stirring at 23°C for 0.5 hours, the solid was filtered off and washed with water (38 ml, 1 volume) and MeOH (38 mL, 1 volume). After drying under vacuum at 50°C, 4-((5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine-2-yl)methyl)morpholine was obtained as a light brown powder, 4-((5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine-2-yl)methyl)morpholine (32.8 g, yield 86%):C 12 H 14 BrClIN5O[M+H] + LCMS calculated value for this: 329.99; measured value: 329.8; 1 H NMR (400MHz, DMSO-d6) δ 12.22 (s, 1H), 8.34 (s, 1H), 6.40 (s, 1H), 3.65 (s, 2H), 3.58 (m, 4H), 2.42 (m, 4H).

[0192] Step 5: Synthesis of 4-((5-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-yl)methyl)morpholine A slurry of 4-((5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine-2-yl)methyl)morpholine (10 g, 30.25 mmol, 1.0 equivalent, assay 94 (w / w)%) and NaH (1.69 g, 60%, 42.35 mmol, 1.4 equivalents) in 38 mL of tetrahydrofuran was cooled to 0-5°C while PhSO2Cl (7.48 g, 42.35 mmol, 1.4 equivalents) was added over 1 hour. After 1.5 hours, HPLC indicated that the reaction was not complete. Gas generation was observed when additional NaH (0.34 g, 0.3 equivalents) was added. When HPLC indicated that the reaction was complete, the reaction mixture was quenched with acetic acid (0.5 g) and a mixture of water (15 mL) and methanol (15 mL). The pH was adjusted to 6.5 with caustic soda, and the product was isolated by filtration. The wet cake was washed with 2-isopropanol (20 mL) and water (20 mL), and the wet product (14.8 g) was dried in a vacuum cabinet to obtain 4-((5-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-yl)methyl)morpholine as a brown solid (12.57 g, 86% yield):C 18 H 18 BrClIN3O3S[M+H] + Calculated LCMS value for this: 469.99; Measured value: 470.0; 1 H NMR(400MHz,DMSO-d6)δ 8.56(s,1H),8.33(m,2H),7.73(m,1H),7.65(m,2H),6.83(s,1H),3.91(s,2H),3.53(m,4H),2.46(m,4H).

[0193] Step 6: Synthesis of 4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde To a suspension of 4-((5-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-yl)methyl)morpholine (5.0 g, 10.6 mmol, 1.0 equivalent) in 50 mL of tetrahydrofuran at -10°C to 0°C, iPrMgCl (6.9 mL, 2 M in tetrahydrofuran, 13.80 mmol, 1.3 equivalents) was added. After stirring for 2 hours, N,N-dimethylformamide (1.55 g, 21.2 mmol, 2.0 equivalents) was added to the reaction solution over 0.5 hours at -0.5°C to 0°C. The mixture was stirred at -5°C to 0°C for 0.5 hours, then warmed to 23°C over 0.5 hours, and stirred at 23°C for 1 hour. 1.5 mL of acetic acid and 10 mL of water were added to adjust the pH to 6-7. 25 mL of MeOH and 15 mL of water were added to the two-phase mixture. After stirring for 1 hour, the product was filtered off and washed with 20 mL of MeOH / water (1 / 1) and 30 mL of water. After drying under vacuum at 50°C, 4-chloro-2-(morpholinomethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde was obtained as an off-white powder (3.39 g, 76% yield):C 19 H 19 ClN3O4S[M+H] + LCMS calculated value for this value: 420.07; measured value: 420.0; 1 H NMR(400MHz,DMSO-d6)δ 10.33(s,1H),8.76(s,1H),8.42(m,2H),7.74(m,1H),7.65(m,2H),6.98(s,1H),3.96(m,4H),3.564(m,4H),2.51(m,4H).

[0194] Example 4. Synthesis of 2,6-difluoro-3,5-dimethoxyaniline [ka] Step 1: Synthesis of methyl pentafluorobenzoate To a solution of pentafluorobenzoic acid (40 kg, 188.6 mol) in 68 L of methanol, SOCl2 (29.2 kg, 245.2 mol, 1.3 equivalents) was added dropwise over 4.0 hours at 20-50°C. The mixture was then heated under reflux for 17 hours. Methanol was removed by vacuum distillation, and the residue was dissolved in methyl t-butyl ether (77 L). The solution was washed with saturated NaHCO3 (37 L), dried over MgSO4, and evaporated to obtain methyl pentafluorobenzoate as a colorless oil (39 kg, 91% yield): 1 H NMR (400MHz, CDCl3) δ 3.90 (s, 3H).

[0195] Step 2: Synthesis of methyl-4-(benzylamino)-2,3,5,6-tetrafluorobenzoic acid Methyl pentafluorobenzoate (39 kg, 172.5 mol) and N,N-diisopropylethylamine (26.8 kg, 207 mol, 1.2 equivalents) were dissolved in N-methylpyrrolidinone (39 L). A solution of benzylamine (18.5 kg, 172.5 mol, 1.0 equivalent) in 19.5 L of N-methylpyrrolidinone was added dropwise over 3.5 hours while maintaining the internal temperature below 50°C. The resulting dense yellow slurry was heated to 65°C and stirred for a further 1 hour. The mixture was poured into a 195 L solution of aqueous acetic acid (10% acetic acid and 90% H2O), the slurry was stirred for 1 hour, and then filtered. The filtered cake was washed with water and heptane and dried under vacuum at 35°C to obtain methyl-4-(benzylamino)-2,3,5,6-tetrafluorobenzoic acid (38 kg, 70% yield). 1 H NMR (400MHz, CDCl3) δ 7.37 (m, 5H), 4.67 (m, 2H), 4.58 (m, 1H), 3.93 (s, 3H).

