Bicyclic heteroaromatic compounds as trpml modulators

Abstract

The present disclosure provides compounds useful as modulators of TRPMLs, such as TPRML1, TRPML2, and / or TRPML3. In some embodiments, the compounds described herein are compounds represented by Formula I: I or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds described herein are useful for treating diseases, disorders, and conditions described herein, such as diseases, disorders, and conditions associated with TRPML modulation.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application No. 63 / 564,383, filed March 12, 2024, the entire contents of which are incorporated herein by reference. Background Technology

[0002] Transient receptor potential (TRP) channels TRPML1, TRPML2, and TRPML3 are Ca 2+ Cation channels are primarily located in intracellular compartments. For example, TRPML1 (also known as MCOLN1) is a Ca2+ channel in lysosomes. 2+ Channels that regulate certain aspects of lysosomal transport, including autophagy. See Wang et al., PNAS, E1373-E1381 (March 2, 2015). Specifically, TRPML1 is an inwardly rectifying current channel that transports cations from the lysosomal lumen to the cytosol. See Di Paolda et al., Cell Calcium 69:112-121 (2018). 2+ Released from lysosomes via TRPML1, it regulates the activity of transcription factor EB. See Medina et al., Nat. Cell. Biol., 17(3):288-299 (2015). Summary of the Invention

[0003] Recent studies have shown that upregulation of autophagy can be beneficial for patients with a variety of diseases and conditions. For example, it has been reported that inducing autophagy promotes the clearance of hepatotoxic α-1-antitrypsin (ATZ) from the liver. See Pastore, et al., EMBO Mol. Med. 5(3): 397-412 (March 2013). In addition, autophagy has recently been found to be useful in the treatment of neurodegenerative diseases, cancer, and heart disease. See Pierzynowska, et al., Metab. Brain Dis., 33(4); 989-1008 (2018) (discussing neurodegenerative diseases); Nelson & Shacka, Curr. Pathobiol. Rep., 1(4): 239-245 (2013) (discussing cancer); Sciaretta, et al., Annual Review of Physiology, 80:1-26 (2018) (discussing heart disease); Maiuri & Kroemer, Cell Death & Differentiation, 26: 680-689 (2019) (generally discussing the therapeutic applications of autophagy).

[0004] This disclosure specifically provides techniques for modulating (e.g., upregulating) autophagy. For example, in some embodiments, this disclosure demonstrates the effectiveness of certain methods of TRPML modulation (e.g., TRPML agonism, including agonism of TRPML1, TRPML2, and / or TRPML3) in enhancing autophagy. Therefore, this disclosure particularly demonstrates that targeting TRPML (e.g., TRPML1, TRPML2, and / or TRPML3) as described herein can enhance autophagy.

[0005] This disclosure also provides techniques for medical purposes, particularly for treating certain diseases, conditions or disorders and / or for identifying, characterizing and / or manufacturing certain agents and / or compositions that can be used to treat such diseases, conditions or disorders, or for containing or delivering them.

[0006] In some embodiments, this disclosure demonstrates that modulating (e.g., stimulating) TRPMLs (e.g., TRPML1, TRPML2 and / or TRPML3) and / or otherwise enhancing autophagy can be used to treat certain diseases, conditions or disorders.

[0007] Therefore, it is necessary to identify methods and mechanisms that promote autophagy. In view of the role of TRPML in autophagy, this paper describes TRPML modulators (e.g., TRPML1, TRPML2, and / or TRPML3) that can be used to promote autophagy and / or treat certain diseases, conditions, or disorders.

[0008] Specifically, this application provides techniques for adjusting TRPMLs (e.g., TRPML1, TRPML2, and / or TRPML3).

[0009] In some embodiments, this disclosure provides a compound represented by formula I: I Or a pharmaceutically acceptable salt thereof, wherein X, R 1 R 3 R 4 L 1 L 2 Rings A and p, individually and in combination, are as defined in the categories and subclasses of this paper.

[0010] In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound represented by Formula I or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, this disclosure provides a method for modulating TRPML in a subject, the method comprising administering the compound described herein to the subject.

[0012] In some embodiments, this disclosure provides a method for treating a disease, condition, or ailment of a subject, the method comprising administering to the subject a compound described herein. Attached Figure Description

[0013] Figure 1 Representative plots depict the abundance of α-synuclein in the striatum of rats treated with the compounds of this disclosure, compared to a control group. Each point represents one rat, and the horizontal line is the median for each treatment group.

[0014] Figure 2 Representative figures are presented, depicting the abundance of TH+ neurons in the substantia nigra hemisphere of rats treated with the disclosed compounds, compared to a control group. Each point represents one rat, and the horizontal line is the median for each treatment group.

[0015] Figure 3 Images of rat brain slices stained with TH+ (tyrosine hydrolase) neurons are presented, showing the abundance of neurons after treatment with the disclosed compounds compared to the control group. The boxed areas represent the substantia nigra of the injected hemisphere.

[0016] Figure 4 A representative graph is presented, depicting the percentage of survival in mice co-treated with the disclosed compound and conduritol-β-epoxide (CBE) compared to the control group and CBE alone.

[0017] Figure 5 A representative figure is presented, depicting the abundance of neurofilament light chains (NfL) in the cerebrospinal fluid of mice treated with the compound of this disclosure and CBE in combination, compared with the control group and CBE alone. Detailed Implementation

[0018] This disclosure particularly provides compounds and compositions as modulators of TRPMLs (e.g., TRPML1, TRPML2, and / or TRPML3). In some embodiments, the TRPML modulator is a TRPML agonist. In some embodiments, the TRPML modulator is a compound represented by formula I: I Or a pharmaceutically acceptable salt thereof, wherein X, R 1 R 3 R 4 L 1 L 2 Rings A and p, individually and in combination, are as described in the categories and subclasses of this paper.

[0019] Compounds and definitions The compounds disclosed herein include those generally described above, and are further illustrated by the classes, subclasses, and species disclosed herein. Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. Furthermore, the general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry”, 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0020] Unless otherwise stated, the structures described herein are intended to include all stereoisomers (e.g., enantiomers or diastereomers) of the structures, as well as all geometric or conformational isomers of the structures. For example, the R and S configurations of each stereocenter are considered as part of this disclosure. Therefore, single stereochemical isomers of the provided compounds, as well as enantiomers, diastereomers, and geometric (or conformational) mixtures, are within the scope of this disclosure. For example, in some cases, Table 1 shows one or more stereoisomers of the compounds, and unless otherwise stated, represents each stereoisomer individually and / or mixtures thereof. Unless otherwise stated, all tautomers of the provided compounds are within the scope of this disclosure.

[0021] Unless otherwise stated, the structures described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures having the structures of the present invention (including hydrogen replaced by deuterium or tritium, or carbon replaced by...) 13 C or 14 Compounds enriched by carbon substitution are within the scope of this disclosure.

[0022] Approximately or about:As used herein, the term "about" or "approximately" when applied to one or more values ​​of interest means a value similar to the stated reference value. Generally, those skilled in the art will understand the degree of difference covered by "about" or "approximately" in the context. For example, in some embodiments, the term "about" or "approximately" may cover a range of values ​​(i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the mentioned value.

[0023] application As used herein, the terms "administering" or "administration" generally refer to administering a composition to a subject to achieve delivery as a composition or an agent contained in a composition to a target site or site of treatment. Those skilled in the art will appreciate the various routes that may be used for administration to a subject (e.g., a human) where appropriate. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some specific embodiments, administration may be bronchial (e.g., via bronchial instillation), buccal, dermal (which may be or include, for example, one or more of the following: topical, intradermal, interdermal, transdermal, etc.), enteric, intra-arterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intravenous, intracardiac, intra-organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., via tracheal instillation), vaginal, vitreous, etc. In some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some specific embodiments, administration may be intravenous. In some specific embodiments, administration may be subcutaneous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve administering a fixed number of doses. In some embodiments, administration may involve intermittent (e.g., multiple doses separated by time) dosing and / or periodic (e.g., individual doses separated by the same time period) dosing. In some embodiments, administration may involve continuous dosing (e.g., infusion) for at least a selected time period. In some embodiments, administration may include a priming-boosting regimen. A priming-boosting regimen may include administering a first dose of a pharmaceutical composition (e.g., an immunogenic composition, such as a vaccine), followed by a second or subsequent dose of the pharmaceutical composition (e.g., an immunogenic composition, such as a vaccine) after a time interval. In the case of an immunogenic composition, a priming-boosting regimen may result in an enhanced immune response in the patient.

[0024] agonists As used herein, the term "agonist" generally refers to an agent whose presence or level is associated with an increased level or activity of the target compared to the level or activity of the target observed in the absence of the agent (or with different levels of the agent). In some embodiments, an agonist is an agent whose presence or level is associated with a target level or activity equivalent to or greater than a specific reference level or activity (e.g., the level or activity observed under appropriate reference conditions, such as the presence of a known agonist, for example, in a positive control). In some embodiments, an agonist may be a direct agonist because it directly exerts its effect on the target (e.g., directly interacts with the target); in some embodiments, an agonist may be an indirect agonist because it indirectly exerts its effect (e.g., through acting on a modulator of the target, such as interacting with a modulator of the target, or interacting with some other component or entity).

[0025] Aliphatic group: The term "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched hydrocarbon chain, substituted or unsubstituted, that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "alicyclic group") that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single or more connection points with the remainder of the molecule. Unless otherwise stated, an aliphatic group contains 1-12 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-6 aliphatic carbon atoms (e.g., C64 ... 1-6 In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-5 In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms (e.g., C46, ​​C56, C6 ... 1-4 In other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-3 In other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-2 Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl or ynyl groups, and their hybrid forms. Preferred aliphatic groups are C1. 1-6 Alkyl group. In some embodiments, the aliphatic group is a divalent group, such as alkylene, alkenylene, or ynylene.

[0026] alkyl: The term "alkyl" as used alone or as part of a larger part refers to having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C4, C5, C6, C7, C8, C9 ... 1-12 C1-10 C 1-8 C 1-6 C 1-4 C 1-3 Or C 1-2 The alkyl group may be optionally substituted with a saturated straight-chain or branched hydrocarbon group. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0027] Alkylene: The term "alkylene" refers to a divalent alkyl group. In some embodiments, "alkylene" is a divalent straight-chain or branched alkyl group. In some embodiments, the "alkylene chain" is a polymethylene group, i.e., (CH2). n - where n is a positive integer, such as 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are optionally replaced by substituents. Suitable substituents include those described below with respect to substituted aliphatic groups, and also those described in this specification. It should be understood that two substituents of an alkylene group can together form a ring system. In some embodiments, two substituents can together form a 3- to 7-membered ring. Substituents can be on the same or different atoms. The suffix “-ene” or “-enyl”, when attached to certain groups herein, is intended to refer to the bifunctional portion of said group. For example, “-ene” or “-enyl” when attached to “cyclopropyl” becomes “cyclopropylene” or “cyclopropylenyl”, and is intended to refer to a bifunctional cyclopropyl group, such as... .

[0028] Alkenyl: The term "alkenyl" used alone or as part of a larger part refers to having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C4, C5, C6, C7, C8, C9 ... 2-12 C 2-10 C 2-8 C 2-6 C 2-4 Or C 2-3 The optional substituted straight-chain, branched, or cyclic hydrocarbon group of the alkenyl group. Exemplary alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. The term "cycloalkenyl" refers to an optional substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0029] alkynyl group:The term "alkynyl" used alone or as part of a larger part refers to a group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C4, C5, C6, C7, C8, C9 ... 2-12 C 2-10 C 2-8 C 2-6 C 2-4 Or C 2-3 The optional substituted straight-chain or branched hydrocarbon group of ). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0030] Aryl: The term "aryl" refers to an aryl group having a total of six to fourteen ring members (e.g., C6-C). 14 The aryl group comprises monocyclic and bicyclic systems, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains three to seven ring members. In some embodiments, the aryl group contains a total of six to twelve ring members (e.g., C6-C1). 12 The term "aryl" is used interchangeably with the term "aryl ring." In some embodiments, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, anthracene, etc., which may have one or more substituents. Unless otherwise stated, "aryl" is a hydrocarbon. In some embodiments, the "aryl" ring system is an aromatic ring (e.g., phenyl) fused to a non-aromatic ring (e.g., cycloalkyl). Examples of fused aryl rings include... , and .

[0031] Double ring "Bicyclic" or "bicyclic system" refers to any bicyclic system, either saturated or having one or more unsaturated units, i.e., a carbon ring or heterocyclic ring, with one or more shared atoms between the two rings of the system. Therefore, the term includes any permitted ring fusion, such as... AdjacentFused or spirocyclic. As used herein, the term “heterocyclic bicycle” is a subset of “bicycle” that requires the presence of one or more heteroatoms in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and may optionally be substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridging bicycle” refers to any bicyclic system that is saturated or partially unsaturated and has at least one bridge, i.e., a carbocyclic or heterocyclic system. According to the IUPAC definition, a “bridge” is an unbranched chain of atoms or an atom or valence bond connecting two bridgeheads, wherein a “bridgehead” is any skeletal atom in the ring system bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridging bicyclic group has 7-12 ring members and 0-4 heteroatoms, said heteroatoms being independently selected from nitrogen, oxygen, or sulfur. Such bridging bicyclic groups are well known in the art and include those listed below, wherein each group is attached to the remainder of the molecule at any substituted carbon or nitrogen atom. Unless otherwise specified, the bridging bicyclic group is optionally substituted with one or more substituents as listed with respect to aliphatic groups. Additionally or alternatively, any substituted nitrogen atom in the bridging bicyclic group is optionally substituted. Exemplary bicycles include: An exemplary bridging dual ring includes: .

[0032] Biological samples:As used herein, the term "biological sample" generally refers to a sample obtained or derived from a biological source of interest (e.g., a tissue or organism or cell culture) described herein. In some embodiments, the source of interest includes an organism, such as an animal or a human. In some embodiments, the biological sample is or comprises biological tissue or fluid. In some embodiments, the biological sample may be or includes bone marrow; blood; blood cells; ascites; tissue or fine-needle biopsy samples; body fluids containing cells; free-floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; rinsing or lavage fluids, such as catheter lavage or bronchoalveolar lavage; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions and / or excretions; and / or cells derived therefrom, etc. In some embodiments, the biological sample is or comprises cells obtained from an individual. In some embodiments, the obtained cells are or comprise cells from the individual from whom the sample was obtained. In some embodiments, the sample is a "primary sample" obtained directly from the target source by any suitable means. For example, in some embodiments, the primary biological sample is obtained by a method selected from the group consisting of: biopsy (e.g., fine-needle aspiration or tissue biopsy), surgery, collection of bodily fluids (e.g., blood, lymph, feces, etc.), etc. In some embodiments, as will be clear from the context, the term "sample" refers to a preparation obtained by processing the primary sample (e.g., by removing one or more components of the primary sample and / or by adding one or more agents to the primary sample). For example, using semi-permeable membrane filtration. Such a "processed sample" may include, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting the primary sample to techniques such as amplification or reverse transcription of mRNA, separation and / or purification of certain components, etc.

[0033] Carrier: As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or medium applied together with the composition. In some exemplary embodiments, the carrier may include sterile liquids, such as water and oils, including petroleum, animal, plant, or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier is or comprises one or more solid components.

[0034] Composition: Those skilled in the art will understand that the term "composition" can be used to refer to a discrete physical entity comprising one or more specified components. Generally, unless otherwise stated, a composition can be in any form, such as a gas, gel, liquid, solid, etc.

[0035] Alicyclic groupAs used herein, the term "alicyclic group" refers to a monocyclic C-shaped group that is fully saturated or contains one or more unsaturated units but is not aromatic. 3-8 Hydrocarbons or bicyclic C 6-12 Hydrocarbons are molecules that have one or more connection points with the rest of the molecule.

[0036] cycloalkyl As used herein, the term "cycloalkyl" refers to an optionally substituted saturated cyclic monocyclic or polycyclic system having about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0037] Dosage form or Unit dosage form: Those skilled in the art will understand that the term "dosage form" can be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) intended for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, this amount is an amount (or a whole portion thereof) of a unit dose suitable for administration according to a dosing regimen determined to be relevant to the desired or beneficial outcome when administered to the relevant population (i.e., in relation to a therapeutic dosing regimen).

[0038] Dosing regimen or Treatment plan: Those skilled in the art will understand that the terms "dosing regimen" and "treatment regimen" can be used to refer to a set of unit doses (usually more than one) administered individually to a subject at typically intervals of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen includes multiple doses, each dose being temporally separated from the other doses. In some embodiments, the individual doses are spaced apart from each other by the same length of time; in some embodiments, a dosing regimen includes multiple doses, and the individual doses are spaced apart by at least two distinct time intervals. In some embodiments, all doses within a dosing regimen have the same unit dose amount. In some embodiments, the different doses within a dosing regimen have different amounts. In some embodiments, a dosing regimen includes a first dose of a first dose amount, followed by one or more additional doses of a second dose amount different from the first dose amount. In some embodiments, a dosing regimen includes a first dose of a first dose amount, followed by one or more additional doses of a second dose amount identical to the first dose amount. In some embodiments, a dosing regimen is associated with the expected or beneficial outcome when administered in a relevant population (i.e., a therapeutic dosing regimen).

[0039] Effective doseThe term "effective amount" refers to an amount of compound sufficient to produce a beneficial or desired result (e.g., therapeutic, ameliorative, inhibitory, or preventative effect). Effective amounts can be administered in one or more doses, by application, or by dosage, and are not intended to be limited to a particular formulation or route of administration.

[0040] excipient: As used herein, the term "excipient" refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or facilitate a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene, ethylene glycol, water, ethanol, etc.

[0041] halogen The term "halogen" or "halogenated" refers to F, Cl, Br, or I.

[0042] Aliphatic base As used herein, the term "heteroaliphatic group" or "heteroaliphatic moiety" refers to an optionally substituted hydrocarbon moiety having one to five heteroatoms in addition to carbon atoms. This moiety may be straight-chain (i.e., unbranched), branched, or cyclic ("heterocyclic") and may be fully saturated or contain one or more unsaturated units, but is not aromatic. The term "heteroatom" means nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. The term "nitrogen" also includes substituted nitrogen. Unless otherwise stated, a heteroaliphatic group contains 1 to 10 carbon atoms, wherein 1 to 3 carbon atoms are optionally and independently substituted with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, the heteroaliphatic group contains 1 to 4 carbon atoms, wherein 1 to 2 carbon atoms are optionally and independently substituted with heteroatoms selected from oxygen, nitrogen, and sulfur. In still other embodiments, the heteroaliphatic group contains 1 to 3 carbon atoms, wherein 1 carbon atom is optionally and independently substituted with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, straight-chain or branched heteroalkyl, heteroalkenyl, and heteroynyl groups. For example, heteroaliphatic groups containing 1 to 10 atoms include the following exemplary groups: -O-CH3, -CH2-O-CH3, -O-CH2-CH2-O-CH2-CH2-O-CH3, etc.

[0043] heteroaryl:The terms “heteroaryl” and “heteroaryl-”, used alone or as part of a larger portion (e.g., “heteroaryl-” or “heteroaryl-”), refer to monocyclic or bicyclic groups having 5 to 10 ring atoms (e.g., 5 to 6-membered monocyclic heteroaryl or 9 to 10-membered bicyclic heteroaryl); sharing 6, 10, or 14 π electrons in the ring array; and having one to five heteroatoms in addition to carbon atoms. Heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiazolyl, thiazolyl, pyridinyl, pyrazinyl, indoleazinyl, purine, naphridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrrolopyridinyl, pyrrolopyrazinyl, thiophenolopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. As used herein, the terms “heteroaryl” and “heteroary-” also include groups in which a heteroaryl ring is fused with one or more aryl, alicyclic or heterocyclic rings, wherein the linking group or linking point is on the heteroaryl ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, inzolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolinyl, carbazoleyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, and benzoisooxazolyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroarylene," any of which includes an optionally substituted ring.

[0044] Heteroatoms: As used herein, the term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of basic nitrogen.

[0045] Heterocyclic rings:As used herein, the terms “heterocycle,” “heterocyclic group,” “heterocyclic ring,” and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic, 6- to 10-membered bicyclic, or 10- to 16-membered polycyclic heterocyclic portion that is saturated or partially unsaturated and has one or more (such as one to four) heteroatoms as defined above, in addition to a carbon atom. When referring to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl), or NR. + (e.g., in N-substituted pyrrolidinyl groups). The heterocycle may be attached to its side group at any heteroatom or carbon atom that produces a stable structure, and any ring atom may optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, azirrobutyl, oxadiazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxalyl, dioxopentyl, diazaphenyl, oxazinyl, thioazinyl, morpholinyl, and thiomorpholinyl. The heterocyclic group may be monocyclic, bicyclic, tricyclic, or polycyclic, preferably monocyclic, bicyclic, or tricyclic, more preferably monocyclic or bicyclic. Bicyclic heterocycles also include groups in which the heterocycle is fused to one or more aryl rings. Exemplary bicyclic heterocyclic groups include indololinyl, isoidololinyl, benzodioxanepentenyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. Bicyclic heterocycles can also be spirocyclic systems (e.g., 7- to 11-membered spirocyclic fused heterocycles that, in addition to having a carbon atom, have one or more heteroatoms as defined above (e.g., one, two, three, or four heteroatoms)). Bicyclic heterocycles can also be bridging ring systems (e.g., 7- to 11-membered bridging heterocycles having one, two, or three bridging atoms).

[0046] regulator As used herein, the term "modulator" refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein). For example, in some embodiments, a modulator can cause an increase or decrease in the activity of a class of molecules compared to the activity in the absence of a modulator. For example, a modulator can be an agonist or antagonist of a specific target, as those terms are defined herein. For example, in some embodiments, a modulator is an agonist. In some embodiments, a modulator is an antagonist.

[0047] oral: As used herein, the phrases “oral administration” and “administered orally” have the meaning as understood in the art as referring to the oral administration of a compound or composition.

[0048] Extragastrointestinal: As used herein, the phrases “parenteral administration” and “administered parenterally” have their meanings as understood in the art, referring to a mode of administration other than enteral and local administration, usually by injection, and including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-bursal, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, spinal, and intrasternal injections and infusions.

[0049] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to cover rings having multiple unsaturated sites, but is not intended to include aromatic (e.g., aryl or heteroaryl) moiety as defined herein.

[0050] patient or Subjects: As used herein, the terms "patient" or "subject" refer to any organism to which the provided composition is applied or may be applied, for example, for experimental, diagnostic, preventative, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. In some embodiments, the patient or subject has or is susceptible to one or more conditions or disorders. In some embodiments, the patient or subject exhibits one or more symptoms of a condition or disorder. In some embodiments, the patient or subject has been diagnosed with one or more conditions or disorders. In some embodiments, the patient or subject is receiving or has received a therapy for the diagnosis and / or treatment of a disease, condition, or disorder.

[0051] Pharmaceutical composition:As used herein, the term "pharmaceutical composition" refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose suitable for administration in a treatment or dosing regimen that, when administered to a relevant population, shows a statistically significant likelihood of achieving a predetermined therapeutic effect. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for: oral administration, such as drench (aqueous or non-aqueous solution or suspension), tablets (e.g., those tablets targeted for absorption via the buccal, sublingual, and systemic routes), pellets, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, such as sterile solutions or suspensions or sustained-release formulations; topical administration, such as in the form of creams, ointments, or controlled-release patches or sprays to the skin, lungs, or mouth; intravaginal or rectal administration, such as in the form of vaginal suppositories, creams, or foams; sublingual; ocular; transdermal; or nasal, pulmonary, and other mucosal surfaces.

[0052] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” means compounds, materials, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0053] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salt" refers to a salt suitable for use in a pharmaceutical context, meaning a salt that, to the extent of reasonable medical judgment, is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, anaphylactic reactions, etc., and that is proportionate to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. in... J. Pharmaceutical SciencesPharmaceutically acceptable salts are described in detail in , 66: 1-19 (1977). Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0054] Furthermore, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are discussed in P. Stahl et al., Camille G. (edited) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences 1977, 66 (1), 1-19; P. Gould, International Journal of Pharmaceutics 1986, 33 , 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC, its website). These publications are incorporated herein by reference.

[0055] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed when appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, low-carbon alkyl sulfonates, and aryl sulfonates.

[0056] Prevention or Prevention: As used herein, the terms “prevent” or “prevention” when used in connection with the occurrence of a disease, condition, and / or disorder refer to reducing the risk of developing a disease, condition, and / or disorder, and / or delaying the onset of one or more features or symptoms of a disease, condition, and / or disorder. Prevention is considered complete when the onset of a disease, condition, or disorder is delayed by a predetermined period of time.

[0057] Replaced or Optional replacement: As described herein, the compounds of the present invention may contain an "optionally substituted" portion. Generally, the term "substituted," regardless of whether it is preceded by the term "optionally," means that one or more hydrogens of the specified portion are replaced by suitable substituents. "Substituted" applies to one or more hydrogens explicitly or implicitly indicated by the structure (e.g., At least refers to ;and At least refers to , , or Unless otherwise specified, a “optionally substituted” group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure may be substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated in this invention are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term “stable” means that a compound remains substantially unchanged when subjected to conditions that allow for its production, detection, and, in some embodiments, its recovery, purification, and use for one or more purposes provided herein. A group described as “substituted” preferably has between one and four substituents, more preferably one or two substituents. A group described as “optionally substituted” may be unsubstituted or “substituted” as described above.

[0058] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently a halogen; –(CH2) 0-4 R ;-(CH2) 0-4 OR ;-O(CH2) 0-4 R -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR )2;-(CH2) 0-4 SR ;-(CH2) 0-4 Ph, which can be replaced by R°; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -Pyridyl group, which can be substituted with R°; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R )2;-(CH2) 0-4 N(R )C(O)R ;-N(R )C(S)R ;-(CH2) 0-4 N(R )C(O)NR 2; -N(R) )C(S)NR 2;-(CH2) 0-4 N(R )C(O)OR ;-N(R )N(R )C(O)R ;-N(R )N(R )C(O)NR 2; -N(R) )N(R )C(O)OR ;-(CH2) 0-4 C(O)R ;C(S)R ;-(CH2) 0-4 C(O)OR ;-(CH2) 0–4 C(O)SR ;-(CH2) 0-4 C(O)OSiR 3; -(CH2) 0-4 OC(O)R ;-OC(O)(CH2) 0- 4SR°;-(CH2) 0-4 SC(O)R ;-(CH2) 0-4 C(O)NR 2; -C(S)NR 2;-C(S)SR°;-SC(S)SR°;-(CH2) 0–4 OC(O)NR 2; -C(O)N(OR) )R ;-C(O)C(O)R ;-C(O)CH2C(O)R ;-C(NOR) )R ;-(CH2) 0-4 SSR ;-(CH2) 0-4 S(O)2R ;-(CH2) 0-4 S(O)2OR ;-(CH2) 0–4 OS(O)2R ;-S(O)2NR 2;-(CH2) 0-4 S(O)R ;-N(R )S(O)2NR 2; -N(R) )S(O)2R ;-N(OR) )R ;-C(NH)NR 2; -P(O)2R ;-P(O)R 2; -OP(O)R 2; -OP(O)(OR )2; SiR 3; -(C 1-4 (linear or branched alkylene)ON(R) )2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R) )2, where each R It can be replaced as defined below, and is independently hydrogen, C 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0- 1Ph, -CH2- (5- to 6-membered heteroaryl ring) or 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur, or, despite the above definition, two independently occurring R Together with one or more intermediate atoms, they form 3 to 12 saturated, partially unsaturated, or aryl monocyclic or bicyclic rings with 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0059] R (or by using two independently occurring R) Suitable monovalent substituents on the ring formed together with their intermediate atoms are independently halogens, -(CH2). 0-2 R ● -(halogenated R) ● -(CH2) 0–2 OH, -(CH2) 0-2 OR ● -(CH2) 0-2 CH(OR ● )2、-O(halogenated R ● -CN, -N3, -(CH2) 0-2 C(O)R ● -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● -(CH2) 0-2 SR ● -(CH2) 0-2 SH, -(CH2) 0-2 NH2、-(CH2) 0-2 NHR ● -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● -(C 1-4 (linear or branched alkylene)C(O)OR ● or -SSR ● , where each R ● It is either unsubstituted or, when previously "halogenated", substituted by only one or more halogens, and independently selected from C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. R Suitable divalent substituents on saturated carbon atoms include =O and =S.

[0060] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O ("oxo"), =S, =NNR. *2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R) * 2)) 2-3 O- or -S(C(R) * 2)) 2-3 S-, where each independently occurring R * Selected from hydrogen; C 1-6 Aliphatic groups, which may be substituted as defined below; or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the ortho-substituted carbon of the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independently occurring R * Selected from hydrogen; C 1-6 Aliphatic group, which may be substituted as defined below; or an unsubstituted 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0061] In R * Suitable substituents on aliphatic groups include halogens, -R ● -(halogenated R) ● -OH, -OR ● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, when previously "halogenated", substituted by only one or more halogens, and is independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0062] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R -NR 2. -C(O)R -C(O)OR -C(O)C(O)R -C(O)CH2C(O)R -S(O)2R -S(O)2NR 2. -C(S)NR 2. -C(NH)NR 2 or -N(R) )S(O)2R ; where each R It is hydrogen on its own; C 1–6 Aliphatic group, which may be substituted as defined below; unsubstituted -OPh; or unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur; or, although defined above, two independently occurring R groups. Together with one or more intermediate atoms, they form unsubstituted 3 to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic rings with 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0063] R Suitable substituents on aliphatic groups include halogens, -R ● -(halogenated R) ● -OH, -OR ● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, when previously "halogenated", substituted by only one or more halogens, and is independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0064] Small molecules: As used herein, the term "small molecule" refers to a low molecular weight organic and / or inorganic compound. Typically, a "small molecule" is a molecule smaller than about 5 kilodaltons (kD). In some embodiments, small molecules are smaller than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, small molecules are smaller than about 800 Daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, small molecules are smaller than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, the small molecule is not a polymer.

[0065] In some embodiments, the small molecule does not contain a polymeric moiety. In some embodiments, the small molecule is not and / or does not contain a protein or polypeptide (e.g., not an oligopeptide or peptide). In some embodiments, the small molecule is not and / or does not contain a polynucleotide (e.g., not an oligonucleotide). In some embodiments, the small molecule is not and / or does not contain a polysaccharide; for example, in some embodiments, the small molecule is not a glycoprotein, proteoglycan, glycolipid, etc. In some embodiments, the small molecule is not a lipid.

