Ret-selective inhibitors and methods of making and using the same

Abstract

This invention provides selective inhibitors of RET, methods for their preparation and uses; this invention provides compounds of formula (I) and pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof, pharmaceutical compositions comprising these compounds, and uses of such compounds in the treatment of RET-related diseases.

Description

[0001] Cross-referencing

[0002] This application claims priority to Chinese Patent Application No. 201910627353.7, filed July 12, 2019, entitled “RET Selective Inhibitor and Preparation Method and Use Thereof,” and Chinese Patent Application No. 201910825867.3, filed September 3, 2019, entitled “RET Selective Inhibitor and Preparation Method and Use Thereof,” the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] This invention relates to compounds that selectively inhibit RET protein activity, as well as methods for preparing these compounds and the use of pharmaceutical compositions thereof. Background Technology

[0004] RET is a proto-oncogene located on chromosome 10. The RET protein encoded by the RET gene is a receptor tyrosine kinase (RTK) located on the cell membrane and belongs to the cadherin superfamily. It plays an important role in the normal development of the peripheral sympathetic and parasympathetic nervous systems of the brain, in the production of calcitonin by thyroid C cells, and is also essential for the thyroid gland, lungs, hematopoietic progenitor cells and other tissues (Nat. Rev. Cancer 2014; 14(3): 173-86.).

[0005] The domain composition of RET proteins is similar to that of other protein tyrosine kinases, containing a typical extracellular domain, a transmembrane segment, followed by an intracellular juxtamembrane segment, a kinase domain, and a C-terminal tail. The extracellular domain contains four cadherin-like domains (CD1 / 2 / 3 / 4) repeating approximately 110 amino acid residues, and a cysteine-rich segment of approximately 150 amino acid residues immediately adjacent to the transmembrane segment. Extracellular Ca2+ exists between CD2 and CD3. 2 + binding site (J.Biol.Chem.2001;276(38):35808-35817).

[0006] RET is the only receptor protein tyrosine kinase with a cadherin-like domain. Although it shares the same domain composition as other protein tyrosine kinases, RET's activation mechanism differs, requiring an additional GDNF family receptor (GDNF / NTRN / ARTN / PSP)-GFR co-receptor (GFR 1 / 2 / 3 / 4). Members of the GDNF family typically exist as disulfide-linked homodimers. The GDNF dimer interacts with two GFR complexes to form a binary complex, which in turn interacts with two RET receptors, ultimately forming a hexamer complex composed of two receptors, two co-receptors, and a ligand dimer (Nat. Rev. Cancer 2014; 14(3): 173-86). In the absence of ligand-mediated stimulation, RET is in a non-phosphorylated inactive state. When the RET protein binds to its ligand GDNF, it causes phosphorylation of the RET protein receptor, activating RET. The activated RET then phosphorylates its substrate, activating downstream signaling pathways. RET protein is involved in signaling pathways including the PI3K-AKT-mTOR pathway and the RAS-RAF-MEK-ERK pathway. The PI3K-AKT-mTOR pathway is involved in cell survival, while the RAS-RAF-MEK-ERK pathway is involved in cell proliferation. Therefore, RET protein plays a certain role in cell survival, migration and proliferation (Cell 2010; 141(7): 1117-1134; Cell.Signal. 2014; 26(8): 1743-1752).

[0007] Variations in the ret gene, which encodes RET protein kinase, including activating point mutations and gene fusions, can lead to overactivation of the RET signaling pathway and uncontrolled cell proliferation, resulting in diseases such as malignant tumors. Chromosomal rearrangements of the ret gene are associated with the development of papillary thyroid carcinoma. Chromosomal rearrangements may lead to breaks in the ret gene, and the kinase domain of the ret gene may fuse with more than a dozen different genes such as kif5b, ccdc6, and ncoa4 to form fusion genes that drive tumor proliferation (Transl Lung Cancer Res. 2015; 4(2): 156-164). ret gene fusions have been found in 5%-40% of papillary thyroid carcinomas (PTCs). Ret gene rearrangements in papillary thyroid carcinomas are associated with ionizing radiation, i.e., this type of cancer occurs when there is nuclear radiation in the environment. Chromosomal rearrangement-induced ret gene fusions also occur in non-small cell lung cancer (NSCLC), with a frequency of approximately 1%-2% in NSCLC. Currently, four ret gene fusion partner genes have been identified: kif5b, ccdc6, ncoa4, and trim33, with the most common kif5b-ret fusion form (Oncologist. 2013; 18(7): 865-875). Point mutations in the ret gene, such as V804M and M918T, can also lead to ret gene activation mutations, primarily found in multiple endocrine neoplasia (MEN2A, MEN2B) and medullary thyroid carcinoma (MTC) (Ann Oncol. 2016; 27(7): 1286-1291). Germ cell ret gene mutations occur in almost all hereditary medullary thyroid carcinomas, including multiple endocrine neoplasia type 2. In acquired medullary thyroid carcinoma, ret gene mutations also occur in 50% of patients (Ann Oncol. 2016; 27(7): 1286-1291).

[0008] Currently, in the United States, it is estimated that approximately 10,000 new cases of tumors carrying RET mutations or RET fusion proteins are diagnosed each year, which is roughly the same as the incidence of chronic myeloid leukemia (Pharmacological Research 2018; 128: 1-17). Several drugs targeting RET have been approved by the FDA for the treatment of cancer: Cabozantinib, Vandetanib, Lenvatinib, Sorafenib, Alectinib, etc. These drugs are multi-kinase inhibitors with anti-RET activity, and their clinical efficacy for RET-targeted therapy is relatively poor, accompanied by toxic side effects due to their significant inhibitory effects on other kinases (such as vascular endothelial growth factor receptor 2 (VEGFR2)) (Nat Rev Clin Oncol. 2018; 15(3): 151-167). Therefore, the development of highly selective RET inhibitors has attracted the research interest of many pharmaceutical companies, and the development of specific RET inhibitors has become an emerging therapeutic approach to improve the treatment efficacy of RET-driven cancers. Summary of the Invention

[0009] This invention provides a selective inhibitor of RET, which is a compound represented by general formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof. This invention also provides a series of compounds represented by general formula (I) and their pharmaceutically acceptable salts, solvates, polymorphs, or isomers, pharmaceutical compositions comprising these compounds, and methods of treating diseases with such compounds.

[0010] In one aspect, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof:

[0011]

[0012] in,

[0013] X and Y are each independently selected from CH and N;

[0014] A is selected from 5-6 membered heteroaryl, 3-12 membered heterocyclic, -OC 1-6 Alkyl, -SC 1-6 Alkyl groups and -SO2-C 1-6 Alkyl groups, wherein the heteroaryl and heterocyclic groups may each optionally be C 1-6 Alkyl, -CN, -OH, -NR 5 R 6 halogen, -OC 1-6 Alkyl, -SC 1-6 Alkyl group, or -SO2-C 1-6 Alkyl substitution, the C1-6 Alkyl groups may optionally be substituted with -OH, halogens, or -(CO)N(CH3)2, and R 5 and R 6 Each is independently selected from H and C. 1-6 alkyl;

[0015] R 1 R 1 '、R 2 and R 2 Each independently is either H or C 1-6 Alkyl, or R 1 and R 1 One of them is with R 2 and R 2 One of them can be linked together to form a bond or -(CH2). m -;

[0016] Z is selected from -(CH2) m -SC 1-6 Alkyl, -(CS)-N(R) 8 2. and -(CH2) n -Ar;

[0017] R 8 Each is independently selected from H and C. 1-6 Alkyl, -OC 1-6 Alkyl groups and -(CH2) m -OC 1-6 alkyl;

[0018] Ar is selected from phenyl, pyridyl, and pyrimidinyl, wherein the phenyl, pyridyl, and pyrimidinyl groups may each optionally be converted to -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -SO-C 1-6 Alkyl group, or -SO2-C 1-6 Alkyl substitution;

[0019] m are each independently selected from 1 and 2;

[0020] n is selected from 0, 1, and 2;

[0021] In some embodiments of the present invention, A is selected from 5-6 membered heteroaryl and 3-12 membered heterocyclic groups, wherein the heteroaryl and heterocyclic groups may each optionally be replaced by C. 1-6 Alkyl, -CN, -OH, -NR 5 R 6 halogen, -OC 1-6 Alkyl, -SC 1-6 Alkyl group, or -SO2-C 1-6 Alkyl substitution, the C1-6 Alkyl groups may optionally be substituted with -OH, halogens, or -(CO)N(CH3)2, and R 5 and R 6 Each is independently selected from H and C. 1-6 alkyl;

[0022] In some embodiments of the present invention, A is selected from 5-6 membered heteroaryl and 4-9 membered heterocyclic groups, wherein the heteroaryl and heterocyclic groups may each optionally be replaced by C. 1-6 Alkyl, -CN, -OH, -NR 5 R 6 halogen, -OC 1-6 Alkyl, -SC 1-6 Alkyl group, or -SO2-C 1-6 Alkyl substitution, the C 1-6 Alkyl groups may optionally be substituted with -OH, halogens, or -(CO)N(CH3)2, and R 5 and R 6 Each is independently selected from H and C. 1-6 alkyl;

[0023] In some embodiments of the present invention, the compounds of the present invention are selected from:

[0024]

[0025]

[0026]

[0027] Or its pharmaceutically acceptable salts, solvates, polymorphs or isomers.

[0028] Another aspect of the present invention relates to pharmaceutical compositions comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier;

[0029] On the other hand, the present invention provides a method for treating RET-related diseases, the method comprising administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a combination thereof; in some embodiments, the RET-related diseases are lung cancer, papillary thyroid carcinoma, medullary thyroid carcinoma, differentiated thyroid carcinoma, recurrent thyroid carcinoma, refractory differentiated thyroid carcinoma, type 2A or 2B multiple endocrine tumors (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal gangliocytoma, and cervical cancer, preferably RET fusion lung cancer or medullary thyroid carcinoma, more preferably small cell lung cancer, non-small cell lung cancer, bronchioloalveolar carcinoma, or lung adenocarcinoma;

[0030] In some embodiments of the present invention, the object of the present invention is a mammal including humans;

[0031] In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof in the preparation of a medicament for treating RET-related diseases; in some embodiments, the RET-related diseases are lung cancer, papillary thyroid carcinoma, medullary thyroid carcinoma, differentiated thyroid carcinoma, recurrent thyroid carcinoma, refractory differentiated thyroid carcinoma, type 2A or 2B multiple endocrine tumors (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal gangliocytoma, or cervical cancer, preferably RET fusion lung cancer or medullary thyroid carcinoma, more preferably small cell lung cancer, non-small cell lung cancer, or bronchioloalveolar carcinoma or lung adenocarcinoma. Invention Details

[0032] Exemplary embodiments utilizing the principles of the invention are set forth in the following detailed description of the invention. The features and advantages of the invention can be better understood by referring to the following summary of the invention.

[0033] It should be understood that the scope of protection of each aspect of the present invention is determined by the claims, and the methods and structures within the scope of these claims, as well as their equivalents, are all within the scope of these claims.

[0034] Unless otherwise defined, all technical terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and publications cited in this document are incorporated herein in their entirety through reference.

[0035] It should be understood that the above summary and the following detailed description are exemplary and explanatory, and not intended to limit any subject matter of the invention. Unless otherwise specified, the singular form includes the plural form. Unless otherwise specified, the use of "or" or "or" means "and / or". Furthermore, the use of the term "comprising" and other forms such as "including," "containing," and "containing" are not limiting.

[0036] Some chemical terms

[0037] The terms “optional,” “optional,” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally substituted alkyl” means “unsubstituted alkyl” or “substituted alkyl.” Furthermore, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or any level between monosubstituted and fully substituted (e.g., -CH2CHF2, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution mode that is spatially impossible and / or cannot be synthesized is introduced.

[0038] Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, nuclear magnetic resonance, high-performance liquid chromatography, infrared and ultraviolet / visible spectroscopy, and pharmacological methods, are employed. Unless specifically defined herein, the terminology, experimental procedures, and techniques used herein in analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of reagent kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein are generally carried out according to conventional methods well known in the art, based on descriptions in several summary and more specific documents cited and discussed herein. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0039] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0040] As used in this article, the terms "group" and "chemical group" refer to a specific part or functional group of a molecule. Chemical groups are often considered as chemical entities that are embedded in or attached to a molecule.

[0041] Some chemical groups named herein may be indicated by abbreviations to represent the total number of carbon atoms. For example, C1-C6 alkyl describes an alkyl group having a total of 1 to 6 carbon atoms, as defined below. The total number of carbon atoms indicated by the abbreviations does not include carbon atoms on possible substituents.

[0042] The terms “halogen,” “halogenated,” or “halogenated” refer to bromine, chlorine, fluorine, or iodine.

[0043] As used herein, the terms "aromatic," "aromatic ring," "aromatic," "aromatic," and "aromatic ring" refer to a planar ring or ring portion of one or more rings having a delocalized electronic conjugated system containing 4n+2 electrons, where n is an integer. An aromatic ring can be formed from 5, 6, 7, 8, 9, or more atoms. Aromatic compounds can be optionally substituted and can be monocyclic or polycyclic with fused rings. The term aromatic compound includes all carbocyclic rings (such as benzene rings) and rings containing one or more heteroatoms (such as pyridine).

[0044] The term "heteroatom" or "heteroatom" as used herein, alone or as part of other components, refers to an atom other than carbon and hydrogen. Heteroatoms are independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.

[0045] The term “dense” or “dense ring” as used alone or in combination in this article refers to a ring structure in which two or more rings share one or more bonds.

[0046] The term “spiral” or “spiral ring” as used alone or in combination in this article refers to a ring structure in which two or more rings share one or more atoms.

[0047] The term "alkyl" as used hereby, either alone or as part of other components (e.g., monoalkylamino), refers to a monovalent saturated hydrocarbon with optional substituted straight or optional substituted branched chains having 1-12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, and connected to other parts of the molecule by single bonds, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, etc.

[0048] The term "cycloalkyl" as used herein, alone or as part of other components, refers to a stable, monovalent, non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms. It may include fused ring, spirocyclic, or bridged ring systems, containing 3-15 cyclic carbon atoms, preferably 3-10 cyclic carbon atoms, more preferably 3-8 cyclic carbon atoms, and may be saturated or unsaturated, linked to other parts of the molecule by single bonds. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0049] The term "heteroaryl" refers to a monocyclic or fused ring with 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, of which 1, 2, 3, or 4 are selected from N, O, and S, and the remaining ring atoms are C, and possessing a fully conjugated π-electron system. Heteroaryl groups can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl, and heterocyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, and triazineyl.

[0050] The terms "heterocyclic group," "heterocyclic alkyl group," and "heterocycle" as used alone or as part of other components herein refer to a stable 3-18 member monovalent non-aromatic ring comprising 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise stated, the heterocyclic group can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may contain fused rings, spirocyclic, or bridged ring systems. The nitrogen, carbon, or sulfur on the heterocyclic group may be selectively oxidized, the nitrogen atom may be selectively quaternized, and the heterocyclic group may be partially or completely saturated. A heterocyclic group can be connected to the rest of the molecule by a single bond via a carbon atom or heteroatom on the ring. Heterocyclic groups containing fused rings may contain one or more aromatic or heteroaromatic rings, provided that the atoms connected to the rest of the molecule are atoms from non-aromatic rings. For the purposes of this application, the heterocyclic group is preferably a stable 4-11 valent monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; more preferably, it is a stable 4-8 valent monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heterocyclic groups include azirheptanyl, azirheptanyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolyl, dioxopentyl, 1,1-dioxo-thiomorpholinyl, imidazoalkyl, imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinoneyl, pyranyl, pyrazolyl, pyrrolidinyl, quinazinyl, quininecycloyl, tetrahydrofuranyl, tetrahydropyranyl, etc.

[0051] The term "polymorph" or "polymorphism" as used in this invention refers to the fact that the compounds of this invention have multiple crystal lattice forms. Some compounds of this invention may have more than one crystal form, and this invention covers all polymorphs or mixtures thereof.

[0052] Intermediate compounds and polymorphs of the compounds of this invention are also within the scope of this invention.

[0053] Unless otherwise specified, the olefin double bonds contained in the compounds of this invention include E and Z isomers.

[0054] It should be understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be R or S configurations. Some compounds of the present invention may also exhibit cis-trans isomerism, which will be apparent to those skilled in the art. It should be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers, as well as mixtures thereof, including racemic mixtures. These isomers can be isolated from mixtures thereof by implementing or modifying known methods, such as chromatography and recrystallization techniques, or they can be prepared separately from suitable isomers of their intermediates.

[0055] The term “pharmaceutically acceptable salt” as used in this article includes both salts with added acid salts and salts with added alkali salts.

[0056] "Pharmaceutically acceptable salts" refer to salts that retain the biological potency and properties of the free base of a compound, are not biologically or otherwise undesirable, and are formed with inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, decanoic acid, hexanoic acid, carbonic acid, cinnamic acid, citric acid, etc. "Pharmaceutically acceptable base salts" refer to salts that retain the biological potency and properties of the free acid of a compound, and are not biologically or otherwise undesirable. These salts are prepared by reacting a free acid with an inorganic or organic base. Salts formed by reacting with an inorganic base include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and manganese salts.

