Compounds for treating PI3Kγ-mediated diseases and their uses

Abstract

This application relates to a PI3Kγ kinase inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite, or prodrug thereof, wherein R1, R2, and R3 are as defined in the specification. This application also relates to the use of the PI3Kγ kinase inhibitor in the preparation of a medicament for treating diseases related to the activity of PI3Kγ kinase and related signaling pathways.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, and more particularly to compounds and their uses for treating cancer, inflammatory diseases or autoimmune diseases. Background Technology

[0002] Phosphatidylinositol-3-kinase (PI3K) plays a crucial role in cell growth, development, division, differentiation, and apoptosis, and is closely related to tumorigenesis and development. Based on structural and substrate specificity, PI3K can be classified into three types: type I, type II, and type III. Type I PI3K is the most extensively studied subtype and has the closest relationship with tumors. Type I PI3K is further divided into IA and IB subtypes. Type IA PI3K contains three catalytic subunits: p110α, p110β, and p110δ, while type IB PI3K has only one catalytic subunit—p110γ. Based on the different catalytic subunits, these PI3Ks are sequentially named PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. In terms of expression, PI3Kα and PI3Kβ are expressed in various cell types, while PI3Kγ is expressed only in the immune system. p110γ plays an important role in the tumor microenvironment, and therefore the development of p110γ inhibitors has become a research hotspot for the foreseeable future.

[0003] The PI3Kγ signaling pathway in macrophages promotes immunosuppression by inhibiting T cell activation, while inhibiting PI3Kγ can activate an immune response and significantly suppress the growth of xenografts. Preclinical studies have shown that PI3Kγ plays a crucial role in maintaining the immunosuppressive state of tumor-associated macrophages in the tumor microenvironment (Kaneda et al., Nature 539(7629), 2016, 437-442). Eganelisib, which targets PI3Kγ, can reprogram key immunosuppressive macrophages (M2) in the tumor microenvironment to transform into anti-tumor macrophages (M1), downregulate immunosuppression, increase immune activity, and ultimately lead to the activation and proliferation of cytotoxic T cells.

[0004] Furthermore, pharmacological or gene blocking of p110γ inhibits inflammation, growth, and metastasis in transplanted and spontaneous tumors, suggesting that PI3Kγ could be an important therapeutic agent in oncology (Schmid et al., Cancer Cell, 2011, 19, 715-27). For example, PI3Kγ has been shown to have high tumor-specific accumulation in human pancreatic ductal adenocarcinoma (PDAC), indicating the role of PI3Kγ in pancreatic cancer (Edling et al., Human Cancer Biology, 2010, 16(2), 4928-37).

[0005] Therefore, the development of PI3Kγ inhibitors can alter the balance of these immunosuppressive cells and promote the activation of anti-tumor immunity. PI3Kγ has become a very attractive drug target, but there is still a need to develop safer and more effective PI3Kγ inhibitors for the prevention and / or treatment of cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine disorders, or neurological diseases. Summary of the Invention

[0006] The purpose of this disclosure is to provide a novel PI3Kγ kinase inhibitor and its use in treating PI3Kγ-mediated diseases selected from cancer, inflammatory diseases, or autoimmune diseases, and to provide a method for treating or preventing PI3Kγ-mediated diseases in subjects.

[0007] On the one hand, this disclosure provides a PI3Kγ kinase inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof.

[0008]

[0009] in, Representing a fused heteroaryl group having 2 or 3 nitrogen atoms, preferably selected from: More preferably selected

[0010] R1 is selected from H, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl, C 1-6 alkylsulfonamide group or C 3-6 Cycloalkylsulfonamide group, preferably hydroxyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkylsulfonamide group or C 3-6 Cycloalkylsulfonamide group, more preferably methoxy group;

[0011] R2 is selected from H, halogen, or C. 1-6 Alkoxy, preferably C 1-3 Alkyl groups, more preferably methoxy groups;

[0012] R3 is selected from

[0013] Where n is 1, 2, or 3;

[0014] W is selected from direct bond, NH, O, -(C=O)- or -NH-(C=O)-;

[0015] R4 is selected from hydroxyl, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkylamino, C 3-6 Cycloalkylamino, C 1-6 Halogenated alkylamino, C 1-6 Hydroxyalkylamino, 5-7 membered heterocyclic groups (e.g., morpholino, piperazine, piperidinyl, etc.), 5-7 membered heterocyclic C 1-3 Alkyl (e.g., morpholinomethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, furanyl, pyrimidinyl, thiophene, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, tetrazolyl, etc.), 5-7 membered heterocyclic alkylamino (e.g., tetrahydropyranylamino, morpholinylamino, piperidinylamino, piperazinylamino, etc.), or heteroarylamino (e.g., pyridinylamino, thiazolylamino, etc.), optionally bound by 1-3 independent R x Group substitution, R x Independently selected from hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino;

[0016] R5 is a substituent on an alkylene group, where m is 0, 1, or 2, and each R5 is independently selected from hydroxyl or halogen, or two R5s together with the carbon atom to which they are attached form a C12 group. 3-6 Cycloalkyl or 4-7 membered heterocyclic groups (e.g., oxobutyl);

[0017] R6 and R7 are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or aralkyl (e.g., benzyl, etc.), or R6 and R7 together with the carbon atoms they are attached to form C 3-6 Cycloalkyl or 5-7-membered heterocyclic groups (e.g., pyrrolidinyl), optionally surrounded by 1-3 independent R groups. y Group substitution, R y Independently selected from oxo, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or 5-7 membered heterocyclic groups (e.g., morpholino).

[0018] In a preferred aspect, this disclosure relates to a PI3Kγ kinase inhibitor, which is a compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite, or prodrug thereof.

[0019]

[0020] in, W, R1, R2, R4, R5, m, and n are defined as above.

[0021] Wherein, the heterocyclic group described in this application is selected from oxacyclobutyl, morpholino, piperazin, piperidinyl or tetrahydropyrano, and the heteroaryl group is selected from pyridinyl, furanyl, pyrimidinyl, thiophene, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, tetrazolyl or thiazolyl.

[0022] In one embodiment, W is a direct bond; R4 is selected from hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, morpholino, piperazino, phenyl, thiopheno, imidazolyl, pyrazolo, triazolo, oxadiazolo, or tetrazolo, optionally surrounded by 1-3 independent R groups. x Group substitution, R x Selected independently from C 1-6 Alkyl; R5 is a substituent on the alkylene group, wherein m is 0, 1, or 2, and each R5 is independently selected from hydroxyl or halogen, or two R5s together with the carbon atom to which they are attached form a C12 group. 3-6 Cycloalkyl or oxocyclic butyl.

[0023] In another embodiment, W is NH; R4 is selected from phenyl, pyridyl or pyrimidinyl; m is 0.

[0024] In yet another implementation, W is 0; R4 is selected from C. 1-6 Alkyl, C 3-6 cycloalkyl C 1-3 Alkyl, phenyl, pyridyl, or pyrazolyl groups, optionally surrounded by 1-3 independent R groups. x Group substitution, R x Independently selected from cyano, halogen, C 1-6 Alkyl or C 1-6 Alkoxy group; m is 0.

[0025] In other embodiments, W is -(C=O)-; R4 is selected from C. 1-6 Alkylamino, C 3-6 Cycloalkylamino, C 1-6 Halogenated alkylamino, C 1-6Hydroxyalkylamino, tetrahydropyranylamino, morpholinylamino, piperidinylamino, piperazinylamino, pyridinylamino, or thiazolylamino, optionally surrounded by 1-3 independent R groups. x Group substitution, R x Selected independently from C 1-6 Alkyl group; m is 0.

[0026] In yet another embodiment, W is -NH-(C=O)-; R4 is selected from C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkylamino, piperidinyl, morpholinomethyl, phenyl, furanyl, thiophene, or imidazolyl, optionally surrounded by 1-3 independent R groups. x Group substitution, R x Selected independently from C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino; m is 0.

[0027] In the above embodiments, n is preferably 2.

[0028] In another preferred aspect, this disclosure relates to a PI3Kγ kinase inhibitor, which is a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite, or prodrug thereof.

[0029]

[0030] Q is selected from N or CH, and W, R1, R2, R4, R5, m and n are as defined above.

[0031] In a preferred aspect, this disclosure relates to a PI3Kγ kinase inhibitor, which is a compound of formula (III) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite, or prodrug thereof.

[0032]

[0033] in, R1 and R2 are defined above.

[0034] R6 and R7 are each independently selected from C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl or benzyl groups, or R6 and R7 together with the carbon atoms they are attached to, form C6. 3-6 Cycloalkyl or pyrrolidinyl, optionally surrounded by 1-3 independently R y Group substitution, Ry Independently selected from oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Hydroxyalkyl or morpholino,

[0035] The heterocyclic group described in this application is selected from oxoheterobutyl, morpholino, piperazinyl, piperidinyl, or tetrahydropyranyl, and the heteroaryl group is selected from pyridinyl, furanyl, pyrimidinyl, thiophene, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, tetrazolyl, or thiazolyl.

[0036] Particularly preferred, this disclosure provides a PI3Kγ kinase inhibitor selected from the following compounds or their pharmaceutically acceptable salts, solvates, polymorphs, esters, acids, isomers, metabolites, or prodrugs:

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045] In another respect, this disclosure relates to a pharmaceutical composition comprising the aforementioned PI3Kγ kinase inhibitor and a pharmaceutically acceptable carrier or excipient.

[0046] In other respects, this disclosure relates to the use of the aforementioned PI3Kγ kinase inhibitor in the preparation of a medicament for treating PI3Kγ-mediated diseases selected from cancer, inflammatory diseases or autoimmune diseases. The cancers mentioned are selected from one or more of the following: hematologic malignancies, brain cancer, gastrointestinal cancers, skin cancer, urinary system cancers, pancreatic cancer, lung cancer, medulloblastoma, basal cell carcinoma, glioma, breast cancer, prostate cancer, testicular cancer, esophageal cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), colon cancer, colorectal cancer, ovarian cancer, melanoma, neuroectodermal tumor, head and neck cancer, soft tissue sarcoma, fibrosarcoma, myoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovoma, mesothelioma, leiomyosarcoma, cervical cancer, uterine cancer, endometrial cancer, bladder cancer, epithelial cancer, squamous cell carcinoma, adenocarcinoma, bronchial carcinoma, renal cell carcinoma, bile duct carcinoma, neuroendocrine carcinoma, carcinoid tumor, diffuse giant cell tumor, glioblastoma, or solid tumor. The inflammatory disease or autoimmune disease is selected from one or more of the following: asthma, emphysema, allergy, dermatitis, arthritis, psoriasis, lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, eczema, scleroderma, Crohn's disease, or multiple sclerosis. Attached Figure Description

[0047] Figure 1 This study demonstrates the effect of the compound on mouse body weight in the MC38 mouse autoimmune model.

[0048] Figure 2 The study demonstrated the inhibitory effect of the compound on tumors in the MC38 mouse autoimmune model.

[0049] Figure 3 The tumor inhibition rate of the compound was shown in the MC38 mouse autoimmune model. Detailed Implementation

[0050] the term

[0051] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains.

[0052] Unless otherwise stated, this invention employs conventional methods within the scope of the art, such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology. Unless specifically defined, nomenclature and laboratory procedures and techniques related to analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are known to those skilled in the art. Generally, the foregoing techniques and steps can be practiced by conventional methods well-known in the art and described in various general and more specific documents, which are cited and discussed herein.

[0053] The term "alkyl" refers to an aliphatic hydrocarbon group, which can be branched or straight-chain alkyl. Depending on the structure, an alkyl group can be a monovalent or divalent group (i.e., an alkylene group). In this invention, the alkyl group is preferably an alkyl group having 1-8 carbon atoms, more preferably a "lower alkyl" having 1-6 carbon atoms, and even more preferably an alkyl group having 1-4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. It should be understood that "alkyl" as used herein includes all possible configurations and conformations of the alkyl group; for example, "propyl" as used herein includes n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl, and tert-butyl, and "pentyl" includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and pent-3-yl, etc.

[0054] The term "alkoxy" refers to an -O-alkyl group, where the alkyl group is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy.

[0055] The term "alkoxyalkyl" refers to an alkyl group as defined herein that has been substituted with an alkoxy group as defined herein.

[0056] The term "cycloalkyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl groups include groups having 3-12 ring atoms. Depending on the structure, a cycloalkyl group can be a monovalent or bivalent group (e.g., a cycloalkylene group). In this invention, the cycloalkyl group is preferably a cycloalkyl group having 3-8 carbon atoms, more preferably a "lower cycloalkyl group" having 3-6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl.

[0057] The term "alkyl (cycloalkyl)" or "cycloalkylalkyl" means that an alkyl group as defined herein is substituted with a cycloalkyl group as defined herein. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc.

[0058] The term "aromatic group" refers to a planar ring with a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. An aromatic ring can consist of five, six, seven, eight, nine, or more than nine atoms. The aromatic group can be optionally substituted. The term "aromatic group" includes carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups.

[0059] As used herein, the term "aryl" refers to an aromatic ring in which every atom constituting the ring is a carbon atom. An aryl ring can consist of five, six, seven, eight, nine, or more than nine atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthraceneyl, fluorenyl, and indene. Depending on the structure, the aryl group can be a monovalent or divalent group (i.e., an arylene).

[0060] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined herein.

[0061] The term "heteroaryl" refers to an aryl group that includes one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaryl" moiety means that at least one skeletal atom on the ring of the aryl group is a nitrogen atom. Depending on its structure, a heteroaryl can be a monovalent or bivalent group (i.e., a hypoaryl). Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, isoydinolyl, pteridinyl, purine, oxadiazolyl, thiazolyl, furazonyl, benzofuranyl, benzothiophene, benzothiazolyl, benzooxazolyl, quinazolinyl, naphridinyl, and furanopyridinyl, etc.

[0062] The term "alkyl (aryl)" or "aralkyl" means that an alkyl group as defined herein is replaced by an aryl group as defined herein. Non-limiting alkyl (aryl) groups include benzyl, phenethyl, etc.

[0063] The term “alkyl (heteroaryl)” or “heteroarylalkyl” means that an alkyl group as defined herein is replaced by a heteroaryl group as defined herein.

[0064] As used herein, the term "heteroalkyl" means an alkyl group in which one or more skeletal chain atoms are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. The heteroatoms (one or more) may be located at any position within the heteroalkyl group or at a position where the heteroalkyl group is attached to the rest of the molecule.

[0065] As used herein, the term "heterocyclic alkyl" or "heterocyclic group" refers to a non-aromatic ring in which one or more of the constituent atoms of the ring are heteroatoms selected from nitrogen, oxygen, and sulfur. Heterocyclic alkyl rings can be monocyclic or polycyclic, consisting of three, four, five, six, seven, eight, nine, or more atoms. Heterocyclic alkyl rings may be optionally substituted. Examples of heterocyclic alkyl groups include, but are not limited to, lactams, lactones, cycloimides, cyclothioimides, cyclocarbamates, tetrahydrothiarans, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxins, 1,3-dioxanes, 1,4-dioxins, 1,4-dioxanes, piperazines, 1,3-oxothiacyclohexane, 1,4-oxothiacyclohexadiene, 1,4-oxothiacyclohexane, tetrahydro-1,4-thiazine, 2H-1,2-oxazines, maleimides, succinimides, barbiturates, and thiobarbiturates. Acids, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrrolidone, pyrrolidine, imidazoline, pyrazole, imidazoline, imidazoline, 1,3-dioxacyclopentene, 1,3-dioxacyclopentene, 1,3-dithiocyclopentene, isoxazoline, isoxazoline, oxazoline, oxazoline, oxazoline, oxazoline ketone, thiazoline, thiazoline, and 1,3-oxothiocyclopentane. Depending on the structure, heterocyclic alkyl groups can be monovalent or bivalent (i.e., heterocyclic alkylene).

[0066] The term "alkyl (heterocyclic alkyl)" or "heterocyclic alkyl alkyl" means that an alkyl group as defined herein is replaced by a heterocyclic alkyl group as defined herein.

[0067] The term "alkoxy (heterocyclic alkyl)" or "heterocyclic alkyl alkoxy" means that the alkoxy group defined herein is substituted with the heterocyclic alkyl group defined herein.

[0068] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0069] The terms "haloalkyl", "haloalkoxy", and "haloheteroalkyl" include structures of alkyl, alkoxy, or heteroalkyl groups in which at least one hydrogen atom is replaced by a halogen atom. In some embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from each other.

[0070] The term "hydroxyl group" refers to the -OH group.

[0071] The term "cyano" refers to the -CN group.

[0072] The term "ester group" refers to a chemical moiety having the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (linked by a ring carbon), and heterocyclic (linked by a ring carbon).

[0073] The term "amino" refers to the -NH2 group.

[0074] The term "aminoacyl" refers to the -CO-NH2 group.

[0075] The term "alkylaminoyl" refers to the -CO-NH-R group, where R is an alkyl group as defined herein.

[0076] The term "amide group" or "amide group" refers to -NR-CO-R', where R and R' are each independently hydrogen, alkyl, aromatic or heteroaryl.

[0077] The term "alkylamino" refers to an amino substituent further replaced by one or two alkyl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen or lower alkyl groups, provided that -NRR' is not -NH2. "Alkylamino" includes groups in compounds in which the nitrogen atom of -NH2 is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, etc. "Dialkylamino" includes groups in which the nitrogen atom of -NH2 is attached to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, etc.

[0078] The terms “arylamino” and “diarylamino” refer to amino substituents that are further replaced by one or two aryl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen, lower alkyl, or aryl, and N is attached to one or two aryl groups respectively.

[0079] The term "cycloalkylamino" refers to an amino substituent that is further replaced by one or two cycloalkyl groups as defined herein.

[0080] The term "heteroalkylamino" refers to an amino substituent that is further replaced by one or two heteroalkyl groups as defined herein.

[0081] The term "arylamino" in this article refers to a group in which R is a lower aryl group and R' is a hydrogen, lower alkyl, aryl, or lower aryl group -NRR'.

[0082] The term “heteroarylamino” refers to an amino substituent that is further replaced by one or two heteroaryl groups as defined herein.

[0083] The term "heterocyclic alkylamino" refers to an amino group as defined herein that has been substituted with a heterocyclic alkyl group as defined herein.

[0084] The term "alkylaminoalkyl" means that an alkyl group as defined herein is replaced by an alkylamino group as defined herein.

[0085] The term "aminoalkyl" refers to an alkyl substituent that is further replaced by one or more amino groups.

[0086] The term "aminoalkoxy" refers to an alkoxy substituent that is further replaced by one or more amino groups.

[0087] The term "hydroxyalkyl" or "hydroxyalkyl group" refers to an alkyl substituent that is further replaced by one or more hydroxyl groups.

[0088] The term "cyanoalkyl" refers to an alkyl substituent that is further replaced by one or more cyano groups.

[0089] The term "acyl" refers to the monovalent group remaining after removing the hydroxyl group from an organic or inorganic oxyacid, with the general formula RM(O)-, where M is usually C.

[0090] The term "carbonyl" or "oxo" refers to an organic functional group (C=O) formed by carbon and oxygen atoms linked by a double bond.

[0091] The term "alkanoyl" or "alkyl carbonyl" refers to a carbonyl group that is further substituted with an alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, and hexanoyl.

[0092] The term "aryl carbonyl" refers to a carbonyl group as defined herein that has been replaced by an aryl group as defined herein.

[0093] The term "alkoxycarbonyl" refers to a carbonyl group that is further replaced by an alkoxy group.

[0094] The term "heterocyclic alkyl carbonyl" refers to a carbonyl group that is further replaced by a heterocyclic alkyl group.

[0095] The terms “alkylaminocarbonyl”, “cycloalkylaminocarbonyl”, “arylaminocarbonyl”, “arylalkylaminocarbonyl”, and “heteroarylaminocarbonyl” refer to carbonyl groups as defined herein that have been substituted by alkylamino, cycloalkylamino, arylamino, arylalkylamino, or heteroarylamino groups as defined herein.

[0096] The terms “alkylcarbonylalkyl” or “alkanoylalkyl” refer to an alkyl group that is further replaced by an alkylcarbonyl group.

[0097] The term "alkylcarbonylalkoxy" or "alkanoylalkoxy" refers to an alkoxy group that is further substituted with an alkyl carbonyl group.

[0098] The term "heterocyclic alkyl carbonyl alkyl" refers to an alkyl group that is further replaced by a heterocyclic alkyl carbonyl group.

[0099] The term "thiol" refers to a -SH group. The term "alkathiol" refers to a thiol group as defined herein that has been substituted with an alkyl group as defined herein.

[0100] The terms "sulfonyl" or "sulfonyl" refer to the functional group of a sulfonic acid after the loss of its hydroxyl group, specifically the -S(=O)2- group.

[0101] The term "sulfonyl" or "sulfinyl" refers to -S(=O)-.

[0102] The terms "aminosulfonyl" or "aminosulfonyl" refer to the -S(=O)2-NH2 group.

[0103] The terms "alkyl sulfoxide" or "alkyl sulfinyl" refer to alkyl-S(=O)-.

[0104] The terms "alkyl sulfonyl" or "alkyl sulfonyl" refer to -S(=O)2-R, where R is an alkyl group.

[0105] The term "alkylaminosulfone" refers to a sulfone group as defined herein that has been replaced by an alkylamino group as defined herein.

[0106] The terms “alkylsulfonylamino” or “alkylsulfonamide”, and “cycloalkylsulfonylamino” or “cycloalkylsulfonamide”, refer to an amino group as defined herein that is substituted with an alkylsulfonyl or cycloalkylsulfonyl group as defined herein, i.e., -NH-S(=O)2-R, where R is alkyl and cycloalkyl, respectively.

[0107] The terms "cycloalkylsulfonyl" and "cycloalkylsulfonyl" refer to -S(=O)2-R, where R is cycloalkyl.

[0108] The term "optional" means that one or more events described below may or may not occur, and includes both the events that occur and the events that do not occur. The terms "optionally substituted" or "substituted" mean that the mentioned group can be substituted by one or more additional groups, each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc. Preferably, the amino protecting group is selected from neopentanoyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl, etc.

[0109] As used herein, a pharmaceutically acceptable form of the disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, esters, acids, isomers, metabolites, prodrugs, and isotopically labeled derivatives of the disclosed compound.