[0066] In some embodiments, the small molecule is a modulator (e.g., an inhibitor or activator). In some embodiments, the small molecule is biologically active. In some embodiments, the small molecule is detectable (e.g., containing at least one detectable moiety). In some embodiments, the small molecule is a therapeutic agent.

[0067] Those skilled in the art will understand upon reading this disclosure that certain small molecule compounds described herein may be provided and / or utilized in any of a variety of forms, such as, for example, crystalline forms (e.g., polymorphs, solvates, etc.), salt forms, protected forms, prodrug forms, ester forms, isomer forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0068] Those skilled in the art will understand that certain small molecule compounds have structures that can exist in one or more stereoisomeric forms. In some embodiments, such small molecules can be utilized according to this disclosure as individual enantiomers, diastereomers, or geometric isomers, or as mixtures of stereoisomers; in some embodiments, such small molecules can be utilized as racemic mixtures other than those disclosed herein.

[0069] Those skilled in the art will understand that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such small molecules can be utilized according to this disclosure either as individual tautomers or in a form that interchanges between tautomeric forms.

[0070] Those skilled in the art will understand that some small molecule compounds allow isotope substitution (e.g., 2 H or 3 H replaces H; 11 C 13 C or 14 C replaces 12 C; 13 N or 15 N replaces 14 N; 17 O or 18 O replaced 16 O; 36 Cl replaced 35 or37 Cl; 18 F replaces 19 F; 131 I replace 127 The structure of (I, etc.). In some embodiments, this small molecule may be utilized according to this disclosure in one or more isotope-modified forms or mixtures thereof.

[0071] In some embodiments, references to a particular small molecule compound may refer to a specific form of the compound. In some embodiments, the particular small molecule compound may be provided and / or utilized in salt form (e.g., an acid addition salt or a base addition salt, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0072] In some embodiments, when the small molecule compound is a compound that is present or found in nature, the compound may be provided and / or utilized according to this disclosure in a form different from that which is present or found in nature. Those skilled in the art will understand that in some embodiments, a formulation of a particular small molecule compound, when containing an absolute or relative amount of the compound or a particular form thereof that differs from the absolute or relative amount (relative to another component of the formulation, including, for example, another form of the compound) present in a target reference formulation (e.g., in a primary sample from a target source, such as a biological or environmental source), is distinctly different from the compound present in the reference formulation or source. Therefore, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered a compound in a form different from a racemic mixture of the compound; a specific salt of a small molecule compound may be considered a form different from another salt form of the compound; a preparation containing only one conformational isomer ((Z) or (E)) containing a double bond may be considered a compound in a form different from another conformational isomer ((E) or (Z)) containing a double bond; a preparation in which one or more atoms are isotopes different from the isotopes present in a reference preparation may be considered a different form; etc.

[0073] Those skilled in the art will also understand that, in small molecule structures, as used herein, symbols... This refers to the junction between two atoms. Alternatively, the symbol... It refers to a ring connection point in a spiral manner.

[0074] treat:As used herein, the terms “treat,” “treatment,” or “treating” refer to any method used to partially or completely alleviate, improve, mitigate, suppress, prevent, or delay the onset of one or more symptoms or features of a disease, condition, and / or disorder, reduce its severity, and / or decrease its incidence. Treatment may be administered to a subject who does not exhibit signs of a disease, condition, and / or disorder. In some embodiments, treatment may be administered to a subject who exhibits only early signs of a disease, condition, and / or disorder, for example, to reduce the risk of developing a pathology associated with said disease, condition, and / or disorder.

[0075] In some implementations, "floating" substituents plotted on the ring indicate that the substituents can be present anywhere on the ring. For example, for something like... The bicyclic moiety allows substituents to be present at any position and to substitute for one or both hydrogen atoms in the CH moiety, the NH moiety, and / or the CH2 moiety. In some embodiments, "floating" substituents drawn on one ring of the bicyclic moiety indicate that the substituents can be present on either ring of the bicyclic moiety (e.g., [missing information]). and (They are equivalent). Substituents can be present at any position on either ring of the bicyclic portion and can replace one or more hydrogen atoms bonded to atoms in one or more rings of the bicyclic portion. For example, for such... The substituents can be present in either ring of the bicyclic moiety and can replace the hydrogen atoms of the CH moiety, the hydrogen atoms of the NH moiety, and / or one or two hydrogen atoms of the CH2 moiety.

[0076] TRPML and autophagy Autophagy is the mechanism by which cells degrade cytoplasmic material and organelles. Several types of autophagy exist: (1) macroautophagy (commonly referred to as autophagy); (2) microautophagy; and (3) chaperone-mediated autophagy. See Eskelinen & Saftig, Biochimica et Biophysica Acta – Mol. Cell Res., 1793(4):664-673 (2009). In macroautophagy, autophagosomes engulf waste material in the cytoplasm and fuse with lysosomes, where substances are delivered for degradation. Lysosomes are subcellular organelles containing more than 50 soluble acidic hydrolases that can digest cellular components. The fusion of lysosomes with autophagosomes partially facilitates the release of ions (including Ca2+) via ion channels in the lysosomal membrane. 2+ ) to activate. See Cao et al., J. Bio. Chem., 292(20)8424-8435 (2017).

[0077] Transient receptor potential lipoprotein-1 (also known as TRPML1 or ML1) is a Ca2+ receptor agonist in lysosomes that regulates autophagy. 2+ Channel. See Wang et al., PNAS, E1373-E1381 (March 2, 2015). Specifically, TRPML1 is an inwardly rectifying current channel that transports cations from the lysosomal lumen to the cytosol. See Di Paolda et al., CellCalcium 69:112-121 (2018). 2+ TRPML1 release from lysosomes, recruitment by ATG16L1, and GABARAP conjugation regulate the activity of transcription factor EB, ultimately inducing autophagy and lysosomal biogenesis. See Goodwin et al., Science Advances, Vol. 7, No. 40 (2021).

[0078] Recent studies have shown that upregulation of autophagy can be beneficial for patients with a variety of diseases and conditions. For example, it has been reported that inducing autophagy promotes the clearance of hepatotoxic α-1-antitrypsin (ATZ) from the liver. See Pastore, et al., EMBO Mol. Med. 5(3): 397-412 (March 2013). In addition, autophagy has recently been found to be useful in the treatment of neurodegenerative diseases, cancer, and heart disease. See Pierzynowska, et al., Metab. Brain Dis., 33(4); 989-1008 (2018) (discussing neurodegenerative diseases); Nelson & Shacka, Curr. Pathobiol. Rep., 1(4): 239-245 (2013) (discussing cancer); Sciaretta, et al., Annual Review of Physiology, 80:1-26 (2018) (discussing heart disease); Maiuri & Kroemer, Cell Death & Differentiation, 26: 680-689 (2019) (generally discussing the therapeutic applications of autophagy). Therefore, there is a need to identify methods and mechanisms that promote autophagy. Given the role of TRPML in autophagy, this article describes TRPML1 modulators that can be used to promote autophagy and / or treat certain diseases, conditions, or disorders.

[0079] This disclosure provides the following insight: TRMPL can represent a particularly desired target, which in particular allows for the modulation (e.g., enhancement) of autophagy in certain circumstances.

[0080] TRPML regulator In some embodiments, this disclosure provides and / or utilizes TRMPL modifiers (e.g., TRPML1, TPRML2, and / or TPRML3), which are small molecule compounds having the chemical structure shown in Formula I: I Or its pharmaceutically acceptable salt, wherein X is N or CR 2 ; R 1 It is a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S; a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S; C6-C 12 Aryl; or C3-C 12 Alicyclic groups, in which R 1 Optionally by one or more R 1a replace; Each R 1a Independently -CN, halogen, -OR a -C(O)N(R) a )2、-N(R a )C(O)R a Optional substituted C1-C6 aliphatic groups, optional substituted C3-C7 alicyclic groups; L 1 It is a bond, N(R) a ), O or optionally substituted C1-C6 aliphatic groups; R 2 It is H, optionally substituted C3-C7 alicyclic group, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted C1- to 6-membered alicyclic group, or optionally substituted 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S. Ring A is a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S; L 2 It is -C(O)-, -C(O)O-, -N(R) a )C(O)-、-C(O)N(R a -S(O)-, -S(O)2-, optional substituted 4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O and S, or optional substituted 4- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S. R 3 It is an optional substituted C1-C6 aliphatic group or an optional substituted 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S; Each R4 Independently, the C1-C6 aliphatic groups are optionally substituted; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; and p can be 0, 1, 2, 3, or 4.

[0081] In some embodiments, this disclosure provides a compound represented by formula I-2: I-2 Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 R 4 Ring A, L 1 L 2 p, individually and in combination, is as described in the categories and subclasses of this paper.

[0082] In some embodiments, this disclosure provides a compound represented by formula II-1: II-1 Or a pharmaceutically acceptable salt thereof, wherein R 1a R 2 R 3 R 4 Ring A, L 2 p, individually and in combination, is as described in the categories and subclasses of this paper.

[0083] In some embodiments, this disclosure provides a compound represented by formula II-2: II-2 Or a pharmaceutically acceptable salt thereof, wherein R 1a R 2 R 3 R 4 and L 2 Individually and in combination as described in the categories and subclasses of this article.

[0084] In some embodiments, this disclosure provides a compound represented by formula III-1: III-1 Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 R 4 and L 2Individually and in combination as described in the categories and subclasses of this article.

[0085] In some embodiments, this disclosure provides a compound represented by formula IV-1: IV-1 Or a pharmaceutically acceptable salt thereof, wherein R 1 R 3 R 4 L 1 L 2 Rings A and p, individually and in combination, are as described in the categories and subclasses of this paper.

[0086] In some embodiments, this disclosure provides a compound represented by formula IV-2: IV-2 Or a pharmaceutically acceptable salt thereof, wherein R 1a R 2 R 3 R 4 Ring A, L 2 p, individually and in combination, is as described in the categories and subclasses of this paper.

[0087] In some embodiments, this disclosure provides a compound represented by formula V-1: V-1 Or a pharmaceutically acceptable salt thereof, wherein X, R 1a R 3 R 4 Ring A, L 2 p, individually and in combination, is as described in the categories and subclasses of this paper.

[0088] As described in this document with respect to any of the provided formulas, X is N or CR. 2 In some implementations, X is N. In some implementations, X is CR. 2 .

[0089] As described in this document with respect to any of the provided formulas, L 1 It is a bond, N(R) a ), O, or optionally substituted C1-C6 aliphatic groups. In some embodiments, L 1 It is a key. In some implementations, L 1 It is -N(R) a In some implementations, L 1 It is -N(H)-. In some implementations, L 1It is -N (C1-C6 aliphatic group). In some implementations, L 1 It is -N(CH3)-. In some implementations, L 1 Yes -O-. In some implementations, L 1 It is an optional substituted C1-C6 aliphatic group. In some embodiments, L 1 It is an optional substituted C1-C6 alkylene group. In some embodiments, L 1 It is -CH2-. In some implementations, L 1 It is a bond or an optional substituted C1-C6 aliphatic group.

[0090] As described in this document with respect to any of the provided formulas, R 1 It is a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S; a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S; C6-C 12 Aryl; or C3-C 12 Alicyclic groups, in which R 1 Optionally by one or more R 1a replace.

[0091] In some implementation schemes, R 1 It is a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, and optionally separated by one or more R 1a Replacement. In some implementations, R 1 It is a bicyclic 7- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R 1 It is a monocyclic 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, and optionally separated by one or more R atoms. 1a Replacement. In some implementations, R 1 It is a monocyclic 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, and is bonded by one or more R atoms. 1a Replacement. In some implementations, R 1 It is a monocyclic 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, and is separated by an R 1a Replacement. In some implementations, R 1 It is a monocyclic 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, and substituted with -CN. In some embodiments, R 1 It is a monocyclic 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, and is modified by -CN, optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C7 alicyclic groups, or -OR. a or -C(O)N(R) a)2 is replaced. In some implementations, R 1 It is a monocyclic 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, and substituted with -CN, -CF3, cyclopropyl, -OCF3, or -C(O)NH2. In some embodiments, R 1 It is a monocyclic 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, and is bonded by one or more R atoms. 1a Replace, where R 1a Selected from -CN, optionally substituted C1-C6 aliphatic groups, optionally substituted C3-C7 alicyclic groups, -OR a and -C(O)N(R) a )2. In some implementation schemes, R 1 It is a monocyclic 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, and is bonded by one or more R atoms. 1a Replace, where R 1a Selected from -CN, -CF3, cyclopropyl, -OCF3, and -C(O)NH2. In some embodiments, R 1 It is pyridyl or pyrazinyl, which is optionally surrounded by one or more R 1a Replacement. In some implementations, R 1 It is pyridyl or pyrazinyl, and is influenced by one or more R groups. 1a Replacement. In some implementations, R 1 yes: or In some implementations, R 1 yes or In some implementations, R 1 yes , , , , or In some implementations, R 1 yes or In some implementations, R 1 yes .

[0092] In some implementation schemes, R 1 It is a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, and optionally separated by one or more R atoms. 1a Replacement. In some implementations, R 1 It is a monocyclic 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, and optionally separated by one or more R atoms. 1a Replacement. In some implementations, R1 It is a monocyclic 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with one or more -CN atoms. In some embodiments, R 1 It is a monocyclic 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with a -CN atom. In some embodiments, R 1 It is a monocyclic 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, and is constituting one or more R atoms. 1a Replacement. In some implementations, R 1 It is a monocyclic 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, and is bounded by an R 1a Replacement. In some implementations, R 1 It is a monocyclic 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, and substituted with one or more -CN atoms. In some embodiments, R 1 It is a monocyclic 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, and substituted with a -CN atom. In some embodiments, R 1 It is an aza-heterocyclic butyl, pyrrolidinyl, piperidinyl, pyrazinyl, tetrahydropyranyl, or morpholinyl group, and optionally is radically oxidized by one or more R groups. 1a Replacement. In some implementations, R 1 It is a tetrahydropyranyl or morpholinyl group, and optionally is separated by one or more R groups. 1a Replacement. In some implementations, R 1 yes or In some implementations, R 1a yes or .

[0093] In some implementation schemes, R 1 It is a bicyclic 7- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, and optionally separated by one or more R atoms. 1a replace.

[0094] In some implementation schemes, R 1 It is C6-C 12 aryl, and optionally by one or more R 1a Replacement. In some implementations, R 1 It is a phenyl group, and optionally is influenced by one or more R groups. 1a Replacement. In some implementations, R 1 It is naphthyl, and optionally is construed by one or more R 1a replace.

[0095] In some implementation schemes, R1 Yes or C3-C 12 Alicyclic group, and optionally by one or more R 1a Replacement. In some implementations, R 1 It is a monocyclic C3-C7 alicyclic group, and optionally surrounded by one or more R groups. 1a Replacement. In some implementations, R 1 It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and optionally converted by one or more R 1a Replacement. In some implementations, R 1 It is Shuanghuan C7-C 12 Alicyclic group, and optionally by one or more R 1a replace.

[0096] In some implementation schemes, R 1 It is a 5- to 1-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S; or a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, wherein R 1 Optionally by one or more R 1a Replacement. In some implementations, R 1 It is a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S; or a 4- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, wherein R 1 Optionally by one or more R 1a Replacement. In some implementations, R 1 It is a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S; or a 4- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, wherein R 1 Optionally by an R 1a Replacement. In some implementations, R 1 It is a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S; or a 4- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, wherein R 1 By an R 1a replace.

[0097] In some implementation schemes, R 1 It is pyridinyl, pyridazinyl, tetrahydropyranyl, or morpholinyl, optionally with one or more R 1a Replacement. In some implementations, R 1 It is pyridinyl, pyridazinyl, tetrahydropyranyl, or morpholinyl, optionally separated by an R 1a Replacement. In some implementations, R 1 It is pyridinyl, pyridazinyl, tetrahydropyranyl, or morpholinyl, which is radicalized by one or more R 1aReplacement. In some implementations, R 1 It is pyridinyl, pyridazinyl, tetrahydropyranyl, or morpholinyl, which is formed by an R 1a replace.

[0098] In some implementation schemes, R 1 yes , , or .

[0099] In some implementation schemes, R 1 yes , , , , , , or .

[0100] As described in this article, each R 1a Independently -CN, halogen, -OR a -C(O)N(R) a )2、-N(R a )C(O)R a Optionally substituted C1-C6 aliphatic groups, Optionally substituted C3-C7 alicyclic groups.

[0101] In some implementation schemes, R 1a Yes - CN.

[0102] In some implementation schemes, R 1a It is a halogen. In some implementations, R 1a It is fluorine, iodine, bromine, or chlorine.

[0103] In some implementation schemes, R 1a Yes - OR a In some implementations, R 1a It is OH. In some implementations, R 1a It is an -O-C1-C6 aliphatic group. In some implementations, R 1a It is -OCH3. In some implementations, R 1a It is -O- (optionally substituted C1-C6 aliphatic group). In some embodiments, R 1a It is -OCF3.

[0104] In some implementation schemes, R 1a It is -C(O)N(R) a )2. In some implementation schemes, R 1a It is -C(O)NH2. In some implementations, R1a It is -C(O)N(H)(CH3). In some implementations, R 1a It is -C(O)N(CH3)2.

[0105] In some implementation schemes, R 1a It is -N(R) a )C(O)R a In some implementations, R 1a It is -N(H)C(O)CH3.

[0106] In some implementation schemes, R 1a It is an optional substituted C1-C6 aliphatic group. In some embodiments, R 1a It is an optional substituted C1-C6 alkyl group. In some embodiments, R 1a It is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 1a It is -CF3.

[0107] In some implementation schemes, R 1a It is an optional C3-C7 alicyclic group that can be substituted. In some embodiments, R 1a It is a C3-C7 alicyclic group. In some implementations, R 1a It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R 1a It is cyclopropyl.

[0108] In some implementations, each R 1a Independently -CN, -OR a -C(O)N(R) a 2. Optional substituted C1-C6 aliphatic groups or optional substituted C3-C7 alicyclic groups. In some embodiments, each R 1a Independently -CN, -OR a -C(O)N(R) a 2. Optional substituted C1-C6 aliphatic groups or C3-C7 alicyclic groups. In some embodiments, each R 1a It can be -CN, -CF3, cyclopropyl, -OCF3 or -C(O)NH2 independently.

[0109] As described in this article, R 2 It is H, an optionally substituted C3-C7 alicyclic group, an optionally substituted phenyl group, an optionally substituted 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S, an optionally substituted C1- to 6-membered alicyclic group, or an optionally substituted 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S.

[0110] In some implementation schemes, R 2 It is H.

[0111] In some implementation schemes, R 2 It is an optional C3-C7 alicyclic group that can be substituted. In some embodiments, R 2 It is a C3-C7 alicyclic group. In some implementations, R 2 It is an optional substituted C3-C7 cycloalkyl group. In some embodiments, R 2 It is a C3-C7 cycloalkyl group. In some embodiments, R 2 It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R 2 yes .

[0112] In some implementation schemes, R 2 It is an optional substituted phenyl group. In some embodiments, R 2 It is phenyl.

[0113] In some implementation schemes, R 2 It is an optionally substituted 5- to 6-membered heteroaryl group, containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R 2 It is a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R 2 It is pyrrole, imidazole, pyrazol, triazol, pyridyl, pyrimidinyl, or pyridazinyl. In some embodiments, R 2 It is pyridyl. In some embodiments, R 2 yes .

[0114] In some implementation schemes, R 2 It is an optional substituted C1-C6 aliphatic group. In some embodiments, R 2 It is a C1-C6 aliphatic group. In some implementations, R 2 It is an optional substituted C1-C6 alkyl group. In some embodiments, R 2 It is a C1-C6 alkyl group. In some embodiments, R 2 It is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 2 It is -CH2-CH3 or -CH3. In some implementations, R 2 It is an optional C1-C6 aliphatic group substituted with a halogen. In some embodiments, R 2 It is -CF3. In some implementations, R2 is -CH2-CH3, -CH3, or -CF3.

[0115] In some implementation schemes, R 2 It is a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, which are optionally substituted. In some embodiments, R 2 It is a 4- to 7-membered heterocyclic ring. In some implementations, R 2 The morpholino group is optionally substituted. In some embodiments, R 2 It is morpholino. In some embodiments, R 2 yes: .

[0116] In some implementation schemes, R 2 It is H; an optionally substituted C3-C7 alicyclic group; an optionally substituted 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S; an optionally substituted C1-C6 alicyclic group; or an optionally substituted 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 2 It is H; a C3-C7 alicyclic group; a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S; an optionally substituted C1- to C6 alicyclic group; or an optionally substituted 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S.

[0117] In some implementation schemes, R 2 It is: -H, -CH3, -CH2-CH3, -CF3, ,or In some implementations, R 2 It is: -H, -CH3, -CH2-CH3, -CF3, , or .

[0118] As described herein, ring A is a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, ring A is an optionally substituted monocyclic 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, ring A is optionally substituted with a piperidinyl or piperazine group. In some embodiments, ring A is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with –(CH2). 0-4 R Replacement. In some embodiments, ring A is a 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally replaced by R. Substitution, wherein R° is a C1-C6 aliphatic group. In some embodiments, ring A is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, ring A is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with -CH3. In some embodiments, ring A is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S.

[0119] In some embodiments, ring A is a 7- to 12-membered bicyclic (e.g., a bridging bicyclic) heterocyclic containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, ring A is a 7- to 8-membered bicyclic (e.g., a bridging bicyclic) heterocyclic containing 1 to 4 heteroatoms selected from N, O, and S.

[0120] In some embodiments, ring A is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, or a 7- to 8-membered bicyclic (e.g., bridging bicyclic) heterocycle containing 1 to 4 heteroatoms selected from N, O, and S.

[0121] In some implementation schemes, one part: yes: ;in Representative and L 2 The connection point.

[0122] In some implementation schemes, one part: yes: , , , , , , , , , or ;in Representative and L 2 The connection point.

[0123] In some implementation schemes, one part: yes: , , , , , , , , , , , , , , , , or ;in Representative and L 2 The connection point.

[0124] In some implementation schemes, one part: yes: , , , , , , , , , , , or ;in Representative and L 2 The connection point.

[0125] In some implementation schemes, one part: yes: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;in Representative and L 2 The connection point.

[0126] In some implementation schemes, one part: yes: , , , , , , , or .

[0127] In some implementation schemes, one part: yes: , , , , , , , ,or .

[0128] In some implementation schemes, one part: yes: , , , , , , , , , , , , , , ,or .

[0129] In some implementation schemes, one part: yes: , , , , , , , , , or .

[0130] In some implementation schemes, one part: yes: , , , , , , or .

[0131] In some implementation schemes, one part: yes: , , , , , , or .

[0132] In some implementation schemes, one part: yes: , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0133] In one implementation, part Selected from: , , , , , , and .

[0134] As described in this article, L 2 It is -C(O)-, -C(O)O-, -N(R) a )C(O)-、-C(O)N(R a -, -S(O)-, -S(O)2-, 4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O and S, or 4- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S.

[0135] In some implementations, L 2 It is -C(O)-.

[0136] In some implementations, L 2 It is -C(O)O-. In some implementations, L 2 It is -C(O)O-*, where * indicates that it is related to R. 3 The connection point.

[0137] In some implementations, L 2 It is -N(R) a )C(O)-.

[0138] In some implementations, L 2 It is -C(O)N(R) a )-.

[0139] In some implementations, L 2 It is -S(O)-.

[0140] In some implementations, L 2 It is -S(O)2-.

[0141] In some implementations, L 2 It is -C(O)-, -C(O)O-, or -S(O)2-.

[0142] In some implementations, L 2 It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted.

[0143] In some implementations, L 2 It is a 4- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which are optionally substituted.

[0144] In some implementations, L 2 It is -C(O)-, -C(O)O-, -S(O)- or -S(O)2-.

[0145] As described in this article, R 3 It is an optionally substituted C1-C6 aliphatic group or an optionally substituted 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 It is a C1-C6 aliphatic group or an optional substituted 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S.

[0146] In some implementation schemes, R 3 It is an optional substituted C1-C6 aliphatic group. In some embodiments, R 3 It is a C1-C6 aliphatic group. In some implementations, R 3 It is an optional C1-C6 aliphatic group substituted with a halogen. In some embodiments, R 3 It is an optional substituted C1-C6 alkyl group. In some embodiments, R 3 It is a C1-C6 alkyl group. In some embodiments, R 3 It is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 3 It is -CH3, -CH(CH3)2, or -C(CH3)3. In some implementations, R 3 yes , , or In some implementations, R 3 It is -C(CH3)3, -CH(CH3)2, or -CH2--C(CH3)3.

[0147] In some implementation schemes, R 3 It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, which are optionally substituted. In some embodiments, R 3 It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, and optionally prefixed with –(CH2). 0–4 R Replacement. In some implementations, R 3 It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with R°, where R° is a C1-C6 aliphatic group. In some embodiments, R... 3 It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with -CH3. In some embodiments, R3 It is an optional substituted oxobutane. In some embodiments, R 3 It is an oxobutane optionally substituted with -CH3. In some embodiments, R 3 It is an oxobutane substituted with -CH3. In some embodiments, R 3 It is a pyrroleyl group. In some embodiments, R 3 It is optionally a substituted oxetane or pyrrole alkyl group. In some embodiments, R 3 It is either an oxane or a pyrrole alkyl group that is optionally substituted with -CH3.

[0148] In some implementation schemes, R 3 yes , , , , , or In some implementations, R 3 yes , , , , or .

[0149] In some implementations, L 2 It is -C(O)-, -C(O)O-, or -S(O)2-, and R 3 It is an optionally substituted C1-C6 aliphatic group or an optionally substituted 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, L 2 It is -C(O)-, -C(O)O-, or -S(O)2-, and R 3 It is an optional substituted C1-C6 aliphatic group. In some embodiments, L 2 It is -C(O)-, -C(O)O-, S(O) or -S(O)2-, and R 3 It is an optionally substituted C1-C6 aliphatic group or an optionally substituted 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, L 2 It is -C(O)-, -C(O)O-, S(O) or -S(O)2-, and R 3 It is a C1-C6 aliphatic group or an optional substituted 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S.

[0150] As described in this article, each R 4 Independently, the C1-C6 aliphatic groups are optionally substituted. In some embodiments, R4 It is an optional substituted C1-C6 alkyl group. In some embodiments, R 4 It is methyl, ethyl, propyl, butyl, pentyl, hexyl, or heptyl. In some embodiments, R 4 It is -CH3. In some implementations, R 4 It is cyclopropyl. In some implementations, R 4 It is methyl, isopropyl, or cyclopropyl.

[0151] As described herein, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1-4. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0152] In some implementation schemes, one part: yes: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0153] In some implementation schemes, one part: yes: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0154] In some implementation schemes, one part: yes: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0155] In some implementation schemes, one part: yes: , or .

[0156] In some implementation schemes, one part: yes: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0157] As described in this article, each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups.

[0158] In some implementation schemes, R a It's H.

[0159] In some implementation schemes, R a It is an optional substituted C1-C6 aliphatic group. In some embodiments, R a It is an optional substituted C1-C6 alkyl group. In some embodiments, R a It is -CH3. In some implementations, R a It is -CF3.

[0160] In some embodiments, the compounds described herein are compounds represented by Formula I, wherein: R 1 It is a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein R 1 Optional by one or more R 1a replace; Each R 1a Independently, it is -CN or halogen; L 1 It is a key; R 2 It is H, an optionally substituted C3-C7 alicyclic group, an optionally substituted C1-C6 alicyclic group, or an optionally substituted 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S. Ring A is a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S; L 2 It is -C(O)-, -C(O)O-, -N(R) a )C(O)-、-C(O)N(R a -, -S(O)-, -S(O)2-; Each R 4 Independently, the C1-C6 aliphatic groups are optionally substituted; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; and p is 0, 1, or 2, and X is N or CR. 2 And R 3 It is an optional substituted C1-C6 aliphatic group or an optional substituted 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S.

[0161] In some embodiments, the compounds described herein are compounds represented by Formula I, wherein: X is N or CR 2 ; R 1 It is a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, or a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, wherein R 1Optional by one or more R 1a replace; Each R 1a Independently -CN, -OR a -C(O)N(R) a 2. The substituted C1-C6 aliphatic group or C3-C7 alicyclic group can be selected; L 1 It is a key; R 2 It is a C3-C7 alicyclic group, a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S, an optionally substituted C1- to 6 alicyclic group, or a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S. Ring A is a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S; L 2 It is -C(O)-, -C(O)O-, -S(O)- or -S(O)2-; R 3 It is a C1-C6 aliphatic group or a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S that are optionally substituted; Each R 4 Independently, they are C1-C6 aliphatic groups; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; and p is 0, 1, or 2.

[0162] In some embodiments, compounds of the formulas described herein (e.g., any of formulas I to V-1) are selected from Table 1: Table 1 In some embodiments, the provided compounds are provided and / or utilized in salt form (e.g., pharmaceutically acceptable salt form). Unless otherwise indicated, references to compounds provided herein should be understood to include references to their salts.

[0163] Uses, formulations and application Pharmaceutically acceptable compositions According to another embodiment, this disclosure provides a composition comprising the compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or excipient. In some embodiments, the composition described herein is formulated for administration to a patient requiring such a composition. In some embodiments, the composition described herein is formulated for oral administration to a patient.

[0164] According to the methods of this disclosure, compounds and compositions are administered in any amount and via any route of administration that effectively treats or reduces the severity of the condition described herein. The exact amount required will vary depending on the subject's species, age and general condition, the severity of the infection, the specific agent, the mode of administration, etc. The compounds described herein are preferably formulated in unit dosage forms to facilitate dosage administration and consistency.

[0165] The pharmaceutical compositions disclosed herein can be administered orally, parenterally, via inhaled aerosol, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracerebralally, or via an implanted reservoir. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously.

[0166] The sterile injectable form of the compositions described herein may be an aqueous or oily suspension. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, parenteral-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Water, Ringer's solution, and isotonic sodium chloride solution may be used among acceptable media and solvents. Furthermore, sterile, non-volatile oils are routinely used as solvents or suspension media.

[0167] To achieve this purpose, any mild, non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Fatty acids (such as oleic acid and its glyceride derivatives) may be used in the preparation of injections, as may natural, pharmaceutically acceptable oils, such as olive oil or castor oil (especially in their polyoxyethylene forms). These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants, such as Tween and Span, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used to achieve the desired formulation.