[0057] Organic bases that form salts include, but are not limited to, primary amines, secondary amines, tertiary amines, and cyclic amines, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purines, piperazine, piperidine, choline, and caffeine. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0058] Crystallization often produces solvates of the compounds of this invention. As used herein, the term "solvate" refers to a combination of one or more molecules of the compounds of this invention and one or more solvent molecules.

[0059] The solvent can be water, in which case the solvate is a hydrate. Alternatively, it can be an organic solvent. Therefore, the compounds of this invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., and the corresponding solvated forms. The compounds of this invention can be true solvates, but in other cases, they may simply retain water or a mixture of water and some other solvents by chance. The compounds of this invention can react in a solvent or precipitate or crystallize in a solvent. The solvates of the compounds of this invention are also included within the scope of this invention.

[0060] As used herein, the term "pharmaceutical composition" refers to a formulation containing the compounds of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals, such as humans. This medium includes all pharmaceutically acceptable carriers.

[0061] As used in this article, the term "acceptable" in relation to formulations, compositions, or ingredients means that it does not have a lasting harmful effect on the overall health of the treated subject.

[0062] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0063] "Pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administrative departments for use in humans and domesticated animals.

[0064] As used herein, the terms “subject,” “patient,” “object,” or “individual” refer to an individual suffering from a disease, disorder, or symptom, including both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans; non-human primates (e.g., chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0065] The term "treatment" as used in this article refers to the treatment of relevant diseases or conditions in mammals, particularly humans, including...

[0066] (i) To prevent mammals, especially those previously exposed to a disease or condition but not yet diagnosed with it, from developing the corresponding disease or condition.

[0067] (ii) To suppress a disease or symptom, that is, to control its development;

[0068] (iii) To alleviate the disease or symptom, that is, to make the disease or symptom subside;

[0069] (iv) Relieve symptoms caused by disease or illness.

[0070] The terms “disease” and “symptom” used in this article may be used interchangeably or have different meanings, because some specific diseases or symptoms do not yet have known causative factors (so the cause of the disease is still unclear), so they cannot be recognized as diseases but can only be regarded as unwanted conditions or syndromes. These syndromes have more or less some specific symptoms that have been confirmed by clinical researchers.

[0071] As used herein, the terms "effective amount," "therapeutic effective amount," or "pharmaceutical effective amount" refer to an amount of at least one drug or compound that, when taken, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition containing the compounds disclosed herein that is clinically necessary to provide significant symptom relief. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation testing.

[0072] As used herein, the terms “administration,” “application,” “dosage,” etc., refer to methods that deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), local administration, and rectal administration. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0073] Preparation of the compounds of the present invention

[0074] The following reaction route illustrates a method for preparing the compounds of the present invention.

[0075] It should be understood that, in the following description, the combination of substituents and / or variables of the molecular formula is permitted only in the case of forming a stable compound.

[0076] Those skilled in the art will also understand that, in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. These functional groups include hydroxyl, amino, mercapto, and carboxyl groups. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butylmethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable amino, amidine, and guanidine protecting groups include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable mercapto protecting groups include -C(O)-R″ (R″ represents alkyl, aryl, or arylalkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable carboxyl protecting groups include alkyl, aryl, or arylalkyl esters. Protecting groups can be added or removed using standard techniques known to those skilled in the art. Example

[0077] The following non-limiting embodiments are merely illustrative and do not limit the invention in any way.

[0078] Unless otherwise specified, temperatures are in Celsius. Reagents were purchased from commercial suppliers such as Sinopharm Chemical Reagents Beijing Co., Ltd., Alfa Aesar, or Beijing Bailingwei Technology Co., Ltd., and these reagents are ready for use without further purification, unless otherwise specified.

[0079] Unless otherwise specified, the following reactions are carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or argon, or using a drying tube; the reaction flask is fitted with a rubber diaphragm to allow for the addition of substrates and reagents via syringe; glassware is dried by drying and / or heating.

[0080] Unless otherwise specified, column chromatography purification used 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; preparative thin-layer chromatography used thin-layer chromatography silica gel pre-plates (HSGF254) produced by Yantai Chemical Industry Research Institute; MS determination was performed using a ThermoLCQ Fleet (ESI) liquid chromatography-mass spectrometry system; optical rotation determination was performed using an SGW-3 automatic polarimeter from Shanghai Shenguang Instrument Co., Ltd.

[0081] NMR data ( 1H NMR was performed using a Varian instrument at 400 MHz. Solvents used for NMR data included CDCl3, CD3OD, D2O, and DMSO-d6, with tetramethylsilane (0.00 ppm) or residual solvents as the reference (CDCl3: 7.26 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm). When indicating peak shape diversity, the following abbreviations are used to represent different peak shapes: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplex), br (broad peak), dd (double doublet), dt (double triplet). If coupling constants are given, they are expressed in Hertz (Hz).

[0082] Abbreviations:

[0083] (±)BINAP (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthyl <![CDATA[Pd(dppf)Cl2]]> 1,1′-Bisdiphenylphosphine ferrocene palladium dichloride TEA Triethylamine TFA Trifluoroacetic acid <![CDATA[NaBH(OAc)3]]> Sodium triacetoxyborohydride DMSO dimethyl sulfoxide KOAc Potassium acetate Toluene Toluene <![CDATA[K2CO3]]> Potassium carbonate <![CDATA[Pd(PPh3)4]]> Tetraphenylphosphine palladium <![CDATA[Cs2CO3]]> cesium carbonate

[0084] Intermediate 1: Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (synthesized according to the method described in patent WO2017 / 11776)

[0085]

[0086] Intermediate 2: Synthesis of 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (synthesized according to the method described in patent WO2017 / 11776)

[0087]

[0088] Intermediate 3: Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-4-(5-(piperazin-1-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (synthesized according to the method described in patent WO2017 / 11776)

[0089]

[0090] Synthesis of Intermediate 4: 4-(5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile

[0091]

[0092] Step 1: (3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)boronic acid

[0093] 3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (371 mg) (synthesized according to patent WO2017 / 11776), pinacol diboronate (508 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg), and potassium acetate (196 mg) were added to a dry dioxane (30 mL) under nitrogen protection. The mixture was heated to 90 °C and stirred overnight, then cooled to room temperature. After filtration, the filter cake was washed with dichloromethane, and the filtrate was evaporated to dryness under reduced pressure to obtain crude 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ylboronic acid (300 mg), which was used directly in the next reaction.

[0094] Step 2: 3-(5-chloropyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0095] At room temperature, cesium carbonate powder (653 mg) was added to a DMSO (10 mL) solution of 2,5-dichloropyrazine (149 mg) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (198 mg), and the mixture was stirred at 85 °C for 4 h. After cooling, the reaction solution was poured into 50 mL of water and extracted with ethyl acetate. The extract was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 (V:V)) to give the title compound (250 mg).

[0096] Step 3: 3-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0097] The 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ylboronic acid (300 mg) from step 1 and the 3-(5-chloropyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (250 mg) from step 2 were dissolved in a mixed solution of dioxane and water (5:1) (50 mL). Under nitrogen protection, tetrakis(triphenylphosphine)palladium (110 mg) and anhydrous potassium carbonate powder (278 mg) were added sequentially. The mixture was then heated to 85 °C and stirred for 2 h. After cooling, the reaction solution was poured into water (150 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 (V:V)) to obtain the title compound (200 mg).

[0098] Step 4: 4-(5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0099] At 0°C, trifluoroacetic acid (4 mL) was slowly added dropwise to a solution of 200 mg of 3-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (200 mg) obtained in step 3 in dichloromethane (20 mL). After the addition was complete, the temperature was raised to room temperature and stirring was continued for 1 h. The reaction solution was concentrated, and the pH was adjusted to weakly alkaline by adding saturated sodium bicarbonate aqueous solution. The resulting solid was filtered and dried to obtain the title compound (140 mg).

[0100] Synthesis of Intermediate 5: 3-Cyano-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0101]

[0102] Step 1: 3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0103] 2,5-Dibromopyridine (4.74 g), 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (2.0 g), tris(dibenzylacetone)dipalladium (0.92 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (1.24 g), and cesium carbonate (6.52 g) were added to toluene (200 mL) under nitrogen protection, heated to 110 °C, and stirred overnight. After cooling to room temperature, the mixture was filtered, the filter cake was washed with dichloromethane, the filtrates were combined and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 4:1 (V:V)) to give 3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (1.2 g).

[0104] Step 2: (6-(6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)boronic acid

[0105] 3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (354 mg), pinacol diborate (510 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg), and potassium acetate (196 mg) were sequentially added to a dry dioxane (50 mL) under nitrogen protection. The reaction mixture was heated to 90 °C and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure to obtain crude (6-(6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)boronic acid, which was directly used in the next reaction.

[0106] Step 3: 3-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0107] The crude (6-(6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)boronic acid was dissolved in 50 mL of a mixed solvent of dioxane and water (4:1) with 238 mg of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridin-3-carboxynitrile (synthesized according to patent WO2017 / 11776) and 278 mg of potassium carbonate. Under nitrogen protection, tetra(triphenylphosphine)palladium (110 mg) was added, and the mixture was heated to 90 °C and stirred for 4 hours. The reaction mixture was cooled to room temperature and poured into 100 mL of water. It was extracted twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 2:1 (V:V)) to give 3-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (300 mg).

[0108] Step 4: 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridin-3-carboxylonitrile trifluoroacetate

[0109] At room temperature, the above-mentioned tert-butyl 3-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (4 mL) was added. The mixture was stirred for 2 hours until the reaction was complete, and the solvent was removed under vacuum. Methyl tert-butyl ether (50 mL) was added to the residue, and the mixture was sonicated. A solid precipitated out. The residue was filtered, and the filter cake was washed twice with methyl tert-butyl ether and dried under vacuum to obtain 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridin-3-carboxynitrile trifluoroacetate. (250 mg)

[0110] Step 5: 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0111] At room temperature, 250 mg of 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxynitrile trifluoroacetate was dissolved in 50 mL of tetrahydrofuran, and 274 mg of 6-methoxy-3-pyridinecarboxaldehyde was added. The mixture was stirred for 5 minutes, followed by the addition of 500 mg of sodium triacetoxyborohydride. The mixture was stirred until the reaction was complete, and the reaction solution was poured into a saturated sodium bicarbonate aqueous solution. The sample was extracted twice with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the sample was purified by column chromatography (eluent: dichloromethane:methanol = 30:1 (V:V)) to give 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile. (200 mg)

[0112] Step 6: 3-Cyano-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0113] At room temperature, 200 mg of 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile was dissolved in 30 mL of DMF, and 300 mg of DIEA was added, followed by 200 mg of N-phenylbis(trifluoromethanesulfonyl)imide. After stirring overnight at room temperature until the reaction was complete, the solution was poured into 50 mL of water and extracted twice with ethyl acetate. The organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 (V:V)) to give 1,3-cyano-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate. (210 mg)

[0114] Intermediate 6: 3-cyano-4-(6-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0115]

[0116] Step 1: 6-hydroxy-4-(6-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0117] The title compound was prepared by replacing 6-methoxy-3-pyridine carboxaldehyde with p-methylsulfonylbenzaldehyde according to step 5 of intermediate 5.

[0118] Step 2: 3-Cyano-4-(6-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0119] The title compound was prepared by replacing 6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile.

[0120] Intermediate 7: 3-cyano-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0121]

[0122] Step 1: 4-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0123] The title compound was prepared by replacing (6-(6-(6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)boronic acid with 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester according to the method of step 3 of intermediate 5.

[0124] Step 2: 6-hydroxy-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile trifluoroacetate

[0125] The title compound was prepared by replacing 3-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester with 4-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester with 4-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester according to step 4 of intermediate 5.

[0126] Step 3: 6-hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0127] The title compound was prepared by replacing 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridin-3-carboxylonitrile trifluoroacetate with 6-hydroxy-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile trifluoroacetate.

[0128] Step 4: 3-Cyano-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0129] The title compound was prepared by replacing 6-hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile according to step 6 of intermediate 5.

[0130] Intermediate 8: 3-cyano-4-(6-(4-(4-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0131]

[0132] Step 1: 6-hydroxy-4-(6-(4-(4-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0133] The title compound was prepared by replacing 6-methoxy-3-pyridine carboxaldehyde with p-methylsulfonylbenzaldehyde according to step 3 of intermediate 7.

[0134] Step 2: 3-Cyano-4-(6-(4-(4-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0135] The title compound was prepared by replacing 6-hydroxy-4-(6-(4-(4-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile according to step 4 of intermediate 7.

[0136] Intermediate 9: 3-cyano-4-(6-(6-(3-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0137]

[0138] Step 1: 6-hydroxy-4-(6-(6-(3-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0139] The title compound was prepared by replacing 6-methoxy-3-pyridine carboxaldehyde with 3-methylsulfonylbenzaldehyde according to step 5 of intermediate 5.

[0140] Step 2: 3-Cyano-4-(6-(6-(3-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0141] The title compound was prepared by replacing 6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(6-(3-(methylsulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile.

[0142] Intermediate 10: 3-cyano-4-(6-(4-(3-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0143]

[0144] Step 1: 6-hydroxy-4-(6-(4-(3-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0145] The title compound was prepared by replacing 6-methoxy-3-pyridine carboxaldehyde with 3-methylsulfonylbenzaldehyde according to step 3 of intermediate 7.

[0146] Step 2: 3-Cyano-4-(6-(4-(3-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0147] The title compound was prepared by replacing 6-hydroxy-4-(6-(4-(3-(methylsulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile according to step 4 of intermediate 7.

[0148] Intermediate 11: 3-cyano-4-(6-(6-(4-(methylthio)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0149]

[0150] Step 1: 6-hydroxy-4-(6-(6-(4-(methylthio)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0151] The title compound was prepared by replacing 6-methoxy-3-pyridine carboxaldehyde with p-methylthiobenzaldehyde according to step 5 of intermediate 5.

[0152] Step 2: 3-Cyano-4-(6-(6-(4-(methylthio)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yltrifluoromethanesulfonate

[0153] The title compound was prepared by replacing 6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(6-(4-(methylthio)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile.

[0154] Intermediate 12: 3-cyano-4-(6-(4-(4-(methylthio)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0155]

[0156] Step 1: 6-hydroxy-4-(6-(4-(4-(methylthio)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0157] The title compound was prepared by replacing 6-methoxy-3-pyridine carboxaldehyde with 4-methylthiobenzaldehyde according to step 3 of intermediate 7.

[0158] Step 2: 3-Cyano-4-(6-(4-(4-(methylthio)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yltrifluoromethanesulfonate

[0159] The title compound was prepared by replacing 6-hydroxy-4-(6-(4-(4-(methylthio)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile according to step 4 of intermediate 7.

[0160] Intermediate 13: 3-cyano-4-(6-(6-((6-(methylthio)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0161]

[0162] Step 1: 6-hydroxy-4-(6-(6-((6-(methylthio)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0163] The title compound was prepared by replacing 6-methoxy-3-pyridine carboxaldehyde with 6-(methylthio)nicotinaldehyde according to step 5 of intermediate 5.

[0164] Step 2: 3-Cyano-4-(6-(6-((6-(methylthio)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0165] The title compound was prepared by replacing 6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(6-((6-(methylthio)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile.

[0166] Intermediate 14: 3-cyano-4-(6-(4-((6-(methylthio)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl-trifluoromethanesulfonate

[0167]

[0168] Step 1: 6-hydroxy-4-(6-(4-((6-(methylthio)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-onitrile

[0169] The title compound was prepared by replacing 6-methoxy-3-pyridine carboxaldehyde with 6-(methylthio)nicotinaldehyde according to step 3 of intermediate 7.

[0170] Step 2: 3-Cyano-4-(6-(4-(4-(methylthio)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yltrifluoromethanesulfonate

[0171] The title compound was prepared by replacing 6-hydroxy-4-(6-(4-((6-(methylthio)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile according to step 4 of intermediate 7.

[0172] Intermediate 15: 3-cyano-4-(6-(6-((5-(methylthio)pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0173]

[0174] Step 1: 6-hydroxy-4-(6-(6-((5-(methylthio)pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0175] The title compound was prepared by replacing 6-methoxy-3-pyridinecarboxaldehyde with 5-(methylthio)pyridine-2-carboxaldehyde according to step 5 of intermediate 5.

[0176] Step 2: 3-Cyano-4-(6-(6-((5-(methylthio)pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl-trifluoromethanesulfonate

[0177] The title compound was prepared by replacing 6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(6-((5-(methylthio)pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile.

[0178] Intermediate 16: 3-cyano-4-(6-(4-((5-(methylthio)pyridin-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl-trifluoromethanesulfonate

[0179]

[0180] Step 1: 6-hydroxy-4-(6-(4-((5-(methylthio)pyridin-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-onitrile

[0181] The title compound was prepared by replacing 6-methoxy-3-pyridinecarboxaldehyde with 5-(methylthio)pyridine-2-carboxaldehyde according to step 3 of intermediate 7.

[0182] Step 2: 3-Cyano-4-(6-(4-((5-(methylthio)pyridin-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0183] The title compound was prepared by replacing 6-hydroxy-4-(6-(4-((5-(methylthio)pyridin-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile according to step 4 of intermediate 7.

