Azaindole inhibitors of wild-type and mutant LRRK2

Abstract

This application discloses a compound that has inhibitory activity against LRRK2. This application also discloses a pharmaceutical composition comprising the compound and a method of treating diseases and conditions using the compound, said diseases and conditions including neurodegenerative diseases and conditions such as Parkinson's disease and brain cancers (e.g., glioma and glioblastoma).

Description

[0001] Related applications

[0002] This application claims the entire contents of U.S. Provisional Application No. 62 / 746,273, filed October 16, 2018, and U.S. Provisional Application No. 62 / 913,578, filed October 10, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to a compound having inhibitory activity against LRRK2, a pharmaceutical composition comprising the compound, and a method of using the compound to treat diseases and conditions. Background Technology

[0004] Parkinson's disease (PD) is a motor disorder caused by the progressive loss of dopamine-producing neurons. It is the second most common neurodegenerative disease in the world, affecting more than one million Americans. More than 60,000 new patients are diagnosed each year (Gandhi et al., J. Neurosci. Res. 87:1283-1295 (2009); (Neurosignals 19:1-15 (2011)). Symptoms associated with Parkinson's disease include movement disorders, tremor, bradykinesia, instability, and other movement-related disorders. Non-motor symptoms also exist, such as cognitive impairment, autonomic dysfunction, and sleep disturbances. These symptoms significantly reduce the quality of life for people with Parkinson's disease.

[0005] Regarding genes associated with PD, the missense mutation of leucine-rich repeat kinase 2 (LRRK2) G2019S is frequently found in both familial and sporadic PD cases. (Healy et al., Lancet Neurol. 7:583-590 (2008)) G2019S mutations increase kinase activity, which may lead to activation of neuronal death signaling pathways (Greggio et al., ASN Neuro 1(1):e00002(2009), Kumar et al., Expert Rev. Mol. Med. 13:e20(2011)). Transgenic G2019SLRRK2 mice aged 12 to 16 months exhibited a Parkinsonian phenotype of progressive degeneration and motor dysfunction of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (Chen et al., Cell Death Differ. 19(10):1623-33(2012)). Summary of the Invention

[0006] The first aspect of this application relates to compounds having a structure represented by formula (I):

[0007]

[0008] in:

[0009] X and Y each independently represent CR1 or CR2, where R1 represents

[0010] Where R represents methyl, ethyl, isopropyl, cyclopropyl or CF3, and R' is O, NH or NMe;

[0011] R2 represents H, halogens (e.g., F, Cl), or CF3; and

[0012] Z represents CR3, where R3 represents

[0013]

[0014] Or its pharmaceutically acceptable salts or stereoisomers.

[0015] The second aspect of this application relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0016] Another aspect of this application relates to a method for treating a disease or condition (e.g., disorder or dysfunction) mediated by abnormal LRRK2 activity, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer to a subject in need of such treatment.

[0017] In some implementations, the disease or condition is described as a neurodegenerative disease or brain cancer.

[0018] Other aspects of this application relate to methods for preparing the said compound.

[0019] Therefore, the compounds of this application can provide pre-treatment for neurodegenerative diseases, such as Parkinson's disease, by inhibiting LRRK2.

[0020] As shown in one or more embodiments, compounds of formula (I) and their pharmaceutically acceptable salts and stereoisomers can inhibit a variety of aberrant kinases, including adaptor-associated protein kinase 1 (AAK1), receptor tyrosine kinase (ABL1(T315I)-phosphorylation), apoptosis signal-regulated kinase 1 (ASK1), ASK2, and aurora kinase A. A, AURKA), AURKB, AURKC, AXL receptor tyrosine kinase (AXL), BMP-2-induced protein kinase (BIKE), BMX (BMX non-receptor tyrosine kinase), cell cycle 2-like protein kinase 5 (CDC2L5), cyclin-dependent kinase 11 (CDK11), checkpoint kinase 2 (CHEK2), citronrho-interacting serine / threonine kinase (CIT), CDC-like kinase 1 (CLK1), CLK2, CLK4, colony-stimulating factor 1 receptor (CSF1R), CSF1R autoinhibition, C-terminal Src kinase (CSK), casein kinase I isoform ε (CSNK1E), casein kinase I isoform γ1 (CSNK1G1), CSNK1G3, dileucine zipper kinase (DLK), death-associated protein kinase-associated 2 (DRAK2), bispecific tyrosine phosphorylation-regulated kinase 1A (DYRK1A), DYRK2, ephrin Type A receptor 2 (EPHA2), FMS-associated tyrosine kinase 1 (FLT1), FLT3, FLT3 (D835H), FLT3 (D835V), FLT3 (D835Y), FLT3 (ITD), FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (N841I), G protein-coupled receptor kinase 4 (GRK4), serine / threonine protein kinase haspin (HASPIN), homeodomain interacting protein kinase 1 (HPK1), enterocellular kinase (ICK), IκB kinase α (IKK-α), IKK-β, interleukin 1 receptor-associated kinase 1 (IRAK1), IRAK4, Janu s-kinase 2 (JAK2) (JH1 domain-catalyzed), JAK3 (JH1 domain-catalyzed), c-JunN-terminal kinase 1 (JNK1), JNK2, JNK3, Tyrosine protein kinase kit (KIT), KIT (L576P), KIT (V559D), KIT (V559D, T670I), KIT autoinhibition, LRRK2, LRRK2 (G2019S), mitogen-activated protein kinase 2 (MAP3K2), MAP3K15, mitogen-activated protein kinase 2 (MAP4K2), MAP4K4, microtubule-associated serine / threonine kinase 1 (MAST1), mitogen-activated protein kinase 1 (MEK1)MEK2, MEK3, MEK4, MEK5, MEK6, maternal embryonic leucine zipper kinase (MELK), met proto-oncogene (MET), MET (M1250T), MET (Y1235D), Misshapen-like kinase 1 (MINK), serine / threonine kinase 2 interacting with mitogen-activated protein kinase (MKNK2), myosin light chain kinase (MLCK), nuclear Dbf2-associated kinase 2 (NDR2), F-κ-B-induced kinase (NIK), p21-activated kinase 4 (PAK4), platelet derivatives Growth factor receptor α (PDGFRA), PDGFRβ (PDGFRB), phosphorylase b kinase γ catalytic chain, skeletal muscle isoform 2 (PHKG2), phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) (E545K), phosphatidylinositol 4-phosphate-5 kinase 1A (PIP5K1A), PIP5K2B, polo-like kinase 4 (PLK4), serine / threonine protein kinase D1 (PRKD1), PRKD2, PRKD3, RET proto-oncogene (RET), (RET)(M918) T), RIO kinase 1 (RIOK1), RIOK2, RIOK3, receptor-interacting serine / threonine protein kinase 1 (RIPK1), RIPK4, diserine / threonine and tyrosine p-protein kinase (RIPK5), rho-associated protein kinase 1 (ROCK1), ROCK2, ribosomal S6 kinase 4 (RSK4) (Kin.Dom.1-N-terminus), serum and glucocorticoid-regulated kinase (SGK), SGK2, serine-arginine protein kinase 1 (SRPK1), SRPK2, SRPK3, serine-arginine protein kinase 1 (SRPK1), SRPK2, SRPK3, and so on. The compound contains at least one of the following: lysine / threonine kinase 16 (STK16), STK39, TGF-β activated kinase 1 (TAK1), TRAF2 and NCK-interacting kinase (TNIK), tropomyosin receptor kinase A (TRKA), TRKB, monopolar spindle 1 (Mps1) kinase (TTK), tyrosine kinase 2 (TYK2) (JH1 domain-catalyzed), unc-51-like autophagy-activated kinase 1 (ULK1), ULK2, ULK3, vascular endothelial growth factor receptor 2 (VEGFR2), and YSK4 (also known as MAP3K19). Therefore, other aspects of this application require the use of the compounds of this application to treat diseases and conditions mediated by abnormal activity of any one or more of these kinases. Detailed Implementation

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. As used in the specification and appended claims, the following terms have the indicated meanings to facilitate understanding of this application, unless otherwise stated.

[0022] As used in the specification and appended claims, the singular forms “a,” “an,” and “the” include the plural objects unless the context clearly indicates otherwise. Thus, for example, reference to “composition” includes a mixture of two or more such compositions, and reference to “inhibitor” includes a mixture of two or more such inhibitors, etc.

[0023] Unless otherwise stated, the term “about” means within 10% of the specific value modified by the term “about” (e.g., within 5%, 2%, or 1%).

[0024] The transitional term "comprising" is synonymous with "including," "containing," or "characterized as," and is inclusive or open-ended, not excluding other unreferenced elements or method steps. Conversely, the transitional term "composed of" excludes any element, step, or component not specified in the claims. The transitional term "substantially composed of" limits the scope of the claims to the specified materials or steps of the claimed invention "and materials or steps that do not substantially affect the essential and novel features."

[0025] Regarding the compounds of this application, the following terms are used herein to further describe their extent and are subject to the following definitions.

[0026] As used herein, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. In one embodiment, the alkyl group is C1 to C2. 18 Group. In other embodiments, the alkyl group is C0 to C6, C0 to C5, C0 to C3, C1 to C6. 12C1 to C8, C1 to C6, C1 to C5, C1 to C4 or C1 to C3 groups (where C0 alkyl refers to a single bond). Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, isopropyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. In some embodiments, the alkyl group is C1 to C3 alkyl. In some embodiments, the alkyl group is C1 to C2 alkyl.

[0027] As used in this article, the term "halogen" (or "halogenated" or "halogenated") refers to fluorine, chlorine, bromine, or iodine.

[0028] In a broader sense, the compounds of this application have a structure represented by formula (I):

[0029]

[0030] in:

[0031] X and Y each independently represent CR1 or CR2, where R1 represents

[0032] Where R represents methyl, ethyl, isopropyl, cyclopropyl, or CF3, and R' represents O, NH, or NMe.

[0033] R2 represents H, halogens (e.g., F, Cl), or CF3; and

[0034] Z represents CR3, where R3 represents

[0035]

[0036] Or its pharmaceutically acceptable salts or stereoisomers.

[0037] In some embodiments, where X represents CR1, Y represents CR2, Z represents CR3, and where R1, R2, and R3 are as described above, the compounds of this application have a structure represented by formula (Ia):

[0038]

[0039] Or its pharmaceutically acceptable salts or stereoisomers.

[0040] In some embodiments, X represents CR2, Y represents CR1, Z represents CR3, and R1, R2, and R3 are as described above. The compound of this application has a structure represented by the following formula (Ib):

[0041]

[0042] Or its pharmaceutically acceptable salts or stereoisomers.

[0043] In some embodiments, the compounds of this application are represented by any of the following structures:

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059] as well as

[0060] Or its pharmaceutically acceptable salts and stereoisomers.

[0061] The compound of formula (I) may be in the form of a free acid or a free base, or a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable" in the context of a salt means a salt of a compound that does not eliminate the biological activity or properties of the compound and is relatively non-toxic, i.e., the salt form of the compound can be administered to a subject without causing adverse biological effects (e.g., dizziness or stomach upset) or interacting harmfully with any other component of the composition comprising it. The term "pharmaceutically acceptable salt" means the product obtained by reacting the compound of this application with a suitable acid or base. Examples of pharmaceutically acceptable salts of the compounds of this application include suitable inorganic bases derived from, for example, Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn, and Mn. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids, such as hydrochlorides, hydrobroms, hydroiodates, nitrates, sulfates, hydrogen sulfates, phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, pantothenates, tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, gluconate disodium, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, 4-methylbenzenesulfonates, or p-toluenesulfonates. Certain compounds of this application can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine, or metformin.

[0062] Compounds of formula (I) may have at least one chiral center and thus may be in stereoisomer form, as used herein, encompassing all isomers of individual compounds that differ only in the spatial orientation of their atoms. The term stereoisomer includes mirror-image isomers (including mirror-image isomers of the (R-) or (S-) configuration of a compound), mixtures of mirror-image isomers (physical mixtures of mirror-image isomers, racemates, or racemic mixtures), cis / trans or E / Z, R / S isomers of a compound, and isomers of a compound with one or more chiral centers that are not mirror images of each other (diastereomeric isomers). The chiral center of a compound may undergo epimerization in vivo. Therefore, for these compounds, a (R-) form of the compound is considered equivalent to a (S-) form of the compound. Thus, the compounds of this application may be prepared and used either as individual isomers and substantially free of other isomers, or as mixtures of various isomers, such as racemic mixtures of stereoisomers.

[0063] In some embodiments, compound formula (I) is an isotopic derivative having at least one desired isotopic substitution of an atom, the substitution amount being higher than the natural abundance of the isotope, i.e., enrichment. In one embodiment, the compound comprises deuterium or multiple deuterium atoms. Due to greater metabolic stability, for example, deuterium (i.e., 2 Substitution with heavier isotopes of H can provide certain therapeutic advantages, such as prolonged half-life in vivo or reduced dose requirements, and may therefore be advantageous in some cases.

[0064] Furthermore, compounds of formula (I) include those using N-oxides, crystalline forms (also known as polymorphs), active metabolites of compounds having the same type of activity, tautomers, and unsolvated and solvated forms in pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). Solvated forms of the conjugates presented herein are also considered to be disclosed herein.

[0065] Synthesis method

[0066] In some aspects, this application relates to methods for preparing compounds of formula (I) of this application or pharmaceutically acceptable salts or stereoisomers thereof. Broadly speaking, compounds of formula (I) and pharmaceutically acceptable salts or stereoisomers thereof can be prepared by any method known to be suitable for the preparation of chemically related compounds. A better understanding of the compounds of this application will be achieved by referring to the synthetic schemes described in conjunction with the various working examples, which illustrate non-limiting methods that can be used to prepare the compounds of this application.

[0067] Pharmaceutical Composition

[0068] On the other hand, this application relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. The compounds of this application can be formulated into several different types of pharmaceutical compositions suitable for any desired administration method and comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier.

[0069] In a broad sense, compounds of formula (I) can be formulated into a given type of composition using conventional pharmaceutical practices, such as conventional mixing, dissolving, granulation, coating, grinding, emulsification, encapsulation, embedding, and compression processes (see, for example, Remington: The Science and Practice of Pharmacy (20th edition), ed. ARGennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988–1999, Marcel Dekker, New York). The type of formulation depends on the route of administration, which can include enteric (e.g., oral, buccal, sublingual, and rectal), parenteral (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im), and intrasternal injection or infusion techniques, intraocular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, intradermal, intravaginal, intraperitoneal, mucosal, nasal, tracheal, bronchial, and inhalation), and topical (e.g., transdermal). Generally, the most suitable route of administration will depend on a number of factors, including, for example, the nature of the agent (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). For example, parenteral (e.g., intravenous) administration may also be advantageous because, for example, in the case of single-dose treatment and / or acute illness, the compound can be administered relatively rapidly.

[0070] In some embodiments, the compound is formulated for oral or intravenous administration (e.g., systemic intravenous injection).

[0071] As is known in the art, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or medium suitable for administering the compound of this application to a mammal. Suitable carriers may include, for example, liquids (aqueous and non-aqueous, or combinations thereof), solids, encapsulation materials, gases, or combinations thereof (e.g., semi-solids), which serve to carry or transport the compound from one organ or part of the body to another organ or part of the body. A carrier is "acceptable" in the sense that it is physiologically inert and compatible with other components of the formulation, and in the sense that it is non-toxic to the subject or patient. Depending on the type of formulation, the composition may contain one or more pharmaceutically acceptable excipients.

[0072] Therefore, compounds of formula (I) can be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, pouches, and suppositories), liquid compositions (e.g., solutions containing the compound, suspensions containing dispersed solid particles of the compound, emulsions, and solutions containing liposomes, micelles or nanoparticles, syrups, and elixirs); semi-solid compositions (e.g., gels, suspensions, and creams); and gases (e.g., propellants for aerosol compositions). The compounds can also be formulated for rapid, intermediate, or prolonged release.

[0073] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with a carrier such as sodium citrate or dicalcium phosphate and additional excipients or additives such as: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; and d) disintegrants, such as crosslinking polymers (e.g., crosslinked polyethylene). The solid compositions may contain: e) retarders, such as paraffin wax; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For capsules, tablets, and pills, the dosage form may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or lactose and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated pills, capsules, pills, and granules may be prepared using coatings and shells such as enteric coatings and other coatings. The above solid compositions may further contain light-blocking agents.

[0074] In some embodiments, the compound of formula (I) can be formulated in hard or soft gelatin capsules. Representative excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearate fumarate, anhydrous lactose, microcrystalline cellulose, and croscarmellose sodium. The gelatin shell may include gelatin, titanium dioxide, iron oxide, and colorants.

[0075] In some embodiments, the compound of formula (I) can be formulated into tablets, which may contain excipients such as lactose monohydrate, microcrystalline cellulose, sodium glycolate starch, magnesium tartrate, and hydrophobic colloidal silica.

[0076] The compound of formula (I) above can be formulated into solutions for parenteral and oral administration, particularly in the water-soluble range. Parenteral administration may also be advantageous because the compound can be administered relatively rapidly, for example, in the case of single-dose treatment and / or acute illness.

[0077] Injectable formulations intended for parenteral administration may include sterile aqueous solutions or oily suspensions. These injectable formulations can be formulated using suitable dispersants or wetting agents and suspending agents according to standard techniques. Sterile injectable formulations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used are water, Ringer's solution (USP), and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids, such as oleic acid, are used in the preparation of injectable formulations. Injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter, or incorporated as a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media before use. The effects of a compound can be prolonged by slowing its absorption, which can be achieved by using a poorly water-soluble liquid suspension or a crystalline or amorphous substance. The absorption of a compound administered parenterally can also be prolonged by suspending it in an oily carrier.

[0078] In some embodiments, the compound of formula (I) can be administered locally rather than systemically, for example, by direct injection of the conjugate into an organ, typically in the form of a long-acting or sustained-release formulation. In specific embodiments, the long-acting formulation is administered via implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. Injectable accumulation formulations are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid, polyorthoester, and polyanhydride. The release rate of the compound can be controlled by varying the ratio of the compound to the polymer and the properties of the specific polymer used. Injectable accumulation formulations can also be prepared by trapping the compound in liposomes or microemulsions that are compatible with body tissues. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, such as in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target the organ and are selectively absorbed by the organ.

[0079] Liquid dosage forms for oral administration include solutions, dispersants, suspensions, emulsions, microemulsions, syrups, and panaceas. In addition to compounds, liquid dosage forms may also contain aqueous or non-aqueous carriers commonly used in the art (depending on the solubility of the compound), such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, sorbitol, and fatty acid esters of polyethylene glycol, and mixtures thereof. Oral compositions may also contain excipients, such as wetting agents, suspending agents, coloring agents, sweeteners, flavoring agents, and fragrances.

[0080] The compound can be formulated for buccal or sublingual administration, examples of which include tablets, lozenges, and gels.

[0081] Compounds of formula (I) can be formulated for inhalation administration. Various forms suitable for inhalation administration include aerosols, mists, and powders. Pharmaceutical compositions can be delivered in aerosol form from a pressurized package or nebulizer using a suitable gaseous propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases). In some embodiments, the dosage unit of the pressurized aerosol can be determined by providing a valve to deliver a measured amount. In some embodiments, capsules and cartridges comprising gelatin, for example for inhalers or blowpipes, can be formulated containing a mixture of the compound and a suitable powder matrix such as lactose or starch.

[0082] Compounds of formula (I) can be formulated for topical administration, as used herein, meaning intradermal administration by applying the formulation to the epidermis. These types of compositions are typically available in the form of ointments, pastes, creams, lotions, gels, solutions, and sprays.

[0083] Representative examples of carriers that can be used to formulate compositions for topical applications include solvents (e.g., alcohols, polyols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffer solutions (e.g., hypotonic or buffered saline). For example, creams can be formulated using saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmitoleic acid, cetyl, or oleyl alcohol. Creams may also contain nonionic surfactants, such as polyoxyethylene 40-stearate.

[0084] In some embodiments, the topical formulation may also contain excipients, examples of which are penetration enhancers. These agents are capable of transporting pharmacologically active compounds across the stratum corneum and into the epidermis or dermis, preferably with little or no systemic absorption. The effectiveness of a wide variety of compounds in enhancing the rate of drug penetration through the skin has been evaluated. See, for example, Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, FL. (1995), which investigated the use and testing of various skin penetration enhancers, and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermaland Topical Drug Delivery Systems, Gosh TK, Pfister WR, Yum SI (eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997). Representative examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe vera compositions (e.g., aloe vera gel), ethanol, isopropanol, octylphenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decyl methyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glyceryl monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

[0085] Representative examples of other excipients that can be used in topical and other types of formulations (within their compatibility range) include preservatives, antioxidants, humectants, emollients, buffers, solubilizers, skin protectants, and surfactants. Suitable preservatives include alcohols, quaternary ammonium compounds, organic acids, parabens, and phenols. Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents such as EDTA and citric acid. Suitable humectants include glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Suitable buffers include citric acid, hydrochloric acid, and lactic acid buffers. Suitable solubilizers include quaternary ammonium chloride, cyclodextrin, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants include vitamin E oil, allantoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0086] Transdermal formulations typically utilize transdermal delivery devices and transdermal delivery patches, in which a compound of formula (I) is formulated in a lipophilic emulsion or buffered aqueous solution, dissolved and / or dispersed in a polymer or binder. Patches can be configured for continuous, pulsatile, or on-demand delivery of the drug. Transdermal delivery of the compound can be accomplished using iontophoresis patches. Transdermal patches provide controlled delivery of the compound, where the absorption rate is slowed by using a rate-controlled membrane or by trapping the compound in a polymer matrix or gel. Absorption enhancers can be used to increase absorption; examples include absorbable, pharmaceutically acceptable solvents that facilitate penetration through the skin.