[0110] The term "pharmaceutically acceptable salt" in this document refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesirable toxicological effects; that is, salts suitable for contact with a subject's tissues within the bounds of reasonable medical judgment without excessive toxicity, irritation, anaphylactic reactions, etc., and consistent with a reasonable benefit / risk ratio. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound, in its free acid or free base form, separately with a suitable base or acid. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds presented herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts of amino groups formed by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbic acid salts, aspartate salts, benzenesulfonates, benzenesulfonates, benzoates, hydrogen sulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionate, diglucuronide, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucohepanoate, glycerophosphates, glucuronide, hemisulfates, heptasulfates, heptahydrates, hydroiodates, 2-hydroxyethanesulfonate, and lacturonic acid. Salts, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, naphthalene-m,n-disulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, dihydroxynaphthalates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, trimethylacetate, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc.

[0111] "Solvate" or "solvent compound" refers to a solvation compound containing a stoichiometric or non-stoichiometric solvent. Some compounds tend to trap solvent molecules in a fixed molar ratio in a crystalline solid state, thus forming a solvate compound. If the solvent is water, the resulting solvate compound is a hydrate; if the solvent is an alcohol, the resulting solvate compound is an alcohol. A "hydrate" is formed by the combination of one or more water molecules with a molecule of the substance, wherein the water retains its molecular state as H₂O.

[0112] The "metabolites" of the compounds disclosed herein are derivatives of the compounds formed when the compounds are metabolized. The term "active metabolite" refers to a biologically active derivative of the compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the sum of processes by which a particular substance is altered by an organism (including, but not limited to, hydrolysis and enzyme-catalyzed reactions, such as oxidation). Thus, enzymes can produce specific structures that are transformed into compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while glucuronyl diphosphate transferases catalyze the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from *The Pharmacological Basis of Therapeutics*, 9th edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from that host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art. In some embodiments, the metabolites of the compound are formed through an oxidation process and correspond to the corresponding hydroxyl-containing compounds. In some implementations, the compound is metabolized into a drug-active metabolite.

[0113] The term “modulation” as used in this article refers to direct or indirect interaction with a target to alter its activity, including, for example, enhancing, inhibiting, limiting, or prolonging the activity of a target.

[0114] The term "prodrug" or "prodrug precursor" refers to derivatives that may not be pharmacologically active, but in some cases can be administered orally or parenterally and subsequently metabolized in vivo to form the pharmacologically active compounds of the present invention. Non-limiting examples of prodrugs include esters, carbonates, hemiesters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals, and ketoacetates, etc.

[0115] "Effective amount" refers to the amount of a drug or pharmaceutical preparation that will elicit a biological or medical response in an investigational tissue, system, animal, or human, such as that of an investigator or physician. Furthermore, the term "therapeutic effective amount" refers to any amount that, compared to a corresponding subject who has not received that amount, results in a treatment, cure, prevention, or relief of disease, disorder, or side effects, or a reduction in the rate of disease or disorder progression. The term also includes amounts that effectively improve normal physiological function.

[0116] As used herein, the term "treatment" refers to the relief of at least one symptom of a disease, disorder, or condition. This term includes administering medication to a subject and / or applying one or more of the compounds described herein to provide management or treatment of the condition. For the purposes of this disclosure, "treatment" may, but does not necessarily, provide a cure; rather, it means that "treatment" can be a form of management of the condition. When the compounds described herein are used to treat harmful proliferating cells (including cancer), "treatment" includes the partial or complete destruction of said harmful proliferating cells, but with minimal impact on normal cells. The desired treatment mechanism for harmful, rapidly proliferating cells (including cancer cells) is apoptosis at the cellular level.

[0117] As used in this article, “prevention” includes the initiation of joint prevention or mitigation of the development of a clinically significant disease or the initiation of a preclinically significant disease stage in an individual at risk. This includes preventative treatment of individuals at risk of disease development.

[0118] The terms "subject" or "patient" include organisms that may suffer from a condition or a condition associated with reduced or insufficient programmed cell death (apoptosis) or that may otherwise benefit from administration of the compounds of the present invention, such as humans and non-human animals. Preferred humans include human patients who suffer from or are predisposed to suffer from the condition or related condition as described herein. The term "non-human animal" includes vertebrates, such as mammals, such as non-human primates, sheep, cattle, dogs, cats, and rodents such as mice, as well as non-mammals such as chickens, amphibians, reptiles, etc.

[0119] The GI used in this article 50 This refers to the drug concentration required to inhibit the growth of 50% of cells, that is, the drug concentration at which the growth of 50% of cells (such as cancer cells) is inhibited or controlled.

[0120] IC used in this article 50 This refers to the amount, concentration, or dose of a specific test compound that achieves 50% inhibition of the maximum effect in the analysis of the measured effect.

[0121] EC used in this article 50 A dose-dependent response refers to a dose, concentration, or amount of a measured compound that elicits a specific response induced, stimulated, or enhanced by that compound at a maximum expression of 50%.

[0122] kinase inhibitors

[0123] This disclosure relates to a PI3Kγ kinase inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof.

[0124]

[0125] in, Representing a fused heteroaryl group having 2 or 3 nitrogen atoms, preferably selected from: More preferably selected

[0126] R1 is selected from H, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl, C 1-6 alkylsulfonamide group or C 3-6 Cycloalkylsulfonamide group, preferably hydroxyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkylsulfonamide group or C 3-6 Cycloalkylsulfonamide group, more preferably methoxy group;

[0127] R2 is selected from H, halogen, or C. 1-6 Alkoxy, preferably C 1-3 Alkyl groups, more preferably methoxy groups;

[0128] R3 is selected from

[0129] Where n is 1, 2, or 3;

[0130] W is selected from direct bond, NH, O, -(C=O)- or -NH-(C=O)-;

[0131] R4 is selected from hydroxyl, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkylamino, C 3-6 Cycloalkylamino, C 1-6 Halogenated alkylamino, C 1-6 Hydroxyalkylamino, 5-7 membered heterocyclic groups (e.g., morpholino, piperazine, piperidinyl, etc.), 5-7 membered heterocyclic C 1-3 Alkyl (e.g., morpholinomethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, furanyl, pyrimidinyl, thiophene, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, tetrazolyl, etc.), 5-7 membered heterocyclic alkylamino (e.g., tetrahydropyranylamino, morpholinylamino, piperidinylamino, piperazinylamino, etc.), or heteroarylamino (e.g., pyridinylamino, thiazolylamino, etc.), optionally bound by 1-3 independent Rx Group substitution, R x Independently selected from hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino;

[0132] R5 is a substituent on an alkylene group, where m is 0, 1, or 2, and each R5 is independently selected from hydroxyl or halogen, or two R5s together with the carbon atom to which they are attached form a C12 group. 3-6 Cycloalkyl or 4-7 membered heterocyclic groups (e.g., oxobutyl);

[0133] R6 and R7 are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or aralkyl (e.g., benzyl, etc.), or R6 and R7 together with the carbon atoms they are attached to form C 3-6 Cycloalkyl or 5-7-membered heterocyclic groups (e.g., pyrrolidinyl), optionally surrounded by 1-3 independent R groups. y Group substitution, R y Independently selected from oxo, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or 5-7 membered heterocyclic groups (e.g., morpholino).

[0134] In a preferred aspect, this disclosure relates to a PI3Kγ kinase inhibitor, which is a compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite, or prodrug thereof.

[0135]

[0136] in, W, R1, R2, R4, R5, m, and n are defined as above.

[0137] Wherein, the heterocyclic group described in this application is selected from oxacyclobutyl, morpholino, piperazin, piperidinyl or tetrahydropyrano, and the heteroaryl group is selected from pyridinyl, furanyl, pyrimidinyl, thiophene, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, tetrazolyl or thiazolyl.

[0138] More specifically, Selected from: More preferably selected

[0139] R1 is selected from H, hydroxyl, halogen, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl, C 1-6 alkylsulfonamide group or C 3-6 Cycloalkylsulfonamide group, preferably hydroxyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkylsulfonamide group or C 3-6 Cycloalkylsulfonamide group, more preferably methoxy group;

[0140] R2 is selected from H, halogen, or C. 1-6 Alkoxy, preferably C 1-3 Alkyl groups, more preferably methoxy groups;

[0141] n is 1, 2, or 3;

[0142] W is selected from direct bond, NH, O, -(C=O)- or -NH-(C=O)-;

[0143] R4 is selected from hydroxyl, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkylamino, C 3-6 Cycloalkylamino, C 1-6 Halogenated alkylamino, C 1-6 Hydroxyalkylamino, morpholino, piperazino, piperidino, morpholinomethyl, phenyl, pyridino, furanyl, pyrimidino, thiophene, imidazolyl, pyrazolo, triazolo, oxadiazolo, tetrazolo, tetrahydropyranylamino, morpholinoamino, piperidinoamino, piperazinoamino, pyridinoamino, or thiazolylamino, optionally separated by 1-3 independent R x Group substitution, R x Independently selected from hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino;

[0144] R5 is a substituent on an alkylene group, where m is 0, 1, or 2, and each R5 is independently selected from hydroxyl or halogen, or two R5s together with the carbon atom to which they are attached form a C12 group. 3-6 Cycloalkyl or oxocyclic butyl.

[0145] In one embodiment, W is a direct bond; R4 is selected from hydroxyl, cyano, C 1-6 Alkyl, C1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, morpholino, piperazino, phenyl, thiopheno, imidazolyl, pyrazolo, triazolo, oxadiazolo, or tetrazolo, optionally surrounded by 1-3 independent R groups. x Group substitution, R x Selected independently from C 1-6 Alkyl; R5 is a substituent on the alkylene group, wherein m is 0, 1, or 2, and each R5 is independently selected from hydroxyl or halogen, or two R5s together with the carbon atom to which they are attached form a C12 group. 3-6 Cycloalkyl or oxocyclic butyl.

[0146] In another embodiment, W is NH; R4 is selected from phenyl, pyridyl or pyrimidinyl; m is 0.

[0147] In yet another implementation, W is 0; R4 is selected from C. 1-6 Alkyl, C 3-6 cycloalkyl C 1-3 Alkyl, phenyl, pyridyl, or pyrazolyl groups, optionally surrounded by 1-3 independent R groups. x Group substitution, R x Independently selected from cyano, halogen, C 1-6 Alkyl or C 1-6 Alkoxy group; m is 0.

[0148] In other embodiments, W is -(C=O)-; R4 is selected from C. 1-6 Alkylamino, C 3-6 Cycloalkylamino, C 1-6 Halogenated alkylamino, C 1-6 Hydroxyalkylamino, tetrahydropyranylamino, morpholinylamino, piperidinylamino, piperazinylamino, pyridinylamino, or thiazolylamino, optionally surrounded by 1-3 independent R groups. x Group substitution, R x Selected independently from C 1-6 Alkyl group; m is 0.

[0149] In yet another embodiment, W is -NH-(C=O)-; R4 is selected from C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkylamino, piperidinyl, morpholinomethyl, phenyl, furanyl, thiophene, or imidazolyl, optionally surrounded by 1-3 independent R groups. x Group substitution, R x Selected independently from C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino; m is 0.

[0150] In the above embodiments, n is preferably 2.

[0151] In another preferred aspect, this disclosure relates to a PI3Kγ kinase inhibitor, which is a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite, or prodrug thereof.

[0152]

[0153] Q is selected from N or CH, and W, R1, R2, R4, R5, m and n are as defined above.

[0154] In a preferred aspect, this disclosure relates to a PI3Kγ kinase inhibitor, which is a compound of formula (III) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite, or prodrug thereof.

[0155]

[0156] in, R1, R2, R6, and R7 are defined above.

[0157] Specifically, Selected from: More preferably selected

[0158] R1 is selected from H, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl, C 1-6 alkylsulfonamide group or C 3-6 Cycloalkylsulfonamide group, preferably hydroxyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkylsulfonamide group or C 3-6 Cycloalkylsulfonamide group, more preferably methoxy group;

[0159] R2 is selected from H, halogen, or C. 1-6 Alkoxy, preferably C 1-3 Alkyl groups, more preferably methoxy groups;

[0160] R6 and R7 are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6Haloalkyl, C 3-6 Cycloalkyl or benzyl groups, or R6 and R7 together with the carbon atoms they are attached to, form C6. 3-6 Cycloalkyl or pyrrolidinyl, optionally surrounded by 1-3 independently R y Group substitution, R y Independently selected from oxo, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or morpholino.

[0161] More preferably, R6 and R7 are each independently selected from C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl or benzyl groups, or R6 and R7 together with the carbon atoms they are attached to, form C6. 3-6 Cycloalkyl or pyrrolidinyl, optionally surrounded by 1-3 independently R y Group substitution, R y Independently selected from oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Hydroxyalkyl or morpholino.

[0162] For each variable, any combination of the aforementioned groups is also considered in this paper. It is understood that the substituents and substitution patterns on the compounds presented herein can be selected by those skilled in the art to provide chemically stable compounds that can be synthesized using techniques known in the art and those described herein.

[0163] This article also describes pharmaceutically acceptable salts, solvates, polymorphs, esters, acids, isomers, metabolites, or prodrugs of this compound.

[0164] In particular, the compounds described herein can be prepared and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reacting with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1 - Formic acid, 2-naphthalenesulfonic acid, tert-butylacetic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthalene acid, stearic acid, mucoconic acid, etc.; (2) Base addition salts, which are formed when the acidic protons in the parent compound are replaced by metal ions, such as alkali metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (e.g., magnesium or calcium) or aluminum ions; or coordinated with organic or inorganic bases, the acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucosamine, etc.; the acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0165] The corresponding equilibrium ions of pharmaceutically acceptable salts can be analyzed and identified using a variety of methods, including but not limited to ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectrometry, mass spectrometry, or any combination thereof.

[0166] The salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or lyophilization in the case of an aqueous solution.

[0167] Screening and characterizing pharmaceutically acceptable salts, polymorphs, and / or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, microscopy, and elemental analysis. Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid states). Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.

[0168] Drug Use

[0169] The PI3Kγ kinase inhibitor disclosed herein may be used in medicaments for the treatment of PI3Kγ-mediated diseases selected from cancer, inflammatory diseases, or autoimmune diseases. The cancers mentioned are selected from one or more of the following: hematologic malignancies, brain cancer, gastrointestinal cancers, skin cancer, urinary system cancers, pancreatic cancer, lung cancer, medulloblastoma, basal cell carcinoma, glioma, breast cancer, prostate cancer, testicular cancer, esophageal cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), colon cancer, colorectal cancer, ovarian cancer, melanoma, neuroectodermal tumor, head and neck cancer, soft tissue sarcoma, fibrosarcoma, myoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovoma, mesothelioma, leiomyosarcoma, cervical cancer, uterine cancer, endometrial cancer, bladder cancer, epithelial cancer, squamous cell carcinoma, adenocarcinoma, bronchial carcinoma, renal cell carcinoma, bile duct carcinoma, neuroendocrine carcinoma, carcinoid tumor, diffuse giant cell tumor, glioblastoma, or solid tumor. The inflammatory disease or autoimmune disease is selected from one or more of the following: asthma, emphysema, allergy, dermatitis, arthritis, psoriasis, lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, eczema, scleroderma, Crohn's disease, or multiple sclerosis.

[0170] In some embodiments, the obstacle to be treated by the methods or compounds disclosed herein is cancer. In some embodiments, the cancer is a solid tumor or soft tissue tumor (e.g., carcinoid, carcinoma, or sarcoma), a hematopoietic tissue tumor (e.g., a heme malignancy) or a metastatic lesion, lymphoma or a metastatic lesion, such as a metastatic lesion of any cancer or tumor disclosed herein. In one embodiment, the cancer is a bone metastasis.

[0171] In some embodiments, the cancer treated by the methods or compounds disclosed herein is a soft tissue tumor, a heme malignancy, or a blood cancer.

[0172] In some embodiments, the solid tumor or soft tissue tumor treated using the methods or compounds disclosed herein is a cancer or tumor selected from one or more of the following: head and neck cancer, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, oral cavity cancer, oropharyngeal cancer, laryngeal cancer, hypopharyngeal cancer, salivary gland cancer, paraganglioma, pancreatic cancer, gastric cancer, skin cancer, esophageal cancer, endometrial cancer, liver and bile duct cancer, bone cancer, intestinal cancer, colon cancer, rectal cancer, ovarian cancer, prostate cancer, lung cancer, breast cancer, lymphatic system tumors, blood cancers, myeloma, central nervous system tumors, brain cancer, or metastatic lesions thereof. In some embodiments, the cancer treated by the methods or compounds disclosed herein is a solid tumor (e.g., carcinoid, carcinoma, or sarcoma) or metastatic lesions thereof. In one embodiment, the cancer is lung cancer (e.g., non-small cell lung cancer or small cell lung cancer); skin cancer; melanoma; prostate cancer; glioblastoma; endometrial cancer; pancreatic cancer (e.g., pancreatic adenocarcinoma (e.g., pancreatic ductal adenocarcinoma (PDA))); renal cell carcinoma; colorectal cancer; breast cancer (e.g., triple-negative breast cancer); thyroid cancer; sarcoma, liver cancer or hepatocellular carcinoma (HCC), head and neck cancer, cervical or vulvar cancer, esophageal cancer, gastric cancer, adrenal cancer or ovarian cancer or metastatic lesions thereof. In one embodiment, the solid tumor is prostate cancer, breast cancer or glioblastoma or metastatic lesions thereof.

[0173] In some implementations, the cancer or tumor being treated is a solid fibrotic tumor selected from one or more of the following: pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), breast cancer, colorectal cancer, colon cancer, lung cancer (e.g., small cell or non-small cell lung cancer), skin cancer, ovarian cancer, prostate cancer, cervical cancer, gastrointestinal cancer (e.g., carcinoid or stromal carcinoma), gastric cancer, head and neck cancer, kidney cancer, brain cancer, or metastatic lesions thereof.

[0174] In one embodiment, the hematopoietic tumor is acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), myelodysplastic disorder, mast cell carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, human lymphotropic virus type I (HTLV-1) leukemia / lymphoma, AIDS-related lymphoma, adult T-cell lymphoma, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, or multiple myeloma (MM). In one embodiment, the cancer is leukemia or lymphoma. In one embodiment, the leukemia is B-cell acute lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic disorder, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), or mast cell carcinoma.

[0175] In one embodiment, the lymphoma is diffuse large B-cell lymphoma, B-cell lymphoblastic lymphoma, small non-cleaved cell lymphoma or Burkitt lymphoma, human lymphotropic virus type I (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, Hodgkin's disease or non-Hodgkin's lymphoma or its metastatic lesions.

[0176] In some embodiments, the obstacle treated by the methods or compounds disclosed herein is an inflammatory disease or an autoimmune disease. In one embodiment, the inflammatory disease or autoimmune disease is asthma, emphysema, allergy, dermatitis, arthritis (e.g., rheumatoid arthritis), psoriasis, lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, eczema, scleroderma, Crohn's disease, or multiple sclerosis. In one embodiment, the obstacle is rheumatoid arthritis. In one embodiment, the obstacle is rheumatoid arthritis, and the amount of the compound effectively improves one or more symptoms associated with rheumatoid arthritis, wherein the symptoms associated with rheumatoid arthritis independently include reduced joint swelling, decreased serum anti-collagen levels, reduced joint pathology, reduced bone resorption, reduced cartilage destruction, reduced pannus, and / or reduced inflammation.

[0177] In some embodiments, the obstacle treated by the methods or compounds disclosed herein is a respiratory disease. In one embodiment, the respiratory disease is asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or bronchiectasis. In one embodiment, the obstacle is asthma.

[0178] In embodiments of the invention, a drug comprising the compound of the invention can be administered to a patient by at least one of injection, oral, inhalation, rectal, and transdermal administration. When treating a patient according to the invention, the amount of the given drug depends on many factors, such as the specific dosing regimen, the type and severity of the disease or condition, and the unique characteristics of the patient or host requiring treatment (e.g., weight). However, depending on the specific surrounding circumstances, including, for example, the specific drug used, the route of administration, the condition being treated, and the patient or host being treated, the dosage can be conventionally determined by methods known in the art. Typically, for adult treatment, the dosage is typically in the range of 0.02-5000 mg / day, for example, about 1-1500 mg / day. This required dosage can be conveniently expressed as a single dose, or concurrent (or over a short period of time) or fractions at appropriate intervals, such as two, three, four, or more doses per day. Those skilled in the art will understand that although the above dosage ranges are given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.

[0179] In some embodiments of the methods or uses disclosed herein, a compound such as any of the compounds described herein is administered to a subject at a dose (e.g., a therapeutically effective dose) of about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, or 0.1-50 mg. In some embodiments, the dose (e.g., a therapeutically effective dose) is about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, 0.1-50 mg, 0.1-75 mg, 0.5-75 mg, 1-75 mg, 0.1-100 mg, 0.5-100 mg, or 1-100 mg. In some embodiments, the dose is about 1-10 mg. In some embodiments, the dose is about 1-50 mg. In some embodiments, the dose is about 1-100 mg.

[0180] Preparation of compounds

[0181] The compounds disclosed herein (including their salts) can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes.

[0182] The reactions used to prepare the compounds disclosed herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis.

[0183] Those skilled in the art can readily determine the appropriate selection of protecting groups.

[0184] The reaction can be monitored using any suitable method known in the art, such as NMR, LC-MS, and TLC.

[0185] The compound can be purified by a variety of methods, including HPLC and normal-phase silica chromatography.

[0186] Common abbreviations:

[0187] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0188] DIPEA: N,N-Diisopropylethylamine

[0189] Example 1 Synthesis of compound 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-phenoxyethyl)urea

[0190]

[0191] 6 mL of methanol was added to a 100 mL round-bottom flask, followed by the addition of N-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)acetamide (1.0 g, 3.2 mmol, 1.0 eq) and 2 mL of ethyl acetate solution of hydrochloric acid while stirring at room temperature. The reaction system was allowed to react at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by vacuum distillation. The crude product was neutralized with saturated NaHCO3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. Vacuum distillation of the organic phase yielded the crude product, which was then subjected to silica gel column chromatography to give 820 mg of the yellow product 5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-amine, with a yield of 95%. MS m / z (ESI): 272.11 [M+H] + .

[0192] Add 30 mL of tetrahydrofuran to a 100 mL round-bottom flask, and then add 5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidine-2-amine (820 mg, 3.0 mmol, 1.0 eq), phenyl chloroformate (562 mg, 3.6 mmol, 1.2 eq), and triethylamine (834 μL, 6.0 mmol, 2.0 eq) with stirring at 0 °C. Continue the reaction at 0 °C for 1 hour. After the reaction is complete, neutralize with 20 mL of water. Extract the mixture three times with 30 mL of ethyl acetate, and combine the organic phases. Wash the organic phases with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dry with anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 704 mg of a yellow product, phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate, in 60% yield. MS m / z (ESI): 392.14 [M+H] + .