[0184] Intermediate 17: Synthesis of 3-cyano-4-(6-(6-((5-methoxypyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0185]

[0186] Step 1: 6-hydroxy-4-(6-(6-((5-methoxypyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0187] At room temperature, 250 mg of 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxynitrile trifluoroacetate was dissolved in 50 mL of tetrahydrofuran, and 274 mg of 5-methoxy-2-pyridinecarboxaldehyde was added. The mixture was stirred for 5 minutes, followed by the addition of 500 mg of sodium triacetoxyborohydride. The mixture was stirred until the reaction was complete, and the reaction solution was poured into a saturated sodium bicarbonate aqueous solution. The sample was extracted twice with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the sample was purified by column chromatography (eluent: dichloromethane:methanol = 30:1 (V:V)) to give 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile. (210 mg)

[0188] Step 6: 3-Cyano-4-(6-(6-((5-methoxypyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0189] At room temperature, 210 mg of 6-hydroxy-4-(6-(6-((5-methoxypyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile was dissolved in 30 mL of DMF, and 300 mg of DIEA was added, followed by 200 mg of N-phenylbis(trifluoromethanesulfonyl)imide. After stirring overnight at room temperature until the reaction was complete, the solution was poured into 50 mL of water and extracted twice with ethyl acetate. The organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 2:1 (V:V)) to give 1,3-cyano-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate (270 mg).

[0190] Intermediate 18: 3-cyano-4-(6-(4-(2-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0191]

[0192] Step 1: 6-hydroxy-4-(6-(4-(2-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0193] The title compound was prepared by replacing 6-methoxy-3-pyridine carboxaldehyde with 2-methylsulfonylbenzaldehyde according to step 3 of intermediate 7.

[0194] Step 2: 3-Cyano-4-(6-(4-(2-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0195] The title compound was prepared by replacing 6-hydroxy-4-(6-(4-(2-(methylsulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile according to step 4 of intermediate 7.

[0196] Intermediate 19: 3-cyano-4-(6-(4-((5-methoxypyridin-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0197]

[0198] Step 1: 6-hydroxy-4-(6-(4-((5-methoxypyridin-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0199] The title compound was prepared by replacing 6-methoxy-3-pyridinecarboxaldehyde with 5-methoxypyridine-2-carboxaldehyde according to step 3 of intermediate 7.

[0200] Step 2: 3-Cyano-4-(6-(4-((5-methoxypyridin-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0201] The title compound was prepared by replacing 6-hydroxy-4-(6-(4-((5-methoxypyridin-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile according to step 4 of intermediate 7.

[0202] Intermediate 20: 3-cyano-4-(6-(6-(2-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0203]

[0204] Step 1: 6-hydroxy-4-(6-(6-(2-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0205] The title compound was prepared by replacing 6-methoxy-3-pyridine carboxaldehyde with 2-methylsulfonylbenzaldehyde according to step 5 of intermediate 5.

[0206] Step 2: 3-Cyano-4-(6-(6-(2-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0207] The title compound was prepared by replacing 6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile with 6-hydroxy-4-(6-(6-(2-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile.

[0208] Intermediate 21: Synthesis of 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(1-difluoromethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile

[0209]

[0210] Step 1: 3-(5-(3-cyano-6-(trifluoromethanesulfonate)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0211] 3-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (432 mg) was dissolved in DMF (20 mL), and DIEA (260 mg) was added, followed by N-phenylbis(trifluoromethanesulfonyl)imide (400 mg). The mixture was stirred at room temperature for 2 hours, poured into water (100 mL), and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 2:1 (V:V)) to give the target compound (450 mg).

[0212] Step 2: 3-(5-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0213] 3-(5-(3-cyano-6-(trifluoromethanesulfonate)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (282 mg), 1-difluoromethylpyrazol-4-boric acid (100 mg), tetrakis(triphenylphosphine)palladium (55 mg), and potassium carbonate (139 mg) were sequentially added to a flask containing dioxane and water (50 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was poured into water (150 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (200 mg).

[0214] Step 3: 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile

[0215] At room temperature, 200 mg of the above-mentioned tert-butyl 3-(5-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid was added.

[0216] Dissolve in dichloromethane (20 mL), add trifluoroacetic acid (4 mL), stir for 2 hours, and remove the solvent under vacuum. Add saturated sodium bicarbonate aqueous solution to the residue until the system is weakly alkaline, filter, and dry the resulting solid of the target compound (130 mg).

[0217] Intermediate 22: Synthesis of 4-(6-(3,8-diazabicyclo[3.2.1]octane-3-yl)pyridin-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile

[0218]

[0219] Step 1: 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-hydroxypyrazolo[1,5-a]pyridine-3-carboxynitrile

[0220] 6-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carboxylonitrile (238 mg), 1-difluoromethylpyrazol-4-boronic acid (200 mg), tetra-triphenylphosphine palladium (110 mg), and potassium carbonate (278 mg) were sequentially added to a flask containing dioxane and water (50 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction solution was poured into water (150 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (v:v)) to obtain the target compound (250 mg).

[0221] Step 2: 3-Cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate

[0222] 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-hydroxypyrazolo[1,5-a]pyridine-3-carboxynitrile (250 mg) was dissolved in DMF (20 mL), and DIEA (300 mg) was added, followed by N-phenylbis(trifluoromethanesulfonyl)imide (400 mg). The mixture was stirred at room temperature for 2 hours, poured into water (50 mL), and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (V:V)) to give the target compound. (300 mg)

[0223] Step 3: 3-Cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ylboronic acid

[0224] 3-Cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (300 mg), pinacol diboronate (254 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg), and potassium acetate (196 mg) were added to a dry dioxane (30 mL) under nitrogen protection, and the mixture was heated to 90 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, the filter cake was washed with dichloromethane, and the filtrate was evaporated to dryness under reduced pressure to obtain the crude target compound, which was used directly in the next reaction.

[0225] Step 4: 3-(5-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester

[0226] The boric acid (150 mg), 3-(5-bromopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (183 mg), tetraphenylphosphine palladium (50 mg), and potassium carbonate (139 mg) obtained above were sequentially added to a flask containing dioxane and water (50 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction solution was poured into water (150 mL) and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (250 mg).

[0227] Step 5: 4-(6-(3,8-diazabicyclo[3.2.1]octane-3-yl)pyridin-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile

[0228] At room temperature, 250 mg of the above-mentioned 3-(5-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester was added.

[0229] Dissolve in dichloromethane (20 mL), add trifluoroacetic acid (5 mL), stir for 1 hour, and remove the solvent under vacuum. Add saturated sodium bicarbonate aqueous solution to the residue until the system is weakly alkaline, filter and dry the resulting solid of the target compound (180 mg).

[0230] Intermediate 23: Synthesis of 4-(5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazin-2-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylon

[0231]

[0232] Step 1: 3-(5-(3-cyano-6-(1-difluoromethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0233] 3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ylboronic acid

[0234] (303 mg) and 3-(5-chloropyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (250 mg) from step 2 of intermediate 4 were dissolved in a mixed solution of dioxane and water (5:1) (50 mL). Under nitrogen protection, tetrakis(triphenylphosphine) palladium (110 mg) and anhydrous potassium carbonate powder (278 mg) were added sequentially. The mixture was then heated to 85 °C and stirred for 2 hours. After cooling to room temperature, the reaction solution was poured into water (150 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1 (V:V)) to obtain the title compound (400 mg).

[0235] Step 2: 4-(5-(3,6-diaza-bicyclo[3.1.1]heptane-3-yl)pyrazin-2-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile

[0236] At 0°C, trifluoroacetic acid (5 mL) was slowly added dropwise to a solution of 400 mg of 3-(5-(3-cyano-6-(1-difluoromethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester in dichloromethane (20 mL). After the addition was complete, the solution was brought to room temperature and stirred for 1 hour. The reaction solution was concentrated, and the pH was adjusted to weakly alkaline by adding saturated sodium bicarbonate aqueous solution. The resulting solid was filtered and dried to obtain the title compound (240 mg).

[0237] Intermediate 24: Synthesis of 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-onitrile

[0238]

[0239] Step 1: 4-(5-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0240] 3-Cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ylboronic acid (303 mg) and tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (342 mg) were dissolved in a mixture of dioxane and water (5:1) (50 mL). Tetraphenylphosphine palladium (110 mg) and anhydrous potassium carbonate powder (278 mg) were added sequentially under nitrogen protection. The mixture was then heated to 85 °C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (150 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1 (V:V)) to obtain the title compound (410 mg).

[0241] Step 2: 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-onitrile

[0242] At 0°C, trifluoroacetic acid (5 mL) was slowly added dropwise to a solution of 410 mg 4-(5-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (410 mg) in dichloromethane (20 mL). After the addition was complete, the mixture was brought to room temperature and stirred for 1 hour. The reaction solution was concentrated, and the pH was adjusted to weakly alkaline by adding saturated sodium bicarbonate aqueous solution. The resulting solid was filtered and dried to obtain the title compound (220 mg).

[0243] Intermediate 25: Synthesis of 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(1-trifluoromethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile

[0244]

[0245] Step 1: 3-(5-(3-cyano-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0246] 3-(5-(3-cyano-6-(trifluoromethanesulfonate)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (282 mg), 1-trifluoromethylpyrazol-4-boric acid (110 mg), tetrakis(triphenylphosphine)palladium (50 mg), and potassium carbonate (139 mg) were sequentially added to a flask containing dioxane and water (40 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was poured into water (150 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (170 mg).

[0247] Step 2: Synthesis of 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(1-trifluoromethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile

[0248] At room temperature, 170 mg of the above-mentioned tert-butyl 3-(5-(3-cyano-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid was added.

[0249] Dissolve in dichloromethane (20 mL), add trifluoroacetic acid (4 mL), stir for 2 hours, and remove the solvent under vacuum. Add saturated sodium bicarbonate aqueous solution to the residue until the system is weakly alkaline, filter, and dry the resulting solid of the target compound (120 mg).

[0250] Example 1: 4-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0251]

[0252] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), acryloyl chloride (15 mg) and triethylamine (30 mg) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (30 mg).

[0253] 1H NMR (400MHz, CDCl3) δ8.64 (1H, d, J = 1.2Hz), 8.38 (1H, d, J = 2.8Hz), 8.26 (1H, s), 7.76-7.78 (2H, m), 7.68 (1H, s), 7.39 (1H, d, J = 1.6Hz), 6.79 (1H , d, J=8.8Hz), 6.62 (1H, dd, J=16.8Hz, 10.4Hz), 6.35 (1H, dd, J=16.8Hz, 2.0Hz), 5.75 (1H, dd, J=10.4Hz, 2.0Hz), 3.99 (3H, s), 3.66-3.88 (8H, m).

[0254] Example 2: 4-(6-(4-(cyclopent-1-en-1-carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0255]

[0256] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), and cyclopent-1-en-1-carboxyl chloride (20 mg) and triethylamine (30 mg) were added. The mixture was then heated to room temperature and stirred for 1 hour. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (40 mg).

[0257] 1 H NMR (400MHz, CDCl3) δ8.63 (1H, s), 8.38 (1H, d, J = 2.4Hz), 8.26 (1H, s), 7.75-7.78 (2H, m), 7.68 (1H, s), 7.39 (1H, s), 6.79 (1 H, d, J = 8.4Hz), 5.92-5.95 (1H, m), 3.99 (3H, s), 3.66-3.82 (8H, m), 2.62-2.68 (2H, m), 2.48-2.52 (2H, m), 1.94-2.02 (2H, m).

[0258] Example 3: 4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0259]

[0260] At 0°C, intermediate 4 (40 mg) was dissolved in THF (10 mL), followed by the addition of 6-methoxynicotinaldehyde (27 mg) and sodium triacetoxyborohydride (75 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (35 mg).

[0261] 1 H NMR (400MHz, CDCl3) δ8.67 (1H, s), 8.56 (1H, s), 8.31 (1H, s), 8.28 (1H, s), 8.11 (1H, s), 7.82 (1H, s), 7.66-7.72 (3H, m), 6.74 (1H, d, J = 8.8Hz), 4.00 (3H, s), 3.77-3.87 (7H, m), 3.58-3.76 (4H, m), 2.69-2.86 (1H, m), 1.66-1.73 (1H, m).

[0262] Example 4: 6-(4-hydroxy-4-methylpiperidin-1-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0263]

[0264] Intermediate 7 (57 mg), 4-methyl-4-hydroxypiperidine (23 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (65 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (25 mg).

[0265] 1H NMR (400MHz, CDCl3) δ8.30 (1H, d, J = 2.8Hz), 8.15 (1H, s), 8.07 (1H, d, J = 2.0Hz), 8.02 (1H, d, J = 2.0Hz), 7.70 (1H, dd, J = 8.8Hz, 2.8Hz), 7.59-7.63 (1H, m), 7.16 (1H, d, J = 2.0 Hz), 6.72-6.75 (2H, m), 3.94 (3H, s), 3.60-3.66 (4H, m), 3.49 (2H, s), 3.27-3.33 (2H, m ), 3.14-3.20 (2H, m), 2.52-2.58 (4H, m), 1.71-1.86 (4H, m), 1.33 (3H, s), 1.15 (1H, s).

[0266] Example 5: 6-(4-(2-hydroxypropane-2-yl)piperidin-1-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0267]

[0268] Intermediate 7 (57 mg), 2-(piperidin-4-yl)prop-2-ol (29 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (65 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (22 mg).

[0269] 1H NMR (400MHz, CDCl3) δ8.30 (1H, d, J = 2.4Hz), 8.15 (1H, s), 8.07 (1H, d, J = 2.0Hz), 7.99 ( 1H, d, J = 2.0Hz), 7.70 (1H, dd, J = 8.8Hz, 2.0Hz), 7.62 (1H, d, J = 8.8Hz), 7.16 (1H, d, J = 1 .6Hz), 6.75 (1H, s), 6.73 (1H, s), 3.94 (3H, s), 3.60-3.70 (6H, m), 3.49 (2H, s), 2.65-2 .72 (2H, m), 2.52-2.58 (4H, m), 1.92 (2H, d, J = 12.0Hz), 1.41-1.62 (3H, m), 1.23 (6H, s).

[0270] Example 6: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-methylcyclopent-1-en-1-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0271]

[0272] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), and 2-methylcyclopent-1-ene-1-carboxyl chloride (23 mg) and triethylamine (30 mg) were added. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (36 mg).

[0273] 1 H NMR (400MHz, CDCl3) δ8.63 (1H, s), 8.38 (1H, d, J = 2.4Hz), 8.25 (1H, s), 7.75-7.78 (2H, m), 7.68 (1H, s), 7.39 (1H, s), 6.80 (1H, d, J = 8.0Hz), 3. 99 (3H, s), 3.78-3.85 (2H, m), 3.64-3.70 (4H, m) 3.53-3.61 (2H, m), 2.5 9-2.65 (2H, m), 2.41 (2H, t, J=7.2Hz), 1.90-1.98 (2H, m), 1.74 (3H, s).

[0274] Example 7: 6-(3-hydroxy-3-methylazacyclobutane-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0275]

[0276] Intermediate 5 (59 mg), 3-methyl-3-acridinol hydrochloride (27 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (15 mg).

[0277] 1 H NMR (400MHz, CDCl3) δ8.37 (1H, d, J = 2.4Hz), 8.15 (1H, s), 8.10 (1H, d, J = 2.4Hz), 7.78 (1H, dd, J = 8.8Hz, 2.4Hz), 7.71 (1H, d, J = 1.6Hz), 7.63 (1H, dd, J = 8.8Hz, 2.4Hz), 6.73 ( 1H, d, J=1.6Hz), 6.71 (1H, d, J=8.4Hz), 6.68 (1H, d, J=8.4Hz), 3.90-3.93 (5H, m), 3.7 6-3.87(6H,m), 3.56-3.64(4H,m), 2.66-2.72(1H,m), 1.67(3H,s), 1.62-1.66(1H,m).

[0278] Example 8: 4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-dimethylpiperazine-1-thiocarboxamide

[0279]

[0280] Intermediate 1 (39 mg) was dissolved in THF (10 mL) at 0 °C, and dimethylaminothiocarbamate chloride (20 mg) and triethylamine (50 mg) were added. The mixture was then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to give the title compound (27 mg).

[0281] 1 H NMR (400MHz, CDCl3) δ8.64 (1H, d, J = 1.6Hz), 8.38 (1H, d, J = 2.4Hz), 8.26 (1H, s), 7.79 (1H, s), 7.77 (1H, dd, J = 8.4Hz, 2.4Hz) , 7.68 (1H, s), 7.40 (1H.dJ=1.6Hz), 6.80 (1H, d, J=8.4Hz), 3.99 (3H, s), 3.74-3.77 (4H, m), 3.63-3.66 (4H, m), 3.20 (6H, s).

[0282] Example 9: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-((5-(methylthio)pyridin-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0283]

[0284] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), followed by the addition of 5-(methylthio)pyridine-2-carboxaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (31 mg).

[0285] 1H NMR (400MHz, CDCl3) δ8.64 (1H, d, J = 1.6Hz), 8.48 (1H, d, J = 2.4Hz), 8.36 (1H, d, J = 2.4Hz), 8.25 (1H , s), 7.81 (1H, dd, J = 8.0Hz, 2.4Hz), 7.79 (1H, s), 7.76 (1H, dd, J = 8.8Hz, 2.4Hz), 7.70 (1H, s), 7.41 ( 1H, d, J = 1.2Hz), 7.34 (1H, d, J = 8.0Hz), 6.79 (1H, d, J = 8.8Hz), 4.43 (2H, d, J = 13.6Hz), 3.99 (3H, s) , 3.98 (2H, s), 3.69 (2H, t, J = 12.8Hz), 3.40 (2H, d, J = 11.2Hz), 2.66 (2H, t, J = 11.2Hz), 2.59 (3H, s).