[0087] Ophthalmic preparations include eye drops.

[0088] Rectal administration formulations include enemas, rectal gels, rectal foams, rectal aerosols, and retention enemas, which may contain conventional suppository bases, such as cocoa butter or other glycerides, and synthetic polymers, such as polyvinylpyrrolidone, PEG, and similar compounds. Rectal or vaginal administration compositions can also be formulated as suppositories, which can be prepared by mixing the compound with suitable non-irritating carriers and excipients such as cocoa butter, fatty acid glycerides, polyethylene glycol, suppository waxes, and mixtures thereof. The compound is solid at ambient temperature and liquid at body temperature, thus melting and releasing the compound in the rectal or vaginal cavity.

[0089] Dosage

[0090] As used herein, the term “therapeutic effective amount” refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof that is effective in producing the desired therapeutic response in a specific patient with a specific disease or disorder. The term “therapeutic effective amount” includes an amount of a compound, a pharmaceutically acceptable salt or stereoisomer thereof, that, when administered, is capable of causing positive alterations in the disease or disorder to be treated (e.g., inhibition and / or reduction of LRRK2 GTP-binding activity and / or LRRK2 protein kinase activity and microglial activation, and inhibition of mutant LRRK2-induced neuronal degeneration), or is sufficient to inhibit or prevent the development or progression of the disease or disorder, or to alleviate, to some extent, further symptoms of one or more diseases or disorders being treated in the subject, or simply kills or inhibits the growth of diseased cells, or reduces the amount of LRRK2 in diseased cells (e.g., basal ganglia and substantia nigra cells). Therapeutic effective amounts of compounds should be low enough to avoid causing excessive or serious side effects, as determined according to established or other reasonable medical standards.

[0091] The total daily dose of the compound of formula (I) and its administration may be determined according to standard medical practice, for example, by the attending physician using reasonable medical judgment. The specific therapeutically effective dose for any particular subject will depend on any of a number of factors, including the disease or condition being treated and its severity (e.g., its current state); the activity of the specific compound used; the specific composition used; the subject's age, weight, general health condition, sex, and diet; the time of administration, route of administration, and rate of excretion of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field (e.g., see Goodman and Gilman's Therapological Basis of Therapeutics, 10th ed., A. Gilman, J. Hardman, and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001).

[0092] Compounds of formula (I) and their pharmaceutically acceptable salts and stereoisomers can be effective over a wide dosage range. In some embodiments, the total daily dose (e.g., for adults) can range from about 0.001 to about 1600 mg, 0.01 to about 1000 mg, 0.01 to about 500 mg, about 0.01 to about 100 mg, about 0.5 to about 100 mg, from 1 to about 100 to 400 mg daily, from about 1 to about 50 mg daily, from about 5 to about 40 mg daily, and from about 10 to about 30 mg daily in other embodiments. Depending on the frequency of daily administration of the compound, a single dose can be formulated to contain the required dosage. For example, capsules can be formulated with about 1 to about 200 mg of the compound (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg). In some embodiments, the compound can be administered at a dose of about 0.01 mg to about 200 mg / kg body weight daily. In some implementations, a dose of 0.1 to 100 mg / kg per day, for example, 1 to 30 mg / kg per day, may be effective at one or more doses per day. For example, an appropriate dose for oral administration may be in the range of 1-30 mg / kg per day, and an appropriate dose for intravenous administration may be in the range of 1-10 mg / kg per day.

[0093] In some embodiments, the daily dose of the compound is from about 37.5 mg to about 50 mg. To facilitate this administration, the compound can be formulated in capsules at doses of 12.5 mg, 25 mg, and 50 mg.

[0094] How to use

[0095] In some respects, compounds of formula (I) and their pharmaceutically acceptable salts and stereoisomers may be used to treat diseases and conditions characterized by or mediated by abnormal LRRK2 activity (e.g., dysfunction or dysregulation (e.g., upregulation)). Dysfunctional protein activity may be due to elevated protein levels relative to a non-pathological state or a mutated form of the protein (e.g., the G2019S mutation). A “disease” is generally considered a subject’s health state in which the subject is unable to maintain homeostasis and whose health continues to deteriorate if the disease is not improved. Conversely, a subject’s “disease” is a health state in which the subject is able to maintain homeostasis, but whose health is less favorable than in the absence of the disease. A disease, if left untreated, does not necessarily lead to a further decline in the animal’s health.

[0096] Therefore, this method involves administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof to a subject in need of it. As used herein, the term “subject” (or “patient”) includes all members of the animal kingdom who are predisposed to or suffer from the indicated disease or condition. In some embodiments, the subject is a mammal, such as a human or a non-human mammal. The method is also applicable to companion animals, such as dogs and cats, and livestock, such as cattle, horses, sheep, goats, pigs, and other domesticated and wild animals. A subject “suffering from or suspected of having” a particular disease or condition may have a sufficient number of risk factors or exhibit a sufficient number of symptoms or signs or combinations thereof so that a medical professional can diagnose or suspect that the subject is suffering from a disease or disorder. Therefore, subjects who suffer from or are suspected of having a particular disease or condition are not necessarily two distinct groups.

[0097] In some embodiments, the compounds of this application and their pharmaceutically acceptable salts and stereoisomers may be used to treat neurodegenerative diseases and conditions. As used herein, the term “neurodegenerative diseases and conditions” refers to conditions characterized by progressive degeneration or death of nerve cells, or both, including problems with motor function (ataxia) or mental function (dementia). Representative examples of such diseases and conditions include Alzheimer’s disease (AD) and dementia associated with AD, Parkinson’s disease (PD) and dementia associated with PD, prion diseases, motor neuron disease (MND), Huntington’s disease (HD), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), primary progressive aphasia (PPA), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), multiple sclerosis (MS), and dementias (e.g., vascular dementia (VaD), Lewy body dementia (LBD), semantic dementia, and frontotemporal dementia (FTD)).

[0098] In other embodiments, the compounds of this application, as well as pharmaceutically acceptable salts and stereoisomers, can be used to treat brain cancer. Representative examples of brain cancer include hemangioblastoma, meningioma, brain metastases, glioma, neuroblastoma, medulloblastoma, and ependymoma.

[0099] Representative examples of gliomas that can be treated in accordance with the method described in this application include recurrent high-grade gliomas, including glioblastoma, anaplastic astrocytoma and anaplastic oligodendroglioma, as well as high-grade pediatric gliomas such as diffuse pontine glioma (DIPG).

[0100] Representative examples of glioblastomas treatable by the manner described in this application include grade II (low-grade astrocytoma), grade III (anaplastic astrocytoma), and grade IV (glioblastoma) and glioblastoma multiforme (GBM).

[0101] Compounds of formula (I) and their pharmaceutically acceptable salts and stereoisomers inhibit a variety of aberrant kinases, including adapter-associated protein kinase 1 (AAK1), receptor tyrosine kinase (ABL1(T315I)-phosphorylation), apoptosis signal-regulated kinase 1 (ASK1), ASK2, aurora kinase A (AURKA), AURKB, AURKC, AXL receptor tyrosine kinase (AXL), BMP-2-induced protein kinase (BIKE), BMX (BMX non-receptor tyrosine kinase), cell cycle 2-like protein kinase 5 (CDC2L5), cyclin-dependent kinase 11 (CDK11), checkpoint kinase 2 (CHEK2), and citronella. rho-interacting serine / threonine kinase (CIT), CDC-like kinase 1 (CLK1), CLK2, CLK4, colony-stimulating factor 1 receptor (CSF1R), CSF1R autoinhibition, C-terminal Src kinase (CSK), casein kinase I isoform ε (CSNK1E), casein kinase I isoform γ1 (CSNK1G1), CSNK1G3, bisleucine zipper kinase (DLK), death-associated protein kinase-associated 2 (DRAK2), bispecific tyrosine phosphorylation-r-regulated kinase 1A (DYRK1A), DYRK2, ephrin Type A receptor 2 (EPHA2), fms-associated tyrosine kinase 1 (FLT1), FLT3, FLT3 (D835H), FLT3 (D835V), FLT3 (D835Y), FLT3 (ITD), FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (N841I), G protein-coupled receptor kinase 4 (GRK4), serine / threonine protein kinase haspin (HASPIN), homologous domain interacting protein kinase 1 (HPK1), enterocyte kinase (ICK), IκB kinase alpha (IKK-α), IKK-β, interleukin 1 receptor-associated kinase 1 (IRAK1), IRAK4, Janus kinase 2 (JAK2) (JH1 domain-catalyzed), JAK3 (JH1 domain-catalyzed), c-Jun N-terminal kinase 1 (JNK1), JNK2, JNK3, Tyrosine protein kinase kit (KIT), KIT (L576P), KIT (V559D), KIT (V559D, T670I), KIT autoinhibition, LRRK2, LRRK2 (G2019S), Mitogen-activated protein kinase kinase 2 (MAP3K2), MAP3K15, Mitogen-activated protein kinase kinase 2 (MAP4K2), MAP4K4, Microtubule-associated serine / threonine kinase 1 (MAST1), Mitogen-activated protein kinase kinase 1 (MEK1), MEK2, MEK3, MEK4, MEK5, MEK6, maternal embryonic leucine zipper kinase (MELK), MET proto-oncogene (MET), MET (M1250T), MET (Y1235D), Misshapen-like kinase 1 (MINK), mitogen-activated protein kinase interacting serine / threonine kinase 2 (MKNK2), myosin light chain kinase (MLCK), nuclear Dbf2-associated kinase 2 (NDR2), FκB-inducible kinase (NIK), p21-activated kinase 4 (PAK4), platelet-derived growth factor receptor α (PDG) FRA), PDGFRβ (PDGFRB), phosphorylase b kinase γ catalytic chain, skeletal muscle isoform 2 (PHKG2), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) (E545K), phosphatidylinositol 4-phosphate 5-kinase 1A (PIP5K1A), PIP5K2B, polo-like kinase 4 (PLK4), serine / threonine protein kinase D1 (PRKD1), PRKD2, PRKD3, ret proto-oncogene (RET), (RET) (M918T), RIO kinase Enzyme 1 (RIOK1), RIOK2, RIOK3, receptor-interacting serine / threonine protein kinase 1 (RIPK1), RIPK4, diserine / threonine and tyrosine protein kinase (RIPK5), rho-associated protein kinase 1 (ROCK1), ROCK2, ribosomal S6 kinase 4 (RSK4) (Kin.Dom.1-N-terminus), serum and glucocorticoid-regulated kinase (SGK), SGK2, serine-arginine protein kinase 1 (SRPK1), SRPK2, SRPK3, serine / threonine At least one of the following: STK16, STK39, TGF-β activated kinase 1 (TAK1), TRAF2 and NCK-interacting kinase (TNIK), tropomyosin receptor kinase A (TRKA), TRKB, monopolar spindle 1 (Mps1) kinase (TTK), tyrosine kinase 2 (TYK2) (JH1 domain-catalyzed), unc-51-like autophagy-activated kinase 1 (ULK1), ULK2, ULK3, vascular endothelial growth factor receptor 2 (VEGFR2), and YSK4 (also known as MAP3K19). Therefore, the compounds of this application, as well as their pharmaceutically acceptable salts and stereoisomers, can be used to treat diseases and conditions mediated by the aberrant activity of any one or more of these kinases. Such diseases and conditions are known in the art.

[0102] The method of this application may require single or multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20 or more doses). For example, the dosing frequency can range from once daily to approximately once every eight weeks. In some embodiments, the dosing frequency ranges from once daily for approximately 1, 2, 3, 4, 5 or 6 weeks, and in other embodiments a 28-day cycle is required, which includes daily dosing for 3 weeks (21 days). In other embodiments, the compound may be administered twice daily (BID) over a two-and-a-half-day period (5 doses in total), or once daily (QD) over a two-day period (2 doses in total). In other embodiments, the compound may be administered once daily (QD) over a five-day period.

[0103] The compounds of this application can be administered to patients as a monotherapy, such as patients with neurodegenerative diseases or conditions or brain cancers (e.g., glioma and glioblastoma). In other embodiments, the subject is treated as a combination therapy, wherein the compounds of this application are administered simultaneously with another active agent. Representative examples of active agents known to treat neurodegenerative diseases and conditions include dopaminergic therapies (e.g., carbidopa-levodopa, pramipexole, ropinirole, and rotigotine, provided as a patch)). Apomorphine and monoamine oxidase B (MAO-B) inhibitors (such as selegiline, Eldepryl, Zelapar, Azilect, and Xadago) are used for PD and movement disorders; cholinesterase inhibitors (such as cogentin or tribenzopyridine) are used for cognitive disorders; antipsychotics are used for behavioral and psychological symptoms of dementia; and drugs designed to slow disease progression, such as riluzole for ALS, cerebellar ataxia, and Huntington's disease; nonsteroidal anti-inflammatory drugs (NSAIDs) for Alzheimer's disease; and caffeine A2A receptor antagonists and CERE-120 (adeno-associated virus serotype 2-neurturin) have neuroprotective effects on Parkinson's disease. Representative examples of known active agents for treating brain cancer include temozolomide (Temodar), bevacizumab (Avastin), lomustine (CCNU, Ceenu), carmustine tablets (BCNU, Gliadel), and Toca 5 (Tocagen). The term "simultaneously" is not limited to precisely simultaneous administration of anti-neurodegenerative or anticancer therapeutic agents. Rather, it means administering them to the subject as part of the same treatment process, such as sequentially and at time intervals, so that they can act together (e.g., synergistically) to provide increased benefit compared to separate administration.

[0104] Drug kit

[0105] The compositions of this application can be assembled into a kit or pharmaceutical system. A kit or pharmaceutical system according to this aspect of the application includes a carrier or packaging, such as a box, carton, tube, or the like, having one or more tightly sealed containers, such as vials, tubes, ampoules, or bottles, containing the compounds or pharmaceutical compositions of this application. The kit or pharmaceutical system of this application may also include printed instructions for using the compounds and compositions.

[0106] Example

[0107] Example 1: Synthesis of 2-methyl-2-(4-(4-(methylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-1H-pyrazol-1-yl)propionitrile (1)

[0108]

[0109] 5-Bromo-4-chloro-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (Int-1)

[0110] Intermediate 1 (Int-1) was prepared according to the procedure described in International Patent Publication No. WO 2018 / 8150914.

[0111]

[0112] 5-Bromo-N-methyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (Int-2)

[0113] 5-Bromo-4-chloro-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.56 mmol) was dissolved in ethylene glycol (5 mL). CH3NH2 (2 M) in THF (2.72 mL, 5.6 mmol) was added, and the mixture was heated to 200 °C for 1 hour under microwave irradiation. The mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over magnesium sulfate, and concentrated to give a yellow oil. The crude product was purified by rapid chromatography using a 5-15% gradient of EtOAc in hexane to give the desired product as a yellow oil (187 mg, 94% yield).

[0114] MS(ESI) m / z 357.43(M+H) + .

[0115]

[0116] 5-Bromo-N-methyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (31 mg, 0.087 mmol) and 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)propionitrile (25 mg, 0.096 mmol) were dissolved in 1,4-dioxane (2 mL) and 2M Na₂CO₃ aqueous solution (0.22 mL, 0.44 mmol). The mixture was degassed using an ultrasonicator before adding Pd(dppf)Cl₂ (8 mg, 0.01 mmol) and t-BuXPhos (7 mg, 0.016 mmol) to the reaction flask. The flask was rinsed with N₂ and the mixture was stirred at 100 °C for 1 hour. The reaction was quenched with H₂O and extracted with EtOAc. The combined organic layers were washed with H₂O and brine, dried over MgSO₄, and concentrated to give a brown oil. The obtained oil was dissolved in DCM (10 mL), and then trifluoroacetic acid (TFA) (1 mL) was added. The mixture was stirred for 1 hour, and then the solvent was removed under reduced pressure. A saturated aqueous solution of NaHCO₃ (2 mL) was added to the dissolved residue in THF (5 mL), and the mixture was stirred at room temperature (rt) for 6 hours. The reaction was quenched with H₂O and extracted with EtOAc. The combined organic layers were washed with H₂O and brine, dried over MgSO₄, and concentrated under reduced pressure to give a brown oil. The crude product was purified by reversed-phase HPLC, eluting with a gradient of 1 to 60% MeCN in H₂O solution to give the desired product as a white solid (8 mg, yield 33%).

[0117] 1 H NMR (500MHz, DMSO) δ12.3(s,1H),8.23(s,1H),7.81(d,J=20Hz,2H),7.35(s,2H),7.0(s,1H),3.28(d,J=5Hz,3H),2.02(s,6H)

[0118] MS(ESI) m / z: 281.62 (M+H) + .

[0119] Example 2: Synthesis of N-methyl-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine (2)

[0120]

[0121] Compound 2 (9 mg, yield 34%) was prepared in a manner similar to that of compound 1 in Example 1.

[0122] 1 H NMR(500MHz,DMSO)δ12.3(s,1H),8.05(s,1H),7.78(s,1H),7.68(s,1H),7.35(s,1H),7.27(s,1H),6. 99(s,1H),4.49(m,1H),3.60(m,2H),3.28(d,J=5Hz,3H),3.19(m,2H),2.84(s,3H),3.38–2.15(m,4H).

[0123] MS(ESI) m / z: 311.41(M+H) + .

[0124] Example 3: Synthesis of N-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine (3)

[0125]

[0126] Compound 3 (9 mg, 35% yield) was prepared in a manner similar to that of Compound 1 in Example 1.

[0127] 1 H NMR(500MHz,DMSO)δ12.32(s,1H),8.04(s,1H),7.79(s,1H),7.64(s,1H),7.34(s,1H),7.3(s,1 H), 6.99 (s, 1H), 4.46 (m, 1H), 3.99 (m, 2H), 3.50 (m, 2H), 3.28 (d, J = 5Hz, 3H), 2.02–1.91 (m, 4H).

[0128] MS(ESI) m / z: 298.83 (M+H) + .

[0129] Example 4: Synthesis of 2-(4-(3-chloro-4-(methylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-1H-pyrazol-1-yl)-2-methylpropionitrile (4)

[0130]

[0131] 5-Bromo-3,4-dichloro-1H-pyrrolo[2,3-b]pyridine (Int-4)

[0132] N-chlorosuccinimide (NCS) (634 mg, 4.75 mmol) was added to a solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (1 g, 4.32 mmol) in DMF (15 mL). The mixture was stirred for 16 hours, and then the reaction was quenched with water (150 mL). The precipitate was filtered, washed with water, and dried under N2 to give the desired product as a light brown solid (1.14 g, 97% yield).

[0133] MS(ESI) m / z: 266.53 (M+H) + .

[0134]

[0135] 5-Bromo-3,4-dichloro-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (Int-5)

[0136] Intermediate 5 (Int-5) was prepared in a manner similar to that of compound Int-1 in Example 1.

[0137] MS(ESI) m / z: 397.34 (M+H) + .

[0138]

[0139] 5-Bromo-3-chloro-N-methyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (Int-6)

[0140] Intermediate 6 (Int-6) was prepared in a manner similar to that of compound Int-2 in Example 1.

[0141] MS(ESI) m / z: 391.59 (M+H) + .

[0142]

[0143] Compound 4 was prepared in a manner similar to that of Compound 1 in Example 1. The desired product was isolated as a yellow solid (4 mg, yield 15%).

[0144] 1 H NMR (500MHz, DMSO) δ12.41(br,1H),8.21(s,1H),7.90(s,1H),7.78(s,1H),7.52(s,1H),6.85(br,1H),2.84(s,3H),2.02(s,6H).

[0145] MS(ESI) m / z: 315.27 (M+H) + .

[0146] Example 5: Synthesis of 3-chloro-N-methyl-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine (5)

[0147]

[0148] Compound 5 was prepared in a manner similar to that of compound 4 in Example 4. The desired product was isolated as a yellow solid (4 mg, yield 16%).

[0149] 1 H NMR(500MHz,DMSO)δ12.38(br,1H),8.07(d,J=5Hz,1H),7.97(s,1H),7.86(s,1H),7.64(s,1H),7.50 (s,1H),6.65(br,1H),4.49(m,1H),3.17(m,2H),3.03(d,J=5Hz,3H),2.84(s,3H),2.33–2.15(m,4H).

[0150] MS(ESI) m / z: 345.68 (M+H) + .

[0151] Example 6: Synthesis of 3-chloro-N-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine (6)

[0152]

[0153] Compound 6 was prepared in a manner similar to that of compound 4 in Example 4. The desired product was isolated as a yellow solid (5 mg, yield 18%).

[0154] MS(ESI) m / z: 332.53 (M+H) + .