[0193] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-phenoxyethylamine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 18 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-phenoxyethyl)urea (compound 1), with a yield of 30%. 1 H NMR (500MHz, DMSO-d6) δ9.43(s,1H),8.93(d,J=7.3Hz,1H),8.54(d,J=1.9Hz,1H),7.97(d,J=1.9Hz,1H),7.54(d,J=7.3Hz,1H ),7.33–7.28(m,2H),7.02–6.91(m,4H),6.64(s,1H),4.06(t,J=5.5Hz,2H),3.95(s,3H),3.92(s,3H),3.54(q,J=5.5Hz,2H). MS m / z(ESI):435.18[M+H] + .

[0194] Example 2 Synthesis of compound 2: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0195]

[0196] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(pyridin-3-yloxy)ethylamine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 2), with a yield of 26%. 1 HNMR(500MHz,DMSO-d6)δ9.54(s,1H),8.93(d,J=7.3Hz,1H),8.54(d,J=1.9Hz,1H), 8.34(d,J=2.9Hz,1H),8.20–8.17(m,1H),7.97(d,J=1.8Hz,1H),7.54(d,J=7.3Hz,1 H),7.45(dd,J=8.4,1.8Hz,1H),7.34(dd,J=8.4,4.6Hz,1H),7.13(t,J=5.3Hz,1H), 6.64(s,1H),4.14(t,J=5.5Hz,2H),3.95(s,3H),3.92(s,3H),3.56(q,J=5.5Hz,2H). MS m / z(ESI):436.17[M+H] + .

[0197] Example 3 Synthesis of compound 3: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(2-fluorophenoxy)ethyl)urea

[0198]

[0199] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(2-fluorophenoxy)-1-ethylamine (22 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(2-fluorophenoxy)ethyl)urea (compound 3), with a yield of 34%. 1 H NMR (500MHz, DMSO-d6) δ9.53(s,1H),8.92(d,J=7.3Hz,1H),8.54(d,J=1.9Hz,1H),7.97(d,J=1.9Hz,1H),7.55(d,J=7.3Hz,1H),7.25–7.20(m,2H) ,7.12(dd,J=17.8,9.9Hz,2H),6.96(dt,J=12.3,4.0Hz,1H),6.64(s,1H) ,4.13(t,J=5.5Hz,2H),3.95(s,3H),3.92(s,3H),3.56(q,J=5.5Hz,2H). MS m / z(ESI):453.17[M+H] + .

[0200] Example 4 Synthesis of compound 4: 1-(2-(2-chlorophenoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)urea

[0201]

[0202] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(2-chlorophenoxy)ethylamine (24 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 18 mg of the yellow product 1-(2-(2-chlorophenoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)urea (compound 4), with a yield of 30%. 1 H NMR(500MHz,DMSO-d6)δ9.49(s,1H),8.91(d,J=7.3Hz,1H),8.54(d,J=1.8Hz,1H ),7.97(d,J=1.7Hz,1H),7.55(d,J=7.3Hz,1H),7.44(dd,J=7.9,1.4Hz,1H),7.3 4–7.27(m,1H),7.21(d,J=8.2Hz,1H),6.97(dd,J=10.9,4.2Hz,2H),6.62(s,1H) ,4.14(t,J=5.5Hz,2H),3.95(s,3H),3.92(s,3H),3.58(dd,J=11.0,5.5Hz,2H). MS m / z(ESI): 469.14 [M+H] + .

[0203] Example 5 Synthesis of compound 5: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea

[0204]

[0205] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-((1-methyl-1H-pyrazol-4-yl)oxy)ethane-1-amine (30 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea (compound 5), with a yield of 53%. 1 H NMR (500MHz, DMSO-d6) δ9.39(s,1H),8.93(d,J=7.3Hz,1H),8.53(d,J=1.9Hz,1H),7.97(d,J=1.9Hz,1H),7.54(d,J=7.3Hz,1H),7.48(s,1 H),7.21(s,1H),6.92(t,J=5.4Hz,1H),6.63(s,1H),3.95(s,3H),3.92(s,3H),3.90(t,J=5.5Hz,2H),3.73(s,3H),3.47(q,J=5.5Hz,2H). MS m / z(ESI):439.18[M+H] + .

[0206] Example 6 Synthesis of compound 6: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-methoxyethyl)urea

[0207]

[0208] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-methoxyethylamine (11 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 27 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-methoxyethyl)urea (compound 6), with a yield of 56%. 1 H NMR (500MHz, DMSO-d6) δ9.33(s,1H),8.93(d,J=7.3Hz,1H),8.53(d,J=1.9Hz,1H),7.97(d,J=1.9Hz,1H),7.53(d,J=7.3Hz,1 H), 6.79 (t, J = 5.3Hz, 1H), 6.62 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.41 (t, J = 5.4Hz, 2H), 3.31 (d, J = 3.5Hz, 2H), 3.29 (s, 3H). MS m / z(ESI):373.16[M+H] + .

[0209] Example 7 Synthesis of compound 7: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-ethoxyethyl)urea

[0210]

[0211] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-ethoxyethylamine (12 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-ethoxyethyl)urea (compound 7), with a yield of 50%. 1 H NMR (500MHz, DMSO-d6) δ9.34(s,1H),8.92(d,J=7.4Hz,1H),8.53(d,J=1.9Hz,1H),7.96(d,J=1.9Hz,1H),7.53(d,J=7.3Hz,1H),6.76(t,J=5.2H z,1H),6.62(s,1H),3.95(s,3H),3.92(s,3H),3.49(dd,J=13.4,6.5Hz,2H),3.45(t,J=4.9Hz,2H),3.30(d,J=5.5Hz,2H),1.15(t,J=7.0Hz,3H). MS m / z(ESI):387.18[M+H] + .

[0212] Example 8 Synthesis of compound 8: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-isopropoxyethyl)urea

[0213]

[0214] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-aminoethyl isopropyl ether (14 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-isopropoxyethyl)urea (compound 8), with a yield of 38%. 1 H NMR (500MHz, DMSO-d6) δ9.41(s,1H),8.91(d,J=7.3Hz,1H),8.53(d,J=1.9Hz,1H),7.96(d,J=1.9Hz,1H),7.53(d,J=7.3Hz,1H),6.79(s,1H ), 6.61(s,1H),3.95(s,3H),3.92(s,3H),3.59(hept,J=6.1Hz,1H),3.44(t,J=5.6Hz,2H),3.28(q,J=5.5Hz,2H),1.13(s,3H),1.11(s,3H). MS m / z(ESI):401.19[M+H] + .

[0215] Example 9 Synthesis of compound 9: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-propoxyethyl)urea

[0216]

[0217] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-N-propoxyethylamine (14 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 17 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-propoxyethyl)urea (compound 9), with a yield of 28%. 1 H NMR (500MHz, DMSO-d6) δ9.38(s,1H),8.91(d,J=7.7Hz,1H),8.53(d,J=1.9Hz,1H),7.97(d,J=1.9Hz,1H),7.54(d,J=7.3Hz,1H),6.79(s,1H),6.6 2(s,1H),3.95(s,3H),3.92(s,3H),3.44(t,J=5.5Hz,2H),3.38(t,J=6.6 Hz, 2H), 3.30 (d, J = 5.5Hz, 2H), 1.59–1.50 (m, 2H), 0.89 (t, J = 7.4Hz, 3H). MS m / z(ESI):401.19[M+H] + .

[0218] Example 10 Synthesis of compound 10: 1-(2-(cyclopropylmethoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)urea

[0219]

[0220] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(cyclopropylmethoxy)ethane-1-amine (16 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 23 mg of the yellow product 1-(2-(cyclopropylmethoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)urea (compound 10), with a yield of 42%. 1 H NMR(500MHz,DMSO-d6)δ9.42(s,1H),8.92(d,J=7.3Hz,1H),8.53(d,J=1.9H z,1H),7.96(d,J=1.8Hz,1H),7.54(d,J=7.3Hz,1H),6.86(s,1H),6.62(s,1 H),3.95(s,3H),3.92(s,3H),3.46(t,J=5.5Hz,2H),3.32–3.29(q,2H),3.2 7(d,J=6.8Hz,2H),1.05–0.98(m,1H),0.49–0.44(m,2H),0.21–0.17(m,2H). MS m / z (ESI): 413.19 [M+H] + .

[0221] Example 11 Synthesis of compound 11: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(3-methoxypropyl)urea

[0222]

[0223] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-methoxypropylamine (12 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 18 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(3-methoxypropyl)urea (compound 11), with a yield of 36%. 1 H NMR (500MHz, DMSO-d6) δ9.33(s,1H),8.92(d,J=7.3Hz,1H),8.53(d,J=1.9Hz,1H),7.96(d,J=1.9Hz,1H),7.53(d,J=7.3Hz,1H),6.78(t,J= 5.6Hz,1H),6.60(s,1H),3.95(s,3H),3.92(s,3H),3.38(t,J=6.2Hz,2H),3.25(s,3H),3.20(dd,J=12.7,6.7Hz,2H),1.69(p,J=6.5Hz,2H). MS m / z(ESI):387.18[M+H] + .

[0224] Example 12 Synthesis of compound 12: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(3-ethoxypropyl)urea

[0225]

[0226] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-ethoxypropylamine (14 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 15 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(3-ethoxypropyl)urea (compound 12), with a yield of 28%. 1 H NMR (500MHz, DMSO-d6) δ9.32(s,1H),8.92(d,J=7.3Hz,1H),8.53(d,J=1.9Hz,1H),7.96(d,J=1.9Hz,1H),7.53(d,J=7.3Hz,1H),6.77(t,J=5.5H z,1H),6.60(s,1H),3.95(s,3H),3.92(s,3H),3.43(q,J=6.9Hz,4H),3.20(dd,J=12.7,6.7Hz,2H),1.69(p,J=6.5Hz,2H),1.12(t,J=7.0Hz,3H). MS m / z(ESI):401.19[M+H] + .

[0227] Example 13 Synthesis of compound 13: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(3-isopropoxypropyl)urea

[0228]

[0229] 2 mL of dimethyl sulfoxide was added to a 25 mL round-bottom flask. Then, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-isopropoxypropylamine (16 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added with stirring at room temperature. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 22 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(3-isopropoxypropyl)urea (compound 13), with a yield of 40%. 1 H NMR(500MHz,DMSO-d6)δ9.30(s,1H),8.92(d,J=7.3Hz,1H),8.53(d,J=1.9Hz ,1H),7.96(d,J=1.9Hz,1H),7.53(d,J=7.3Hz,1H),6.72(t,J=5.5Hz,1H),6. 60(s,1H),3.95(s,3H),3.92(s,3H),3.57–3.49(m,1H),3.41(t,J=6.2Hz,2H ), 3.20 (dd, J = 12.7, 6.7 Hz, 2H), 1.66 (p, J = 6.5 Hz, 2H), 1.09 (d, J = 6.1 Hz, 6H). MS m / z (ESI): 415.21 [M+H] + .

[0230] Example 14 Synthesis of compound 14: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(3-isobutoxypropyl)urea

[0231]

[0232] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-isobutoxypropylamine (18 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 24 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(3-isobutoxypropyl)urea (compound 14), with a yield of 43%. 1 H NMR (500MHz, DMSO-d6) δ9.34 (s, 1H), 8.92 (d, J = 7.3Hz, 1H), 8.53 (d, J = 1.9Hz, 1H), 7. 97(d,J=1.9Hz,1H),7.53(d,J=7.3Hz,1H),6.80(t,J=5.5Hz,1H),6.61(s,1H),3.95( s,3H),3.92(s,3H),3.42(t,J=6.2Hz,2H),3.21(dd,J=12.7,6.6Hz,2H),3.15(d,J=6 .6Hz, 2H), 1.80 (dp, J = 13.3, 6.7Hz, 1H), 1.70 (p, J = 6.5Hz, 2H), 0.86 (d, J = 6.7Hz, 6H). MS m / z(ESI):429.23[M+H] + .

[0233] Example 15 Synthesis of compound 15: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-morpholinoethyl)urea

[0234]

[0235] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), N-(2-aminoethyl)morpholine (18 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 23 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-morpholinoethyl)urea (compound 15), with a yield of 41%. 1 H NMR (500MHz, DMSO-d6) δ9.48(s,1H),8.91(d,J=7.3Hz,1H),8.53(d,J=1.9Hz,1H),7.96(d,J=1.9Hz,1H),7.53(d,J =7.3Hz,1H),6.78(s,1H),6.62(s,1H),3.95(s,3H),3.92(s,3H),3.61(m,4H),3.27(q,J=5.3Hz,2H),2.42(m,6H). MS m / z(ESI):428.20[M+H] + .

[0236] Example 16 Synthesis of compound 16: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)urea

[0237]

[0238] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 1-methyl-4-ethylaminopyrazole (18 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)urea (compound 16), with a yield of 36%. 1 H NMR (500MHz, DMSO-d6) δ9.37(s,1H),8.91(d,J=7.3Hz,1H),8.53(d,J=1.9Hz,1H),7.96(d,J=1.9Hz,1H),7.54(d,J=7.3Hz,2H),7 .31(s,1H),6.81(t,J=5.5Hz,1H),6.61(s,1H),3.95(s,3H),3.92(s,3H),3.79(s,3H),3.33–3.28(m,2H),2.59(t,J=7.1Hz,2H). MS m / z(ESI):423.19[M+H] + .

[0239] Example 17 Synthesis of compound 17: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(thiophen-3-yl)ethyl)urea

[0240]

[0241] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-aminoethylthiophene (18 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(thiophen-3-yl)ethyl)urea (compound 17), with a yield of 45%. 1 H NMR(500MHz,DMSO-d6)δ9.39(s,1H),8.91(d,J=7.3Hz,1H),8.53(d,J=1.9Hz,1H ),7.96(d,J=1.9Hz,1H),7.53(d,J=7.3Hz,1H),7.49(dd,J=4.9,2.9Hz,1H),7.27 (d,J=1.8Hz,1H),7.07(dd,J=4.9,1.1Hz,1H),6.82(t,J=5.3Hz,1H),6.61(s,1H ), 3.95 (s, 3H), 3.92 (s, 3H), 3.41 (dd, J = 12.9, 7.0Hz, 2H), 2.80 (t, J = 7.1Hz, 2H). MS m / z (ESI): 425.14 [M+H] + .

[0242] Example 18 Synthesis of compound 18: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(1-methyl-1H-imidazol-4-yl)ethyl)urea

[0243]

[0244] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 1-methylhistamine di-p-toluenesulfonate (28 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(1-methyl-1H-imidazol-4-yl)ethyl)urea (compound 18), with a yield of 36%. 1 H NMR (500MHz, DMSO-d6) δ9.34(s,1H),8.91(d,J=7.3Hz,1H),8.53(d,J=1.9Hz,1H),7.97(d,J=1.9Hz,1H),7.54(t,J=10.5Hz,2H ), 6.95 (s, 1H), 6.75 (t, J = 5.3Hz, 1H), 6.62 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.62 (s, 3H), 3.38 (q, J = 5.9Hz, 2H), 2.65 (s, 2H). MSm / z(ESI):423.19[M+H] + .

[0245] Example 19 Synthesis of compound 19: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(1-propyl-1H-imidazol-4-yl)ethyl)urea

[0246]

[0247] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(1-propyl-1H-imidazol-4-yl)ethane-1-amine (21 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 20 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(1-propyl-1H-imidazol-4-yl)ethyl)urea (compound 19), in a yield of 36%. MS m / z (ESI): 451.22 [M+H] + .

[0248] Example 20 Synthesis of compound 20: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-(3-methyl-1,2,4-oxadiazol-5-yl)propyl)urea

[0249]

[0250] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-(3-methyl-1,2,4-oxadiazol-5-yl)propane-1-amine (25 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to give 22 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-(3-methyl-1,2,4-oxadiazol-5-yl)propyl)urea (compound 20), yield 39%. MS m / z (ESI): 438.19 [M+H] +.

[0251] Example 21 Synthesis of compound 21: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(phenylamino)ethyl)urea

[0252]

[0253] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), N-phenylethylenediamine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(phenylamino)ethyl)urea (compound 21), with a yield of 54%. 1 H NMR(500MHz,DMSO-d6)δ9.39(s,1H),8.91(dd,J=7.3,0.6Hz,1H),8.53(d,J=2.0H z,1H),7.97(d,J=1.9Hz,1H),7.53(d,J=7.3Hz,1H),7.08(dd,J=8.4,7.4Hz,2H),6 .85(t,J=5.5Hz,1H),6.66–6.59(m,3H),6.53(t,J=7.2Hz,1H),5.69(t,J=5.7Hz,1 H), 3.95 (s, 3H), 3.92 (s, 3H), 3.34 (dd, J = 12.3, 6.3Hz, 2H), 3.15 (q, J = 6.3Hz, 2H). MS m / z(ESI): 434.19 [M+H] + .

[0254] Example 22 Synthesis of compound 22: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea

[0255]

[0256] 2 mL of dimethyl sulfoxide was added to a 25 mL round-bottom flask. Then, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), N-(2-pyridyl)ethylenediamine (20 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added with stirring at room temperature. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 28 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea (compound 22), with a yield of 50%. 1 H NMR (500MHz, DMSO-d6) δ9.35(s,1H),8.91(d,J=7.3Hz,1H),8.53(d,J=1.9Hz,1H),7.97(dd,J=8.2,3.0Hz,2H),7.53(d,J=7.3Hz,1H),7.3 7(ddd,J=8.7,7.1,1.9Hz,1H),6.82(d,J=5.1Hz,1H),6.65–6.56(m,2H),6.52–6.43(m,2H),3.95(s,3H),3.92(s,3H),3.38–3.32(m,4H). MS m / z(ESI):435.19[M+H] + .

[0257] Example 23 Synthesis of compound 23: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea

[0258]

[0259] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), N1-(pyrimidin-2-yl)ethane-1,2-diamine (20 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 34 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (compound 23), with a yield of 61%. 1 H NMR(500MHz,DMSO-d6)δ9.38(s,1H),8.91(d,J=7.3Hz,1H),8.53(d,J=1.9Hz ,1H),8.28(d,J=4.7Hz,2H),7.97(d,J=1.9Hz,1H),7.53(d,J=7.3Hz,1H),7. 20(t,J=5.4Hz,1H),6.86(t,J=5.4Hz,1H),6.62(s,1H),6.57(t,J=4.7Hz,1H ), 3.95 (s, 3H), 3.92 (s, 3H), 3.39 (dd, J = 11.4, 5.6Hz, 2H), 3.36–3.33 (m, 2H). MS m / z(ESI): 436.18 [M+H] + .

[0260] Example 24 Synthesis of N-(2-methoxy-5-(2-(3-(2-phenoxyethyl)ureo)pyrazol[1,5-A]pyrimidin-5-yl)pyridin-3-yl)methanesulfonamide compound 24

[0261]

[0262] In a 100 mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. While stirring at room temperature, 5-chloropyrazole[1,5-A]pyrimidin-2-amine (100 mg, 0.59 mmol, 1.0 eq), N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridin-3-yl)methanesulfonamide (232 mg, 0.71 mmol, 1.2 eq), potassium carbonate (164 mg, 1.18 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (34 mg, 0.03 mmol, 0.05 eq) were added. The reaction mixture was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The combined organic phases were extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to give 168 mg of the yellow product N-(5-(2-aminopyrazolo[1,5-A]pyrimidin-5-yl)-2-methoxypyridin-3-yl)methanesulfonamide, in 85% yield. MS m / z (ESI): 335.09 [M+H] + .

[0263] Add 30 mL of tetrahydrofuran to a 100 mL round-bottom flask, and then add N-(5-(2-aminopyrazolo[1,5-A]pyrimidin-5-yl)-2-methoxypyridin-3-yl)methanesulfonamide (50 mg, 0.15 mmol, 1.0 eq), phenyl chloroformate (28 mg, 0.18 mmol, 1.2 eq), and triethylamine (42 μL, 0.3 mmol, 2.0 eq) with stirring at 0 °C. Continue the reaction at 0 °C for 1 hour. After the reaction is complete, neutralize with 20 mL of water. Extract the mixture three times with 30 mL of ethyl acetate, and combine the organic phases. Wash the organic phases with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dry with anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 34 mg of a yellow product, phenyl(5-(6-methoxy-5-(methylsulfonamido)pyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate, in 50% yield. MS m / z (ESI): 455.11 [M+H] + .

[0264] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(6-methoxy-5-(methylsulfonamido)pyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)carbamate (15 mg, 0.032 mmol, 1.0 eq), 2-phenoxyethylamine (5 mg, 0.035 mmol, 1.1 eq), and triethylamine (9 μL, 0.064 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 15 mg of the yellow product N-(2-methoxy-5-(2-(3-(2-phenoxyethyl)ureo)pyrazol[1,5-A]pyrimidin-5-yl)pyridin-3-yl)methanesulfonamide (compound 24), with a yield of 68%. 1 H NMR (500MHz, DMSO-d6) δ9.47 (s, 1H), 9.42 (s, 1H), 8.93 (d, J = 7.3Hz, 1H), 8.7 9(d,J=2.2Hz,1H),8.39(d,J=2.2Hz,1H),7.49(d,J=7.3Hz,1H),7.34–7.27( m,2H),7.00(dd,J=15.4,6.6Hz,3H),6.95(t,J=7.3Hz,1H),6.64(s,1H),4.0 6(t,J=5.5Hz,2H), 4.00(d,J=5.7Hz,3H), 3.54(q,J=5.5Hz,2H), 3.09(s,3H). MS m / z (ESI): 498.16 [M+H] + .

[0265] Example 25 Synthesis of compound 25: 1-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)-3-(2-phenoxyethyl)urea

[0266]

[0267] In a 100 mL round-bottom flask, 15 mL of 1,4-dioxane and 3 mL of water were added. While stirring at room temperature, 6-bromo-[1,2,4]triazolo[1,5-A]pyridine-2-amine (500 mg, 2.35 mmol, 1.0 eq), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)pyridine (747 mg, 2.82 mmol, 1.2 eq), potassium carbonate (648 mg, 4.7 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (139 mg, 0.12 mmol, 0.05 eq) were added. The reaction system was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The combined organic phases were extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 568 mg of the yellow product 6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazole[1,5-A]pyridin-2-amine, in 89% yield. MS m / z (ESI): 272.11 [M+H] + .