[0286] Example 10: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-((6-(methylthio)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0287]

[0288] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), followed by the addition of 6-(methylthio)nicotinaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (21 mg).

[0289] 1 H NMR (400MHz, CDCl3) δ 8.62 (1H, s), 8.39 (1H, s), 8.36 (1H, d, J = 2.8Hz), 8.26 (1H, s), 7.78 (1H, s), 7.74 (1H, dd, J = 8.8Hz, 2.8Hz), 7.67 (1H, s), 7. 54 (1H, d, J = 8.4Hz), 7.38 (1H, s), 7.18 (1H, d, J = 8.0Hz), 6.77 (1H, d, J = 9 .2Hz), 3.99 (3H, s), 3.63-3.68 (4H, m), 3.51 (2H, s), 2.54-2.60 (7H, m).

[0290] Example 11: 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-(methylthio)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0291]

[0292] At 0 °C, 50 mg of 6-hydroxy-4-(6-(6-((6-(methylthio)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile was dissolved in 10 mL of dioxane. 1 mL of 2,2-dimethylethylene oxide and 50 mg of potassium carbonate were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours in a sealed tube. After cooling, the reaction mixture was poured into water and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the title compound (15 mg).

[0293] 1 H NMR (400MHz, CDCl3) δ8.39-8.42 (2H, m), 8.21 (1H, s), 8.15 (1H, d, J = 1.6Hz), 7.77 (1H, dd, J = 8.8Hz, 2. 8Hz), 7.52-7.57 (1H, m), 7.16 (1H, d, J = 2.4Hz), 7.14 (1H, d, J = 8.0Hz), 6.67 (1H, d, J = 8.4Hz), 3.87 (2H s), 3.72-3.85 (4H, m), 3.52-3.64 (4H, m), 2.65-2.71 (1H, m), 2.55 (3H, s), 2.05 (1H, s), 1.65 (1H, d, J = 8.0Hz), 1.39 (6H, s).

[0294] Example 12: 4-(6-(4-(2-(methoxymethyl)cyclopent-1-en-1-carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0295]

[0296] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), and 2-(methoxymethyl)cyclopent-1-ene-1-carboxyl chloride (20 mg) and triethylamine (30 mg) were added. The mixture was then heated to room temperature and stirred for 1 hour. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (30 mg).

[0297] 1 H NMR (400MHz, CDCl3) δ8.64 (1H, d, J = 1.2Hz), 8.38 (1H, d, J = 2.4Hz), 8.26 (1H, s) , 7.76-7.79 (2H, m), 7.68 (1H, s), 7.39 (1H, d, J = 1.2Hz), 6.80 (1H, d, J = 8.8Hz), 3 .99(3H,s), 3.98(2H,s), 3.78-3.84(2H,m), 3.63-3.71(4H,m), 3.53-3.59(2H,m ), 3.33 (3H, s), 2.66 (2H, t, J = 7.6Hz), 2.51 (2H, t, J = 7.6Hz), 1.95-2.03 (2H, m).

[0298] Example 13: 6-(3-cyanozazecyclobutane-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0299]

[0300] Intermediate 5 (59 mg), 3-cyanozycyclobutane hydrochloride (24 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (15 mg).

[0301] 1H NMR (400MHz, CDCl3) δ8.37 (1H, d, J=2.4Hz), 8.19 (1H, s), 8.10 (1H, s), 7.78 (1H, dd, J=8.8Hz, 2.4Hz), 7.74 (1H, d, J=2.0Hz), 7.57-7.71 (1H , m), 6.67-6.73 (3H, m), 4.27 (2H, t, J = 7.2Hz), 4.16 (2H, t, J = 7.2Hz), 3.92 (3H, s), 3.49-3.90 (9H, m), 2.58-2.82 (1H, m), 1.62-1.71 (1H, m).

[0302] Example 14: 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0303]

[0304] Intermediate 5 (59 mg), 2-oxa-6-azaspiro[3.3]heptane (20 mg), tris(dibenzylacetone)dipalladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (65 mg) were added sequentially to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (25 mg).

[0305] 1 H NMR (400MHz, CDCl3) δ8.37 (1H, d, J = 2.8Hz), 8.15 (1H, s), 8.10 (1H, d, J = 2.0Hz), 7.77 (1H, dd, J = 8.8Hz, 2.8Hz), 7.61-7.74 (2H, m), 6. 67-6.74(3H,m), 4.87(4H,s), 4.09(4H,s), 3.92(3H,s), 3.77-3.90(4H,m), 3.55-3.70(4H,m), 2.67-2.83(1H,m), 1.65-1.70(1H,m).

[0306] Example 15: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(3-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0307]

[0308] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), followed by the addition of 3-methylsulfonylbenzaldehyde (37 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to give the title compound (31 mg).

[0309] 1 H NMR (400MHz, CDCl3) δ8.63 (1H, d, J = 1.2Hz), 8.36 (1H, d, J = 2.8Hz), 8.26 (1H, s), 7 .97 (1H, s), 7.86 (1H, d, J = 7.6Hz), 7.78 (1H, s), 7.74 (1H, dd, J = 8.8Hz, 2.4Hz), 7.6 9 (1H, d, J = 7.6Hz), 7.68 (1H, s), 7.56 (1H, t, J = 7.6Hz), 7.39 (1H, d, J = 1.2Hz), 6.77 (1H, d, J = 8.8Hz), 3.99 (3H, s), 3.65-3.69 (6H, m), 3.08 (3H, s), 2.58-2.60 (4H, m).

[0310] Example 16: 6-(1-methyl-1H-pyrazole-4-yl)-4-(6-(4-(4-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0311]

[0312] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), followed by the addition of 4-methylsulfonylbenzaldehyde (37 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to give the title compound (29 mg).

[0313] 1 H NMR (400MHz, CDCl3) δ8.63 (1H, d, J = 1.6Hz), 8.36 (1H, d, J = 2.8Hz), 8.26 (1H, s), 7.92 (2H, d, J = 8.4Hz), 7.78 (1H, s), 7.75 (1H, dd, J = 8.8Hz, 2.4Hz) , 7.67 (1H, s), 7.60 (2H, d, J = 8.0Hz), 7.39 (1H, d, J = 1.2Hz), 6.78 (1H, d, J =8.8Hz), 3.99 (3H, s), 3.63-3.71 (6H, m), 3.08 (3H, s), 2.56-2.62 (4H, m).

[0314] Example 17: 6-(1-methyl-1H-pyrazole-4-yl)-4-(6-(4-(4-(methylthio)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0315]

[0316] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), followed by the addition of 4-methylthiobenzaldehyde (30 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (23 mg).

[0317] 1 H NMR (400MHz, CDCl3) δ8.62 (1H, d, J = 1.2Hz), 8.35 (1H, d, J = 2.4Hz), 8.25 (1H, s), 7.78 (1H, s), 7.73 (1H, dd, J = 8.8Hz, 2.4Hz), 7.67 (1H, s), 7.38 (1H, d, J = 1 .2Hz), 7.29 (2H, d, J = 8.4Hz), 7.24 (2H, d, J = 8.4Hz), 6.76 (1H, d, J = 8.4Hz), 3 .98(3H,s), 3.63-3.71(4H,m), 3.54(2H,s), 2.54-2.62(4H,m), 2.49(3H,s).

[0318] Example 18: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-((6-(ethylthio)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0319]

[0320] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), followed by the addition of 6-(ethylthio)nicotinaldehyde (34 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (26 mg).

[0321] 1 H NMR (400MHz, CDCl3) δ8.62 (1H, d, J = 1.6Hz), 8.38 (1H, d, J = 2.0Hz), 8.35 (1H, d, J = 2.4Hz) , 8.25 (1H, s), 7.78 (1H, s), 7.73 (1H, dd, J = 8.8Hz, 2.4Hz), 7.67 (1H, s), 7.50-7.56 (1H, m) , 7.38 (1H, d, J = 1.2Hz), 7.16 (1H, d, J = 8.4Hz), 6.76 (1H, d, J = 8.8Hz), 3.98 (3H, s), 3.61-3 .71 (4H, m), 3.51 (2H, s), 3.17 (2H, q, J = 7.6Hz), 2.52-2.60 (4H, m), 1.38 (3H, t, J = 7.6Hz).

[0322] Example 19: 6-(morpholin-1-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0323]

[0324] Intermediate 7 (57 mg), morpholine (17 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (65 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (15 mg).

[0325] 1 H NMR (400MHz, CDCl3) δ8.30 (1H, d, J = 2.8Hz), 8.17 (1H, s), 8.08 (1H, s), 7.99 (1H, d, J = 2.0Hz), 7.70 (1H, dd, J = 8.8Hz, 2.4Hz), 7.57-7.69 (1H, m), 7.1 3 (1H, d, J=2.0Hz), 6.73-6.76 (2H, m), 3.94 (3H, s), 3.88-3.90 (4H, m), 3. 59-3.72(4H,m), 3.42-3.58(2H,m), 3.13-3.16(4H,m), 2.49-2.65(4H,m).

[0326] Example 20: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(6-(3-(methylsulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0327]

[0328] At 0°C, intermediate 2 (39 mg) was dissolved in THF (10 mL), followed by the addition of 3-methylsulfonylbenzaldehyde (37 mg) and sodium triacetoxyborohydride (75 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (31 mg).

[0329] 1H NMR (400MHz, CDCl3) δ8.64 (1H, d, J = 1.2Hz), 8.43 (1H, d, J = 2.4Hz), 8.27 (1H, s) , 7.99 (1H, s), 7.79-7.84 (3H, m), 7.68-7.72 (2H, m), 7.52 (1H, t, J=7.6Hz), 7.42 (1H, d, J = 1.2Hz), 6.71 (1H, d, J = 8.8Hz), 3.99 (3H, s), 3.81-3.91 (4H, m), 3.77 (2 H, s), 3.62-3.70 (2H, m), 3.07 (3H, s), 2.77-2.84 (1H, m), 1.71 (1H, d, J=9.2Hz).

[0330] Example 21: 6-(1-methyl-1H-pyrazole-4-yl)-4-(6-(4-(2-(methylthio)ethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0331]

[0332] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), followed by the addition of 3-methylthiopropionaldehyde (21 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (33 mg).

[0333] 1 H NMR (400MHz, CDCl3) δ8.63 (1H, d, J = 1.2Hz), 8.36 (1H, d, J = 2.8Hz), 8.26 (1H, s), 7.78 (1H, s), 7.75 (1H, dd, J = 8.8Hz, 2.8Hz) , 7.67 (1H, s), 7.39 (1H, d, J = 1.2Hz), 6.78 (1H, d, J = 8.8Hz), 3.99 (3H, s), 3.63-3.74 (4H, m), 2.56-2.74 (8H, m), 2.16 (3H, s).

[0334] Example 22: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(6-((5-(methylthio)pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0335]

[0336] At 0°C, intermediate 2 (40 mg) was dissolved in THF (10 mL), followed by the addition of 5-methylthiopyridine-2-carboxaldehyde (31 mg) and sodium triacetoxyborohydride (75 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (33 mg).

[0337] 1 H NMR (400MHz, CDCl3) δ8.67 (1H, d, J = 1.6Hz), 8.45 (1H, d, J = 2.8Hz), 8.43 (1H, d, J = 2.4Hz), 8.2 9 (1H, s), 7.86 (1H, dd, J = 8.8Hz, 2.4Hz), 7.80 (1H, s), 7.76 (1H, dd, J = 8.4Hz, 2.4Hz), 7.70 (1H, s), 7.42 (1H, d, J = 1.6Hz), 7.35 (1H, d, J = 8.4Hz), 6.75 (1H, d, J = 8.8Hz), 4.38 (2H, d, J = 6.0Hz) , 3.98-4.01 (5H, m), 3.88-3.92 (4H, m), 3.25-3.31 (1H, m), 2.57 (3H, s), 1.86 (1H, d, J = 6.0Hz).

[0338] Example 23: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-((6-(methylthio)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0339]

[0340] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), followed by the addition of 6-(methylthio)nicotinaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (27 mg).

[0341] 1 H NMR (400MHz, CDCl3) δ8.64 (1H, d, J = 1.2Hz), 8.39 (1H, d, J = 2.8Hz), 8.27 (1 H, s), 8.22 (1H, d, J = 2.4Hz), 7.77-7.80 (2H, m), 7.68 (1H, s), 7.40 (1H, d, J = 1.6Hz), 7.20 (1H, dd, J=8.8Hz, 2.8Hz), 7.13 (1H, d, J=8.8Hz), 6.84 (1H, d, J=8.8Hz), 3.99 (3H, s), 3.82-3.85 (4H, m), 3.27-3.30 (4H, m), 2.56 (3H, s).

[0342] Example 24: 6-(1-methyl-1H-pyrazole-4-yl)-4-(6-(4-(2-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0343]

[0344] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), followed by the addition of 2-methylsulfonylbenzaldehyde (37 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (34 mg).

[0345] 1 H NMR (400MHz, CDCl3) δ8.63 (1H, d, J = 1.6Hz), 8.36 (1H, d, J = 2.8Hz), 8.25 (1H, s), 8.14 (1 H, d, J=8.0Hz), 7.78 (1H, s), 7.74 (1H, dd, J=8.8Hz, 2.4Hz), 7.67 (1H, s), 7.60 (1H, t, J=7 .2Hz), 7.51 (1H, t, J = 7.6Hz), 7.45 (1H, d, J = 7.2Hz), 7.38 (1H, d, J = 1.2Hz), 6.77 (1H, d, J=9.2Hz), 4.02 (2H, s), 3.99 (3H, s), 3.58-3.65 (4H, m), 3.46 (3H, s), 2.64-2.72 (4H, m).

[0346] Example 25: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0347]

[0348] At 0°C, intermediate 2 (39 mg) was dissolved in THF (10 mL), followed by the addition of 4-methylsulfonylbenzaldehyde (37 mg) and sodium triacetoxyborohydride (75 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (30 mg).

[0349] 1 H NMR (400MHz, CDCl3) δ8.65 (1H, s), 8.44 (1H, d, J = 2.8Hz), 8.28 (1H, s), 7.90 (2H, d, J = 8.4Hz), 7.81 (1H, dd, J = 8.8Hz, 2.4Hz), 7.80 (1H, s), 7.69 (1H, s) , 7.59-7.65 (2H, m), 7.42 (1H, d, J = 1.2Hz), 6.71 (1H, d, J = 8.4Hz), 3.99 (3H , s), 3.55-3.95 (8H, m), 3.05 (3H, s), 2.66-2.86 (1H, m), 1.66-1.74 (1H, m).

[0350] Example 26: 6-(3,3-difluoroazacyclobutane-1-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0351]

[0352] Intermediate 7 (57 mg), 3,3-difluorotrimethylimine hydrochloride (26 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (14 mg).

[0353] 1 H NMR (400MHz, CDCl3) δ8.30 (1H, d, J = 2.0Hz), 8.17 (1H, s), 8.08 (1H, d, J = 2.0Hz), 7.76 (1H, d, J = 2.0Hz), 7.70 (1H, dd, J = 9.2Hz, 2.4H z), 7.59-7.65 (1H, m), 6.70-6.76 (3H, m), 4.30 (4H, t, J = 11.6Hz), 3.94 (3H, s), 3.60-3.71 (4H, m), 3.50 (2H, s), 2.50-2.62 (4H, m).

[0354] Example 27: 6-(3-methoxyazacyclobutane-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0355]

[0356] Intermediate 5 (59 mg), 3-methoxyazacyclobutane (18 mg), tris(dibenzylacetone)dipalladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (65 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (10 mg).

[0357] 1H NMR (400MHz, CDCl3) δ8.39 (1H, s), 8.11-8.15 (2H, m), 7.81 (1H, d, J = 7.6Hz), 7.66-7.75 (2H, m), 6.78 (1H, d, J = 7.6Hz), 6.74 (1H, d, J = 2.0Hz ), 6.71 (1H, d, J = 8.8Hz), 4.37-4.43 (1H, m), 4.17 (2H, t, J = 6.8Hz), 3.62-4.05 (13H, m), 3.36 (3H, s), 2.53-2.66 (1H, m), 1.76-1.84 (1H, m).

[0358] Example 28: 6-(3-hydroxy-3-(trifluoromethyl)azacyclobutane-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0359]

[0360] Intermediate 5 (59 mg), 3-trifluoromethyl-3-acridinol hydrochloride (35 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (17 mg).

[0361] 1 H NMR (400MHz, CDCl3) δ8.37 (1H, d, J = 2.4Hz), 8.16 (1H, s), 8.10 (1H, s), 7.65-7.79 (3H, m), 6.67-6.74 (3H, m), 4.28 ( 2H, d, J = 8.4Hz), 3.97 (2H, d, J = 8.4Hz), 3.78-3.94 (7H, m), 3.54-3.72 (4H, m), 2.66-2.86 (1H, m), 1.65-1.72 (1H, m).

[0362] Example 29: 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(4-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-α]pyridin-3-onitrile

[0363]

[0364] At 0 °C, 49 mg of 6-hydroxy-4-(6-(4-(4-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile was dissolved in 10 mL of dioxane, followed by the addition of 1 mL of 2,2-dimethylethylene oxide and 50 mg of potassium carbonate in a sealed tube. The mixture was heated to 60 °C and stirred for 12 hours. After cooling, the reaction mixture was poured into water and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (13 mg).