[0155] Example 7: Synthesis of 2-methyl-2-(4-(4-(methylamino)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)propionitrile (7)

[0156]

[0157] 4-Chloro-3-iodo-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (Int-7)

[0158] 4-Chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (1 g, 4.53 mmol) and N-iodosuccinimide (NIS) (1.12 g, 4.99 mmol) were stirred together in acetone (20 mL) at room temperature for 2 hours. The reaction was quenched by adding H₂O (100 mL) and a saturated aqueous solution of sodium thiosulfate (20 mL). The precipitate was filtered, washed with H₂O, and dried under N₂ to give the desired product as a white solid, which could be used directly without further purification (1.5 g, 96% yield).

[0159] MS(ESI) m / z: 347.87 (M+H) + .

[0160]

[0161] 4-Chloro-3-iodo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (Int-8)

[0162] Intermediate 8 (Int-8) was prepared in a manner similar to that of compound Int-1 in Example 1.

[0163] MS(ESI) m / z: 477.56 (M+H) + .

[0164]

[0165] 3-Iodo-N-methyl-5-(trifluoromethyl)-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (Int-9)

[0166] Intermediate 9 (Int-9) was prepared in a manner similar to that of compound Int-2 in Example 1.

[0167] MS(ESI) m / z: 472.26 (M+H) + .

[0168]

[0169] Compound 7 was prepared in a manner similar to that of Compound 1 in Example 1. The desired product was isolated as a yellow solid (10 mg, yield 28%).

[0170] 1H NMR (500MHz, DMSO) δ12.21(br,1H),8.30(s,1H),8.17(s,1H),7.78(s,1H),7.43(s,1H),5.90(br,1H),2.71(s,3H),2.01(s,6H).

[0171] MS(ESI) m / z: 349.62 (M+H) + .

[0172] Example 8: Synthesis of N-methyl-3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (8)

[0173]

[0174] Compound 8 was prepared in a manner similar to that of Compound 1 in Example 1. The desired product was isolated as a yellow solid (8 mg, 20% yield).

[0175] MS(ESI) m / z: 379.32 (M+H) + .

[0176] Example 9: Synthesis of 3-chloro-5-(3-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine (17)

[0177]

[0178] A degassed solution of 5-bromo-3-chloro-N-methyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (Int-6) (50 mg, 0.127 mmol), 4-bromo-3-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (43.4 mg, 0.166 mmol), bis(pinacol)diboron (48.7 mg, 0.192 mmol), and Cs₂CO₃ (208 mg, 0.639 mmol) in 1,4-dioxane (0.8 mL) and H₂O (0.2 mL) was supplemented with Pd(OAc)₂ (4.3 mg, 0.019 mmol) and... (13.76 mg, 0.038 mmol). The mixture was recharged with N2 and stirred at 90 °C for rt until the reaction was complete (approximately 1 hour). The mixture was then cooled to room temperature, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. TFA (1 mL) was added to a DCM (10 mL) solution of the crude product (Int-11). The reaction was stirred at room temperature for 1 hour (until the starting material was consumed). The solvent was removed under reduced pressure, and the residue was dissolved in THF (5 mL). A saturated aqueous solution of NaHCO3 (2 mL) was added, and the mixture was stirred at room temperature for 6 hours. The mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over MgSO4, and condensed under reduced pressure. The crude product was dissolved in DMSO-d6, filtered, and then purified by reversed-phase HPLC using a gradient of 1 to 60% acetonitrile (CAN) in water to give 9 mg of the desired product in 99.4% yield (17).

[0179] 1 H NMR(500MHz,DMSO-d6)δ12.43(br,1H),7.80(s,1H),7.78(s,1H),7.51(s,1H),6.95(br,1H),4.29 -4.23(m,1H),3.98-3.95(m,2H),3.82(s,3H),3.49-3.44(m,2H),2.89(s,3H),2.01-1.89(m,4H).

[0180] MS(ESI) m / z: 362.12 (M+H) + .

[0181] Example 10: Synthesis of 3-chloro-5-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine (9)

[0182]

[0183] Compound 9 (16.3 mg, yield 23%) was prepared in a manner similar to that of compound 17 in Example 9.

[0184] 1 H NMR(500MHz,DMSO-d6)δ12.43(br,1H),9.18(br,1H),8.28(s,1H),7.54(s,1H),6 .58(s,1H),3.82(s,3H),3.25(s,3H),2.68(q,J=10Hz,2H),1.25(t,J=10Hz,3H).

[0185] MS(ESI) m / z: 290.1 ​​(M+H) + .

[0186] Example 11: Synthesis of 3-chloro-5-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-N-isopropyl-1H-pyrrolo[2,3-b]pyridine-4-amine (10)

[0187]

[0188] Compound 10 (17.7 mg, yield 16%) was prepared in a manner similar to that of compound 17 in Example 9.

[0189] 1 H NMR(500MHz,DMSO-d6)δ12.34(br,1H),8.88(br,1H),8.36(s,1H),7.54(s,1H),6.62(s,1H),4 .42-4.38(m,1H),3.82(s,3H),2.68(q,J=10Hz,2H),1.26(t,J=10Hz,3H),1.22(d,J=5Hz,6H).

[0190] MS(ESI) m / z: 318.01 (M+H) + .

[0191] Example 12: Synthesis of 3-chloro-N-methyl-5-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine (11)

[0192]

[0193] Compound 11 (6.1 mg, yield 18%) was prepared in a manner similar to that of compound 17 in Example 9.

[0194] 1 H NMR (500MHz, DMSO-d6) δ12.43(br,1H),8.26(s,1H),7.85(d,J=5Hz,1H),7.54(s,1H),6.72(d,J=5Hz,1H),3.93(s,3H),3.19(s,3H).

[0195] MS(ESI) m / z: 262.01 (M+H) + .

[0196] Example 13: Synthesis of 3-chloro-N-isopropyl-5-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine (12)

[0197]

[0198] Compound 12 (10.7 mg, yield 34%) was prepared in a manner similar to that of compound 17 in Example 9.

[0199] 1 H NMR(500MHz,DMSO-d6)δ12.34(br,1H),8.35(s,1H),7.86(d,J=5Hz,1H),7.55(s ,1H),6.76(d,J=5Hz,1H),4.38-4.28(m,1H),3.94(s,3H),1.20(d,J=10Hz,6H).

[0200] MS(ESI) m / z: 290.04 (M+H) + .

[0201] Example 14: Synthesis of 3-chloro-5-(3-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-N-methyl-1H-pyrrolline[2,3-b]pyridine-4-amine (13)

[0202]

[0203] Compound 13 (8.4 mg, yield 6%) was prepared in a manner similar to that of compound 17 in Example 9.

[0204] 1 H NMR(500MHz,DMSO-d6)δ12.41(br,1H),7.86(s,1H),7.81(s,1H),7.53(s,1H),7.05(br,1H),4.35-4.28(m,1H ),3.96-3.93(m,2H),2.81(s,3H),1.98-1.92(m,4H),1.91-1.87(m,2H),1.64-1.59(m,1H),0.78-0.73(m,4H).

[0205] MS(ESI) m / z: 372.16 (M+H) + .

[0206] Example 15: Synthesis of 3-(3-chloro-4-(methylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-methyl-1H-indazole-5-onitrile (14)

[0207]

[0208] Compound 14 (14 mg, 8% yield) was prepared in a manner similar to that of compound 17 in Example 9.

[0209] 1 H NMR(500MHz,DMSO-d6)δ12.42(br,1H),8.33(s,1H),8.11(s,1H),7.95(d,J=10Hz ,1H),7.81(d,J=10Hz,1H),7.55(s,1H),7.22(br,1H),4.19(s,3H),2.58(s,3H).

[0210] MS(ESI) m / z: 336.96 (M+H) + .

[0211] Example 16: Synthesis of 3-(3-chloro-4-(methylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-5-methoxy-1-methyl-1H-indazole (15)

[0212]

[0213] Compound 15 (4.7 mg, 9% yield) was prepared in a manner similar to that of compound 17 in Example 9.

[0214] 1 H NMR(500MHz,DMSO-d6)δ12.41(br,1H),8.07(s,1H),7.65(d,J=10Hz,1H),7.54( s,1H),7.13(d,J=10Hz,1H),7.02(s,1H),4.09(s,3H),3.76(s,3H),2.62(s,3H).

[0215] MS(ESI) m / z: 341.98 (M+H) + .

[0216] Example 17: Synthesis of 3-chloro-5-(5-methoxy-2-methyl-2H-indazol-3-yl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine (16)

[0217]

[0218] Compound 16 (6.3 mg, yield 12%) was prepared in a manner similar to that of compound 17 in Example 9.

[0219] 1H NMR (500MHz, DMSO-d6) δ12.21(br,1H),7.92(s,1H),7.55(d,J=10Hz,1H),7.54(s,1H),6.95(d,J=10Hz,1H),3.91(s,3H),3.71(s,3H),2.54(s,3H).

[0220] MS(ESI) m / z: 342.04 (M+H) + .

[0221] Example 18: Synthesis of 3-(3-chloro-4-(methylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-1-methyl-1H-pyrazol-4-onitrile (18)

[0222]

[0223] Compound 18 (16.7 mg, yield 14%) was prepared in a manner similar to that of compound 17 in Example 9.

[0224] 1 H NMR (500MHz, DMSO-d6) δ12.32(br,1H),8.64(s,1H),8.00(s,1H),7.51(s,1H),7.06(br,1H),3.97(s,3H),2.70(s,3H).

[0225] MS(ESI) m / z: 286.94 (M+H) + .

[0226] Example 19: Synthesis of 3-chloro-N-methyl-5-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (19)

[0227]

[0228] Compound 19 (16 mg, yield 28%) was prepared in a manner similar to that of compound 17 in Example 9.

[0229] 1 H NMR (500MHz, DMSO-d6) δ12.34(br,1H),8.05(d,J=10Hz,2H),7.94(s,1H),7.65(d,J=10Hz,2H),7.52(s,1H),6.76(br,1H),2.61(s,3H),2.58(s,3H).

[0230] MS(ESI) m / z: 340.15 (M+H)+ .

[0231] Example 20: Synthesis of 3-(3-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-N-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (20)

[0232]

[0233] Compound 20 (2 mg, 5% yield) was prepared in a manner similar to that of compound 17 in Example 9.

[0234] 1 H NMR(500MHz,DMSO-d6)δ12.13(br,1H),8.28(s,1H),7.74(s,1H),7.24(s,1H),6.16(br,1H),4.26 -4.23(m,1H),3.97-3.95(m,2H),3.83(s,3H),3.48-3.43(m,2H),2.80(s,3H),2.00-1.88(m,4H).

[0235] MS(ESI) m / z: 396.27 (M+H) + .

[0236] Example 21: Synthesis of N-methyl-3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (21)

[0237]

[0238] Compound 21 (11 mg, yield 28%) was prepared in a manner similar to that of compound 17 in Example 9.

[0239] 1 H NMR (500MHz, DMSO-d6) δ12.36(br,1H),8.30(s,1H),8.02(d,J=5Hz,2H),7.68(d,J=5Hz,2H),7.61(s,1H),2.60(s,3H),1.93(br,1H).

[0240] MS(ESI) m / z: 374.12 (M+H) + .

[0241] Example 22: Synthesis of (4-(3-chloro-4-(methylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-3-methoxyphenyl)(morpholinyl) methyl ketone (22)

[0242]

[0243] Compound 22 (21 mg, yield 18%) was prepared in a manner similar to that of compound 17 in Example 9.

[0244] 1 H NMR(500MHz,DMSO-d6)δ12.46(br,1H),7.80(s,1H),7.53(s,1H),7.39(d,J=5 Hz,1H),7.11(s,1H),7.06(d,J=5Hz,1H),3.80(s,3H),3.63(br),2.60(s,3H).

[0245] MS(ESI) m / z: 401.24 (M+H) + .

[0246] Example 23: Synthesis of (3-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(morpholinyl) methyl ketone (23)

[0247]

[0248] Compound 23 (7.8 mg, yield 49%) was prepared in a manner similar to that of compound 17 in Example 9.

[0249] 1 H NMR(500MHz,DMSO-d6)δ12.22(br,1H),8.26(s,1H),7.35(d,J=10Hz,1H),7.33( s,1H),7.09(s,1H),7.05(d,J=10Hz,1H),6.19(br,1H),3.75(br),3.64(br,6H).

[0250] MS(ESI) m / z: 435.31 (M+H) + .

[0251] Example 24: Synthesis of N-methyl-3-(4-morpholinylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (24)

[0252]

[0253] Compound 24 (8 mg, 15% yield) was prepared in a manner similar to that of compound 17 in Example 9.

[0254] 1H NMR (500MHz, DMSO-d6) δ12.63(br,1H),8.32(s,1H),8.24(d,J=5Hz,1H),8.03(s,1H),7.35(d,J=5Hz,1H),7.13(s,1H).

[0255] MS(ESI) m / z: 378.13 (M+H) + .

[0256] Example 25: Synthesis of 3-chloro-N-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine (25)

[0257]

[0258] Compound 25 (9 mg, yield 21%) was prepared in a manner similar to that of compound 17 in Example 9.

[0259] 1 H NMR(500MHz,DMSO-d6)δ12.33(br,1H),8.04(s,1H),7.92(s,1H),7.64(s,1H),7.53(s,1H),5.87(br,1H),4.49 -4.43(m,1H),3.98-3.94(m,2H),3.69-3.64(m,2H),2.01-1.98(m,4H),1.96-1.92(m,1H),1.04(d,J=10Hz,6H).

[0260] MS(ESI) m / z: 360.23 (M+H) + .

[0261] Example 26: Synthesis of aza-indole intermediates int-12 to int-16

[0262]

[0263] 5-Bromo-N-ethyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (int-12)

[0264] Intermediate 12 (int-12) was synthesized in a manner similar to that of intermediate int-2 in Example 1. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give int-12 (4 g, 97% yield) as a yellow oil.

[0265] 1H NMR (400MHz, CDCl3) δ8.16(s,1H),7.16(d,J=3.8Hz,1H),6.69(d,J=3.8Hz,1H),5.63(s,2H),3. 86-3.79(m,2H),3.62-3.54(m,2H),1.45(t,J=7.2Hz,3H),0.99-0.93(m,2H),0.02-0.03(m,9H).

[0266] LCMS: m / z 371.9 [M+1] + ...

[0267]

[0268] 5-Bromo-N-isopropyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (int-13)

[0269] Intermediate 13 (int-13) was synthesized in a manner similar to intermediate int-2 in Example 1. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to give int-13 (3.8 g, yield 30%) as a yellow solid.

[0270] 1 H NMR (400MHz, CDCl3) δ8.18(s,1H),7.18(d,J=3.7Hz,1H),6.62(d,J=3.8Hz,1H),5.63(s,2H), 4.20-4.05(m,1H),3.55-3.45(m,2H),1.55(d,J=6.0Hz,6H),0.98-0.94(m,2H),-0.06(s,9H).

[0271] LCMS: m / z 384.2 [M+1] + .

[0272]

[0273] 5-Bromo-N-isopropyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (int-14)

[0274] Intermediate 14 (int-14) was synthesized in a manner similar to intermediate int-2 in Example 1. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1). Yellow oily int-14 was given (2.85 g, yield 32%).

[0275] 1 H NMR (400MHz, CDCl3) δ8.15(s,1H),7.17(d,J=3.7Hz,1H),7.04(d,J=3.7Hz,1H),5.64(s,2H),5.34(br s,1H),3.64-3.54(m,2H),3.16-3.06(m,1H),1.05-0.91(m,4H),0.89-0.80(m,2H),0.05-0.04(m,9H).

[0276] LCMS: m / z 382.2 [M+1] + .

[0277]

[0278] 5-Bromo-N-(2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (int-15)

[0279] Intermediate 15 (int-15) was synthesized in a manner similar to intermediate int-2 in Example 1. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). Int-15 (4 g, 72% yield) was obtained as a yellow oil.

[0280] 1 H NMR (400MHz, CDCl3) δ8.12(s,1H),7.12(d,J=3.8Hz,1H),6.60(d,J=3.8Hz,1H),5.58(s,2H),5.33(brs,1H ),3.95-3.85(m,2H),3.72-3.67(m,2H),3.58-3.49(m,2H),3.44(s,3H),0.99-0.83(m,2H),-0.06(s,9H).

[0281] LCMS:m / z 400.0[M+1] + .

[0282]

[0283] 5-Bromo-N-cyclopentyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (int-16)

[0284] Intermediate 16 (int-16) was synthesized in a manner similar to intermediate int-2 in Example 1. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1). Yellow oily int-16 was given (3.9 g, yield 73%).

[0285] 1 H NMR (400MHz, CDCl3) δ8.11(s,1H),7.12(d,J=3.8Hz,1H),6.62(d,J=3.8Hz,1H),5.58(s,2H),4.97(brs,1H),4.56-4.4 5(m,1H),3.57-3.52(m,2H),2.15-2.05(m,2H),1.87-1.78(m,2H),1.77-1.64(m,4H),0.94-0.88(m,2H),-0.05(s,9H).

[0286] LCMS:m / z 410.1[M+1] + .

[0287] Example 27: Synthesis of intermediate bis(pinacol)bisboron (Bpin) intermediates (int-21 to int-41)

[0288]

[0289] (3S,4R)3-fluoro-4-((methanesulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (int-17)

[0290] To a mixture of 3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl (3S,4R)-tert-butyl (40 g, 182.44 mmol), triethylamine (TEA) (36.92 g, 364.88 mmol, 50.79 mmol) was added to MsCl (25.08 g, 218.93 mmol, 16.94 mL) in DCM (500 mL) at -30 °C and N2. The mixture was then stirred at -30 °C for 2 h. TLC (petroleum ether / ethyl acetate = 1 / 1) showed that the reactants were completely consumed and new spots were observed. The mixture was poured into ice water (800 mL) and extracted with DCM (300 mL × 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give int-17 (54 g, 181.61 mmol, 99% yield) as a white solid.

[0291]

[0292] (3S,4S)3-fluoro-4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (int-18)

[0293] Cs₂CO₃ (88.76 g, 272.41 mmol) was added to a mixture of int-17 (54 g, 181.61 mmol) and 4-iodo-1H-pyrazole (35.23 g, 181.61 mmol) in DMF (600 mL). The mixture was then stirred at 100 °C for 5 hours. LC-MS showed that the reactants were completely consumed, with 55% of the desired mass detected. The mixture was poured into ice water (1000 mL) and extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with brine (1000 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give int-18 (49 g, 121.50 mmol, yield 67%) as a colorless oil.

[0294]

[0295] (3S,4S)-3-fluoro-4-(4-iodo-1H-pyrazol-1-yl)piperidine (int-19)

[0296] At 0 °C, HCl / EtOAc (4 M, 100 mL) was added to a solution of int-18 (12.4 g, 31.38 mmol) in EtOAc (50 mL). The mixture was then stirred at 15 °C for 2 h. LC-MS showed that the reactants were completely consumed, with 86% of the desired mass detected. The residue was concentrated under vacuum to give int-19 (9.6 g, 28.95 mmol, 92% yield, HCl) as a white solid.

[0297]

[0298] (3S,4S)-3-fluoro-4-(4-iodo-1H-pyrazol-1-yl)-1-(oxecyclobut-3-yl)piperidine (int-20)

[0299] A mixture of int-19 (4.8 g, 14.48 mmol, HCl), 3-oxetane (3.13 g, 43.43 mmol), and NaOAc (1.43 g, 17.37 mmol) in MeOH (50 mL) was degassed, washed three times with N2, and then stirred at 15 °C for 1 h. NaBH3CN (2.73 g, 43.43 mmol) was then added to the mixture, and the reaction was stirred at 15 °C for 16 h. LC-MS showed that the reactants were completely consumed, and 75% of the desired mass was detected. The mixture was poured into ice water (300 mL) and extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give int-20 (3.6 g, 10.05 mmol, yield 69%) as a white solid.

[0300]

[0301] (3S,4S)-3-fluoro-1-(oxacyclobut-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)piperidine (int-21)

[0302] XPHOS-PD-G2 (806.61 mg, 1.03 mmol) was added to a mixture of int-20 (3.6 g, 10.25 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,31,2-dioxapentane) (3.90 g, 15.38 mmol), and KOAc (3.02 g, 30.76 mmol) in DMSO (40 mL) under nitrogen atmosphere. The mixture was stirred at 50 °C for 2 hours. LCMS showed that the reactants were completely consumed and 62% of the desired mass was detected. The mixture was poured into H2O (100 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give int-21 (3.2 g, 8.29 mmol, yield 81%) as a yellow solid.

[0303] 1H NMR (400MHz, CDCl3) δ7.84(s,1H),7.79(s,1H),5.02-4.81(m,1H),4.70-4.66(m,2H),4.64-4.59(m,2H),4.23-4.08( m,1H),3.71-3.59(m,1H),3.24-3.12(m,1H),2.87-2.74(m,1H),2.37-2.25(m,1H),2.18-1.97(m,3H),1.32(s,12H).

[0304] LCMS:m / z 352.0[M+1] + .

[0305]

[0306] (3S,4S)3-fluoro-4-(4-iodo-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (int-22)

[0307] Lithium diisopropylamide (LDA) (2M, 31.63 mL) was added to a solution of int-18 (10 g, 25.30 mmol) in THF (120 mL) at -65 °C and N2. The mixture was stirred at -65 °C for 1 hour. MeI (24.24 g, 170.80 mmol, 10.63 mL) was added to the mixture at -65 °C and N2. The reaction was stirred at 15 °C for 1 hour. LCMS showed that the reactants were completely consumed and 81% of the desired mass was detected. The reaction mixture was poured into ice water (400 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine (400 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give int-22 as a white solid (10 g, 23.70 mmol, yield 94%).