[0196] Step 3: Synthesis of 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoic acid Methyl-4-(benzylamino)-2,3,5,6-tetrafluorobenzoic acid (38 kg, 121.3 mol) in methanol (72 L) was stirred at room temperature under N2, and a solution of NaOMe (25 wt%, 110.8 kg, 545.85 mol, 4.5 equivalents) in methanol was added dropwise over 3.0 hours while maintaining the temperature below 50°C. After heating to 65-70°C for 18 hours, 18 L of water was added to the reaction mixture, and the resulting solution was stirred for 1 hour. The solvent was removed by vacuum distillation. Water (54 L) was added, and the resulting solution was acidified to pH 2 with 37% HCl. The mixture was extracted three times with ethyl acetate (54 kg each). The combined organic extracts were washed with water (43 L), concentrated and dried to form a solid. The solid was ground with heptane (43 L) to remove impurities. The solid was collected and dried under vacuum at 40°C to obtain 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoic acid (35 kg, 86% yield): 1 H NMR (400MHz, CDCl3) δ 12.74 (s, 1H), 7.37 (m, 5H), 6.62 (s, 1H), 4.67 (m, 2H), 3.96 (s, 6H).

[0197] Step 4: Synthesis of n-benzyl-2,6-difluoro-3,5-dimethoxyaniline 17 kg of 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoic acid was heated in its raw state at 75-85°C for 3-4 hours under a nitrogen atmosphere. After the reaction was complete, 40 L of methyl t-butyl ether and 20 L of 1 M NaOH were added. The mixture was stirred at room temperature for 30 minutes. The organic layer was separated and washed with water (20 L) and brine (20 L). The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was ground with heptane and dried under vacuum at 35°C to obtain N-benzyl-2,6-difluoro-3,5-dimethoxyaniline (12 kg, 82% yield). 1 H NMR (400MHz, CDCl3) δ 7.35 (m, 5H), 6.09 (m, 1H), 4.53 (m, 2H), 4.00 (s, 1H), 3.85 (s, 6H).

[0198] Step 5: Synthesis of 2,6-difluoro-3,5-dimethoxyaniline N-benzyl-2,6-difluoro-3,5-dimethoxyaniline (24 kg, 85.9 mol) was dissolved in a mixed solvent of ethanol (120 L) and acetic acid (20 L), to which ammonium formate (13.2 kg) and 1.68 kg of Pd / C were added. The mixture was heated at 50°C for 2-3 hours. The reaction mixture was then filtered through Celite®, washed with ethanol (1.2 L x 2), and concentrated. The crude product was added to 80 L of water, and the resulting slurry was filtered. The crude product was added to 60 L of methyl t-butyl ether and 2.5 kg of activated carbon, and the mixture was heated under reflux for 3 hours. After filtering and concentration, the resulting solid was added to 36 L of heptane and stirred at room temperature for 2 hours. The mixture was filtered and dried under vacuum at 35°C to obtain 2,6-difluoro-3,5-dimethoxyaniline as a light brown solid (15.2 kg, 93% yield):C8H 10 F2NO2[M+H] + Calculated LCMS value for this: 190.16; Measured value: 190.1; 1 H NMR (400MHz, DMSO-d6) δ 6.16 (m, 1H), 5.18 (s, 2H), 3.78 (s, 6H).

[0199] Example 5. Alternative synthesis of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (compound 1) [ka]

[0200] Step 1: 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde [ka]

[0201] A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (CAS#958230-19-8, Lakestar Tech, Lot: 124-132-29: 3.0 g, 17 mmol) and ethylamine (10 M in water, 8.3 mL, 83 mmol) in 2-methoxyethanol (20 mL, 200 mmol) was heated to 130 °C and stirred overnight. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was treated with 1 N HCl (30 mL), stirred at room temperature for 1 hour, and then neutralized with saturated NaHCO3 aqueous solution. The precipitate was collected by filtration, washed with water, and dried to obtain the desired product (2.9 g, 92%). 10 H 12 N3O[M+H] + LC-MS calculated value for m / z: 190.1; measured value: 190.1.

[0202] Step 2: 5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridine-4-amine [ka]

[0203] A mixture of 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (7.0 g, 37 mmol), 2,6-difluoro-3,5-dimethoxyaniline (9.1 g, 48 mmol), and [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid (Aldrich, catalog no. 21360: 2 g, 7 mmol) in xylene (250 mL) was heated under reflux, and water was removed azeotropically using a Dean-Stark for 2 days, at which point LC-MS indicated that the reaction was complete. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (500 mL), and then 2.0 M lithium tetrahydroaluminate (37 mL, 74 mmol) in THF was slowly added. The resulting mixture was stirred at 50°C for 3 hours and then cooled to room temperature. The reaction product was quenched by adding water, a 15% aqueous NaOH solution, and water. The mixture was filtered and washed with THF. The filtrate was concentrated, the residue was washed with CH2Cl2, and then filtered to obtain the pure product (11 g, 82%). 18 H 21 F2N4O2[M+H] + LC-MS calculated value for m / z: 363.2; measured value: 363.1.

[0204] Step 3: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one [ka]

[0205] A solution of triphosgene (5.5 g, 18 mmol) in tetrahydrofuran (30 mL) was slowly added to a mixture of 5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine (5.6 g, 15 mmol) in tetrahydrofuran (100 mL) at 0 °C, and then the mixture was stirred at room temperature for 6 hours. The mixture was cooled to 0 °C, and then 1.0 M sodium hydroxide in water (100 mL, 100 mmol) was slowly added. The reaction mixture was stirred at room temperature overnight, and the precipitate formed was collected by filtration, washed with water, and then dried to afford the first batch of the desired purified product. The organic layer in the filtrate was separated, and the aqueous layer was extracted with methylene chloride. The combined organic layers were concentrated, the residue was triturated with methylene chloride, then filtered and dried to give another batch of the product (total 5.5 g, 92%). C 19 H 19 F2N4O3[M+H] + LC-MS calculated value for m / z: 389.1; measured value 389.1.

[0206] Step 4: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0207] A solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (900 mg, 2.32 mmol) in N,N-dimethylformamide (20 mL) cooled to 0°C was mixed with sodium hydride (185 mg, 4.63 mmol, 60 wt% contained in mineral oil). The resulting mixture was stirred at 0°C for 30 minutes, and then benzenesulfonyl chloride (0.444 mL, 3.48 mmol) was added. The reaction mixture was stirred at 0°C for 1.5 hours, at which point LC-MS indicated that the reaction to the desired product was complete. The reaction was quenched with saturated NH4Cl solution and diluted with water. The white precipitate was collected by filtration, then washed with water and hexane, and dried to obtain the desired product (1.2 g, 98%) as a white solid, which was used in the next step without further purification. 25 H 23 F2N4O5S[M+H] + LC-MS calculated value for m / z: 529.1; measured value: 529.1.