[0365] 1 H NMR (400MHz, CDCl3) δ 8.33 (1H, d, J = 2.8Hz), 8.19 (1H, s), 8.13 (1H, d, J = 2.4Hz), 7.92 (2H, d, J = 8.0Hz), 7.70 (1H, dd, J = 9.2Hz, 2.8Hz), 7.59 (2H, d, J=8.4Hz), 7.13 (1H, d, J=2.0Hz), 6.75 (1H, d, J=8.4Hz), 3.85 (2H, s), 3.6 4-3.68 (6H, m), 3.07 (3H, s), 2.56-2.59 (4H, m), 2.05 (1H, s), 1.38 (6H, s).

[0366] Example 30: 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(7-oxa-2-aza-spiro[3.5]non-2-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0367]

[0368] Intermediate 5 (59 mg), 7-oxa-2-azaspiro[3.5]nonane hydrochloride (33 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (19 mg).

[0369] 1 H NMR (400MHz, CDCl3) δ8.38 (1H, d, J = 2.8Hz), 8.14 (1H, s), 8.12 (1H, s), 7.73-7.94 (2H, m), 7.70 (1H, d, J = 2.0Hz), 6.7 3-6.76 (2H, m), 6.69 (1H, d, J=8.8Hz), 3.42-4.15 (19H, m), 2.70-3.10 (1H, m), 1.86-1.89 (4H, m), 1.70-1.78 (1H, m).

[0370] Example 31: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(6-(4-(methylthio)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0371]

[0372] At 0°C, intermediate 2 (39 mg) was dissolved in THF (10 mL), followed by the addition of 4-methylthiobenzaldehyde (37 mg) and sodium triacetoxyborohydride (75 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (32 mg).

[0373] 1 H NMR (400MHz, CDCl3) δ8.66 (1H, d, J = 1.2Hz), 8.46 (1H, s), 8.28 (1H, s), 7.87 (1H, d, J = 9.2Hz), 7.80 (1H, s), 7.70 (1H, s), 7.56-7.64 (2H, m), 7.43 (1 H, d, J = 1.2Hz), 7.25-7.27 (2H, m), 6.74 (1H, d, J = 9.2Hz), 4.37-4.55 (2H, m), 3.86-4.11(9H, m), 3.35-3.61(1H, m), 2.48(3H, s), 1.64-1.68(1H, m).

[0374] Example 32: 6-(3-cyanozyracyclobutane-1-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0375]

[0376] Intermediate 7 (57 mg), 3-cyanozycyclobutane hydrochloride (24 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (12 mg).

[0377] 1 H NMR (400MHz, CDCl3) δ8.39 (1H, s), 8.15 (1H, s), 8.12 (1H, s), 7.80 (1H, d, J = 9.2Hz), 7.70 (1H, s) , 7.26 (1H, s), 6.74-6.81 (2H, m), 6.70 (1H, d, J = 9.2Hz), 3.51-4.09 (14H, m), 1.78-1.90 (4H, m).

[0378] Example 33: 6-(3-methoxyazine-1-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0379]

[0380] Intermediate 7 (57 mg), 3-methoxyazacyclobutane (18 mg), tris(dibenzylacetone)dipalladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (65 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (12 mg).

[0381] 1H NMR (400MHz, CDCl3) δ8.29 (1H, d, J = 2.4Hz), 8.12 (1H, s), 8.08 (1H, s), 7.68- 7.72 (2H, m), 7.58-7.67 (1H, m), 6.73-6.77 (2H, m), 6.70 (1H, d, J = 2.0Hz), 4. 35-4.41 (1H, m), 4.15 (2H, t, J = 6.8Hz), 3.94 (3H, s), 3.75 (2H, dd, J = 8.0Hz, 4 .8Hz), 3.58-3.70(4H, m), 3.44-3.57(2H, m), 3.35(3H, s), 2.48-2.66(4H, m).

[0382] Example 34: 6-(3-hydroxy-3-methylazacyclobutane-1-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0383]

[0384] Intermediate 6 (64 mg), 3-methyl-3-acridinol hydrochloride (27 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (19 mg).

[0385] 1 H NMR (400MHz, CDCl3) δ8.37 (1H, d, J = 2.4Hz), 8.15 (1H, s), 7.89 (2H, d, J = 8.8Hz), 7.78 (1H, dd, J = 8.8Hz, 2.6Hz), 7.72 (1H, d, J = 2.0Hz), 7.58-7.64 (2H, m), 6.73 (1H , d, J=2.0Hz), 6.68 (1H, d, J=8.8Hz), 3.91 (2H, d, J=8.0Hz), 3.70-3.88 (8H, m), 3. 56-3.68 (2H, m), 3.04 (3H, s), 2.68-2.84 (1H, m), 2.08 (1H, s), 1.64-1.72 (4H, m).

[0386] Example 35: 6-(3-cyanozyrazine-1-yl)-4-(6-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0387]

[0388] Intermediate 6 (64 mg), 3-cyanozycyclobutane hydrochloride (24 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (22 mg).

[0389] 1 H NMR (400MHz, CDCl3) δ8.37 (1H, d, J = 2.4Hz), 8.19 (1H, s), 7.89 (2H, d, J = 7.6Hz), 7.78 (1H, dd, J = 9.2Hz, 2.8Hz), 7.74 (1H, d, J = 1.6Hz), 7.55-7.6 6(2H,m), 6.68-6.70(2H,m), 4.26(2H,t,J=7.6Hz), 4.15(2H,t,J=6.8Hz ), 3.49-3.92 (9H, m), 3.05 (3H, s), 2.68-2.84 (1H, m), 1.66-1.72 (1H, m).

[0390] Example 36: 6-(3,3-difluoroazacyclobutane-1-yl)-4-(6-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0391]

[0392] Intermediate 6 (64 mg), 3,3-difluorotrimethylimine hydrochloride (26 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (24 mg).

[0393] 1 H NMR (400MHz, CDCl3) δ8.38 (1H, d, J=2.4Hz), 8.19 (1H, s), 7.89 (2H, d, J=8.0Hz), 7.77-7.80 (2H, m), 7.60 (2H, d, J=8.0Hz), 6.73 (1H, d, J=2.0Hz ), 6.69 (1H, d, J = 8.8Hz), 4.31 (4H, t, J = 11.6Hz), 3.70-3.88 (6H, m), 3.56-3.67 (2H, m), 3.04 (3H, s), 2.68-2.82 (1H, m), 1.68 (1H, d, J = 7.6Hz).

[0394] Example 37: 6-(3-(dimethylamino)pyrrolidone-1-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0395]

[0396] Intermediate 7 (57 mg), N,N-dimethylpyrrolidone-3-amine (23 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (65 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (12 mg).

[0397] 1H NMR (400MHz, CDCl3) δ8.32 (1H, d, J = 2.4Hz), 8.10 (1H, s), 8.07 (1H, s), 7.71-7.74 (2 H, m), 7.61 (1H, dd, J=8.0Hz, 2.0Hz), 6.88 (1H, s), 6.72-6.76 (2H, m), 3.93 (3H, s), 3 .61-3.66(4H,m), 3.41-3.51(4H,m), 3.31-3.38(1H,m), 3.20(1H,t,J=8.0Hz), 2.87 -2.96(1H,H), 2.52-2.58(4H,m), 2.32(6H,s), 2.21-2.30(1H,m), 1.96-2.04(1H,m).

[0398] Example 38: 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0399]

[0400] At 0°C, 50 mg of 6-hydroxy-4-(6-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile was dissolved in 10 mL of dioxane. 1 mL of 2,2-dimethyl ethylene oxide and 50 mg of potassium carbonate were added sequentially. The mixture was heated to 60°C and stirred for 12 hours in a sealed tube. After cooling, the reaction mixture was poured into water and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1).

[0401] (V∶V)) Purification yielded the title compound (14 mg).

[0402] 1H NMR (400MHz, CDCl3) δ8.40 (1H, d, J = 2.8Hz), 8.22 (1H, s), 8.16 (1H, d, J = 2.0Hz), 7. 89 (2H, d, J = 8.0Hz), 7.78 (1H, dd, J = 8.8Hz, 2.4Hz), 7.61 (2H, d, J = 8.0Hz), 7.16 (1H , d, J = 2.4Hz), 6.69 (1H, d, J = 8.4Hz), 3.72-3.87 (8H, m), 3.57-3.70 (2H, m), 3.05 (3 H, s), 2.69-2.84 (1H, m), 1.99-2.09 (1H, brs), 1.70 (1H, d, J=8.4Hz), 1.40 (6H, s).

[0403] Example 39: 6-(3,3-difluoropyrrolidone-1-yl)-4-(6-(4-(4-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-α]pyridin-3-onitrile

[0404]

[0405] Intermediate 8 (62 mg), 3,3-difluorotrimethylimine hydrochloride (26 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (16 mg).

[0406] 1 H NMR (400MHz, CDCl3) δ 8.30 (1H, d, J = 2.4Hz), 8.17 (1H, s), 7.92 (2H, d, J = 8.0Hz), 7.76 (1H, d, J = 2.0Hz), 7.70 (1H, dd, J = 9.2Hz, 2.8Hz), 7.60 (2H, d, J = 8.0Hz), 6.75 (1H, d, J = 8.8Hz), 6.71 (1H, d, J = 2.0Hz), 4.29 (4H, t, J = 11.6Hz), 3.62-3.70 (6H, m), 3.07 (3H, s), 2.56-2.61 (4H, m).

[0407] Example 40: 6-(3-cyanozyne-1-yl)-4-(6-(4-(4-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-α]pyridin-3-nitrile

[0408]

[0409] Intermediate 8 (62 mg), 3-cyanozycyclobutane hydrochloride (24 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (18 mg).

[0410] 1 H NMR (400MHz, CDCl3) δ8.29 (1H, d, J = 2.4Hz), 8.16 (1H, s), 7.92 (2H, d, J = 8.0H z), 7.72 (1H, d, J = 2.0Hz), 7.70 (1H, dd, J = 8.8Hz, 2.0Hz), 7.60 (2H, d, J = 8.0H z), 6.75 (1H, d, J = 8.8Hz), 6.67 (1H, d, J = 2.0Hz), 4.25 (2H, dd, J = 8.0Hz, 6.8H z), 4.14 (2H, t, J=6.8Hz), 3.62-3.72 (7H, m), 3.07 (3H, s), 2.54-2.63 (4H, m).

[0411] Example 41: 6-(1-methyl-1H-pyrazol-4-yl)-4-(5-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0412]

[0413] At 0°C, intermediate 4 (40 mg) was dissolved in THF (10 mL), followed by the addition of 4-methylsulfonylbenzaldehyde (27 mg) and sodium triacetoxyborohydride (75 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (30 mg).

[0414] 1 H NMR (400MHz, CDCl3) δ8.67 (1H, d, J = 1.6Hz), 8.55 (1H, d, J = 1.2Hz), 8.31 (1H, s), 8.27 (1H, d, J = 1.2Hz), 7.89 (2H, d, J = 8.4Hz), 7.81 (1H, s), 7.71 (1H, s), 7.65 (1H , d, J=1.2Hz), 7.60 (2H, d, J=8.4Hz), 3.99 (3H, s), 3.84-3.87 (4H, m), 3.75 (2H, s) ), 3.67 (2H, d, J = 11.6Hz), 3.05 (3H, s), 2.76-2.83 (1H, m), 1.70 (1H, d, J = 9.2Hz).

[0415] Example 42: 6-(1-methyl-1H-pyrazol-4-yl)-4-(5-(4-(4-(methanesulfonyl)benzyl)piperazin-1-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0416]

[0417] At 0°C, intermediate 3 (39 mg) was dissolved in THF (10 mL), followed by the addition of 4-methylsulfonylbenzaldehyde (27 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (33 mg).

[0418] 1H NMR (400MHz, CDCl3) δ8.65 (1H, d, J = 1.6Hz), 8.47 (1H, d, J = 1.6Hz), 8.31 (1H, d, J = 1.2Hz), 8.30 (1H, s), 7.93 (2H, d, J = 8.0Hz), 7.80 (1H, s) , 7.69 (1H, s), 7.63 (1H, d, J = 1.6Hz), 7.60 (2H, d, J = 8.4Hz), 3.99 (3H, s), 3.73-3.76 (4H, m), 3.66 (2H, s), 3.07 (3H, s), 2.59-2.61 (4H, m).

[0419] Example 43: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(6-(2-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0420]

[0421] At 0°C, intermediate 2 (39 mg) was dissolved in THF (10 mL), followed by the addition of 2-methylsulfonylbenzaldehyde (37 mg) and sodium triacetoxyborohydride (75 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (20 mg).

[0422] 1 H NMR (400MHz, CDCl3) δ8.65 (1H, s), 8.45 (1H, d, J = 1.6Hz), 8.28 (1H, s), 8.10 (1H, d, J = 8 .0Hz), 7.80-7.84(2H, m), 7.70(1H, s), 7.57(1H, t, J=7.6Hz), 7.44-7.51(2H, m), 7.43( 1H, s), 6.75 (1H, d, J = 9.2Hz), 4.11 (2H, s), 4.00 (3H, s), 3.95 (2H, d, J = 12.4Hz), 3.79- 3.84 (2H, m), 3.62-3.69 (2H, m), 3.37 (3H, s), 2.57-2.64 (1H, m), 1.69 (1H, d, J = 8.4Hz).

[0423] Example 44: 6-(1-ethyl-1H-pyrazol-4-yl)-4-(6-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0424]

[0425] Intermediate 6 (64 mg), 1-ethylpyrazole-4-boric acid (21 mg), tetra-triphenylphosphine palladium (11 mg), and potassium carbonate (28 mg) were sequentially added to a flask containing dioxane and water (20 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the target compound (34 mg).

[0426] 1 H NMR (400MHz, CDCl3) δ8.66 (1H, d, J = 1.2Hz), 8.44 (1H, d, J = 2.0Hz), 8.28 (1H, s), 7.90 (2H , d, J = 8.4Hz), 7.81-7.84 (2H, m), 7.72 (1H, s), 7.63 (2H, d, J = 8.4Hz), 7.73 (1H, d, J = 1.2H z), 6.72 (1H, d, J = 8.4Hz), 4.26 (2H, q, J = 7.2Hz), 3.82-3.86 (4H, m), 3.78 (2H, s), 3.62-3 .69 (2H, m), 3.05 (3H, s), 2.78-2.86 (1H, m), 1.71 (1H, d, J = 8.8Hz), 1.57 (3H, t, J = 7.2Hz).

[0427] Example 45: 6-(1-difluoromethyl-1H-pyrazol-4-yl)-4-(6-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0428]

[0429] Intermediate 6 (64 mg), 1-difluoromethylpyrazole-4-boric acid (23 mg), tetraphenylphosphine palladium (11 mg), and potassium carbonate (28 mg) were added sequentially to a flask containing dioxane and water (20 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the target compound (27 mg).

[0430] 1 H NMR (400MHz, CDCl3) δ8.72 (1H, s), 8.44 (1H, d, J = 2.4Hz), 8.32 (1H, s), 8.14 (1H, s), 7 .98 (1H, s), 7.89 (2H, d, J = 8.4Hz), 7.82 (1H, dd, J = 8.8Hz, 2.4Hz), 7.62 (2H, d, J = 8.0H z), 7.73 (1H, s), 7.26 (1H, t, J = 60.8Hz), 6.72 (1H, d, J = 8.8Hz), 3.81-3.88 (4H, m), 3. 76 (2H, s), 3.59-3.68 (2H, m), 3.06 (3H, s), 2.74-2.80 (1H, m), 1.70 (1H, d, J=9.2Hz).

[0431] Example 46: 6-(3,3-difluoroazacyclobutane-1-yl)-4-(6-(6-((5-methoxypyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0432]

[0433] Intermediate 17 (59 mg), 3,3-difluorotrimethylimine hydrochloride (26 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (24 mg).

[0434] 1H NMR (400MHz, DMSO-d6) δ8.52 (1H, s), 8.39 (1H, d, J = 2.0Hz), 8.27 (1H, d, J = 2.0Hz), 8.18 (1H, s), 7.82 (1H, dd, J = 9.2Hz, 2.4Hz), 7.36-7.45 (2H, m) , 7.08 (1H, d, J = 1.6Hz), 6.77 (1H, d, J = 9.2Hz), 4.38 (4H, t, J = 8.0Hz), 3.7 4-3.83(7H,m), 3.50-3.68(4H,m), 2.54-2.64(1H,m), 1.59-1.64(1H,m).

[0435] Example 47: 6-(1-difluoromethyl-1H-pyrazol-4-yl)-4-(6-(4-(3-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0436]

[0437] Intermediate 10 (62 mg), 1-difluoromethylpyrazole-4-boric acid (23 mg), tetraphenylphosphine palladium (11 mg), and potassium carbonate (28 mg) were added sequentially to a flask containing dioxane and water (20 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the target compound (31 mg).

[0438] 1 H NMR (400MHz, CDCl3) δ8.70 (1H, s), 8.37 (1H, d, J = 2.4Hz), 8.30 (1H, s), 1.13 (1H, s), 7.96-7.99 (2H, m), 7.87 (1H, d, J = 8.0Hz), 7.69-7. 76 (2H, m), 7.56 (1H, s), 7.41 (1H, s), 7.25 (1H, t, J = 60.8Hz), 6.78 (1H, d, J = 9.2Hz), 3.64-3.72 (6H, m), 3.09 (3H, s), 2.58-2.63 (4H, m).