[0308]

[0309] (3S,4S)-3-fluoro-4-(4-iodo-5-methyl-1H-pyrazol-1-yl)piperidine (int-23)

[0310] At 0 °C, HCl / EtOAc (4 M, 100 mL) was added to a solution of int-22 (14.4 g, 35.19 mmol) in EtOAc (50 mL), and the mixture was stirred at 15 °C for 2 hours. LC-MS showed that the reactants were completely consumed and 98% of the desired mass was detected. The mixture was concentrated under vacuum to give int-23 (12.16 g, 35.19 mmol, 100% yield, HCl) as a white solid.

[0311]

[0312] (3S,4S)-3-fluoro-4-(4-iodo-5-methyl-1H-pyrazole-1-yl)-1-(oxecyclobut-3-yl)piperidine (int-24)

[0313] A mixture of int-23 (12.16 g, 35.19 mmol, HCl), 3-oxetane (7.61 g, 105.56 mmol), NaOAc (3.46 g, 42.22 mmol) in MeOH (130 mL) was degassed and purged twice with N2, then stirred at 15 °C for 1 h. NaBH3CN (6.63 g, 105.56 mmol) was then added, and the reaction was stirred at 15 °C for 16 h. LC-MS showed complete consumption of the reactants, with 81% of the desired mass detected. The mixture was poured into ice water (800 mL). The aqueous phase was extracted with ethyl acetate (400 mL × 2). The combined organic phases were washed with brine (800 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was ground with EtOAc (15 mL) to give int-24 (10 g, 27.38 mmol, 78% yield) as a white solid.

[0314]

[0315] (3S,4S)-3-fluoro-4-(5-methyl-4-(4,4,5,5-–tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)-1-(oxacyclobut-3-yl)piperidine (int-25)

[0316] Under nitrogen atmosphere, XPHOS-PD-G2 (1.08 g, 1.37 mmol) was added to a mixture of int-24 (5 g, 13.69 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxapentane) (5.22 g, 20.54 mmol), and KOAc (4.03 g, 41.08 mmol) in DMSO (50 mL). The mixture was then stirred and incubated at 50 °C for 4 hours. LC-MS showed that the reactants were completely consumed and 55% of the desired mass was detected. The mixture was poured into H2O (100 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give int-25 (4.1 g, 11.23 mmol, yield 82%) as a yellow solid.

[0317] 1 H NMR (400MHz, CDCl3) δ7.77(s,1H),5.14-4.89(m,1H),4.70-4.60(m,4H),4.17-4.00(m,1H),3.72-3. 59(m,1H),3.27-3.12(m,1H),2.89-2.75(m,1H),2.47-2.46(m,3H),2.20-1.84(m,4H),1.31(s,12H).

[0318] LCMS: m / z 366.2 [M+1] + .

[0319]

[0320]

[0321] (3S,4S)4-(5-chloro-4-iodo-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (int-26)

[0322] LDA (2M, 91.72mL) was added to a solution of int-18 (29g, 73.38mmol) in THF (300mL) at -65°C and N2, and the mixture was stirred at -65°C for 1 hour. 1,1,1,2,2,2-hexachloroethane (52.11g, 220.14mmol, 24.94mL) was added to the mixture at -65°C, and the resulting mixture was stirred at 15°C for 1 hour under N2 atmosphere. TLC (petroleum ether / ethyl acetate = 5 / 1) showed complete consumption of the reactants and new spots were observed. The mixture was poured into ice-HCl (1M, 600mL). The aqueous phase was extracted with ethyl acetate (300mL × 2). The combined organic phases were washed with brine (600mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give int-26 as a yellow solid (25 g, 58.19 mmol, yield 79%).

[0323]

[0324] (3S,4S)-4-(5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborcycloalkyl-2-yl)-1H-pyrazol-1-yl)-3-fluoro-1-(oxecyclobut-3-yl)piperidine (int-29)

[0325] Int-29 was prepared in a manner similar to that of int-26 as described above. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give int-29 as a yellow solid (367 mg, 523.38 μmol, yield 40%).

[0326] 1 H NMR(400MHz, CDCl3)δ7.83(s,1H),5.20-4.96(m,1H),4.74-4.57(m,4H),4.49-4.33(m,1H),3.71-3.58( m,1H),3.28-3.15(m,1H),2.89-2.76(m,1H),2.40-2.23(m,1H),2.18-1.92(m,3H),1.42-1.29(s,12H).

[0327] LCMS: m / z 386.3 [M+1] + .

[0328]

[0329] 1-((3S,4S)-3-fluoro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)acetone (int-33)

[0330] At 0 °C and N2, TEA (3 equivalents) and acetyl chloride (1.1 equivalents) were added to a DCM solution of intermediate int-19 (1 equivalent). The mixture was stirred at room temperature for 16 hours. LCMS showed that the reactants were completely consumed. The mixture was poured into ice water. The aqueous phase was extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to give int-30.

[0331] Under nitrogen atmosphere, 4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxapentane) (1.5 eq), KOAc (3 eq), and XPHOS-PD-G2 (0.1 eq) were added to a DMSO solution of int-30 (1 equivalence). The mixture was then stirred at 40–60 °C for 2–16 hours. LC-MS showed complete consumption of the reactants. The mixture was poured into water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give int-33 (3.0 g, 62% yield in two steps) as a white solid.

[0332] 1 H NMR (400MHz, CDCl3) δ7.84 (s, 1H), 7.79-7.78 (d, J = 2.8Hz, 1H), 5.04-4.46 (m, 2H), 4.39-4.26 (m ,1H),4.22-3.87(m,1H),3.40-3.16(m,1H),3.03-2.76(m,1H),2.33-2.14(m,5H),1.32(s,12H).

[0333] LCMS (Method 1): m / z 338.0 [M+1] + .

[0334]

[0335] 1-((3S,4S)-3-fluoro-4-(5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)acetone (INT-34)

[0336] Int-34 was prepared in a manner similar to that of int-33 described above. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give int-34 as a white solid (2.3 g, 76% yield in two steps).

[0337] 1 H NMR(400MHz, CDCl3)δ7.75(s,1H),5.09-4.56(m,2H),4.34-3.91(m,2H),3.36-3.16(m,1H),2 .92-2.73(m,1H),2.49-2.23(m,4H),2.15(d,J=5.0Hz,3H),2.09-1.94(m,1H),1.31(s,12H).

[0338] LCMS (Method 1): m / z 352.1[M+1] + .

[0339]

[0340] 1-((3S,4S)-4-(5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)acetone (int-35)

[0341] Int-35 was prepared in a manner similar to that of int-33 described above. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give int-35 as a yellow solid (1.0 g, 39% yield in two steps).

[0342] LCMS (Method 1): m / z 372.1 [M+1] + .

[0343]

[0344] At 0 °C, (COCl)₂ (1.5 equivalents) and DMF (0.1 equivalents) were added to a DCM solution of compound A (1 equivalent). The mixture was stirred at 25 °C for 1 hour and concentrated under reduced pressure. The resulting residue was added dropwise at 0 °C to a mixture of morpholine (1 equivalent) and TEA (3 equivalents) in DCM. The mixture was stirred at 25 °C for 16 hours. TLC showed that the reaction was complete. The mixture was then diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate int-36.

[0345] Intermediate int-36 (1 eq) and 4,4,5,5-tetramethyl-2-(a solution of 4,4,5,5-5-tetramethyl-1,3,2-dioxaborane-2-yl) were added to dioxane in the form of -1,3,2-dioxaborane (1.5 eq), Pd(dppf)Cl2 (0.1 eq), and KOAc (3 eq). The mixture was stirred at 100 °C for 16 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure and purified by column chromatography to give int-37.

[0346]

[0347] Morpholinyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborborane-2-yl)phenyl) methyl ketone (int-38)

[0348] Int-38 was prepared in a manner similar to that of int-37 described above. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give int-38 as a yellow solid (4.5 g, 94% yield in 3 steps).

[0349] 1 H NMR (400MHz, CDCl3) δ7.78 (d, J = 7.3Hz, 2H), 7.31 (d, J = 7.3Hz, 2H), 3.79-3.27 (m, 8H), 1.26 (s, 12H).

[0350] LCMS:m / z 318.0[M+1] + .

[0351]

[0352] (4-(4-mercaptopiridin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)methyl ketone (int-39)

[0353] Int-39 was prepared in a manner similar to that of int-37 described above. The crude product was purified by column chromatography (SiO2, dichloromethane / methanol = 100 / 1 to 50 / 1) to give int-39 as a dark brown solid (7.43 g, 77% yield in 3 steps).

[0354] 1H NMR (400MHz, CDCl3) δ7.89-7.78(m,2H),7.39-7.33(m,2H),4.84-4.61(m,1H),3.80- 3.65(m,5H),3.13-2.62(m,2H),2.62-2.27(m,5H),2.09-1.43(m,4H),1.26(s,12H).

[0355] LCMS:m / z 401.1[M+1] + .

[0356]

[0357] (3-Methoxy-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)(morpholino)methyl ketone (int-40)

[0358] Int-40 was prepared in a manner similar to that of int-37 as described above. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give int-40 (6.78 g, 45% yield in 3 steps) as a yellow gel.

[0359] 1 H NMR (400MHz, CDCl3) δ7.68 (d, J = 7.3Hz, 1H), 6.96-6.89 (m, 2H), 3.84 (s, 3H), 3.83-3.71 (m, 4H), 3.66-3.39 (m, 4H), 1.34 (s, 12H).

[0360] LCMS (Method 1): m / z 348.0 [M+1] + .

[0361]

[0362] (3-Methoxy-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (int-41)

[0363] Int-41 was prepared in a manner similar to that of int-37 as described above. The crude product was purified by column chromatography (SiO2, dichloromethane / methanol = 100 / 1 to 50 / 1) to give int-41 as a dark brown solid (5.70 g, 46% yield in 3 steps).

[0364] 1H NMR (400MHz, CDCl3) δ7.68 (d, J = 7.3Hz, 1H), 6.94-6.87 (m, 2H), 4.83-4.65 (m, 1H), 3.87-3.84 (m, 3H), 3.74 (br t,J=4.5Hz,4H),3.08-2.94(m,1H),2.86-2.74(m,1H),2.57(br s,4H),2.48-2.41(m,1H),2.07(s,1H),2.02-1.95(m,1H),1.79(br d,J=9.5Hz,1H),1.59-1.51(m,1H),1.36(s,12H).

[0365] LCMS (Method 1): m / z 431.2 [M+1] + .

[0366] Example 28: A general method for synthesizing compounds 26-69 from a suitable azaindole intermediate from Example 26 and a bis(pinacol)diboron (Bpin)-intermediate from Example 27.

[0367] General procedure for coupling reaction

[0368]

[0369] Procedure 1: Add BPin intermediate (1 equivalent), SPhos Pd G3 (0.1 eq), and K3PO4 (3 eq) to a mixture of indole intermediate (1 equivalent) in n-BuOH and H2O (10:1, 0.1M-0.2M). Stir the reaction mixture at 60°C or 50°C for 16 hours under N2 atmosphere. Filter the mixture and concentrate under vacuum. Purify the residue by column chromatography to give intermediate int-42.

[0370] Procedure 2: Add BPin intermediate (1 equivalent), K3PO4 (3 equivalents), and Ad2nBuP PdG3 (0.1 equivalents) to a THF (0.1M-0.2M) solution of indole-indole intermediate (1 equivalent). Stir the reaction mixture at 60°C for 16 h under N2 atmosphere. Filter the mixture and concentrate under vacuum. Purify the residue by column chromatography to give intermediate int-42.

[0371] Procedure 3: Add BPin intermediate (1.5 equivalents), Pd(dppf)Cl2 (0.1 eq), and K2CO3 (2 eq) to a mixture of azidoindole intermediate (1 equivalent) in dioxane and H2O (10:1, 0.1M–0.2M). Heat the reaction mixture to 100 °C and stir under N2 atmosphere for 4–12 hours. Cool the mixture to room temperature and filter. Concentrate the resulting solution under vacuum. Purify the residue by column chromatography to give intermediate int-42.

[0372] General procedure for deprotection of 2-(trimethylsilyl)ethoxymethyl (SEM)

[0373]

[0374] Procedure 4: Add HCl / dioxane (4M, 2mL, 15-20 equivalents) to a solution of int-42 (1 equivalent) in DCM (0.1M to 0.2M). Stir the mixture at 30°C for 4 hours. Monitor the reaction by LCMS. Concentrate the crude mixture under vacuum. Dissolve the resulting residue in EtOH (0.1M to 0.2M) and treat with NH3·H2O (28% purity, 40 to 50 equivalents). Stir the mixture at 60°C for 2 hours, cool to room temperature, and concentrate under vacuum. Purify the crude product by reversed-phase HPLC to obtain the desired product.

[0375] Procedure 5: Add TFA (90 to 100 equivalents) to a solution of int-42 (1 equivalent) in DCM (0.1 M to 0.2 M). Stir the mixture at 40 °C for 4 hours. Monitor the reaction by LCMS. Concentrate the crude mixture under vacuum. Dissolve the resulting residue in EtOH (0.1 M to 0.2 M) and treat with NH3·H2O (28% purity, 40 to 50 equivalents). Stir the mixture at 60 °C for 2 hours, cool to room temperature, and concentrate under vacuum. Purify the crude product by reversed-phase HPLC to obtain the desired product.

[0376] Example 29: Synthesis of 5-(1-((3S,4S)-3-fluoro-1-(oxa-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine (26)

[0377]

[0378] Compound 26 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (10.75 mg, 26% yield in 3 steps).

[0379] 1HNMR (400MHz, DMSO-d6) δ11.15(s,1H),7.97(s,1H),7.69(s,1H),7.63(s,1H),7.10(d,J=3.6Hz,1H),6.67(d,J=3.2Hz,1H),5.53 -5.49(m,1H),5.10-4.90(m,1H),4.60-4.25(m,5H),3.60-3.50(m,1H),3.25-3.10(m,4H),2.85-2.75(m,1H),2.15-1.90(m,4H).

[0380] LCMS:m / z 371.1[M+1] + .

[0381] Example 30: Synthesis of N-ethyl-5-(1-((3S,4S)-3-fluoro-1-(oxetanebut-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine (27)

[0382]

[0383] Compound 27 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (91.18 mg, 22% yield in 3 steps).

[0384] 1 H NMR (400MHz, CDCl3) δ9.91-9.34(m,1H),7.89(s,1H),7.70(s,1H),7.60(s,1H ),7.11(d,J=3.6Hz,1H),6.65(d,J=3.6Hz,1H),5.07-4.86(m,1H),4.73-4.62( m,5H),4.34-4.12(m,1H),3.76-3.64(m,3H),3.28-3.20(m,1H),2.93-2.85(m, 1H),2.47-2.35(m,1H),2.27(m,1H),2.18-2.05(m,2H),1.29(t,J=7.2Hz,3H).

[0385] LCMS: m / z 385.2 [M+1] + .

[0386] Example 31: Synthesis of 5-(1-((3S,4S)-3-fluoro-1-(oxacyclobut-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-N-isopropyl-1H-pyrrolo[2,3-b]pyridine-4-amine (28)

[0387]

[0388] Compound 28 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (85.0 mg, 24% yield in 3 steps).

[0389] 1 H NMR (400MHz, CDCl3) δ9.70(brs,1H),7.89(s,1H),7.69(s,1H),7.59(s,1H),7.12(d,J=3.7Hz,1H),6.58(d,J=3.7Hz,1H),5.06-4.85(m,1H),4.76- 4.55(m,5H),4.37-4.16(m,2H),3.68(m,1H),3.28-3.20(m,1H),2.95-2.8 5(m,1H),2.42(m,1H),2.32-2.23(m,1H),2.19-2.05(m,2H),1.28(m,6H).

[0390] LCMS: m / z 399.2 [M+1] + .

[0391] Example 32: Synthesis of N-cyclopropyl-5-(1-(((3S,4S)-3-fluoro-1-(oxacyclobut-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine (29)

[0392]

[0393] Compound 29 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (85.0 mg, 25% yield in 3 steps).

[0394] 1 H NMR(400MHz, CDCl3)δ9.77(brs,1H),7.89(s,1H),7.66(s,1H),7.56(s,1H),7.12( d,J=3.5Hz,1H),7.01(d,J=3.7Hz,1H),5.11-4.86(m,2H),4.74-4.62(m,4H),4.20( m,1H),3.67(m,1H),3.27-3.20(m,1H),3.05-2.98(m,1H),2.92-2.85(m,1H),2.47- 2.35(m,1H),2.26(m,1H),2.17-2.04(m,2H),0.94-0.87(m,2H),0.75-0.67(m,2H).

[0395] LCMS: m / z 397.2 [M+1] + .

[0396] Example 33: Synthesis of 5-(1-((3S,4S)-3-fluoro-1-(oxacyclobut-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-N-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (30)

[0397]

[0398] Compound 30 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (124.0 mg, 30% yield in 3 steps).

[0399] 1 H NMR(400MHz, CDCl3)δ9.20(brs,1H),7.92(s,1H),7.71(s,1H),7.63(s,1H), 7.11(d,J=3.5Hz,1H),6.61(d,J=3.7Hz,1H),5.12-4.86(m,2H),4.73-4.62( m,4H),4.21(m,1H),3.84(m,2H),3.71-3.61(m,3H),3.36(s,3H),3.27-3.20 (m,1H),2.92-2.85(m,1H),2.47-2.34(m,1H),2.26(m,1H),2.17-2.06(m,2H)

[0400] LCMS: m / z 415.2 [M+1] + .

[0401] Example 34: Synthesis of N-cyclopentyl-5-(1-((3S,4S)-3-fluoro-1-(oxacyclobut-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine (31)

[0402]

[0403] Compound 31 was synthesized by procedures 1 and 5 in Example 28 and was obtained as a white solid (115.2 mg, 28% yield in 3 steps).

[0404] 1H NMR (400MHz, CDCl3) δ9.38-9.14(m,1H),7.88(s,1H),7.68(s,1H),7.58(s,1H),7. 11(d,J=3.7Hz,1H),6.63(d,J=3.7Hz,1H),5.05-4.83(m,1H),4.75-4.61(m,5H),4 .54-4.43(m,1H),4.28-4.13(m,1H),3.67(m,1H),3.30-3.16(m,1H),2.95-2.82(m ,1H),2.49-2.35(m,1H),2.33-2.23(m,1H),2.18-1.98(m,4H),1.71-1.48(m,6H).

[0405] LCMS: m / z 425.2 [M+1] + .

[0406] Example 35: Synthesis of 5-(1-((3S,4S)-3-fluoro-1-(oxacyclobut-3-yl)piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-4-amino (32)

[0407]

[0408] Compound 32 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (81.0 mg, 56% yield in 3 steps).

[0409] 1 H NMR (400MHz, CDCl3) δ9.25(brs,1H),7.77(s,1H),7.57(s,1H),7.10(d,J=3.6Hz,1H),6.75(d,J=3.6Hz,1H),5.17-4.96(m,1H),4.7 3-4.64(m,4H),4.54(m,1H),4.19-4.08(m,1H),3.69(m,1H),3.32-3.21(m,4H),2.90(m,1H),2.61-2.48(m,1H),2.22-2.05(m,6H).

[0410] LCMS: m / z 385.2 [M+1] + .

[0411] Example 36: Synthesis of 1-((3S,4S)-3-fluoro-4-(4-(4-(methylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidin-1-yl)aceto-1-one (33)

[0412]

[0413] Compound 33 was synthesized by procedures 1 and 5 in Example 28, yielding a yellow solid (90.0 mg, 23% yield in 3 steps).

[0414] 1 H NMR (400MHz, DMSO-d6) δ13.86(brs,1H),12.17(s,1H),8.08(s,1H),7.74(s,1H),7.69(s,1H),7.29(d,J=4Hz,1H),7.11(s ,1H),6.98(d,J=1.6Hz,1H),4.83-4.69(m,1H),4.68-4.63(m,1H),4.6-4.26(m,2H),3.40-3.31(m,5H),2.16-2.04(m,5H).

[0415] LCMS: m / z 357.1 [M+1] + .

[0416] Example 37: Synthesis of 1-((3S,4S)-4-(4-(4-(ethylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)ethyl-1-one (34)

[0417]

[0418] Compound 34 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (154.0 mg, 38% yield in 3 steps).

[0419] 1H NMR(400MHz, CDCl3)δ9.64(brs,1H),7.87(s,1H),7.70(s,1H),7.59(d,J=5.1 Hz,1H),7.11(d,J=3.7Hz,1H),6.65(d,J=3.7Hz,1H),5.10-4.62(m,3H),4.46 -4.32(m,1H),4.29-3.96(m,1H),3.76-3.69(m,2H),3.40-3.22(m,1H),2.99- 2.77(m,1H),2.43-2.26(m,2H),2.19(d,J=3.3Hz,3H),1.29(t,J=7.2Hz,3H).

[0420] LCMS: m / z 371.2 [M+1] + .