[0268] Add 25 mL of tetrahydrofuran to a 100 mL round-bottom flask, and then add 6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazole[1,5-A]pyridine-2-amine (542 mg, 2.0 mmol, 1.0 eq), phenyl chloroformate (374 mg, 2.4 mmol, 1.2 eq), and triethylamine (556 μL, 4.0 mmol, 2.0 eq) with stirring at 0 °C. Continue the reaction at 0 °C for 1 hour. After the reaction is complete, neutralize with 20 mL of water. Extract the mixture three times with 30 mL of ethyl acetate, and combine the organic phases. Wash the organic phases with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dry with anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 391 mg of a yellow product, phenyl (6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)carbamate, in 50% yield. MS m / z (ESI): 392.14 [M+H] + .

[0269] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-phenoxyethylamine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 20 mg of the yellow product 1-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)-3-(2-phenoxyethyl)urea (compound 25), in a yield of 36%. MS m / z (ESI): 435.18 [M+H] + .

[0270] Example 26 Synthesis of compound 26: 1-(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)-3-(2-phenoxyethyl)urea

[0271]

[0272] In a 100 mL round-bottom flask, 15 mL of 1,4-dioxane and 3 mL of water were added. While stirring at room temperature, 6-chloroimidazolo[1,2-B]pyridazin-2-amine (500 mg, 2.97 mmol, 1.0 eq), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)pyridine (944 mg, 3.56 mmol, 1.2 eq), potassium carbonate (819 mg, 5.94 mmol, 2.0 eq), and tetraphenylphosphine palladium (173 mg, 0.15 mmol, 0.05 eq) were added. The reaction system was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 700 mg of the yellow product 6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-amine, in 87% yield. MS m / z (ESI): 272.11 [M+H] + .

[0273] Add 25 mL of tetrahydrofuran to a 100 mL round-bottom flask, and then add 6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-amine (542 mg, 2.0 mmol, 1.0 eq), phenyl chloroformate (374 mg, 2.4 mmol, 1.2 eq), and triethylamine (556 μL, 4.0 mmol, 2.0 eq) with stirring at 0 °C. Continue the reaction at 0 °C for 1 hour. After the reaction is complete, neutralize with 20 mL of water. Extract the mixture three times with 30 mL of ethyl acetate, and combine the organic phases. Wash the organic phases with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dry with anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 438 mg of a yellow product, phenyl (6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)carbamate, in 56% yield. MS m / z (ESI): 392.14 [M+H] + .

[0274] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-phenoxyethylamine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to give 18 mg of the yellow product 1-(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)-3-(2-phenoxyethyl)urea (compound 26), yield 32%. MS m / z (ESI): 435.18 [M+H] + .

[0275] Example 27 Synthesis of compound 27: 1-(6-(5,6-dimethoxypyridin-3-yl)-1Hbenzo[D]imidazol-2-yl)-3-(2-phenoxyethyl)urea

[0276]

[0277] In a 100 mL round-bottom flask, 15 mL of 1,4-dioxane and 3 mL of water were added. While stirring at room temperature, 6-bromo-1H-benzo[D]imidazol-2-amine (500 mg, 2.36 mmol, 1.0 eq), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)pyridine (750 mg, 2.83 mmol, 1.2 eq), potassium carbonate (651 mg, 4.72 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (139 mg, 0.12 mmol, 0.05 eq) were added. The reaction system was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 549 mg of the yellow product 6-(5,6-dimethoxypyridin-3-yl)-1Hbenzo[D]imidazol-2-amine, in 86% yield. MS m / z (ESI): 271.12 [M+H] + .

[0278] Add 25 mL of tetrahydrofuran to a 100 mL round-bottom flask, and then add 6-(5,6-dimethoxypyridin-3-yl)-1Hbenzo[D]imidazol-2-amine (500 mg, 1.85 mmol, 1.0 eq), phenyl chloroformate (347 mg, 2.22 mmol, 1.2 eq), and triethylamine (514 μL, 3.7 mmol, 2.0 eq) with stirring at 0 °C. Continue the reaction at 0 °C for 1 hour. After the reaction is complete, neutralize with 20 mL of water. Extract the mixture three times with 30 mL of ethyl acetate, and combine the organic phases. Wash the organic phases with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dry with anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 325 mg of a yellow product, phenyl (6-(5,6-dimethoxypyridin-3-yl)-1H-benzo[D]imidazol-2-yl)carbamate, in 45% yield. MS m / z (ESI): 391.14 [M+H] + .

[0279] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(6-(5,6-dimethoxypyridin-3-yl)-1Hbenzo[D]imidazol-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-phenoxyethylamine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 17 mg of a yellow product, 1-(6-(5,6-dimethoxypyridin-3-yl)-1Hbenzo[D]imidazol-2-yl)-3-(2-phenoxyethyl)urea (compound 27), in 30% yield. MS m / z (ESI): 434.18 [M+H] + .

[0280] Example 28 Synthesis of compound 28: 1-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)-3-(2-phenoxyethyl)urea

[0281]

[0282] In a 100 mL round-bottom flask, 15 mL of 1,4-dioxane and 3 mL of water were added. While stirring at room temperature, 7-bromo-[1,2,4]triazolo[1,5-A]pyridine-2-amine (500 mg, 2.35 mmol, 1.0 eq), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridine (748 mg, 2.82 mmol, 1.2 eq), potassium carbonate (648 mg, 4.7 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (139 mg, 0.12 mmol, 0.05 eq) were added. The reaction mixture was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The combined organic phases were extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, and then dried over anhydrous Na₂SO₄. Vacuum distillation of the organic phase yielded a crude product, which was then subjected to silica gel column chromatography to give 536 mg of the yellow product 7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazol[1,5-A]pyridin-2-amine, in 84% yield. MS m / z (ESI): 272.11 [M+H] + .

[0283] Add 25 mL of tetrahydrofuran to a 100 mL round-bottom flask, and then add 7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazole[1,5-A]pyridine-2-amine (500 mg, 1.84 mmol, 1.0 eq), phenyl chloroformate (347 mg, 2.2 mmol, 1.2 eq), and triethylamine (512 μL, 3.68 mmol, 2.0 eq) with stirring at 0 °C. Continue the reaction at 0 °C for 1 hour. After the reaction is complete, neutralize with 20 mL of water. Extract the mixture three times with 30 mL of ethyl acetate, and combine the organic phases. Wash the organic phases with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dry with anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 374 mg of a yellow product, phenyl (7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)carbamate, in 52% yield. MS m / z (ESI): 392.14 [M+H] + .

[0284] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-phenoxyethylamine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 16 mg of the yellow product 1-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)-3-(2-phenoxyethyl)urea (compound 28), with a yield of 29%. 1H NMR(500MHz,DMSO-d6)δ10.07(s,1H),8.85(d,J=7.1Hz,1H),8.52(t,J=5.6Hz, 1H),8.24(d,J=2.0Hz,1H),8.05(d,J=1.3Hz,1H),7.76(d,J=2.0Hz,1H),7.56( dd,J=7.1,1.9Hz,1H),7.32–7.27(m,2H),7.01(d,J=7.9Hz,2H),6.93(t,J=7.3 Hz, 1H), 4.09 (t, J = 5.5Hz, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.62 (q, J = 5.5Hz, 2H). MS m / z (ESI): 435.18 [M+H] + .

[0285] Example 29 Synthesis of compound 29: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-phenoxyethyl)urea

[0286]

[0287] 20 mL of dichloromethane was added to a 100 mL round-bottom flask. Then, 2-(4-bromopyridin-2-yl)acetonitrile (1.0 g, 5.0 mmol, 1.0 eq) and 2,4,6-trimethylbenzenesulfonylhydroxylamine (1.4 g, 6.5 mmol, 1.3 eq) were added separately with stirring at room temperature. The reaction system was allowed to react at room temperature for 14 hours. After the reaction was complete, the filtered yellow product was dissolved in 15 mL of methanol, and potassium carbonate (1.38 g, 10 mmol, 2.0 eq) was added with stirring at room temperature. The reaction system was then allowed to react for another 8 hours at room temperature. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 550 mg of the yellow product 5-bromopyrazole[1,5-A]pyridine-2-amine, in a yield of 52%. MS m / z (ESI): 211.98 [M+H] + .

[0288] In a 100 mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. While stirring at room temperature, 5-bromopyrazole[1,5-A]pyridine-2-amine (550 mg, 2.61 mmol, 1.0 eq), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)pyridine (1.37 g, 5.2 mmol, 2.0 eq), potassium carbonate (718 mg, 5.2 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (151 mg, 0.13 mmol, 0.05 eq) were added. The reaction mixture was then incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 675 mg of a yellow product, 5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridine-2-amine, in 88% yield. MS m / z (ESI): 271.12 [M+H] + .

[0289] Add 30 mL of tetrahydrofuran to a 100 mL round-bottom flask, and then add 5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridine-2-amine (700 mg, 2.60 mmol, 1.0 eq), phenyl chloroformate (484 mg, 3.1 mmol, 1.2 eq), and triethylamine (722 μL, 5.2 mmol, 2.0 eq) with stirring at 0 °C. Continue the reaction at 0 °C for 1 hour. After the reaction is complete, neutralize with 20 mL of water. Extract the mixture three times with 30 mL of ethyl acetate, and combine the organic phases. Wash the organic phases with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dry with anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 600 mg of a yellow product, phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in 60% yield. MS m / z (ESI): 391.14 [M+H] + .

[0290] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-phenoxyethylamine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 22 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-phenoxyethyl)urea (compound 29), with a yield of 39%. 1 H NMR(500MHz,DMSO-d6)δ9.31(s,1H),8.50(d,J=7.2Hz,1H),8.13(d,J=2.0Hz,1 H),7.87(d,J=1.3Hz,1H),7.64(d,J=2.0Hz,1H),7.33–7.26(m,2H),7.13(dd,J= 7.3,2.1Hz,1H),7.07(s,1H),6.99(d,J=7.8Hz,2H),6.95(t,J=7.3Hz,1H),6.57 (s, 1H), 4.05 (t, J = 5.5Hz, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.53 (q, J = 5.5Hz, 2H). MS m / z(ESI): 434.18 [M+H] + .

[0291] Example 30 Synthesis of compound 30: 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea

[0292]

[0293] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (100 mg, 0.21 mmol, 1.0 eq), 2-(3-methyl-[1,2,4]oxadizazol-5-yl)-ethylamine (41 mg, 0.25 mmol, 1.2 eq), and triethylamine (58 μL, 0.42 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 32 mg of the yellow product 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea (compound 30), with a yield of 33%. 1 H NMR (500MHz, DMSO-d6) δ9.27(s,1H),8.88(d,J=2.0Hz,1H),8.53(d,J=7.2Hz,1H),8.44(d,J=2.0Hz,1H),7.97(d,J=1.3Hz,1H),7.1 9(dd,J=7.2,2.0Hz,1H),6.89(s,1H),6.59(s,1H),4.05(s,3H),3.57(q,J=6.4Hz,2H),3.11(t,J=6.6Hz,2H),2.33(d,J=4.4Hz,3H). MS m / z(ESI):462.15[M+H] + .

[0294] Example 31 Synthesis of compound 31: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(2-fluorophenoxy)ethyl)urea

[0295]

[0296] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(2-fluorophenoxy)ethylamine (22 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(2-fluorophenoxy)ethyl)urea (compound 31), with a yield of 52%. 1 H NMR(500MHz, DMSO-d6)δ9.29(s,1H),8.48(d,J=7.2Hz,1H),8.13(d,J=2.0Hz,1H),7.88(d,J=1.5Hz,1H),7.64(d,J=2.0Hz,1H),7.25–7.20(m,2H), 7.16–7.11(m,2H),7.06(s,1H),6.96(dt,J=12.4,4.5Hz,1H),6.56(s,1H ), 4.13 (t, J = 5.5Hz, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.56 (q, J = 5.5Hz, 2H). MS m / z(ESI):452.17[M+H] + .

[0297] Example 32 Synthesis of compound 32: 1-(2-(2-chlorophenoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea

[0298]

[0299] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(2-chlorophenoxy)ethylamine (25 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product 1-(2-(2-chlorophenoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (compound 32), with a yield of 42%. 1 HNMR(500MHz,DMSO-d6)δ9.34(s,1H),8.48(d,J=7.2Hz,1H),8.13(d,J=2.0Hz,1H),7.88( d,J=1.5Hz,1H),7.64(d,J=2.0Hz,1H),7.44(dd,J=7.9,1.5Hz,1H),7.33–7.28(m,1H),7.2 1(dd,J=8.3,1.1Hz,1H),7.14(dd,J=7.3,2.0Hz,1H),7.08(s,1H),6.97(td,J=7.7,1.3Hz ,1H),6.54(s,1H),4.14(t,J=5.5Hz,2H),3.92(s,3H),3.91(s,3H),3.58(q,J=5.6Hz,2H). MS m / z(ESI):468.14[M+H] + .

[0300] Example 33 Synthesis of compound 33: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0301]

[0302] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-(2-aminoethoxy)pyridine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 28 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 33), with a yield of 50%. 1 H NMR(500MHz,DMSO-d6)δ9.25(s,1H),8.50(d,J=7.2Hz,1H),8.35(d,J=2.9Hz,1H),8.18(dd, J=4.6,1.2Hz,1H),8.13(d,J=2.0Hz,1H),7.87(d,J=1.4Hz,1H),7.64(d,J=2.0Hz,1H),7.45 (ddd,J=8.5,3.0,1.2Hz,1H),7.34(dd,J=8.5,4.6Hz,1H),7.13(dd,J=7.3,2.1Hz,1H),7.01 (s,1H),6.56(s,1H),4.14(t,J=5.5Hz,2H),3.92(s,3H),3.91(s,3H),3.56(q,J=5.5Hz,2H). MS m / z(ESI):435.18[M+H] + .

[0303] Example 34 Synthesis of compound 34: 1-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-yloxy)ethyl)urea

[0304]

[0305] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(2-pyridyloxy)ethylamine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 28 mg of the yellow product 1-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-yloxy)ethyl)urea (compound 34), with a yield of 50%. 1 HNMR(500MHz,DMSO-d6)δ9.21(s,1H),8.49(d,J=7.2Hz,1H),8.17(dd,J=4.8,1.7H z,1H),8.12(d,J=2.0Hz,1H),7.87(d,J=1.4Hz,1H),7.75–7.69(m,1H),7.64(d,J=2 .0Hz,1H),7.13(dd,J=7.3,2.1Hz,1H),7.02–6.93(m,2H),6.86(d,J=8.3Hz,1H),6 .56(s,1H),4.33(t,J=5.5Hz,2H),3.92(s,3H),3.91(s,3H),3.54(q,J=5.6Hz,2H). MS m / z(ESI):435.18[M+H] + .

[0306] Example 35 Synthesis of compound 35: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-4-yloxy)ethyl)urea

[0307]

[0308] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(pyridin-4-yloxy)ethylamine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-4-yloxy)ethyl)urea (compound 35), with a yield of 53%. 1 H NMR(500MHz,DMSO-d6)δ9.27(s,1H),8.50(d,J=7.2Hz,1H),8.39(dd,J=4.8, 1.5Hz,2H),8.12(d,J=2.0Hz,1H),7.87(d,J=1.4Hz,1H),7.64(d,J=2.0Hz,1H ),7.13(dd,J=7.3,2.1Hz,1H),7.02(dd,J=4.8,1.5Hz,3H),6.56(s,1H),4.15 (t, J=5.5Hz, 2H), 3.93 (d, J=10.3Hz, 3H), 3.91 (s, 3H), 3.56 (q, J=5.5Hz, 2H). MS m / z (ESI): 435.18 [M+H] + .

[0309] Example 36 Synthesis of compound 36: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(4-methoxyphenoxy)ethyl)urea

[0310]

[0311] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(4-methoxyphenoxy)ethylamine (24 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 28 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(4-methoxyphenoxy)ethyl)urea (compound 36), with a yield of 47%. 1 H NMR(500MHz,DMSO-d6)δ9.24(s,1H),8.50(d,J=7.2Hz,1H),8.12(d,J=2.0Hz ,1H),7.87(d,J=1.4Hz,1H),7.64(d,J=2.0Hz,1H),7.13(dd,J=7.3,2.1Hz,1 H),6.99(s,1H),6.95–6.90(m,2H),6.89–6.84(m,2H),6.56(s,1H),3.99(t, J=5.5Hz,2H),3.92(s,3H),3.91(s,3H),3.70(s,3H),3.50(q,J=5.5Hz,2H). MS m / z(ESI): 464.19 [M+H] + .

[0312] Example 37 Synthesis of compound 37: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(2-methoxyphenoxy)ethyl)urea

[0313]

[0314] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-methoxyphenoxyethylamine (24 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(2-methoxyphenoxy)ethyl)urea (compound 37), with a yield of 50%. 1 H NMR(500MHz,DMSO-d6)δ9.26(s,1H),8.49(d,J=7.2Hz,1H),8.12(d,J=2.0Hz,1H) ,7.87(d,J=1.4Hz,1H),7.64(d,J=2.0Hz,1H),7.13(dd,J=7.3,2.1Hz,1H),7.00( ddd,J=17.1,7.8,1.7Hz,3H),6.90(dtd,J=19.6,7.5,1.7Hz,2H),6.57(s,1H),4. 03(t,J=5.5Hz,2H),3.92(s,3H),3.91(s,3H),3.78(s,3H),3.53(q,J=5.5Hz,2H). MS m / z(ESI): 464.19 [M+H] + .

[0315] Example 38 Synthesis of compound 38: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(3-fluorophenoxy)ethyl)urea

[0316]

[0317] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(3-fluorophenoxy)ethylamine (22 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(3-fluorophenoxy)ethyl)urea (compound 38), with a yield of 42%. 1 H NMR(500MHz,DMSO-d6)δ9.24(s,1H),8.50(d,J=7.2Hz,1H),8.13(d,J=2.0Hz,1H), 7.87(d,J=1.4Hz,1H),7.64(d,J=2.0Hz,1H),7.32(dd,J=15.5,8.2Hz,1H),7.13(dd ,J=7.3,2.0Hz,1H),6.97(s,1H),6.90–6.82(m,2H),6.77(td,J=8.4,2.2Hz,1H),6 .56(s,1H),4.08(t,J=5.5Hz,2H),3.92(s,3H),3.91(s,3H),3.54(q,J=5.5Hz,2H). MS m / z(ESI):452.17[M+H] + .

[0318] Example 39 Synthesis of compound 39: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(4-fluorophenoxy)ethyl)urea

[0319]

[0320] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(4-fluorophenoxy)ethylamine (22 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 27 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(4-fluorophenoxy)ethyl)urea (compound 39), with a yield of 46%. 1 H NMR (500MHz, DMSO-d6) δ9.23(s,1H),8.50(d,J=7.2Hz,1H),8.13(d,J=2.0Hz,1H),7.87(d,J=1.5Hz,1H),7.64(d,J=2.0Hz,1H),7.16–7.10( m,3H),7.01(ddd,J=6.8,5.4,3.2Hz,2H),6.97(s,1H),6.56(s,1H),4.03(t,J=5.5Hz,2H),3.92(s,3H),3.91(s,3H),3.52(q,J=5.5Hz,2H). MS m / z(ESI):452.17[M+H] + .

[0321] Example 40 Synthesis of compound 40: 1-(2-(3-cyanophenoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea

[0322]

[0323] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-(2-aminoethoxy)benzonitrile (23 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product 1-(2-(3-cyanophenoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (compound 40), with a yield of 50%. 1 H NMR(500MHz,DMSO-d6)δ9.26(s,1H),8.50(d,J=7.2Hz,1H),8.12(d,J=1.9Hz,1H),7 .87(d,J=1.3Hz,1H),7.64(d,J=1.8Hz,1H),7.50(dd,J=13.5,5.2Hz,2H),7.41(d,J =7.5Hz,1H),7.35(dd,J=8.4,2.4Hz,1H),7.13(dd,J=7.3,1.9Hz,1H),7.00(s,1H), 6.56(s,1H),4.14(t,J=5.5Hz,2H),3.92(s,3H),3.91(s,3H),3.55(q,J=5.5Hz,2H). MS m / z(ESI):459.18[M+H] + .

[0324] Example 41 Synthesis of compound 41: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea

[0325]

[0326] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-((1-methyl-1H-pyrazol-4-yl)oxy)ethane-1-amine (30 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 26 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea (compound 41), with a yield of 46%. 1 H NMR (500MHz, DMSO-d6) δ9.22(s,1H),8.50(d,J=7.2Hz,1H),8.12(d,J=2.0Hz,1H),7.87(d,J=1.5Hz,1H),7.64(d,J=2.0Hz,1H),7.48(s,1H),7.20( s,1H),7.13(dd,J=7.3,2.1Hz,1H),6.96(s,1H),6.57(s,1H),3.92(s,3H ), 3.91 (s, 3H), 3.89 (d, J = 5.4Hz, 2H), 3.73 (s, 3H), 3.46 (q, J = 5.5Hz, 2H). MS m / z(ESI):438.19[M+H] + .

[0327] Example 42 Synthesis of compound 42: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(3-phenoxypropyl)urea

[0328]

[0329] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-phenoxypropylamine (21 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(3-phenoxypropyl)urea (compound 42), with a yield of 52%. 1 H NMR(500MHz,DMSO-d6)δ9.15(s,1H),8.46(d,J=7.2Hz,1H),8.12(d,J=2.0Hz, 1H),7.86(d,J=1.5Hz,1H),7.64(d,J=2.0Hz,1H),7.33–7.25(m,2H),7.12(dd, J=7.3,2.1Hz,1H),6.94(dd,J=16.4,8.0Hz,3H),6.86(s,1H),6.54(s,1H),4. 07–4.00(m,2H),3.92(s,3H),3.91(s,3H),3.33(s,2H),1.92(p,J=6.5Hz,2H). MS m / z(ESI): 448.20 [M+H] + .

[0330] Example 43 Synthesis of compound 43: 1-(2-(cyclopropylmethoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea

[0331]

[0332] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(cyclopropylmethoxy)ethane-1-amine (16 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product 1-(2-(cyclopropylmethoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (compound 43), with a yield of 47%. 1 H NMR(500MHz,DMSO-d6)δ9.19(s,1H),8.49(d,J=7.2Hz,1H),8.12(d,J=2.0Hz,1 H),7.87(d,J=1.4Hz,1H),7.64(d,J=2.0Hz,1H),7.13(dd,J=7.3,2.1Hz,1H),6. 83(s,1H),6.55(s,1H),3.92(s,3H),3.91(s,3H),3.47(t,J=5.5Hz,2H),3.29(d d, J=11.8, 6.2Hz, 4H), 1.06–0.98 (m, 1H), 0.50–0.45 (m, 2H), 0.21–0.17 (m, 2H). MS m / z(ESI): 412.20 [M+H] + .