[0439] Example 48: 6-(1-difluoromethyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0440]

[0441] Intermediate 18 (62 mg), 1-difluoromethylpyrazole-4-boric acid (23 mg), tetraphenylphosphine palladium (11 mg), and potassium carbonate (28 mg) were sequentially added to a flask containing dioxane and water (20 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the target compound (32 mg).

[0442] 1 H NMR (400MHz, CDCl3) δ8.71 (1H, s), 8.38 (1H, d, J = 2.4Hz), 8.30 (1H, s), 8.13-8.16 (2H, m), 7.97 (1H, s), 7.75 (1H, dd, J = 8.8Hz, 2.4Hz), 7.61 (1H, t, J = 7.6Hz), 7.53 ( 1H, t, J=7.6Hz), 7.46 (1H, d, J=7.6Hz), 7.41 (1H, s), 7.26 (1H, t, J=60.8Hz), 6.79 (1H, d, J = 8.4Hz), 4.03 (2H, s), 3.60-3.68 (4H, m), 3.47 (3H, s), .66-2.72 (4H, m).

[0443] Example 49: 6-(1-difluoromethyl-1H-pyrazol-4-yl)-4-(6-(4-(4-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0444]

[0445] Intermediate 8 (62 mg), 1-difluoromethylpyrazole-4-boric acid (23 mg), tetraphenylphosphine palladium (11 mg), and potassium carbonate (28 mg) were added sequentially to a flask containing dioxane and water (20 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the target compound (22 mg).

[0446] 1H NMR (400MHz, CDCl3) δ8.70 (1H, s), 8.37 (1H, d, J = 2.8Hz), 8.30 (1H, s), 8.13 (1H, s), 7.96 (1H, s), 7.93 (2H, d, J = 7.6Hz), 7.75 (1H, dd, J = 8.8Hz, 2.8Hz ), 7.61 (2H, d, J = 8.0Hz), 7.41 (1H, s), 7.26 (1H, t, J = 60.8Hz), 6.78 (1H, d, J=8.8Hz), 3.68-3.72 (4H, m), 3.67 (2H, s), 3.08 (3H, s), 2.58-2.63 (4H, m).

[0447] Example 50: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(6-((6-(methylthio)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0448]

[0449] At 0°C, intermediate 2 (40 mg) was dissolved in THF (10 mL), followed by the addition of 6-(methylthio)pyridine-3-carboxaldehyde (31 mg) and sodium triacetoxyborohydride (75 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (13 mg).

[0450] 1 H NMR (400MHz, CDCl3) δ8.67 (1H, s), 8.45 (1H, s), 8.44 (1H, s), 8.29 (1H, s), 7.87 ( 1H, d, J = 8.8Hz), 7.80 (1H, s), 7.77 (1H, d, J = 8.4Hz), 7.70 (1H, s), 7.43 (1H, s), 7 .36 (1H, d, J = 8.4Hz), 6.76 (1H, d, J = 8.4Hz), 4.38 (2H, d, J = 6.0Hz), 3.98-4.02 (5 H, m), 3.85-3.96 (4H, m), 3.26-3.32 (1H, m), 2.58 (3H, s), 1.87 (1H, d, J=10.0Hz).

[0451] Example 51: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-((6-(methylthio)pyridin-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0452]

[0453] At 0°C, intermediate 1 (39 mg) was dissolved in THF (10 mL), followed by the addition of 6-(methylthio)pyridine-2-carboxaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (33 mg).

[0454] 1 H NMR (400MHz, CDCl3) δ8.63 (1H, s), 8.36 (1H, d, J = 2.8Hz), 8.26 (1H, s), 7.79 (1H, s), 7.75 (1H, dd, J = 8.8Hz, 2.8Hz), 7.68 (1H, s), 7.50 (1H, t, J = 7.6Hz ), 7.39 (1H, s), 7.19 (1H, d, J = 7.2Hz), 7.07 (1H, d, J = 7.6Hz), 6.78 (1H, d, J =9.2Hz), 3.99 (3H, s), 3.67-3.76 (6H, m), 2.65-2.73 (4H, m), 2.57 (3H, s).

[0455] Example 52: 6-(3,3-difluoroazacyclobutane-1-yl)-4-(6-(4-((5-methoxypyridin-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0456]

[0457] Intermediate 19 (57 mg), 3,3-difluorotrimethylimine hydrochloride (26 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (10 mg).

[0458] 1 H NMR (400MHz, CDCl3) δ8.27-8.36 (2H, m), 8.16 (1H, s), 7.76 (1H, d, J = 1.2Hz), 7.71 (1H, d, J = 7.6Hz), 7.37 (1H, d, J = 7.6Hz), 7 .17-7.22 (1H, m), 6.71-6.76 (2H, m) 4.30 (4H, t, J = 11.2Hz), 3.95 (3H, s), 3.87 (2H, s), 3.60-3.76 (4H, m), 2.56-2.70 (4H, m).

[0459] Example 53: 6-(1H-pyrazol-4-yl)-4-(6-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0460]

[0461] Intermediate 6 (64 mg), 1H-pyrazole-4-boronic acid (17 mg), tetraphenylphosphine palladium (11 mg), and potassium carbonate (28 mg) were added sequentially to a flask containing dioxane and water (20 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (v:v)) to obtain the target compound (17 mg).

[0462] 1H NMR (400MHz, CDCl3) δ 8.70 (1H, s), 8.44 (1H, d, J = 2.4Hz), 8.29 (1H, s), 7.92 (2H, s), 7.89 (2H, d, J = 8.0Hz), 7.83 (1H, dd, J = 8.8Hz, 2.4Hz), 7.61 (2H, d, J =8.0Hz), 7.45 (1H, s), 6.71 (1H, d, J = 8.8Hz), 3.79-3.87 (4H, m), 3.75 (2H, s ), 3.60-3.68 (2H, m), 3.05 (3H, s), 2.72-2.80 (1H, m), 1.69 (1H, d, J = 8.8Hz).

[0463] Example 54: 2-(4-(3-cyano-4-(6-(4-(4-(4-(methanesulfonyl)benzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazin-1-yl)-N,N-dimethylacetamide

[0464]

[0465] Intermediate 8 (62 mg), N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)acetamide (42 mg), tetraphenylphosphine palladium (11 mg), and potassium carbonate (28 mg) were added sequentially to a flask containing dioxane and water (20 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (v:v)) to obtain the target compound (27 mg).

[0466] 1 H NMR (400MHz, CDCl3) δ8.65 (1H, d, J = 1.2Hz), 8.35 (1H, d, J = 2.8Hz), 8.25 (1H, s) , 7.93 (2H, d, J = 8.0Hz), 7.87 (1H, s), 7.82 (1H, s), 7.73 (1H, dd, J = 8.8Hz, 2.8Hz) , 7.62 (2H, d, J = 8.0Hz), 7.41 (1H, d, J = 1.2Hz), 6.77 (1H, d, J = 8.8Hz), 5.05 (2H, s ), 3.65-3.75(6H,m), 3.13(3H,s), 3.07(3H,s), 3.02(3H,s), 2.59-2.67(4H,m).

[0467] Example 55: 6-(1-difluoromethyl-1H-pyrazol-4-yl)-4-(6-(6-(3-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0468]

[0469] Intermediate 9 (64 mg), 1-difluoromethylpyrazole-4-boric acid (23 mg), tetraphenylphosphine palladium (11 mg), and potassium carbonate (28 mg) were added sequentially to a flask containing dioxane and water (20 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the target compound (25 mg).

[0470] 1 H NMR (400MHz, CDCl3) δ8.72 (1H, d, J = 1.6Hz), 8.44 (1H, d, J = 2.4Hz), 8.31 (1H, s), 8.14 (1H , s), 7.99 (1H, s), 7.97 (1H, s), 7.81-7.84 (2H, m), 7.69-7.73 (1H, m), 7.53 (1H, t, J = 8.0Hz ), 7.44 (1H, d, J = 1.2Hz), 7.25 (1H, t, J = 60.4Hz), 6.72 (1H, d, J = 8.4Hz), 3.81-3.92 (4H, m ), 3.77 (2H, s), 3.62-3.70 (2H, m), 3.07 (3H, s), 2.76-2.86 (1H, m), 1.71 (1H, d, J = 8.0Hz).

[0471] Example 56: 6-(1-difluoromethyl-1H-pyrazol-4-yl)-4-(6-(6-(2-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0472]

[0473] Intermediate 20 (64 mg), 1-difluoromethylpyrazole-4-boric acid (23 mg), tetraphenylphosphine palladium (11 mg), and potassium carbonate (28 mg) were sequentially added to a flask containing dioxane and water (20 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the target compound (35 mg).

[0474] 1 H NMR (400MHz, CDCl3) δ8.71 (1H, d, J = 1.6Hz), 8.45 (1H, d, J = 2.4Hz), 8.31 (1H, s), 8.14 (1H, s), 8.09 (1H, d, J = 8.0Hz), 7.97 (1H, s), 7.82 (1H, dd, J = 8.8Hz, 2.4Hz), 7.45-7.58 (3H, m), 7.43 (1 H, d, J = 1.2Hz), 7.25 (1H, t, J = 60.8Hz), 6.74 (1H, d, J = 8.8Hz), 4.12 (2H, s), 3.95 (2H, d, J = 12. 4Hz), 3.83 (2H, s), 3.61-3.72 (2H, m), 3.36 (3H, s), 2.58-2.66 (1H, m), 1.69 (1H, d, J = 9.2Hz).

[0475] Example 57: 6-(1-methyl-1H-pyrazole-4-yl)-4-(6-(8-(4-(methanesulfonyl)benzyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridinylpyridinyl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile

[0476]

[0477] Step 1: 3-(5-bromopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0478] 2,5-Dibromopyridine (4.74 g), 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.12 g), tris(dibenzylacetone)dipalladium (0.92 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (1.24 g), and cesium carbonate (6.52 g) were added to toluene (200 mL) under nitrogen protection, heated to 110 °C, and stirred overnight. After cooling to room temperature, the mixture was filtered, the filter cake was washed with dichloromethane, the filtrates were combined and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 4:1 (V:V)) to give 3-(5-bromopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.4 g).

[0479] Step 2: 3-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-tert-butyl ester-31,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0480] 3-(5-bromopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (37 mg), (3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)boric acid (40 mg), tetrakis(triphenylphosphine)palladium (11 mg), and potassium carbonate (28 mg) were added sequentially to a flask containing dioxane and water (20 mL, v / v ratio 5:1). The reaction flask was purged three times with nitrogen. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (33 mg).

[0481] Step 3: 4-(6-(3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile trifluoroacetate

[0482] At room temperature, the product obtained in step two was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred for 2 hours until the reaction was complete. The solvent was then removed by vacuum distillation. Methyl tert-butyl ether (5 mL) was added to the residue, and the mixture was sonicated. A solid precipitated out. The residue was filtered, and the filter cake was washed twice with methyl tert-butyl ether and dried under vacuum to obtain the target product (20 mg).

[0483] Step 4: 6-(1-methyl-1H-pyrazole-4-yl)-4-(6-(8-(4-(methanesulfonyl)benzyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridinylpyridinyl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile

[0484]

[0485] At 0°C, the product (20 mg) from step 3 was dissolved in THF (5 mL), and 4-methylsulfonylbenzaldehyde (15 mg) and sodium triacetoxyborohydride (50 mg) were added sequentially. The mixture was then stirred at room temperature for 12 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the title compound (10 mg).

[0486] 1 H NMR (400MHz, CDCl3) δ8.62 (1H, d, J = 1.2Hz), 8.36 (1H, d, J = 2.4Hz), 8.26 (1H, s), 7. 92 (2H, d, J = 8.0Hz), 7.78 (1H, s), 7.74 (1H, dd, J = 8.4Hz, 2.4Hz), 7.63-7.71 (3H, m), 7.38 (1H, d, J = 1.6Hz), 6.68 (1H, d, J = 8.4Hz), 3.99 (3H, s), 3.88-3.95 (2H, m), 3.70- 3.77(2H,m), 3.20-3.39(4H,m), 3.07(3H,s), 2.04-2.11(2H,m), 1.79-1.86(2H,m).

[0487] Example 58: 6-(3-hydroxy-3-methylazacyclobutane-1-yl)-4-(6-(6-((2-methoxypyrimidin-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0488]

[0489] Step 1: 6-hydroxy-4-(6-(6-((2-methoxypyrimidin-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0490] At room temperature, 430 mg of 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxynitrile trifluoroacetate was dissolved in 50 mL of tetrahydrofuran, and 276 mg of 2-methoxypyrimidine-5-carboxaldehyde was added. The mixture was stirred for 5 minutes, followed by the addition of 500 mg of sodium triacetoxyborohydride. The mixture was stirred until the reaction was complete, and the reaction solution was poured into a saturated sodium bicarbonate aqueous solution. The sample was extracted twice with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by column chromatography (eluent: dichloromethane:methanol = 30:1 (V:V)) to give 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (230 mg).

[0491] Step 2: 3-Cyano-4-(6-(6-(((2-methoxypyrimidin-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate

[0492] At room temperature, 227 mg of 6-hydroxy-4-(6-(6-((2-methoxypyrimidin-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile was dissolved in 30 mL of DMF, and 258 mg of DIEA was added, followed by 357 mg of N-phenylbis(trifluoromethanesulfonyl)imide. After stirring overnight at room temperature until the reaction was complete, the solution was poured into 150 mL of water and extracted twice with ethyl acetate. The organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 (V:V)) to give 3-cyano-4-(6-(6-((2-methoxypyrimidin-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate (210 mg).

[0493] Step 3: 6-(3-hydroxy-3-methylazacyclobutane-1-yl)4-(6-(6-((2-methoxypyrimidin-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0494] The product obtained in step 2 (59 mg), 3-methyl-3-acridinol hydrochloride (27 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (21 mg).

[0495] 1 H NMR (400MHz, CDCl3) δ 8.54 (2H, s), 8.38 (1H, d, J = 2.4Hz), 8.15 (1H, s), 7.79 (1H, dd, J = 8.8Hz, 2.4Hz), 7.72 (1H, d, J = 1.6Hz), 6.74 (1H, d, J = 2.0Hz), 6. 69 (1H, d, J = 8.4Hz), 4.00 (3H, s), 3.91 (2H, d, J = 8.0Hz), 3.78-3.89 (6H, m) , 3.58-3.72 (4H, m), 2.69-2.82 (1H, m), 1.69 (1H, d, J = 8.0Hz), 1.67 (3H, s).

[0496] Example 59: 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(6-(4-(methylthio)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0497]

[0498] At 0°C, intermediate 2 (40 mg) was dissolved in THF (10 mL), followed by the addition of 4-methylthiobenzaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (30 mg).

[0499] 1H NMR (400MHz, CDCl3) δ8.66 (1H, d, J = 1.2Hz), 8.45 (1H, d, J = 2.4Hz), 8.27 (1H, s) , 7.85 (1H, dd, J = 8.4Hz, 2.4Hz), 7.80 (1H, s), 7.70 (1H, s), 7.50 (2H, d, J = 8.0Hz) , 7.43 (1H, d, J = 1.2Hz), 7.24 (2H, d, J = 8.0Hz), 6.73 (1H, d, J = 8.4Hz), 4.18-4.3 2(2H,m), 3.80-4.09(9H,m), 3.16-3.30(1H,m), 2.47(3H,s), 1.82-1.89(1H,m).

[0500] Example 60: 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(6-((6-(methylthio)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0501]

[0502] At 0°C, intermediate 21 (43 mg) was dissolved in THF (10 mL), followed by the addition of 6-(methylthio)nicotinaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (27 mg).

[0503] 1 H NMR (400MHz, CDCl3) δ8.72 (1H, d, J = 1.6Hz), 8.44 (1H, d, J = 2.4Hz), 8.41 (1H, d, J = 2.0Hz), 8 .31 (1H, s), 8.14 (1H, s), 7.97 (1H, s), 7.82 (1H, dd, J = 8.8Hz, 2.4Hz), 7.64-7.70 (1H, m), 7. 43 (1H, d, J = 1.6Hz), 7.25 (1H, t, J = 60.4Hz), 7.16 (1H, d, J = 8.4Hz), 6.71 (1H, d, J = 8.8Hz), 3 .84-3.94(4H,m), 3.62-3.73(4H,m), 2.78-2.86(1H,m), 2.55(3H,s), 1.71(1H,d,J=8.4Hz).

[0504] Example 61: (E)-4-(6-(6-(4-methoxybut-2-enoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0505]

[0506] At 0°C, intermediate 2 (40 mg) was dissolved in THF (10 mL), and (E)-4-methoxybut-2-enoic acid (12 mg) and triethylamine (30 mg) were added. The mixture was then heated to room temperature and stirred for 1 hour. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (37 mg).