[0208] Step 5: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde [ka]

[0209] A solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one (1.75 g, 3.31 mmol) in tetrahydrofuran (80 mL) was treated at -78 °C with freshly prepared lithium diisopropylamide (1 M in tetrahydrofuran (THF), 3.48 mL, 3.48 mmol). The resulting mixture was stirred at -78 °C for 30 min, then N,N-dimethylformamide (1.4 mL, 18 mmol) was added slowly. The reaction mixture was stirred at -78 °C for 30 min and then quenched with water and extracted with EtOAc. The organic extracts were combined, washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluting with 0 - 20% EtOAc in DCM to give the desired product as a white solid (1.68 g, 91%). C 26 H 23 F2N4O6S(M+H) + LC-MS calculated value for m / z: 557.1; found: 556.9.

[0210] Step 6: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0211] To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde (1.73 g, 3.11 mmol) in dichloromethane (50 mL), morpholine (0.95 mL, 11 mmol) was added, followed by acetic acid (2 mL, 30 mmol). The resulting yellow solution was stirred overnight at room temperature, and then sodium triacetoxyborohydride (2.3 g, 11 mmol) was added. The mixture was stirred at room temperature for 3 hours, at which point LC-MS indicated that the reaction was complete and the desired product had been formed. The reaction product was quenched with saturated NaHCO3 and then extracted with ethyl acetate (RINKAN). The organic extracts were combined and then washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluting with 0-40% ethyl acetate in DCM to obtain the desired product as a white solid (1.85 g, 95%). 30 H 32 F2N5O6S(M+H) + LC-MS calculated value for m / z: 628.2; measured value: 628.0.

[0212] Step 7: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (1.5 g, 2.4 mmol) in tetrahydrofuran (40 mL), tetra-n-butylammonium fluoride (1 M, in THF, 7.2 mL, 7.2 mmol) was added. The resulting solution was stirred at 50°C for 1.5 hours, then cooled to room temperature and quenched with water. The mixture was extracted with dichloromethane (DCM), the organic extracts were combined, and then washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 0-10% MeOH in DCM to obtain the desired product as a white solid, which was further purified by preparative HPLC (pH=2, acetonitrile / H2O). 24 H 28 F2N5O4(M+H) + LC-MS calculated value for m / z: 488.2; measured value: 488.0. 1 H NMR(500MHz,DMSO)δ 12.09(s,1H),8.06(s,1H),7.05(t,J=8.1Hz,1H),6.87(s,1H),4.78(s,2H),4.50(s,2H),4.17(q,J=6. 8Hz,2H),3.97(br,2H),3.89(s,6H),3.65(br,2H),3.37(br,2H),3.15(br,2H),1.37(t,J=6.8Hz,3H).

[0213] Example 6. Synthesis of 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9-ethyl-2-morpholine-4-ylmethyl-8-oxo-6,7,8,9-tetrahydro-3,4,7,9-tetraazacyclopenta[a]naphthalene-3-sulfonic acid dimethylamide [ka]

[0214] Step 1. Synthesis of 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9-ethyl-8-oxo-6,7,8,9-tetrahydro-3,4,7,9-tetraazacyclopenta[a]naphthalene-3-sulfonic acid dimethylamide [ka]

[0215] A 200L glass reactor was assembled using an overhead stirrer, condenser, thermocouple, dropping funnel, and nitrogen inlet, and each apparatus was purged with nitrogen. Drinking water (3.1L) and sodium hydroxide (3093g) were added to the reactor, and the mixture was stirred at approximately 71°C until a solution was obtained. The reaction mixture was cooled to approximately 30°C, and THF (15.0L) was added. The reaction mixture was cooled to 10°C, and 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (3000g) and n-Bu4N + HSO4 - (262g) was added continuously while maintaining the temperature at approximately 10°C. The material was rinsed in the reactor with THF (15.0L) while maintaining the temperature at approximately 7°C. N,N-dimethylsulfamoyl chloride (1.244L) was added while maintaining the temperature at approximately 7°C. The reaction mixture was heated to approximately 17°C and stirred at approximately 22°C for 7 hours. Drinking water (120.0L) was added while maintaining the temperature at approximately 20°C, and the reaction mixture was stirred at approximately 18°C ​​for 1 hour. The reaction mixture was filtered, and the filter cake was washed four times with drinking water (30.0L each time). The product was air-dried on a filter for 14.5 hours to obtain crude 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-N,N-dimethyl-2-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-7-sulfonamide (4694 g).

[0216] Purification: A 100L glass reactor was assembled using an overhead stirrer, condenser, thermocouple, dropping funnel, and nitrogen inlet, and each apparatus was purged with nitrogen. CH2Cl2 (37.5L) and silica gel (15,000g) were loaded onto a chromatography column and thoroughly mixed to elute the silica gel surface. Sea sand (4,000g) and magnesium sulfate (6,000g) were sequentially packed into the column. Crude 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-N,N-dimethyl-2-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-7-sulfonamide (6118g) and CH2Cl2 (22.5L) were thoroughly mixed until a solution was obtained, and then the solution was packed into the column. Since the elution rate was found to be too slow, the magnesium sulfate and solution were removed from the column and filtered. The filter cake was washed with CH2Cl2 (20 L), and the filtrate was packed into the column. The container was rinsed with CH2Cl2 (2.5 L), and this rinse was packed into the column. The column was eluted with siRNA / CH2Cl2 (prepared separately from 9.4 L of siRNA and 178.1 L of CH2Cl2). The desired fraction was partially concentrated under vacuum at approximately 45°C until the remaining target total volume was 24 L (approximately 4 L per 1 kg of packed 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-N,N-dimethyl-2-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-7-sulfonamide) (using two rotor vaporizers for convenience). The distillation residue (24 L) was added to a 100 L reactor, and the temperature was adjusted to approximately 28°C. Heptane (54 L) was added, and the reaction mixture was stirred at approximately 24°C for 1 hour. The reaction mixture was filtered, and the filter cake was washed with heptane (24 L). The product was air-dried on a filter for approximately 3 hours to obtain the product (5382 g). 21 H 23 F2N5O5S[M+H] + LCMS calculated value for this: 495.5; measured value: 495.1. 1H NMR (400MHz, DMSO-d6) δ8.12(s, 1H), 7.72(s, 1H), 7.07(t, 1H), 6.89(s, 1H), 4.83(s, 2H), 4.14(t, 2H), 3.91(s, 6H), 2.96(s, 6H), 1.35(t, 3H).