[0421] Example 38: Synthesis of 1-((3S,4S)-3-fluoro-4-(4-(4-(isopropylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazol-1-yl)piperidin-1-yl)aceto-1-one (35)

[0422]

[0423] Compound 35 was synthesized by procedures 1 and 5 in Example 28 to give a white solid (180.0 mg, 52% yield in 3 steps).

[0424] 1 H NMR (400MHz, CDCl3) δ9.36(brs,1H),7.88(s,1H),7.68(s,1H),7.59(d,J=5.4Hz,1H),7.12(d,J=3.6Hz,1H),6.58(d,J=3.6Hz,1H),5.11-4.80(m,1 H),4.76-4.51(m,2H),4.45-4.20(m,3H),3.99(m,1H),3.41-3.22(m,1H), 3.00-2.78(m,1H),2.48-2.25(m,2H),2.19(d,J=2.4Hz,3H),1.28(m,6H).

[0425] LCMS: m / z 385.2 [M+1] + .

[0426] Example 39: Synthesis of 1-((3S,4S)-4-(4-(4-(cyclopropylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)aceto-1-one (36)

[0427]

[0428] Compound 36 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (160.0 mg, 46% yield in 3 steps).

[0429] 1 H NMR (400MHz, CDCl3) δ9.46(brs,1H),7.88(s,1H),7.65(s,1H),7.55(d,J=4.1Hz,1H),7.11(d,J=3.6Hz,1H),7.01(d,J=3.6Hz,1H),5.13-4.57( m,3H),4.44-3.94(m,2H),3.41-3.21(m,1H),3.06-2.77(m,2H),2.44-2 .22(m,2H),2.18(d,J=3.4Hz,3H),0.95-0.87(m,2H),0.74-0.66(m,2H).

[0430] LCMS: m / z 383.2 [M+1] + .

[0431] Example 40: Synthesis of 1-((3S,4S)-3-fluoro-4-(4-(4-((((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethyl-1-one (37)

[0432]

[0433] Compound 37 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (160.0 mg, 46% yield in 3 steps).

[0434] 1H NMR(400MHz, CDCl3)δ9.26(brs,1H),7.91(s,1H),7.71(s,1H),7.63(d,J=5 .6Hz,1H),7.12(d,J=3.7Hz,1H),6.61(d,J=3.7Hz,1H),5.11-4.56(m,3H), 4.45-3.95(m,2H),3.84(m,2H),3.67-3.58(m,2H),3.41-3.36(m,3H),3.36 -3.22(m,1H),3.01-2.79(m,1H),2.44-2.25(m,2H),2.19(d,J=3.3Hz,3H).

[0435] LCMS:m / z 401.2[M+1] + .

[0436] Example 41: Synthesis of 1-((3S,4S)-4-(4-(4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)aceto-1-one (38)

[0437]

[0438] Compound 38 was synthesized by procedures 1 and 5 in Example 28 and was obtained as a white solid (148.0 mg, 55% yield in 3 steps).

[0439] 1 H NMR (400MHz, CDCl3) δ9.33(brs,1H),7.89(s,1H),7.69(s,1H),7.59(d,J=5.3Hz,1H),7.12(d,J=3.5Hz,1H),6.65(d,J=3.1Hz,1H),5.21-4.59(m,3H ),4.57-3.93(m,3H),3.45-3.21(m,1H),3.03-2.76(m,1H),2.50-2.26(m, 2H),2.20(s,3H),2.14-1.98(m,2H),1.89-1.72(m,4H),1.62-1.47(m,2H).

[0440] LCMS:m / z 411.2[M+1] + .

[0441] Example 42: Synthesis of 1-((3S,4S)-3-fluoro-4-(5-methyl-4-(4-(methylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl-1H-pyrazol-1-yl)piperidin-1-yl)aceto-1-one (39)

[0442]

[0443] Compound 39 was synthesized by procedures 1 and 5 in Example 28, yielding a yellow solid (133.0 mg, 31% yield in 3 steps).

[0444] 1 HNMR(400MHz,DMSO-d6)δ11.22-11.10(m,1H),7.53-7.51(m,1H),7.46-7.44(m,1H),7.12-7.08(m,1H),6.68-6.63(m,1H),5.31 -5.20(m,1H),5.08-4.36(m,3H),4.29-3.81(m,1H),3.33-3.25(m,1H),3.13-3.07(m,3H),2.97-2.79(m,1H),2.15-1.91(m,8H).

[0445] LCMS: m / z 371.2 [M+1] + .

[0446] Example 43: Synthesis of 1-((3S,4S)-4-(4-(4-(ethylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)ethyl-1-one (40)

[0447]

[0448] Compound 40 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (70.0 mg, 3-step yield of 26%).

[0449] 1H NMR(400MHz, CDCl3)δ9.45(brs,1H),7.79(s,1H),7.56(s,1H),7.11(d,J= 3.5Hz,1H),6.65(d,J=3.7Hz,1H),5.16-4.64(m,2H),4.42-4.23(m,3H),4. 01(d,J=12.3Hz,1H),3.69(m,2H),3.42-3.20(m,1H),2.98-2.72(m,1H),2. 57-2.29(m,1H),2.22(s,3H),2.19(d,J=2.1Hz,3H),1.26(t,J=7.2Hz,3H).

[0450] LCMS: m / z 385.2 [M+1] + .

[0451] Example 44: Synthesis of 1-((3S,4S)-3-fluoro-4-(4-(4-(isopropylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)aceto-1-one (41)

[0452]

[0453] Compound 41 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (65.0 mg, 23% yield in 3 steps).

[0454] 1 H NMR (400MHz, CDCl3) δ9.38(brs,1H),7.80(s,1H),7.55(s,1H),7.12(d,J=3.5Hz,1H),6.58(d,J=3.7Hz,1H),5.13-4.66(m,2H),4.4 0-4.21(m,4H),4.05-3.98(m,1H),3.40-3.22(m,1H),2.94-2.77(m,1H),2.59-2.31(m,1H),2.21(s,3H),2.19(s,3H),1.24(m,6H).

[0455] LCMS: m / z 399.2 [M+1] + .

[0456] Example 45: Synthesis of 1-((3S,4S)-4-(4-(4-(cyclopropylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)aceto-1-one (42)

[0457]

[0458] Compound 42 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (74.0 mg, 25% yield in 3 steps).

[0459] 1 HNMR(400MHz, CDCl3)δ9.49(brs,1H),7.79(s,1H),7.52(s,1H),7.12(d,J=3.5Hz,1H),7.00(d,J=3.7Hz,1H),5.14-4.64(m,3H) ,4.38-3.97(m,2H),3.40-3.22(m,1H),3.04-2.77(m,2H),2.57-2.28(m,1H),2.19(m,7H),0.92-0.86(m,2H),0.69-0.63(m,2H).

[0460] LCMS: m / z 397.2 [M+1] + .

[0461] Example 46: Synthesis of 1-((3S,4S)-3-fluoro-4-(4-(4-((((2-methoxyethyl)amino)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)aceto-1-one (43)

[0462]

[0463] Compound 43 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (92.0 mg, 31% yield in 3 steps).

[0464] 1 HNMR (400MHz, CDCl3) δ9.45(brs,1H),7.82(s,1H),7.56(s,1H),7.12(d,J=3.7Hz,1H),6.61(d,J=3.5Hz,1H),5.17-4.61(m,3H),4. 44-3.96(m,2H),3.90-3.74(m,2H),3.67-3.53(m,2H),3.45-3.21(m,4H),2.99-2.76(m,1H),2.63-2.29(m,1H),2.28-2.12(m,7H).

[0465] LCMS: m / z 415.2 [M+1] + .

[0466] Example 47: Synthesis of 1-((3S,4S)-4-(4-(4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)ethyl-1-one (44)

[0467]

[0468] Compound 44 was synthesized by procedures 1 and 5 in Example 28, yielding a white solid (55.0 mg, 3-step yield of 18%).

[0469] 1 HNMR (400MHz, CDCl3) δ9.39(brs,1H),7.79(s,1H),7.54(s,1H),7.12(d,J=3.5Hz,1H),6.63(d,J=3.7Hz,1H),5.14-4.66(m,2H),4.5 1-3.98(m,4H),3.40-3.22(m,1H),2.94-2.75(m,1H),2.60-2.31(m,1H),2.20(d,J=6.8Hz,7H),1.75-1.60(m,6H),1.55-1.42(m,2H).

[0470] LCMS: m / z 425.2 [M+1] + .

[0471] Example 48: Synthesis of 1-((3S,4S)-4-(5-chloro-4-(4-(methylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)ethyl-1-one (45)

[0472]

[0473] Compound 45 was synthesized by procedures 2 and 5 in Example 28 to obtain a compound as a yellow solid (101.0 mg, 37% yield in 3 steps).

[0474] 1HNMR(400MHz, CDCl3)δ13.71(brs,1H),8.65-8.61(m,1H),7.71-7.66(m,1H),7.61-7.56(m,1H),7.23-7.19(m,1H),6.82-6.77(m,1H),5.36-5 .27(m,1H),5.18-4.78(m,2H),4.72-4.62(m,1H),4.35-3.97(m,1H),3. 42(d,J=5.3Hz,3H),3.39(s,1H),2.94-2.77(m,1H),2.40-2.15(m,5H).

[0475] LCMS:m / z 391.1[M+1] + .

[0476] Example 49: Synthesis of (4-(4-(methylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)phenyl)(morpholinyl)methyl ketone (46)

[0477]

[0478] Compound 46 was synthesized via procedures 3 and 4 in Example 28, and was obtained as a grayish-white solid (47.43 mg, 19% yield in 3 steps). Compound 46 was isolated as a formate.

[0479] 1 HNMR(400MHz,DMSO-d6)δ11.23(s,1H),8.15(s,1H),7.61(s,1H),7.48-7.42(m,4H),7.13 -7.13(m,1H),6.70-6.70(m,1H),5.66-5.65(m,1H),3.54-3.45(m,8H),3.08-3.06(m,3H).

[0480] LCMS: m / z 336.9 [M+1] + .

[0481] Example 50: Synthesis of (4-(4-(ethylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)phenyl)(morpholinyl)methyl ketone (47)

[0482]

[0483] Compound 47 was synthesized via procedures 3 and 4 in Example 28 and was obtained as a grayish-white solid (47.43 mg, 19% yield in 3 steps). The hydrochloride salt (HCl salt) of compound 47 was isolated.

[0484] 1 HNMR(400MHz,DMSO-d6)δ14.06(s,1H),12.41(s,1H),7.75(s,1H),7.57-7.54(m,2H),7.50-7.48(m,2H) ,7.38-7.37(m,1H),7.29(m,1H),6.89-6.89(m,1H),3.62(m,8H),3.50-3.47(m,2H),1.23-1.19(m,3H).

[0485] LCMS: m / z 351.2 [M+1] + .

[0486] Example 51: Synthesis of (4-(4-(isopropylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)phenyl)(morpholinyl)methyl ketone (48)

[0487]

[0488] Compound 48 was synthesized using procedures 3 and 4 in Example 28, yielding a yellow solid (14.69 mg, 16% yield in 3 steps). Compound 48 was isolated as an HCl salt.

[0489] 1 HNMR (400MHz, DMSO-d6) δ14.25 (s, 1H), 12.49 (s, 1H), 7.75 (s, 1H), 7.57-7.52 (m, 4H), 7.51-7.38 (m, 1H), 6.89 (m, 1H), 6.69-6.67 (m, 1H), 4.37-4.37 (m, 1H), 3.62-3.47 (m, 8H), 1.25-1.23 (m, 6H).

[0490] LCMS: m / z 365.5 [M+1] + .

[0491] Example 52: Synthesis of (4-(4-(cyclopropylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)phenyl)(morpholinyl)methyl ketone (49)

[0492]

[0493] Compound 49 was synthesized by procedures 3 and 4 in Example 28, yielding a white solid (13.80 mg, 8% yield in 3 steps).

[0494] 1HNMR(400MHz, CDCl3)δ9.1(s,1H),7.84(s,1H),7.52-7.50(m,2H),7.48-7.44(m,2H),7.13-7.12(m,1H),7. 04-7.03(m,1H),4.889(s,1H),3.75-3.65(m,8H),3.01-2.99(m,1H),0.91-0.88(m,2H),0.69-0.65(m,2H).

[0495] LCMS:m / z 363.3[M+1] + .

[0496] Example 53: Synthesis of (4-(4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholinyl) ketone (50)

[0497]

[0498] Compound 50 was synthesized by procedures 3 and 4 in Example 28, yielding a yellow solid (56.46 mg, 3-step yield of 28%).

[0499] 1 HNMR(400MHz,DMSO-d6)δ11.31(s,1H),7.67(s,1H),7.51-7.45(m,4H),7.19(m, 1H),6.59-6.58(m,1H),5.35-5.32(m,1H),3.63-3.55(m,12H),3.5-3.21(m,3H).

[0500] LCMS:m / z 381.0[M+1] + .

[0501] Example 54: Synthesis of 4-(4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)phenyl)(morpholinyl)methyl ketone (51)

[0502]

[0503] Compound 51 was synthesized by procedures 3 and 4 in Example 28 and obtained as a pink solid (26.81 mg, 3-step yield of 14%).

[0504] 1H NMR (400MHz, CDCl3) δ8.98-8.82(m,1H),7.84(s,1H),7.59-7.46(m,4H),7.14(m,1H),6.67(m, 1H),4.60-4.43(m,2H),4.02-3.55(m,8H),2.15-1.96(m,2H),1.67(s,4H),1.56-1.47(m,2H).

[0505] LCMS: m / z 391.2 [M+1] + .

[0506] Example 55: Synthesis of (4-(4-(methylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (52)

[0507]

[0508] Compound 52 was synthesized using procedures 3 and 4 in Example 28, yielding a yellow solid (86.0 mg, 21% yield in 3 steps). Compound 52 was isolated as a formate.

[0509] 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),8.15(s,2H),7.62(s,1H),7.47–7.40(m,4H),7.14(d,J=3.6Hz,1H),6.71(d,J=3.6Hz,1H),5.72-5.65( m,1H),4.55-4.25(m,4H),3.90-3.68(m,4H),3.59-3.56(m,4H),3.08(d,J=5.2Hz,3H),2.84(brs,1H),1.94-1.71(m,2H),1.47-1.30(m,2H).

[0510] LCMS:m / z 420.0[M+1] + .

[0511] Example 56: Synthesis of (4-(4-(ethylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (53)

[0512]

[0513] Compound 53 was synthesized using procedures 3 and 4 in Example 28, yielding a yellow solid (43.24 mg, 17% yield in 3 steps). Compound 53 was isolated as an HCl salt.

[0514] 1 H NMR(400MHz,DMSO-d6)δ14.00(s,1H),12.44-12.27(m,1H),7.78(s,1H),7.56-7.49(m,4H),7.40-7.37(m,1H),7.35-7.29(m,1H),6.92-6.88(m ,1H),4.05-3.81(m,8H),3.80-3.72(m,2H),3.16-2.98(m,4H),2.90-2. 77(m,1H),2.25-2.09(m,2H),1.78-1.68(m,2H),1.22(t,J=6.8Hz,3H).

[0515] LCMS:m / z 434.3[M+1] + .

[0516] Example 57: Synthesis of (4-(4-(isopropylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (54)

[0517]

[0518] Compound 54 was synthesized using procedures 3 and 4 in Example 28, yielding a yellow solid (135.0 mg, 36% yield in 3 steps). Compound 54 was isolated as an HCl salt.

[0519] 1 H NMR(400MHz,DMSO-d6)δ14.32(s,1H),12.52(s,1H),11.93(s,1H),7.77(s,1H),7.57-7 .52(m,4H),7.41-7.37(m,1H),6.92-6.86(m,1H),6.78-6.66(m,1H),4.75-4.54(m,1H), 4.46-4.30(m,1H),3.98-3.92(m,4H),3.90-3.64(m,1H),3.53-3.35(m,3H),3.20-3.02 (m,3H),2.93-2.75(m,1H),2.29-2.06(m,2H),1.84-1.67(m,2H),1.25(d,J=6.0Hz,6H).

[0520] LCMS: m / z 448.4 [M+1] + .

[0521] Example 58: Synthesis of (4-(4-(cyclopropylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (55)

[0522]

[0523] Compound 55 was synthesized using procedures 3 and 4 in Example 28, yielding a yellow solid (135.0 mg, 36% yield in 3 steps). Compound 55 was isolated as an HCl salt.

[0524] 1 H NMR(400MHz,DMSO-d6)δ14.32(s,1H),12.47(s,1H),11.83(s,1H),7.78(s,1H),7.53-7.46(m,4H),7.39 -7.35(m,1H),7.24-7.21(m,1H),4.77-4.51(m,1H),4.05-3.70(m,6H),3.51-3.38(m,3H),3.16-3.01(m 4H),2.92-2.72(m,1H),2.30-2.05(m,2H),1.82-1.68(m,2H),0.95-0.81(m,2H),0.78-0.71(m,2H).

[0525] LCMS: m / z 446.4 [M+1] + .

[0526] Example 59: Synthesis of (4-(4-(((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (56)

[0527]

[0528] Compound 56 was synthesized using procedures 3 and 4 in Example 28, yielding a yellow solid (22.63 mg, 8% yield in 3 steps). Compound 56 was isolated as an HCl salt.

[0529] 1H NMR (400MHz, MeOH-d4) δ = 7.75 (s, 1H), 7.68-7.62 (m, 2H), 7.61-7.56 (m, 2H), 7.34(m,1H),6.98(m,J=4.0Hz,1H),4.14-4.06(m,2H),3.95-3.85(m,4H),3. 65(t,J=4.8Hz,2H),3.62-3.50(m,3H),3.35-3.33(m,3H),3.32-3.31(m,2H) ,3.30-3.17(m,3H),3.06-2.90(m,1H),2.48-2.14(m,2H),1.94-1.69(m,2H).

[0530] LCMS: m / z 464.4 [M+1] + .

[0531] Example 60: Synthesis of (4-(4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (57)

[0532]

[0533] Compound 57 was synthesized using procedures 3 and 4 in Example 28, yielding a white solid (76.0 mg, 39% yield in 3 steps). Compound 57 was isolated as a formate.

[0534] 1 H NMR(400MHz,DMSO-d6)δ11.31(brs,1H),8.15(s,2H),7.68(s,1H),7.47(m,4H),7.20(brs,1H),6.63(m,1H),4.87(m,1 H),4.60-4.36(m,1H),4.35-4.19(m,1H),3.81-3.50(m,8H),3.15-2.99(m,4H),1.98-1.71(m,4H),1.65-1.32(m,8H).

[0535] LCMS: m / z 474.2 [M+1] + .

[0536] Example 61: Synthesis of (3-methoxy-4-(4-(methylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)phenyl)(morpholinyl) methyl ketone (58)

[0537]

[0538] Compound 58 was synthesized via procedures 3 and 4 in Example 28 and was obtained as a light brown solid (65.0 mg, 29% yield in 3 steps). Compound 58 was isolated as a formate.

[0539] 1 H NMR (400MHz, DMSO-d6) δ11.19(s,1H),8.15(s,1H),7.50(s,1H),7.20(d,J=7.6Hz,1H),7.11(d,J=3.6Hz,1H),7.08(d,J= 1.2Hz,1H),7.02(m,1H),6.67(d,J=3.6Hz,1H),5.20-5.34(m,1H),3.74(s,3H),3.54-3.71(m,8H),3.04(d,J=5.2Hz,3H).

[0540] LCMS: m / z 367.4 [M+1] + .

[0541] Example 62: Synthesis of (4-(4-(ethylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)-3-methoxyphenyl)(morpholinyl) methyl ketone (59)

[0542]

[0543] 1 H NMR (400MHz, CDCl3) δ14.51-14.31(m,1H),11.87-11.69(m,1H),7.59-7.51(m,1H),7.27-7.24(m,1H),7.22- 7.18(m,1H),7.16-7.08(m,2H),6.75-6.69(m,1H),5.16-5.09(m,1H),3.97-3.45(m,13H),1.38-1.27(m,3H).

[0544] LCMS:m / z 381.1[M+1] + .

[0545] Example 63: Synthesis of (4-(4-(isopropylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)-3-methoxyphenyl)(morpholinyl) methyl ketone (60)

[0546]

[0547] Compound 60 was synthesized using procedures 3 and 4 in Example 28, yielding a yellow solid (33.58 mg, 11% yield in 3 steps). Compound 60 was isolated as an HCl salt.

[0548] 1 H NMR (400MHz, DMSO-d6) δ14.13(s,1H),12.46(s,1H),7.68(s,1H),7.39-7.33(m,2H),7.17-7.14(m,1H),7.13-7.09(m ,1H),6.90-6.84(m,1H),6.54-6.27(m,1H),4.47-4.30(m,1H),3.79(s,3H),3.72-3.41(m,8H),1.23(t,J=6.8Hz,6H).

[0549] LCMS: m / z 395.3 [M+1] + .

[0550] Example 64: Synthesis of (4-(4-(cyclopropylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)-3-methoxyphenyl)(morpholinyl) methyl ketone (61)

[0551]

[0552] Compound 61 was synthesized by procedures 3 and 4 in Example 28, yielding a white solid (32.69 mg, 15% yield in 3 steps).