[0168] Injectable formulations may be sterilized, for example, by filtration through a bacterial trapping filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which may be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[0169] To prolong the effects of the compounds disclosed herein, it is often necessary to slow the absorption of compounds injected subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous substances. The absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of parenteral-administered compound forms can be achieved by dissolving or suspending the compound in an oil-based medium. Injectable reservoir forms are prepared by forming microcapsule matrices of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. The rate of compound release can be controlled depending on the compound-to-polymer ratio and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Reservoir-type injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0170] In some embodiments, the pharmaceutically acceptable compositions provided are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions described herein may be administered without food. In other embodiments, the pharmaceutically acceptable compositions described herein may be administered with food. The pharmaceutically acceptable compositions described herein can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are often added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are intended for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavoring agents, or coloring agents may also be added.

[0171] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or the following substances: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain silicates, and sodium carbonate; e) dissolution delayers, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) adsorbents, such as kaolin and bentonite; and / or i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0172] Similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules with coatings and shells such as enteric coatings and other coatings known in the field of pharmaceutical formulation can be prepared. These may optionally contain emulsifiers and may also have compositions that optionally delay or preferentially release the active ingredient in a portion of the intestine. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0173] The active compound can also be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical formulation field. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose, or starch. It is common practice that such dosage forms may also contain additional substances besides inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also contain buffers. They may optionally contain light-blocking agents and may also be compositions that, at a site in the intestine, optionally release only or preferentially the active ingredient in a delayed manner. Examples of encapsulation compositions that can be used include polymers and waxes.

[0174] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0175] Alternatively, the pharmaceutically acceptable compositions described herein can be used in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0176] Compositions for rectal or vaginal application are preferably suppositories, which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or suppository waxes. The suppository is solid at ambient temperature but liquid at body temperature, and thus melts and releases the active compound in the rectal or vaginal cavity.

[0177] The pharmaceutically acceptable compositions described herein can also be applied topically, especially when the therapeutic target includes diseases of areas or organs easily accessible by topical application, including the eyes, skin, or lower intestine. Suitable topical formulations are readily prepared for each of these areas or organs.

[0178] Local application to the lower intestine can be achieved with rectal suppositories (see above) or with suitable enema formulations. Topical transdermal patches may also be used.

[0179] For topical application, the provided pharmaceutically acceptable compositions may be formulated into suitable ointments containing an active ingredient suspended or dissolved in one or more carriers. Carriers for the topical application of the compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the provided pharmaceutically acceptable compositions may be formulated into suitable lotions or creams containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, dehydrated sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanool, benzyl alcohol, and water.

[0180] For ophthalmic applications, the provided pharmaceutically acceptable composition can be formulated into a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably, into a solution in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzyl chlorobenzyl ammonium. Alternatively, for ophthalmic applications, the pharmaceutically acceptable composition can be formulated into an ointment such as petrolatum.

[0181] The pharmaceutically acceptable compositions described herein can also be administered via nasal aerosol or inhaler. Such compositions are prepared using techniques well-known in the field of pharmaceutical formulation, and can be prepared into solutions in physiological saline using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0182] Dosage forms for topical or transdermal application of the compounds disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic preparations, ear drops, and eye drops are also covered within the scope of this disclosure. Furthermore, this disclosure covers the use of transdermal patches, which have the added advantage of controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0183] Applications and uses This application provides for a variety of uses and applications of the compounds and / or compositions described herein, for example, based on their activity and / or properties as described herein. In some embodiments, such uses may include therapeutic and / or diagnostic uses. Alternatively, in some embodiments, such uses may include research, manufacturing, and / or other technical uses.

[0184] Among other embodiments, this disclosure provides techniques for modulating TRPML activity (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof). In some embodiments, this application relates to a method for modulating TRPML activity (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) in a subject, the method comprising administering a compound or composition provided herein to the subject. In some embodiments, this application relates to a method for modulating TRPML1 activity in a subject, the method comprising administering a compound or composition provided herein to the subject. In some embodiments, this application relates to a method for modulating TRPML2 activity in a subject, the method comprising administering a compound or composition provided herein to the subject. In some embodiments, this application relates to a method for modulating TRPML3 activity in a subject, the method comprising administering a compound or composition provided herein to the subject. In some embodiments, this application relates to a method for modulating the activity of TRPML1, TRPML2, and / or TRPML3 in a subject, the method comprising administering a compound or composition provided herein to the subject.

[0185] Diseases, symptoms and illnesses This disclosure confirms that the compounds and / or compositions described herein can be used in medicine (e.g., for the treatment of one or more diseases, conditions or disorders).

[0186] As described herein, this disclosure provides in particular the insight that targeting (e.g., stimulating) TRPMLs (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) can be a particularly effective strategy for regulating (e.g., enhancing) autophagy, lysosomal biogenesis, and / or lysosomal exocytosis.

[0187] In some embodiments, a disease, condition, or ailment that can be treated as described herein may be or include a disease, condition, or ailment associated with a deficiency of TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof). Furthermore, in some embodiments, this disclosure identifies a deficiency of TRMPL (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) as associated with a specific disease, condition, or ailment, some or all of which may be treatable according to this disclosure.

[0188] In some implementations, the treatments provided herein involve administering the TRMPL1 modulators described herein to effectively regulate the activity of TRMPLs (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) in lysosomes and / or increase the amount of autophagy.

[0189] In some implementations, the disease, condition, or ailment for which the treatment described herein is applicable is or includes liver disease, neurodegenerative disease, cancer, or heart disease.

[0190] In some implementations, the diseases, conditions, or disorders applicable to the treatments described herein are or include lysosomal storage diseases such as Niemann-Pick C (NPC) disease, Gaucher disease, Fabry disease, cholesterol ester storage diseases, Batten disease, and Pompe disease.

[0191] In some implementations, the diseases, conditions, or disorders for which the treatments described herein are applicable are common age-related neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease.

[0192] In some implementations, the disease, condition, or disorder suitable for the treatment described herein is a type IV mucopolysaccharidosis (ML4) neurodegenerative lysosomal storage disease caused by mutations in TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof).

[0193] In some implementations, the diseases, conditions, or disorders to which the treatments described herein are applicable involve reactive oxygen species or oxidative stress.

[0194] In some embodiments, this application relates to the use of the compounds and / or compositions described herein in the manufacture of a medicament, for example, for modulating the activity of TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof).

[0195] In some embodiments, this application relates to the use of the compounds and / or compositions described herein in the manufacture of a medicament intended to treat a disease, condition, or ailment, for example, by modulating the activity of TRPMLs (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof); in some embodiments, the disease, condition, or ailment is liver disease, neurodegenerative disease, cancer, or heart disease.

[0196] In some implementations, the disease, symptom, or disorder is a muscle disease, liver disease, metabolic disease, atherosclerotic disease, inflammatory bowel disease, neurodegenerative disease, or neoplastic disease. In some implementations, the disease, symptom, or disorder is a muscle disease. In some implementations, the muscle disease is muscular dystrophy. In some implementations, the muscular dystrophy is Duchenne muscular dystrophy.

[0197] In some implementations, the disease, symptom, or illness is an infectious disease. In some implementations, the infectious disease is Helicobacter pylori (Helicobacter pylori). Heliobacter pylori ) or Mycobacterium tuberculosis ( Mycobacterium tuberculosis ) infection.

[0198] In some implementation schemes, the disease, symptom, or illness is tuberculosis.

[0199] Exemplary Implementation The following numbered embodiments, while not restrictive, are examples of certain aspects of this disclosure: Implementation Scheme 1. A compound represented by Formula I: I Or its pharmaceutically acceptable salt, wherein X is N or CR 2 ; R 1 It is a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S; a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S; C6-C 12 Aryl; or C3-C 12 Alicyclic groups, in which R 1 Optionally by one or more R 1a replace; Each R 1a Independently -CN, halogen, -OR a -C(O)N(R) a )2、-N(R a )C(O)R aOptional substituted C1-C6 aliphatic groups, optional substituted C3-C7 alicyclic groups; L 1 It is a bond, N(R) a ), O or optionally substituted C1-C6 aliphatic groups; R 2 It is H, optionally substituted C3-C7 alicyclic group, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted C1- to 6-membered alicyclic group, or optionally substituted 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S. Ring A is a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S; L 2 It is -C(O)-, -C(O)O-, -N(R) a )C(O)-、-C(O)N(R a -S(O)-, -S(O)2-, optional substituted 4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O and S, or optional substituted 4- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S. R 3 It is an optional substituted C1-C6 aliphatic group or an optional substituted 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S; Each R 4 Independently, the C1-C6 aliphatic groups are optionally substituted; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; and p can be 0, 1, 2, 3, or 4.

[0200] Implementation Scheme 2. The compound as described in Implementation Scheme 1, wherein L 1 It is a key.

[0201] Implementation Scheme 3. The compound as described in Implementation Scheme 1 or 2, wherein R 1 It is a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, and optionally surrounded by one or more R atoms. 1a replace.

[0202] Implementation Scheme 4. The compound as described in any of Implementation Schemes 1-3, wherein R 1 It is a monocyclic 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, and is bonded by one or more R atoms. 1a replace.

[0203] Implementation Scheme 5. The compound as described in any of Implementation Schemes 1-4, wherein R 1 It was R 1a Substituted pyridine.

[0204] Implementation Scheme 6. The compound as described in any of Implementation Schemes 1-5, wherein R 1a Yes - CN.

[0205] Implementation Scheme 7. The compound as described in any of Implementation Schemes 1-6, wherein R 1 yes: , , , , , , or .

[0206] Implementation Scheme 8. The compound as described in any of Implementation Schemes 1-7, wherein R 2 It is an optional C3-C7 alicyclic group that can be substituted.

[0207] Implementation Scheme 9. The compound as described in any of Implementation Schemes 1-8, wherein R 2 Selected from: -H, -CH3, -CH2-CH3, -CF3, and Implementation Scheme 10. The compound as described in any of Implementation Schemes 1-9, wherein ring A is a monocyclic 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S.

[0208] Implementation Scheme 11. The compound as described in any of Implementation Schemes 1-10, wherein ring A is piperidine or piperazine.

[0209] Implementation Scheme 12. The compound as described in any of Implementation Schemes 1-11, wherein ring A is piperidine.

[0210] Implementation Scheme 13. The compound as described in any of Implementation Schemes 1-9, wherein ring A is a bridging bicyclic 6- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S.

[0211] Implementation Scheme 14. The compound as described in any of Implementation Schemes 1-13, wherein p is 0.

[0212] Implementation Scheme 15. The compound as described in any of Implementation Schemes 1-13, wherein p is 1 or 2.

[0213] Implementation Scheme 16. The compound as described in any of Implementation Schemes 1-13 or 15, wherein each R 4 It is -CH3.

[0214] Implementation Scheme 17. The compound as described in any of Implementation Schemes 1-16, wherein L 2 It is -C(O)-, -C(O)O-*, or -S(O)2-, where * indicates a partial R 3 The connection point.

[0215] Implementation Scheme 18. The compound as described in any of Implementation Schemes 1-17, wherein L 2 It is -C(O)O-*, where * indicates a partial R 3 The connection point.

[0216] Implementation Scheme 19. The compound as described in any of Implementation Schemes 1-18, wherein R 3 It is an optional C1-C6 aliphatic group that can be substituted.

[0217] Implementation Scheme 20. The compound as described in any of Implementation Schemes 1-19, wherein R 3 yes: , , , , , or .

[0218] Implementation Scheme 21. The compound as described in any of Implementation Schemes 1-20, wherein a portion thereof: yes: , , , , , , , , , or ;in Representative and L 2 The connection point.

[0219] Implementation Scheme 22. The compound as described in any of Implementation Schemes 1-21, wherein a portion thereof: yes: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0220] Implementation Scheme 23. The compound as described in any of Implementation Schemes 1-12 or 14-22, wherein yes: , or .

[0221] Implementation Scheme 24. A compound as described in any of Implementation Schemes 1-23, wherein the compound is represented by Formula I-2: I-2 Or its pharmaceutically acceptable salt.

[0222] Implementation Scheme 25. A compound as described in any of Implementation Schemes 1-24, wherein the compound is represented by Formula II-1: II-1 Or its pharmaceutically acceptable salt.

[0223] Implementation Scheme 26. A compound as described in any of Implementation Schemes 1-12 or 14-25, wherein the compound is represented by Formula II-2: II-2 Or its pharmaceutically acceptable salt.

[0224] Implementation Scheme 27. A compound as described in any of Implementation Schemes 1-12 or 14-26, wherein the compound is represented by Formula III-1: III-1 Or its pharmaceutically acceptable salt.

[0225] Implementation Scheme 28. The compound as described in any of Implementation Schemes 1-27, wherein the compound or a pharmaceutically acceptable salt thereof is selected from Table 1.

[0226] Implementation Scheme 29. A pharmaceutical composition comprising a compound as described in any one of Implementation Schemes 1-28 and a pharmaceutically acceptable carrier or excipient.

[0227] Implementation Scheme 30. A method for modulating TRMPL in a subject, the method comprising administering to the subject a compound as described in any of Implementation Schemes 1-28 or a pharmaceutical composition as described in Implementation Scheme 29.

[0228] Implementation Scheme 31. A method for treating a disease, symptom, or ailment of a subject, the method comprising administering to the subject a compound as described in any of Implementation Schemes 1-28 or a pharmaceutical composition as described in Implementation Scheme 29.

[0229] Implementation Scheme 32. The method as described in Implementation Scheme 31, wherein the disease, symptom, or ailment is a lysosomal storage disorder.

[0230] Implementation Scheme 33. The method as described in Implementation Scheme 32, wherein the lysosomal storage disease is selected from Niemann-Pick C disease, Gaucher disease, Barten disease, cholesterol ester storage disease, Fabry disease, and Pompe disease.

[0231] Implementation Scheme 34. The method as described in Implementation Scheme 31, wherein the disease, symptom, or ailment is a common age-related neurodegenerative disease.

[0232] Implementation Scheme 35. The method as described in Implementation Scheme 31 or 34, wherein the disease, symptom or ailment is selected from Alzheimer's disease, Parkinson's disease and Huntington's disease.

[0233] Implementation Scheme 36. The method as described in Implementation Scheme 31 or 32, wherein the disease, symptom or disorder is a type IV mucopolysaccharidosis (ML4) neurodegenerative lysosomal storage disease caused by a mutation in TRPML.

[0234] Implementation Scheme 37. The method as described in Implementation Scheme 31, wherein the disease, symptom, or ailment is a muscle disease, liver disease, metabolic disease, atherosclerotic disease, inflammatory bowel disease, neurodegenerative disease, tumor disease, or infectious disease.

[0235] Implementation Scheme 38. The method as described in Implementation Scheme 37, wherein the disease, symptom, or ailment is a muscle disease.

[0236] Implementation Scheme 39. The method as described in Implementation Scheme 38, wherein the muscle disease is muscular dystrophy.

[0237] Implementation Scheme 40. The method as described in Implementation Scheme 39, wherein the muscular dystrophy is Duchenne muscular dystrophy.

[0238] Implementation Scheme 41. The method as described in Implementation Scheme 31, wherein the disease, symptom, or ailment is an infectious disease.

[0239] Implementation Scheme 42. The method as described in Implementation Scheme 41, wherein the infectious disease is an infection of Helicobacter pylori or Mycobacterium tuberculosis.

[0240] Implementation Scheme 43. A compound represented by Formula I: I Or its pharmaceutically acceptable salt, wherein X is N or CR 2 ; R 1 It is a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S; a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S; C6-C 12 Aryl; or C3-C 12 Alicyclic groups, where R 1 Optionally by one or more R 1a replace; Each R 1a Independently -CN, halogen, -OR a -C(O)N(R) a )2、-N(R a )C(O)R a Optional substituted C1-C6 aliphatic groups, optional substituted C3-C7 alicyclic groups; L 1 It is a bond, N(R) a ), O or optionally substituted C1-C6 aliphatic groups; R 2 It is H, optionally substituted C3-C7 alicyclic group, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted C1- to 6-membered alicyclic group, or optionally substituted 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S. Ring A is a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S; L 2 It is -C(O)-, -C(O)O-, -N(R) a )C(O)-、-C(O)N(R a -S(O)-, -S(O)2-, optional substituted 4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O and S, or optional substituted 4- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S. R 3 It is an optional substituted C1-C6 aliphatic group or an optional substituted 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S; Each R 4 Independently, the C1-C6 aliphatic groups are optionally substituted; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; and p can be 0, 1, 2, 3, or 4.

[0241] Implementation Scheme 44. The compound as described in Implementation Scheme 43, wherein L 1 It is a key.

[0242] Implementation Scheme 45. The compound as described in Implementation Scheme 43 or 44, wherein R 1 It is a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, and optionally surrounded by one or more R atoms. 1a replace.

[0243] Implementation Scheme 46. The compound as described in any of Implementation Schemes 43-45, wherein R 1 It is a monocyclic 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, and is bonded by one or more R atoms. 1a replace.

[0244] Implementation Scheme 47. The compound as described in any of Implementation Schemes 43-46, wherein R 1 It was R 1a Substituted pyridinyl group.

[0245] Implementation Scheme 48. The compound as described in any of Implementation Schemes 43-47, wherein R 1a Yes - CN.

[0246] Implementation Scheme 49. The compound as described in any of Implementation Schemes 43-48, wherein R 1 yes: , , , , , , or .

[0247] Implementation Scheme 50. The compound as described in any of Implementation Schemes 43-49, wherein R 2 It is an optional C3-C7 alicyclic group that can be substituted.

[0248] Implementation Scheme 51. The compound as described in any of Implementation Schemes 43-50, wherein R 2 Selected from: -H, -CH3, -CH2-CH3, -CF3, , and .

[0249] Implementation Scheme 52. The compound as described in any of the embodiments 43-51, wherein ring A is a monocyclic 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S.

[0250] Implementation Scheme 53. The compound as described in any of Implementation Schemes 43-52, wherein ring A is piperidinyl or piperazineyl.

[0251] Implementation Scheme 54. The compound as described in any of Implementation Schemes 43-53, wherein ring A is piperidinyl.

[0252] Implementation Scheme 55. The compound as described in any of the embodiments 43-51, wherein ring A is a bridging bicyclic 6- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S.

[0253] Implementation Scheme 56. The compound as described in any of Implementation Schemes 43-55, wherein p is 0.

[0254] Implementation Scheme 57. The compound as described in any of Implementation Schemes 43-55, wherein p is 1 or 2.

[0255] Implementation Scheme 58. The compound as described in any of Implementation Schemes 43-55 or 57, wherein each R 4 It is -CH3.

[0256] Implementation Scheme 59. The compound as described in any of Implementation Schemes 43-58, wherein L 2 It is -C(O)-, -C(O)O-*, -S(O)-, or -S(O)2-, where * indicates a partial R 3 The connection point.

[0257] Implementation Scheme 60. The compound as described in any of Implementation Schemes 43-59, wherein L 2 It is -C(O)O-*, where * indicates a partial R 3 The connection point.

[0258] Implementation Scheme 61. The compound as described in any of Implementation Schemes 43-60, wherein R 3 It is an optional C1-C6 aliphatic group that can be substituted.

[0259] Implementation Scheme 62. The compound as described in any of Implementation Schemes 43-61, wherein R 3 yes: , , , , or .

[0260] Implementation Scheme 63. The compound as described in any of Implementation Schemes 43-62, wherein a portion thereof: yes: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;in Representative and L 2 The connection point.

[0261] Implementation Scheme 64. The compound as described in any of Implementation Schemes 43-63, wherein a portion thereof: yes: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0262] Implementation Scheme 65. The compound as described in any of Implementation Schemes 43-54 or 56-64, wherein yes: , or .

[0263] Implementation Scheme 66. A compound as described in any of Implementation Schemes 43-65, wherein the compound is represented by Formula I-2: I-2 Or its pharmaceutically acceptable salt.

[0264] Implementation Scheme 67. A compound as described in any of Implementation Schemes 43-66, wherein the compound is represented by Formula II-1: II-1 Or its pharmaceutically acceptable salt.

[0265] Implementation Scheme 68. A compound as described in any of Implementation Schemes 43-54 or 56-67, wherein the compound is represented by Formula II-2: II-2 Or its pharmaceutically acceptable salt.

[0266] Implementation Scheme 69. A compound as described in any of Implementation Schemes 43-54 or 56-68, wherein the compound is represented by Formula III-1. III-1 Or its pharmaceutically acceptable salt.

[0267] Implementation Scheme 70. A compound as described in any of Implementation Schemes 43-65, wherein the compound is represented by Formula IV-1. IV-1 Or its pharmaceutically acceptable salt.

[0268] Implementation Scheme 71. A compound as described in any of Implementation Schemes 43-65 or 70, wherein the compound is represented by Formula IV-2. IV-2 Or its pharmaceutically acceptable salt.

[0269] Implementation Scheme 72. A compound as described in any of Implementation Schemes 43-71, wherein the compound is represented by Formula V-1. V-1 Or its pharmaceutically acceptable salt.

[0270] Implementation Scheme 73. The compound as described in any of Implementation Schemes 43-72, wherein the compound or a pharmaceutically acceptable salt thereof is selected from Table 1.

[0271] Implementation Scheme 74. A pharmaceutical composition comprising a compound as described in any of Implementation Schemes 43-73 and a pharmaceutically acceptable carrier or excipient.

[0272] Implementation Scheme 75. A method for modulating TRMPL in a subject, the method comprising administering to the subject a compound as described in any of Implementation Schemes 43-73 or a pharmaceutical composition as described in Implementation Scheme 74.

[0273] Implementation Scheme 76. A method of treating a disease, symptom, or ailment of a subject, the method comprising administering to the subject a compound as described in any of Implementation Schemes 43-73 or a pharmaceutical composition as described in Implementation Scheme 74.

[0274] Implementation Scheme 77. The method as described in Implementation Scheme 76, wherein the disease, symptom, or ailment is a lysosomal storage disorder.

[0275] Implementation Scheme 78. The method as described in Implementation Scheme 77, wherein the lysosomal storage disease is selected from Niemann-Pick C disease, Gaucher disease, Barten disease, cholesterol ester storage disease, Fabry disease, and Pompe disease.

[0276] Implementation Scheme 79. The method as described in Implementation Scheme 76, wherein the disease, symptom, or ailment is a common age-related neurodegenerative disease.

[0277] Implementation Scheme 80. The method as described in Implementation Scheme 76 or 79, wherein the disease, symptom or ailment is selected from Alzheimer's disease, Parkinson's disease and Huntington's disease.

[0278] Implementation Scheme 81. The method as described in Implementation Scheme 76 or 77, wherein the disease, symptom or disorder is a type IV mucopolysaccharidosis (ML4) neurodegenerative lysosomal storage disease caused by a mutation in TRPML.

[0279] Implementation Scheme 82. The method as described in Implementation Scheme 76, wherein the disease, symptom, or ailment is a muscle disease, liver disease, metabolic disease, atherosclerotic disease, inflammatory bowel disease, neurodegenerative disease, tumor disease, or infectious disease.

[0280] Implementation Scheme 83. The method as described in Implementation Scheme 82, wherein the disease, symptom, or ailment is a muscle disease.

[0281] Implementation Scheme 84. The method as described in Implementation Scheme 83, wherein the muscle disease is muscular dystrophy.

[0282] Implementation Scheme 85. The method as described in Implementation Scheme 84, wherein the muscular dystrophy is Duchenne muscular dystrophy.

[0283] Implementation Scheme 86. The method as described in Implementation Scheme 76, wherein the disease, symptom, or ailment is an infectious disease.

[0284] Implementation Scheme 87. The method as described in Implementation Scheme 86, wherein the infectious disease is an infection of Helicobacter pylori or Mycobacterium tuberculosis.

[0285] Example As described in the following examples, in some exemplary embodiments, the compounds are prepared according to the following general procedure. It should be understood that although the general method described depicts the synthesis of certain compounds of this disclosure, the following general method and other methods known to those skilled in the art can be applied to all compounds described herein, as well as the subclasses and species of each of these compounds.

[0286] Abbreviation Table Example 1. Synthesis of an exemplary compound. Example 1.1. Synthesis of (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (I-1). Ethyl 1-amino-3-cyclopropyl-1H-pyrrole-2-carboxylate. At 0 °C, a solution of ethyl 3-cyclopropyl-1H-pyrrole-2-carboxylate (2.5 g, 13.9 mmol, 1 eq) in DMF (120 mL) was added to a suspension of sodium hydride (0.50 g, 20.8 mmol, 1.5 eq) in DMF (25 mL). The reaction mixture was stirred at 0 °C for 30 min, and then aminodiphenylphosphine ester (5.5 g, 23.7 mmol, 1.7 eq) was added fractionally. The reaction mixture was then stirred at rt for 12 h. The reaction progress was monitored by TLC. After the reaction was complete, DMF was removed under reduced pressure, and the residue was diluted with water (300 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (250 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain ethyl 1-amino-3-cyclopropyl-1H-pyrrole-2-carboxylate (2.9 g, crude product). The product was used directly in the next step without further purification.

[0287] 5-Cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-ol. A solution of ethyl 1-amino-3-cyclopropyl-1H-pyrrole-2-carboxylate (2.9 g, 14.9 mmol, 1 eq) in formamide (29 mL) was stirred at 165 °C for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to RT and diluted with cold water (100 mL) with stirring. The precipitate formed was filtered and dried under vacuum to give 5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-ol (1.97 g, crude). The product was used directly in the next step without further purification.

[0288] 7-Bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-ol. A mixture of 5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-ol (1.8 g, 10.3 mmol, 1.0 equiv) and NBS (1.7 g, 9.8 mmol, 0.95 equiv) in DMF (40 volumes, 72 mL) was stirred at room temperature for 4.0 h. The reaction was shown to be complete by LCMS. The reaction was quenched by adding saturated aqueous sodium sulfite solution (50 mL). Then, water (40 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (40 mL × 2). The combined organic layers were washed with water (100 mL × 3) and brine (100 mL × 1), and then dried over Na2SO4. After filtration, the filtrate was concentrated under vacuum to obtain 2.5 g of crude 7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-ol as a white solid. The product was used directly in the next step without further purification.

[0289] 7-Bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine. A mixture of methyl 7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-ol (1.5 g, 5.9 mmol, 1.0 equiv) in phosphorus oxychloride (15 mL, 10 volumes) was stirred at 130 °C for 2.0 h. LC-MS showed the reaction was complete. After the reaction was complete, the reaction mixture was diluted with cold water (30 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (30 mL × 1) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 7-bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine (1.4 g, crude) as a yellow solid. The product was used directly in the next step without further purification.

[0290] (S)-4-(7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester. A mixture of 7-bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine (1.4 g, 5.1 mmol, 1.0 equiv), (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.1 g, 5.6 mmol, 1.1 equiv), and DIEA (1.33 g, 10.3 mmol, 2.0 equiv) in DMF (14 mL, 10 volumes) was stirred at 85 °C for 3 hours. The reaction progress was monitored by TLC. LCMS showed that the reaction was complete. After the reaction was complete, the reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (50 mL × 1) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a crude product, which was purified by reversed-phase chromatography to give (S)-4-(7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (700 mg, crude) as a yellow solid. The product was used directly in the next step without further purification.

[0291] 2-(Trimethylstanyl)pyridin-4-carboxylonitrile. A solution of 2-bromopyridin-4-carboxylonitrile (1.0 g, 5.464 mmol, 1.0 equiv) in toluene (20.0 mL) was placed in a 40 mL vial, and hexamethyldistinane (3.6 g, 10.928 mmol, 2.0 equiv) was added at room temperature. The mixture was bubbled with N2 for 1 minute, and then Pd(PPh3)4 (0.32 g, 0.273 mmol, 0.05 equiv) was added at room temperature. The mixture was again bubbled with N2 for 1 minute. The resulting mixture was stirred overnight at 80 °C. The mixture was cooled to room temperature and then concentrated under reduced pressure. This yielded 1.7 g (crude) 2-(trimethylstanyl)pyridin-4-carboxylonitrile as a brownish-yellow solid.

[0292] (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylpiperazin-1-carboxylic acid tert-butyl ester (I-1). A mixture of (S)-4-(7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylpiperazin-1-carboxylic acid tert-butyl ester (200 mg, 0.458 mmol, 1.0 equiv) and 2-(trimethylstanyl)pyridin-4-carboxylonitrile (244.68 mg, 0.9 mmol, 2 equiv) in dioxane (4 ml, 20 volumes) was stirred at room temperature. The mixture was degassed three times using nitrogen and vacuum circulation. Tetra(triphenylphosphine)palladium(0) (53 mg, 0.046 mmol, 0.1 equiv) was added to a flask at room temperature. The mixture was degassed using nitrogen and vacuum circulation three times. The resulting mixture was heated to 110 °C. The mixture was stirred at 110 °C for 24 h. LCMS showed that the reaction was complete. The mixture was cooled to rt. The mixture was filtered. Water (20 mL) was added to the filtrate, and the mixture was extracted with EA (20 mL × 2). The combined organic layers were washed with water (50 mL × 3) and brine (50 mL × 1) and dried over Na2SO4. After filtration, the filtrate was concentrated under vacuum to give (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester. The product was purified by preparative HPLC under the following conditions. Column: Xselect CSH F-Phenyl OBD column 30*150 mm 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B to 65% B over 12 min; Wavelength: 254 nm / 220 nm; RT1 (min): 9.27, Detector: UV 210 nm, yielding (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (I-1) (84.6 mg, 15.1%) as a light yellow solid. 1 H-NMR (400 MHz, DMSO- d6) δ 8.91– 8.84 (m, 2H), 8.21 (s, 1H), 7.76 (dd, J = 4.9, 1.6 Hz, 1H), 7.60 (ddd, J =18.6, 11.0, 7.0 Hz, 1H), 7.15 (s, 1H), 4.69 (s, 1H), 4.02 (s, 1H), 3.94 (d, J= 13.5 Hz, 1H), 3.83 (d, J = 13.4 Hz, 1H), 3.48 (t, J = 11.5 Hz, 1H), 3.02(s, 1H), 2.16 – 2.06 (m, 1H), 1.44 (s, 9H), 1.20 (d, J = 6.6 Hz, 3H), 1.14 –1.01 (m, 1H), 0.88 (p, J = 5.0, 4.4 Hz, 1H), 0.83 – 0.76 (m, 1H). LC-MS: [M+H]+ = 460.55.