[0217] Step 2. Synthesis of 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9-ethyl-2-formyl-8-oxo-6,7,8,9-tetrahydro-3,4,7,9-tetraazacyclopenta[a]naphthalene-3-sulfonic acid dimethylamide [ka]

[0218] A 22 L glass reactor and a 200 L glass reactor were assembled using overhead stirring, a condenser, thermocouples, a dropping funnel, and a nitrogen inlet, and each apparatus was purged with nitrogen. THF (2.38 L) and N,N-diisopropylamine (0.82 L) were packed into the 22 L glass reactor, and the mixture was cooled to -72°C. A 2.5 M solution of n-BuLi in hexane (2.13 L) was packed in while maintaining the temperature at approximately -70°C. The reaction mixture was stirred at -71°C for approximately 7 minutes, and then heated to -2°C over 3.5 hours to form a 1 M LDA solution.

[0219] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-N,N-dimethyl-2-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-7-sulfonamide (gross 1075 g, 93.07 wt%, net 1001 g) and THF (10.0 L) were added to the first rotor vaporizer and rotated at approximately 63°C for approximately 28 minutes without collecting the solvent until a solution was obtained. 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-N,N-dimethyl-2-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3',2':5,6]pyrido-[4,3-d]pyrimidine-7-sulfonamide (gross 1075 g, 93.07 wt%, net 1001 g) and THF (10.0 L) were packed into the second rotor vaporizer and rotated at approximately 61°C for approximately 35 minutes without collecting the solvent until a solution was obtained. Both mixtures were concentrated under reduced pressure at approximately 50°C. THF (10.0 L per rotor vaporizer) was packed into each rotor vaporizer and both mixtures were concentrated under reduced pressure at approximately 50°C. THF (10.0 L) was added to the first rotor vaporizer and the mixture was rotated at approximately 64°C for 14 minutes without collecting the solvent until a solution was obtained. THF (10.0 L) was added to the second rotor vaporizer, and the mixture was rotated at approximately 64°C for 14 minutes without collecting the solvent until a solution was obtained. GC-mediated PCT passed for residual CH2Cl2. Both solutions were transferred to a 200 L reactor using THF (26 L) to assist the transfer. The reaction mixture was cooled to -65°C. While maintaining the temperature at approximately -64°C, 1 M LDA solution (4.84 L) was added over approximately 1 hour, and the reaction mixture was stirred at -65°C for 2.25 hours. While maintaining the temperature at approximately -65°C, DMF (1.56 L) was added over 30 minutes. The reaction mixture was stirred at -64°C for 31 minutes and then warmed to -12°C over approximately 2 hours. Separately, an aqueous solution of ammonium chloride was prepared by thoroughly mixing ammonium chloride (160 g) with drinking water (1.6 L). While maintaining the temperature at approximately -5°C, an aqueous ammonium chloride solution was filled over 17 minutes, and the reaction mixture was warmed to 19°C over approximately 7.5 hours. The reaction mixture was partially concentrated under vacuum at approximately 45°C (two rotor vaporizers were used for convenience).A total volume of 36 L was collected by distillation (approximately 18 L per 1 kg of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-N,N-dimethyl-2-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-7-sulfonamide packing). The distillation residue was packed into a 200 L reactor, the temperature was adjusted to approximately 23°C, and the reaction mixture was stirred at 23°C for approximately 2 hours. Drinking water (20.0 L) was added over approximately 1 hour, and the reaction mixture was stirred at approximately 23°C. The reaction mixture was filtered, and the filter cake was washed twice with drinking water (10.0 L per wash). The product was air-dried on the filter for approximately 3.5 hours to obtain the crude product (2028 g). The crude product was slurryed in MTBE at 46-53°C for 1 hour, then cooled to room temperature, filtered, and washed with MTBE to obtain 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9-ethyl-2-formyl-8-oxo-6,7,8,9-tetrahydro-3,4,7,9-tetraaza-cyclopenta[a]naphthalene-3-sulfonic acid dimethylamide:C. 22 H 23 F2N5O6S[M+H] + LCMS calculated value for this value: 524.13; measured value: 524.80. 1 H NMR(400MHz,DMSO-d6)δ 10.24(s,1H),8.31(s,1H),7.50(s,1H),7.05(m,1H),4.86(s,2H),4.17(m,2H),3.86(s,6H),3.04(s,6H),1.29(m,3H).