[0553] 1 H NMR (400MHz, CDCl3) δ9.13(s,1H),7.80(s,1H),7.29(s,1H),7.13-7.10(m,1H),7.09-7.08(m,1H),7.06-7.03(m,1H),7.02-6.99(m,1H),4.53(br s,1H),3.92-3.64(m,11H),3.05-2.98(m,1H),0.92-0.81(m,2H),0.69-0.59(m,2H).

[0554] LCMS: m / z 393.2 [M+1] + .

[0555] Example 65: Synthesis of (3-methoxy-4-(4-(((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholinyl) ketone (62)

[0556]

[0557] Compound 62 was synthesized by procedures 3 and 4 in Example 28, yielding a white solid (37.02 mg, 3-step yield of 18%).

[0558] 1 H NMR (400MHz, CDCl3) δ14.41-14.25(m,1H),11.94-11.81(m,1H),7.61(m,1H),7.27-7.24(m,1H),7.21(brs,1H) ,7.14-7.07(m,2H),6.71-6.67(m,1H),5.77-5.50(m,1H),3.98-3.66(m,12H),3.60(m,3H),3.34-3.30(m,3H).

[0559] LCMS:m / z 411.1[M+1] + .

[0560] Example 66: Synthesis of (4-(4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)-3-methoxyphenyl)(morpholinyl) methyl ketone (63)

[0561]

[0562] Compound 63 was synthesized via procedures 3 and 4 in Example 28 to obtain a white solid (21.0 mg, 7% yield in 3 steps). Compound 63 was isolated as an HCl salt.

[0563] 1 H NMR(400MHz, CDCl3)δ14.32(s,1H),11.90-11.68(m,1H),7.64-7.49(m,1H),7.27-7.19(m,2H),7.17-7.07(m,2H), 6.74-6.66(m,1H),5.15-5.04(m,1H),4.57-4.47(m,1H),3.92-3.47(m,11H),2.20-1.95(m,2H),1.77-1.45(m,6H).

[0564] LCMS:m / z 421.1[M+1] + .

[0565] Example 67: Synthesis of (3-methoxy-4-(4-(methylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (64)

[0566]

[0567] Compound 64 was synthesized using procedures 3 and 4 in Example 28, yielding a yellow solid (190.0 mg, 34% yield in 3 steps). Compound 64 was isolated as a formate.

[0568] 1 H NMR (400MHz, DMSO-d6) δ11.28(s,1H),8.16(s,2H),7.51(s,1H),7.19(d,J=7.6Hz, 1H),7.12(d,J=3.6Hz,1H),7.04-7.08(m,1H),7.00(dd,J=7.6,1.6Hz,1H),6.68(d ,J=3.6Hz,1H),5.48-5.38(m,1H),4.89-4.26(m,8H),3.74(s,3H),3.66-3.61(m,4 H),3.05(d,J=4.4Hz,3H),2.98-2.84(m,1H),2.00–1.79(m,2H),1.53-1.39(m,2H).

[0569] LCMS:m / z 450.0[M+1] + .

[0570] Example 68: Synthesis of (4-(4-(ethylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-3-methoxyphenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (65)

[0571]

[0572] Compound 65 was synthesized by procedures 3 and 4 in Example 28 and was obtained as a pale yellow solid (10.83 mg, 5% yield in 3 steps).

[0573] 1 H NMR(400MHz, CDCl3)δ7.75(brs,1H),7.32-7.29(m,2H),7.15-7.04(m,3H ),6.68(m,1H),4.91-4.60(m,1H),4.32(m,1H),4.09-3.90(m,1H),3.82(s ,3H),3.79-3.73(m,4H),3.70(m,2H),3.25-2.82(m,2H),2.65-2.56(m,4 H),2.50(m,1H),2.08-1.91(m,2H),1.63-1.49(m,2H),1.31-1.21(m,3H).

[0574] LCMS: m / z 464.2 [M+1]+ .

[0575] Example 69: Synthesis of (4-(4-(isopropylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-3-methoxyphenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (66)

[0576]

[0577] Compound 66 was synthesized using procedures 3 and 4 in Example 28, yielding 95.0 mg of a yellow solid, with a 3-step yield of 25%. Compound 66 was isolated as an HCl salt.

[0578] 1 H NMR(400MHz,DMSO-d6)δ14.13(s,1H),12.45(s,1H),11.89(s,1H),7.70(s,1H),7.39 -7.34(m,2H),7.15(s,1H),7.12-7.08(m,1H),6.90-6.85(m,1H),6.56-6.29(m,1H), 4.48-4.26(m,2H),4.04-3.85(m,5H),3.80(s,3H),3.53-3.36(m,3H),3.20-3.00(m, 3H),2.91-2.73(m,1H),2.30-2.07(m,2H),1.86-1.70(m,2H),1.23(t,J=7.2Hz,6H).

[0579] LCMS: m / z 478.4 [M+1] + .

[0580] Example 70: Synthesis of (3-methoxy-4-(4-(((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholinyl) ketone (67)

[0581]

[0582] Compound 67 was synthesized using procedures 3 and 4 in Example 28, yielding a yellow solid (23.06 mg, 6% yield in 3 steps). Compound 67 was isolated as a TFA salt.

[0583] 1H NMR(400MHz,MeOH-d4)δ7.62(s,1H),7.38-7.34(m,1H),7.31-7.25(m,2H),7.17-7. 15(m,1H),7.15-7.11(m,1H),4.19-3.96(m,3H),3.96-3.84(m,2H),3.82(s,3H),3.6 0-3.51(m,2H),3.36-3.30(m,3H),3.29-3.17(m,2H),3.14-3.05(m,1H),3.02-2.84 (m,1H),2.41-2.12(m,2H),1.87-1.73(m,2H),1.08-0.91(m,2H),0.77-0.69(m,2H).

[0584] LCMS: m / z 476.3 [M+1] + .

[0585] Example 71: Synthesis of (3-methoxy-4-(4-(((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (68)

[0586]

[0587] Compound 68 was synthesized by procedures 3 and 4 in Example 28, yielding a yellow solid (42.0 mg, 21% yield in 3 steps).

[0588] 1 H NMR (400MHz, CDCl3) δ8.89-8.83(m,1H),7.85-7.82(m,1H),7.32-7.28(m,1H),7.12-7 .04(m,3H),6.65-6.61(m,1H),4.85-4.68(m,1H),4.65-4.59(m,1H),4.08-3.90(m,1H) ,3.83-3.77(m,5H),3.77-3.73(m,4H),3.61-3.51(m,2H),3.33-3.31(m,3H),3.20-2. 79(m,2H),2.61-2.57(m,4H),2.53-2.43(m,1H),2.10-1.80(m,2H),1.59-1.41(m,2H).

[0589] LCMS: m / z 494.2 [M+1] + .

[0590] Example 72: Synthesis of (4-(4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-3-methoxyphenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (69)

[0591]

[0592] Compound 69 was synthesized using procedures 3 and 4 in Example 28, yielding a white solid (45.0 mg, 18% yield in 3 steps). Compound 69 was isolated as a formate.

[0593] 1 H NMR (400MHz, CDCl3) δ13.70(brs,1H),8.46(s,2H),7.56(s,1H),7.25-7.19(m,2H),7.14-7.03(m,2H),6.66(d,J=3.5Hz,1H),5.01-4.88(m ,1H),4.84-4.66(m,1H),4.61-4.46(m,1H),4.04-3.68(m,8H),3.23- 2.78(m,2H),2.74-2.56(m,5H),2.16-1.89(m,4H),1.76-1.42(m,8H).

[0594] LCMS:m / z 504.3[M+1] + .

[0595] Example 73: General method for synthesizing compounds 70 to 113

[0596]

[0597] Procedure 6: Add NCS (1.2 equivalents) to a solution of compound X (1 equivalent) in CH3CN (0.1 M to 0.2 M). Stir the mixture at 80 °C for 5 hours. Cool the mixture to room temperature, concentrate under vacuum, and then purify by reversed-phase HPLC to obtain the desired product.

[0598] Procedure 7: Add NCS (1.2 equivalents) to a solution of compound X (1 equivalent) in THF (0.1 M to 0.2 M). Stir the mixture at room temperature for 2 hours. Concentrate the mixture under vacuum and then purify it by reversed-phase HPLC to obtain the desired product.

[0599]

[0600] Procedure 8: Add NCS (1.2 equivalents) to a solution of intermediate int-42 (see Example 28) (1 equivalent) in CH3CN (0.1 M to 0.2 M). Stir the mixture at 80 °C for 5 hours. Cool the mixture to room temperature, concentrate under vacuum, and then purify by reversed-phase HPLC to obtain intermediate int-43.

[0601] Add HCl / dioxane (4M, 2 mL, 15 to 20 equivalents) to a solution of int-43 (1 equivalent) in DCM (0.1 M to 0.2 M). Stir the mixture at 30 °C for 4 hours. Monitor the reaction by LCMS. Concentrate the mixture under vacuum. Dissolve the resulting residue in EtOH (0.1 M to 0.2 M) and treat with NH3·H2O (28% purity, 40 to 50 equivalents). Stir the reaction at 60 °C for 2 hours. Concentrate the crude mixture under vacuum and purify by reversed-phase HPLC to obtain the desired product.

[0602] Example 74: Synthesis of 3-chloro-5-(1-(((3S,4S)-3-fluoro-1-(oxetanebut-3-yl)piperidinbut-4-yl)-1H-pyrazol-4-yl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine (70)

[0603]

[0604] Compound 70 was synthesized by procedure 6 in Example 73 to obtain a compound as a yellow solid (13.0 mg, 13% yield in one step).

[0605] 1 H NMR (400MHz, DMSO-d6) δ11.61(brs,1H),7.93(s,1H),7.68(s,1H),7.79(s,1H),7.61(d,J=3.7Hz,1H),7.32(s,1H),5.49-5.45(m ,1H),4.58-4.44(m,5H),3.60–3.59(m,1H),3.31–3.28(m,1H),2.64-2.63(d,J=5.6Hz,1H),2.52-2.49(m,3H),2.07-2.03(m,4H).

[0606] LCMS:m / z 405.1[M+1] + .

[0607] Example 75: Synthesis of 3-chloro-N-ethyl-5-(1-(((3S,4S)-3-fluoro-1-(oxetanebut-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine (71)

[0608]

[0609] Compound 71 was synthesized by procedure 7 in Example 73 and obtained as a white solid (25.57 mg, 36% yield in one step).

[0610] 1 H NMR(400MHz, CDCl3)δ9.95(brs,1H),7.96(s,1H),7.69(s,1H),7.61(s,1H), 7.07(s,1H),5.26(t,J=4.9Hz,1H),5.04-4.84(m,1H),4.74-4.61(m,4H),4.1 9(m,1H),3.67(m,1H),3.26-3.19(m,1H),3.06-2.96(m,2H),2.92-2.85(m,1 H),2.46-2.34(m,1H),2.25(m,1H),2.17-2.05(m,2H),1.10(t,J=7.2Hz,3H).

[0611] LCMS: m / z 419.2 [M+1] + .

[0612] Example 76: Synthesis of 3-chloro-5-(1-((3S,4S)-3-fluoro-1-(oxetanebut-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-N-isopropyl-1H-pyrrolo[2,3-b]pyridine-4-amine (72)

[0613]

[0614] Compound 72 was synthesized by procedure 7 in Example 73 and obtained as a grayish-white solid (16.78 mg, 35% yield in one step).

[0615] 1 H NMR (400MHz, CDCl3) δ10.19(brs,1H),7.99(s,1H),7.73(s,1H),7.67(s,1H),7.09(s,1H),5.08-4.84(m,2H),4.75-4.61(m,4H),4.26- 4.15(m,1H),3.72-3.50(m,2H),3.27-3.19(m,1H),2.92-2.86(m,1H),2.47-2.34(m,1H),2.26(m,1H),2.18-2.05(m,2H),1.04(m,6H).

[0616] LCMS: m / z 433.2 [M+1] + .

[0617] Example 77: Synthesis of 3-chloro-N-cyclopropyl-5-(1-((3S,4S)-3-fluoro-1-(oxacyclobut-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine (73)

[0618]

[0619] Compound 73 was synthesized by procedure 7 in Example 73, yielding a yellow solid (14.06 mg, 19% yield in one step).

[0620] 1 H NMR (400MHz, CDCl3) δ10.05(brs,1H),7.94(s,1H),7.66(s,1H),7.56(s,1H),7.03(s,1H),5.85(m,1H),5.04-4.83(m,1H),4.73-4.61(m,4H),4. 24-4.12(m,1H),3.67(m,1H),3.26-3.17(m,1H),2.92-2.83(m,1H),2.4 5-2.33(m,2H),2.28-2.19(m,1H),2.17-2.00(m,2H),0.43-0.35(m,4H).

[0621] LCMS:m / z 431.1[M+1] + .

[0622] Example 78: Synthesis of 3-chloro-5-(1-((3S,4S)-3-fluoro-1-(oxetanebut-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-N-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridine-4-amine (74)

[0623]

[0624] Compound 74 was synthesized by procedure 7 in Example 73, yielding a yellow solid (21.0 mg, 52% yield in one step).

[0625] 1H NMR(400MHz, CDCl3)δ9.65(brs,1H),7.98(s,1H),7.70(s,1H),7.63(s,1H),7. 08(s,1H),5.77(t,J=5.5Hz,1H),5.06-4.83(m,1H),4.74-4.68(m,2H),4.64(m, 2H),4.26-4.10(m,1H),3.67(m,1H),3.45-3.38(m,2H),3.33(s,3H),3.26-3.0 8(m,3H),2.93-2.82(m,1H),2.48-2.32(m,1H),2.25(m,1H),2.17-2.03(m,2H).

[0626] LCMS: m / z 449.2 [M+1] + .

[0627] Example 79: Synthesis of 3-chloro-N-cyclopentyl-5-(1-((3S,4S)-3-fluoro-1-(oxacyclobut-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine (75)

[0628]

[0629] Compound 75 was synthesized by procedure 6 in Example 73 to obtain a yellow solid (15.03 mg, 1-step yield 25%).

[0630] Method A yielded 15.03 mg of a yellow solid in a 25% yield in one step.

[0631] 1 H NMR(400MHz, CDCl3)δ7.94(s,1H),7.70(s,1H),7.63(s,1H),7.06(s,1H) ,5.41(d,J=9.6Hz,1H),5.04-4.84(m,1H),4.74-4.62(m,4H),4.20(m,1H) ,3.81-3.60(m,2H),3.27-3.19(m,1H),2.93-2.84(m,1H),2.48-2.33(m,1 H),2.25(m,1H),2.17-2.04(m,2H),1.70-1.57(m,4H),1.51-1.37(m,4H).

[0632] LCMS: m / z 459.2 [M+1] + .

[0633] Example 80: Synthesis of 3-chloro-5-(1-((3S,4S)-3-fluoro-1-(oxetanebut-3-yl)piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine (76)

[0634]

[0635] Compound 76 was synthesized by procedure 7 in Example 73 and obtained as a grayish-white solid (22.68 mg, 1-step yield 25%).

[0636] 1 H NMR (400MHz, CDCl3) δ10.46(brs,1H),7.85(s,1H),7.57(s,1H),7.05(s,1H),5.57(m,1H),5.14-4.91(m,1H),4.75- 4.62(m,4H),4.16-4.05(m,1H),3.69(m,1H),3.27-3.19(m,1H),2.94-2.86(m,1H),2.60(m,4H),2.21-2.01(m,6H).

[0637] LCMS: m / z 419.2 [M+1] + .

[0638] Example 81: Synthesis of 1-((3S,4S)-4-(4-(3-chloro-4-(methylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)aceto-1-one (77)

[0639]

[0640] Compound 77 was synthesized via procedure 6 in Example 73 and obtained as a brown oil (26.48 mg, 43% yield in one step).

[0641] Method A yielded 11.23 mg of a yellow solid in a 15% yield in one step.

[0642] 1H NMR (400MHz, CDCl3) δ10.07(brs,1H),7.95(s,1H),7.69(s,1H),7.60(d,J=3.5Hz,1H),7.07(s,1H),5.31-4.58(m,3H),4 .42-3.95(m,2H),3.44-3.17(m,1H),3.07-2.74(m,3H),2.46-2.23(m,2H),2.19(d,J=2.9Hz,3H),1.11(t,J=7.2Hz,3H).

[0643] LCMS:m / z 405.1[M+1] + .

[0644] Example 82: Synthesis of 1-((3S,4S)-4-(4-(3-chloro-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)ethyl-1-one (78)

[0645]

[0646] Compound 78 was synthesized by procedure 6 in Example 73, yielding a yellow solid (11.23 mg, 15% yield in one step).

[0647] 1 H NMR (400MHz, CDCl3) δ10.07(brs,1H),7.95(s,1H),7.69(s,1H),7.60(d,J=3.5Hz,1H),7.07(s,1H),5.31-4.58(m,3H),4 .42-3.95(m,2H),3.44-3.17(m,1H),3.07-2.74(m,3H),2.46-2.23(m,2H),2.19(d,J=2.9Hz,3H),1.11(t,J=7.2Hz,3H).

[0648] LCMS:m / z 405.1[M+1] + .

[0649] Example 83: Synthesis of 1-((3S,4S)-4-(4-(3-chloro-4-(isopropylamino))-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)ethyl-1-one (79)

[0650]

[0651] Compound 79 was synthesized by procedure 7 in Example 73 to obtain a yellow solid (50.02 mg, 1-step yield 27%).

[0652] 1 H NMR (400MHz, CDCl3) δ10.12(brs,1H),7.97(s,1H),7.73(s,1H),7.66(d,J=3.8Hz,1H),7.09(s,1H),5.10-4.59(m,3H),4.43- 3.93(m,2H),3.53(m,1H),3.40-3.22(m,1H),2.98-2.76(m,1H),2.43-2.24(m,2H),2.19(d,J=2.7Hz,3H),1.08-1.02(m,6H).

[0653] LCMS:m / z 419.1[M+1] + .

[0654] Example 84: Synthesis of 1-((3S,4S)-4-(4-(3-chloro-4-(cyclopropylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl) ethyl-1-one (80)

[0655]

[0656] Compound 80 was synthesized by procedure 7 in Example 73, yielding a yellow solid (22.29 mg, 13% yield in one step).

[0657] 1 H NMR (400MHz, CDCl3) δ9.98(brs,1H),7.93(s,1H),7.66(s,1H),7.55(d,J=2.2Hz,1H),7.03(s,1H),5.86(s,1H),5.12-4.61( m,2H),4.42-3.94(m,2H),3.40-3.19(m,1H),2.95-2.74(m,1H),2.41-2.22(m,3H),2.18(d,J=2.1Hz,3H),0.45-0.33(m,4H).

[0658] LCMS:m / z 417.1[M+1] + .

[0659] Example 85: Synthesis of 1-((3S,4S)-4-(4-(3-chloro-4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)ethyl-1-one (81)

[0660]

[0661] Compound 81 was synthesized by procedure 7 in Example 73, yielding a yellow solid (35.0 mg, 1-step yield 39%).

[0662] 1 H NMR (400MHz, CDCl3) δ9.89 (brs, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.64 (d, J = 3.0Hz, 1H), 7.09 (s, 1H), 5.79 (s, 1H), 5. 19-4.58(m,2H),4.47-3.93(m,2H),3.45-3.12(m,8H),2.98-2.75(m,1H),2.46-2.24(m,2H),2.20(d,J=3.0Hz,3H).

[0663] LCMS: m / z 435.1 [M+1] + .

[0664] Example 86: Synthesis of 1-((3S,4S)-4-(4-(3-chloro-4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl) ethyl-1-one (82)

[0665]

[0666] Compound 82 was synthesized by procedure 6 in Example 73, yielding a yellow solid (14.9 mg, 10% yield in one step).

[0667] 1 H NMR(400MHz, CDCl3)7.93(s,1H),7.70(s,1H),7.62(d,J=3.1Hz,1H),7.06(s,1H),5.46-5.38(m,1H),5.14-4.59(m,2H),4.44-3.95(m ,2H),3.79-3.64(m,1H),3.41-3.21(m,1H),2.98-2.76(m,1H),2.47-2.22(m,2H),2.19(m,3H),1.70-1.56(m,4H),1.53-1.34(m,4H).

[0668] LCMS: m / z 445.2 [M+1] + .

[0669] Example 87: Synthesis of 1-((3S,4S)-4-(4-(3-chloro-4-(methylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)aceto-1-one (83)

[0670]

[0671] Compound 83 was synthesized by procedure 7 in Example 73, yielding a yellow solid (25.11 mg, yield 24% in one step).

[0672] 1 HNMR(400MHz,DMSO-d6)δ11.59(s,1H),7.65(s,1H),7.47(s,1H),7.31(s,1H),5.62 -5.51(m,1H),5.05-3.80(m,4H),2.96-2.71(m,1H),2.47(s,3H),2.14-1.98(m,8H).

[0673] LCMS:m / z 405.1[M+1] + .

[0674] Example 88: Synthesis of 1-((3S,4S)-4-(4-(3-chloro-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)ethyl-1-one (84)

[0675]

[0676] Compound 84 was synthesized by procedure 7 in Example 73, yielding a white solid (12.71 mg, 24% yield in one step).