[0293] The following compounds were prepared in a manner similar to that described in Example 1.1 above regarding (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (I-1): 1-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]piperidine-4-carboxylic acid tert-butyl ester (I-5) (60.3 mg, 28.1%) was a white solid. In step 6, piperidine-4-carboxylic acid tert-butyl ester was used instead of (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester. 1 H-NMR: (400 MHz, DMSO- d 6 , ppm ): δ 8.91 –8.83 (m, 2H), 8.19 (s, 1H), 7.76 (dd, J = 5.0, 1.5 Hz, 1H), 7.13 (s, 1H), 4.19 (d, J = 13.1 Hz, 2H), 3.22 (t, J= 12.0 Hz, 2H), 2.62 – 2.54 (m, 1H),2.14 – 2.04 (m, 1H), 2.02 – 1.91 (m, 2H), 1.76 – 1.61 (m, 2H), 1.42 (s, 9H),1.13 – 1.04 (m, 2H), 0.90 – 0.80 (m, 2H). LC-MS: (ES, m / z ): [M+H]+ = 445.

[0294] Example 1.2. Synthesis of (2S,4S)-1-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidine-4-carboxylic acid tert-butyl ester (I-2). 7-Bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine. Prepared in a manner similar to that described in steps 1-4 of Example 1.1 above.

[0295] (2 S 4 S )-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-yl}-2-methylpiperidin-4-carboxylate methyl ester. Under a nitrogen atmosphere, at room temperature, 7-bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine (1.1 g, 4.036 mmol, 1.0 equiv), (2... S 4 S A solution of methyl 2-methylpiperidin-4-carboxylate (0.70 g, 4.440 mmol, 1.1 equiv) and DIEA (2.09 g, 16.144 mmol, 4.0 equiv) in DMF (20 mL) was prepared. The reaction mixture was heated to 85 °C and stirred for 3 h. LCMS showed that the reaction was complete. The reaction mixture was cooled to RT. Water (100 mL) was added to the reaction mixture, and the reaction was extracted with EA (2 × 20 mL). The combined organic layers were washed with water (2 × 15 mL) and brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give a crude product (2 g) that was brown and oily. S 4 S Methyl 7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate (1.8 g, 113.4%). The crude product was used directly in the next step without further purification.

[0296] (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid. Methyl (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (1.8 g, 4.577 mmol, 1.0 equiv) in THF (18 mL) and H₂O (18 mL) was added to a 100 mL three-necked round-bottom flask at room temperature under a nitrogen atmosphere. Then, LiOH (0.33 g, 13.731 mmol, 3.0 equiv) was added to the mixture. The reaction was stirred at room temperature for 2 h. LCMS showed the reaction was complete. Water (50 mL) was added to the reaction mixture, and the reaction was extracted with EA (2 × 20 mL). The aqueous phase was acidified to pH 1 with an aqueous HCl solution (1 mol / L). The mixture was extracted with EA (2 × 20 mL). The combined organic layers were washed with water (15 mL) and brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to give the crude product (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (1.5 g, 86.4%). The crude product was used directly in the next step without further purification.

[0297] (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid tert-butyl ester. Under a nitrogen atmosphere, a solution of (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (750.0 mg, 1.978 mmol, 1.0 equiv), Boc₂O (647.4 mg, 2.967 mmol, 1.5 equiv), and DMAP (724.8 mg, 5.934 mmol, 3.0 equiv) in t-BuOH (15 mL) was added to a 40 mL vial at room temperature. The reaction was stirred at room temperature for 12 h. LCMS showed the reaction was complete. Water (60 mL) was added to the reaction mixture, and the reaction was extracted with EA (2 × 20 mL). The combined organic layers were washed with water (15 mL) and brine (20 mL), and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1), to give a grayish-white, foamy tert-butyl (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylic acid (690 mg, 80.1%).

[0298] (2S,4S)-1-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidine-4-carboxylic acid tert-butyl ester (I-2). Prepared in a manner similar to that described in step 7 of Example 1.1 above, but using (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylic acid tert-butyl ester instead of (S)-4-(7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylpiperidine-1-carboxylic acid tert-butyl ester; (78.9 mg, 36.9%), as a grayish-white solid. 1 H-NMR (400 MHz, DMSO- d 6 , ppm ): δ 8.91 – 8.84 (m, 2H), 8.28 (s, 1H), 7.76 (dd, J = 4.9, 1.5 Hz, 1H),7.14 (s, 1H), 4.17 – 4.10 (m, 1H), 3.75 (d, J= 8.8 Hz, 1H), 3.48 – 3.40 (m,1H), 2.60 (t, J = 6.6 Hz, 1H), 2.23 (hept, J = 5.0 Hz, 1H), 2.12 – 2.04 (m,1H), 1.83 (p, J = 7.7, 6.4 Hz, 3H), 1.44 (s, 9H), 1.25 (d, J = 6.4 Hz, 3H), 1.11 – 1.04 (m, 2H), 0.98 – 0.91 (m, 1H), 0.76 – 0.67 (m, 1H). LC-MS: (ES, m / z ): [M+H]+ = 459.

[0299] Example 1.3. Synthesis of 2-{5-cyclopropyl-4-[(2S,4S)-2-methyl-4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-3). (2S,4R)-4-(methanesulfonyloxy)-2-methylpiperidine-1-carboxylic acid tert-butyl ester. A solution of (2S,4R)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (9.0 g, 41.803 mmol, 1.0 equiv) in DMF (90 mL) was placed in a 250 mL three-necked round-bottom flask. The solution was treated with TEA (8.46 g, 83.606 mmol, 2.0 equiv) at room temperature under a nitrogen atmosphere, followed by fractional addition of MsCl (9.58 g, 83.606 mmol, 2.0 equiv) at 0 °C. The resulting mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (12 g) was used in the next step without further purification.

[0300] (2S,4S)-4-(isopropylthio)-2-methylpiperidin-1-carboxylic acid tert-butyl ester. In another flask, 2-propanethiol (6.23 g, 81.806 mmol, 2.0 equiv) in DMF was cooled to 0 °C. NaH (1.08 g, 44.993 mmol, 1.1 equiv) was added to the mixture, and the mixture was stirred at room temperature for 2 h. Then, (2S,4R)-4-(methanesulfonyloxy)-2-methylpiperidin-1-carboxylic acid tert-butyl ester (12.0 g, 40.903 mmol, 1.0 equiv) was dissolved in DMF and slowly added to the thiolate solution. After the addition was complete, the mixture was stirred until the reaction was complete. Water and ethyl acetate were added to the mixture, and the organic phase was dried over sodium sulfate and concentrated to give the residue. The residue was purified by rapid column chromatography to obtain (2S,4S)-4-(isopropylthio)-2-methylpiperidine-1-carboxylic acid tert-butyl ester (9 g, 80.5%).

[0301] (2S,4S)-2-methyl-4-(propane-2-sulfonyl)piperidine-1-carboxylic acid tert-butyl ester. Under a nitrogen atmosphere and at 0 °C, fractionally aliquots of m-CPBA (14.83 g, 85.943 mmol, 2.5 equiv) were added to a mixture of (2S,4S)-4-(isopropylthio)-2-methylpiperidine-1-carboxylic acid tert-butyl ester (9.4 g, 34.377 mmol, 1 equiv) in DCM (94 mL). The resulting mixture was stirred for 3 h at room temperature under a nitrogen atmosphere. The reaction was quenched with aqueous Na₂SO₃ at 0 °C. The resulting mixture was extracted with DCM. The combined organic layers were washed with aqueous Na₂SO₃ (until m-CPBA was removed), washed with aqueous NaHCO₃, and dried over anhydrous MgSO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA to give tert-butyl (2S,4S)-2-methyl-4-(propane-2-sulfonyl)piperidine-1-carboxylate (5.5 g, 52.4%), which was a light yellow oil.

[0302] (2S,4S)-4-(isopropylsulfonyl)-2-methylpiperidine hydrochloride. At room temperature, tert-butyl (2S,4S)-2-methyl-4-(propane-2-sulfonyl)piperidine-1-carboxylate (2.0 g, 6.548 mmol, 1.0 equiv) and HCl (gas) were added to a 40 mL vial in 1,4-dioxane (20 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was then concentrated under vacuum. The crude product (1.3 g) was used in the next step without further purification.

[0303] 7-Bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine. Prepared in a manner similar to that described in steps 1-4 of Example 1.1 above.

[0304] (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-yl}-2-methyl-4-(propane-2-sulfonyl)piperidine. At room temperature, a solution of 7-bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine (600.0 mg, 2.202 mmol, 1.0 equiv), (2S,4S)-4-(isopropylsulfonyl)-2-methylpiperidine hydrochloride (540.0 mg, 2.642 mmol, 1.2 equiv), and TEA (0.60 mL, 4.317 mmol, 2.0 equiv) in DMF (6 mL) was added to a 40 mL vial. The resulting mixture was stirred at 85 °C for 3 h. The mixture was cooled to room temperature. The mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture (600 mg) was used in the next step without further purification.

[0305] 2-{5-cyclopropyl-4-[(2S,4S)-2-methyl-4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (I-3). Prepared in a manner similar to that described in step 7 of Example 1.1 above, but using (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methyl-4-(propane-2-sulfonyl)piperidine instead of (S)-4-(7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester; (87.3 mg, 40.4%), as a yellow solid. 1 H-NMR: (400 MHz, DMSO- d 6 ppm ) δ 8.87 – 8.82 (m, 2H), 8.34 (s, 1H), 7.74 (dd, J = 5.2, 1.2 Hz,1H), 7.14 (s, 1H), 4.02 (dt, J = 12.9, 4.2 Hz, 1H), 3.80 (ddt, J= 11.7, 9.3,5.7 Hz, 1H), 3.61 (tt, J = 11.2, 4.1 Hz, 1H), 3.47 – 3.37 (m, 1H), 3.28 –3.14 (m, 1H), 2.30 (td, J = 8.3, 4.1 Hz, 1H), 2.17 (d, J = 12.9 Hz, 1H), 2.09(dd, J = 10.9, 4.6 Hz, 1H), 1.80 (qd, J = 15.2, 13.6, 10.0 Hz, 2H), 1.36 (d, J = 6.0 Hz, 3H), 1.27 (dd, J = 6.8, 2.7 Hz, 6H), 1.13 – 1.02 (m, 2H), 0.96(dt, J = 8.5, 3.9 Hz, 1H), 0.69 – 0.59 (m, 1H). LC-MS: (ES, m / z ): [M+H]+ =465.

[0306] The following compounds were prepared in a manner similar to that described in Example 1.3 above regarding 2-{5-cyclopropyl-4-[(2S,4S)-2-methyl-4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (I-3): 2-{5-cyclopropyl-4-[4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-4) (30 mg, 9.4%) is a white solid. In step 5, commercially available (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester was used instead of (2S,4S)-4-(isopropylsulfonyl)-2-methylpiperidine hydrochloride. 1 H-NMR: (300MHz, DMSO- d 6 ppm ) δ 8.92 – 8.83 (m, 2H), 8.21 (s, 1H), 7.76 (dd, J = 4.9, 1.6Hz, 1H), 7.14 (s, 1H), 4.42 (d, J= 13.0 Hz, 2H), 3.65 (t, J = 5.7 Hz, 1H), 3.42 (p, J = 6.8 Hz, 1H), 3.24 (q, J = 13.1, 12.4 Hz, 2H), 2.20 – 1.99 (m,3H), 1.86 – 1.69 (m, 2H), 1.27 (d, J = 6.8 Hz, 6H), 1.17 – 1.05 (m, 2H), 0.86(td, J = 6.5, 6.1, 4.1 Hz, 2H). LC-MS: (ES, m / z ): [M+H]+ = 451.

[0307] 2-{5-cyclopropyl-4-[4-(2-methylpropane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (I-6) (57.3 mg, 27.2%) was a yellow solid. Commercially available tert-butyl 4-bromopiperidin-1-carboxylate was used instead of (2S,4R)-4-(methanesulfonyloxy)-2-methylpiperidin-1-carboxylate, and 2-methyl-2-propanethiol was used instead of propanethiol in step 2. 1 H-NMR: (400 MHz, DMSO- d 6 ppm ) δ 9.00 (s, 1H),8.78 (d, 1H), 8.11 (s, 1H), 7.38 (d, 1H), 7.17 (s, 1H), 4.49 (m, 2H), 3.45(m, 1H), 3.23 (m, 2H), 3.08 (m, 3H), 2.30-2.10 (m, 5H), 1.54 (s, 9H), 1.12(m, 2H), 0.90 (m, 2H). LC-MS: (ES, m / z ): [M+H]+ = 465.

[0308] Example 1.4. Synthesis of 6-{5-cyclopropyl-4-[4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridazin-4-carboxylonitrile (I-7). 6-Chloropyridazine-4-carboxamide. Under a nitrogen atmosphere, a solution of 6-chloropyridazine-4-carboxylic acid (25.0 g, 157.689 mmol, 1.0 equiv), TEA (31.91 g, 315.378 mmol, 2.0 equiv), and isopropyl chloroformate (32.31 g, 236.534 mmol, 1.5 equiv) in THF (500 mL) was added to a 1 L three-necked round-bottom flask. The resulting mixture was stirred at room temperature for 2 h. Ammonia solution (25% in H2O, 250 mL) was added to the above solution. The resulting mixture was stirred overnight at 40 °C. The mixture was quenched by adding water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by grinding with DCM (25 mL). The precipitate was collected by filtration and washed with DCM (3 × 25 mL) to give 6-chloropyridazine-4-carboxamide (11.2 g, 43.7%) as a brown solid.

[0309] 6-Chloropridazine-4-carboxynitrile. A solution of 6-chloropyridazine-4-carboxamide (11.2 g, 71.084 mmol, 1.0 equiv) in phosphorus oxychloride (112 mL) was added to a 500 mL three-necked round-bottom flask and stirred at 80 °C for 3.5 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (0.1% FA), 5% to 100% gradient over 24 min; detector: UV 254 nm. This yielded 4.8 g (46.3%) of 6-chloropyridazine-4-carboxynitrile as a brown solid.

[0310] 1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-4-(propane-2-sulfonyl)piperidine. Prepared in a manner similar to that described in step 5 of Example 1.3 above, but using 4-(isopropylsulfonyl)piperidine hydrochloride instead of (2S,4S)-4-(isopropylsulfonyl)-2-methylpiperidine hydrochloride. 4-(isopropylsulfonyl)piperidine hydrochloride was prepared in a manner similar to that described in steps 2-4 of Example 1.3 above, but using tert-butyl 4-bromopiperidine-1-carboxylate as the starting material instead of (2S,4R)-4-(methanesulfonyloxy)-2-methylpiperidine-1-carboxylate.

[0311] 1-[5-cyclopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-4-(propane-2-sulfonyl)piperidine. Under a nitrogen atmosphere, at room temperature, 1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-4-(propane-2-sulfonyl)piperidine (300.0 mg, 0.702 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentane (267.4 mg, 1.053 mmol, 1.0 equiv) were added to a 40 mL vial. A solution of 1 mmol, 1.5 equiv), Pd(PPh3)Cl2 (51.4 mg, 0.070 mmol, 0.1 equiv) and AcOK (206.7 mg, 2.106 mmol, 3.0 equiv) in DMF (1 mL) and dioxane (2 mL). The resulting mixture was stirred at 100 °C for 3 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE / EA (1:1) to give a yellow solid 1-[5-cyclopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-4-(propane-2-sulfonyl)piperidine (0.15 g, 45.0%).

[0312] 6-{5-cyclopropyl-4-[4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridazin-4-carboxylonitrile. Under a nitrogen atmosphere, at room temperature, a solution of 1-[5-cyclopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-4-(propane-2-sulfonyl)piperidine (200.0 mg, 0.422 mmol, 1.0 equiv), 6-chloropyridazin-4-carboxynitrile (70.6 mg, 0.506 mmol, 1.2 equiv), K₂CO₃ (174.8 mg, 1.266 mmol, 3.0 equiv), and Pd(dppf)Cl₂ (23.3 mg, 0.042 mmol, 0.1 equiv) in dioxane (2 mL) and H₂O (0.5 mL) was added to a 20 mL vial. The resulting mixture was stirred at 80 °C for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by reversed-phase rapid column chromatography under the following conditions (column: Xbridge Prep phenyl OBD column, 30*150 nm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 45% B over 15 min; wavelength: 254 nm / 220 nm; RT1 (min): 11.5). This yielded a yellow solid, 6-{5-cyclopropyl-4-[4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridazin-4-carboxylonitrile (23.2 mg, 12.1%). 1 H-NMR: (300 MHz, DMSO- d 6, ppm ) δ 9.53 (d, J = 1.9 Hz, 1H), 9.08 (d, J = 2.0 Hz, 1H), 8.21 (s,1H), 7.33 (s, 1H), 4.44 (d, J = 13.1 Hz, 2H), 3.74 – 3.61 (m, 1H), 3.48 –3.25 (m, 3H), 2.21 – 2.03 (m, 3H), 1.86 – 1.73 (m, 2H), 1.27 (d, J = 6.7 Hz, 6H), 1.13 (dd, J= 7.9, 2.2 Hz, 2H), 0.96 – 0.85 (m, 2H). LC-MS: (ES, m / z ): [M+H] + = 452.

[0313] The following compounds were prepared in a manner similar to that described in Example 1.4 above for 6-{5-cyclopropyl-4-[4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridazin-4-carboxylonitrile (I-7): 6-{5-cyclopropyl-4-[(2S,4S)-2-methyl-4-(propane-2-sulfonyl)piperidin-1-yl]-4aH,5H-pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridazin-4-carboxylonitrile (I-8) (44 mg, 22.9%), is a pale yellow solid. In step 3, (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methyl-4-(propane-2-sulfonyl)piperidine is used instead of 1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-4-(propane-2-sulfonyl)piperidine. 1 H-NMR: (400 MHz, DMSO- d 6 ppm ) δ 9.53 (s, 1H), 9.08 (s, 1H), 8.35 (s, 1H), 7.36 (s, 1H), 4.06 (d, J = 13.0 Hz, 1H), 3.77-3.91 (m, 1H), 3.68-3.56 (m, 1H), 3.34-3.24 (m, 1H), 2.37-2.27 (m, 1H), 2.24 – 2.04 (m, 2H), 1.85(d, J = 16.1 Hz, 2H), 1.38 (d, J = 5.9 Hz, 3H), 1.33 – 1.20 (m, 6H), 1.16 –0.96 (m, 3H), 0.78-0.63 (m, 1H). LC-MS: (ES, m / z ): [M+H]+ = 466.

[0314] (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methyl-4-(propane-2-sulfonyl)piperidine was prepared in a manner similar to the procedure described above in steps 1-5 of Example 1.3.

[0315] 6-{5-cyclopropyl-4-[4-(oxetane-3-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridazin-4-carboxylonitrile (I-13) (15 mg, 10.3%), is a yellow solid. In step 3, 1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-4-(oxetane-3-sulfonyl)piperidine was used as the starting material instead of 1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-4-(propane-2-sulfonyl)piperidine. 1 H-NMR: (400 MHz, DMSO- d 6, ppm ) δ 9.52 (s, 1H), 9.08 (s, 1H), 8.20 (s, 1H), 7.33 (s, 1H), 4.90 (q, 1H), 4.76 (d, 2H), 4.44 (d, 2H), 4.45 (d, 2H), 3.52(t, 1H), 3.32 (t, 2H), 2.06-2.11 (m, 3H), 1.72-1.76 (m, 2H), 1.30 (d, 2H), 1.12 (s, 2H). LC-MS: (ES, m / z ): [M+H] + = 466.

[0316] 1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-yl}-4-(oxecyclobutane-3-sulfonyl)piperidine was prepared in a manner similar to the procedure described below in steps 1-4 of Example 1.7.

[0317] Example 1.5. Synthesis of 2-[5-(morpholin-4-yl)-4-[4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]pyridine-4-carboxylonitrile (I-10). Methyl 1-amino-3-bromopyrrole-2-carboxylate. A solution of methyl 3-bromo-1H-pyrrole-2-carboxylate (25.0 g, 122.535 mmol, 1.0 equiv) in DMF (250 mL) was placed in a 1 L three-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere at 20 °C. NaH (3.82 g, 159.296 mmol, 1.3 equiv, 60 wt%) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 0.5 h under a nitrogen atmosphere. Diphenyl aminophosphate (34.29 g, 147.042 mmol, 1.2 equiv) in DMF (500 mL) was added to the mixture at 0 °C after 10 min. The final reaction mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product was detected by LCMS. The mixture was cooled to 0°C. The reaction was quenched at 0°C with water / ice (750 mL). The resulting mixture was diluted with ethyl acetate (750 mL). The aqueous layer was extracted with EtOAc (2 × 750 mL). The combined organic layers were washed with brine (5 × 750 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1), to give methyl 1-amino-3-bromopyrrole-2-carboxylate (22.3 g, 78.9%) as a grayish-white solid.

[0318] 5-Bromopyrrolo[2,1-f][1,2,4]triazine-4-ol. A solution of methyl 1-amino-3-bromopyrrolo-2-carboxylate (22.3 g, 96.718 mmol, 1.0 equiv, 95 wt%) in formamide (111.5 mL) was added to a 250 mL three-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. The final reaction mixture was stirred at 180 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product was detected by LCMS. The mixture was cooled to 20 °C. The precipitated solid was collected by filtration and washed with water (3 × 50 mL) to give 5-bromopyrrolo[2,1-f][1,2,4]triazine-4-ol (20 g, 91.8%) as a brown solid.

[0319] 4-(benzyloxy)-5-bromopyrrolo[2,1-f][1,2,4]triazine. A solution of 5-bromopyrrolo[2,1-f][1,2,4]triazine-4-ol (10.0 g, 45.322 mmol, 1.0 equiv, 97 wt%) in 200 mL DMF was placed in a 500 mL three-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. K₂CO₃ (12.53 g, 90.644 mmol, 2.0 equiv) was added fractionally to the mixture at 20°C. The resulting mixture was stirred at 20°C for another 5 min. BnBr (11.63 g, 67.983 mmol, 1.5 equiv) was added dropwise to the mixture at 20°C. The final reaction mixture was stirred at 80°C for 16 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was cooled to 20°C. The reaction was quenched at 0°C with water / ice (300 mL). The resulting mixture was diluted with ethyl acetate (30 mL). The aqueous layer was extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with brine (5 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, Ultimate XB-C18 column: 50*250 mm, 10 µm; mobile phase: MeCN / water (0.1% FA), 20% to 100% gradient over 20 min; detector: UV 210 / 254 nm, to obtain 11 g, 77.4% brown solid 4-(benzyloxy)-5-bromopyrrolo[2,1-f][1,2,4]triazine.

[0320] 4-[4-(benzyloxy)pyrrolo[2,1-f][1,2,4]triazine-5-yl]morpholine. At 20°C, a solution of 4-(benzyloxy)-5-bromopyrrolo[2,1-f][1,2,4]triazine (12.0 g, 38.271 mmol, 1.0 equiv, 97 wt%) in t-AmOH (360 mL) was placed in a 1 L three-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. At 20°C, fractionally aliquots of K3PO4 (40.62 g, 191.355 mmol, 5.0 equiv) were added to the mixture. The resulting mixture was stirred at 20°C for another 5 min. At 20°C, morpholine (6.67 g, 76.542 mmol, 2.0 equiv) was added dropwise to the mixture. At 20°C, a single addition of the third-generation t-BuXPhos precatalyst (4.57 g, 5.741 mmol, 0.15 equiv) was made to the mixture. The final reaction mixture was stirred at 110°C for 16 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product was detected by LCMS. The mixture was cooled to 20°C. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: Ultimate XB-C18 column: 50*250 mm, 10 µm; mobile phase: MeCN / water (0.1% FA), 20% to 100% gradient over 20 min; detector: UV 210 / 254 nm, yielding a grayish-white solid 4-[4-(benzyloxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl]morpholine (5.2 g, 42.5%).

[0321] 5-(morpholino-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol. A solution of 4-[4-(benzyloxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl]morpholine (2.2 g, 6.876 mmol, 1.0 equiv, 97%) in EtOH (66 mL) was placed in a 250 mL three-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere at 20 °C. Pd(OH)₂ / C (2.2 g) was added to the mixture in a single addition at 20 °C. The mixture was hydrogenated at 50 °C for 14 h using a hydrogen balloon under a hydrogen atmosphere. The reaction was monitored by LCMS. The desired product was detected by LCMS. The mixture was cooled to 20 °C. The resulting mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 1.1 g, 70.5% of 5-(morpholino-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-ol, which was a grayish-white solid.

[0322] 7-Bromo-5-(morpholin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol. At 0 °C, a solution of 5-(morpholin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (1.5 g, 6.607 mmol, 1.0 equiv) in 15 mL DMF was placed into a 40 mL vial purged with and maintained under an inert nitrogen atmosphere. At 0 °C, a solution of NBS (1.12 g, 6.277 mmol, 0.95 equiv) in 15 mL DMF was added dropwise to the mixture over 30 min. The final reaction mixture was stirred at 25 °C for 12 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product was detected by LCMS. The mixture was cooled to 20 °C. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: Ultimate XB-C18 column: 50*250 mm, 10µm; mobile phase: MeCN / water (0.1% FA), 30% to 60% gradient over 30 min; detector: UV 210 / 254 nm, yielding 1.16 g, 56.9% brown solid 7-bromo-5-(morpholino-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-ol.

[0323] 4-(propane-2-sulfonyl)piperidine hydrochloride was prepared in a manner similar to that described in steps 2-4 of Example 1.3 above, but using tert-butyl 4-bromopiperidine-1-carboxylate as the starting material instead of (2S,4R)-4-(methanesulfonyloxy)-2-methylpiperidine-1-carboxylate.

[0324] 4-(7-bromo-4-[4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-5-ylmorpholine. At 20°C, a solution of 7-bromo-5-(morpholine-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (280.0 mg, 0.908 mmol, 1.0 equiv) in DMF (5.6 mL) was placed in a 40 mL vial purged with and maintained under an inert nitrogen atmosphere. At 20°C, 4-(propane-2-sulfonyl)piperidine (173.7 mg, 0.908 mmol, 1.0 equiv) was added to the mixture in a single dose. At 20°C, DBU (691.2 mg, 4.540 mmol, 5.0 equiv) was added to the mixture in a single dose. PyBOP (945.0 mg, 1.816 mmol, 2.0 equiv) was added to the mixture at 20 °C in a single step. The final reaction mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product was detected by LCMS. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: UltimateXB-C18 column: 50*250 mm, 10 µm; mobile phase: MeCN / water (0.1% FA), 25% to 55% gradient over 30 min; detector: UV 210 / 254 nm, to obtain 4-(7-bromo-4-[4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine-5-ylmorpholine (370 mg, 83.7%) as a grayish-white solid.

[0325] 2-[5-(morpholin-4-yl)-4-[4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]pyridin-4-carboxylonitrile (I-10). Prepared in a manner similar to that described in step 7 of Example 1.1 above, but using 4-(7-bromo-4-[4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-5-ylmorpholine instead of (S)-4-(7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester; (22.4 mg, 11.9%), as a yellow solid. 1 H-NMR: (300 MHz, DMSO- d 6, ppm ) δ 8.94 (d, J = 5.1 Hz, 1H), 8.11 (d, J= 7.1 Hz, 2H), 7.93 (s, 1H), 7.80 (d, J = 5.1 Hz, 1H), 4.75 (d, J = 13.1 Hz, 2H), 3.67 (d, J = 13.1 Hz, 5H), 3.42 (s, 1H), 3.21 (s, 2H), 3.03 (s, 4H), 2.08 (d, J = 12.6 Hz, 2H), 1.74 (d, J = 12.0 Hz, 2H), 1.27 (d, J = 6.7 Hz, 6H). LC-MS: (ES, m / z ): [M+H] + = 496.

[0326] Example 1.6. Synthesis of 6-[5-(morpholin-4-yl)-4-[4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]pyridazin-4-carboxylonitrile (I-11). 4-(4-[4-(propane-2-sulfonyl)piperidin-1-yl]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-5-ylmorpholine (I-11). Prepared in a manner similar to that described in steps 3-4 of Example 1.4 above, except that in step 3, 4-(7-bromo-4-[4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-5-ylmorpholine was used as the starting material instead of 1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-4-(propane-2-sulfonyl)piperidine; (22.4 mg, 11.9%), as a yellow solid. 1 H-NMR: (300 MHz, DMSO- d 6, ppm ) δ 8.94 (d, J = 5.1 Hz, 1H), 8.11 (d, J = 7.1Hz, 2H), 7.93 (s, 1H), 7.80 (d, J = 5.1 Hz, 1H), 4.75 (d, J = 13.1 Hz, 2H), 3.67 (d,J = 13.1 Hz, 5H), 3.42 (s, 1H), 3.21 (s, 2H), 3.03 (s, 4H), 2.08 (d, J = 12.6 Hz, 2H), 1.74 (d, J = 12.0 Hz, 2H), 1.27 (d, J = 6.7 Hz, 6H). LC-MS:(ES, m / z ): [M+H] + = 496.

[0327] 4. (7-Bromo-4-[4-(propane-2-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine-5-ylmorpholine was prepared in a manner similar to that described in steps 1-7 of Example 1.5 above.

[0328] Example 1.7. Synthesis of 2-{5-cyclopropyl-4-[4-(oxacyclobutane-3-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-12). 4-(oxetanebut-3-ylthio)piperidin-1-carboxylic acid tert-butyl ester. Under a nitrogen atmosphere, fractionally added aliquots of NaH (0.73 g, 18.253 mmol, 2.5 equiv, 60%) to a solution of N,N-dimethylformamide (80 mL) at 0 °C. Then, under a N2 atmosphere, tert-butyl 4-thiopiperidin-1-carboxylic acid (1.75 g, 8.031 mmol, 1.1 equiv) and 3-bromooxetane (1.0 g, 7.301 mmol, 1.0 equiv) were added at room temperature. The resulting mixture was stirred for another 2 hours at room temperature. The reaction was quenched by adding an aqueous solution of NH4Cl (300 mL) at 0 °C. The resulting mixture was washed with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded crude tert-butyl 4-(oxetane-3-ylthio)piperidine-1-carboxylate (1.3 g, 13.7%), which was a yellow oil.

[0329] 4-(oxetane-3-sulfonyl)piperidine-1-carboxylate tert-butyl ester. Prepared in a manner similar to that described in step 3 of Example 1.3 above, but using 4-(oxetane-3-ylthio)piperidine-1-carboxylate tert-butyl ester instead of (2S,4S)-4-(isopropylthio)-2-methylpiperidine-1-carboxylate tert-butyl ester.