[0220] Step 3. Synthesis of 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9-ethyl-2-morpholine-4-ylmethyl-8-oxo-6,7,8,9-tetrahydro-3,4,7,9-tetraazacyclopenta[a]naphthalene-3-sulfonic acid dimethylamide A 200 L glass reactor was assembled using an overhead stirrer, condenser, thermocouple, dropping funnel, and nitrogen inlet, and each apparatus was purged with nitrogen. Methylene chloride (20.0 L) and 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9-ethyl-2-formyl-8-oxo-6,7,8,9-tetrahydro-3,4,7,9-tetraazacyclopenta[a]naphthalene-3-sulfonic acid dimethylamide (2000 g) were placed in the reactor, and the mixture was stirred at 18°C ​​until a solution was obtained. Morpholine (1.7 L) was added to the reaction mixture. Acetic acid (2.0 L) was added over 34 minutes while maintaining the temperature at approximately 32°C. The reaction mixture was stirred at approximately 27°C for 4 hours. Sodium triacetoxyborohydride (1620 g) was added over 40 minutes while maintaining the temperature at approximately 28°C. The reaction mixture was stirred at approximately 24°C for 2.5 hours. Separately, sodium bicarbonate (2800 g) and drinking water (40.0 L) were thoroughly mixed until a solution was obtained to prepare the solution. The solution was added over 36 minutes while maintaining the temperature at approximately 19°C until the pH reached 8-9. The reaction mixture was stirred at approximately 18°C ​​for 30 minutes. The phases were separated. The organic phase was extracted three times with methylene chloride (10.0 L per extraction). The combined organic phase was washed with drinking water (20.0 L). Separately, a solution was prepared by thoroughly mixing sodium chloride (2001 g) and drinking water (20.0 L) until a solution was obtained. The organic phase was washed with sodium chloride solution and then dried with MgSO4 (600 g). This mixture was filtered, and the filter cake was washed with methylene chloride (6.0 L). The combined filtrate and washing solution were concentrated under reduced pressure at 38°C to obtain crude 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9-ethyl-2-morpholine-4-ylmethyl-8-oxo-6,7,8,9-tetrahydro-3,4,7,9-tetraazacyclopenta[a]naphthalene-3-sulfonic acid dimethylamide (2200 g).Chromatography using 0-40% ethyl ammonium compounds in DCM yielded 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9-ethyl-2-morpholine-4-ylmethyl-8-oxo-6,7,8,9-tetrahydro-3,4,7,9-tetraaza-cyclopenta[a]naphthalene-3-sulfonic acid dimethylamide:C. 26 H 32 F2N6O6S[M+H] + Calculated LCMS value for this: 595.21; Measured value: 474.2. 1 H NMR(400MHz,DMSO-d6)δ 8.10(s,1H),7.05(t,1H),6.81(s,1H),4.80(s,2H),4.12(m,2H),3.91( s, 6H), 3.79 (s, 2H), 3.57 (m, 4H), 3.10 (s, 6H), 2.50 (m, 4H), 1.35 (m, 3H).

[0221] Example 7.3 Synthesis of 3-(2,6-difluoro-3-hydroxy-5-methoxyphenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (Compound 2) [ka]

[0222] A mixture of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-N,N-dimethyl-8-(morpholine-4-ylmethyl)-2-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-7-sulfonamide (44.88 g, 75.48 mmol) in 1,4-dioxane (400 mL, 4000 mmol) was stirred under N2 with a mixture of 12.0 M hydrogen chloride (1260 mL, 1510 mmol) in water, and water (1260 mL, 6990 mmol) was added via an addition funnel (internal temperature reached 35°C). The resulting solution was heated at 80°C for 18 hours. LC-MS showed that no starting material remained. The reaction mixture was cooled to room temperature, the organic solvent was concentrated, and the resulting HCl aqueous solution was diluted with 200 mL of 2N HCl solution. The resulting aqueous solution was extracted with DCM (3 x 80 mL), and the combined DCM phase was re-extracted with 6N HCl (80 mL). The combined HCl aqueous solution was stirred and cooled to 0-5°C with ice water. The acidic solution was neutralized by adding 25% NaOH (~200 mL) dropwise to pH > 12. The resulting solid (deprotected unreacted starting material or compound 1) was filtered and washed with water (3 x 250 mL). The basic aqueous solution was acidified to approximately pH 6 with HCl aqueous solution and extracted with DCM (3 x 30 mL). The combined DCM solution was dried over Na2SO4 and concentrated. Next, the crude product was slurryed with MTBE, filtered, washed again with MTBE, and dried overnight in a vacuum oven at 50°C to obtain 3-(2,6-difluoro-3-hydroxy-5-methoxyphenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (277 mg):C 23 H 26 F2N5O4[M+H] + Calculated LCMS value for this value: 474.47; Measured value: 474.2. 1H NMR(400MHz,DMSO-d6)δ 11.40(s,1H),9.95(s,1H),7.99(s,1H),6.78(m,1H),6.42(s,1H),4.76( s, 2H), 4.09 (m, 2H), 3.80 (s, 3H), 3.60 (m, 6H), 2.41 (m, 4H), 1.28 (m, 3H).

[0223] Example 8. Synthesis of 3-(2,6-difluoro-3,5-bis(methoxy-d3)phenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (compound 6) [ka]

[0224] Step 1. Synthesis of 3-(2,6-difluoro-3,5-dihydroxyphenyl)-1-ethyl-8-(morpholinomethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one A solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholinomethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (2.0 g, 3.2 mmol) in 25.0 mL of DCM was stirred while adding BBr3 (3.10 mL, 10.0 equivalents) (neat) dropwise at -78°C. After 30 minutes, the dry ice bath was removed and the reaction mixture was slowly warmed to room temperature. After 2 hours, HPLC showed that the starting material had disappeared. Next, the reaction mixture was cooled to 0°C, carefully treated with 20 mL of ice water, and stirred for 30 minutes. The resulting solid was filtered, washed with water, and dried overnight in a funnel. The crude product was treated with 20% MeOH in DCM (10 mL), stirred for 20 minutes, then filtered and dried to obtain 3-(2,6-difluoro-3,5-dihydroxyphenyl)-1-ethyl-8-(morpholinomethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one as a white solid (1.208 g, yield 61%). 28 H 28 F2N5O6S[M+H] + Calculated LCMS value for this material: 600.17; measured value: 600.4. This material was used in the next process without further purification.

[0225] Step 2: Synthesis of 3-(2,6-difluoro-3,5-bis(methoxy-d3)phenyl)-1-ethyl-8-(morpholinomethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one

[0226] 3-(2,6-difluoro-3,5-dihydroxyphenyl)-1-ethyl-8-(morpholinomethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (1.20 g, 2.00 mmol) and NaH (60% dispersion in mineral oil, 216 mg, 9.01 mmol) were stirred under N2 at room temperature for 15 minutes (to dissolve everything), and then MeI-D 3 (0.263 mL, 4.20 mmol) was added dropwise. After stirring at room temperature for 1 hour, the reaction mixture was cooled to 0°C, 30 mL of ice water was added, and the resulting solid was stirred for 30 minutes. The resulting solid was filtered, washed with water, and dried. The crude product was purified by biotage chromatography using 0-6% MeOH in DCM to obtain 3-(2,6-difluoro-3,5-bis(methoxy-d3)phenyl)-1-ethyl-8-(morpholinomethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one as a white solid (950 mg, yield 75%):C 30 H 26 D6F2N5O6S[M+H] + LCMS calculated value for this value: 634.23; measured value: 634.5. 1 ¹H NMR (400MHz, DMSO-d6) δ chromatography): 8.07 (s, 1H), 7.70 (m, 1H), 7.63 (m, 2H), 7.05 (m, 1H), 6.89 (s, 1H), 4.76 (s, 2H), 4.09 (m, 2H), 3.93 (s, 2H), 3.60 (m, 4H), 2.50 (m, 4H), 1.28 (m, 3H).