[0677] 1HNMR(400MHz, CDCl3)δ10.17(brs,1H),7.84(s,1H),7.55(s,1H),7.06(s,1H),5.38(s,1H),5.14-4.66(m,2H),4.3 7-3.97(m,2H),3.39-3.20(m,1H),2.94-2.74(m,3H),2.59-2.30(m,1H),2.24-2.16(m,7H),1.06(t,J=7.2Hz,3H).

[0678] LCMS:m / z 419.1[M+1] + .

[0679] Example 89: Synthesis of 1-((3S,4S)-4-(4-(3-chloro-4-(isopropylamino))-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)ethyl-1-one (85)

[0680]

[0681] Compound 85 was synthesized by procedure 7 in Example 73 and obtained as a grayish-white solid (15.05 mg, 1-step yield 29%).

[0682] 1 HNMR(400MHz, CDCl3)δ10.36(brs,1H),7.86(s,1H),7.57(s,1H),7.08(s,1H),5.26-5.17(m,1H),5.14-4.66(m,2H),4 .37-3.96(m,2H),3.38-3.22(m,2H),2.92-2.74(m,1H),2.59-2.31(m,1H),2.20(d,J=13.6Hz,7H),1.03-0.94(m,6H).

[0683] LCMS:m / z 433.1[M+1] + .

[0684] Example 90: Synthesis of 1-((3R,4R)-4-(4-(3-chloro-4-(cyclopropylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)ethyl-1-one (86)

[0685]

[0686] Compound 86 was synthesized by procedure 7 in Example 73 and obtained as a grayish-white solid (14.91 mg, 20% yield in one step).

[0687] 1 HNMR(400MHz, CDCl3)δ9.95(brs,1H),7.84(d,J=1.9Hz,1H),7.56(s,1H),7.03(s,1H),5.87(s,1H),5.13-4.67(m,2H ),4.35-3.97(m,2H),3.37-3.21(m,1H),2.90-2.72(m,1H),2.57-2.29(m,1H),2.26-2.16(m,8H),0.44-0.24(m,4H).

[0688] LCMS:m / z 431.1[M+1] + .

[0689] Example 91: Synthesis of 1-((3S,4S)-4-(4-(3-chloro-4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)ethyl-1-one (87)

[0690]

[0691] Compound 87 was synthesized by procedure 7 in Example 73 and obtained as a grayish-white solid (16.90 mg, 19% yield in one step).

[0692] 1 HNMR(400MHz, CDCl3)δ10.11(brs,1H),7.85(s,1H),7.55(s,1H),7.07(s,1H),5.93-5.86(m,1H),5.15-4.66(m,2H),4.37-3 .96(m,2H),3.37(t,J=5.1Hz,2H),3.34-3.22(m,4H),2.99(m,2H),2.92-2.74(m,1H),2.59-2.29(m,1H),2.25-2.16(m,7H).

[0693] LCMS: m / z 449.1 [M+1] + .

[0694] Example 92: Synthesis of 1-((3S,4S)-4-(4-(3-chloro-4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl]-5-methyl-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl) ethyl-1-one (88)

[0695]

[0696] Compound 88 was synthesized by procedure 7 in Example 73 and obtained as a grayish-white solid (13.76 mg, 30% yield in one step).

[0697] 1 HNMR(400MHz, CDCl3)δ10.16(brs,1H),7.84(d,J=1.6Hz,1H),7.57(s,1H),7.06(s,1H),5.50(m,1H),5.14-4.66(m,2H),4.37- 3.98(m,2H),3.55-3.45(m,1H),3.38-3.22(m,1H),2.92-2.74(m,1H),2.59-2.30(m,1H),2.25-2.15(m,7H),1.63-1.31(m,8H).

[0698] LCMS: m / z 459.2 [M+1] + .

[0699] Example 93: Synthesis of 1-((3S,4S)-4-(5-chloro-4-(3-chloro-4-(methylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-3-fluoropiperidin-1-yl)aceto-1-one (89)

[0700]

[0701] Compound 89 was synthesized by procedure 7 in Example 73 and obtained as a grayish-white solid (19.37 mg, 1-step yield 25%).

[0702] 1 H NMR (400MHz, CDCl3) δ10.55(brs,1H),7.85(s,1H),7.67(s,1H),7.05(s,1H),5.71(m,1H),5.13-4.55 (m,3H),4.33-3.96(m,1H),3.44-3.22(m,1H),2.98-2.80(m,1H),2.64(d,J=5.5Hz,3H),2.19(m,5H).

[0703] LCMS: m / z 425.1 [M+1] + .

[0704] Example 94: Synthesis of (4-(3-chloro-4-(methylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)phenyl)(morpholinyl) methyl ketone (90)

[0705]

[0706] Compound 90 was synthesized by procedure 8 in Example 73 and obtained as a pink solid (32.0 mg, 14% yield in 2 steps).

[0707] 1 HNMR (400MHz, DMSO-d6) δ11.68(brs,1H),7.78(s,1H),7.46(s,4H),7.37(d,J=2.0Hz,1H),5.69(m,1H),3.73-3.44(m,8H),2.48(d,J=5.4Hz,3H).

[0708] LCMS:m / z 371.0[M+1] + .

[0709] Example 95: Synthesis of (4-(3-chloro-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)phenyl)(morpholinyl)methyl ketone (91)

[0710]

[0711] Compound 91 was synthesized by procedure 8 in Example 73 to obtain a yellow solid (21.0 mg, 7% yield in 2 steps).

[0712] 1 HNMR(400MHz, CDCl3)δ9.89-9.51(m,1H),7.84(s,1H),7.48-7.37(m,4H),7.00( s,1H),5.34(m,1H),3.86-3.47(m,8H),2.76-2.64(m,2H),0.98(t,J=7.2Hz,3H).

[0713] LCMS: m / z 385.2 [M+1] + .

[0714] Example 96: Synthesis of (4-(3-chloro-4-(isopropylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)phenyl)(morpholinyl)methyl ketone (92)

[0715]

[0716] Compound 92 was synthesized by procedure 8 in Example 73 to obtain a yellow solid (39.13 mg, 23% yield in 2 steps).

[0717] 1 HNMR (400MHz, CDCl3) δ9.92 (brs, 1H), 7.93 (d, J = 2.1Hz, 1H), 7.59-7.55 (m, 2H), 7.53-7.48 (m,2H),7.10(s,1H),5.20(m,1H),3.83-3.61(m,9H),3.23-3.21(m,1H),1.00-0.96(m,6H).

[0718] LCMS:m / z 399.1[M+1] +

[0719] Example 97: Synthesis of (4-(3-chloro-4-(cyclopropylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)phenyl)(morpholinyl)methyl ketone (93)

[0720]

[0721] Compound 93 was synthesized by procedure 8 in Example 73, yielding a yellow solid (22.36 mg, 2-step yield 15%).

[0722] 1 HNMR(400MHz, CDCl3)δ9.98(s,1H),8.00-7.87(m,1H),7.56-7.51(m,2H),7.48-7.43 (m,2H),7.10-7.01(m,1H),5.91(s,1H),3.74(m,8H),2.15(m,1H),0.39-0.21(m,4H).

[0723] LCMS:m / z 397.1[M+1] + .

[0724] Example 98: Synthesis of (4-(3-chloro-4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholinyl) methyl ketone (94)

[0725]

[0726] Compound 94 was synthesized by procedure 6 in Example 73 and obtained as a yellow solid (17.0 mg, 78% yield in one step).

[0727] 1 HNMR(400MHz, CDCl3)δ9.58(brs,1H),7.93(s,1H),7.57-7.43(m,4H),7.08(s,1H) ,5.97(m,1H),3.96-3.51(m,8H),3.36(m,2H),3.32(s,3H),2.91(q,J=5.2Hz,2H).

[0728] LCMS: m / z 415.2 [M+1] + .

[0729] Example 99: Synthesis of (4-(3-chloro-4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)phenyl)(morpholinyl) methyl ketone (95)

[0730]

[0731] Compound 95 was synthesized by procedure 8 in Example 73 to obtain a yellow solid (26.21 mg, 15% yield in 2 steps).

[0732] 1 H NMR (400MHz, CDCl3) δ9.82-9.68(m,1H),7.91-7.89(m,1H),7.57-7.53(m,2H),7.51-7.47(m,2H) ,7.09-7.07(m,1H),5.52-5.43(m,1H),3.97-3.55(m,8H),3.47-3.36(m,1H),1.56-1.33(m,8H).

[0733] LCMS: m / z 425.2 [M+1] + .

[0734] Example 100: Synthesis of (4-(3-chloro-4-(methylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (96)

[0735]

[0736] Compound 96 was synthesized by procedure 8 in Example 73 and obtained as a yellow solid (13.0 mg, 5% yield in 2 steps).

[0737] 1H NMR (400MHz, CDCl3) δ10.65-10.16(m,1H),7.93(s,1H),7.55-7.43(m,4H),7.07(s,1H),5.64(m,1H),4.91-4.61(m,1H),4.0 7-3.83(m,1H),3.78-3.72(m,4H),3.19-2.79(m,2H),2.68-2.53(m,7H),2.48(m,1H),2.07-1.84(m,2H),1.64-1.45(m,2H).

[0738] LCMS: m / z 454.3 [M+1] + .

[0739] Example 101: Synthesis of (4-(3-chloro-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (97)

[0740]

[0741] Compound 97 was synthesized by procedure 8 in Example 73 and obtained as a grayish-white solid (16.0 mg, 6% yield in 2 steps).

[0742] 1 H NMR(400MHz, CDCl3)δ9.89(brs,1H),7.93(s,1H),7.54-7.42(m,4H),7.08(s,1H),5.40(m,1H),4.89-4.54(m,1H),4.10-3.82(m ,1H),3.79-3.67(m,4H),3.19-2.85(m,4H),2.65-2.53(m,4H),2.48(m,1H),2.10-1.78(m,2H),1.58-1.42(m,2H),1.06(m,3H).

[0743] LCMS: m / z 468.2 [M+1] + .

[0744] Example 102: Synthesis of (4-(3-chloro-4-(isopropylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (98)

[0745]

[0746] Compound 98 was synthesized by procedure 8 in Example 73 to obtain a white solid (24.48 mg, 2-step yield 9%).

[0747] 1 H NMR(400MHz, CDCl3)δ10.09(brs,1H),7.93(s,1H),7.58-7.53(m,2H),7.51-7.46(m,2H),7.10(s,1H),5.19(m,1H),4.92-4.61(m,1H),4 .08-3.78(m,1H),3.78-3.71(m,4H),3.33-2.81(m,3H),2.61-2.44(m,5H),2.08-1.82(m,2H),1.60-1.48(m,2H),0.97(d,J=6.2Hz,6H).

[0748] LCMS: m / z 482.2 [M+1] + .

[0749] Example 103: Synthesis of (4-(3-chloro-4-(cyclopropylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (99)

[0750]

[0751] Compound 99 was synthesized via procedure 8 in Example 73 and obtained as a yellow solid (11.0 mg, 7% yield in 2 steps). Compound 99 was isolated as a formate.

[0752] 1 H NMR (400MHz, DMSO-d6) δ11.85-11.63(m,1H),8.17(s,2H),7.81(s,1H),7.50-7.45(m,2H),7.43-7.34(m,3H),5.79(d,J=2.8Hz,1H),4.63-4 .29(m,1H),3.83-3.50(m,8H),3.10-2.78(m,4H),2.14-2.06(m,1H), 1.92-1.68(m,2H),1.46-1.28(m,2H),0.30(m,2H),0.21-0.12(m,2H).

[0753] LCMS: m / z 480.2 [M+1] + .

[0754] Example 104: Synthesis of (4-(3-chloro-4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (100)

[0755]

[0756] Compound 100 was synthesized via procedure 6 in Example 73 and obtained as a brown gel (24.0 mg, 9% yield in one step). Compound 100 was isolated as a formate.

[0757] 1 H NMR (400MHz, DMSO-d6) δ11.75(brs,1H),8.16(s,2H),7.83(s,1H),7.49-7.44(m,4H),7.41(s,1H),5.70-5. 67(m,1H),4.50-4.44(m,1H),3.80-3.20(m,15H),2.86-2.82(m,4H),1.95-1.70(m,2H),1.47-1.30(m,2H).

[0758] LCMS:m / z 498.2[M+1] + .

[0759] Example 105: Synthesis of (4-(3-chloro-4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (101)

[0760]

[0761] Compound 101 was synthesized by procedure 8 in Example 73, yielding a white solid (8.59 mg, 4% yield in 2 steps).

[0762] 1 H NMR (400MHz, CDCl3) δ9.87-9.33(m,1H),7.91(s,1H),7.55-7.50(m,2H),7.49-7.45(m,2H),7.07(s,1H),5.56-5. 35(m,1H),4.88-4.67(m,1H),4.02-3.81(m,1H),3.80-3.67(m,4H),3.55-3.31(m,1H),3.25-2.70(m,2H),2.58(br s,4H),2.52-2.43(m,1H),2.09-1.83(m,2H),1.56-1.21(m,10H).

[0763] LCMS:m / z 508.2[M+1] + .

[0764] Example 106: Synthesis of (4-(3-chloro-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridyl-5-yl)-3-methoxyphenyl)(morpholinyl) methyl ketone (102)

[0765]

[0766] Compound 102 was synthesized by procedure 6 in Example 73 to obtain a yellow solid (20.67 mg, 10% yield in one step).

[0767] 1 H NMR (400MHz, CDCl3) δ10.02 (brs, 1H), 7.81 (s, 1H), 7.33 (d, J = 7.7Hz, 1H), 7.12-6.95 ( m,3H),5.45(m,J=5.1Hz,1H),3.84(s,11H),2.81-2.72(m,2H),1.05(t,J=7.2Hz,3H).

[0768] LCMS:m / z 415.1[M+1] + .

[0769] Example 107: Synthesis of (4-(3-chloro-4-(isopropylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxyphenyl)(morpholinyl) methyl ketone (103)

[0770]

[0771] Compound 103 was synthesized by procedure 8 in Example 73 to obtain a grayish-white solid (44.71 mg, 17% yield in 2 steps).

[0772] 1 H NMR (400MHz, CDCl3) δ9.97-9.87(m,1H),7.85-7.79(m,1H),7.38-7.34(m,1H),7.12- 7.00(m,3H),5.31-5.25(m,1H),3.83(s,11H),3.26-3.13(m,1H),1.06-0.85(m,6H).

[0773] LCMS:m / z 429.1[M+1] + .

[0774] Example 108: Synthesis of (4-(3-chloro-4-(cyclopropylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-3-methoxyphenyl)(morpholinyl) methyl ketone (104)

[0775]

[0776] Compound 104 was synthesized by procedure 8 in Example 73 to obtain a white solid (6.0 mg, 9% yield in 2 steps).

[0777] 1 H NMR (400MHz, CDCl3) δ9.82(brs,1H),7.76(s,1H),7.29(d,J=7.4Hz,1H),6.98-6.91(m,3H),5.94(d,J=1.6Hz,1H),3.87-3.38(m,11H),2.03(br dd,J=3.5,6.3Hz,1H),0.42-0.31(m,1H),0.28-0.15(m,2H),0.06--0.08(m,1H).

[0778] LCMS:m / z 427.1[M+1] + .

[0779] Example 109: Synthesis of (4-(3-chloro-4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxyphenyl)(morpholinyl) ketone (105)

[0780]

[0781] Compound 105 was synthesized by procedure 8 in Example 73 to obtain a white solid (34.0 mg, 18% yield in 2 steps).

[0782] 1 H NMR (400MHz, DMSO-d6) δ11.65(brs,1H),7.64(s,1H),7.36(d,J=2.0Hz,1H),7.30(d,J=7.6Hz,1H),7.09(d,J=1.1Hz,1H), 7.03(m,1H),5.67(t,J=5.4Hz,1H),3.77(s,3H),3.71-3.43(m,8H),3.25(t,J=5.3Hz,2H),3.16(s,3H),2.88-2.78(m,2H).

[0783] LCMS: m / z 445.0 [M+1] + .

[0784] Example 110: Synthesis of (4-(3-chloro-4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-3-methoxyphenyl)(morpholinyl) methyl ketone (106)

[0785]

[0786] Compound 106 was synthesized by procedure 8 in Example 73 and obtained as a pink solid (12.46 mg, 4% yield in 2 steps).

[0787] 1 H NMR (400MHz, CDCl3) δ9.90-9.25(m,1H),7.82-7.80(m,1H),7.39-7.30(m,1H),7.11-7.05(m,1H) ,7.05-6.98(m,2H),5.59-5.52(m,1H),3.86-3.76(m,11H),3.45-3.31(m,1H),1.50-1.29(m,8H).

[0788] LCMS: m / z 455.1 [M+1] + .

[0789] Example 111: Synthesis of (4-(3-chloro-4-(methylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-3-methoxyphenyl)(4-morpholinylpiperidin-1-yl)yl)methyl ketone (107).

[0790]

[0791] Compound 107 was synthesized by procedure 6 in Example 73, yielding a yellow solid (13.0 mg, 10% yield in one step). Compound 107 was isolated as a formate.

[0792] 1 H NMR (400MHz, CDCl3) δ8.41(s,1H),7.59(s,1H),7.29(s,2H),7.08(s,1H),7.04-6.97(m,2H),4.87-4.63(m,1H),3.98-3.85(m,1H ),3.82(s,3H),3.78-3.72(m,4H),3.19-2.98(m,3H),2.66-2.58(m,7H),2.57-2.48(m,1H),2.11-1.84(m,2H),1.67-1.42(m,2H).

[0793] LCMS: m / z 484.4 [M+1] + .

[0794] Example 112: Synthesis of (4-(3-chloro-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-3-methoxyphenyl)(4-morpholinylpiperidin-1-yl)yl)methyl ketone (108)

[0795]

[0796] Compound 108 was synthesized using procedure 8 in Example 73 to obtain a yellow solid (20.0 mg, 6% yield in 2 steps). Compound 108 was isolated as a formate.

[0797] 1 H NMR(400MHz, CDCl3)δ8.48(s,1H),7.62(s,1H),7.30(s,2H),7.10(s,1H),7.05-7.00(m,2H),4.93-4.59(m,1H ),4.02-3.69(m,9H),3.22-2.76(m,5H),2.68-2.57(m,4H),2.12-1.84(m,2H),1.70-1.38(m,2H),1.10(m,3H).

[0798] LCMS:m / z 498.2[M+1] + .

[0799] Example 113: Synthesis of (4-(3-chloro-4-(isopropylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-3-methoxyphenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (109)

[0800]

[0801] Compound 109 was synthesized using procedure 8 in Example 73, yielding a yellow solid (10.38 mg, 4% yield in 2 steps). Compound 109 was isolated as a formate.

[0802] 1 H NMR (400MHz, CDCl3) δ8.33 (s, 2H), 7.52 (s, 1H), 7.22 (d, J = 7.6Hz, 2H), 7.05-6.93 (m, 3H), 4.83-4.54 (m, 1H), 3.77-3.65 (m, 9H), 3.30-3.20(m,1H),3.10-2.73(m,2H),2.64-2.55(m,4H),2.49(m,1H),2.03-1.78(m,2H),1.64-1.37(m,2H),1.03-0.78(m,6H).

[0803] LCMS (Method 4): m / z 512.3 [M+1] + .

[0804] Example 114: Synthesis of (4-(3-chloro-4-(cyclopropylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxyphenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (110)

[0805]

[0806] Compound 110 was synthesized by procedure 8 in Example 73 to obtain a white solid (14.0 mg, 7% yield in 2 steps).

[0807] 1 H NMR (400MHz, CDCl3) δ10.04-9.82(m,1H),7.77(s,1H),7.27(m,1H),7.04-6.87(m,3H),5.92(br s,1H),4.86-4.55(m,1H),3.96-3.59(m,8H),3.15-2.73(m,2H),2.64-2.32(m,5 H),2.34-2.30(m,3H),1.52-1.31(m,2H),0.46-0.15(m,3H),0.10-0.06(m,1H).

[0808] LCMS (Method 4): m / z 510.2 [M+1] + .

[0809] Example 115: Synthesis of (4-(3-chloro-4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxyphenyl)(4-morpholinylpiperidin-1-yl)methyl ketone (111)

[0810]

[0811] Compound 111 was synthesized by procedure 8 in Example 73 and obtained as a yellow solid (40.0 mg, 42% yield in 2 steps).

[0812] 1H NMR (400MHz, CDCl3) δ9.52-9.32(m,1H),7.82(s,1H),7.32(d,J=7.6Hz,1H),7.08-6.97(m,3H),6.03-5.95(m ,1H),4.92-4.56(m,1H),4.11-3.67(m,8H),3.40-3.25(m,5H),3.16-2.98(m,1H),2.97-2.84(m,3H),2.59(br s,4H),2.52-2.41(m,1H),2.09-1.81(m,2H),1.57-1.43(m,2H).

[0813] LCMS (Method 1): m / z 528.4 [M+1] + .

[0814] Example 116: Synthesis of (4-(3-chloro-4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridinyl-5-yl)-3-methoxyphenyl)(4-morpholinylpiperidin-1-yl)yl)methyl ketone (112)

[0815]

[0816] Compound 112 was synthesized using procedure 8 in Example 73, yielding a yellow solid (7.77 mg, 3% yield in 2 steps). Compound 112 was isolated as a formate.