[0333] Example 44 Synthesis of compound 44: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(3-ethoxypropyl)urea

[0334]

[0335] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-ethoxypropylamine (14 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(3-ethoxypropyl)urea (compound 44), with a yield of 38%. 1 H NMR(500MHz,DMSO-d6)δ9.17(s,1H),8.50(d,J=7.2Hz,1H),8.12(d,J=2.0Hz ,1H),7.86(d,J=1.3Hz,1H),7.64(d,J=2.0Hz,1H),7.12(dd,J=7.3,2.1Hz,1 H),6.84(s,1H),6.54(s,1H),3.92(s,3H),3.91(s,3H),3.42(q,J=6.9Hz,4H ), 3.19 (dd, J = 12.7, 6.7 Hz, 2H), 1.68 (p, J = 6.6 Hz, 2H), 1.12 (t, J = 7.0 Hz, 3H). MS m / z(ESI): 400.20 [M+H] + .

[0336] Example 45 Synthesis of compound 45: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-isopropoxy)urea

[0337]

[0338] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-isopropoxypropylamine (16 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 22 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-isopropoxy)urea (compound 45), with a yield of 41%. 1 H NMR(500MHz,DMSO-d6)δ9.12(s,1H),8.50(d,J=7.2Hz,1H),8.12(d,J=2.0Hz,1H) ,7.86(d,J=1.5Hz,1H),7.64(d,J=2.0Hz,1H),7.12(dd,J=7.3,2.1Hz,1H),6.75( s,1H),6.53(s,1H),3.92(s,3H),3.91(s,3H),3.57–3.48(m,1H),3.41(t,J=6.2H z, 2H), 3.19 (dd, J = 12.7, 6.7Hz, 2H), 1.66 (p, J = 6.5Hz, 2H), 1.09 (d, J = 6.1Hz, 6H). MS m / z(ESI): 414.21 [M+H] + .

[0339] Example 46 Synthesis of compound 46: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-morpholinoethyl)urea

[0340]

[0341] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), N-(2-aminoethyl)morpholine (18 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-morpholinoethyl)urea (compound 46), with a yield of 36%. 1 H NMR (500MHz, DMSO-d6) δ9.26 (s, 1H), 8.49 (d, J = 7.2Hz, 1H), 8.12 (d, J = 2.0Hz, 1H), 7.86 (d, J = 1.4Hz, 1H), 7.64 (d, J = 2.0Hz, 1H) ,7.13(dd,J=7.3,2.1Hz,1H),6.81(s,1H),6.53(s,1H),3.92(s,3H),3.91(s,3H),3.61(s,4H),3.30–3.24(m,2H),2.42(s,6H). MS m / z(ESI):427.21[M+H] + .

[0342] Example 47 Synthesis of compound 47: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(3-morpholinopropyl)urea

[0343]

[0344] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), N-(3-aminopropyl)morpholine (20 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 23 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(3-morpholinopropyl)urea (compound 47), with a yield of 40%. 1 H NMR (500MHz, DMSO-d6) δ9.17(s,1H),8.50(d,J=7.2Hz,1H),8.12(d,J=2.0Hz,1H),7.86(d,J=1.5Hz,1H),7.64(d,J=2.0Hz,1H),7.12(dd,J=7.3,2. 0Hz,1H),6.82(s,1H),6.54(s,1H),3.92(s,3H),3.91(s,3H),3.55(d,J=4 2.2Hz, 4H), 3.18 (dd, J = 12.4, 6.4Hz, 2H), 2.50–2.14 (m, 6H), 1.63 (s, 2H). MS m / z(ESI):441.23[M+H] + .

[0345] Example 48 Synthesis of compound 48: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-(piperazin-1-yl)propyl)urea

[0346]

[0347] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 4-(3-aminopropyl)piperazine-1-carboxylic acid tert-butyl ester (34 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography, yielding 15 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-(piperazin-1-yl)propyl)urea (compound 48), with a yield of 27%. 1 H NMR(500MHz,DMSO-d6)δ9.15(s,1H),8.49(d,J=7.2Hz,1H),8.12(d,J=1.9Hz,1 H),7.86(d,J=1.3Hz,1H),7.64(d,J=1.8Hz,1H),7.12(dd,J=7.3,1.9Hz,1H),6 .76(s,1H),6.54(s,1H),3.91(d,J=5.0Hz,6H),3.17(dd,J=12.6,6.5Hz,2H),2 .88(t,J=4.8Hz,4H),2.42(s,4H),2.33(t,J=7.0Hz,2H),1.61(p,J=6.9Hz,2H). MS m / z(ESI): 440.24 [M+H] + .

[0348] Example 49 Synthesis of compound 49: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(phenylamino)ethyl)urea

[0349]

[0350] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), N-phenylethylenediamine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(phenylamino)ethyl)urea (compound 49), with a yield of 53%. 1 H NMR (500MHz, DMSO-d6) δ9.23(s,1H),8.49(d,J=7.2Hz,1H),8.12(d,J=2.0Hz,1H),7.87(d ,J=1.4Hz,1H),7.64(d,J=2.0Hz,1H),7.13(dd,J=7.3,2.1Hz,1H),7.08(dd,J=8.3,7.4Hz ,2H),6.90(s,1H),6.62(d,J=7.7Hz,2H),6.57(s,1H),6.53(t,J=7.3Hz,1H),5.70(t,J=5 .6Hz, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.34 (t, J = 4.4Hz, 2H), 3.15 (dd, J = 12.3, 6.3Hz, 2H). MS m / z(ESI):433.20[M+H] + .

[0351] Example 50 Synthesis of compound 50: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea

[0352]

[0353] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), N-(2-pyridyl)ethylenediamine (20 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 28 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea (compound 50), with a yield of 50%. 1 HNMR(500MHz,DMSO-d6)δ9.21(s,1H),8.49(d,J=7.2Hz,1H),8.12(d,J=2.0Hz,1 H),7.98(d,J=4.1Hz,1H),7.87(d,J=1.5Hz,1H),7.64(d,J=2.0Hz,1H),7.42–7.3 6(m,1H),7.12(dd,J=7.3,2.1Hz,1H),6.87(s,1H),6.68(s,1H),6.55(s,1H),6.5 0(dd,J=13.4,7.3Hz,2H),3.92(s,3H),3.91(s,3H),3.35(dd,J=9.1,4.8Hz,4H). MS m / z(ESI): 434.19 [M+H] + .

[0354] Example 51 Synthesis of compound 51: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-ylamino)ethyl)urea

[0355]

[0356] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), N-(3-pyridyl)ethylenediamine (20 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-ylamino)ethyl)urea (compound 51), with a yield of 54%. 1 HNMR(500MHz,DMSO-d6)δ9.23(s,1H),8.48(d,J=7.2Hz,1H),8.12(d,J=1.8Hz,1H),8.01(d, J=2.7Hz,1H),7.87(s,1H),7.76(d,J=4.3Hz,1H),7.64(d,J=1.8Hz,1H),7.13(dd,J=7.2,1. 9Hz,1H),7.08(dd,J=8.2,4.6Hz,1H),6.97(d,J=8.3Hz,1H),6.87(s,1H),6.56(s,1H),5.98 (t,J=5.6Hz,1H),3.92(s,3H),3.91(s,3H),3.36–3.33(m,2H),3.18(dd,J=12.0,5.8Hz,2H). MS m / z(ESI):434.19[M+H] + .

[0357] Example 52 Synthesis of compound 52: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea

[0358]

[0359] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), N1-(pyrimidin-2-yl)ethane-1,2-diamine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 34 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (compound 52), with a yield of 61%. 1 H NMR(500MHz,DMSO-d6)δ9.19(s,1H),8.49(d,J=7.2Hz,1H),8.27(d,J=4.6Hz,2 H),8.12(d,J=2.0Hz,1H),7.87(d,J=1.4Hz,1H),7.64(d,J=2.0Hz,1H),7.21(t, J=5.4Hz,1H),7.12(dd,J=7.3,2.1Hz,1H),6.86(s,1H),6.57(t,J=4.7Hz,1H),6 .55(s,1H),3.92(s,3H),3.91(s,3H),3.38(t,J=5.4Hz,2H),3.36–3.33(m,2H). MS m / z (ESI): 435.19 [M+H] + .

[0360] Example 53 Synthesis of compound 53: 1-(2-(1H-pyrazol-1-yl)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea

[0361]

[0362] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-pyrazol-1-ylethylamine (16 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 28 mg of the yellow product 1-(2-(1H-pyrazol-1-yl)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea (compound 53), with a yield of 53%. 1 H NMR(500MHz,DMSO-d6)δ9.27(s,1H),8.47(d,J=7.2Hz,1H),8.12(d,J=1.8H z,1H),7.87(s,1H),7.75(d,J=2.0Hz,1H),7.64(d,J=1.7Hz,1H),7.49(s,1H ),7.13(dd,J=7.2,1.9Hz,1H),6.87(s,1H),6.55(s,1H),6.26(d,J=1.9Hz, 1H), 4.23 (t, J = 6.1Hz, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.56 (q, J = 6.0Hz, 2H). MS m / z(ESI):408.18[M+H] + .

[0363] Example 54 Synthesis of compound 54: 1-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea

[0364]

[0365] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-[1,2,4]triazol-1-ethylamine (16 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 33 mg of the yellow product 1-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea (compound 54), with a yield of 62%. 1 H NMR (500MHz, DMSO-d6) δ9.22(s,1H),8.53(s,1H),8.48(d,J=7.2Hz,1H),8.12(d,J=1.9Hz,1H),8.02(s,1H),7.87(d,J=1.3Hz,1H),7.64(d, J=1.9Hz,1H),7.13(dd,J=7.3,2.0Hz,1H),6.81(s,1H),6.53(s,1H),4.31(t,J=5.9Hz,2H),3.92(s,3H),3.91(s,3H),3.58(q,J=5.9Hz,2H). MS m / z(ESI):409.17[M+H] + .

[0366] Example 55 Synthesis of compound 55: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea

[0367]

[0368] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(3-methyl-[1,2,4]oxadizazol-5-yl)-ethylamine (28 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to give 28 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea (compound 55), yield 44%. MS m / z (ESI): 424.17 [M+H] + .

[0369] Example 56 Synthesis of compound 56: 1-(2-(2H-tetrazol-5-yl)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea

[0370]

[0371] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(5-tetrazolyl)ethylamine (21 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product 1-(2-(2H-tetrazole-5-yl)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea (compound 56), with a yield of 57%. 1H NMR (500MHz, DMSO-d6) δ9.23(s,1H),8.49(d,J=7.2Hz,1H),8.12(d,J=1.9Hz,1H),7.87(d,J=1.3Hz,1H),7.64(d,J=1.9Hz,1H),7. 13(dd,J=7.3,2.0Hz,1H),6.93(s,1H),6.55(s,1H),3.91(s,3H),3.91(s,3H),3.55(dd,J=12.7,6.5Hz,2H),3.06(t,J=6.7Hz,2H). MS m / z(ESI):410.17[M+H] + .

[0372] Example 57 Synthesis of compound 57: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(3-phenylpropyl)urea

[0373]

[0374] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-phenyl-1-propylamine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. Vacuum distillation of the organic phase yielded a crude product, which was then subjected to silica gel column chromatography to obtain a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazole[1,5-A]pyridine-2-yl)

[0375] 28 mg of 3-(3-phenylpropyl)urea (compound 57) was obtained, with a yield of 50%. 1H NMR(500MHz,DMSO-d6)δ9.15(s,1H),8.51(d,J=7.2Hz,1H),8.12(d,J=2.0Hz,1H),7. 86(d,J=1.4Hz,1H),7.64(d,J=2.0Hz,1H),7.29(t,J=7.5Hz,2H),7.24(d,J=6.9Hz,2H ),7.18(t,J=7.2Hz,1H),7.12(dd,J=7.3,2.1Hz,1H),6.88(s,1H),6.54(s,1H),3.91 (d, J=4.6Hz, 6H), 3.15 (dd, J=12.8, 6.8Hz, 2H), 2.67–2.60 (m, 2H), 1.82–1.72 (m, 2H). MS m / z(ESI):432.20[M+H] + .

[0376] Example 58 Synthesis of compound 58: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(3-(1-methyl-1H-pyrazol-4-yl)propyl)urea

[0377]

[0378] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), [3-(1-methyl-1H-pyrazol-4-yl)propyl]amine (19 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(3-(1-methyl-1H-pyrazol-4-yl)propyl)urea (compound 58), with a yield of 44%. 1H NMR(500MHz,DMSO-d6)δ9.12(s,1H),8.51(d,J=7.2Hz,1H),8.12(d,J=2.0Hz,1H ),7.86(d,J=1.6Hz,1H),7.64(d,J=2.0Hz,1H),7.48(s,1H),7.26(s,1H),7.12( dd,J=7.3,2.0Hz,1H),6.82(s,1H),6.54(s,1H),3.92(s,3H),3.91(s,3H),3.77 (s,3H),3.15(dd,J=12.8,6.7Hz,2H),2.43(t,J=7.5Hz,2H),1.72–1.64(m,2H). MSm / z(ESI): 436.21 [M+H] + .

[0379] Example 59 Synthesis of compound 59: 1-(3-(1H-pyrazol-1-yl)propyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea

[0380]

[0381] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-(1H-pyrazol-1-yl)propane-1-amine (18 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 28 mg of the yellow product 1-(3-(1H-pyrazol-1-yl)propyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea (compound 59), with a yield of 51%. 1H NMR(500MHz,DMSO-d6)δ9.17(s,1H),8.51(d,J=7.2Hz,1H),8.12(d,J=2.0Hz,1H),7.86(d ,J=1.5Hz,1H),7.76(d,J=2.1Hz,1H),7.64(d,J=2.0Hz,1H),7.44(d,J=1.6Hz,1H),7.12(d d,J=7.3,2.1Hz,1H),6.87(d,J=5.2Hz,1H),6.55(s,1H),6.24(t,J=2.0Hz,1H),4.17(t,J= 6.9Hz, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.11 (dd, J = 12.7, 6.6Hz, 2H), 1.95 (p, J = 6.9Hz, 2H). MS m / z(ESI):422.19[M+H] + .

[0382] Example 60 Synthesis of compound 60: 1-(3-(1H-1,2,4-triazol-1-yl)propyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea

[0383]

[0384] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-(1H-1,2,4-triazole)-1-propylamine (18 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to give 24 mg of the yellow product 1-(3-(1H-1,2,4-triazol-1-yl)propyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea (compound 60), yield 44%. MS m / z (ESI): 423.19 [M+H] + .

[0385] Example 61 Synthesis of compound 61: N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)-2-morpholine acetamide

[0386]

[0387] In a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added. Then, under stirring at room temperature, 1-(2-aminoethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (50 mg, 0.14 mmol, 1.0 eq), 4-morpholine acetate hydrochloride (25 mg, 0.17 mmol, 1.2 eq), HATU (65 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 28 mg of the yellow product N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)-2-morpholine acetamide (compound 61), yield 41%. MS m / z (ESI): 484.54 [M+H] + .

[0388] Example 62 Synthesis of compound 62: N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureoyl)ethyl)-1-methylpiperidine-4-carboxamide

[0389]

[0390] In a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added. Then, under stirring at room temperature, 1-(2-aminoethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (50 mg, 0.14 mmol, 1.0 eq), 1-methylpiperidin-4-carboxylic acid (22 mg, 0.17 mmol, 1.2 eq), HATU (65 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 25 mg of the yellow product N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)-1-methylpiperidin-4-carboxamide (compound 62), in a yield of 37%. MS m / z (ESI): 482.57 [M+H] + .

[0391] Example 63 Synthesis of compound 63: N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)cyclopropaneformamide

[0392]

[0393] In a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added. Then, under stirring at room temperature, 1-(2-aminoethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (50 mg, 0.14 mmol, 1.0 eq), cyclopropylformyl chloride (18 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 25 mg of the yellow product N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)cyclopropaneformamide (compound 63), yield 42%. MS m / z (ESI): 425.47 [M+H] + .

[0394] Example 64 Synthesis of N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)cyclobutane formamide compound 64

[0395]

[0396] In a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added. Then, under stirring at room temperature, 1-(2-aminoethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (50 mg, 0.14 mmol, 1.0 eq), cyclobutylformyl chloride (20 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)cyclobutaneformamide (compound 64), 32 mg, in 52% yield. MS m / z (ESI): 439.50 [M+H] + .

[0397] Example 65 Synthesis of compound 65: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(1-methyl-2-oxopyrrolidine-3-yl)urea

[0398]

[0399] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-amino-1-methylpyrrolidone-2-one toluenesulfonate (40 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(1-methyl-2-oxopyrrolidine-3-yl)urea (compound 65), with a yield of 47%. 1 H NMR (500MHz, DMSO-d6) δ9.27(s,1H),8.52(d,J=7.2Hz,1H),8.13(d,J=2.0Hz,1H),7. 87(d,J=1.6Hz,1H),7.64(d,J=2.0Hz,1H),7.14(dd,J=7.3,2.1Hz,1H),6.98(d,J=5. 8Hz,1H),6.57(s,1H),4.28(dd,J=16.3,9.3Hz,1H),3.92(s,3H),3.91(s,3H),3.30( dd,J=6.7,3.0Hz,2H),2.78(s,3H),2.46–2.39(m,1H),1.81(dq,J=12.1,9.4Hz,1H). MS m / z(ESI):411.18[M+H] + .

[0400] Example 66 Synthesis of compound 66: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,4S)-4-hydroxy-4-methylcyclohexyl)urea

[0401]

[0402] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), cis-4-amino-1-methylcyclohexanol (18 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,4S)-4-hydroxy-4-methylcyclohexyl)urea (compound 66), with a yield of 36%. 1 HNMR(500MHz,DMSO-d6)δ8.99(s,1H),8.51(d,J=7.2Hz,1H),8.12(d,J=2.0Hz,1H) ,7.86(d,J=1.5Hz,1H),7.64(d,J=1.9Hz,1H),7.11(dd,J=7.3,2.0Hz,1H),6.68(d, J=7.0Hz,1H),6.55(s,1H),4.08(s,1H),3.92(s,3H),3.91(s,3H),3.50–3.42(m,1H ),1.67–1.61(m,2H),1.54(dt,J=12.1,7.1Hz,4H),1.40–1.32(m,2H),1.12(s,3H). MSm / z(ESI):426.21[M+H] + .

[0403] Example 67 Synthesis of compound 67: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-hydroxy-4-methylcyclohexyl)urea

[0404]

[0405] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), trans-4-amino-1-methylcyclohexanol (18 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-hydroxy-4-methylcyclohexyl)urea (compound 67), with a yield of 36%. 1 HNMR(500MHz,DMSO-d6)δ9.11(s,1H),8.49(d,J=7.2Hz,1H),8.12(d,J=2.0Hz,1H),7.86(d,J=1.4Hz ,1H),7.64(d,J=2.0Hz,1H),7.11(dd,J=7.3,2.0Hz,1H),6.97(d,J=7.1Hz,1H),6.57(s,1H),4.19(s ,1H),3.92(s,3H),3.91(s,3H),3.69–3.63(m,1H),1.84(qd,J=7.7,3.6Hz,2H),1.55(ddd,J=12.0,8 .3,3.6Hz,2H),1.44(ddd,J=12.7,8.4,3.9Hz,2H),1.35(dtd,J=12.0,7.9,3.7Hz,2H),1.15(s,3H). MS m / z(ESI):426.21[M+H] + .

[0406] Example 68 Synthesis of compound 68: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-morpholinocyclohexyl)urea

[0407]

[0408] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), trans-1-amino-4-(morpholino-4-yl)cyclohexane (16 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 22 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-morpholinocyclohexyl)urea (compound 68), in a yield of 37%. MS m / z (ESI): 481.26 [M+H] + .

[0409] Example 69 Synthesis of compound 69: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-hydroxycyclohexyl)urea

[0410]

[0411] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), trans-4-aminocyclohexanol (16 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 22 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-hydroxycyclohexyl)urea (compound 69), with a yield of 42%. 1HNMR(500MHz,DMSO-d6)δ8.98(s,1H),8.50(d,J=7.2Hz,1H),8.12(d,J=2.0Hz,1H ),7.86(d,J=1.5Hz,1H),7.64(d,J=2.0Hz,1H),7.11(dd,J=7.3,2.0Hz,1H),6.64( d,J=7.3Hz,1H),6.55(s,1H),4.53(d,J=4.3Hz,1H),3.92(s,3H),3.91(s,3H),3.4 9–3.41(m,2H),1.89(d,J=11.0Hz,2H),1.83(d,J=10.9Hz,2H),1.29–1.18(m,4H). MS m / z(ESI): 412.20 [M+H] + .

[0412] Example 70 Synthesis of compound 70: 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,4S)-4-hydroxycyclohexyl)urea

[0413]

[0414] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), cis-4-aminocyclohexanol (16 mg, 0.14 mmol, 1.1 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,4S)-4-hydroxycyclohexyl)urea (compound 70), with a yield of 38%. 1HNMR(500MHz,DMSO-d6)δ9.02(s,1H),8.51(d,J=7.2Hz,1H),8.13(d,J=2.0Hz,1H),7.86(d,J=1.5Hz,1H),7.64(d,J=2.0Hz,1H),7.12(dd,J =7.3, 2.0Hz, 1H), 6.84 (d, J = 5.7Hz, 1H), 6.57 (s, 1H), 4.49 (d, J = 3.4Hz, 1H), 3.92 (d, J = 4.9Hz, 6H), 3.65 (d, J = 2.8Hz, 2H), 1.64–1.53 (m, 8H). MS m / z(ESI):412.20[M+H] + .

[0415] Example 71 Synthesis of compound 71: 1-(5-(5-hydroxy-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-phenoxyethyl)urea

[0416]

[0417] In a 100 mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. While stirring at room temperature, 5-bromopyrazole[1,5-A]pyridine-2-amine (430 mg, 2.04 mmol, 1.0 eq), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridine-3-ol (615 mg, 2.45 mmol, 1.2 eq), potassium carbonate (563 mg, 4.08 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol, 0.05 eq) were added. The reaction system was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 340 mg of a yellow product, 5-(2-aminopyrazole[1,5-A]pyridin-5-yl)-2-methoxypyridin-3-ol, in a yield of 67%. MS m / z (ESI): 257.10 [M+H] + .