[0227] Step 3: Synthesis of 3-(2,6-difluoro-3,5-bis(methoxy-d3)phenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one 3-(2,6-difluoro-3,5-bis(methoxy-d3)phenyl)-1-ethyl-8-(morpholinomethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (1000 mg, 1.578 mmol) and 1N sodium hydroxide in water (6312 μl, 6.31 mmol) were added to 1,4-dioxane (10.0 mL). The solution was heated to 74°C (internal temperature) for 15 hours. LC-MS indicated completion of the reaction. The clear, pale yellow solution was cooled to room temperature (as the mixture cooled, the solid began to precipitate from the solution) to obtain an off-white suspension. Water (10.0 mL) was added at 20-25°C, and the resulting solid was stirred for 30 minutes. The solid was filtered and washed six times with water, and the pH of the final wash was checked (pH = approximately 7). Crude 1H NMR of the product (0.70 g) showed the presence of some dioxane.

[0228] Crude 3-(2,6-difluoro-3,5-bis(methoxy-d3)phenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (0.70 g, 1.418 mmol) in DCM (3.88 ml, 60.3 mmol) was heated to 22-36°C to obtain a clear solution. After about 5 minutes, MTBE (0.693 ml, 5.82 mmol) was added. After stirring for about 1 hour, a precipitate formed, and the mixture was stirred for a further 30 minutes. The mixture was filtered, washed with MTBE, washed with heptane, and dried in a vacuum oven under N2 at 50°C to obtain the product (0.63 g, 81% yield, 96% HPLC purity). The crude solid was purified using biotage chromatography with 0-10% MeOH in DCM, the fractions were combined and concentrated, and dried in a vacuum oven at 50°C to obtain 3-(2,6-difluoro-3,5-bis(methoxy-d3)phenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one with 99.5% HPLC purity:C 24 H 22D6F2N5O4[M+H] + LCMS calculated value for this: 494.24; measured value: 494.2. 1 ¹H NMR (400MHz, DMSO-d6) δ 11.75 (chromatography 9(s,1H), 7.05(m,1H), 6.89(s,1H), 4.76(s,2H), 4.09(m,2H), 3.60(m,6H), 2.50(m,4H), 1.28(m,3H).

[0229] Compound 6 may also be prepared according to Example 1, using 2,6-difluoro-3,5-bis(methoxy-d3)aniline instead of 2,6-difluoro-3,5-dimethoxyaniline. 2,6-difluoro-3,5-bis(methoxy-d3)aniline can be prepared according to Example 4, Step 3, using sodium methoxide-d3 instead of sodium methoxide.

[0230] Example A FGFR enzyme assay To detect product formation, the inhibitory efficacy of the exemplary compounds was determined using a discontinuous enzyme assay to measure peptide phosphorylation, employing FRET measurement. Inhibitors were serially diluted with DMSO, and 0.2 μL volumes were transferred to the wells of a 384-well plate. For FGFR isoforms containing phosphorylated and unphosphorylated proteins (FGFR-1, FGFR-2, FGFR-3 wild-type, and mutant isoforms, FGFR-4), 5 μL / well of enzyme diluted with assay buffer (50 mM HEPES, 10 mM MgCl2, 1 mM EGTA, 0.01% Tween-20, 5 mM DTT, pH 7.5) was added to the plate and pre-incubated with the inhibitor at ambient temperature for 5–15 minutes. Appropriate controls (enzyme blank and enzyme without inhibitor) were placed in the plate. The reaction was initiated by adding a 5 μL / well volume of assay buffer containing both the biotinylated EQEDEPEGDYFEWLE (SEQ ID NO: 1) peptide substrate and ATP. The reaction concentration of the peptide substrate was 500 nM at 10 μL / well, while the ATP concentration was maintained near or below the Km of ATP for each FGFR isoform. The ATP Km values ​​for each FGFR isoform were determined in advance in a series of separate experiments. The reaction plates were incubated at 25°C for 1 hour, and the reaction was terminated by adding a 5 μL / well quench solution (50 mM Tris, 150 mM NaCl, 0.5 mg / mL BSA, pH 7.8; 45 mM EDTA, 600 nM staurosporine, 3.75 nM Eu antibody PY20, and 180 nM APC-streptavidin Perkin-Elmer-Lance reagent). Before scanning with the PheraStar plate reader (BMG Labtech), the plates were allowed to equilibrate at ambient temperature for approximately 10 minutes.

[0231] The data was analyzed using either GraphPad prism or XLfit. The IC was calculated by fitting the data to a four-parameter logistic equation to generate a sigmoid dose-response curve with a variable Hill coefficient. 50The value was derived. Prism's equation: Y = Bottom + (Top - Bottom) / (1 + 10^((Log IC) 50 -X)*Hill slope)); XLfit equation: Y = (A + ((BA) / (1 + ((X / C)^D)))) (where X is the logarithm of the inhibitor concentration and Y is the response).