[0817] 1 H NMR (400MHz, CDCl3) δ8.42-8.41 (m, 2H), 7.59 (s, 1H), 7.30 (d, J = 8.1Hz, 2H), 7 .12-7.00(m,3H),4.92-4.61(m,1H),3.82(s,3H),3.80-3.74(m,4H),3.50(br s,1H),3.11-2.80(m,4H),2.70-2.61(m,4H),2.60-2.50(m,1H),2.10-1.89(m,2H),1.72-1.31(m,10H).

[0818] LCMS (Method 5): m / z 538.3 [M+1] + .

[0819] Example 117: LRRK2 inhibition of the inventive compound of this application

[0820] The inventive compounds of this application were subjected to IC testing. 50Experiments. Results are shown in Table 1. Exemplary kits for this assay include the Adapta™ screening protocol and the assay conditions for Invitrogen™ (Fisher Scientific™, catalog number PV5099).

[0821] All LRRK2 kinase inhibition assays used Promega ADP-Glo TM The assay was performed using a kinase assay system (catalog number: V4475). Inhibitors were tested at 12 concentrations on a 5-fold serial dilution series (50 μM, 10 μM, 2 μM, 400 nM, 80 nM, 16 nM, 3.2 nM, 640 pM, 128 pM, 25.6 pM, 5.12 pM, and 1.024 pM), with PF06447475 as a positive control. For the LRRK2 wild-type (WT) enzyme assay, each inhibitor was mixed with 0.2 μg / μL of substrate (LRRKtide, SignalChem, Richmond, BC, Canada) and 10 μmol / L of ATP (Invitrogen). TM 24 ng of LRRK2 WT enzyme (Thermo Fisher Scientific, PR8604B) was mixed in 384-well plates. For LRRK G2019S, each compound was mixed with 0.2 μg / μL of substrate, 25 μmol / L of ATP, and 16 ng of LRRK2 G2019S enzyme (SignalChem, L10-12GG). All samples were diluted with kinase reaction buffer (40 mmol / L TrisHCl, 10 mmol / L MgCl2, and 0.1 μg / μL BSA). After incubation at 25°C for 2 hours, ADP-Glo ​​was added. TM (Promega, Madison, WI) reagent was used, and the sample was incubated at room temperature for 40 minutes. Finally, the kinase detection reagent was added, and the resulting mixture was allowed to react at room temperature for 10 minutes. Synergy was used. TM The luminescence signal was detected using a Neo2 microplate reader (Bio-Tek). Inhibition curves of the compounds were fitted using Graphpad Prism 8.0 software.

[0822] Table 1. IC50 of the inventive compounds of this application 50 .

[0823]

[0824] Table 2. Enzyme activities against LRRK2 WT and LRRK2 G2019S (IC50).

[0825]

[0826] The data in Tables 1 and 2 show that the inventive compounds of this application effectively inhibit wild-type LRRK2 and LRRK2(G2019S) mutants in enzyme assays.

[0827] Example 118: Kinase Analysis

[0828] pass The kinase selectivity of inventive compounds 77, 96, and 101 of this application was evaluated. A near-comprehensive assessment of 468 kinases was conducted. Analysis. Results are shown in Table 3. The control percentage (control %) of the inventive compound of this application at 1 μM in DMSO was determined by Equation 1.

[0829] Equation 1

[0830] Control % = (Inventive compound of this application - Positive control) / (Negative control - Positive control) x 100%,

[0831] The positive control is a compound with a control percentage of 0% relative optical units (RLU), while the negative control (i.e., DMSO) is a compound with a control percentage of 100% RLU. The selectivity of the enzyme in this application is defined as follows: when the observed control percentage is less than 35% (<35%), the inventive compound of this application is considered to be active against the enzyme.

[0832] Table 3. Kinase profile analysis using compounds 77, 96 and 101 of this application.

[0833] Kinases Compound 96 Compound 77 Compound 101 AAK1 23 36 67 ABL1 (E255K)-phosphorylated 92 73 100 ABL1 (F317I)-non-phosphorylated 100 100 100 ABL1 (F317I)-phosphorylated 100 81 100 ABL1 (F317L)-non-phosphorylated 100 95 10 ABL1 (F317L)-phosphorylated 81 91 43 ABL1 (H396P)-non-phosphorylated 76 36 100 ABL1 (H396P)-phosphorylated 100 81 100 ABL1 (M351T)-phosphorylated 71 75 93 ABL1 (Q252H)-non-phosphorylated 64 50 92 ABL1 (Q252H)-phosphorylated 100 95 100 ABL1 (T315I)-non-phosphorylated 100 100 85 ABL1 (T315I)-phosphorylated 52 31 95 ABL1 (Y253F)-phosphorylated 98 79 100 ABL1 -non-phosphorylated 63 54 98 ABL1 -phosphorylated 88 62 97 ABL2 100 92 99 ACVR1 81 100 100 ACVR1B 74 83 98 ACVR2A 97 99 95 ACVR2B 91 77 100 ACVRL1 100 100 100

[0834] Table 3 (continued)

[0835] ADCK3 100 100 68 ADCK4 100 100 100 AKT1 100 100 96 AKT2 100 100 84 AKT3 100 95 99 ALK 46 40 75 ALK (C1156Y) 37 47 66 ALK (L1196M) 51 91 94 AMPK-alpha1 75 100 78 AMPK-alpha2 66 99 55 ANKK1 51 73 100 ARK5 64 86 67 ASK1 5.9 4.3 94 ASK2 42 30 100 AURKA 36 35 82 AURKB 53 24 100 AURKC 49 26 71 AXL 33 8.5 40 BIKE 0.85 0.4 6.8 BLK 100 100 100 BMPR1A 66 93 87 BMPR1B 54 47 95 BMPR2 53 40 98 BMX 93 88 34 BRAF 90 91 84 BRAF (V600E) 87 98 99 BRK 78 95 86 BRSK1 100 100 100 BRSK2 95 100 94 BTK 78 68 100 BUB1 86 80 100 CAMK1 87 84 98 CAMK1B 87 74 69 CAMK1D 69 85 100 CAMK1G 98 100 93 CAMK2A 96 100 92 CAMK2B 100 100 99 CAMK2D 100 100 93 CAMK2G 95 90 96

[0836] Table 3 (continued)

[0837] CAMK4 100 100 87 CAMKK1 78 74 87 CAMKK2 82 79 88 CASK 94 95 100 CDC2L1 96 99 94 CDC2L2 100 91 92 CDC2L5 100 100 2.1 CDK11 68 96 35 CDK2 100 100 100 CDK3 89 95 97 CDK4 98 85 100 CDK4-cyclin D1 73 74 100 CDK4-cyclin D3 100 98 99 CDK5 97 91 94 CDK7 90 94 93 CDK8 82 100 59 CDK9 87 83 96 CDKL1 78 76 100 CDKL2 97 95 100 CDKL3 100 94 100 CDKL5 92 94 70 CHEK1 84 89 83 CHEK2 22 56 92 CIT 11 6.8 21 CLK1 33 84 59 CLK2 11 57 65 CLK3 98 88 97 CLK4 11 72 42 CSF1R 73 74 28 CSF1R-autoinhibited 49 30 3.2 CSK 44 22 100 CSNK1A1 100 96 89 CSNK1A1L 48 79 100 CSNK1D 90 84 92 CSNK1E 17 68 81 CSNK1G1 19 81 92 CSNK1G2 93 81 73 CSNK1G3 16 24 93 CSNK2A1 72 75 100

[0838] Table 3 (continued)

[0839] CSNK2A2 92 90 100 CTK 100 97 95 DAPK1 74 73 80 DAPK2 82 72 100 DAPK3 96 79 88 DCAMKL1 77 79 90 DCAMKL2 78 89 99 DCAMKL3 99 95 84 DDR1 100 100 61 DDR2 79 86 100 DLK 24 14 65 DMPK 36 36 52 DMPK2 91 80 100 DRAK1 56 81 100 DRAK2 19 47 92 DYRK1A 69 58 4 DYRK1B 100 100 89 DYRK2 12 49 100 EGFR 100 95 97 EGFR (E746-A750del) 93 100 97 EGFR (G719C) 100 91 91 EGFR (G719S) 100 100 100 EGFR (L747-E749del, A750P) 100 100 88 EGFR (L747-S752del, P753S) 77 92 100 EGFR (L747-T751del, Sins) 76 88 100 EGFR (L858R) 100 100 96 EGFR (L858R, T790M) 98 99 100 EGFR (L861Q) 90 96 89 EGFR (S752-I759del) 98 100 100 EGFR (T790M) 83 93 100 EIF2AK1 100 100 100 EPHA1 81 83 76 EPHA2 100 96 30 EPHA3 100 90 82 EPHA4 100 96 88 EPHA5 100 96 98 EPHA6 98 93 43 EPHA7 96 78 96 EPHA8 96 94 93

[0840] Table 3 (continued)

[0841] EPHB1 100 93 95 EPHB2 97 98 97 EPHB3 100 100 79 EPHB4 100 100 62 EPHB6 99 55 100 ERBB2 80 63 92 ERBB3 86 88 55 ERBB4 100 100 97 ERK1 100 100 98 ERK2 95 91 93 ERK3 85 87 100 ERK4 94 90 93 ERK5 81 100 100 ERK8 100 92 91 ERN1 73 56 86 FAK 65 90 71 FER 100 100 100 FES 95 95 72 FGFR1 85 87 77 FGFR2 94 72 54 FGFR3 82 64 67 FGFR3(G697C) 55 51 74 FGFR4 59 61 85 FGR 95 80 94 FLT1 33 21 51 FLT3 6.7 3.3 4.9 FLT3(D835H) 9.9 7.9 41 FLT3(D835V) 2.9 0.5 6.4 FLT3(D835Y) 11 9.7 33 FLT3(ITD) 8.1 6.2 41 FLT3(ITD,D835V) 3.6 2.5 55 FLT3(ITD,F691L) 0 0 49 FLT3(K663Q) 15 15 28 FLT3(N841I) 14 1 2.6 FLT3(R834Q) 52 45 75 FLT3-container 93 53 62 FLT4 66 47 100 FRK 84 100 100 FYN 96 94 87

[0842] Table 3 (continued)

[0843] GAK 99 100 99 GCN2(Kin.Dom.2,S808G) 54 34 100 GRK1 63 60 84 GRK2 94 93 100 GRK3 92 93 94 GRK4 28 21 14 GRK7 100 100 94 GSK3A 65 98 42 GSK3B 63 69 100 HASPIN 1.3 9.8 22 HCK 100 100 96 HIPK1 68 70 92 HIPK2 74 81 100 HIPK3 79 85 100 HIPK4 64 84 79 HPK1 84 6.7 53 HUNK 100 100 100 ICK 35 35 100 IGF1R 100 91 86 IKK-alpha 14 17 49 IKK-beta 32 28 93 IKK-epsilon 68 64 99 INSR 71 53 68 INSRR 96 92 84 IRAK1 41 33 100 IRAK3 76 40 37 IRAK4 62 26 100 ITK 93 71 90 JAK1(JH1 horse-drawn carriage) 100 98 90 JAK1(JH2 horse-drawn carriage) 94 57 47 JAK2(JH1-hybrid) 29 7.9 100 JAK3(JH1 inlet-chain) 7.8 8.2 62 JNK1 0.05 1.1 7.1 JNK2 0.85 17 8.8 JNK3 0.35 1.9 7.6 KIT 11 4.8 58 KIT(A829P) 53 46 100 KIT(D816H) 75 51 92 KIT(D816V) 86 46 95

[0844] Table 3 (continued)

[0845] KIT(L576P) 19 10 46 KIT(V559D) 4.5 2.8 50 KIT(V559D,T670I) 27 9.7 71 KIT(V559D,V654A) 94 53 100 KIT switchgear 64 23 100 LATS1 100 91 100 LATS2 78 86 82 LCK 100 96 100 LIMK1 100 100 76 LIMK2 100 97 99 LKB1 91 88 78 LOK 88 99 81 LRRK2 2.6 15 33 LRRK2(G2019S) 3.2 11 22 LTK 62 75 72 LYN 100 99 100 LZK 89 61 76 MAK 97 100 87 MAP3K1 73 56 100 MAP3K1 1.8 1.4 100 MAP3K2 29 25 35 MAP3K3 51 44 47 MAP3K4 68 91 71 MAP4K2 1.1 20 20 MAP4K3 83 94 74 MAP4K4 19 58 78 MAP4K5 39 77 88 MAPKAPK2 100 100 51 MAPKAPK5 100 100 100 MARK1 72 71 80 MARK2 60 86 68 MARK3 84 82 89 MARK4 38 36 82 MAST1 24 50 70 MEK1 12 29 94 MEK2 19 31 87 MEK3 4.2 36 33 MEK4 7.3 45 28 MEK5 7.3 3.2 100

[0846] Table 3 (continued)

[0847] MEK6 16 60 95 MILK 16 20 30 MERTK 42 45 41 ALSO 84 63 16 MET(M1250T) 78 49 23 MET(Y1235D) 83 56 30 MINK 6 17 62 MKK7 79 67 100 MKNK1 100 97 100 MKNK2 22 56 94 MLCK 5 13 100 MLK1 96 91 96 MLK2 39 62 69 MLK3 99 93 100 MRCKA 100 100 100 MRCKB 93 86 82 MST1 81 93 82 MST1R 88 100 77 MST2 99 100 74 MST3 74 72 86 MST4 99 67 100 MTOR 78 60 95 MUSK 100 100 67 MYLK 85 72 83 MYLK2 51 79 94 MYLK4 100 90 95 MYO3A 64 69 100 MYO3B 73 96 93 NDR1 69 74 84 NDR2 19 21 63 NEK1 100 96 100 NEK1 100 100 100 NEK1 96 97 100 NEK2 100 100 100 NEK3 82 68 95 NEK4 65 82 100 NEK5 99 79 99 NEK6 88 92 100 NEK7 100 100 95

[0848] Table 3 (continued)

[0849] NEK9 100 100 98 NIK 13 55 88 NIM1 50 69 99 NLK 100 95 88 OSR1 66 75 100 p38-alpha 92 100 100 p38-beta 58 95 92 p38-delta 99 96 94 p38-gamma 92 97 79 PAK1 99 99 100 PAK2 96 100 80 PAK3 74 97 86 PAK4 31 65 100 PAK6 100 99 99 PAK7 41 100 95 PCTK1 86 85 100 PCTK2 97 100 96 PCTK3 100 100 96 PDGFRA 45 11 92 PDGFRB 21 20 83 PDPK1 68 94 94 PFCDPK1 (Plasmodium falciparum) 94 86 95 PFPK5 (Plasmodium falciparum) 100 100 100 PFTAIRE2 100 100 91 PFTK1 100 100 100 PHKG1 86 100 87 PHKG2 19 52 100 PIK3C2B 96 100 96 PIK3C2G 94 100 92 PIK3CA 100 100 99 PIK3CA(C420R) 75 75 100 PIK3CA(E542K) 100 100 98 PIK3CA(E545A) 62 80 98 PIK3CA(E545K) 31 18 79 PIK3CA(H1047L) 92 97 100 PIK3CA(H1047Y) 84 70 100 PIK3CA(I800L) 64 56 80 PIK3CA(M1043I) 81 66 100 PIK3CA(Q546K) 100 100 93

[0850] Table 3 (continued)

[0851] PIK3CB 100 100 100 PIK3CD 84 85 100 PIK3CG 100 99 95 PIK4CB 58 59 100 PIKFYVE 66 53 98 PIM1 100 95 95 PIM2 100 100 94 PIM3 100 99 96 PIP5K1A 16 7.7 12 PIP5K1C 49 37 57 PIP5K2B 4.9 3.4 12 PIP5K2C 63 93 77 PKAC-alpha 100 100 100 PKAC-beta 100 100 90 PKMYT1 100 98 97 PKN1 95 100 100 PKN2 87 51 75 PKNB (Mycobacterium tuberculosis) 61 30 89 PLK1 64 65 98 PLK2 100 85 100 PLK3 99 78 84 PLK4 27 27 78 PRKCD 94 100 88 PRKCE 66 51 70 PRKCH 92 83 73 PRKCI 69 67 100 PRKCQ 76 91 45 PRKD1 19 58 48 PRKD2 13 90 59 PRKD3 13 56 35 PRKG1 100 100 89 PRKG2 100 100 100 PRKR 70 68 82 PRKX 100 100 82 PRP4 47 14 38 PYK2 92 89 78 QSK 76 76 97 RAF1 100 91 91 RET 80 27 85

[0852] Table 3 (continued)

[0853] RET(M918T) 72 33 95 RET(V804L) 59 45 97 RET(V804M) 61 52 99 RIOK1 0.15 0 11 RIOK2 26 73 28 RIOK3 36 24 50 RIPK1 44 19 47 RIPK2 99 100 100 RIPK4 7.8 1.3 100 RIPK5 8.6 31 50 ROCK1 4.7 20 63 ROCK2 1.4 8.9 81 ROS1 89 74 73 RPS6KA4 (Kin.Dom.1-N-terminal) 100 97 84 RPS6KA4 (Kin.Dom.2-C-terminal) 65 90 99 RPS6KA5 (Kin.Dom.1-N-terminal) 100 100 90 RPS6KA5 (Kin.Dom.2-C-terminal) 100 100 96 RSK1 (Kin.Dom.1-N-terminal) 100 93 80 RSK1 (Kin.Dom.2-C-terminal) 100 99 88 RSK2 (Kin.Dom.1-N-terminal) 54 54 65 RSK2 (Kin.Dom.2-C-terminal) 97 98 83 RSK3 (Kin.Dom.1-N-terminal) 78 80 66 RSK3 (Kin.Dom.2-C-terminal) 78 100 77 RSK4 (Kin.Dom.1-N-terminal) 77 32 100 RSK4 (Kin.Dom.2-C-terminal) 91 98 88 S6K1 87 50 100 SBK1 63 44 67 SGK 7.3 17 86 SgK110 100 100 100 SGK2 30 43 65 SGK3 48 37 96 SIK 87 94 100 SIK2 85 100 84 SLK 68 86 78 SNARK 64 96 33 SNRK 100 100 100 SRC 100 99 100 SRMS 100 90 72 SRPK1 17 10 27

[0854] Table 3 (continued)

[0855] SRPK2 16 12 60 SRPK3 17 16 9.9 STK16 2 2.9 13 STK33 100 100 100 STK35 50 63 99 STK36 99 100 96 STK39 9.7 16 80 SYK 100 100 100 TAK1 6.9 21 6.1 TAOK1 96 100 99 TAOK2 69 69 81 TAOK3 91 95 88 TBK1 91 57 90 TEC 100 100 93 TESK1 74 89 99 TGFBR1 56 60 100 TGFBR2 100 100 100 TIE1 93 97 92 TIK2 81 80 97 TLK1 95 95 90 TLK2 100 99 100 TNIK 14 29 89 TNK1 83 80 50 TNK2 94 100 98 TNNI3K 74 65 100 TRKA 11 0.65 49 TRKB 48 23 100 TRKC 82 51 100 TRPM6 82 89 100 TSSK1B 100 99 41 TSSK3 45 65 98 TTK 3.6 34 54 TXK 81 81 84 TYK2 (JH1 domain - catalysis) 29 15 100 TYK2 (JH2 domain - pseudokinase) 89 84 100 TYRO3 100 100 56 ULK1 3.8 3.1 73 ULK2 8.7 15 98 ULK3 10 5.5 92

[0856] Table 3 (continued)

[0857] VEGFR2 4.2 2.8 33 VPS34 51 35 100 VRK2 79 66 100 WEE1 88 97 100 WEE2 100 95 94 WNK1 80 67 90 WNK2 100 92 100 WNK3 73 86 92 WNK4 84 77 100 YANK1 100 100 100 YANK2 100 100 100 YANK3 99 97 57 YES 100 100 100 YSK1 97 84 100 YSK4 2.2 2.6 63 ZAK 75 70 86 ZAP70 100 100 55

[0858] All patent and non-patent publications indicate the level of expertise of those skilled in the art. All these publications are incorporated herein by reference to the same degree as each individual publication is specifically and individually indicated to be incorporated by reference.

[0859] Although this application has been described herein with reference to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of this application. Therefore, it should be understood that various modifications can be made to the exemplary embodiments, and other arrangements can be designed, without departing from the spirit and scope of this application as defined by the appended claims.

Claims

1. A compound having a structure represented by Formula (la): wherein: R1represents R2represents H or halogen, and R3represents wherein R represents ethyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound of claim 1, selected from the group consisting of:

3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

4. The composition of claim 3, in the form of a tablet or capsule. or a pharmaceutically acceptable salt or stereoisomer thereof.

5. The composition of claim 3, wherein the pharmaceutically acceptable carrier is a liquid.

6. Use of a compound of claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of any one of claims 3 to 5, in the manufacture of a medicament for the treatment of a disease or disorder involving abnormal activity of LRRK2, wherein the disease is a neurodegenerative disease or a brain cancer.

7. The use of claim 6, wherein the disease is a neurodegenerative disease.

8. The use of claim 7, wherein the neurodegenerative disease is Parkinson’s disease.

9. The use of claim 6, wherein the disease is a brain cancer.

10. The use of claim 9, wherein the brain cancer is a glioma.

11. The use of claim 9, wherein the brain cancer is a glioblastoma. ​ ​

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