[0418] In a 100 mL round-bottom flask, 20 mL of tetrahydrofuran was added. Then, 5-(2-aminopyrazole[1,5-A]pyridin-5-yl)-2-methoxypyridine-3-ol (340 mg, 1.33 mmol, 1.0 eq), phenyl chloroformate (250 mg, 1.6 mmol, 1.2 eq), and triethylamine (370 μL, 2.66 mmol, 2.0 eq) were added with stirring at 0 °C. The reaction mixture was then incubated at 0 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixture was extracted three times with 30 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 290 mg of a yellow product, phenyl (5-(5-hydroxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in 58% yield. MS m / z (ESI): 377.12 [M+H] + .

[0419] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-hydroxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (150 mg, 0.4 mmol, 1.0 eq), 2-phenoxyethylamine (60 mg, 0.44 mmol, 1.1 eq), and triethylamine (111 μL, 0.08 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 90 mg of the yellow product 1-(5-(5-hydroxy-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-phenoxyethyl)urea (compound 71), yield 54%. MS m / z (ESI): 420.17 [M+H] + .

[0420] Example 72 Synthesis of 2-methoxy-N-methyl-5-(2-(3-(2-phenoxyethyl)ureo)pyrazol[1,5-A]pyridin-5-yl)nicotinamide compound 72

[0421]

[0422] Add 1 mL of tetrahydrofuran to a 25 mL round-bottom flask. While stirring at room temperature, add 2-methoxy-5-(2-(3-(2-phenoxyethyl)ureo)pyrazolo[1,5-A]pyridin-5-yl)nicotinic acid (10 mg, 0.022 mmol, 1.0 eq), HATU (11 mg, 0.03 mmol, 1.2 eq), DIPEA (8 μL, 0.044 mmol, 2.0 eq), and a tetrahydrofuran solution of methylamine (15 μL, 0.03 mmol, 1.2 eq, 2 mol / L). Let the reaction mixture react at room temperature for 14 hours. After the reaction is complete, dilute the reaction mixture with 10 mL of water. Extract the mixture three times with 20 mL of ethyl acetate and combine the organic phases. Wash the organic phases with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dry with anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 6 mg of the yellow product 2-methoxy-N-methyl-5-(2-(3-(2-phenoxyethyl)ureo)pyrazol[1,5-A]pyridin-5-yl)nicotinamide (compound 72), with a yield of 60%. 1 H NMR(500MHz,DMSO-d6)δ9.26(s,1H),8.71(d,J=2.6Hz,1H),8.50(t,J=6.8Hz,1H),8 .43(d,J=2.6Hz,1H),8.31(d,J=4.6Hz,1H),7.88(d,J=1.3Hz,1H),7.34–7.25(m,2H) ,7.10(dd,J=7.3,2.1Hz,1H),6.99(d,J=7.8Hz,3H),6.94(t,J=7.3Hz,1H),6.59(s,1 H), 4.05 (t, J = 5.5Hz, 2H), 4.02 (s, 3H), 3.53 (q, J = 5.5Hz, 2H), 2.84 (t, J = 3.6Hz, 3H). MS m / z(ESI):461.19[M+H] + .

[0423] Example 73 Synthesis of compound 73: 1-(5-(5-hydroxy-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea

[0424]

[0425] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-hydroxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (150 mg, 0.4 mmol, 1.0 eq), N1-(pyrimidin-2-yl)ethane-1,2-diamine (61 mg, 0.44 mmol, 1.1 eq), and triethylamine (111 μL, 0.8 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 43 mg of the yellow product 1-(5-(5-hydroxy-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (compound 73), with a yield of 26%. 1 H NMR (500MHz, DMSO-d6) δ9.71 (s, 1H), 9.18 (s, 1H), 8.46 (d, J = 7.2Hz, 1H), 8.27 (d, J=4.7Hz,2H),8.02(d,J=2.2Hz,1H),7.72(d,J=1.3Hz,1H),7.43(d,J=2.2Hz,1H) ,7.20(t,J=5.4Hz,1H),6.99(dd,J=7.2,2.0Hz,1H),6.87(s,1H),6.56(t,J=4.7H z,1H),6.54(s,1H),3.93(s,3H),3.38(dd,J=11.3,5.6Hz,2H),3.36–3.32(m,2H). MSm / z(ESI): 421.17 [M+H] + .

[0426] Example 74 Synthesis of N-(2-methoxy-5-(2-(3-(2-(pyrimidin-2-ylamino)ethyl)ureo)pyrazolo[1,5-A]pyridin-5-yl)pyridin-3-yl)methanesulfonamide compound 74

[0427]

[0428] In a 100 mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. While stirring at room temperature, 5-bromopyrazole[1,5-A]pyridine-2-amine (306 mg, 1.45 mmol, 1.0 eq), N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridin-3-yl)methanesulfonamide (570 mg, 1.74 mmol, 1.2 eq), potassium carbonate (400 mg, 2.9 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (81 mg, 0.07 mmol, 0.05 eq) were added. The reaction mixture was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The combined organic phases were extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to give 410 mg of the yellow product N-(5-(2-aminopyrazolo[1,5-A]pyridin-5-yl)-2-methoxypyridin-3-yl)methanesulfonamide, in 85% yield. MS m / z (ESI): 334.10 [M+H] + .

[0429] In a 100 mL round-bottom flask, 10 mL of tetrahydrofuran was added. Then, under stirring at 0 °C, N-(5-(2-aminopyrazolo[1,5-A]pyridin-5-yl)-2-methoxypyridin-3-yl)methanesulfonamide (300 mg, 0.9 mmol, 1.0 eq), phenyl chloroformate (172 mg, 1.1 mmol, 1.2 eq), and triethylamine (250 μL, 1.8 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 0 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixture was extracted three times with 30 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 260 mg of a yellow product, phenyl(5-(6-methoxy-5-(methylsulfonamido)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in 64% yield. MS m / z (ESI): 454.12 [M+H] + .

[0430] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(6-methoxy-5-(methylsulfonamido)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.11 mmol, 1.0 eq), N-(pyrimidin-2-yl)ethane-1,2-diamine (18 mg, 0.13 mmol, 1.2 eq), and triethylamine (31 μL, 0.22 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 33 mg of the yellow product N-(2-methoxy-5-(2-(3-(2-(pyrimidin-2-ylamino)ethyl)ureo)pyrazolo[1,5-A]pyridin-5-yl)pyridin-3-yl)methanesulfonamide (compound 74), with a yield of 60%. 1 H NMR(500MHz,DMSO-d6)δ9.37(s,1H),9.21(s,1H),8.50(d,J=7.2Hz,1H),8.40(d,J =2.3Hz,1H),8.28(d,J=4.6Hz,2H),7.95(d,J=2.3Hz,1H),7.81(d,J=1.3Hz,1H),7. 22(t,J=5.4Hz,1H),7.04(dd,J=7.3,2.0Hz,1H),6.86(s,1H),6.57(dd,J=6.1,3.3 Hz, 2H), 3.98 (s, 3H), 3.40 (dd, J = 11.3, 5.6Hz, 2H), 3.37–3.34 (m, 2H), 3.10 (s, 3H). MS m / z(ESI): 498.17 [M+H] + .

[0431] Example 75 Synthesis of compound 75: 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea

[0432]

[0433] In a 100 mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. While stirring at room temperature, 5-bromopyrazole[1,5-A]pyridine-2-amine (200 mg, 0.95 mmol, 1.0 eq), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)-3-(trifluoromethyl)pyridine (346 mg, 1.14 mmol, 1.2 eq), potassium carbonate (262 mg, 1.9 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol, 0.05 eq) were added. The reaction system was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 200 mg of a yellow product, 5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridin-2-amine, in 68% yield. MS m / z (ESI): 309.10 [M+H] + .

[0434] 10 mL of tetrahydrofuran was added to a 100 mL round-bottom flask. Then, 5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridine-2-amine (160 mg, 0.52 mmol, 1.0 eq), phenyl chloroformate (97 mg, 0.62 mmol, 1.2 eq), and triethylamine (145 μL, 1.04 mmol, 2.0 eq) were added with stirring at 0 °C. The reaction mixture was then incubated at 0 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixture was extracted three times with 30 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 125 mg of a yellow product, phenyl (5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in 56% yield. MS m / z (ESI): 429.12 [M+H] + .

[0435] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (60 mg, 0.14 mmol, 1.0 eq), N1-(pyrimidin-2-yl)ethane-1,2-diamine (23 mg, 0.17 mmol, 1.2 eq), and triethylamine (58 μL, 0.42 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography, yielding 28 mg of the yellow product 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (compound 75), with a yield of 42%. 1 H NMR (500MHz, DMSO-d6) δ9.23 (s, 1H), 8.88 (d, J = 2.2Hz, 1H), 8.53 (d, J = 7.2Hz, 1H), 8.44 (d, J = 2.1Hz, 1H), 8.28 (d, J = 4.5Hz, 2H), 7.96 (d, J = 1. 4Hz,1H),7.22(t,J=5.4Hz,1H),7.18(dd,J=7.3,2.1Hz,1H),6.84(s,1H),6.59(s,1H),6.57(t,J=4.7Hz,1H),4.05(s,3H),3.42–3.34(m,4H). MS m / z(ESI):473.17[M+H] + .

[0436] Example 76 Synthesis of compound 76: 1-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea

[0437]

[0438] In a 100 mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. While stirring at room temperature, 5-bromopyrazole[1,5-A]pyridine-2-amine (350 mg, 1.66 mmol, 1.0 eq), 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridine (546 mg, 2.16 mmol, 1.3 eq), potassium carbonate (458 mg, 3.32 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (92 mg, 0.08 mmol, 0.05 eq) were added. The reaction system was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 380 mg of the yellow product 5-(5-fluoro-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridine-2-amine, in 89% yield. MS m / z (ESI): 259.10 [M+H] + .

[0439] 10 mL of tetrahydrofuran was added to a 100 mL round-bottom flask. Then, 5-(5-fluoro-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridine-2-amine (200 mg, 0.77 mmol, 1.0 eq), phenyl chloroformate (145 mg, 0.93 mmol, 1.2 eq), and triethylamine (214 μL, 1.54 mmol, 2.0 eq) were added with stirring at 0 °C. The reaction mixture was then incubated at 0 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixture was extracted three times with 30 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 175 mg of a yellow product, phenyl (5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in 60% yield. MS m / z (ESI): 379.12 [M+H] + .

[0440] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (80 mg, 0.21 mmol, 1.0 eq), N1-(pyrimidin-2-yl)ethane-1,2-diamine (35 mg, 0.25 mmol, 1.2 eq), and triethylamine (58 μL, 0.42 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 50 mg of the yellow product 1-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (compound 76), with a yield of 57%. 1 H NMR(500MHz,DMSO-d6)δ9.20(s,1H),8.51(d,J=7.2Hz,1H),8.46(d,J=2.0Hz ,1H),8.27(d,J=4.6Hz,2H),8.17(dd,J=11.9,2.0Hz,1H),7.89(d,J=1.4Hz, 1H),7.21(t,J=5.3Hz,1H),7.12(dd,J=7.3,2.0Hz,1H),6.81(s,1H),6.57(t ,J=4.7Hz,2H),4.00(s,3H),3.38(dd,J=11.3,5.6Hz,2H),3.36–3.32(m,2H). MS m / z(ESI): 423.17 [M+H] + .

[0441] Example 77 Synthesis of N-(2-methoxy-5-(2-(3-(2-(pyrimidin-2-ylamino)ethyl)ureo)pyrazol[1,5-A]pyridin-5-yl)pyridin-3-yl)cyclopropanesulfonamide compound 77

[0442]

[0443] In a 100 mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. While stirring at room temperature, 5-bromopyrazole[1,5-A]pyridine-2-amine (263 mg, 1.2 mmol, 1.0 eq), N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzoic acid-2-yl)pyridin-3-yl)cyclopropanesulfonamide (530 mg, 1.5 mmol, 1.2 eq), potassium carbonate (331 mg, 2.4 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol, 0.05 eq) were added. The reaction system was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 375 mg of the yellow product N-(5-(2-aminopyrazolo[1,5-A]pyridin-5-yl)-2-methoxypyridin-3-yl)cyclopropanesulfonamide, in 87% yield. MS m / z (ESI): 360.11 [M+H] + .

[0444] In a 100 mL round-bottom flask, 10 mL of tetrahydrofuran was added. Then, under stirring at 0 °C, N-(5-(2-aminopyrazolo[1,5-A]pyridin-5-yl)-2-methoxypyridin-3-yl)cyclopropanesulfonamide (200 mg, 0.56 mmol, 1.0 eq), phenyl chloroformate (105 mg, 0.67 mmol, 1.2 eq), and triethylamine (156 μL, 1.12 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 0 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixture was extracted three times with 30 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 150 mg of a yellow product, phenyl(5-(5-(cyclopropanesulfonamido)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in 56% yield. MS m / z (ESI): 480.13 [M+H] + .

[0445] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(cyclopropanesulfonamido)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.1 mmol, 1.0 eq), N1-(pyrimidin-2-yl)ethane-1,2-diamine (17 mg, 0.13 mmol, 1.2 eq), and triethylamine (29 μL, 0.2 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 28 mg of the yellow product N-(2-methoxy-5-(2-(3-(2-(pyrimidin-2-ylamino)ethyl)ureo)pyrazol[1,5-A]pyridin-5-yl)pyridin-3-yl)cyclopropanesulfonamide (compound 77), with a yield of 54%. 1 H NMR(500MHz,DMSO-d6)δ9.39(s,1H),9.21(s,1H),8.50(d,J=7.2Hz,1H),8.42(d,J=2.3Hz,1 H),8.27(t,J=6.6Hz,2H),7.98(d,J=2.3Hz,1H),7.81(d,J=1.2Hz,1H),7.22(t,J=5.3Hz,1H ),7.04(dd,J=7.2,2.0Hz,1H),6.86(s,1H),6.61–6.54(m,2H),3.99(s,3H),3.40(dd,J=11. 2,5.6Hz,2H),3.35(dd,J=10.2,4.4Hz,2H),2.80(dq,J=7.8,4.9Hz,1H),0.99–0.90(m,4H). MS m / z(ESI):524.18[M+H] + .

[0446] Example 78 Synthesis of compound 78: 1-(5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea

[0447]

[0448] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)carbamate (60 mg, 0.17 mmol, 1.0 eq), N1-(pyrimidin-2-yl)ethane-1,2-diamine (28 mg, 0.2 mmol, 1.2 eq), and triethylamine (47 μL, 0.34 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product 1-(5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (compound 78), with a yield of 45%. 1 H NMR (500MHz, DMSO-d6) δ9.30 (s, 1H), 8.60 (d, J = 2.4Hz, 1H), 8.49 (d, J = 7.2Hz, 1H), 8.11 (dd, J = 8.7, 2.6Hz, 1H), 7.82 (d, J = 1.3Hz, 1H), 7.08 (d d,J=7.2,2.0Hz,1H),7.01(s,1H),6.93(d,J=8.7Hz,1H),6.57(s,1H),3.92(s,3H),3.58(q,J=6.4Hz,2H),3.12(t,J=6.6Hz,2H),2.34(s,3H). MS m / z(ESI):405.18[M+H] + .

[0449] Example 79 Synthesis of compound 79: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea

[0450]

[0451] In a 100 mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. While stirring at room temperature, 5-bromopyrazole[1,5-A]pyridine-2-amine (420 mg, 2.0 mmol, 1.0 eq), 3-(difluoromethoxy)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)pyridine (780 mg, 2.6 mmol, 1.3 eq), potassium carbonate (552 mg, 4.0 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol, 0.05 eq) were added. The reaction system was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 552 mg of a yellow product, 5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridine-2-amine, in 90% yield. MS m / z (ESI): 307.10 [M+H] + .

[0452] 10 mL of tetrahydrofuran was added to a 100 mL round-bottom flask. Then, 5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridine-2-amine (100 mg, 0.33 mmol, 1.0 eq), phenyl chloroformate (62 mg, 0.4 mmol, 1.2 eq), and triethylamine (92 μL, 0.66 mmol, 2.0 eq) were added with stirring at 0 °C. The reaction mixture was then incubated at 0 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixture was extracted three times with 30 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 100 mg of a yellow product, phenyl (5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in 71% yield. MS m / z (ESI): 427.12 [M+H] + .

[0453] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), N1-(pyrimidin-2-yl)ethane-1,2-diamine (20 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 23 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (compound 79), with a yield of 41%. 1 H NMR (500MHz, DMSO-d6) δ9.20 (s, 1H), 8.51 (t, J = 5.1Hz, 2H), 8.27 (d, J = 4.6Hz, 2H), 8. 02(d,J=2.0Hz,1H),7.89(d,J=1.5Hz,1H),7.45(s,0.25H),7.30(s,0.5H),7.21(t,J =5.4Hz,1H),7.15(s,0.25H),7.12(dd,J=7.3,2.1Hz,1H),6.82(t,1H),6.57(m,J=5. 7,3.7Hz,2H),3.99(s,3H),3.38(q,J=11.4,5.7Hz,2H),3.34(q,J=10.4,4.7Hz,2H). MS m / z(ESI):471.17[M+H] + .

[0454] Example 80 Synthesis of compound 80: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea

[0455]

[0456] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (100 mg, 0.23 mmol, 1.0 eq), N-(2-pyridyl)ethylenediamine (39 mg, 0.28 mmol, 1.2 eq), and triethylamine (65 μL, 0.47 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea (compound 80), with a yield of 23%. 1 H NMR(500MHz,DMSO-d6)δ9.23(s,1H),8.51(t,J=4.7Hz,2H),8.02(d,J=2.0Hz,1H),7 .98(d,J=4.1Hz,1H),7.89(d,J=1.4Hz,1H),7.45(s,0.25H),7.42–7.36(m,1H),7.3 0(s,0.5H),7.15(s,0.25H),7.12(dd,J=7.3,2.1Hz,1H),6.85(s,1H),6.71(s,1H), 6.58(s,1H),6.50(dd,J=14.4,7.8Hz,2H),3.99(s,3H),3.35(dd,J=9.6,5.1Hz,4H). MS m / z(ESI):470.18[M+H] + .

[0457] Example 81 Synthesis of compound 81: 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea

[0458]

[0459] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (100 mg, 0.21 mmol, 1.0 eq), N-(2-pyridyl)ethylenediamine (34 mg, 0.25 mmol, 1.0 eq), and triethylamine (58 μL, 0.42 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 35 mg of the yellow product 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea (compound 81), with a yield of 35%. 1 H NMR (500MHz, DMSO-d6) δ9.24(s,1H),8.88(d,J=2.0Hz,1H),8.53(d,J=7.2Hz,1H),8.44(d,J=2.0Hz,1H),7.97(d,J=5.8Hz,2H),7.39(t,J=7.0Hz,1H), 7.18(dd,J=7.2,1.9Hz,1H),6.84(d,J=13.2Hz,1H),6.69(s,1H),6.59(s,1 H), 6.50 (dd, J = 13.6, 7.6Hz, 2H), 4.05 (s, 3H), 3.34 (dd, J = 10.1, 5.5Hz, 4H). MS m / z(ESI):472.17[M+H] + .

[0460] Example 82 Synthesis of 1-(5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea compound 82

[0461]

[0462] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)carbamate (60 mg, 0.17 mmol, 1.0 eq), 2-(3-methyl-[1,2,4]oxadizol-5-yl)ethylamine (33 mg, 0.2 mmol, 1.2 eq), and triethylamine (47 μL, 0.34 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 28 mg of the yellow product 1-(5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea (compound 82), with a yield of 42%. 1 H NMR (500MHz, DMSO-d6) δ9.30 (s, 1H), 8.60 (d, J = 2.4Hz, 1H), 8.49 (d, J = 7.2Hz, 1H), 8.11 (dd, J = 8.7, 2.6Hz, 1H), 7.82 (d, J = 1.3Hz, 1H), 7.08 (d d,J=7.2,2.0Hz,1H),7.01(s,1H),6.93(d,J=8.7Hz,1H),6.57(s,1H),3.92(s,3H),3.58(q,J=6.4Hz,2H),3.12(t,J=6.6Hz,2H),2.34(s,3H). MS m / z(ESI):394.16[M+H] + .

[0463] Example 83 Synthesis of compound 83: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea

[0464]

[0465] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (100 mg, 0.23 mmol, 1.0 eq), 2-(3-methyl-[1,2,4]oxadizazol-5-yl)-ethylamine (46 mg, 0.28 mmol, 1.2 eq), and triethylamine (65 μL, 0.48 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 28 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea (compound 83), with a yield of 26%. 1 H NMR(500MHz,DMSO-d6)δ9.26(s,1H),8.51(dd,J=6.6,4.8Hz,2H),8.02(d,J=2.1Hz,1H),7.89(d,J=1.4Hz,1H),7.45(s,0.25H),7.30(s,0.5H), 7.15(s,0.25H),7.13(dd,J=7.3,2.1Hz,1H),6.90(s,1H),6.57(s,1H), 3.99(s,3H),3.56(q,J=6.5Hz,2H),3.11(t,J=6.6Hz,2H),2.33(s,3H). MS m / z(ESI):460.15[M+H] + .

[0466] Example 84 Synthesis of 1-(5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea compound 84

[0467]

[0468] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)carbamate (60 mg, 0.17 mmol, 1.0 eq), 2-((1-methyl-1H-pyrazol-4-yl)oxy)ethane-1-amine (28 mg, 0.2 mmol, 1.2 eq), and triethylamine (47 μL, 0.34 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 8 mg of the yellow product 1-(5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea (compound 84), with a yield of 11%. 1 H NMR(500MHz,DMSO-d6)δ9.19(s,1H),8.60(d,J=2.4Hz,1H),8.50(d,J=7.2Hz,1H),8.12(dd,J=8.7,2.6Hz,1H),7.82(d,J=1.3Hz,1H),7.47(s,1H),7 .20(s,1H),7.08(dd,J=7.3,2.0Hz,1H),6.93(d,J=8.6Hz,2H),6.56(s,1H ), 3.91 (s, 3H), 3.89 (d, J = 5.4Hz, 2H), 3.73 (s, 3H), 3.46 (q, J = 5.5Hz, 2H). MS m / z(ESI):408.18[M+H] + .