[0330] 4-(oxetane-3-sulfonyl)piperidine. At room temperature, tert-butyl 4-(oxetane-3-sulfonyl)piperidine-1-carboxylate (300.0 mg, 0.982 mmol, 1.0 equiv) was added to a 40 mL vial in dichloromethane (6 mL). 2,2,2-trifluoroacetic acid (0.75 mL) was added dropwise to the mixture at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The mixture was concentrated under vacuum. The crude product, 4-(oxetane-3-sulfonyl)piperidine (400 mg), was used directly in the next step without further purification.

[0331] 2-{5-cyclopropyl-4-[4-(oxetane-3-sulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (I-12). Prepared in a manner similar to that described in steps 6-7 of Example 1.1 above, except that in step 6, 4-(oxetane-3-sulfonyl)piperidine was used as the starting material instead of (S)-3-methylpiperazine-1-carboxylate tert-butyl ester; (40 mg, 22.0%), as a white solid. 1 H-NMR: (400 MHz, DMSO- d 6, ppm ) δ9.00 (s, 1H), 8.78 (d, 1H), 8.09 (s, 1H), 7.38 (d, 1H), 7.16 (s, 1H), 5.09(m, 2H), 4.89 (m, 2H), 4.56 (m, 3H), 3.08 (m, 3H), 2.2 – 1.90 (m, 6H), 1.1(m, 2H), 0.89 (m, 2H). LC-MS: (ES, m / z ): [M+H] + = 465.

[0332] Example 1.8. Synthesis of 6-{5-cyclopropyl-4-[4-(3-methyloxacyclobut-3-ylsulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridazin-4-carboxylonitrile (I-14). 4-(3-Methyloxetane-3-ylsulfonyl)piperidine-1-carboxylate tert-butyl ester. At room temperature, a solution of 4-(oxetane-3-sulfonyl)piperidine-1-carboxylate tert-butyl ester (700.0 mg, 2.292 mmol, 1.0 equiv) in 2 mL of THF was added to an 8 mL vial. Under a nitrogen atmosphere, LiHMDS (421.9 mg, 2.521 mmol, 1.1 equiv) was added dropwise to the stirred mixture at -78 °C. The mixture was stirred for 20 min at -78 °C under a nitrogen atmosphere. Iodomethane (357.9 mg, 2.521 mmol, 1.1 equiv) was added dropwise to the mixture at -78 °C over 10 min. The mixture was stirred for another 2 h at -78 °C, during which time the reaction temperature naturally rose to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain tert-butyl 4-(3-methyloxetane-3-ylsulfonyl)piperidine-1-carboxylate (220 mg, 30.1%) as a white solid.

[0333] 1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-4-(3-methyloxetane-3-ylsulfonyl)piperidine. Prepared in a manner similar to that described in steps 3-4 of Example 1.7 above, except that in step 3, tert-butyl 4-(3-methyloxetane-3-ylsulfonyl)piperidine-1-carboxylate is used as the starting material instead of tert-butyl 4-(oxetane-3-sulfonyl)piperidine-1-carboxylate.

[0334] 6-{5-cyclopropyl-4-[4-(3-methyloxacyclobut-3-ylsulfonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridazin-4-carboxylonitrile (I-14). Prepared in a manner similar to that described in steps 3-4 of Example 1.4 above, except that in step 3, 1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-4-(3-methyloxacyclobut-3-ylsulfonyl)piperidine was used as the starting material instead of 1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-4-(propane-2-sulfonyl)piperidine; (8 mg, 15.2%), in the form of a yellow solid. 1 H-NMR: (400 MHz, DMSO- d 6, ppm) δ 9.63 (s, 1H), 9.62 (s, 1H), 8.31 (s, 1H), 7.43 (s,1H), 5.02 (d, 2H), 4.59 (d, 2H), 4.52 (d, 2H), 3.98 (t, 1H), 3.34 (t, 2H), 2.17 (s, 1H), 2.05 (d, 2H), 1.93 (s, 5H), 1.22 (d, 2H), 1.20 (s, 2H). LC-MS:(ES, m / z ): [M+H] + = 480.

[0335] Example 1.9. Synthesis of 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2,4-dimethylpiperidin-1-yl]-5-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-20) (2S,4R)-1-(7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,4-dimethylpiperidin-4-carboxylate. A solution of (2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylate (1.0 g, 2.723 mmol, 1.0 equiv) in 20 mL of THF was placed in a 50 mL three-necked round-bottom flask. Then, under a nitrogen atmosphere, LDA (2.04 mL, 4.084 mmol, 1.5 equiv) was added at -78 °C and maintained for 15 min. Subsequently, iodomethane (0.46 g, 3.268 mmol, 1.2 equiv) was added dropwise at -78 °C. The resulting mixture was stirred for 2 h at -78 °C under a nitrogen atmosphere. The reaction was quenched by adding water (10 mL) at room temperature. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (0.1% FA), 10% to 50% gradient over 10 min; detector: UV 254 nm. This yielded methyl (2S,4R)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylate (700 mg, yield 67.4%) as a yellow solid.

[0336] (2S,4R)-1-(7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,4-dimethylpiperidin-4-carboxylic acid. A solution of methyl (2S,4R)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (700.0 mg, 1.836 mmol, 1.0 equiv) and LiOH (131.9 mg, 5.508 mmol, 3.0 equiv) in MeOH (3.5 mL) and water (3.5 mL) was placed in a 20 mL vial. The solution was then stirred at 60 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 3 with a 2 mol / L aqueous HCl solution. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (0.1% TFA), 10% to 50% gradient over 10 min; detector: UV 254 nm. This yielded (2S,4R)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (650 mg, 71.1% yield) as a yellow solid.

[0337] 1-((2S,4R)-1-(7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,4-dimethylpiperidin-4-yl)-2,2-dimethylprop-1-one. A solution of thionyl chloride (421.1 mg, 3.540 mmol, 2.0 equiv) and (2S,4R)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (650.0 mg, 1.770 mmol, 1.0 equiv) in DCM (8.4 mL) was placed in a 20 mL vial. The solution was stirred for 1 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in THF (8.4 mL), and CuCl (17.5 mg, 0.177 mmol, 0.1 equiv) and tert-butylmagnesium (1.03 g, 8.850 mmol, 5.0 equiv) were added. The resulting mixture was stirred at 0 °C for 2 h under a nitrogen atmosphere. The reaction was quenched by adding water (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (10 mmol / L NH₄HCO₃), 10% to 85% gradient over 20 min; detector: UV 254 nm. This yielded a yellow solid, 1-[(2S,4R)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-yl]-2,2-dimethylprop-1-one (160 mg, yield 22.2%).

[0338] 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2,4-dimethylpiperidin-1-yl]-5-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-20). A solution of 2-(trimethylstanyl)pyridin-4-carboxylonitrile (126.0 mg, 0.471 mmol, 1.2 equiv) and 1-[(2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-yl]-2,2-dimethylprop-1-one (160.0 mg, 0.393 mmol, 1.0 equiv) and tetrakis(triphenylphosphine)palladium(0) (45.0 mg, 0.039 mmol, 0.1 equiv) in 1,4-dioxane (3 mL) was placed in a 20 mL vial. The solution was stirred overnight at 100 °C under a nitrogen atmosphere and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (36 mg) was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22% B to 45% B over 7 min; wavelength: 254 nm / 220 nm). This yielded a white solid 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2,4-dimethylpiperidin-1-yl]-5-methylpyrrolo[2,1-f][1,2,4]triazine-7-yl}pyridin-4-carboxylonitrile (5.5 mg, yield 3.25%). LC-MS: (ES, m / z ):431.2 [M+H] + ; 1 H-NMR (400 MHz, DMSO- d 6, ppm ): δ 8.89 (s, 1H), 8.87-8.86 (m,1H), 8.21 (s, 1H), 7.79-7.69 (m, 1H), 7.37 (s, 1H), 4.29-4.27 (m, 1H), 3.61-3.45 (m, 2H), 2.47 (s, 3H), 2.31-2.22 (m, 2H), 1.88-1.84 (m, 1H), 1.50-1.45(m, 1H), 1.30 (s, 3H), 1.26 (s, 9H), 1.15 (d, J = 6.3 Hz, 4H).

[0339] Example 1.10. Synthesis of 2-{4-[(2S)-4-(2,2-dimethylpropionyl)-2,4-dimethylpiperidin-1-yl]-5-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-24) Methyl (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidine-4-carboxylate. Under a nitrogen atmosphere, a solution of methyl (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate (400.0 mg, 1.049 mmol, 1.0 equiv) in THF (8 mL) was added to a 40 mL vial at room temperature. Under a nitrogen atmosphere, LDA (2 M in THF) (2.1 mL, 1.049 mmol, 1.0 equiv) was added to the mixture at -78 °C. The reaction mixture was stirred at -78 °C for 30 min. Then, a solution of iodomethane (297.8 mg, 2.098 mmol, 2.0 equiv) in 1 mL THF was added dropwise, and the mixture was stirred for another 30 min. The reaction was quenched by adding water (4 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give a yellow oil of (2S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylate (350 mg, 84.4% yield).

[0340] (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid. At room temperature, a solution of methyl (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (350.0 mg, 0.885 mmol, 1.0 equiv) and LiOH (1 M in H₂O, 3.5 mL) in THF (7 mL) was added to a 100 mL round-bottom flask. The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 4 with a 1 mol / L aqueous HCl solution. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethyl-piperidine-4-carboxylic acid (320 mg, crude product) as a yellow solid.

[0341] 1-[(2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-yl]-2,2-dimethylprop-1-one. At room temperature, a solution of (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (320.0 mg, 0.839 mmol, 1.0 equiv) and SOCl2 (199.7 mg, 1.678 mmol, 2.0 equiv) in DCM (3.2 mL) was added to a 40 mL vial. The resulting mixture was stirred at room temperature for 1 h. The mixture was then concentrated under reduced pressure. Under a nitrogen atmosphere, the residue was added to THF (6.4 mL) at room temperature. Then, CuCl (8.4 mg, 0.084 mmol, 0.1 equiv) and tert-butylmagnesium (1.7 mL, 7.760 mmol, 1.9 equiv) were added at 0 °C and stirred for 10 min. The reaction was quenched by adding water (5 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give a yellow oily 1-[(2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-yl]-2,2-dimethylprop-1-one (103 mg, yield 26.8%).

[0342] 2-{4-[(2S)-4-(2,2-dimethylpropionyl)-2,4-dimethylpiperidin-1-yl]-5-ethylpyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-24). Under a nitrogen atmosphere, at room temperature, a solution of 1-[(2S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-yl]-2,2-dimethylprop-1-one (100.0 mg, 0.237 mmol, 1.0 equiv), 2-(trimethylmethylenetinyl)pyridin-4-carboxynitrile (76.0 mg, 0.284 mmol, 1.2 equiv), and Pd(PPh3)4 (27.4 mg, 0.024 mmol, 0.1 equiv) in dioxane (2 mL) was added to an 8 mL vial. The resulting mixture was stirred overnight at 100 °C. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: Xbridge PrepOBD C18 column: 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 68% B to 98% B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 9.18. This yielded 2-{4-[(2S)-4-(2,2-dimethylpropionyl)-2,4-dimethylpiperidin-1-yl]-5-ethylpyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxynitrile (12.0 mg, yield 11.4%) as a white solid. LC-MS: (ES, m / z ): 445.25 [M+H] + ; 1 H-NMR (400 MHz, DMSO- d 6, ppm ): δ 8.94 – 8.86 (m,2H), 8.26 (s, 1H), 7.76 (dd, J = 4.9, 1.5 Hz, 1H), 7.46 (s, 1H), 4.22 (s,1H), 3.48 (dt, J = 10.4, 4.8 Hz, 2H), 2.87 (q, J = 7.4 Hz, 2H), 2.22 (dt, J =14.5, 7.4 Hz, 2H), 1.88 (dd, J= 14.0, 3.9 Hz, 1H), 1.50 (ddd, J = 13.1, 8.2,4.2 Hz, 1H), 1.29 (d, J = 21.5 Hz, 15H), 1.15 (d, J = 6.3 Hz, 3H).

[0343] Example 1.11 Synthesis of 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2,4-dimethylpiperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-25) Methyl (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidine-4-carboxylate. A solution of methyl (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate (500.0 mg, 1.41 mmol, 1.0 equiv) and LDA (1.4 mL, 2.83 mmol, 2.0 equiv, 2 M) in THF (12.5 mL) was placed in a 50 mL three-necked round-bottom flask. The solution was stirred at -78 °C for 1 h under a nitrogen atmosphere. Iodomethane (602.0 mg, 4.24 mmol, 3.0 equiv) was added dropwise to the mixture over 5 min at -78 °C. The resulting mixture was stirred at -78 °C for 1 h. The reaction was quenched with an aqueous NH4Cl solution at -78 °C, and then slowly heated to room temperature. The aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (10 mmol / L NH4HCO3), 10% to 70% gradient over 15 min; detector: UV 254 nm, to give a light brown oily (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylate (450 mg, 86.6% yield).

[0344] (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid. A solution of methyl (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (400.0 mg, 1.08 mmol, 1.0 equiv) and LiOH·H₂O (91.0 mg, 2.17 mmol, 2.0 equiv) in THF (4 mL) and H₂O (1.2 mL) was placed in a 20 mL vial. The solution was stirred at 50 °C for 3 h under a nitrogen atmosphere. The mixture was acidified to pH 5 with aqueous HCl. The resulting mixture was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (5:1), to give (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazine-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (300 mg, 78.0%), which was a light yellow oil.

[0345] 1-[(2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-yl]-2,2-dimethylprop-1-one. A solution of (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (250.0 mg, 0.72 mmol, 1.0 equiv) and thionyl chloride (168.0 mg, 1.44 mmol, 2.0 equiv) in DCM (5 mL) was placed in a 20 mL vial. The solution was stirred at 30 °C for 1 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was redissolved in THF (5 mL), and CuCl (7.0 mg, 0.07 mmol, 0.1 equiv) was added fractionally at 0 °C under a nitrogen atmosphere. Then, tert-butylmagnesium (2.5 mL, 1 M in THF) was added dropwise to the mixture at 0 °C for 10 min. The resulting mixture was stirred at 0 °C for another 1 h. The reaction was quenched with an aqueous solution of NH4Cl at 0 °C. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to give 1-[(2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-yl]-2,2-dimethylprop-1-one (140 mg, yield 50.4%) as a grayish-white solid.

[0346] 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2,4-dimethylpiperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-25). A solution of 2-(trimethylstanyl)pyridin-4-carboxylonitrile (135.0 mg, 0.50 mmol, 2.0 equiv), 1-[(2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-yl]-2,2-dimethylprop-1-one (100.0 mg, 0.25 mmol, 1.0 equiv), and Pd(PPh3)4 (29.0 mg, 0.02 mmol, 0.1 equiv) in dioxane (5 mL) was placed in a 20 mL vial. The solution was stirred overnight at 110 °C under a nitrogen atmosphere and then cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with MeOH (2 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (10 mmol / L NH4HCO3), 10% to 90% gradient over 10 min; detector: UV 254 nm, yielding 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2,4-dimethylpiperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (11.6 mg, 11.0% yield) as a white solid. (ES, m / z ): 417.30 [M+H] + ; 1 H-NMR (400 MHz, DMSO- d 6, ppm ): δ 8.99 (s, 1H), 8.88 (dd, J = 4.9, 1.0 Hz,1H), 8.14 (s, 1H), 7.75 (dd, J = 5.0, 1.5 Hz, 1H), 7.47 (d, J = 4.9 Hz, 1H), 7.11 (d, J= 5.0 Hz, 1H), 4.85 – 4.76 (m, 1H), 4.54 – 4.50 (m, 1H), 3.52 –3.42 (m, 1H), 2.37 – 2.23 (m, 2H), 1.88 – 1.83(m, 1H), 1.75 – 1.66 (m, 1H), 1.25 – 1.25 (m, 12H), 1.20 (s, 3H).

[0347] Example 1.12 2-{5-cyclopropyl-4-[(2 S 4 S Synthesis of 4-(2,2-dimethylpropionyl)-2-methylpiperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine-7-yl}pyridine-4-carboxylonitrile (I-19) Ethyl 1-amino-3-cyclopropylpyrrole-2-carboxylate. A suspension of NaH (8.37 g, 209.24 mmol, 1.5 equiv, 60 wt%) in DMF (500 mL) was placed in a 1 L three-necked round-bottom flask. The solution was cooled to 0 °C. Then, ethyl 3-cyclopropyl-1H-pyrrole-2-carboxylate (25.0 g, 139.49 mmol, 1.0 equiv) was added at 0 °C and stirred for 30 min. Subsequently, aminodiphenylphosphine ester (55.3 g, 237.14 mmol, 1.7 equiv) was added in three fractions at 0 °C. The reaction was heated to room temperature and stirred for 16 h. LC-MS showed the reaction was complete. The reaction mixture was poured into 2 L of H₂O. The solution was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with water (5 x 200 mL) and brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product, ethyl 1-amino-3-cyclopropylpyrrole-2-carboxylate (30.0 g, crude product), which was brown and oily.

[0348] 5-Cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-ol. A solution of ethyl 1-amino-3-cyclopropylpyrrole-2-carboxylate (30.0 g, 154.45 mmol, 1.0 equiv) in formamide (300 mL) was added to a 1 L three-necked round-bottom flask. The mixture was stirred at 165 °C for 16 h. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with cold water (1 L) with stirring. The precipitate formed was filtered and dried under vacuum to give 5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-ol (24.0 g, crude). The product was used directly in the next step without further purification.

[0349] 7-Bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-ol. A solution of 5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-ol (24.0 g, 136.99 mmol, 1.0 equiv) in DMF (900 mL) was placed in a 2 L three-necked round-bottom flask. The solution was cooled to 0 °C and NBS (23.16 g, 130.14 mmol, 0.95 equiv) was added to the mixture. The reaction was stirred at room temperature for 4 h. The reaction was shown to be complete by LCMS. The reaction was quenched by adding an aqueous sodium sulfite solution (1.1 L), and water (1.1 L) was added to the mixture and extracted with EA (3 × 300 mL). The combined organic layers were washed with water (5 × 300 mL) and brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to obtain 30 g of 7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-ol (90% purity), which was a grayish-white solid. The product was used directly in the next step without further purification.

[0350] 7-Bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine. A solution of methyl 7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-ol (30.0 g, 118.07 mmol, 1.0 equiv) in phosphorus oxychloride (300 mL) was placed in a 1 L three-necked round-bottom flask. The mixture was stirred at 130 °C for 2 hours. LC-MS showed the reaction was complete. The reactants were diluted with cold water (2 L) and extracted with ethyl acetate (2 × 300 mL). The combined organic layers were washed with brine (300 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a yellow solid. The crude product was purified by silica gel column chromatography and eluted with PE / EA (5:1) to give 20 g of 7-bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine (yield 62%) as a yellow solid.

[0351] (2 S 4 S )-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-yl}-2-methylpiperidin-4-carboxylate methyl ester. Under a nitrogen atmosphere, at room temperature, 7-bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine (1.2 g, 4.40 mmol, 1.0 equiv), (2... S 4 S A solution of methyl 2-methylpiperidin-4-carboxylate hydrochloride (0.94 g, 4.84 mmol, 1.1 equiv) and DIEA (2.28 g, 17.61 mmol, 4.0 equiv) in DMF (20 mL) was prepared. The reaction mixture was heated to 85 °C and stirred for 3 h. LCMS showed that the reaction was complete. The reaction mixture was cooled to room temperature. Water (100 mL) was added to the reaction mixture and extracted with EA (2 × 20 mL). The combined organic layers were washed with water (2 × 15 mL) and brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give a crude product (2 g) that was brown and oily. S 4 S Methyl 7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate (1.6 g, yield 90.7%). The crude product was used directly in the next step without further purification.

[0352] (2S, 4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid. Under a nitrogen atmosphere, at room temperature, place the mixture into a 100 mL three-necked round-bottom flask... (2S, 4S) A solution of methyl 1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylate (1.8 g, 4.068 mmol, 1.0 equiv) in THF (16 mL) and H2O (16 mL) was prepared. LiOH (0.29 g, 12.20 mmol, 3.0 equiv) was then added to the mixture. The reaction was stirred at room temperature for 2 h. LCMS showed the reaction was complete. Water (50 mL) was added to the reactants and the mixture was extracted with EA (2 × 20 mL). The aqueous phase was acidified to pH 1 with an aqueous solution of HCl (1 mol / L). The mixture was extracted with EA (2 × 20 mL). The combined organic layers were washed with water (15 mL) and brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give the crude product. (2S, 4S) -1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (1.4 g, crude). The crude product was used directly in the next step without further purification.

[0353] 1-[(2 S 4 S )-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one. Under a nitrogen atmosphere, at room temperature, DCM (28 mL) was added to a 50 mL three-necked round-bottom flask containing (2 S 4 S1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (1.4 g, 3.69 mmol, 1.0 equiv). Then, thionyl chloride (0.54 mL, 7.45 mmol, 2.02 equiv) was added. The reaction was stirred for 1 h. LCMS showed that the reaction was complete. The solution was concentrated under vacuum to give the crude product. The residue was used for the next step. The residue was dissolved in THF (28 mL). Then, CuCl (0.04 g, 0.369 mmol, 0.1 equiv) was added and stirred for 10 min. After that, tert-butylmagnesium (10.8 mL, 18.46 mmol, 5.0 equiv) was added and stirred for 2 h. LCMS showed that the reaction was complete. The mixture was poured into water (50 mL) and extracted with EA (2 × 20 mL). The combined organic layers were washed with water (15 mL) and brine (20 mL), and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to obtain a grayish-white solid, 1-[(2 S 4 S )-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f] [1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one (1.2 g, yield 77.5%).

[0354] 2-(trimethylstanyl)pyridine-4-carboxylonitrile. Under nitrogen, a solution of 2-bromopyridine-4-carboxylonitrile (1.0 g, 5.46 mmol, 1.0 equiv) in toluene (20 mL) was added to a 50 mL three-necked flask. Then, hexamethyldistinane (3.58 g, 10.93 mmol, 2.0 equiv) was added at room temperature. The mixture was purged with nitrogen three times. Then, Pd(PPh3)4 (0.32 g, 0.277 mmol, 0.05 equiv) was added at room temperature. The mixture was purged with nitrogen three times. Under nitrogen, the resulting mixture was stirred overnight at 80 °C. The mixture was cooled to room temperature. The mixture was concentrated under reduced pressure. This yielded 2-(trimethylstanyl)pyridine-4-carboxylonitrile (2.8 g, crude product) as a brownish-yellow solid. The crude product was used directly in the next step without further purification.

[0355] 2-{5-cyclopropyl-4-[(2 S 4 S)-4-(2,2-dimethylpropionyl)-2-methylpiperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine-7-yl}pyridin-4-carboxylonitrile. Add 1-[(2...]into a 20 mL vial of dioxane (5 mL). S 4 S 1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one (120.0 mg, 0.286 mmol, 1.0 equiv), 2-(trimethylmethylenetinyl)isonicotinonitrile (154 mg, 0.572 mmol, 2.0 equiv), and Pd(PPh3)4 (33.1 mg, 0.029 mmol, 0.1 equiv). The reactants were heated to 110 °C and stirred for 12 h. The reaction was complete as indicated by LCMS. The reactants were cooled to room temperature. Water (25 mL) was added to the reactants and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give the crude product. The crude product was purified by rapid preparative HPLC under the following conditions (column: XBridge Prep Shield RP18 OBD column: 19*250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 50% B to 80% B within 15 min; wavelength: 254 nm / 220 nm; RT1 (min): 13.9), yielding a pure product 2-{5-cyclopropyl-4-[(2 S 4 S )-4-(2,2-dimethylpropionyl)-2-methylpiperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine-7-yl}pyridin-4-carboxylonitrile (20.4 mg, yield 16.1%). LC-MS-PH-CSM-SMC-2024-01-V0037: (ES, m / z ): 443 [M+H] + ; 1 H-NMR (400 MHz, DMSO- d 6 , ppm ): δ 8.93 – 8.85 (m, 2H), 8.38 (s, 1H), 7.77 (dd, J = 4.9, 1.5Hz, 1H), 7.17 (s, 1H), 3.96 (dt, J= 12.7, 4.0 Hz, 1H), 3.75 (ddd, J = 11.6,5.9, 3.5 Hz, 1H), 3.28 (td, J = 10.3, 4.1 Hz, 1H), 3.19 – 3.06 (m, 1H), 2.39– 2.31 (m, 1H), 1.83 – 1.54 (m, 4H), 1.28 (d, J = 5.9 Hz, 3H), 1.13 (s, 9H), 1.11 – 1.04 (m, 2H), 1.04 – 0.96 (m, 1H), 0.66 – 0.59 (m, 1H).

[0356] Example 1.13 Synthesis of 2-{5-cyclopropyl-4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2,4-dimethylpiperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-16) (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-yl}-2-methylpiperidin-4-carboxylate methyl ester. Under a nitrogen atmosphere, a solution of 7-bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine (1.4 g, 5.14 mmol, 1.0 equiv), (2S,4S)-2-methylpiperidin-4-carboxylate methyl ester hydrochloride (1.09 g, 5.63 mmol, 1.1 equiv), and DIEA (2.66 g, 20.55 mmol, 4.0 equiv) in DMF (27 mL) was added to a 40 mL vial at room temperature. The reaction mixture was heated to 85 °C and stirred for 3 h. LC-MS showed the reaction was complete. The reaction mixture was then cooled to room temperature. Water (100 mL) was added to the reactants and extracted with EA (2 × 20 mL). The combined organic layers were washed with water (5 × 15 mL) and brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give a crude product that was brown and oily. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give methyl (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate (2 g, 99.0% yield) as a yellow solid.

[0357] Methyl (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidine-4-carboxylate. Under a nitrogen atmosphere, a solution of (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate (1.0 g, 2.54 mmol, 1.0 equiv) in 20 mL of THF was added to a 50 mL three-necked round-bottom flask at room temperature. The reaction mixture was cooled to -78 °C. Then, LDA (0.65 g, 6.10 mmol, 2.4 equiv) was added and the mixture was stirred for 30 min. Afterward, methyl iodoform (1.08 g, 7.63 mmol, 3.0 equiv) was added. The reactants were heated to rt and stirred at room temperature for 1 h. LCMS showed that the reaction was complete. The reactants were poured into water (50 mL) and extracted with EA (3 × 15 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give methyl (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylate (600 mg, yield 57.9%) as a yellow solid.

[0358] (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid. Methyl (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (600.0 mg, 1.47 mmol, 1.0 equiv) was added to a 40 mL vial containing 6 mL of THF and 6 mL of H₂O at room temperature. Then, LiOH (105.8 mg, 4.42 mmol, 3.0 equiv) was added. The reaction mixture was heated to 60 °C and stirred for 12 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water (20 mL). The solution was acidified to pH 1 with 1 N HCl (aq.). The mixture was extracted with EA (2 × 20 mL). The combined organic layers were washed with water (4 × 15 mL) and brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to give the crude product (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (500 mg, crude). The crude product was used directly in the next step without further purification.

[0359] 1-[(2 S 4 S )-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-yl]-2,2-dimethylprop-1-one. Under a nitrogen atmosphere, at room temperature, DCM (22 mL) of (2) S 4 S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (500.0 mg, 1.27 mmol, 1.0 equiv). Then, thionyl chloride (0.18 mL, 2.48 mmol, 1.95 equiv) was added. The reaction was stirred for 1 h. LCMS showed that the reaction was complete. The solution was concentrated under vacuum to give the crude product. The residue was used for the next step. The residue was dissolved in THF (22 mL). Then, CuCl (12.6 mg, 0.127 mmol, 0.1 equiv) was added and stirred for 10 min. After that, tert-butylmagnesium (742.9 mg, 6.36 mmol, 5.0 equiv) was added and stirred for 2 h. LCMS showed that the reaction was complete. The mixture was poured into water (50 mL) and extracted with EA (2 × 20 mL). The combined organic layers were washed with water (15 mL) and brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give a yellow oily 1-[(2 S 4 S )-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f] [1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-yl]-2,2-dimethylprop-1-one (120 mg, yield 21.8%).

[0360] 2-{5-cyclopropyl-4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2,4-dimethylpiperidin-1-yl]pyrrolo[2,1-f] [1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile. A solution of 1-[(2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-yl]-2,2-dimethylprop-1-one (120.0 mg, 0.277 mmol, 1.0 equiv), 2-(trimethylmethylenetinyl)isonicotinonitrile (148 mg, 0.554 mmol, 2.0 equiv), and Pd(PPh3)4 (32.0 mg, 0.028 mmol, 0.1 equiv) in 1,4-dioxane (10 mL) was placed in a 40 mL vial. The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction was complete as indicated by LCMS. The reaction mixture was cooled to room temperature. Water (25 mL) was added to the reaction mixture and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid preparative HPLC under the following conditions (column: Xselect CSH Prep C18 OBD column, 19*250 nm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 65% B to 95% B over 12 min; wavelength: 254 nm / 220 nm; RT1 (min): 12), yielding a pure product 2-{5-cyclopropyl-4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2,4-dimethylpiperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxynitrile (18.1 mg, yield 14.3%) as a yellow solid. LC-MS: (ES, m / z ): 457 [M+H] + ; 1 H-NMR (400 MHz, DMSO- d 6 , ppm ): δ 8.92 – 8.84 (m, 2H), 8.21 (s, 1H), 7.75 (dd, J = 5.0, 1.5 Hz, 1H),7.13 (s, 1H), 4.46 (td, J = 6.8, 4.3 Hz, 1H), 3.77 (dt, J= 13.6, 4.7 Hz,1H), 3.64 (ddd, J = 13.4, 9.9, 3.1 Hz, 1H), 2.38 – 2.28 (m, 1H), 2.28 – 2.20(m, 1H), 2.14 (td, J = 8.3, 4.3 Hz, 1H), 1.87 (dd, J = 14.1, 4.3 Hz, 1H),1.47 (ddd, J = 13.7, 9.6, 3.8 Hz, 1H), 1.30 (s, 3H), 1.26 (s, 9H), 1.16 (d, J = 6.4 Hz, 3H), 1.11 – 1.00 (m, 2H), 0.97 – 0.87 (m, 1H), 0.72 (ddt, J = 7.2, 5.2, 2.5 Hz, 1H).

[0361] Example 1.14. Synthesis of (2S,4S)-1-[7-(4-cyanopyridin-2-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidine-4-carboxylic acid tert-butyl ester (I-16) 7-Bromo-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazine-4-one. A solution of 5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazine-4-one (5.0 g, 33.52 mmol, 1.0 equiv) and NBS (6.56 g, 36.88 mmol, 1.1 equiv), TFA (0.76 g, 6.71 mmol, 0.2 equiv) in DCM (100 mL) was placed in a 250 mL three-necked round-bottom flask. The solution was stirred for 20 min at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by grinding with MeOH (50 mL). The precipitated solid was collected by filtration and washed with MeOH (3 × 10 mL). This yielded 5.5 g of 7-bromo-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazine-4-one as a white solid, with a yield of 71.9%.