[0507] 1 H NMR (400MHz, CDCl3) δ8.63 (1H, d, J = 1.2Hz), 8.37 (1H, d, J = 2.4Hz), 8.25 (1H, s), 7.78 (1H, s), 7.76 (1H, d d, J=8.8Hz, 2.4Hz), 7.68 (1H, s), 7.38 (1H, d, J=1.2Hz), 6.88 (1H, dt, J=15.6Hz, 4.0Hz), 6.65 (1H, d, J=8 .8Hz), 6.16 (1H, dt, J=15.6Hz, 2.0Hz), 4.64-4.72 (2H, m), 4.17 (1H, d, J=12.0Hz), 4.06-4.09 (2H, m), 3. 98 (3H, s), 3.88-3.91 (2H, m), 3.64-3.71 (1H, m), 3.39 (3H, s), 2.78-2.84 (1H, m), 1.73 (1H, d, J = 8.8Hz).

[0508] Example 62: (E)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(6-(4-methoxybut-2-enoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0509]

[0510] At 0°C, intermediate 21 (43 mg) was dissolved in THF (10 mL), and (E)-4-methoxybut-2-enoic acid (12 mg) and triethylamine (30 mg) were added. The mixture was then heated to room temperature and stirred for 1 hour. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (39 mg).

[0511] 1 H NMR (400MHz, CDCl3) δ8.70 (1H, d, J = 1.2Hz), 8.38 (1H, d, J = 2.4Hz), 8.29 (1H, s), 8.13 (1H, s), 7.96 (1H, s), 7 .76 (1H, dd, J = 8.8Hz, 2.4Hz), 7.39 (1H, d, J = 1.6Hz), 7.25 (1H, t, J = 60.4Hz), 6.89 (1H, dt, J = 15.2Hz, 4.0Hz) , 6.64 (1H, d, J = 8.8Hz), 6.16 (1H, dt, J = 15.2Hz, 2.0Hz), 4.64-4.72 (2H, m), 4.18 (1H, d, J = 10.8Hz), 4.06-4. 09 (2H, m), 3.88-3.92 (2H, m), 3.67 (1H, d, J = 10.8Hz), 3.39 (3H, s), 2.78-2.84 (1H, m), 1.74 (1H, d, J = 8.8Hz).

[0512] Example 63: 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-((6-(methanesulfonyl)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0513]

[0514] At 0°C, intermediate 24 (42 mg) was dissolved in THF (10 mL), followed by the addition of 6-(methanesulfonyl)nicotinaldehyde (37 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (25 mg).

[0515] 1H NMR (400MHz, CDCl3) δ8.72 (1H, s), 8.70 (1H, d, J = 1.6Hz), 8.36 (1H, d, J = 2.4H z), 8.29 (1H, s), 8.13 (1H, s), 8.07 (1H, s), 8.02 (1H, d, J = 7.2Hz), 7.96 (1H, s) ), 7.75 (1H, dd, J = 9.2Hz, 2.4Hz), 7.40 (1H, d, J = 1.6Hz), 7.25 (1H, t, J = 60.4H z), 6.78 (1H, d, J = 8.8Hz), 3.64-3.74 (6H, m), 3.25 (3H, s), 2.58-2.64 (4H, m).

[0516] Example 64: 6-(3,3-difluoroazacyclobutane-1-yl)-4-(6-(6-(3-(methylsulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0517]

[0518] Intermediate 9 (64 mg), 3,3-difluorotrimethylimine hydrochloride (26 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (29 mg).

[0519] 1 H NMR (400MHz, CDCl3) δ8.38 (1H, d, J = 2.4Hz), 8.19 (1H, s), 7.98 (1H, s), 7.82 (1H, d, J=8.0Hz), 7.77-7.80 (2H, m), 7.69 (1H, d, J=6.8Hz), 7.52 (1H, t, J=8.0Hz), 6.75 (1H , d, J=2.0Hz), 6.69 (1H, d, J=9.2Hz), 4.31 (4H, t, J=11.6Hz), 3.78-3.88 (4H, m), 3.7 2(2H,s), 3.58-3.68(2H,m), 3.06(3H,s), 2.73-2.82(1H,m), 1.69(1H,d,J=8.4Hz).

[0520] Example 65: 4-(6-(6-(3-(methylsulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(3-hydroxy-3-methylaza-1-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0521]

[0522] Intermediate 9 (64 mg), 3-methyl-3-acridinol hydrochloride (27 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (21 mg).

[0523] 1 H NMR (400MHz, CDCl3) δ8.37 (1H, d, J = 2.4Hz), 8.15 (1H, s), 7.98 (1H, s), 7.81 (1H, d, J = 7.6Hz), 7 .78 (1H, dd, J = 8.8Hz, 2.4Hz), 7.71 (1H, d, J = 2.0Hz), 7.67 (1H, d, J = 8.0Hz), 7.51 (1H, t, J = 8.0Hz ), 6.74 (1H, d, J = 2.0Hz), 6.68 (1H, d, J = 8.8Hz), 3.91 (2H, d, J = 8.0Hz), 3.77-3.87 (6H, m), 3.73 (2H, s), 3.58-3.66 (2H, m), 3.06 (3H, s), 2.72-2.79 (1H, m), 1.67 (1H, d, J = 9.2Hz), 1.66 (3H, s).

[0524] Example 66: 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(6-((5-(methylthio)pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0525]

[0526] At 0°C, intermediate 21 (43 mg) was dissolved in THF (10 mL), followed by the addition of 5-(methylthio)pyridine-2-carboxaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (31 mg).

[0527] 1 H NMR (400MHz, CDCl3) δ8.74 (1H, s), 8.45 (1H, d, J = 2.4Hz), 8.43 (1H, s), 8.32 (1H, s), 8.1 5 (1H, s), 7.98 (1H, s), 7.86 (1H, dd, J = 8.8Hz, 2.4Hz), 7.76 (1H, d, J = 8.0Hz), 7.43 (1H, s) , 7.35 (1H, d, J = 8.0Hz), 7.26 (1H, t, J = 60.4Hz), 6.75 (1H, d, J = 8.8Hz), 4.38 (2H, d, J = 5. 6Hz), 3.99 (2H, s), 3.89 (4H, s), 3.24-3.32 (1H, m), 2.56 (3H, s), 1.86 (1H, d, J = 10.4Hz).

[0528] Example 67: 6-(3,3-difluoroazacyclobutane-1-yl)-4-(6-(6-(2-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0529]

[0530] Intermediate 20 (64 mg), 3,3-difluorotrimethylimine hydrochloride (26 mg), tris(dibenzylacetone)palladium (9 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (12 mg), and cesium carbonate (98 mg) were sequentially added to a flask containing toluene (20 mL). The reaction flask was purged three times with nitrogen. The mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (19 mg).

[0531] 1H NMR (400MHz, CDCl3) δ8.39 (1H, d, J = 2.0Hz), 8.18 (1H, s), 8.09 (1H, d, J = 8.0Hz) , 7.76-7.79 (2H, m), 7.43-7.60 (3H, m), 6.75 (1H, d, J = 2.0Hz), 6.72 (1H, d, J = 8.8 Hz), 4.31 (4H, t, J = 11.6Hz), 4.06-4.19 (2H, m), 3.90-3.99 (2H, m), 3.76-3.88 (2 H, m), 3.59-3.71 (2H, m), 3.34 (3H, s), 2.52-2.72 (1H, m), 1.71 (1H, d, J=9.2Hz).

[0532] Example 68: 4-(6-(6-(4-(methylsulfinyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0533]

[0534] At 0°C, intermediate 21 (43 mg) was dissolved in THF (10 mL), followed by the addition of 4-methylsulfinylbenzaldehyde (34 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (32 mg).

[0535] 1 H NMR (400MHz, CDCl3) δ8.72 (1H, s), 8.44 (1H, d, J = 2.4Hz), 8.31 (1H, s), 8.14 (1H, s), 7.97 (1H, s), 7.82 (1H, dd, J = 8.8Hz, 2.4Hz), 7.58-7.64 (4H, m), 7.43 (1H, d, J = 1.2Hz), 7.25 (1H, t, J = 60.4Hz), 6.72 (1H, d, J = 8.4Hz), 3.83-3.98 (4H, m), 3.79 ( 2H, s), 3.63-3.73 (2H, m), 2.82-2.92 (1H, m), 2.72 (3H, s), 1.73 (1H, d, J=9.2Hz).

[0536] Example 69: 6-(1-difluoromethyl-1H-pyrazol-4-yl)-4-(6-(8-(4-(methanesulfonyl)benzyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0537]

[0538] At 0°C, intermediate 22 (45 mg) was dissolved in THF (15 mL), and 4-methylsulfonylbenzaldehyde (37 mg) and sodium triacetoxyborohydride (100 mg) were added sequentially. The mixture was then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to give the title compound (30 mg).

[0539] 1 H NMR (400MHz, CDCl3) δ8.70 (1H, d, J = 1.2Hz), 8.36 (1H, d, J = 2.8Hz), 8.29 (1H, s), 8.12 (1H, s) , 7.96 (1H, s), 7.92 (2H, d, J = 8.0Hz), 7.74 (1H, dd, J = 8.8Hz, 2.8Hz), 7.67 (2H, d, J = 8.0Hz), 7 .40 (1H, s), 7.25 (1H, t, J = 60.4Hz), 6.68 (1H, d, J = 8.8Hz), 3.91 (2H, d, J = 11.2Hz), 3.74 (2H, s), 3.35 (2H, s), 3.26 (2H, d, J=11.2Hz), 3.07 (3H, s), 2.04-2.10 (2H, m), 1.78-1.85 (2H, m).

[0540] Example 70: 4-(5-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazin-2-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0541]

[0542] At 0°C, intermediate 23 (43 mg) was dissolved in THF (15 mL), and 4-methylsulfonylbenzaldehyde (37 mg) and sodium triacetoxyborohydride (100 mg) were added sequentially. The mixture was then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to give the title compound (17 mg).

[0543] 1 H NMR (400MHz, CDCl3) δ8.74 (1H, d, J = 1.6Hz), 8.57 (1H, d, J = 1.6Hz), 8.35 (1H, s), 8. 28 (1H, d, J = 1.6Hz), 8.16 (1H, s), 7.99 (1H, s), 7.90 (2H, d, J = 8.8Hz), 7.67 (1H, d, J = 1.2Hz), 7.60 (2H, d, J=8.0Hz), 7.26 (1H, t, J=60.4Hz), 3.82-3.90 (4H, m), 3.76 (2H , s), 3.68 (2H, d, J = 12.8Hz), 3.05 (3H, s), 2.77-2.84 (1H, m), 1.71 (1H, d, J = 9.2Hz).

[0544] Example 71: 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(6-((6-(methylthio)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0545]

[0546] At 0°C, intermediate 21 (43 mg) was dissolved in THF (10 mL), followed by the addition of 6-(methylthio)pyridine-3-carboxaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (32 mg).

[0547] 1H NMR (400MHz, CDCl3) δ8.68 (1H, d, J = 1.6Hz), 8.31 (1H, d, J = 2.8Hz), 8.28 (1H, s), 8.11 (1H, s), 7.94 (1H, s), 7.89 (1H, d, J = 2.8Hz), 7.71 (1H, dd, J = 8.8Hz, 2.8Hz), 7.37 (1H, s), 7.23 (1H, t, J = 60.4Hz), 7.03 (1H, d, J = 8.4Hz), 6.81 (1H, dd, J = 8.8Hz, 3.2Hz), 6.56 (1H, d, J = 8.8Hz), 4.49 (2H, d, J = 6.0Hz) , 4.06 (2H, d, J = 12.0Hz), 3.55-3.63 (2H, m), 2.88-2.94 (1H, m), 2.49 (3H, s), 1.82 (1H, d, J = 8.8Hz).

[0548] Example 72: 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(6-((2-(methylthio)pyridin-4-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0549]

[0550] Intermediate 21 (43 mg) was dissolved in THF (10 mL) at 0 °C, followed by the addition of 2-(methylthio)pyridine-4-carboxaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (33 mg).

[0551] 1H NMR (400MHz, CDCl3) δ8.71 (1H, d, J = 1.6Hz), 8.43 (1H, d, J = 2.8Hz), 8.35 (1H, d, J = 4.8Hz), 8.31 (1H, s), 8.13 (1H, s), 7.97 (1H, s), 7.81 (1H, dd, J = 8.8Hz, 2.4Hz), 7.43 (1H, d, J = 1.6H z), 7.25 (1H, t, J = 60.4Hz), 7.23 (1H, s), 7.01 (1H, d, J = 4.0Hz), 6.70 (1H, d, J = 9.2Hz), 3.7 7-3.84 (4H, m), 3.56-3.66 (4H, m), 2.73-2.82 (1H, m), 2.56 (3H, s), 1.68 (1H, d, J = 8.8Hz).

[0552] Example 73: 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(8-((6-(methylthio)pyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0553]

[0554] At 0 °C, intermediate 22 (45 mg) was dissolved in THF (15 mL), and 6-(methylthio)pyridine-3-carboxaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg) were added sequentially. The mixture was then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to give the title compound (14 mg).

[0555] 1H NMR (400MHz, CDCl3) δ8.69 (1H, d, J = 1.6Hz), 8.41 (1H, d, J = 2.0Hz), 8.35 (1H, d, J = 2.4Hz), 8.29 (1H, s), 8.12 (1H, s), 7.95 (1H, s), 7.72 (1H, dd, J = 8.8Hz, 2.4Hz), 7.64 (1H, dd, J = 8.4Hz, 2.0Hz), 7.39 (1H, d, J = 1 .6Hz), 7.25 (1H, t, J = 60.4Hz), 7.18 (1H, d, J = 8.4Hz), 6.66 (1H, d, J = 9.2Hz), 3.88 (2H, d, J = 10.4Hz), 3.5 5(2H,s), 3.28-3.34(2H,m), 3.18(2H,d,J=11.2Hz), 2.58(3H,s), 1.98-2.08(2H,m), 1.75-1.8](2H,m).

[0556] Example 74: 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(6-((6-(methylthio)pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0557]

[0558] At 0°C, intermediate 21 (43 mg) was dissolved in THF (10 mL), followed by the addition of 6-(methylthio)pyridine-2-carboxaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (20 mg).

[0559] 1H NMR (400MHz, CDCl3) δ8.71 (1H, d, J = 1.6Hz), 8.44 (1H, d, J = 2.4Hz), 8.31 (1H, s), 8.14 ( 1H, s), 7.97 (1H, s), 7.82 (1H, dd, J=8.8Hz, 2.4Hz), 7.47 (1H, t, J=8.0Hz), 7.42 (1H, d, J=1.6Hz), 7.25 (1H, t, J=60.4Hz), 7.12-7.17 (1H, m), 7.06 (1H, d, J=7.2Hz), 6.73 (1H, d, J=8.4Hz), 3.53-4.03 (8H, m), 2.73-2.93 (1H, m), 2.54 (3H, s), 1.73 (1H, d, J=8.8Hz).

[0560] Example 75: 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-((6-(methylthio)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0561]

[0562] At 0°C, intermediate 24 (42 mg) was dissolved in THF (10 mL), followed by the addition of 6-(methylthio)pyridine-3-carboxaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (36 mg).

[0563] 1 H NMR (400MHz, CDCl3) δ8.69 (1H, d, J = 1.6Hz), 8.39 (1H, d, J = 1.6Hz), 8.36 (1H, d, J = 2. 8Hz), 8.29 (1H, s), 8.12 (1H, s), 7.96 (1H, s), 7.73 (1H, dd, J = 8.8Hz, 2.8Hz), 7.54 (1 H, dd, J=8.4Hz, 2.0Hz), 7.39 (1H, d, J=1.6Hz), 7.25 (1H, t, J=60.4Hz), 7.17 (1H, d, J =8.4Hz), 6.76 (1H, d, J=8.8Hz), 3.64-3.66 (4H, m), 3.51 (2H, s), 2.54-2.58 (7H, m).

[0564] Example 76: 6-(1-(methyl)-1H-pyrazol-4-yl)-4-(6-(6-((6-(methanesulfonyl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0565]

[0566] At 0°C, intermediate 2 (42 mg) was dissolved in THF (10 mL), followed by the addition of 6-(methanesulfonyl)nicotinaldehyde (37 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (21 mg).

[0567] 1 H NMR (400MHz, CDCl3) δ8.73 (1H, s), 8.65 (1H, d, J = 1.6Hz), 8.44 (1H, d, J = 2.4Hz), 8.28 (1H, s), 8.01-8.09 (2H, m), 7.82 (1H, dd, J = 8.8Hz, 2.4Hz), 7.79 (1H, s), 7.6 9 (1H, s), 7.42 (1H, d, J = 1.6Hz), 6.71 (1H, d, J = 8.8Hz), 3.99 (3H, s), 3.77-3.84 ( 6H, m), 3.62-3.70 (2H, m), 3.23 (3H, s), 2.73-2.82 (1H, m), 1.71 (1H, d, J = 8.4Hz).

[0568] Example 77: 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(6-((6-(methanesulfonyl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0569]

[0570] At 0°C, intermediate 21 (43 mg) was dissolved in THF (10 mL), followed by the addition of 6-(methanesulfonyl)nicotinaldehyde (37 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (23 mg).

[0571] 1 H NMR (400MHz, CDCl3) δ8.73 (1H, s), 8.72 (1H, d, J = 1.6Hz), 8.44 (1H, d, J = 2.4Hz), 8.31 (1H, s), 8 .14 ​​(1H, s), 8.04 (1H, d, J = 7.6Hz), 8.01 (1H, dd, J = 7.6Hz, 1.6Hz), 7.97 (1H, s), 7.82 (1H, dd, J = 9 .2Hz, 2.4Hz), 7.43 (1H, d, J = 1.6Hz), 7.26 (1H, t, J = 60.4Hz), 6.71 (1H, d, J = 8.4Hz), 3.78-3.82 (4H, m), 3.76 (2H, s), 3.60-3.69 (2H, m), 3.23 (3H, s), 2.71-2.79 (1H, m), 1.70 (1H, d, J = 8.8Hz).