[0469] Example 85 Synthesis of compound 85: 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea

[0470]

[0471] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (60 mg, 0.14 mmol, 1.0 eq), 2-((1-methyl-1H-pyrazol-4-yl)oxy)ethane-1-amine (22 mg, 0.15 mmol, 1.1 eq), and triethylamine (39 μL, 0.28 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea (compound 85), with a yield of 45%. 1 H NMR (500MHz, DMSO-d6) δ9.31(s,1H),8.88(d,J=2.1Hz,1H),8.54(d,J=7.2Hz,1H),8.44(d,J=2.1Hz,1H),7.96(d,J=1.5Hz,1H),7.48(s,1H) ,7.20(s,1H),7.18(dd,J=7.3,2.0Hz,1H),7.00(s,1H),6.61(s,1H),4.05(s,3H),3.90(t,J=5.5Hz,2H),3.73(s,3H),3.46(q,J=5.5Hz,2H). MS m / z(ESI):476.17[M+H] + .

[0472] Example 86 Synthesis of compound 86: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(2-(1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea

[0473]

[0474] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (100 mg, 0.23 mmol, 1.0 eq), 2-((1-methyl-1H-pyrazol-4-yl)oxy)ethane-1-amine (40 mg, 0.28 mmol, 1.2 eq), and triethylamine (65 μL, 0.47 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(2-(1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea (compound 86), with a yield of 28%. 1 H NMR(500MHz,DMSO-d6)δ9.23(s,1H),8.52(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H), 8.02(d,J=2.0Hz,1H),7.89(d,J=1.5Hz,1H),7.48(s,1H),7.45(s,0.25H),7.30(s ,0.5H),7.20(s,1H),7.15(s,0.25H),7.12(dd,J=7.3,2.1Hz,1H),6.92(s,1H),6. 59(s,1H),3.99(s,3H),3.90(t,J=5.4Hz,2H),3.73(s,3H),3.46(q,J=5.4Hz,2H). MS m / z(ESI): 474.17 [M+H] + .

[0475] Example 87 Synthesis of compound 87: 1-(2-(1H-pyrazol-1-yl)ethyl)-3-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea

[0476]

[0477] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (100 mg, 0.21 mmol, 1.0 eq), 2-pyrazol-1-ylethylamine (28 mg, 0.25 mmol, 1.2 eq), and triethylamine (58 μL, 0.42 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 35 mg of the yellow product 1-(2-(1H-pyrazol-1-yl)ethyl)-3-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea (compound 87), with a yield of 37%. 1 H NMR(500MHz,DMSO-d6)δ9.26(s,1H),8.88(d,J=2.1Hz,1H),8.51(d,J=7.2Hz ,1H),8.44(d,J=2.1Hz,1H),7.97(d,J=1.3Hz,1H),7.74(d,J=2.1Hz,1H),7.4 9(d,J=1.4Hz,1H),7.18(dd,J=7.2,2.0Hz,1H),6.75(s,1H),6.58(s,1H),6.2 6(t,J=2.0Hz,1H), 4.23(t,J=6.1Hz,2H), 4.05(s,3H), 3.56(q,J=5.9Hz,2H). MS m / z (ESI): 446.16 [M+H] + .

[0478] Example 88 Synthesis of compound 88: 1-(2-(1H-pyrazol-1-yl)ethyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-a]pyridin-2-yl)urea

[0479]

[0480] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (100 mg, 0.23 mmol, 1.0 eq), 2-pyrazol-1-ylethylamine (31 mg, 0.28 mmol, 1.2 eq), and triethylamine (65 μL, 0.47 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 27 mg of the yellow product 1-(2-(1H-pyrazol-1-yl)ethyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-a]pyridin-2-yl)urea (compound 88), with a yield of 26%. 1 H NMR(500MHz,DMSO-d6)δ9.25(s,1H),8.52–8.48(m,2H),8.02(d,J=2.0Hz,1H),7.8 9(d,J=1.4Hz,1H),7.74(d,J=2.1Hz,1H),7.49(d,J=1.4Hz,1H),7.45(s,0.25H),7. 30(s,0.5H),7.15(s,0.25H),7.12(dd,J=7.3,2.1Hz,1H),6.76(s,1H),6.57(s,1H ), 6.26 (t, J = 2.0Hz, 1H), 4.23 (t, J = 6.1Hz, 2H), 3.99 (s, 3H), 3.56 (q, J = 5.9Hz, 2H). MSm / z(ESI):444.16[M+H] + .

[0481] Example 89 Synthesis of N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)cyclopentaneformamide compound 89

[0482]

[0483] In a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added. Then, under stirring at room temperature, 1-(2-aminoethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (50 mg, 0.14 mmol, 1.0 eq), cyclopentylformyl chloride (23 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 28 mg of the yellow product N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)cyclopentanecarboxamide (compound 89), yield 44%. MS m / z (ESI): 453.52 [M+H] + .

[0484] Example 90 Synthesis of compound 90: N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)cyclohexaneformamide

[0485]

[0486] In a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added. Then, under stirring at room temperature, 1-(2-aminoethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (50 mg, 0.14 mmol, 1.0 eq), cyclohexylformyl chloride (25 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)cyclohexaneformamide (compound 90), 31 mg, in 48% yield. MS m / z (ESI): 467.55 [M+H] + .

[0487] Example 91 Synthesis of compound 91: N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)benzamide

[0488]

[0489] In a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added. Then, under stirring at room temperature, 1-(2-aminoethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (50 mg, 0.14 mmol, 1.0 eq), benzoyl chloride (24 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)benzamide (compound 91), 30 mg, in 47% yield. MS m / z (ESI): 461.50 [M+H] + .

[0490] Example 92 Synthesis of compound 92: N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)thiophene-2-carboxamide

[0491]

[0492] In a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added. Then, under stirring at room temperature, 1-(2-aminoethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (50 mg, 0.14 mmol, 1.0 eq), 2-thiophenecarboxyl chloride (25 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)thiophene-2-carboxamide (compound 92), 27 mg, in 41% yield. MS m / z (ESI): 467.52 [M+H] + .

[0493] Example 93 Synthesis of compound 93: 1-(5-(pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-acyloxy)ethyl)urea

[0494]

[0495] In a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. While stirring at room temperature, 1-(5-bromopyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (50 mg, 0.13 mmol, 1.0 eq), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (33 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetraphenylphosphine palladium (8 mg, 0.007 mmol, 0.05 eq) were added. The reaction mixture was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The combined organic phases were extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, and then dried over anhydrous Na₂SO₄. Vacuum distillation of the organic phase yielded a crude product, which was then subjected to silica gel column chromatography to give 20 mg of the yellow product 1-(5-(pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-acyloxy)ethyl)urea (compound 93), yield 41%. MS m / z (ESI): 375.41 [M+H] + .

[0496] Example 94 Synthesis of compound 94: 1-(5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0497]

[0498] In a 100 mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. While stirring at room temperature, 5-bromopyrazole[1,5-A]pyridine-2-amine (400 mg, 1.9 mmol, 1.0 eq), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)pyridine (536 mg, 2.3 mmol, 1.2 eq), potassium carbonate (524 mg, 3.8 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (116 mg, 0.10 mmol, 0.05 eq) were added. The reaction system was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 393 mg of the yellow product 5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridine-2-amine, in 86% yield. MS m / z (ESI): 241.11 [M+H] + .

[0499] In a 100 mL round-bottom flask, 10 mL of tetrahydrofuran was added. Then, 5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridine-2-amine (390 mg, 1.6 mmol, 1.0 eq), phenyl chloroformate (304 mg, 1.95 mmol, 1.2 eq), and triethylamine (445 μL, 3.2 mmol, 2.0 eq) were added with stirring at 0 °C. The reaction mixture was then incubated at 0 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixture was extracted three times with 30 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 440 mg of a yellow product, phenyl (5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)carbamate, in 76% yield. MS m / z (ESI): 361.13 [M+H] + .

[0500] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)carbamate (60 mg, 0.17 mmol, 1.0 eq), 2-(pyridin-3-yloxy)ethylamine (28 mg, 0.2 mmol, 1.2 eq), and triethylamine (47 μL, 0.34 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product 1-(5-(6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 94), with a yield of 37%. 1 H NMR(500MHz,DMSO-d6)δ9.31(s,1H),8.61(d,J=2.3Hz,1H),8.51(d,J=7.2Hz,1H),8.36 (d,J=2.8Hz,1H),8.19(d,J=4.4Hz,1H),8.11(dd,J=8.7,2.5Hz,1H),7.82(s,1H),7.45 (dd,J=8.4,1.8Hz,1H),7.34(dd,J=8.4,4.6Hz,1H),7.08(dd,J=7.2,1.8Hz,2H),6.94( d, J=8.7Hz, 1H), 6.59 (s, 1H), 4.16 (t, J=5.5Hz, 2H), 3.92 (s, 3H), 3.58 (q, J=5.5Hz, 2H). MS m / z(ESI):405.17[M+H] + .

[0501] Example 95 Synthesis of compound 95: 1-(5-(5-ethoxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0502]

[0503] In a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. While stirring at room temperature, 1-(5-bromopyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (50 mg, 0.13 mmol, 1.0 eq), 3-ethoxy-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (45 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (8 mg, 0.007 mmol, 0.05 eq) were added. The reaction mixture was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The combined organic phases were extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was then subjected to silica gel column chromatography to give 20 mg of the yellow product 1-(5-(5-ethoxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 95), yield 34%. MS m / z (ESI): 449.49 [M+H] + .

[0504] Example 96 Synthesis of compound 96: 1-(5-(5-isopropoxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0505]

[0506] In a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. While stirring at room temperature, 1-(5-bromopyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (50 mg, 0.13 mmol, 1.0 eq), 3-isopropoxy-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)pyridine (47 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (8 mg, 0.007 mmol, 0.05 eq) were added. The reaction mixture was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The combined organic phases were extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, and then dried over anhydrous Na₂SO₄. Vacuum distillation of the organic phase yielded a crude product, which was then subjected to silica gel column chromatography to give 26 mg of the yellow product 1-(5-(5-isopropoxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 96), yield 46%. MS m / z (ESI): 463.52 [M+H] + .

[0507] Example 97 Synthesis of compound 97: 1-(5-(5,6-diethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0508]

[0509] In a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. While stirring at room temperature, 1-(5-bromopyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (50 mg, 0.13 mmol, 1.0 eq), 2,3-diethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (47 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (8 mg, 0.007 mmol, 0.05 eq) were added. The reaction mixture was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The combined organic phases were extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was then subjected to silica gel column chromatography to give 25 mg of the yellow product 1-(5-(5,6-diethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 97), yield 42%. MS m / z (ESI): 463.52 [M+H] + .

[0510] Example 98 Synthesis of N-(2-methoxy-5-(2-(3-(2-(pyridin-3-acyloxy)ethyl)ureo)pyrazol[1,5-A]pyridin-5-yl)pyridin-3-yl)methanesulfonamide compound 98

[0511]

[0512] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(6-methoxy-5-(methylsulfonamido)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.11 mmol, 1.0 eq), 2-(pyridin-3-yloxy)ethylamine (18 mg, 0.13 mmol, 1.2 eq), and triethylamine (30 μL, 0.22 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain a yellow product N-(2-methoxy-5-(2-(3-(2-(pyridin-3-acyloxy)ethyl))ureido)pyrazol[1,5-A]pyridin-5-yl)pyridin-3-yl)methanesulfonamide (compound 98) 33 mg, with a yield of 60%. 1 H NMR(500MHz,DMSO-d6)δ9.40(s,1H),9.27(s,1H),8.52(d,J=7.2Hz,1H),8.41(d,J=2.2Hz,1H) ,8.35(d,J=2.9Hz,1H),8.19(d,J=4.5Hz,1H),7.95(d,J=2.2Hz,1H),7.82(d,J=1.1Hz,1H),7. 45(dd,J=8.4,1.8Hz,1H),7.34(dd,J=8.4,4.6Hz,1H),7.05(dd,J=7.2,1.9Hz,1H),7.01(s,1H ), 6.60 (s, 1H), 4.15 (t, J = 5.5Hz, 2H), 3.98 (s, 3H), 3.57 (dd, J = 11.0, 5.4Hz, 2H), 3.11 (s, 3H). MS m / z(ESI):498.16[M+H] + .

[0513] Example 99 Synthesis of N-(2-methoxy-5-(2-(3-(2-(pyridin-3-oxy)ethyl)ureo)pyrazol[1,5-A]pyridin-5-yl)pyridin-3-yl)cyclopropanesulfonamide compound 99

[0514]

[0515] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(cyclopropanesulfonamido)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.10 mmol, 1.0 eq), 2-(pyridin-3-yloxy)ethylamine (17 mg, 0.12 mmol, 1.2 eq), and triethylamine (28 μL, 0.2 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 30 mg of the yellow product N-(2-methoxy-5-(2-(3-(2-(pyridin-3-oxy)ethyl)ureo)pyrazol[1,5-A]pyridin-5-yl)pyridin-3-yl)cyclopropanesulfonamide (compound 99), in 58% yield. MS m / z (ESI): 524.17 [M+H] + .

[0516] Example 100 Synthesis of compound 100: 1-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0517]

[0518] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (60 mg, 0.16 mmol, 1.0 eq), 2-(pyridin-3-yloxy)ethylamine (26 mg, 0.19 mmol, 1.2 eq), and triethylamine (44 μL, 0.32 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 23 mg of the yellow product 1-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 100), with a yield of 34%. 1H NMR (500MHz, DMSO-d6) δ9.28 (s, 1H), 8.52 (d, J = 7.2Hz, 1H), 8.45 (d, J = 2.0Hz, 1H), 8. 36(d,J=2.9Hz,1H),8.18(ddd,J=13.9,8.2,1.6Hz,2H),7.89(d,J=1.4Hz,1H),7.45( ddd,J=8.4,2.9,1.2Hz,1H),7.34(dd,J=8.4,4.6Hz,1H),7.13(dd,J=7.3,2.1Hz,1H) ,6.99(s,1H),6.60(s,1H),4.15(t,J=5.5Hz,2H),4.01(s,3H),3.57(q,J=5.5Hz,2H). MS m / z(ESI):423.16[M+H] + .

[0519] Example 101 Synthesis of compound 101: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0520]

[0521] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (100 mg, 0.23 mmol, 1.0 eq), 2-(pyridin-3-yloxy)ethylamine (39 mg, 0.28 mmol, 1.2 eq), and triethylamine (65 μL, 0.47 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 101), with a yield of 23%. 1H NMR(500MHz,DMSO-d6)δ9.27(s,1H),8.51(dd,J=12.7,4.7Hz,2H),8.34(d,J=2.9Hz,1H),8.1 8(dd,J=4.6,1.2Hz,1H),8.02(d,J=2.1Hz,1H),7.89(d,J=1.4Hz,1H),7.46–7.43(m,1H),7.4 3(s,0.25H),7.34(dd,J=8.4,4.6Hz,1H),7.30(s,0.5H),7.15(s,0.25H),7.13(dd,J=7.3,2. 1Hz, 1H), 6.99 (s, 1H), 6.59 (s, 1H), 4.14 (t, J = 5.5Hz, 2H), 3.99 (s, 3H), 3.56 (q, J = 5.5Hz, 2H). MS m / z(ESI):471.16[M+H] + .

[0522] Example 102 Synthesis of compound 102: 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-oxy)ethyl)urea

[0523]

[0524] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (100 mg, 0.21 mmol, 1.0 eq), 2-(pyridin-3-yloxy)ethylamine (35 mg, 0.25 mmol, 1.2 eq), and triethylamine (58 μL, 0.42 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 31 mg of the yellow product 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-oxy)ethyl)urea (compound 102), with a yield of 31%. 1H NMR (500MHz, DMSO-d6) δ9.27(s,1H),8.88(d,J=2.1Hz,1H),8.54(d,J=7.2Hz,1H),8. 44(d,J=2.0Hz,1H),8.34(d,J=2.9Hz,1H),8.20–8.16(m,1H),7.97(d,J=1.4Hz,1H), 7.45(dd,J=8.4,1.8Hz,1H),7.34(dd,J=8.4,4.6Hz,1H),7.19(dd,J=7.3,2.0Hz,1H) ,6.97(s,1H),6.60(s,1H),4.14(t,J=5.5Hz,2H),4.05(s,3H),3.56(q,J=5.4Hz,2H). MS m / z(ESI):473.15[M+H] + .

[0525] Example 103 Synthesis of compound 103: 1-(5-(6-chloro-5-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0526]

[0527] In a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. While stirring at room temperature, 1-(5-bromopyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (50 mg, 0.13 mmol, 1.0 eq), 2-chloro-3-methoxypyridin-5-boronic acid pinacol ester (43 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetraphenylphosphine palladium (8 mg, 0.007 mmol, 0.05 eq) were added. The reaction system was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 12 mg of a yellow product, 1-(5-(6-chloro-5-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 103), in 21% yield. MS m / z (ESI): 439.88 [M+H] + .

[0528] Example 104 Synthesis of compound 104: 1-(5-(5-methylpyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0529]

[0530] In a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. While stirring at room temperature, 1-(5-bromopyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (50 mg, 0.13 mmol, 1.0 eq), 3-methylpyridin-5-boronic acid pinacol ester (35 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (8 mg, 0.007 mmol, 0.05 eq) were added. The reaction system was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 25 mg of a yellow product, 1-(5-(5-methylpyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 104), in 50% yield. MS m / z (ESI): 389.44 [M+H] + .

[0531] Example 105 Synthesis of compound 105: 1-(5-(5-fluoropyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0532]

[0533] In a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. While stirring at room temperature, 1-(5-bromopyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (50 mg, 0.13 mmol, 1.0 eq), 5-fluoropyridine-3-boronic acid linalool ester (36 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetraphenylphosphine palladium (8 mg, 0.007 mmol, 0.05 eq) were added. The reaction mixture was then incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 24 mg of the yellow product 1-(5-(5-fluoropyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 105), in a yield of 47%. MS m / z (ESI): 393.40 [M+H] + .

[0534] Example 106 Synthesis of compound 106: 1-(5-(5-(difluoromethoxy)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0535]

[0536] In a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. While stirring at room temperature, 1-(5-bromopyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (50 mg, 0.13 mmol, 1.0 eq), 3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)pyridine (30 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium (8 mg, 0.007 mmol, 0.05 eq) were added. The reaction mixture was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The combined organic phases were extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was then subjected to silica gel column chromatography to give 27 mg of the yellow product 1-(5-(5-(difluoromethoxy)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 106), yield 47%. MS m / z (ESI): 441.42 [M+H] + .

[0537] Example 107 Synthesis of compound 107: N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)furan-2-carboxamide

[0538]

[0539] In a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added. Then, under stirring at room temperature, 1-(2-aminoethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (50 mg, 0.14 mmol, 1.0 eq), furfural chloride (22 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 20 mg of the yellow product N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)furan-2-carboxamide (compound 107), yield 32%. MS m / z (ESI): 451.46 [M+H] + .

[0540] Example 108 Synthesis of compound 108: 1-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0541]

[0542] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-(2-aminoethoxy)pyridine (22 mg, 0.16 mmol, 1.2 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to give 27 mg of the yellow product 1-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 108), yield 47%. MS m / z (ESI): 436.45 [M+H] + .

[0543] Example 109 Synthesis of compound 109: 1-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0544]

[0545] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-(2-aminoethoxy)pyridine (22 mg, 0.16 mmol, 1.2 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 30 mg of the yellow product 1-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 109), in 53% yield. MS m / z (ESI): 436.45 [M+H] + .

[0546] Example 110 Synthesis of compound 110: 1-(6-(5,6-dimethoxypyridin-3-yl)-1H-benzo[D]imidazol-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0547]

[0548] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(6-(5,6-dimethoxypyridin-3-yl)-1Hbenzo[D]imidazol-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-(2-aminoethoxy)pyridine (22 mg, 0.16 mmol, 1.2 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 10 mg of a yellow product, 1-(6-(5,6-dimethoxypyridin-3-yl)-1H-benzo[D]imidazol-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 110), in 18% yield. MS m / z (ESI): 435.46 [M+H] + .

[0549] Example 111 Synthesis of compound 111: 1-(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea

[0550]

[0551] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 3-(2-aminoethoxy)pyridine (22 mg, 0.16 mmol, 1.2 eq), and triethylamine (36 μL, 0.26 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 15 mg of a yellow product, 1-(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (compound 111), in a yield of 26%. MS m / z (ESI): 436.45 [M+H] + .

[0552] Example 112 Synthesis of compound 112: N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureoyl)ethyl)-1-methyl-1H-imidazolium-4-carboxamide

[0553]

[0554] In a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added. Then, under stirring at room temperature, 1-(2-aminoethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (50 mg, 0.14 mmol, 1.0 eq), 1-methyl-4-imidazolium carboxylic acid (21 mg, 0.17 mmol, 1.2 eq), HATU (65 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 22 mg of the yellow product N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)ethyl)-1-methyl-1H-imidazolium-4-carboxamide (compound 112), in a yield of 34%. MS m / z (ESI): 465.49 [M+H] + .

[0555] Example 113 Synthesis of compound 113: 1-(6-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)-[1,2,4]triazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-oxy)ethyl)urea

[0556]

[0557] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), 2-(pyridin-3-yloxy)ethylamine (18 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(6-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)-[1,2,4]triazol[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-oxy)ethyl)urea (compound 113), with a yield of 35%. 1 H NMR (500MHz, DMSO-d6) δ10.10(s,1H),9.24(d,J=0.9Hz,1H),8.54(t,J=5.6Hz,1H),8.50(d,J=2.1Hz ,1H),8.37(d,J=2.9Hz,1H),8.17(dd,J=4.6,1.1Hz,1H),8.07(d,J=2.0Hz,1H),8.04(dd,J=9.2,1.8 Hz,1H),7.75(d,J=9.3Hz,1H),7.47(ddd,J=8.5,2.9,1.2Hz,1H),7.44(s,0.25H),7.33(dd,J=8.4,4 .6Hz, 1H), 7.29 (s, 0.5H), 7.15 (s, 0.25H), 4.19 (t, J = 5.5Hz, 2H), 3.99 (s, 3H), 3.65 (q, J = 5.5Hz, 2H). MS m / z(ESI):472.15[M+H] + .

[0558] Example 114 Synthesis of compound 114: 1-(6-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)-3-(2-(pyridin-3-oxy)ethyl)urea

[0559]

[0560] In a 100 mL round-bottom flask, 15 mL of 1,4-dioxane and 3 mL of water were added. While stirring at room temperature, 6-chloroimidazolo[1,2-B]pyridazin-2-amine (500 mg, 3.0 mmol, 1.0 eq), 3-(difluoromethoxy)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridine (1084 mg, 3.6 mmol, 1.2 eq), potassium carbonate (828 mg, 6.0 mmol, 2.0 eq), and tetraphenylphosphine palladium (173 mg, 0.15 mmol, 0.05 eq) were added. The reaction system was incubated at 90 °C for 4 hours. After the reaction was complete, the mixture was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 506 mg of the yellow product 6-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-amine, in 55% yield. MS m / z (ESI): 308.10 [M+H] + .