[0362] (2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylate methyl ester. A solution of 7-bromo-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (4.0 g, 17.54 mmol, 1.0 equiv) and (2S,4S)-2-methylpiperidin-4-carboxylate methyl ester hydrochloride (3.74 g, 19.29 mmol, 1.1 equiv), PyBOP (10.04 g, 19.29 mmol, 1.1 equiv), and TEA (8.87 g, 87.70 mmol, 5.0 equiv) in MeCN (100 mL) was placed in a 250 mL three-necked round-bottom flask. The solution was stirred overnight at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (0.1% TFA), 10% to 100% gradient over 30 min; detector: UV 254 nm. This yielded a yellow oily methyl (2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate (3.7 g, yield 57.4%).

[0363] (2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid. A solution of methyl (2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (3.2 g, 8.71 mmol, 1.0 equiv) and lithium hydroxide (630.0 mg, 26.14 mmol, 3.0 equiv) in THF (96 mL) and water (32 mL) was placed in a 100 mL three-necked round-bottom flask. The solution was stirred for 1 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 2 with aqueous citric acid. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na₂SO₄. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (0.1% TFA), 10% to 50% gradient over 20 min; detector: UV 254 nm. This yielded (2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (2.8 g, 91.0% yield) as a yellow solid.

[0364] 1-[(2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one. A solution of (2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxyl chloride (500.0 mg, 1.35 mmol, 1.0 equiv), di-tert-butyl dicarbonate (619.3 mg, 2.84 mmol, 2.0 equiv), and DMAP (17.3 mg, 0.14 mmol, 0.1 equiv) in t-BuOH (10 mL) was placed in a 40 mL vial. This solution was stirred at room temperature for 4 h under a nitrogen atmosphere. The reaction was quenched by adding water (20 mL) at room temperature. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (0.1% TFA), 10% to 50% gradient over 10 min; detector: UV 254 nm. This yielded a yellow oily 1-[(2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one (260 mg, yield 49.10%).

[0365] (2S,4S)-1-[7-(4-cyanopyridin-2-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidin-4-carboxylic acid tert-butyl ester. A solution of (2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid tert-butyl ester (170.0 mg, 0.415 mmol, 1.0 equiv) and 2-(trimethyl-methylenetinyl)pyridin-4-carboxylonitrile (145.0 mg, 0.620 mmol, 1.5 equiv), tetrakis(triphenylphosphine)palladium(0) (48.0 mg, 0.042 mmol, 0.1 equiv) in 1,4-dioxane (5 mL) was placed in a 20 mL vial. The solution was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was quenched by adding water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (54 mg) was purified by preparative HPLC under the following conditions (column: XBridgeShield RP18 OBD column, 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 44% B over 7 min; wavelength: 254 nm / 220 nm). This yielded (2S,4S)-1-[7-(4-cyanopyridin-2-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidin-4-carboxylic acid tert-butyl ester (19 mg, yield 10.4%) as a white solid. LC-MS: (ES, m / z ): 433 [M+H] + ; 1 H-NMR: (300 MHz, DMSO- d 6, ppm ) δ 8.96 – 8.83 (m, 2H), 8.29 (s, 1H), 7.75 (dd, J =4.9, 1.6 Hz, 1H), 7.40 (s, 1H), 3.97-3.91 (m, 1H), 3.63-3.55 (m, 1H), 3.30-3.22 (m, 1H), 2.61-2.52 (m, 1H), 2.13-2.02 (m, 1H), 1.93-1.75 (m, 3H), 1.44(s, 8H), 1.23 (d,J = 6.3 Hz, 4H).

[0366] Example 1.15 Synthesis of 2-(5-cyclopropyl-4-((1R,3s,5S)-3-tertivalyl-8-azabicyclo[3.2.1]oct-8-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)isonicotinonitrile (I-28) 1-((1R,3s,5S)-8-(7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-2,2-dimethylprop-1-one. At 20°C, a solution of (1R,3S,5S)-8-(7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (500.0 mg, 1.279 mmol, 1.0 equiv) in DCM (5 mL) was placed in a 20 mL vial purged with and maintained under an inert nitrogen atmosphere. SOCl2 (304.0 mg, 2.558 mmol, 2.0 equiv) was added to the mixture at 20 °C. The mixture was stirred at 20 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS (quenched with MeOH). The reactants were concentrated under reduced pressure and dissolved in THF (5 mL) at 20 °C. CuCl (95.0 mg, 0.959 mmol, 0.75 equiv) was added to the mixture at 20 °C, and t-BuMgCl (2.4 mL, 2.430 mmol, 1.9 equiv, 1.7 M) was slowly added dropwise to the reactants at 20 °C. The final reaction mixture was stirred at 20 °C for 2 h under a nitrogen atmosphere. The desired product was detected by LCMS. The mixture was cooled to 0 °C. The reaction was quenched at 0 °C with water / ice (10 mL). The mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: Ultimate XB-C18 column: 50*250 mm, 10 µm; mobile phase: MeCN / water (0.1% NH4HCO3), 70% to 100% gradient over 40 min; detector: UV 210 / 254 nm. This yielded a yellow solid, 1-((1R,3s,5S)-8-(7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-2,2-dimethylprop-1-one (300 mg, yield 54.4%).

[0367] 2-(5-cyclopropyl-4-((1R,3s,5S)-3-tervapotranilyl-8-azabicyclo[3.2.1]oct-8-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)isonicotinonitrile. At 20°C, a solution of 1-((1R,3s,5S)-8-(7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-2,2-dimethylprop-1-one (300.0 mg, 0.696 mmol, 1.0 equiv) in 1,4-dioxane (6 mL) was placed in a 40 mL vial purged with and maintained under an inert nitrogen atmosphere. At 20°C, 2-(trimethylstanyl)isonicotinonitrile (371.7 mg, 1.39 mmol, 2.0 equiv) was added to the above mixture. At 20°C, Pd(PPh3)4 (80.9 mg, 0.070 mmol, 0.1 equiv) was added to the above mixture. The final reaction mixture was stirred at 110°C for 16 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product was detected by LCMS. The mixture was cooled to 30°C. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: Ultimate XB-C18 column: 50*250 mm, 10 µm; mobile phase: MeCN / water (0.05% TFA), 60% to 90% gradient over 40 min; detector: UV210 / 254 nm. This yielded 2-(5-cyclopropyl-4-((1R,3s,5S)-3-tervaline-8-azabicyclo[3.2.1]oct-8-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)isonicotinonitrile (18 mg, yield 5.7%) as a yellow solid. LCMS:(ES, m / z ):455.25 [M+H] + . 1 H-NMR: (300 MHz, THF- d 8, ppm ) δ 8.95 (dd, J = 1.5, 1.0 Hz, 1H), 8.64 (dd, J = 4.9, 1.0 Hz, 1H), 7.93 (s, 1H), 7.36 (dd, J = 4.9,1.5 Hz, 1H), 7.13 (s, 1H), 4.88 (t, J = 3.8 Hz, 2H), 3.47 (s, 2H), 2.16 (tt, J= 8.2, 5.2 Hz, 1H), 2.01–1.85 (m, 4H), 1.86–1.71 (m, 2H), 1.68–1.50 (m,2H), 1.05 (s, 9H), 1.01– 0.93 (m, 2H), 0.82– 0.71 (m, 2H).

[0368] Example 1.16. Synthesis of 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2-methylpiperidin-1-yl]-5-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-16) 1-[(2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one. A solution of (2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (500.0 mg, 1.42 mmol, 1.0 equiv) and thionyl chloride (336.8 mg, 2.83 mmol, 2.0 equiv) in DCM (10 mL) was placed in a 20 mL vial. This solution was stirred for 1 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in THF (10 mL), and CuCl (140.1 mg, 1.42 mmol, 1.0 equiv) and tert-butylmagnesium (314.3 mg, 2.69 mmol, 1.9 equiv) were added. The mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. The reaction was quenched by adding water (10 mL) at 0 °C. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na₂SO₄. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (0.1% FA), 10% to 100% gradient over 20 min; detector: UV 254 nm. This yielded a yellow oily 1-[(2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one (262 mg, yield 44.7%).

[0369] 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2-methylpiperidin-1-yl]-5-methylpyrrolo[2,1-f][1,2,4]triazine-7-yl}pyridine-4-carboxylonitrile. A solution of 1-[(2S,4S)-1-{7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one (220.0 mg, 0.559 mmol, 1.0 equiv) and 2-(trimethyl-methylenetinyl)pyridin-4-carboxynitrile (179.2 mg, 0.671 mmol, 1.2 equiv), tetrakis(triphenylphosphine)palladium(0) (64.6 mg, 0.056 mmol, 0.1 equiv) in 1,4-dioxane (40 mL) was placed in a 20 mL vial. The solution was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was quenched by adding water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (54 mg) was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 54% B over 7 min; wavelength: 254 nm / 220 nm). This yielded 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2-methylpiperidin-1-yl]-5-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxynitrile (16.7 mg, yield 7.2%) as a white solid. LC-MS (ES, m / z ): 417.15 [M+H] + ; 1 H-NMR (300 MHz, DMSO- d 6, ppm ) δ 8.96 – 8.82 (m, 2H), 8.37(s, 1H), 7.81 – 7.71 (m, 1H), 7.43 (s, 1H), 3.72 – 3.62 (m, 2H), 3.31 – 3.21(m, 1H), 3.1 – 3.0 (m, 1H), 2.52 (s, 3H), 1.85 – 1.54 (m, 3H), 1.23 (d, J=5.9 Hz, 3H), 1.13 (s, 9H).

[0370] Example 1.17. Synthesis of (2S,4S)-1-[7-(4-cyanopyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidine-4-carboxylic acid tert-butyl ester (I-15) Methyl (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate. A solution of (2S,4S)-2-methylpiperidine-4-carboxylate (2.83 g, 17.98 mmol, 1.1 equiv), 7-bromo-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (3.5 g, 16.35 mmol, 1.0 equiv), PyBOP (9.36 g, 17.98 mmol, 1.1 equiv), and Et3N (13.24 g, 130.82 mmol, 8.0 equiv) in ACN (70 mL) was placed in a 250 mL three-necked round-bottom flask. The solution was stirred at 80 °C for 4 h under a nitrogen atmosphere. The resulting mixture was diluted with water (300 mL). The mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1), to give methyl (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazine-4-yl}-2-methylpiperidine-4-carboxylate (3.3 g, 57.1%) as a light brown solid.

[0371] (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid. A solution of methyl (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (3.3 g, 9.34 mmol, 1.0 equiv) and LiOH·H₂O (0.78 g, 18.68 mmol, 2.0 equiv) in THF (66 mL) and H₂O (16.5 mL) was added to a 100 mL three-necked round-bottom flask and stirred at room temperature for 5 h under a nitrogen atmosphere. The mixture was acidified to pH 5 with concentrated aqueous HCl. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (5:1) to give (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazine-4-yl}-2-methylpiperidin-4-carboxylic acid (2.5 g, 80.6%) as a light brown solid.

[0372] (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate. A solution of (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylic acid (300.0 mg, 0.88 mmol, 1.0 equiv), di-tert-butyl dicarbonate (386.0 mg, 1.76 mmol, 2.0 equiv), and DMAP (324.0 mg, 2.65 mmol, 3.0 equiv) in tert-butanol (6 mL) was placed in a 20 mL vial. The solution was stirred at 30 °C for 1 h under a nitrogen atmosphere. The resulting mixture was diluted with water (40 mL). The mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1), to give a light brown oily (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylic acid tert-butyl ester (250 mg, yield 71.5%).

[0373] 2-(trimethylstanyl)pyridin-4-carboxylonitrile. A solution of 2-bromopyridin-4-carboxylonitrile (1.0 g, 5.46 mmol, 1.0 equiv), hexamethyldistinane (3.58 g, 10.92 mmol, 2.0 equiv), and Pd(PPh3)4 (0.32 g, 0.27 mmol, 0.05 equiv) in toluene (20 mL) was placed in a 40 mL vial. The solution was stirred overnight at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. This yielded 1.5 g (crude) 2-(trimethylstanyl)pyridin-4-carboxylonitrile as a brownish-yellow solid.

[0374] (2S,4S)-1-[7-(4-cyanopyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidin-4-carboxylic acid tert-butyl ester. A solution of (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid tert-butyl ester (200.0 mg, 0.50 mmol, 1.0 equiv), 2-(trimethylmethylenetinyl)pyridin-4-carboxylonitrile (270.0 mg, 1.01 mmol, 2.0 equiv), and Pd(PPh3)4 (58.0 mg, 0.05 mmol, 0.1 equiv) in dioxane (10 mL) was placed in a 20 mL vial. The solution was stirred overnight at 110 °C under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (2 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1), to give (2S,4S)-1-[7-(4-cyanopyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidin-4-carboxylic acid tert-butyl ester (24.5 mg, 10.8%) as a white solid. LC-MS: (ES, m / z ): 419.15 [M+H] + ; 1 H-NMR: (400 MHz, DMSO- d 6, ppm ): δ 8.98 (s, 1H), 8.88 (dd, J = 4.9, 1.0 Hz, 1H), 8.14 (s, 1H), 7.75 (dd, J = 5.0, 1.5 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 7.08 (d, J= 5.0 Hz, 1H), 4.91 – 4.87 (m, 1H), 4.57 – 4.49(m, 1H), 3.52 – 3.40 (m, 1H), 2.61 – 2.57 (m, 1H), 2.17 – 1.88 (m, 4H), 1.44(s, 9H), 1.32 (d, J = 6.6 Hz, 3H).

[0375] Example 1.18. Synthesis of (2S,4S)-1-[7-(4-cyanopyridin-2-yl)-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidine-4-carboxylic acid tert-butyl ester (I-17) 5-Bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine. Under a nitrogen atmosphere, a solution of 5-bromo-3H-pyrrolo[2,1-f][1,2,4]triazine-4-one (5.0 g, 23.36 mmol, 1.0 equiv) in phosphorus oxychloride (50 mL) was added to a 250 mL three-necked round-bottom flask at room temperature. The resulting mixture was stirred at 80 °C for 4 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1), to give 4.0 g (73.7%) of 5-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine as a yellow solid.

[0376] (2S,4S)-1-{5-bromopyrrolo[2,1-f][1,2,4]triazine-4-yl}-2-methylpiperidin-4-carboxylate methyl ester. Under a nitrogen atmosphere, a solution of 5-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (4.0 g, 17.21 mmol, 1.0 equiv), (2S,4S)-2-methylpiperidin-4-carboxylate methyl ester (2.7 g, 17.21 mmol, 1.0 equiv), and DIEA (6.67 g, 51.62 mmol, 3.0 equiv) in DMF (80 mL) was added to a 250 mL three-necked round-bottom flask at room temperature. The resulting mixture was stirred at 85 °C for 3 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to give methyl (2S,4S)-1-{5-bromopyrrolo[2,1-f][1,2,4]triazine-4-yl}-2-methylpiperidine-4-carboxylate (4.8 g, yield 79.0%) as a yellow solid.

[0377] (2S,4S)-1-{5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate methyl ester was added to a 100 mL three-necked round-bottom flask containing toluene (50 mL), H₂O (5 mL), (4.7 g, 13.31 mmol, 1.0 equiv), potassium ethyltrifluoroborate (3.62 g, 26.61 mmol, 2.0 equiv), and Cs₂CO₃ (8.67 g, 26.61 mmol, 2.0 equiv). Then, CataCXium A Pd G2 (0.89 g, 1.33 mmol, 0.1 equiv) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (20:1), to give methyl (2S,4S)-1-{5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate (2.3 g, yield 57.2%) as a yellow oil.

[0378] Methyl (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate. At room temperature, a solution of methyl (2.3 g, 7.61 mmol, 1.0 equiv) in DMF (23 mL) was added to a 100 mL round-bottom flask. At room temperature, fractions of NBS (1.35 g, 7.61 mmol, 1.0 equiv) were added to the mixture over 5 min, and the mixture was stirred for 30 min. At room temperature, the reaction mixture was poured into water (30 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded a yellow, oily methyl (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate (2.0 g, crude).

[0379] (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid. At room temperature, a solution of methyl (2.0 g, 5.25 mmol, 1.0 equiv) of (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid in THF (40 mL) was added to a 100 mL round-bottom flask. The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 4 with an aqueous HCl solution (1 mol / L). The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylic acid (2.1 g, crude product), which was a yellow solid.

[0380] (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid tert-butyl ester. Under a nitrogen atmosphere, a solution of (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (0.6 g, 1.63 mmol, 1.0 equiv), (Boc)₂O (0.53 g, 2.45 mmol, 1.5 equiv), and DMAP (0.04 g, 0.327 mmol, 0.2 equiv) in tert-butanol (12 mL) was added to a 20 mL vial at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure and purified by preparative TLC (PE / EA 5:1) to give (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylic acid tert-butyl ester (130 mg, yield 18.8%) as a yellow oil.

[0381] (2S,4S)-1-[7-(4-cyanopyridin-2-yl)-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidin-4-carboxylic acid tert-butyl ester. Under a nitrogen atmosphere, at room temperature, a solution of (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid tert-butyl ester (130.0 mg, 0.307 mmol, 1.0 equiv), 2-(trimethylmethylenetinyl)pyridin-4-carboxylonitrile (98.4 mg, 0.368 mmol, 1.2 equiv), and Pd(PPh3)4 (35.5 mg, 0.031 mmol, 0.1 equiv) in dioxane (2.6 mL) was added to a 20 mL vial. The resulting mixture was stirred overnight at 100 °C. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: Xbridge Prep OBD C18 column: 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3·H2O); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 66% B to 96% B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 8.8. This yielded a yellow solid (2S,4S)-1-[7-(4-cyanopyridin-2-yl)-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidin-4-carboxylic acid tert-butyl ester (31.0 mg, yield 22.6%). LC-MS: (ES, m / z ): 447.25 [M+H] + ; 1 H-NMR: (300 MHz, DMSO- d 6, ppm ) δ 8.96 – 8.86 (m, 2H), 8.36 (s, 1H), 7.78 (dd, J =4.9, 1.5 Hz, 1H), 7.51 (s, 1H), 3.86 – 3.84 (m, 1H), 3.33 – 3.55 (m, 1H) 3.21 – 3.10 (m, 1H), 2.98 – 2.84 (m, 2H), 2.56 – 2.54 (m, 1H), 2.07 (d, J = 13.8Hz, 1H), 1.88 – 1.62 (m, 3H), 1.44 (s, 9H), 1.32 (t,J = 7.5 Hz, 3H), 1.22(d, J = 6.3 Hz, 3H).

[0382] Example 1.19. Synthesis of 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2-methylpiperidin-1-yl]-5-ethylpyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-22) 1-[(2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one. At room temperature, (2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (1.5 g, 4.08 mmol, 1.0 equiv) and SOCl2 (0.97 g, 8.17 mmol, 2.0 equiv) from DCM (15 mL) were added. The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. Under a nitrogen atmosphere, the residue was added to THF (30 mL) at room temperature. Then, CuCl (4 mg, 0.408 mmol, 0.1 equiv) and tert-butylmagnesium (7.5 mL, 7.76 mmol, 1.9 equiv) were added at 0 °C and stirred for 10 min. The reaction was quenched by adding water (50 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give 1-[(2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one (1 g, 60.1% yield) as a yellow solid.

[0383] 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2-methylpiperidin-1-yl]-5-ethylpyrrolo[2,1-f][1,2,4]triazine-7-yl}pyridine-4-carboxylonitrile. Under a nitrogen atmosphere, at room temperature, 1-[(2S,4S)-1-{7-bromo-5-ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one (200.0 mg, 0.491 mmol, 1.0 equiv), 2-(trimethylsteryl)pyridin-4-carboxylonitrile (157.3 mg, 0.589 mmol, 1.2 equiv), and Pd(PPh3)4 (56.7 mg, 0.049 mmol, 0.1 equiv) from dioxane (4 mL) were added. The resulting mixture was stirred overnight at 100 °C. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: XSelect CSH Prep C18 OBD column: 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 62% B to 90% B in 12 min; wavelength: 254 nm / 220 nm; RT1 (min): 9.18. This yielded a yellow solid, 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2-methylpiperidin-1-yl]-5-ethylpyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxynitrile (101.5 mg, yield 48.0%). LC-MS: (ES, m / z ): 431.30 [M+H] + ; 1 H-NMR: (300 MHz, DMSO- d 6, ppm ) δ 8.97 – 8.87 (m, 2H), 8.43 (s, 1H), 7.79 (dd, J = 4.9, 1.5 Hz, 1H), 7.52 (s, 1H), 3.70 – 3.62 (m, 2H), 3.34 – 3.33 (m, 1H), 3.03 – 2.92 (m, 3H), 1.78 –1.59 (m, 4H), 1.33 (t, J = 7.5 Hz, 3H), 1.22 (d, J = 5.9 Hz, 3H), 1.14 (s, 9H).

[0384] Example 1.20. Synthesis of 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2-methylpiperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-23) 1-[(2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one. A solution of (2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (500 mg, 1.47 mmol, 1 equiv) and thionyl chloride (350 mg, 2.94 mmol, 2 equiv) in DCM (10 mL) was stirred for 1 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was redissolved in THF (10 mL), and CuCl (109 mg, 1.10 mmol, 0.75 equiv) was added fractionally at 0 °C under a nitrogen atmosphere. Then, tert-butylmagnesium (327 mg, 2.80 mmol, 1.9 equiv, 1 M) was added dropwise to the mixture at 0 °C for 10 min. The resulting mixture was stirred at 0 °C for another 1 h. The reaction was quenched with saturated NH4Cl (aq.) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give 1-[(2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one (300 mg, yield 53.66%) as a grayish-white solid.

[0385] 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2-methylpiperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile. A solution of 1-[(2S,4S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-yl]-2,2-dimethylprop-1-one (120 mg, 0.31 mmol, 1 equiv), 2-(trimethylsteryl)pyridin-4-carboxylonitrile (168 mg, 0.63 mmol, 2 equiv), and Pd(PPh3)4 (36 mg, 0.03 mmol, 0.1 equiv) in dioxane (6 mL) was stirred overnight at 110 °C under a nitrogen atmosphere. The mixture was then cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with MeOH (2 × 10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (10 mmol / L NH4HCO3), 10% to 80% gradient over 20 min; detector: UV 254 nm. This yielded 2-{4-[(2S,4S)-4-(2,2-dimethylpropionyl)-2-methylpiperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (27.4 mg, 21.15%) as a white solid. LC-MS: (ES, m / z ): 403.15 [M+H] + . 1 H-NMR: (400 MHz, DMSO- d 6, ppm ): δ9.00 (s, 1H), 8.88 (d, J = 5.0 Hz, 1H), 8.14 (s, 1H), 7.75 (d, J = 5.0, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.07 (d, J = 5.0 Hz, 1H), 4.74 – 4.54 (m, 2H), 3.46– 3.36 (m, 1H), 3.26 – 3.14 (m, 1H), 2.08 – 1.95 (m, 1H), 1.90 – 1.81 (m,1H), 1.71– 1.61 (m, 2H), 1.37 (d, J = 6.2 Hz, 3H), 1.07 (s, 9H).

[0386] Example 1.21 Synthesis of (1R,3S,5S)-8-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (I-29) (1R,3S,5S)-8-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-8-azabicyclo[3.2.1]octane-3-carboxylonitrile. At 25°C, a solution of (1R,3S,5S)-8-azabicyclo[3.2.1]octane-3-carboxylonitrile hydrochloride (1.0 g, 5.792 mmol, 1.0 equiv) in 10 mL of DMF was placed in a 50 mL three-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. DIEA (2.25 g, 17.409 mmol, 3.0 equiv) was added to the mixture. At 25 °C, 7-bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine (1.74 g, 6.385 mmol, 1.1 equiv) was added to the above mixture. The final reaction mixture was stirred at 25 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product was detected by LCMS. The mixture was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / H2O (0.05% TFA), 40% to 70% gradient over 30 min; detector: UV 210 nm. This yielded (1R,3S,5S)-8-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-8-azabicyclo[3.2.1]octane-3-carboxylonitrile (1.5 g, yield 68.9%), a light yellow solid.

[0387] (1R,3S,5S)-8-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-8-azabicyclo[3.2.1]octane-3-carboxylic acid. At 25°C, a solution of (1R,3S,5S)-8-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-8-azabicyclo[3.2.1]octane-3-carboxylonitrile (1.5 g, 4.029 mmol, 1.0 equiv) in 1,4-dioxane (15 mL) was added to a 50 mL three-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. H₂SO₄ (15 mL, 50 w / w%) was added to the mixture. The final reaction mixture was stirred for 3 h at 100°C under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The reaction was quenched at 0°C with water / ice (50 mL). The mixture was adjusted to pH 8 with 2 mol / L NaOH aqueous solution. The mixture was washed with EtOAc (100 mL). The aqueous layer was collected; the mixture was adjusted to pH 5 with 1 mol / L HCl aqueous solution. The mixture was extracted with EtOAc (2 × 50 mL), and the organic layer was washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (1R,3S,5S)-8-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-8-azabicyclo[3.2.1]octane-3-carboxylic acid (1.0 g, yield 62.2%) as a pale yellow solid.

[0388] (1R,3S,5S)-8-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-8-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester. At 25°C, a solution of (1R,3S,5S)-8-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-8-azabicyclo[3.2.1]octane-3-carboxylic acid (0.3 g, 0.767 mmol, 1.0 equiv) in THF (2 mL) was placed in a 10 mL two-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. DMAP (0.03 g, 0.230 mmol, 0.3 equiv) was added to the mixture. At 25°C, a solution of Boc₂O (0.20 g, 0.920 mmol, 1.2 equiv) in 1 mL of THF was added to the above mixture. The final reaction mixture was stirred at 25°C for 12 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched at 25°C with 5 mL of 10% citric acid aqueous solution. The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 5 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded a light yellow solid (1R,3S,5S)-8-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-8-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (0.27 g, yield 75.6%).

[0389] (1R,3S,5S)-8-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-8-azabicyclo[3.2.1]tert-butyl octane-3-carboxylate. At 25°C, a solution of (1R,3S,5S)-8-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-8-azabicyclo[3.2.1]tert-butyl octane-3-carboxylate (0.27 g, 0.604 mmol, 1.0 equiv) in 1,4-dioxane (5.4 mL) was placed in a 20 mL vial purged with and maintained under an inert nitrogen atmosphere. At 25°C, 2-(trimethyltinyl)pyridin-4-carboxynitrile (0.32 g, 1.208 mmol, 2.0 equiv) was added to the above mixture. The solution was degassed (bubbled with nitrogen). At 25°C, Pd(PPh3)4 (0.07 g, 0.060 mmol, 0.1 equiv) was added to the above mixture. The final reaction mixture was stirred at 100°C for 12 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was cooled to 25°C. The resulting mixture was filtered; the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: Ultimate XB-C18 column: 50*250 mm, 10 µm; mobile phase: MeCN / water (0.05% TFA), 60% to 90% gradient over 30 min; detector: UV 210 / 254 nm, yielding (1R,3S,5S)-8-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (0.0139 g, yield 5.2%) as a white solid. LCMS: (ES, m / z ): 471.20 [M+H] + ; 1 H-NMR: (300 MHz, DMSO- d 6, ppm ) δ 8.91 – 8.81 (m, 2H), 8.14 (s, 1H), 7.74 (dd, J = 4.9, 1.5 Hz, 1H), 7.13 (s, 1H), 4.90 (s, 2H), 2.83 (tt, J = 11.7, 6.1 Hz, 1H), 2.14 – 1.74 (m,9H), 1.39 (s, 9H), 1.08 (dt, J= 8.5, 3.0 Hz, 2H), 0.92 – 0.81 (m, 2H).

[0390] Example 1.22. Synthesis of 2-{5-cyclopropyl-4-[(2S)-2-methyl-4-(2-methylpropane-2-sulfonyl)piperazin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile (I-54) (2S)-2-methyl-4-(2-methylpropane-2-sulfinyl)piperazine-1-carboxylate tert-butyl ester. A solution of (2S)-2-methylpiperazine-1-carboxylate (3.0 g, 15.0 mmol, 1.0 equiv) in DCM (60 mL) was placed in a 250 mL three-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. The mixture was cooled to 0 °C, and then 2-methylpropane-2-sulfinyl chloride (2.32 g, 16.5 mmol, 1.1 equiv) and NaHCO3 (3.77 g, 44.9 mmol, 3.0 equiv) were added to the mixture at 0 °C. After addition, the mixture was warmed to room temperature and stirred overnight. The mixture was quenched with 1 mol / L HCl aqueous solution and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 2.8 g (61% yield) of (2S)-2-methyl-4-(2-methylpropane-2-sulfinyl)piperazine-1-carboxylic acid tert-butyl ester, a yellow solid.

[0391] (2S)-2-methyl-4-(2-methylpropane-2-sulfinyl)piperazine-1-carboxylate tert-butyl ester. A solution of (2S)-2-methyl-4-(2-methylpropane-2-sulfinyl)piperazine-1-carboxylate tert-butyl ester (3.3 g, 10.8 mmol, 1.0 equiv) in DCM (33 mL) was placed in a 100 mL three-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. The mixture was cooled to 0 °C, and then 3-chloroperoxybenzoic acid (2.24 g, 13.0 mmol, 1.2 equiv) was added to the mixture at 0 °C. After addition, the mixture was heated to room temperature and stirred for 2 h. The mixture was quenched with an aqueous sodium bicarbonate solution and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1). This yielded tert-butyl (2S)-2-methyl-4-(2-methylpropane-2-sulfonyl)piperazine-1-carboxylate (3.0 g, 86% yield) as a white solid.

[0392] (3S)-3-methyl-1-(2-methylpropane-2-sulfonyl)piperazine. A solution of (2S)-2-methyl-4-(2-methylpropane-2-sulfonyl)piperazine-1-carboxylic acid tert-butyl ester (1.6 g, 4.99 mmol, 1.0 equiv) in hydrogen chloride (4.0 M in 1,4-dioxane) (32 mL) was placed in a 40 mL vial purged with and maintained under an inert nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. This yielded a yellow oily (3S)-3-methyl-1-(2-methylpropane-2-sulfonyl)piperazine (1.0 g, 90% yield).