[0572] Example 78: 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(6-((5-(methanesulfonyl)pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0573]

[0574] At 0°C, intermediate 21 (43 mg) was dissolved in THF (10 mL), followed by the addition of 5-(methanesulfonyl)pyridine-2-carboxaldehyde (37 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (26 mg).

[0575] 1H NMR (400MHz, CDCl3) δ9.05 (1H, d, J = 2.0Hz), 8.71 (1H, d, J = 1.6Hz), 8.43 (1H, d, J = 2.4Hz), 8.3 0 (1H, s), 8.18 (1H, dd, J = 8.0Hz, 2.4Hz), 8.14 (1H, s), 7.97 (1H, s), 7.80 (1H, dd, J = 8.8Hz, 2.4H z), 7.68 (1H, d, J = 8.0Hz), 7.42 (1H, d, J = 1.6Hz), 7.26 (1H, t, J = 60.4Hz), 6.72 (1H, d, J = 8.8Hz) , 3.86-3.94 (6H, m), 3.61-3.71 (2H, m), 3.10 (3H, s), 2.76-2.84 (1H, m), 1.72 (1H, d, J = 8.4Hz).

[0576] Example 79: 6-(1-(methyl)-1H-pyrazol-4-yl)-4-(6-(6-((5-(methylsulfonyl)pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0577]

[0578] At 0°C, intermediate 2 (42 mg) was dissolved in THF (10 mL), followed by the addition of 5-(methanesulfonyl)pyridine-2-carboxaldehyde (37 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (28 mg).

[0579] 1H NMR (400MHz, DMSO-d6) δ9.22 (1H, s), 8.94 (1H, s), 8.64 (1H, s), 8.43 (1H, s), 8.38 (1H, s), 8.28 (1H, d, J = 7.6Hz), 8.33 (1H, s), 7.87 (1H, d, J = 8.0Hz), 7.78 ( 1H, s), 7.75 (1H, d, J = 8.4Hz), 6.80 (1H, d, J = 8.4Hz), 3.86 (3H, s), 3.72-3.84 ( 6H, m), 3.48-3.64 (2H, m), 3.29 (3H, s), 2.42-2.52 (1H, m), 1.60-1.70 (1H, m).

[0580] Example 80: 6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-((5-(methanesulfonyl)pyridin-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0581]

[0582] At 0°C, intermediate 24 (42 mg) was dissolved in THF (10 mL), followed by the addition of 5-(methanesulfonyl)pyridine-2-carboxaldehyde (37 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (25 mg).

[0583] 1 H NMR (400MHz, CDCl3) δ9.01 (1H, d, J = 2.4Hz), 8.70 (1H, d, J = 1.6Hz), 8.37 (1H, d , J=2.8Hz), 8.29 (1H, s), 8.22 (1H, dd, J=8.4Hz, 2.0Hz), 8.13 (1H, s), 7.96 (1H, s), 7.73-7.76 (2H, m), 7.40 (1H, d, J = 1.6Hz), 7.25 (1H, t, J = 60.4Hz), 6.79 (1H , d, J = 9.2Hz), 3.84 (2H, s), 3.68-3.75 (4H, m), 3.13 (3H, s), 2.64-2.70 (4H, m).

[0584] Example 81: 4-(6-(4-(4-(methylthio)benzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0585]

[0586] At 0°C, intermediate 24 (42 mg) was dissolved in THF (10 mL), followed by the addition of 4-methylthiobenzaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (35 mg).

[0587] 1 H NMR (400MHz, CDCl3) δ8.69 (1H, d, J = 1.6Hz), 8.36 (1H, d, J = 2.8Hz), 8.29 (1H, s ), 8.12 (1H, s), 7.96 (1H, s), 7.73 (1H, dd, J = 8.8Hz, 2.8Hz), 7.39 (1H, d, J = 1.2H z), 7.27-7.31 (2H, m), 7.24 (1H, t, J = 60.4Hz), 7.23 (2H, d, J = 8.4Hz), 6.76 (1H , d, J = 8.8Hz), 3.62-3.70 (4H, m), 3.53 (2H, s), 2.54-2.60 (4H, m), 2.49 (3H, s).

[0588] Example 82: 6-(1-difluoromethyl-1H-pyrazol-4-yl)-4-(6-(6-(4-(methylthio)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0589]

[0590] At 0°C, intermediate 21 (43 mg) was dissolved in THF (20 mL), followed by the addition of 4-methylthiobenzaldehyde (31 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (33 mg).

[0591] 1 H NMR (400MHz, CDCl3) δ8.73 (1H, s), 8.46 (1H, s), 8.31 (1H, s), 8.15 (1H, s), 7. 98 (1H, s), 7.85 (1H, d, J = 7.2Hz), 7.47-7.55 (2H, m), 7.44 (1H, d, J = 1.2Hz), 7 .25-7.26(2H,m), 7.24(1H,t,J=60.4Hz), 6.73(1H,d,J=9.2Hz), 4.13-4.37( 2H, m), 3.78-4.10 (6H, m), 3.10-3.38 (1H, m), 2.47 (3H, s), 1.80-1.90 (1H, m)

[0592] Example 83: 4-(6-(6-(4-nitrobenzyl)-3,6-diaza-bicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0593]

[0594] At 0°C, intermediate 21 (43 mg) was dissolved in THF (20 mL), followed by the addition of 4-nitrobenzaldehyde (30 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (34 mg).

[0595] 1H NMR (400MHz, CDCl3) δ8.72 (1H, d, J = 1.6Hz), 8.44 (1H, d, J = 2.8Hz), 8.31 (1H, s), 8. 18 (2H, d, J = 8.8Hz), 8.13 (1H, s), 7.97 (1H, s), 7.82 (1H, dd, J = 8.8Hz, 2.8Hz), 7.58 ( 2H, d, J=7.6Hz), 7.43 (1H, d, J=1.2Hz), 7.26 (1H, t, J=60.4Hz), 6.71 (1H, d, J=8.8H z), 3.73-3.88 (6H, m), 3.59-3.68 (2H, m), 2.72-2.82 (1H, m), 1.70 (1H, d, J = 9.2Hz).

[0596] Example 84: 4-(6-(6-(4-(methanesulfonyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0597]

[0598] At 0°C, intermediate 25 (45 mg) was dissolved in THF (20 mL), followed by the addition of 4-methylsulfonylbenzaldehyde (37 mg) and sodium triacetoxyborohydride (100 mg), and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (33 mg).

[0599] 1 H NMR (400MHz, CDCl3) δ8.72 (1H, d, J = 1.6Hz), 8.44 (1H, d, J = 2.4Hz), 8.32 (1H, s), 8.1 3 (1H, s), 8.07 (1H, s), 7.89 (2H, d, J = 8.4Hz), 7.81 (1H, dd, J = 8.8Hz, 2.4Hz), 7.60 (2 H, d, J = 8.4Hz), 7.41 (1H, d, J = 1.2Hz), 6.71 (1H, d, J = 8.4Hz), 3.78-3.84 (4H, m), 3.7 4(2H,s), 3.58-3.68(2H,m), 3.05(3H,s), 2.72-2.78(1H,m), 1.69(1H,d,J=8.4Hz).

[0600] Bioactivity experiment

[0601] RET compound bioactivity assay method

[0602] 1. The effect of compounds on RET WT In vitro enzyme activity assay

[0603] The compound in this patent affects RET WT Enzymatic activity inhibits IC 50 Value determination was performed using homogeneous time-resolved fluorescence (HTRF). The compound was serially diluted 5-fold with 100% DMSO starting at 0.2 mM (total of 7 concentrations). 2 μL of each concentration was added to 48 μL of reaction buffer (50 mM HEPES pH 7.5, 0.1 mM Na3VO4, 5 mM MgCl2, 1 mM DTT, 0.001% Tween 20, and 100 μg / mL BSA) and mixed thoroughly. 2.5 μL was then added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), followed by 5 μL of GST-RET. WT (658-1114aa, final concentration 0.5nM), centrifuged and mixed, then 2.5 μL of ATP (final concentration 25 μM) and TK Peptide Substrate mixture (final concentration 1 μM, purchased from Cisbio) was added to start the reaction, with a total reaction volume of 10 μL. The 384-well plate was placed in an incubator at 23°C for 2 hours, then 5 μL of TK Antibody (purchased from Cisbio) and 5 μL of Streptavidin-XL665 (purchased from Cisbio) were added to stop the reaction. After incubation for another 1 hour, fluorescence values ​​were read on an Envision (purchased from PerkinElmer) (320 nm excitation, detection of emission light at 665 nm and 620 nm, the ratio of the two is the enzyme activity signal). RET of each compound was measured at 7 concentrations. WT The enzymatic activity signal was obtained, and the IC50 of the compound was calculated using GraphPad Prism software. 50 value.

[0604] 2. The effect of compounds on RET V804M In vitro enzyme activity assay

[0605] The compound in this patent affects RET V804M Enzymatic activity inhibits IC 50Value determination was performed using homogeneous time-resolved fluorescence (HTRF). The compound was serially diluted 5-fold with 100% DMSO starting at 0.2 mM (total of 7 concentrations). 2 μL of each concentration was added to 48 μL of reaction buffer (50 mM HEPES pH 7.5, 0.1 mM Na3VO4, 5 mM MgCl2, 1 mM DTT, 0.001% Tween 20, 20 nM SEB (purchased from Cisbio), and 100 μg / mL BSA) and mixed thoroughly. 2.5 μL was added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), followed by 5 μL of GST-RET. V804M (658-1114aa, final concentration 0.02nM), centrifuged and mixed, then 2.5 μL of ATP (final concentration 1.5 μM) and TK Peptide Substrate mixture (final concentration 1 μM, purchased from Cisbio) was added to start the reaction, with a total reaction volume of 10 μL. The 384-well plate was placed in an incubator at 23°C for 1 hour, then 5 μL of TK Antibody (purchased from Cisbio) and 5 μL of Streptavidin-XL665 (purchased from Cisbio) were added to stop the reaction. After incubation for another 1 hour, fluorescence values ​​were read on an Envision (purchased from PerkinElmer) (320 nm excitation, detection of emission light at 665 nm and 620 nm, the ratio of the two is the enzyme activity signal). RET of each compound was measured at 7 concentrations. V804M The enzymatic activity signal was obtained, and the IC50 of the compound was calculated using GraphPad Prism software. 50 value.

[0606] 3. Determination of the in vitro enzymatic activity of the compound against VEGFR2

[0607] The compound in this patent inhibits the enzymatic activity of VEGFR2 by IC50. 50Value determination was performed using homogeneous time-resolved fluorescence (HTRF) technique. The compound was serially diluted 5-fold with 100% DMSO starting at 1 mM (totaling 7 concentrations). 2 μL of each concentration was added to 48 μL of reaction buffer (50 mM HEPES pH 7.5, 0.1 mM Na3VO4, 5 mM MgCl2, 1 mM MnCl2, 1 mM DTT, 0.001% Tween 20, and 100 μg / mL BSA) and mixed thoroughly. Add 2.5 μL to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), then add 5 μL of GST-VEGFR2 (final concentration 0.1 nM), centrifuge to mix, and then add 2.5 μL of ATP (final concentration 2.5 μM) and TK Peptide Substrate mixture (final concentration 1 μM, purchased from Cisbio) to start the reaction, with a total reaction volume of 10 μL. Incubate the 384-well plate at 23°C for 1.5 hours, then add 5 μL of TK Antibody (purchased from Cisbio) and 5 μL of Streptavidin-XL665 (purchased from Cisbio) to stop the reaction. After incubating for another 1 hour, read the fluorescence value on an Envision (purchased from PerkinElmer) (320 nm excitation, detection of emission light at 665 nm and 620 nm, the ratio of the two is the enzyme activity signal). The enzymatic activity signal of VEGFR2 for each compound was measured at seven concentrations, and the IC50 of the compound was calculated using GraphPad Prism software. 50 value.

[0608] 4. Assay of the compound's proliferative activity in TT cells

[0609] Human thyroid cancer cell line TT cells were cultured in Ham's F-12K medium supplemented with 15% fetal bovine serum (FBS, purchased from Biological Industries, BI) and 1% penicillin / streptomycin antibiotics (P / S, purchased from Life Technology) at 37°C and 5% CO2. The day before compound detection, TT cells were seeded at a concentration of 5000 cells / 195 μL / well in 96-well plates (#3917, purchased from Corning). Twenty-four hours later, the compound was serially diluted 3-fold with 100% DMSO, starting at 10 mM (totaling 10 concentrations). 2 μL of each concentration was then added to 48 μL of Ham's F-12K medium for further dilution. Five μL of each diluted compound was added to the prepared cell suspension. The compound and cells were incubated together in a cell culture incubator for 120 h (5 days). After aspirating the culture medium, 25 μL of Cell-TiterGlo (G7570, purchased from Promega) reagent was added, and the cells were incubated again for 5-10 minutes. Fluorescence values ​​were then read on Envision, and the IC50 of the compound's inhibitory effect on cell proliferation was calculated using GraphPad Prism software. 50 value.

[0610] 5. Assay of the proliferation activity of the compound in KIF5B-RET / HEK293T cells

[0611] The RET fusion cell line KIF5B-RET / HEK293T, constructed using lentiviral infection, was cultured in DMEM medium supplemented with 10% fetal bovine serum (FBS, purchased from Biological Industries, BI) and 1% penicillin / streptomycin antibiotics (P / S, purchased from Life Technology) at 37°C and 5% CO2. The day before compound detection, KIF5B-RET / HEK293T cells were seeded at a concentration of 2000 cells / 195 μL / well in 96-well plates (#3917, purchased from Coming). Twenty-four hours later, the compound was serially diluted 3-fold starting at 10 mM with 100% DMSO (totaling 10 concentrations). 2 μL of each concentration was then added to 48 μL of DMEM medium for further dilution. Five μL of each diluted compound was added to the prepared cell suspension. The compound and cells were incubated together in a cell culture incubator for 72 hours (3 days). After aspirating the culture medium, 25 μL of Cell-Titer Glo (G7570, purchased from Promega) reagent was added, and the cells were incubated again for 5-10 minutes. Fluorescence values ​​were then read on Envision, and the IC50 of the compound's inhibitory effect on cell proliferation was calculated using GraphPad Prism software. 50 value.

[0612] Protein activity and cell biology data

[0613]

[0614]

[0615] "-" indicates that it has not been tested.

[0616] 6. Pharmacokinetic data of the compound:

[0617] Male SD rats were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. Rats were divided into groups of three and orally administered a suspension of the test sample (5 mg / kg, MC 0.5%) via gavage. Animals were fasted overnight before the experiment, from 10 hours before administration to 4 hours after administration. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After anesthesia with isoflurane using a small animal anesthesia machine, 0.3 mL of whole blood was collected through the fundus venous plexus and placed in heparin anticoagulant tubes. The samples were centrifuged at 4000 rpm for 5 min at 4°C. Plasma was transferred to centrifuge tubes and stored at -80°C until analysis. Protein extraction from the plasma was performed using protein precipitation, and the extract was analyzed by LC / MS.

[0618]

[0619] Industrial applicability

[0620] This invention provides a RET-selective inhibitor, its preparation, and its uses. The invention also provides a series of compounds represented by general formula (I) and their pharmaceutically acceptable salts, solvates, polymorphs, or isomers, pharmaceutical compositions comprising these compounds, and methods for treating diseases with such compounds. The RET-selective inhibitor provided by this invention exhibits high activity, strong resistance to drug resistance, and few clinical side effects, effectively overcoming the problem of drug resistance in tumor treatment, and possesses good economic value and application prospects.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: in, X and Y are each independently selected from CH and N; A is selected from 5-6 membered heteroaryl groups, wherein the heteroaryl group may optionally be converted by C. 1-6 Alkyl, -CN, -OH, -NR 5 R 6 halogen, -OC 1-6 Alkyl, -SC 1-6 Alkyl group, or -SO2-C 1-6 Alkyl substitution, the C 1-6 Alkyl groups may optionally be substituted with -OH, halogens, or -(CO)N(CH3)2, and R 5 and R 6 Each is independently selected from H and C. 1-6 alkyl; R 1 R 1’ R 2 and R 2’ Each independently is either H or C. 1-6 Alkyl, or R 1 and R 1’ One of them with R 2 and R 2’ One of them can be linked together to form a bond or -(CH2). m -; Z is selected from R 8 Each is independently selected from H and C. 1-6 Alkyl, -OC 1-6 Alkyl groups and -(CH2) m -OC 1-6 alkyl; m is independently selected from 1 and 2.

2. Selected from the following compounds: Or its pharmaceutically acceptable salt.

3. A pharmaceutical composition comprising a compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 in the preparation of a medicament for treating diseases related to RET.

5. The use according to claim 4, wherein the RET-related disease is lung cancer, papillary thyroid carcinoma, medullary thyroid carcinoma, differentiated thyroid carcinoma, recurrent thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal gangliocytoma, or cervical cancer.

6. The use according to claim 4, wherein the RET-related disease is RET fusion carcinoma or medullary thyroid carcinoma.

7. The use according to claim 4, wherein the RET-related disease is small cell lung cancer or non-small cell lung cancer.

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