[0232] Table 1 below shows the FGFR inhibition data for various compounds in this disclosure. The symbol "+" indicates IC 50 This indicates that the impedance is less than 10 nM. "++" indicates an IC that is 10 nM or greater but less than 100 nM. 50 This indicates that the IC has a impedance of 100nM or more but less than 500nM. 50 This indicates; and "++++" indicates an IC with a power of 500nM or more but less than 1000nM. 50 This indicates. [Table 1]

[0233] Example B: KATOIII whole blood pFGFR2α ELISA assay To measure tyrosine-phosphorylated fibroblast growth factor receptor 2 alpha (FGFR2α) in the KATO III spike whole blood assay, KATO III cells were purchased from ATCC and maintained in Iscove medium containing 20% ​​FBS (Gibco / Life Technologies). To measure the inhibition of FGFR2α activity by the test compound, cells were divided into 5 × 10⁶ cells in Iscove, 0.2% FBS. 6The cells were resuspended at a concentration of cells / ml. Next, 50 μL of cells were spiked in 2 ml polypropylene assay blocks (Costar) with and without a range of test compounds and 300 μL of human heparinized whole blood (Biological Specialty Corp, Colmar PA) in a 96-deep well 1 / 2 ml polypropylene assay block (Costar). After incubation at 37°C for 4 hours, the erythrocytes were lysed with Qiagen EL buffer, and the cell lysates were resuspended for 30 minutes in lysis buffer (Cell Signaling) containing a standard protease inhibitor cocktail (Calbiochem / EMD) and PMSF (Sigma). The lysates were transferred to standard V-bottom propylene tissue culture plates and frozen overnight at -80°C. The samples were tested with R&D Systems DuoSet IC Human Phospho-FGF R2α ELISA, and the plates were measured using a SpectraMax M5 microplate set to 450 nm with a wavelength correction of 540. Using GraphPad Prism 5.0 software, IC is obtained by fitting the inhibitor inhibition percentage versus the logarithmic curve of the inhibitor concentration. 50 The decision was implemented.

[0234] KATOIII whole blood pFGFR2α ELISAIC 50 The data is shown in Table 2 below. The symbol "+" indicates IC 50 This indicates that the impedance is less than 50 nM. "++" indicates an IC that is 50 nM or greater but less than 250 nM. 50 This indicates that the IC has a impedance of 250nM or more but less than 500nM. 50 This indicates that the IC has a impedance of 500nM or more but less than 1000nM. 50 This indicates that the IC has a impedance of 1000nM or more but less than 3000nM. 50 This indicates. [Table 2]

[0235] Example C: Determination of permeability and P-gp-mediated transport in Caco-2 cells Caco-2 cells were grown in DMEM medium at a seeding density of 14,000 cells / well in 96-well transwell plates. To measure permeability in the absorption direction (AB), the HBSS test compound was added to the donor compartment (apical side), and 4% BSA of HBSS was added to the receiver compartment (basal side). To determine whether the compound was a P-gp substrate, permeability values ​​were measured in both the AB and BA directions in the absence of 4% BSA (bidirectional transport assay). Digoxin and cyclosporine A were included as positive controls for P-gp substrates and inhibitors, respectively, to ensure P-gp function in the bidirectional transport assay. Various concentrations of the test compound were added to the donor compartment (apical side for AB transport and basal side for BA transport), while the HBSS solution was added to the receiver compartment (basal side for AB transport and apical side for BA transport). In the AB-direction permeability study, the donor volume was 0.075 mL and the receiver volume was 0.25 mL. Incubation was performed at 37°C for 120 minutes. Transepithelial electrical resistance (TEER) was measured before and after the 120-minute incubation to confirm the integrity of the cell monolayer. At the end of the incubation period, the samples were removed from both the donor and receiver sides and mixed with acetonitrile for protein precipitation. The supernatant was collected after centrifugation for analysis using LC-MS / MS. The permeability coefficient (Papp) value from the Caco-2 study was determined using the following formula. Papp(cm / s) = (F*VD) / (SA*MD) Here, the flux (F, mass / time) is calculated from the slope of the cumulative amount of the target compound on the receiver side, SA is the surface area of ​​the cell membrane, VD is the volume of the donor, and MD is the initial volume of solution in the donor chamber.

[0236] The outflow ratio from the Caco-2 study was calculated as the ratio of Papp measured in the BA direction to Papp in the AB direction.

[0237] Permeability data for various compounds in this disclosure in Caco-2 cells are shown in Table 3 below. [Table 3]

[0238] The P-gp-mediated transport data for various compounds of this disclosure in Caco-2 cells are shown in Tables 4 and 5 below. [Table 4] [Table 5]

[0239] The efflux ratio of compound 1 at 30 μM is 0.64. In contrast, the efflux ratio of compound 2 at 30 μM is 19. This indicates that compound 2 is a more effective substrate for Pgp transport than compound 1, and that compound 2 is not sufficiently absorbed into the bloodstream. Compound 2 may be a candidate for IV administration or hepatic artery infusion for the treatment of diseases and disorders (e.g., cholangiocarcinoma).

[0240] Furthermore, while compound 1 exhibits a permeability of 11 Pm in Caco-2 cells, compound 2 exhibits a permeability of 0.5 Pm in Caco-2 cells. Considering the slight differences in compound structure, the large difference in permeability and efflux rates between compound 1 and compound 2 is unexpected.

[0241] Example D: Study on the absorption, metabolism, and excretion of Compound 1 in humans. [14C] An open-label study was conducted to evaluate the mass balance, pharmacokinetics, and metabolite profile of a single oral administration of compound 1. [ka]

[0242] Each of the seven male subjects received a single oral dose of 11 mg of compound 1 tablet along with a solution of compound 1 (approximately 250 μCi) after fasting overnight. Blood / plasma, urine, and feces were collected from the participants for 4 to 10 days after administration.

[0243] Human release criteria include the recovery of at least 90% of the administered radioactive dose, and the recovery of less than 1% of the administered radioactive dose in excrement (combined urine and feces) from two consecutive 24-hour urine and fecal collection samples.

[0244] 12.6% of the administered dose was recovered in urine, and 82.4% was recovered in feces. Overall recovery of radioactive decay in urine and feces was 95.1% in a 240-hour study. Rapid absorption was observed, with peaks in total radioactive and plasma compound 1 concentrations occurring approximately 2.0 hours after administration.

[0245] Figure 1 shows the mean cumulative percentage of radioactive doses recovered in urine and feces at specified intervals after a single oral administration of 13 mg (250 μCi) of [14C] compound 1 to healthy male subjects.

[0246] Figure 2 shows the mean radioactivity (nM equivalent) in blood or plasma and the concentration of compound 1 (nM) in plasma after a single oral administration of approximately 13 mg of [14C] compound 1 to fasted healthy male volunteers. The total radioactive decay and half-life of compound 1 in plasma were approximately 10 hours. The ratio of plasma compound 1 concentration to total plasma radioactivity was approximately 0.7, indicating that compound 1 is the major circulating component in plasma. The radioactivity ratio of blood to plasma (approximately 0.8) indicated a low correlation between radioactivity and blood cells.