[0393] (2S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methyl-4-(2-methylpropane-2-sulfonyl)piperazine. A solution of 7-bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine (650.0 mg, 2.39 mmol, 1.0 equiv) in DMF (13 mL) was placed in a 40 mL vial purged with and maintained under an inert nitrogen atmosphere. (3S)-3-methyl-1-(2-methylpropane-2-sulfonyl)piperazine (578.1 mg, 2.62 mmol, 1.1 equiv) and DIEA (1.23 g, 9.54 mmol, 4.0 equiv) were added to the mixture. The resulting mixture was stirred at 85 °C for 3 h. The reaction mixture was cooled to room temperature. The reaction mixture was purified rapidly by reverse-phase reaction under the following conditions (A: water containing 0.1% NH4HCO3, B: ACN; 50% B-100% B, 40 min). This yielded (2S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methyl-4-(2-methylpropane-2-sulfonyl)piperazine (900 mg, 83% yield) as a yellow solid.

[0394] 2-{5-cyclopropyl-4-[(2S)-2-methyl-4-(2-methylpropane-2-sulfonyl)piperazin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile. A solution of (2S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methyl-4-(2-methylpropane-2-sulfonyl)piperazine (900.0 mg, 1.97 mmol, 1.0 equiv) in 1,4-dioxane (18 mL) was placed in a 40 mL vial purged with and maintained under an inert nitrogen atmosphere. Then, 2-(trimethylsilyl)pyridin-4-carboxylonitrile (789.5 mg, 2.96 mmol, 1.5 equiv) was added to the mixture. The mixture was bubbled with N2 for 5 min, then Pd(PPh3)4 (227.9 mg, 0.197 mmol, 0.1 equiv) was added, followed by bubbling with N2 for 5 min. The resulting mixture was stirred overnight at 110 °C. The reaction mixture was cooled to room temperature. The reaction mixture was purified by reverse-phase rapid purification using a YMC-Actus Triart C18 ExRS30*150 mm, 5 μm column under the following conditions: mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3 H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 51% B to 81% B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 9.18. This yielded 2-{5-cyclopropyl-4-[(2S)-2-methyl-4-(2-methylpropane-2-sulfonyl)piperazin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (117.4 mg, 12% yield) as a yellow solid. LC-MS: (ES, m / z ): 480.20 [M+H] + ; 1 H-NMR: (400 MHz, DMSO- d 6 ppm ) δ 8.90 – 8.85 (m, 2H), 8.22 (s, 1H), 7.76 (dd, J = 4.9, 1.6 Hz, 1H), 7.15 (s, 1H), 4.71 (d, J = 7.2 Hz, 1H), 3.99 (d, J = 13.4Hz, 1H), 3.75 (d, J= 12.4 Hz, 1H), 3.63 – 3.42 (m, 3H), 3.34 – 3.26 (m, 1H), 2.13 (dq, J = 8.2, 4.5, 3.1 Hz, 1H), 1.40 – 1.22 (m, 12H), 1.18 – 1.01 (m,2H), 0.88 (p, J = 4.8, 4.3 Hz, 1H), 0.80 (dt, J = 11.1, 5.3 Hz, 1H).

[0395] Example 1.23. Synthesis of (2S,4S)-1-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2,4-dimethylpiperidine-4-carboxylic acid tert-butyl ester (I-55) (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-yl}-2-methylpiperidin-4-carboxylate methyl ester. Under a nitrogen atmosphere, a solution of 7-bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine (1.1 g, 4.04 mmol, 1.0 equiv), (2S,4S)-2-methylpiperidin-4-carboxylate methyl ester hydrochloride (0.86 g, 4.44 mmol, 1.1 equiv), and DIEA (2.09 g, 16.1 mmol, 4.0 equiv) in DMF (20 mL) was added to a 40 mL vial at room temperature. The reaction mixture was heated to 85 °C and stirred for 3 h. LC-MS showed the reaction was complete. The reaction mixture was then cooled to room temperature. Water (100 mL) was added to the reactants and extracted with EA (2 × 20 mL). The combined organic layers were washed with water (5 × 15 mL) and brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to give a crude product that was brown and oily. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give methyl (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate (1.5 g, yield 94.5%) as a yellow solid.

[0396] Methyl (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidine-4-carboxylate. Under a nitrogen atmosphere, a solution of (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate (1.5 g, 3.81 mmol, 1.0 equiv) in 30 mL THF was added to a 50 mL three-necked round-bottom flask at room temperature. The reaction mixture was cooled to -78 °C. Then, LDA (4.58 mL, 9.15 mmol, 2.4 equiv) was added and the mixture was stirred for 30 min. Afterward, methyl iodoform (1.62 g, 11.4 mmol, 3.0 equiv) was added. The reactants were heated to rt and stirred at room temperature for 1 h. LCMS showed that the reaction was complete. The reactants were poured into water (50 mL) and extracted with EA (3 × 15 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give methyl (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylate (1.5 g, 96.6% yield) as a yellow solid.

[0397] (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid. A solution of methyl (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (1.5 g, 3.68 mmol, 1.0 equiv) in THF (15 mL) and H₂O (15 mL) was added to a 40 mL vial under a nitrogen atmosphere at room temperature. Then, LiOH (0.26 g, 11.0 mmol, 3.0 equiv) was added. The reaction mixture was heated to 60 °C and stirred for 12 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water (20 mL). The solution was acidified to pH 1 with a 1 mol / L HCl aqueous solution. The mixture was extracted with EA (2 × 20 mL). The combined organic layers were washed with water (4 × 15 mL) and brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to give the crude product (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (1 g, yield 69.0%). The crude product was used directly in the next step without further purification.

[0398] (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid ester was added to a 20 mL vial at room temperature under a nitrogen atmosphere. The reaction mixture consisted of (500.0 mg, 1.27 mmol, 1.0 equiv) of (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid, (416.0 mg, 1.91 mmol, 1.5 equiv) and (233.0 mg, 1.91 mmol, 1.5 equiv) of DMAP in 5 mL of 2-methylprop-2-ol. The reaction mixture was heated to 70 °C and stirred overnight. LC-MS showed the reaction was complete. The mixture was cooled to room temperature. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (10 mmol / L NH4HCO3), 70% to 95% gradient over 30 min; detector: UV 254 nm. This yielded (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid tert-butyl ester (380 mg, 66.5% yield) as a yellow solid.

[0399] (2S,4S)-1-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2,4-dimethylpiperidin-4-carboxylic acid tert-butyl ester. A solution of (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid tert-butyl ester (380.0 mg, 0.846 mmol, 1.0 equiv) and 2-(trimethylmethylenetinyl)pyridin-4-carboxylonitrile (339.0 mg, 1.27 mmol, 1.5 equiv) in 1,4-dioxane (3.8 mL) was placed in a 20 mL vial. Then, Pd(PPh3)4 (97.7 mg, 0.085 mmol, 0.1 equiv) was added at room temperature. The mixture was purged with N2 for 1 min. The reaction mixture was heated to 110 °C and stirred for 12 h. LCMS showed that the reaction was complete. The reaction mixture was cooled to room temperature. Water (25 mL) was added to the reaction mixture and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (10 mmol / L NH4HCO3), 70% to 100% gradient over 30 min; detector: UV 254 nm. This yielded (2S,4S)-1-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2,4-dimethylpiperidin-4-carboxylic acid tert-butyl ester (115.7 mg, yield 29.0%) as a yellow solid. LC-MS (ES, m / z ): 473.30 [M+H] + ; 1 H-NMR-PH-CSM-SMC-2024-01-V0061: (400 MHz, DMSO- d 6 , ppm ) δ 8.90 – 8.79 (m, 2H), 8.14 (s, 1H), 7.72 (dd, J = 4.9, 1.5 Hz, 1H), 7.09 (s, 1H), 4.74 (td, J = 8.1, 4.3 Hz, 1H), 3.96 (dt, J= 13.9, 3.7 Hz, 1H), 3.52 – 3.38 (m, 1H), 2.15 (dd, J = 13.5, 2.4 Hz, 2H), 2.06 (tt, J = 8.2, 5.1 Hz, 1H), 1.78 (dd, J = 13.9, 5.3 Hz, 1H), 1.45 (s,9H), 1.50 – 1.35 (m, 1H), 1.13 (t, J = 3.5 Hz, 6H), 1.09 – 1.03 (m, 2H), 0.91 – 0.85 (m, 1H), 0.77 (ddt, J = 9.5, 6.6, 3.6 Hz, 1H).

[0400] Example 1.24. Synthesis of (1S,4R,5R)-2-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-azabicyclo[2.2.2]tert-butyl octane-5-carboxylate and (1S,4R,5S)-2-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-azabicyclo[2.2.2]tert-butyl octane-5-carboxylate * = Stereochemistry unknown (1S,4S)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-one. Under a nitrogen atmosphere, a solution of p-methoxyaniline (33.0 g, 268 mmol, 1.1 equiv), cyclohexenone (46.8 g, 487 mmol, 2.0 equiv), L-proline (8.41 g, 73 mmol, 0.3 equiv), and formaldehyde solution (7.31 g, 243 mmol, 1.0 equiv) in DMSO (960 mL) was added to a 2 L three-necked round-bottom flask at room temperature and maintained for 5 min. The final reaction mixture was irradiated with microwave at 50 °C for 24 h. The mixture was cooled to room temperature. The reaction was quenched by adding water (400 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 400 mL). The resulting mixture was washed with brine (3 × 400 mL). The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1). The crude product (12 g) was purified by preparative SFC to give (1S,4S)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-one (6.3 g, yield 11.2%) as a light yellow solid.

[0401] (1S,4S)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-en-5-yl ester of trifluoromethanesulfonic acid. A solution of (1S,4S)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-one (4.0 g, 17.3 mmol, 1.0 equiv) in THF (80 mL) was placed in a 250 mL round-bottom flask, and then LiHMDS (20.7 mL, 20.7 mmol, 1.2 equiv) was added dropwise at -78 °C under a N2 atmosphere. The reaction mixture was stirred at -78 °C for 1 h. Then, 1,1,1-trifluoro- N -phenyl- NA solution of (trifluoromethane)sulfonylmethanesulfonamide (7.41 g, 20.8 mmol, 1.2 equiv) in THF (40 mL) was prepared and the mixture was stirred for 30 min. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water (40 mL), and the mixture was extracted with diethyl ether / EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (10 mL) and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give a pale yellow solid of (1S,4S)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-en-5-yl ester (4.1 g, 65.3% yield).

[0402] (1S,4R)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-en-5-carboxylic acid tert-butyl ester. A solution of trifluoromethanesulfonic acid (1S,4S)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-en-5-yl ester (4.1 g, 11.3 mmol, 1.0 equiv) in DMF (41 mL) and tert-butanol (41 mL) was placed in a pressure vessel, followed by the addition of dichlorobis(triphenylphosphine)palladium(II) (0.79 g, 1.13 mmol, 0.1 equiv), and then CO was introduced. The mixture was hydrogenated overnight at room temperature under a carbon monoxide pressure of 5 bar, filtered through a Celite pad, and concentrated under reduced pressure. The crude product was rapidly purified by reverse-phase chromatography under the following conditions (column: C18 silica gel; mobile phase: MeCN / water (0.1% TFA), 30% to 70% gradient over 30 min; detector: UV 210 nm) to obtain a light brown solid (1S,4R)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-ene-5-carboxylic acid tert-butyl ester (1 g, yield 28.1%).

[0403] (1S,4R)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octane-5-carboxylic acid tert-butyl ester. A solution of (1S,4R)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octane-5-ene-5-carboxylic acid tert-butyl ester (1.0 g, 3.17 mmol, 1.0 equiv) in MeOH (10 mL) was placed in a 250 mL round-bottom flask, and then Pd / C (10%, 100 mg) was added under a nitrogen atmosphere. Hydrogen was then introduced under a hydrogen atmosphere using a hydrogen balloon at room temperature for 3 h, followed by filtration through a Celite pad and concentration under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (0.1% TFA), 30% to 70% gradient over 30 min; detector: UV 210 nm. This yielded a light brown, oily (1S,4R)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octane-5-carboxylic acid tert-butyl ester (1 g, yield 90.0%).

[0404] (1S,4R)-2-azabicyclo[2.2.2]octane-5-carboxylic acid tert-butyl ester. A stirred solution of (1S,4R)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octane-5-carboxylic acid tert-butyl ester (800.0 mg, 2.52 mmol, 1.0 equiv) in MeCN (40 mL) was placed in a 100 mL three-necked round-bottom flask. Then, under nitrogen atmosphere and at 0 °C, cerium(IV) ammonium nitrate (4.14 g, 7.56 mmol, 3 equiv) in H₂O (40 mL) was added dropwise. The resulting mixture was stirred for 3 h under nitrogen atmosphere and at 0 °C. The pH of the mixture was adjusted to 10 with an aqueous solution of NaOH (2 mol / L). The aqueous layer was extracted with CH₂Cl₂ (5 × 100 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (5:1) to give (1S,4R)-2-azabicyclo[2.2.2]octane-5-carboxylic acid tert-butyl ester (161 mg, yield 30.2%), which was a dark red oil.

[0405] (1S,4R,5*)-2-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-azabicyclo[2.2.2]octane-5-carboxylic acid tert-butyl ester. Add a solution of (1S,4R)-2-azabicyclo[2.2.2]octane-5-carboxylic acid tert-butyl ester (116.0 mg, 0.549 mmol, 1.0 equiv), DIEA (284.0 mg, 2.20 mmol, 4.0 equiv), and 7-bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine (150.0 mg, 0.549 mmol, 1.0 equiv) in DMF (1.16 mL) to a 20 mL vial. Stir the solution overnight at 85 °C under a nitrogen atmosphere. The reaction was quenched by adding water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 5:1) to give (1S,4R,5*)-2-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-azabicyclo[2.2.2]octane-5-carboxylic acid tert-butyl ester (peaks 1 and 2, 68 mg each) as a yellow solid.

[0406] (1S,4R,5*)-2-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-azabicyclo[2.2.2]octane-5-carboxylic acid tert-butyl ester (diastereomer 1 (I-56')). A solution of (1S,4R,5*)-2-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-azabicyclo[2.2.2]octane-5-carboxylate (peak 1, 68.0 mg, 0.152 mmol, 1.0 equiv), 2-(trimethylstanyl)pyridin-4-carboxynitrile (81.1 mg, 0.304 mmol, 2.0 equiv), and tetrakis(triphenylphosphine)palladium(0) (17.6 mg, 0.015 mmol, 0.1 equiv) in dioxane (680 μL) was placed in an 8 mL vial and stirred at 110 °C for 3 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 5:1) to obtain the crude product. The crude product was purified by reverse-phase rapid purification under the following conditions (A: water containing 0.05% TFA; B: ACN; 132-1T TFA-A-XS-2.416-2.657) to give a pale yellow solid (1S,4R,5*)-2-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-azabicyclo[2.2.2]octane-5-carboxylic acid tert-butyl ester (diastereomer 1 (I-56'), 2.2 mg, yield 3.1%, purity 98.5%). LC-MS: (ES, m / z 471.20 [M+H] + ; 1 H-NMR: (300 MHz, methanol- d 4, ppm ) δ 8.92 (t, J =1.2 Hz, 1H), 8.78 (dd, J = 5.0, 1.0 Hz, 1H), 7.97 (s, 1H), 7.57 (dd, J = 5.0,1.5 Hz, 1H), 7.23 (s, 1H), 4.74 (s, 1H), 4.09 (d, J= 12.1 Hz, 1H), 3.96 –3.84 (m, 1H), 2.85 – 2.71 (m, 1H), 2.53 (ddt, J = 13.9, 5.8, 3.1 Hz, 1H),2.41 (d, J = 2.9 Hz, 1H), 2.24 – 2.11 (m, 1H), 2.11 – 1.92 (m, 2H), 1.89 –1.80 (m, 3H), 1.37 (s, 9H), 1.11 (ddd, J = 10.6, 5.2, 2.4 Hz, 2H), 0.94 –0.81 (m, 2H).

[0407] (2S,4R,5*)-2-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-azabicyclo[2.2.2]octane-5-carboxylic acid tert-butyl ester (diastereomer 1 (I-57')). A solution of (2S,4R,5*)-2-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-azabicyclo[2.2.2]octane-5-carboxylate tert-butyl ester (peak 1, 68.0 mg, 0.152 mmol, 1.0 equiv), 2-(trimethylstanyl)pyridin-4-carboxynitrile (81.1 mg, 0.304 mmol, 2.0 equiv), and tetrakis(triphenylphosphine)palladium(0) (17.6 mg, 0.015 mmol, 0.1 equiv) in dioxane (680 μL) was placed in an 8 mL vial and stirred at 110 °C for 3 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 5:1) to obtain the crude product. The crude product was purified by reverse-phase rapid purification under the following conditions (A: water containing 0.05% TFA; B: ACN; 132-1T TFA-A-XS-2.416-2.657) to obtain (1S,4R,5*)-2-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-azabicyclo[2.2.2]octane-5-carboxylic acid tert-butyl ester (diastereomer 2 (I-57'), 2.2 mg, yield 3.1%, purity 98.5%) as a light yellow solid. LC-MS: (ES, m / z 471.25 [M+H] + ; 1 H-NMR: (300 MHz, methanol- d 4, ppm ) δ 8.91 – 8.86(m, 1H), 8.81 (dd, J = 5.0, 1.0 Hz, 1H), 8.13 (s, 1H), 7.61 (dd, J = 5.0, 1.5Hz, 1H), 7.29 (d, J = 0.8 Hz, 1H), 7.14 (t, J = 3.9 Hz, 1H), 3.81 – 3.65 (m,2H), 3.04 (d, J = 20.3 Hz, 1H), 2.42 – 2.15 (m, 3H), 2.01 – 1.86 (m, 1H), 1.81 – 1.62 (m, 3H), 1.48 (s, 9H), 1.22 – 1.09 (m, 2H), 0.95 – 0.78 (m, 2H).

[0408] Example 1.25. Synthesis of (2R,4S)-1-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidine-4-carboxylate (I-58) (2R,4R)-4-(methanesulfonyloxy)-2-methylpiperidine-1-carboxylic acid tert-butyl ester. A solution of (2R,4R)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (3.0 g, 13.934 mmol, 1.0 equiv) and triethylamine (2.82 g, 27.868 mmol, 2.0 equiv) in DCM (60 mL) was placed in a 100 mL three-necked round-bottom flask. Then, methanesulfonyl chloride (2.39 g, 20.901 mmol, 1.5 equiv) was added to the mixture at room temperature. The mixture was stirred overnight at room temperature. Water (25 mL) was added to the reactants, and the mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography and eluted with PE / EA (3:1) to give (2R,4R)-4-(methanesulfonyloxy)-2-methylpiperidine-1-carboxylic acid tert-butyl ester (3.5 g, yield 85.6%) as a white solid.

[0409] (2R,4S)-4-cyano-2-methylpiperidin-1-carboxylic acid tert-butyl ester. A solution of (2R,4R)-4-(methanesulfonyloxy)-2-methylpiperidin-1-carboxylic acid tert-butyl ester (3.0 g, 10.226 mmol, 1.0 equiv) in 24 mL of DMSO was placed in a 40 mL vial. Then, KCN (1.46 g, 22.497 mmol, 2.2 equiv) was added at room temperature. The reaction mixture was heated to 80 °C and stirred for 4 h. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature. An aqueous solution of NaHCO3 (25 mL) was added to the reaction mixture, and the mixture was extracted with EA (3 × 10⁻⁶ m). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography and eluted with PE / EA (3:1) to give tert-butyl (2R,4S)-4-cyano-2-methylpiperidine-1-carboxylate (320 mg, yield 14.0%) as a white solid.

[0410] (2R,4S)-2-methylpiperidin-4-carboxynitrile. A solution of (2R,4S)-4-cyano-2-methylpiperidin-1-carboxylic acid tert-butyl ester (320.0 mg, 1.427 mmol, 1.0 equiv) in hydrogen chloride (4.0 M in 1,4-dioxane) (3 mL, 12.000 mmol, 8.4 equiv) was added to a 20 mL vial. The reaction was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The resulting mixture was concentrated under reduced pressure. This yielded (2R,4S)-2-methylpiperidin-4-carboxynitrile (crude product) as a white solid. The crude product was used directly in the next step without further purification.

[0411] (2R,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-4-yl}-2-methylpiperidin-4-carboxylonitrile. Under a nitrogen atmosphere, 7-bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine (395.0 mg, 1.449 mmol, 1.0 equiv), (2R,4S)-2-methylpiperidin-4-carboxylonitrile hydrochloride (180.0 mg, 1.449 mmol, 1.0 equiv), and DIEA (749.3 mg, 5.796 mmol, 4.0 equiv) in DMF (8 mL) were added to a 40 mL vial at room temperature. The reaction mixture was heated to 85 °C and stirred for 3 h. LC-MS showed the reaction was complete. The reaction mixture was then cooled to room temperature. Water (100 mL) was added to the reactants and extracted with EA (2 × 20 mL). The combined organic layers were washed with water (5 × 15 mL) and brine (20 mL), and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to give a crude product that was brown and oily. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give a yellow solid (2R,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxynitrile (300 mg, yield 57.5%).

[0412] (2R,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid. Under a nitrogen atmosphere, (2R,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxynitrile (300.0 mg, 0.833 mmol, 1.0 equiv) in EtOH (1.5 mL) and H₂O (1.5 mL) was added to an 8 mL vial at room temperature. Then, KOH (186.9 mg, 3.332 mmol, 4.0 equiv) was added to the mixture. The reaction mixture was heated to 100 °C and stirred for 3 h. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (20 mL). The solution was acidified to pH 1 with a 1 mol / L HCl aqueous solution. The mixture was extracted with EA (2 × 20 m). The combined organic layers were washed with water (4 × 15 mL) and brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to give the crude product (2R,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (250 mg). The crude product was used directly in the next step without further purification.

[0413] (2R,4S)-1-{5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid ester was added to an 8 mL vial at room temperature under a nitrogen atmosphere. The solution of (2R,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid (250.0 mg, 0.659 mmol, 1.0 equiv), di-tert-butyl dicarbonate (215.8 mg, 0.989 mmol, 1.5 equiv), and DMAP (120.8 mg, 0.989 mmol, 1.5 equiv) in 2-methylprop-2-ol (2.5 mL) was added. The reaction was stirred at room temperature for 1 h. LC-MS showed that the reaction was complete. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (10 mmol / L NH4HCO3), 70% to 95% gradient over 30 min; detector: UV 254 nm. This yielded (2R,4S)-1-{5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylic acid tert-butyl ester (220 mg, 93.6% yield) as a yellow solid.

[0414] (2R,4S)-1-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidin-4-carboxylate. A solution of (2R,4S)-1-{5-cyclopropylpyrrolo[2,1-f][1,2,4]tri-azin-4-yl}-2-methylpiperidin-4-carboxylate tert-butyl ester (270.0 mg, 0.620 mmol, 1.0 equiv) and 2-(trimethylstanyl)pyridin-4-carboxylonitrile (248.3 mg, 0.930 mmol, 1.5 equiv) in 1,4-dioxane (5.4 mL) was added to a 20 mL vial. Then, Pd(PPh3)4 (71.7 mg, 0.062 mmol, 0.1 equiv) was added at room temperature. The mixture was replaced with N2 for 1 min. The reactants were heated to 110 °C and stirred for 12 h. LC-MS showed the reaction was complete. The reactants were cooled to room temperature. The reactants were purified under the following conditions: column: C18 silica gel; mobile phase: MeCN / water (10 mmol / L NH4HCO3), 70% to 100% gradient over 30 min; detector: UV 254 nm. This yielded (2R,4S)-1-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylpiperidin-4-carboxylic acid tert-butyl ester (80.4 mg, yield 28.3%) as a white solid. LC-MS: (ES, m / z 459.30 [M+H] + ; 1 H-NMR: (400 MHz, DMSO- d 6 , ppm ) δ 8.90 – 8.80 (m, 2H), 8.16 (s, 1H), 7.74 (dd, J = 5.0, 1.5 Hz,1H), 7.11 (s, 1H), 4.86 (dd, J = 7.1, 3.7 Hz, 1H), 4.12 – 4.01 (m, 1H), 3.41(td, J = 13.4, 2.7 Hz, 1H), 2.80 (dtd, J = 12.0, 8.4, 3.8 Hz, 1H), 2.08 –2.00 (m, 1H), 1.94 (dd, J = 13.4, 3.3 Hz, 1H), 1.82 (dd, J= 8.8, 3.7 Hz,2H), 1.63 – 1.50 (m, 1H), 1.41 (s, 9H), 1.25 (d, J = 6.8 Hz, 3H), 1.08 (dq, J = 5.5, 3.0 Hz, 2H), 0.93 – 0.76 (m, 2H).

[0415] Example 1.26. Synthesis of (1R,3R,5S)-6-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-6-azabicyclo[3.1.1]heptane-3-carboxylate tert-butyl ester and (1R,3S,5S)-6-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-6-azabicyclo[3.1.1]heptane-3-carboxylate * = Stereochemistry unknown ((2S,4R)-1-benzylazetane-2,4-diyl)bis(methylene)dimethane sulfonate. A solution of ((2S,4R)-1-benzylazetane-2,4-diyl)diethanol (25.0 g, 0.121 mol, 1.0 equiv) and TEA (48.8 g, 0.484 mol, 4.0 equiv) in DCM (250 mL) was placed in a 500 mL three-necked round-bottom flask purged with N2 and maintained at this atmosphere. The mixture was cooled to 0 °C and MsCl (34.4 g, 0.302 mol, 2.5 equiv) was added dropwise. The mixture was stirred at this temperature for 2 h and quenched with an aqueous solution of NaHCO3 (200 mL). The separated aqueous layer was extracted with DCM (2 × 100 mL), and the combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. This yielded 35 g (crude product) of a yellow oily ((2S,4R)-1-benzylazetane-2,4-diyl)bis(methylene)dimethanesulfonate.

[0416] (2S,4R)-1-benzylmethyl-2,4-bis(bromomethyl)azacyclobutane. A solution of ((2S,4R)-1-benzylmethylazacyclobutane-2,4-diyl)bis(methylene)dimethanesulfonate (25.0 g, 0.069 mol, 1.0 equiv) in acetone (625 mL) was placed in a 1 L three-necked round-bottom flask purged with N2 and maintained at this atmosphere. Then, LiBr (118.5 g, 1.38 mol, 20.0 equiv) was added, and the mixture was heated to 60 °C. After stirring overnight, the mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by column chromatography, eluting with EA:PE = 0–5%. This yielded 15 g (66% yield) of (2S,4R)-1-benzylmethyl-2,4-bis(bromomethyl)azacyclobutane as a yellow solid.

[0417] Ethyl 6-benzyl-3-cyano-6-azabicyclo[3.1.1]heptane-3-carboxylate. A solution of (2S,4R)-1-benzyl-2,4-bis(bromomethyl)azabicyclobutane (17.0 g, 0.051 mol, 1.0 equiv) and ethyl 2-cyanoacetate (5.8 g, 0.051 mol, 1.0 equiv) in DMF (255 mL) was placed in a 1 L three-necked round-bottom flask purged with N2 and maintained at this atmosphere. Then, K2CO3 (21.2 g, 0.154 mol, 3.0 equiv) was added. The mixture was heated to 80 °C and stirred for 8 h. After cooling to room temperature, the mixture was filtered, and the filtrate was diluted with EA (1 L) and washed with H2O (3 × 300 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography, eluting with EA:PE = 0-30%. This yielded 3.9 g (27% yield) of ethyl 6-benzyl-3-cyano-6-azabicyclo[3.1.1]heptane-3-carboxylate as a grayish-white solid.

[0418] 6-Phenylenemethyl-3-cyano-6-azabicyclo[3.1.1]heptane-3-carboxylic acid. A solution of ethyl 6-phenylmethyl-3-cyano-6-azabicyclo[3.1.1]heptane-3-carboxylic acid (4.0 g, 0.014 mol, 1.0 equiv) in THF (40 mL) was placed in a 250 mL three-necked round-bottom flask purged with N2 and maintained at this atmosphere. Then, a solution of LiOH (0.51 g, 0.021 mol, 1.5 equiv) in H2O (20 mL) was added dropwise, and the mixture was stirred for 1 h. The mixture was concentrated to remove THF. The aqueous layer was adjusted to pH 3 with citric acid and extracted with EA (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. This yielded 2.7 g (75% yield) of yellow oily 6-benzyl-3-cyano-6-azabicyclo[3.1.1]heptane-3-carboxylic acid.

[0419] 6-Phenylenemethyl-6-azabicyclo[3.1.1]heptane-3-carboxylic acid. A solution of 2.1 g (8.2 mmol, 1.0 equiv) in DMF (21 mL) was placed in a 100 mL three-necked round-bottom flask purged with N2 and maintained at this atmosphere. The mixture was heated to 140 °C and stirred for 2 h. After cooling to room temperature, the mixture was concentrated. This yielded 2 g (crude product) of 6-phenylmethyl-6-azabicyclo[3.1.1]heptane-3-carboxylic acid as a yellow solid.

[0420] 6-Azabicyclo[3.1.1]heptane-3-carboxylonitrile. A solution of 2 g (crude) of 6-benzyl-6-azabicyclo[3.1.1]heptane-3-carboxylonitrile in MeOH (40 mL) was placed in a 100 mL round-bottom flask. Then, Pd / C (0.4 g) was added, and the system was purged three times with H₂. The mixture was then heated to 50 °C and stirred overnight under H₂ atmosphere. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. This yielded 1.5 g (crude) of oily 6-azabicyclo[3.1.1]heptane-3-carboxylonitrile.

[0421] 6-(7-bromo-5-cyclopropylpyrrolo[1,2-f][1,2,4]triazine-4-yl)-6-azabicyclo[3.1.1]heptane-3-carboxylonitrile. A suspension of 6-azabicyclo[3.1.1]heptane-3-carboxylonitrile (1.3 g, 10.6 mmol, 1.0 equiv), 7-bromo-4-chloro-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazine (3.2 g, 11.7 mmol, 1.1 equiv), and DIEA (4.13 g, 31.9 mmol, 3.0 equiv) in DMF (13 mL) was placed in a 100 mL three-necked round-bottom flask and stirred at 85 °C for 3 h. The reaction was complete as indicated by LC-MS. The reactants were poured into 50 mL of water. The solution was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE:EA = 1:1, to give 2.3 g (60% yield) of 6-(7-bromo-5-cyclopropylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-6-azabicyclo[3.1.1]heptane-3-carboxylonitrile as a yellow solid.

[0422] 6-(7-bromo-5-cyclopropylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-6-azabicyclo[3.1.1]heptane-3-carboxylic acid. A suspension of 6-(7-bromo-5-cyclopropylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-6-azabicyclo[3.1.1]heptane-3-carboxynitrile (2.3 g, 3.07 mmol, 1.0 equiv) and KOH (0.7 g, 12.3 mmol, 4.0 equiv) in EtOH (11.5 mL) / H2O (11.5 mL) was added to a 50 mL three-necked round-bottom flask and stirred at 100 °C for 16 h. The reaction was completed by LCMS. After cooling to room temperature. The reactants were poured into 30 mL of water, and the pH was adjusted to 1 with HCl. The solution was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 1.7 g (70% yield) of 6-(7-bromo-5-cyclopropylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-6-azabicyclo[3.1.1]heptane-3-carboxylic acid as a yellow solid.

[0423] 6-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-6-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester. A suspension of 6-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-6-azabicyclo[3.1.1]heptane-3-carboxylic acid (200.0 mg, 0.530 mmol, 1.0 equiv) in tert-butanol (4 mL) was placed in an 8 mL vial, followed by the addition of DMAP (0.10 g, 0.795 mmol, 1.5 equiv) and ditert-butyl dicarbonate (174.0 mg, 0.795 mmol, 1.5 equiv). The mixture was stirred at 25 °C for 2 h. The reaction was completed by LCMS. The reactants were rapidly purified by reverse-phase chromatography under the following conditions (column: Regular C18, 20*40um, 330 g; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: ACN; flow rate: 100 mL / min; gradient: 60% B to 100% B over 20 min; wavelength: 254 nm / 210 nm; RT (min): 15) to obtain a yellow oily tert-butyl 6-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-6-azabicyclo[3.1.1]heptane-3-carboxylate (180 mg, 78% yield).

[0424] 6-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-6-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester. A suspension of 6-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-6-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (180.0 mg, 0.415 mmol, 1.0 equiv) and 2-(trimethylstanyl)pyridin-4-carboxynitrile (166.0 mg, 0.622 mmol, 1.5 equiv) in 1,4-dioxane (1.8 mL) was placed in an 8 mL vial. The mixture was purged with N2 for 2 min, and then Pd(PPh3)4 (48.0 mg, 0.042 mmol, 0.1 equiv) was added. The mixture was then purged with N2 for 2 min, and the reaction was stirred at 110 °C for 16 h. The reaction was completed by LCMS. After cooling to room temperature... The reactants were rapidly purified by reverse-phase chromatography under the following conditions (column: Regular C18, 20*40 μm, 330 g; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: ACN; flow rate: 100 mL / min; gradient: 75% B to 100% B over 30 min; wavelength: 254 / 210 nm; RT (min): 23) to obtain a yellow solid, tert-butyl 6-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-6-azabicyclo[3.1.1]heptane-3-carboxylate (40.0 mg, yield 21%, purity 99.1%).

[0425] (1R,3*,5S)-6-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-6-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (diastereomer 1 (I-59')). 6-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-6-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (40.0 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IF, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: isocratic 50; wavelength: 220 / 254 nm; RT1 (min): 8.706; Sample solvent: EtOH--HPLC; Sample volume: 2 mL; Number of operations: 2) and lyophilized to obtain (1R,3*,5S)-6-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-6-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (diastereomer 1 (I-59'), 18.9 mg, yield 47%) as a grayish-white solid. LC-MS: (ES, m / z 457.25 [M+H] + ; 1 H-NMR: (400MHz, DMSO- d 6 , ppm δ 8.93 (s, 1H), 8.86 (d, J = 4.9 Hz, 1H), 8.06 (s, 1H), 7.74 (dd, J = 4.9, 1.4 Hz, 1H), 7.16 (s, 1H), 5.02 (s, 1H), 4.12 (dd, J =10.4, 3.8 Hz, 1H), 3.44 (d, J = 10.5 Hz, 1H), 2.87 (s, 1H), 2.72 – 2.65 (m,1H), 2.16 (t, J = 11.4 Hz, 1H), 2.08 (hept, J = 5.1 Hz, 1H), 2.01 (dt, J=12.7, 4.3 Hz, 1H), 1.72 – 1.60 (m, 2H), 1.43 (s, 9H), 1.08 – 0.92 (m, 3H), 0.71 (dd, J = 9.4, 5.3 Hz, 1H).

[0426] (1R,3*,5S)-6-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-6-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (diastereomer 2 (I-60')). 6-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-6-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (40.0 mg, 0.088 mmol, 1.0 equiv) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IF, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: isocratic 50; wavelength: 220 / 254 nm; RT2 (min): 13.677; sample solvent: EtOH--HPLC; loading volume: 2 mL; Number of operations: 2) and lyophilized to obtain (1R,3*,5S)-6-[7-(4-cyanopyridin-2-yl)-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl]-6-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (diastereomer 2 (I-60'), 17.2 mg, yield 43%, purity 99.5%) as a grayish-white solid. LC-MS: (ES, m / z 457.25 [M+H] + ; 1 H-NMR: (400 MHz, DMSO- d 6 , ppm ) δ 8.93 (d, J = 1.4Hz, 1H), 8.86 (d, J = 5.0 Hz, 1H), 8.06 (s, 1H), 7.74 (dd, J = 5.0, 1.5 Hz,1H), 7.16 (s, 1H), 5.02 (s, 1H), 4.12 (dd, J= 10.5, 3.8 Hz, 1H), 3.44 (d, J = 10.5 Hz, 1H), 2.87 (d, J = 3.4 Hz, 1H), 2.69 (dd, J = 9.0, 5.0 Hz, 1H), 2.16 (t, J = 11.4 Hz, 1H), 2.08 (hept, J = 5.1 Hz, 1H), 2.01 (dt, J = 12.7,4.3 Hz, 1H), 1.73 – 1.60 (m, 2H), 1.43 (s, 9H), 1.10 – 0.92 (m, 3H), 0.70 (p, J = 5.9, 5.3 Hz, 1H).

[0427] Example 1.27. Synthesis of 2-{5-cyclopropyl-4-[(1R,3R,5S)-3-(2,2-dimethylpropionyl)-6-azabicyclo[3.1.1]hept-6-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile and 2-{5-cyclopropyl-4-[(1R,3S,5S)-3-(2,2-dimethylpropionyl)-6-azabicyclo[3.1.1]hept-6-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile * = Stereochemistry unknown 6-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-6-azabicyclo[3.1.1]heptane-3-carboxylic acid (400.0 mg, 1.06 mmol, 1.0 equiv) in DCM (8 mL) was added to a 40 mL vial, followed by the addition of thionyl chloride (252.0 mg, 2.12 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 h. LCMS showed that the reaction was complete. The resulting mixture was concentrated under reduced pressure to give 6-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-6-azabicyclo[3.1.1]heptane-3-carboxyl chloride (410.0 mg, crude product) as a yellow solid.

[0428] 1-(6-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-6-azabicyclo[3.1.1]heptane-3-yl)-2,2-dimethylprop-1-one. A solution of 6-{7-bromo-5-cyclopropyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl}-6-azabicyclo[3.1.1]heptane-3-carboxyl chloride (410.0 mg, 1.04 mmol, 1.0 equiv) in THF (8.2 mL) was placed in a 50 mL three-necked round-bottom flask. Then, CuCl (10.3 mg, 0.104 mmol, 0.1 equiv) was added and the mixture was stirred for 10 min. Afterward, tert-butylmagnesium (5.2 mL, 5.18 mmol, 5.0 equiv) was added and the mixture was stirred for 2 h. LCMS showed the reaction was complete. The mixture was poured into water (20 mL) and extracted with EA (20 mL × 2). The combined organic layers were washed with water (15 mL) and brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give a yellow oily crude product 1-(6-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-6-azabicyclo[3.1.1]hept-3-yl)-2,2-dimethylprop-1-one (300.0 mg, yield 69.0%).

[0429] 2-{5-cyclopropyl-4-[3-(2,2-dimethylpropionyl)-6-azabicyclo[3.1.1]hept-6-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridine-4-carboxylonitrile. A suspension of 1-(6-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-6-azabicyclo[3.1.1]hept-3-yl)-2,2-dimethylprop-1-one (300.0 mg, 0.719 mmol, 1.0 equiv) and 2-(trimethylstanyl)pyridin-4-carboxynitrile (288.0 mg, 1.08 mmol, 1.5 equiv) in 1,4-dioxane (3 mL) was placed in an 8 mL vial. The mixture was purged with N2 for 2 min, and Pd(PPh3)4 (83.1 mg, 0.072 mmol, 0.1 equiv) was added. The mixture was then purged with N2 for 2 min, and the reaction was stirred at 110 °C for 16 h. The reaction was completed by LCMS. The mixture was then cooled to room temperature. The reactants were rapidly purified by reverse-phase chromatography under the following conditions (column: Regular C18, 20*40 μm, 330 g; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: ACN; flow rate: 100 mL / min; gradient: 75% B to 100% B over 30 min; wavelength: 254 nm / 210 nm; RT (min): 23) to obtain a yellow solid 2-{5-cyclopropyl-4-[3-(2,2-dimethylpropionyl)-6-azabicyclo[3.1.1]hept-6-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (40 mg, yield 12.6%).

[0430] 2-{5-cyclopropyl-4-[(1R,3*,5S)-3-(2,2-dimethylpropionyl)-6-azabicyclo[3.1.1]hept-6-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (diastereomer 1 (I-61')). 2-{5-cyclopropyl-4-[3-(2,2-dimethylpropionyl)-6-azabicyclo[3.1.1]hept-6-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (40.0 mg, 0.091 mmol, 1.0 equiv) was purified by preparative chiral HPLC under the following conditions (column: CHIRAL ART Cellulose-SZ, 2.0*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: isocratic 50; wavelength: 220 / 254 nm; sample solvent: EtOH--HPLC; loading volume: 0.8 mL; Number of operations: 6) and lyophilized to obtain a grayish-white solid 2-{5-cyclopropyl-4-[(1R,3*,5S)-3-(2,2-dimethylpropionyl)-6-azabicyclo[3.1.1]hept-6-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (diastereomer 1 (I-61'), 16.3 mg, yield 40.8%, purity 99.6%). LC-MS: (ES, m / z ): 441.25 [M+H] + ; 1 H-NMR: (400 MHz, DMSO- d 6 , ppm ) δ8.92 (t, J = 1.2 Hz, 1H), 8.86 (dd, J = 5.0, 1.0 Hz, 1H), 8.05 (s, 1H), 7.73(dd, J = 4.9, 1.5 Hz, 1H), 7.16 (s, 1H), 4.95 (s, 1H), 4.10 (dd, J = 10.2, 3.6 Hz, 1H), 3.54 (d, J = 9.9 Hz, 1H), 3.32 – 3.29 (m, 1H), 2.64 (s, 1H), 2.17 (t, J = 10.7 Hz, 1H), 2.07 (td,J = 8.4, 4.4 Hz, 1H), 1.88 (d, J = 9.9Hz, 1H), 1.85 – 1.76 (m, 1H), 1.68 (d, J = 10.0 Hz, 1H), 1.11 (s, 9H), 1.07 –0.96 (m, 2H), 0.93 (dt, J = 9.8, 4.8 Hz, 1H), 0.69 (h, J = 5.1 Hz, 1H).

[0431] 2-{5-cyclopropyl-4-[(1R,3*,5S)-3-(2,2-dimethylpropionyl)-6-azabicyclo[3.1.1]hept-6-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (diastereomer 2 (I-62')). 2-{5-cyclopropyl-4-[3-(2,2-dimethylpropionyl)-6-azabicyclo[3.1.1]hept-6-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (40.0 mg, 0.091 mmol, 1.0 equiv) was purified by preparative chiral HPLC under the following conditions (column: CHIRAL ART Cellulose-SZ, 2.0*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: isocratic 50; wavelength: 220 / 254 nm; sample solvent: EtOH--HPLC; loading volume: 0.8 mL; Number of operations: 6) and lyophilized to obtain 2-{5-cyclopropyl-4-[(1R,3*,5S)-3-(2,2-dimethylpropionyl)-6-azabicyclo[3.1.1]hept-6-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (diastereomer 2 (I-62'), 17.4 mg, yield 43.5%, purity 99.7%) as a grayish-white solid. LC-MS: (ES, m / z ): 441.25 [M+H] + ; 1 H-NMR: (400 MHz, DMSO- d 6 , ppm ) δ8.92 (d, J = 1.4 Hz, 1H), 8.86 (dd, J= 5.0, 1.0 Hz, 1H), 8.05 (s, 1H), 7.73(dd, J = 5.0, 1.6 Hz, 1H), 7.16 (s, 1H), 4.95 (s, 1H), 4.10 (dd, J = 10.1, 3.5 Hz, 1H), 3.53 (d, J = 10.3 Hz, 1H), 3.32 – 3.29 (m, 1H), 2.64 (s, 1H), 2.17 (t, J = 10.7 Hz, 1H), 2.07 (d, J = 8.1 Hz, 1H), 1.88 (d, J = 10.0 Hz, 1H), 1.80 (d, J = 7.3 Hz, 1H), 1.68 (d, J = 10.0 Hz, 1H), 1.11 (s, 9H), 1.07– 0.96 (m, 2H), 0.92 (q, J = 4.8 Hz, 1H), 0.74 – 0.65 (m, 1H).

[0432] Example 1.28. Synthesis of 2-{5-cyclopropyl-4-[(2S,4S)-2,4-dimethyl-4-(pyrrolidine-1-carbonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (I-63) (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (100.0 mg, 0.254 mmol, 1.0 equiv) and thionyl chloride (60.5 mg, 0.508 mmol, 2.0 equiv) in DCM (2.0 mL) were placed in an 8 mL vial. The solution was stirred for 1 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. This yields (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidine-4-carboxyl chloride (110 mg, crude product), which is a white solid.

[0433] (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethyl-4-(pyrrolidine-1-carbonyl)piperidine. A solution of pyrrolidine (34.5 mg, 0.486 mmol, 2.0 equiv) in DCM (2.0 mL) was placed in an 8 mL vial. Then, under a nitrogen atmosphere, DIEA (313.9 mg, 2.430 mmol, 10.0 equiv) was added at room temperature and maintained for 5 min. Following this, (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidine-4-formyl chloride (100.0 mg, 0.243 mmol, 1.0 equiv) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was extracted with CH2Cl2 (3 × 2 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethyl-4-(pyrrolidine-1-carbonyl)piperidine (60 mg, crude) as a white solid.

[0434] 2-{5-cyclopropyl-4-[(2S,4S)-2,4-dimethyl-4-(pyrrolidine-1-carbonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile. A solution of (2S,4S)-1-{7-bromo-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethyl-4-(pyrrolidine-1-carbonyl)piperidine (100.0 mg, 0.224 mmol, 1.0 equiv) and 2-(trimethylstanyl)pyridin-4-carboxylonitrile (179.4 mg, 0.672 mmol, 3.0 equiv) in 1,4-dioxane (1.0 mL) was placed in an 8 mL vial. Then, under a nitrogen atmosphere, Pd(PPh3)4 (25.9 mg, 0.022 mmol, 0.1 equiv) was added at room temperature. The resulting mixture was stirred overnight at 110 °C under a nitrogen atmosphere. The mixture was then cooled to room temperature. Column: Xselect CSH C18 OBD column, 30*150 mm 5 μm; Mobile phase A: water (10 mmol / L NH4HCO + 0.05% NH3 H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 49% B to 79% B over 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.02. This yielded 17.1 mg of 2-{5-cyclopropyl-4-[(2S,4S)-2,4-dimethyl-4-(pyrrolidine-1-carbonyl)piperidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyridin-4-carboxylonitrile (16% yield) as a yellow solid. LC-MS: (ES, m / z 470.30 [M+H] + ; 1 H-NMR: (400 MHz, DMSO- d 6 , ppm ) δ 8.89 (dt, J = 1.6, 0.7 Hz, 1H), 8.86 (dd, J = 4.9, 1.0 Hz, 1H),8.15 (s, 1H), 7.74 (dd, J = 5.0, 1.5 Hz, 1H), 7.11 (s, 1H), 4.76 – 4.66 (m,1H), 3.95 (d, J = 13.8 Hz, 1H), 3.68 (t, J= 12.6 Hz, 2H), 3.61-3.50 (m, 1H), 3.41-3.31 (m, 3H), 2.46 – 2.28 (m, 2H), 2.12 – 2.02 (m, 1H), 1.98 – 1.60 (m,4H), 1.41 – 1.26 (m, 1H), 1.18 (s, 3H), 1.10 (dd, J = 19.1, 7.1 Hz, 3H), 1.08-1.01 (m, 2H), 0.94 – 0.84 (m, 1H), 0.80 – 0.75 (m, 1H).

[0435] Example 1.29. (2) S 4 S Synthesis of 1-[7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2,4-dimethylpiperidine-4-carboxylic acid tert-butyl ester (I-64) (2 S 4 S )-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylate methyl ester. Under a nitrogen atmosphere, at room temperature, 7-bromo3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (2.0 g, 9.345 mmol, 1.0 equiv), (2... S 4 S A solution of methyl 2-methylpiperidin-4-carboxylate hydrochloride (1.99 g, 10.280 mmol, 1.1 equiv) and benzotriazol-1-yl-oxytripyrrolylphosphine hexafluorophosphate (5.35 g, 10.280 mmol, 1.1 equiv) in MeCN (40 mL) was then added. Et3N (7.57 g, 74.760 mmol, 8.0 equiv) was added. The reaction mixture was heated to 80 °C and stirred for 4 h. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature. Water (100 mL) was added to the reaction mixture and extracted with EA (2 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to obtain a brown solid (2 S 4 S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidine-4-carboxylate (1.9 g, yield 57.6%).

[0436] (2 S 4 S )-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidine-4-carboxylate methyl ester. Under a nitrogen atmosphere, at room temperature, (2) S 4 S A solution of methyl 1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2-methylpiperidin-4-carboxylate (1.9 g, 5.379 mmol, 1.0 equiv) in THF (60 mL) was added. The reaction mixture was cooled to -78 °C. Then, LDA (2.0 M in THF) (1.38 g, 12.910 mmol, 2.4 equiv) was added and the mixture was stirred at -78 °C for 30 min. Subsequently, CH3I (2.29 g, 16.134 mmol, 3.0 equiv) was added to the mixture. The reaction mixture was heated to 25 °C and stirred for 1 h. LCMS showed that the reaction was complete. The reaction was quenched with water (100 mL) and extracted with EA (2 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to obtain a crude product (2) that was a brown solid. S 4 S Methyl 2,4-dimethylpiperidine-4-carboxylate (1.2 g, yield 60.7%) was obtained from 1-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidine-4-carboxylate. The crude product was used in the next step without further purification.

[0437] (2 S 4 S )-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid. Under a nitrogen atmosphere, at room temperature, (2) S 4 SA solution of methyl 1-{7-bromopyrrolo[2,1-f][1,2,4]triazine-4-yl}-2,4-dimethylpiperidin-4-carboxylate (1.2 g, 3.268 mmol, 1.0 equiv) in THF (12 mL) and water (12 mL) was prepared. LiOH (234.8 mg, 9.803 mmol, 3.0 equiv) was then added to the mixture. The reaction mixture was heated to 60 °C and stirred for 12 h. LCMS showed the reaction was complete. Water (30 mL) was added to the reaction mixture and extracted with EA (2 × 10 mL). The aqueous phase was acidified to pH = 1 with an aqueous solution of HCl (1 mol / L). The mixture was extracted with EA (2 × 20 mL). The combined organic layers were washed with water (15 mL) and brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give the crude product (2 g). S 4 S )-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (1.4 g, crude). The crude product was used directly in the next step without further purification.

[0438] (2 S 4 S )-1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidine-4-carboxylic acid tert-butyl ester. Under a nitrogen atmosphere, at room temperature, (2) S 4 S A solution of 1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid (1.4 g, 3.964 mmol, 1.0 equiv) in THF (28 mL). Then, ( E )-(tert-butoxy)- N ', N - Bis(propyl-2-methylammonium) (4.76 g, 23.784 mmol, 6.0 equiv) was added to the mixture. The reaction mixture was heated to 70 °C and stirred for 2 h. LCMS showed that the reaction was complete. The reaction mixture was cooled to room temperature and filtered. Water (60 mL) was added to the filtrate, and the mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with water (15 mL) and brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give a grayish-white solid (2... S 4 S)-1-{7-bromopyrrolo[2,1-f][1,2,4]triazine-4-yl}-2,4-dimethylpiperidine-4-carboxylic acid tert-butyl ester (1.4 g, yield 86.3%).

[0439] (2 S 4 S )-1-{7-bromo-5-iodopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidine-4-carboxylic acid tert-butyl ester. Add (2) to a 50 mL three-necked round-bottom flask. S 4 S A solution of tert-butyl 1-(7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,4-dimethylpiperidin-4-carboxylate (740.0 mg, 1.808 mmol, 1.0 equiv), trifluoroacetic acid (20.6 mg, 0.181 mmol, 0.1 equiv), and 1-iodopyrrolidine-2,5-dione (427.1 mg, 1.898 mmol, 1.05 equiv) in DMF (14.8 mL) was prepared. The solution was stirred at room temperature for 12 h. The reaction was shown to be complete by LCMS. The reaction was quenched by adding 20 mL of aqueous NaHCO3 solution, and water (40 mL) was added to the mixture and extracted with EA (2 × 40 mL). The combined organic layers were washed with water (3 × 100 mL) and brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to obtain a yellow oily substance (2). S 4 S )-1-{7-bromo-5-iodopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid tert-butyl ester (950 mg, crude). The product was used directly in the next step without further purification.

[0440] (2 S 4 S )-1-[7-bromo-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2,4-dimethylpiperidin-4-carboxylic acid tert-butyl ester. Add (2) to a 25 mL three-necked round-bottom flask. S 4 SA solution of 1-{7-bromo-5-iodopyrrolo[2,1-f][1,2,4]triazin-4-yl}-2,4-dimethylpiperidin-4-carboxylic acid tert-butyl ester (300.0 mg, 0.561 mmol, 1.0 equiv) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (538.4 mg, 2.805 mmol, 5.0 equiv) in DMF (6 mL) was prepared. The solution was stirred at room temperature. The mixture was degassed three times using nitrogen and vacuum circulation. Then, CuI (106.7 mg, 0.561 mmol, 1.0 equiv) and KF (97.7 mg, 1.683 mmol, 3.0 equiv) were added to the flask at room temperature. The mixture was degassed three times using nitrogen and vacuum circulation. The resulting mixture was heated to 80 °C. The mixture was stirred at 80 °C for 3 h. LCMS showed that the reaction was complete. Cool the mixture to room temperature. Filter the mixture. Add water (20 mL) to the filtrate and extract with EA (2 × 20 mL). Wash the combined organic layers with water (3 × 50 mL) and brine (50 mL), and dry over anhydrous Na₂SO₄. After filtration, concentrate the filtrate under vacuum to obtain a yellow oily substance (2... S 4 S 1-[7-bromo-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2,4-dimethylpiperidin-4-carboxylic acid tert-butyl ester (400 mg, crude). The product was used directly in the next step without further purification.

[0441] (2 S 4 S )-1-[7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2,4-dimethylpiperidin-4-carboxylic acid tert-butyl ester. Add (2) to a 20 mL vial. S 4 SA solution of 1-[7-bromo-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2,4-dimethylpiperidin-4-carboxylic acid tert-butyl ester (400.0 mg, 0.838 mmol, 1.0 equiv) and 2-(trimethyl-steryl)pyridine-4-carboxynitrile (671.0 mg, 2.514 mmol, 3.0 equiv) in 1,4-dioxane (8 mL) was prepared. The solution was stirred at room temperature. The mixture was degassed three times using nitrogen and vacuum circulation. Then, Pd(PPh3)4 (96.8 mg, 0.084 mmol, 0.1 equiv) was added to the flask at room temperature. The mixture was degassed three times using nitrogen and vacuum circulation. The resulting mixture was heated to 110 °C. The mixture was stirred at 110 °C for 24 h. The reaction was completed by LCMS. The mixture was cooled to room temperature. Filter the mixture. Add water (20 mL) to the filtrate and extract with EA (2 × 20 mL). Wash the combined organic layers with water (3 × 50 mL) and brine (50 mL), and dry over anhydrous Na₂SO₄. After filtration, concentrate the filtrate under vacuum to obtain (2 S 4 S )-1-[7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2,4-dimethylpiperidin-4-carboxylic acid tert-butyl ester. The product was purified by a rapid preparative PLC under the following conditions: column: XBridge Shiel...

Claims

1. A compound represented by formula I: I Or its pharmaceutically acceptable salt, wherein X is N or CR 2 ; R 1 It is a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S; a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S; C6-C 12 Aryl; or C3-C 12 Alicyclic groups, where R 1 Optionally by one or more R 1a replace; Each R 1a Independently -CN, halogen, -OR a -C(O)N(R) a )2、-N(R a )C(O)R a Optional substituted C1-C6 aliphatic groups, optional substituted C3-C7 alicyclic groups; L 1 It is a bond, N(R) a ), O or optionally substituted C1-C6 aliphatic groups; R 2 It is H, optionally substituted C3-C7 alicyclic group, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted C1- to 6-membered alicyclic group, or optionally substituted 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S. Ring A is a 4- to 12-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S; L 2 It is -C(O)-, -C(O)O-, -N(R) a )C(O)-、-C(O)N(R a -S(O)-, -S(O)2-, optional substituted 4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from N, O and S, or optional substituted 4- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S. R 3 It is an optional substituted C1-C6 aliphatic group or an optional substituted 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S; Each R 4 Independently, the C1-C6 aliphatic groups are optionally substituted; Each R a Independently selected from H and optionally substituted C1-C6 aliphatic groups; and p can be 0, 1, 2, 3, or 4.

2. The compound of claim 1, wherein L 1 It is a key.

3. The compound of claim 1 or 2, wherein R 1 It is a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, and optionally separated by one or more R 1a replace.

4. The compound of claim 3, wherein R 1 It is a monocyclic 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, and is bonded by one or more R atoms. 1a replace.

5. The compound of claim 4, wherein R 1 It was R 1a Substituted pyridinyl group.

6. The compound according to any one of claims 1 to 5, wherein R 1a Yes - CN.

7. The compound of claim 1, wherein R 1 yes: , , , , , , or .

8. The compound according to any one of claims 1 to 7, wherein R 2 It is an optional C3-C7 alicyclic group that can be substituted.

9. The compound of claim 1, wherein R 2 Selected from: -H, -CH3, -CH2-CH3, -CF3, , and .

10. The compound according to any one of claims 1 to 9, wherein ring A is a monocyclic 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O and S.

11. The compound of claim 10, wherein ring A is piperidinyl or piperazineyl.

12. The compound of claim 11, wherein ring A is piperidinyl.

13. The compound according to any one of claims 1 to 9, wherein ring A is a bridging bicyclic 6- to 10-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O and S.

14. The compound according to any one of claims 1 to 13, wherein p is 0.

15. The compound according to any one of claims 1 to 13, wherein p is 1 or 2.

16. The compound of claim 15, wherein each R 4 It is -CH3.

17. The compound according to any one of claims 1 to 16, wherein L 2 It is -C(O)-, -C(O)O-*, -S(O)-, or -S(O)2-, where * indicates a partial R 3 The connection point.

18. The compound of claim 17, wherein L 2 It is -C(O)O-*, where * indicates a partial R 3 The connection point.

19. The compound according to any one of claims 1 to 18, wherein R 3 It is an optional C1-C6 aliphatic group that can be substituted.

20. The compound of claim 19, wherein R 3 yes: , , , , or .

21. The compound of claim 1, wherein a portion thereof: yes: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;in Representative and L 2 The connection point.

22. The compound of claim 1, wherein a portion thereof: yes: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

23. The compound of claim 22, wherein... yes: , or .

24. The compound of claim 1, wherein the compound is represented by formula I-2: I-2 Or its pharmaceutically acceptable salt.

25. The compound of claim 1, wherein the compound is represented by formula II-1: II-1 Or its pharmaceutically acceptable salt.

26. The compound of claim 1, wherein the compound is represented by formula II-2: II-2 Or its pharmaceutically acceptable salt.

27. The compound of claim 1, wherein the compound is represented by formula III-1. III-1 Or its pharmaceutically acceptable salt.

28. The compound of claim 1, wherein the compound is represented by formula IV-1. IV-1 Or its pharmaceutically acceptable salt.

29. The compound of claim 1, wherein the compound is represented by formula IV-2. IV-2 Or its pharmaceutically acceptable salt.

30. The compound of claim 1, wherein the compound is represented by formula V-1. V-1 Or its pharmaceutically acceptable salt.

31. The compound of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof is selected from Table 1.

32. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 31 and a pharmaceutically acceptable carrier or excipient.

33. A method for modulating TRMPL in a subject, the method comprising administering to the subject a compound as described in any one of claims 1-31 or a pharmaceutical composition as described in claim 32.

34. A method of treating a disease, symptom, or ailment of a subject, the method comprising administering to the subject a compound as claimed in any one of claims 1 to 31 or a pharmaceutical composition as claimed in claim 32.

35. The method of claim 34, wherein the disease, symptom, or ailment is a lysosomal storage disorder.

36. The method of claim 35, wherein the lysosomal storage disease is selected from Niemann-Pick C disease, Gaucher disease, Barten disease, cholesterol ester storage disease, Fabry disease, and Pompe disease.

37. The method of claim 34, wherein the disease, condition, or ailment is a common age-related neurodegenerative disease.

38. The method of claim 34 or 37, wherein the disease, symptom or ailment is selected from Alzheimer's disease, Parkinson's disease and Huntington's disease.

39. The method of claim 34, wherein the disease, symptom, or disorder is mucopolysaccharidosis type IV (ML4), a neurodegenerative lysosomal storage disease caused by a mutation in TRPML.

40. The method of claim 34, wherein the disease, symptom, or ailment is a muscle disease, liver disease, metabolic disease, atherosclerotic disease, inflammatory bowel disease, neurodegenerative disease, tumor disease, or infectious disease.

41. The method of claim 40, wherein the disease, symptom, or ailment is a muscle disease.

42. The method of claim 41, wherein the muscle disease is muscular dystrophy.

43. The method of claim 42, wherein the muscular dystrophy is Duchenne muscular dystrophy.

44. The method of claim 34, wherein the disease, symptom, or ailment is an infectious disease.

45. The method of claim 44, wherein the infectious disease is an infection of Helicobacter pylori or Mycobacterium tuberculosis.

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