[0247] As shown below, four minor circulating metabolites (<10% of compound-related substances) were observed. [ka]

[0248] Compound 2-1 is a glucuronide derivative of Compound 2. Compound 2-2 is a sulfonic acid derivative of Compound 2. Compound 1-1 is a keto derivative of Compound 1. The circles surrounding specific parts of the chemical structure indicate options for the attachment of glucuronide, sulfonic acid, and keto groups.

[0249] The percentage doses of each compound isolated from blood / plasma samples are shown in the table below. [Table 6]

[0250] Figure 3 shows the mass spectra of the human circulating metabolites of compound 1.

[0251] 12.6% of the administered dose was recovered in the urine. Two metabolites of compound 1 were isolated from the urine, as shown below. [ka]

[0252] The circles around specific parts of the chemical structure indicate options for the bonding of glucuronide and sulfonic acid groups. The percentage doses of each compound isolated from the urine sample are shown in the table below. [Table 7]

[0253] Figure 4 shows the mass spectrum of the metabolite of compound 1 isolated from urine.

[0254] 82.4% of the administered dose was recovered in the feces. The following metabolites of compound 1 were isolated from the feces. [ka]

[0255] Compound 4-1 is a keto derivative of Compound 4. Compound 2-3 is a keto derivative of Compound 2. Compound 1-2 is a dihydroxylated derivative of Compound 1. Circles surrounding specific parts of the chemical structure indicate options for hydroxyl and keto group bonding.

[0256] [Table 8]

[0257] Figure 5 shows the mass spectra of metabolites of compound 1 isolated from feces.

[0258] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. All references, including all patents, patent applications, and publications cited herein, are incorporated herein by reference in their entirety. Furthermore, this application also encompasses the following aspects. [Aspect 1] Compounds, including the following: 3-(2,6-difluoro-3-hydroxy-5-methoxyphenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one; and 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-4-hydroxy-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one The compound selected from, or a pharmaceutically acceptable salt thereof. [Aspect 2] The compound according to Embodiment 1, wherein the compound is 3-(2,6-difluoro-3-hydroxy-5-methoxyphenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one, or a pharmaceutically acceptable salt thereof. [Aspect 3] A compound according to Embodiment 1, wherein the compound is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-4-hydroxy-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one, or a pharmaceutically acceptable salt thereof. [Aspect 4] Compounds of formula II: [ka] In this formula, one CH group is replaced by a CX group, an NH group is replaced by an NX group, or an OH group is replaced by an OX group; where X is a group selected from the following: [ka] A compound selected from the above, or a pharmaceutically acceptable salt thereof. [Aspect 5] A compound according to Embodiment 4, or a pharmaceutically acceptable salt thereof, wherein X is

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Claims

1. A compound that is 3-(2,6-difluoro-3-hydroxy-5-methoxyphenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one, or a pharmaceutically acceptable salt thereof.

2. A composition comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

3. The composition according to claim 2, which is suitable for oral administration.

4. The composition according to claim 2, which is suitable for intravenous administration.

5. The composition according to claim 2, which is suitable for arterial administration.

6. The composition according to claim 5, wherein the arterial administration is hepatic artery injection.

7. A pharmaceutical agent for inhibiting an FGFR enzyme, comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof, or the composition described in any one of claims 2 to 6.

8. A pharmaceutical for treating cancer in a patient requiring treatment for cancer, comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof, or the composition described in any one of claims 2 to 6.

9. The pharmaceutical product according to claim 8, wherein the cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma, Waldenström macroglobulinemia, hairy cell lymphoma, Burkitt lymphoma, glioblastoma, melanoma, and rhabdomyosarcoma.

10. A pharmaceutical for treating myeloproliferative disorders in patients requiring treatment for myeloproliferative disorders, comprising the compound described in claim 1, a pharmaceutically acceptable salt thereof, or the composition described in any one of claims 2 to 6.

11. The pharmaceutical product according to claim 10, wherein the myeloproliferative disorder is selected from polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

12. A pharmaceutical for treating bone disorder or chondrocyte disorder in a patient requiring treatment for such disorder, comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof, or the composition described in any one of claims 2 to 6.

13. The pharmaceutical product according to claim 12, wherein the bone disorder or chondrocyte disorder is selected from achondroplasia, hypochondrodysplasia, dwarfism, thanatophoric dysplasia (TD), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Behle-Stevenson gyroscal syndrome, Pfeiffer syndrome, and craniosynostosis syndrome.

14. A pharmaceutical for treating hypophosphatemic disorders in patients requiring treatment for hypophosphatemic disorders, comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof, or the composition described in any one of claims 2 to 6.

15. The pharmacopoeia according to claim 14, wherein the hypophosphatemic disorder is X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, or tumor-induced osteomalacia.

16. A pharmaceutical for treating cholangiocarcinoma in a patient requiring treatment for cholangiocarcinoma, comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof, or the composition described in any one of claims 2 to 6.

17. The pharmaceutical product according to claim 16, wherein the cholangiocarcinoma is progressive or metastatic cholangiocarcinoma.

18. A pharmaceutical for treating myeloid / lymphoid tumors in patients requiring treatment for myeloid / lymphoid tumors, comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof, or the composition described in any one of claims 2 to 6.

19. The pharmaceutical product according to claim 18, wherein the myeloid / lymphoid tumor is 8p11 myeloproliferative syndrome.

20. The pharmacopoeia according to claim 18, wherein the myeloid / lymphoid tumor is related to eosinophilia.

21. Compound 2 having the following formula: 【Chemistry 1】 or a process for preparing the salt thereof: a) Compound F1 having the following formula: 【Chemistry 2】 The following compound F2 is formed by reacting it with an amino protective agent: 【Transformation 3】 or to provide a salt thereof, wherein P １ It is an amino protecting group; b) Compound F2 is reacted with DMF in the presence of B1, which is a base, to form compound F3 having the following formula: 【Chemistry 4】 To provide a salt thereof; c) Compound F3 is reacted with morpholine in the presence of the reducing agent RA1 to obtain compound F4 having the following formula: 【Transformation 5】 To provide a salt thereof; d) The process comprising reacting compound F4 with hydrochloric acid.

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