[0561] Add 25 mL of tetrahydrofuran to a 100 mL round-bottom flask, and then add 6-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-amine (200 mg, 0.65 mmol, 1.0 eq), phenyl chloroformate (122 mg, 0.78 mmol, 1.2 eq), and triethylamine (181 μL, 1.3 mmol, 2.0 eq) with stirring at 0 °C. Continue the reaction at 0 °C for 1 hour. After the reaction is complete, neutralize with 20 mL of water. Extract the mixture three times with 30 mL of ethyl acetate, and combine the organic phases. Wash the organic phases with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dry with anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 181 mg of a yellow product, phenyl(6-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)carbamate, in 65% yield. MS m / z (ESI): 428.12 [M+H] + .

[0562] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(6-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), 2-(pyridin-3-yloxy)ethylamine (18 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was then incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(6-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)-3-(2-(pyridin-3-oxy)ethyl)urea (compound 114), with a yield of 35%. 1 H NMR (500MHz, DMSO-d6) δ9.30(s,1H),8.74(d,J=2.1Hz,1H),8.34(d,J=2.9Hz,1H),8.20(d,J= 1.9Hz,1H),8.18(dd,J=4.6,1.1Hz,1H),8.07(s,1H),8.01(d,J=9.4Hz,1H),7.78(d,J=9.4Hz, 1H),7.47(s,0.25H),7.44(ddd,J=8.5,2.9,1.2Hz,1H),7.34(dd,J=8.5,4.6Hz,1H),7.32(s,0 .5H), 7.17 (s, 0.25H), 6.91 (s, 1H), 4.14 (t, J = 5.5Hz, 2H), 4.01 (s, 3H), 3.56 (q, J = 5.5Hz, 2H). MS m / z(ESI):472.15[M+H] + .

[0563] Example 115 Synthesis of compound 115: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-morpholinocyclohexyl)urea

[0564]

[0565] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), trans-1-amino-4-(morpholino-4-yl)-cyclohexane (24 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 25 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-morpholinocyclohexyl)urea (compound 115), in 40% yield. MS m / z (ESI): 517.24 [M+H] + .

[0566] Example 116 Synthesis of compound 116: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,4S)-4-morpholinocyclohexyl)urea

[0567]

[0568] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), cis-4-aminocyclohexanol (15 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,4S)-4-morpholinocyclohexyl)urea (compound 116), with a yield of 37%. 1H NMR(500MHz,DMSO-d6)δ9.05(s,1H),8.53(d,J=7.2Hz,1H),8.50(d,J=2.0Hz, 1H),8.02(d,J=1.6Hz,1H),7.88(s,1H),7.45(s,0.25H),7.31(s,0.5H),7.16 (s,0.25H),7.11(dd,J=7.2,1.9Hz,1H),6.83(d,J=5.6Hz,1H),6.58(s,1H),4 .47(d,J=3.3Hz,1H),3.99(s,3H),3.63(s,2H),1.57(td,J=17.9,11.0Hz,8H). MS m / z (ESI): 448.18 [M+H] + .

[0569] Example 117 Synthesis of compound 117: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-hydroxycyclohexyl)urea

[0570]

[0571] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), trans-4-aminocyclohexanol (15 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 23 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-hydroxycyclohexyl)urea (compound 117), with a yield of 43%. 1H NMR(500MHz,DMSO-d6)δ9.04(s,1H),8.53(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.0 3(d,J=2.0Hz,1H),7.88(d,J=1.7Hz,1H),7.46(s,0.25H),7.31(s,0.5H),7.16(s,0.25 H),7.11(dd,J=7.3,2.0Hz,1H),6.67(d,J=7.3Hz,1H),6.57(s,1H),4.55(d,J=4.3Hz, 1H), 3.99 (s, 3H), 3.49–3.41 (m, 2H), 1.85 (dd, J=29.1, 10.9Hz, 4H), 1.30–1.16 (m, 4H). MS m / z(ESI):448.18[M+H] + .

[0572] Example 118 Synthesis of compound 118: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,3S)-3-hydroxycyclopentyl)urea

[0573]

[0574] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (1S,3S)-3-aminocyclopentanol (18 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,3S)-3-hydroxycyclopentyl)urea (compound 118), with a yield of 38%. 1H NMR(500MHz,DMSO-d6)δ9.00(s,1H),8.52(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.02(d,J=2.0Hz,1H) ,7.88(d,J=1.5Hz,1H),7.45(s,0.25H),7.31(s,0.5H),7.16(s,0.25H),7.11(dd,J=7.3,2.1Hz,1H),6.7 9(d,J=7.3Hz,1H),6.59(s,1H),4.53(d,J=3.8Hz,1H),4.23–4.15(m,2H),3.99(s,3H),2.06(dt,J=13.7, 7.7Hz,1H),1.95–1.83(m,2H),1.58–1.52(m,1H),1.51–1.44(m,1H),1.34(ddt,J=13.1,8.9,6.7Hz,1H). MS m / z(ESI):434.16[M+H] + .

[0575] Example 119 Synthesis of compound 119: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)urea

[0576]

[0577] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)-1-aminocyclopentane (24 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 22 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)urea (compound 119), with a yield of 38%.1 H NMR (500MHz, DMSO-d6) δ9.13(s,1H),8.53(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.03(d,J=2.0Hz,1H),7.88(d,J=1.4Hz,1H) ,7.46(s,0.25H),7.31(s,0.5H),7.17(s,0.25H),7.12(dd,J=7.3,2.1Hz,1H),6.83(d,J=6.8Hz,1H),6.60(s,1H),4.66(d,J=4. 7Hz,1H),4.60(t,J=5.2Hz,1H),4.42(d,J=4.9Hz,1H),3.99(s,3H),3.92–3.85(m,1H),3.69(q,J=4.9Hz,1H),3.59(dd,J=11.7, 5.4Hz,1H),3.42(dtd,J=16.1,10.6,5.4Hz,2H),2.14(dt,J=13.1,8.6Hz,1H),1.96–1.89(m,1H),1.09(dt,J=13.2,8.1Hz,1H). MS m / z(ESI):480.17[M+H] + .

[0578] Example 120 Synthesis of compound 120: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,4S)-4-hydroxy-4-methylcyclohexyl)urea

[0579]

[0580] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), cis-4-amino-1-methylcyclohexanol (17 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 24 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,4S)-4-hydroxy-4-methylcyclohexyl)urea (compound 120), with a yield of 44%. 1 H NMR(500MHz,DMSO-d6)δ9.00(s,1H),8.53(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.02(d,J =2.0Hz,1H),7.88(d,J=1.4Hz,1H),7.46(s,0.25H),7.31(s,0.5H),7.16(s,0.25H),7.11(d d,J=7.3,2.1Hz,1H),6.65(d,J=7.1Hz,1H),6.58(s,1H),4.08(s,1H),3.99(s,3H),3.50–3. 42(m,1H),1.67–1.61(m,2H),1.54(dt,J=12.0,7.2Hz,4H),1.40–1.32(m,2H),1.12(s,3H). MS m / z(ESI):462.20[M+H] + .

[0581] Example 121 Synthesis of compound 121: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-hydroxy-4-methylcyclohexyl)urea

[0582]

[0583] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), trans-4-amino-1-methylcyclohexanol (17 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-hydroxy-4-methylcyclohexyl)urea (compound 121), with a yield of 45%. 1 H NMR(500MHz,DMSO-d6)δ9.09(s,1H),8.51(d,J=7.2Hz,1H),8.49(d,J=2.1Hz,1H),8.02(d,J=2.0Hz,1H),7.8 8(d,J=1.4Hz,1H),7.46(s,0.25H),7.31(s,0.5H),7.16(s,0.25H),7.11(dd,J=7.3,2.0Hz,1H),6.91(d,J=7 .1Hz,1H),6.58(s,1H),4.19(s,1H),3.99(s,3H),3.68–3.62(m,1H),1.84(qd,J=7.7,3.6Hz,2H),1.54(ddd, J=12.0,8.2,3.6Hz,2H),1.44(ddd,J=12.7,8.5,3.9Hz,2H),1.35(dtd,J=12.0,7.9,3.8Hz,2H),1.15(s,3H). MS m / z(ESI):462.20[M+H] + .

[0584] Example 122 Synthesis of compound 122: 1-((1S,4S)-4-aminocyclohexyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea

[0585]

[0586] Add 2 mL of dichloromethane to a 100 mL round-bottom flask, and then add tert-butyl((1S,4S)-4-(3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)cyclohexyl)carbamate (50 mg, 0.09 mmol, 1.0 eq) and 2 mL of trifluoroacetic acid while stirring at room temperature. The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the crude product was obtained by vacuum distillation. Neutralization was performed using saturated NaHCO3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The crude product was obtained by vacuum distillation of the organic phase. The crude product was then subjected to silica gel column chromatography, yielding a yellow product of 1-((1S,4S)-4-aminocyclohexyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (compound 122) 10 mg, yield 25%. MS m / z (ESI): 447.20 [M+H] + .

[0587] Example 123 Synthesis of compound 123: 1-((1R,4R)-4-aminocyclohexyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea

[0588]

[0589] Add 2 mL of dichloromethane to a 100 mL round-bottom flask, and then add tert-butyl((1R,4R)-4-(3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureo)cyclohexyl)carbamate (50 mg, 0.09 mmol, 1.0 eq) and 2 mL of trifluoroacetic acid while stirring at room temperature. The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the crude product was obtained by vacuum distillation. Neutralization was performed using saturated NaHCO3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography to yield 13 mg of a yellow product, 1-((1R,4R)-4-aminocyclohexyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (compound 123), in 33% yield. MS m / z (ESI): 447.20 [M+H] + .

[0590] Example 124 Synthesis of compound 124: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,3S)-3-hydroxycyclobutyl)urea

[0591]

[0592] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), cis-3-aminocyclobutanol (16 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 15 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,3S)-3-hydroxycyclobutyl)urea (compound 124), with a yield of 27%. 1 H NMR (500MHz, DMSO-d6) δ9.18(s,1H),8.53(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.03( d,J=2.0Hz,1H),7.88(d,J=1.5Hz,1H),7.47(s,0.25H),7.32(s,0.5H),7.18(s,0.25H), 7.12(dd,J=7.3,2.1Hz,1H),7.09(d,J=7.8Hz,1H),6.59(s,1H),5.10(d,J=6.3Hz,1H),3 .99(s,3H),3.84–3.77(m,1H),3.72–3.63(m,1H),2.60–2.54(m,2H),1.75–1.67(m,2H). MS m / z(ESI):420.15[M+H] + .

[0593] Example 125 Synthesis of compound 125(R)-1-(1-cyclopropyl-2-hydroxyethyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea

[0594]

[0595] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (R)-2-amino-2-cyclopropylethanol (18 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 17 mg of the yellow product (R)-1-(1-cyclopropyl-2-hydroxyethyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea (compound 125), with a yield of 33%. 1 H NMR(500MHz,DMSO-d6)δ8.91(s,1H),8.30(d,J=7.2Hz,1H),8.27(d,J=2.1Hz,1H),7.79(d,J=2.0Hz,1H), 7.65(d,J=1.5Hz,1H),7.23(s,0.25H),7.08(s,0.5H),6.94(s,0.25H),6.88(dd,J=7.3,2.0Hz,1H),6.53( d,J=8.1Hz,1H),6.36(s,1H),4.59(t,J=5.3Hz,1H),3.76(s,3H),3.10(s,2H),2.97(ddt,J=11.4,7.4,3. 7Hz,1H),0.80–0.72(m,1H),0.23–0.14(m,2H),0.11(dt,J=9.3,5.1Hz,1H),-0.00(td,J=8.6,4.8Hz,1H). MS m / z(ESI):434.16[M+H] + .

[0596] Example 126 Synthesis of (S)-1-(1-cyclopropyl-2-hydroxyethyl)-3-(5-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea compound 126

[0597]

[0598] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (S)-2-amino-2-cyclopropylethanol (18 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 16 mg of the yellow product (S)-1-(1-cyclopropyl-2-hydroxyethyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea (compound 126), with a yield of 31%. 1 H NMR (500MHz, DMSO-d6) δ8.92(s,1H),8.30(d,J=7.2Hz,1H),8.27(d,J=2.1Hz,1H),7.80(d,J=2.0Hz ,1H),7.65(d,J=1.5Hz,1H),7.23(s,0.25H),7.09(s,0.5H),6.94(s,0.25H),6.88(dd,J=7.3,2.1H z,1H),6.53(d,J=8.0Hz,1H),6.36(s,1H),4.59(t,J=5.3Hz,1H),3.76(s,3H),3.10(s,3H),3.00–2 .94(m,1H),0.80–0.72(m,1H),0.23–0.14(m,2H),0.11(td,J=8.9,5.1Hz,1H),0.02–-0.03(m,1H). MSm / z(ESI):434.16[M+H] + .

[0599] Example 127 Synthesis of compound 127 (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxypropane-2-yl)urea

[0600]

[0601] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (R)-2-amino-1-propanol (10 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 16 mg of the yellow product (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxypropane-2-yl)urea (compound 127), with a yield of 33%. 1 H NMR (500MHz, DMSO-d6) δ9.12(s,1H),8.52(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.03(d, J=2.0Hz,1H),7.88(d,J=1.5Hz,1H),7.46(s,0.25H),7.31(s,0.5H),7.17(s,0.25H),7.11( dd,J=7.3,2.1Hz,1H),6.70(d,J=7.5Hz,1H),6.60(s,1H),4.82(t,J=5.3Hz,1H),3.99(s,3H ),3.78–3.71(m,1H),3.42(dt,J=9.9,4.9Hz,1H),3.38–3.34(m,1H),1.10(d,J=6.7Hz,3H). MS m / z(ESI):408.15[M+H] + .

[0602] Example 128 Synthesis of compound 128(R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxybutane-2-yl)urea

[0603]

[0604] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (R)-2-aminobutanol (13 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 23 mg of the yellow product (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxybutane-2-yl)urea (compound 128), with a yield of 45%. 1 H NMR(500MHz,DMSO-d6)δ9.07(s,1H),8.52(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.02(d,J=2.0Hz,1H) ,7.88(d,J=1.4Hz,1H),7.45(s,0.25H),7.30(s,0.5H),7.15(s,0.25H),7.11(dd,J=7.3,2.1Hz,1H),6. 59(s,1H),6.57(d,J=7.7Hz,1H),4.75(t,J=5.3Hz,1H),3.99(s,3H),3.60–3.54(m,1H),3.45(dt,J=9.2 ,4.6Hz,1H),3.37(dd,J=10.7,5.4Hz,1H),1.63–1.55(m,1H),1.44–1.36(m,1H),0.89(t,J=7.4Hz,3H). MSm / z(ESI):422.16[M+H] + .

[0605] Example 129 Synthesis of (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxybutane-2-yl)urea compound 129

[0606]

[0607] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (S)-2-aminobutanol (13 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxybutane-2-yl)urea (compound 129), with a yield of 49%. 1 H NMR(500MHz,DMSO-d6)δ9.07(s,1H),8.52(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.02(d,J=2.0Hz,1H), 7.88(d,J=1.4Hz,1H),7.45(s,0.25H),7.30(s,0.5H),7.15(s,0.25H),7.11(dd,J=7.3,2.1Hz,1H),6.58( d,J=10.6Hz,2H),4.75(t,J=5.3Hz,1H),3.99(s,3H),3.57(td,J=7.8,4.2Hz,1H),3.45(dt,J=9.3,4.6Hz, 1H), 3.37 (dd, J=10.7, 5.4Hz, 1H), 1.59 (td, J=13.4, 6.7Hz, 1H), 1.45–1.36 (m, 1H), 0.89 (t, J=7.4Hz, 3H). MS m / z(ESI):422.16[M+H] + .

[0608] Example 130 Synthesis of compound 130 (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-phenylpropane-2-yl)urea

[0609]

[0610] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (S)-2-amino-3-phenyl-1-propanol (21 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 30 mg of the yellow product (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-phenylpropan-2-yl)urea (compound 130), with a yield of 52%. 1 H NMR (500MHz, DMSO-d6) δ9.10(s,1H),8.52(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.02(d,J=2.0Hz,1H),7.87(d, J=1.3Hz,1H),7.45(s,0.25H),7.30(d,J=3.1Hz,2H),7.27(s,2H),7.26(s,0.5H),7.19(t,J=6.9Hz,1H),7.15(s, 0.25H),7.12(dd,J=7.3,2.1Hz,1H),6.70(d,J=6.8Hz,1H),6.55(s,1H),4.91(t,J=5.2Hz,1H),3.99(s,3H),3.88 (d, J=7.0Hz, 1H), 3.40 (ddd, J=19.2, 10.6, 5.7Hz, 2H), 2.88 (dd, J=13.6, 6.4Hz, 1H), 2.73 (dd, J=13.6, 7.5Hz, 1H). MS m / z(ESI):484.18[M+H] + .

[0611] Example 131 Synthesis of compound 131 (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-phenylpropane-2-yl)urea

[0612]

[0613] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (R)-2-amino-3-phenyl-1-propanol (21 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 27 mg of the yellow product (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-phenylpropan-2-yl)urea (compound 131), with a yield of 47%. 1 H NMR (500MHz, DMSO-d6) δ9.11(s,1H),8.52(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.02(d,J=2.0Hz,1H),7.87(d,J =1.4Hz,1H),7.45(s,0.25H),7.30(t,J=3.8Hz,2H),7.27(d,J=3.9Hz,2H),7.26(s,0.5H),7.21–7.17(m,1H),7.15 (s,0.25H),7.12(dd,J=7.3,2.1Hz,1H),6.73(d,J=5.6Hz,1H),6.55(s,1H),4.91(t,J=5.2Hz,1H),3.99(s,3H),3. 92–3.84(m,1H),3.44–3.39(m,1H),3.39–3.35(m,1H),2.88(dd,J=13.6,6.4Hz,1H),2.73(dd,J=13.6,7.5Hz,1H). MS m / z(ESI):484.18[M+H] + .

[0614] Example 132 Synthesis of compound 132 (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-methylbutane-2-yl)urea

[0615]

[0616] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (R)-1-(1-hydroxy-3-methylbut-2-yl)urea (15 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 20 mg of the yellow product (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-methylbutane-2-yl)urea (compound 132), with a yield of 38%. 1 H NMR(500MHz,DMSO-d6)δ9.09(s,1H),8.52(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.02(d,J=2 .0Hz,1H),7.88(d,J=1.4Hz,1H),7.45(s,0.25H),7.30(s,0.5H),7.15(s,0.25H),7.11(dd,J=7 .3,2.1Hz,1H),6.58(s,2H),4.69(t,J=5.2Hz,1H),3.99(s,3H),3.50(tdd,J=15.6,10.3,5.1Hz ,2H), 3.39(dt,J=10.8,5.5Hz,1H), 1.90(dd,J=13.1,6.6Hz,1H), 0.90(dd,J=10.6,6.8Hz,6H). MS m / z(ESI):436.18[M+H] + .

[0617] Example 133 Synthesis of compound 133 (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-methylbutane-2-yl)urea

[0618]

[0619] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (S)-1-(1-hydroxy-3-methylbut-2-yl)urea (15 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 22 mg of the yellow product (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-methylbutane-2-yl)urea (compound 133), with a yield of 42%. 1 H NMR(500MHz,DMSO-d6)δ9.09(s,1H),8.52(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.02(d, J=2.0Hz,1H),7.88(d,J=1.4Hz,1H),7.45(s,0.25H),7.30(s,0.5H),7.16(s,0.25H),7.11 (dd,J=7.3,2.1Hz,1H),6.58(s,2H),4.69(t,J=5.2Hz,1H),3.99(s,3H),3.55–3.45(m,2H) ,3.39(dt,J=10.8,5.5Hz,1H), 1.90(dd,J=13.0,6.7Hz,1H), 0.90(dd,J=10.5,6.8Hz,6H). MS m / z(ESI):436.18[M+H] + .

[0620] Example 134 Synthesis of compound 134: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1-(hydroxymethyl)cyclopropyl)methyl)urea

[0621]

[0622] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (1-(aminomethyl)cyclopropyl)methanol (14 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1-(hydroxymethyl)cyclopropyl)methyl)urea (compound 134), with a yield of 48%. 1 H NMR(500MHz,DMSO-d6)δ9.24(s,1H),8.53(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H), 8.03(d,J=1.9Hz,1H),7.89(d,J=1.4Hz,1H),7.47(s,0.25H),7.32(s,0.5H),7.17( s,0.25H),7.12(dd,J=7.3,2.0Hz,1H),6.92(s,1H),6.59(s,1H),4.65(t,J=5.6Hz ,1H),3.99(s,3H),3.32(d,J=5.6Hz,2H),3.19(d,J=5.6Hz,2H),0.44–0.36(m,4H). MS m / z(ESI):434.16[M+H] + .

[0623] Example 135 Synthesis of compound 135 (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2,3-dihydroxypropyl)urea

[0624]

[0625] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (S)-3-amino-1,2-propanediol (13 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 25 mg of the yellow product (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2,3-dihydroxypropyl)urea (compound 135), with a yield of 49%. 1 H NMR (500MHz, DMSO-d6) δ9.29(s,1H),8.53(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.03(d,J=1.8 Hz,1H),7.89(d,J=1.2Hz,1H),7.47(s,0.25H),7.33(s,0.5H),7.18(s,0.25H),7.12(dd,J=7.3, 2.0Hz,1H),6.87(s,1H),6.60(s,1H),4.92(d,J=4.8Hz,1H),4.65(t,J=5.7Hz,1H),3.99(s,3H), 3.55(dq,J=11.1,5.6Hz,1H), 3.39(dd,J=10.9,5.5Hz,2H), 3.35–3.30(m,1H), 3.08–3.01(m,1H). MS m / z(ESI):424.14[M+H] + .

[0626] Example 136 Synthesis of compound 136(R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2,3-dihydroxypropyl)urea

[0627]

[0628] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (R)-3-amino-1,2-propanediol (13 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 23 mg of the yellow product (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2,3-dihydroxypropyl)urea (compound 136), with a yield of 45%. 1 H NMR (500MHz, DMSO-d6) δ9.23(s,1H),8.53(d,J=7.2Hz,1H),8.50(d,J=1.8Hz,1H),8.03(d,J=1 .3Hz,1H),7.89(s,1H),7.46(s,0.25H),7.31(s,0.5H),7.16(s,0.25H),7.12(dd,J=7.2,1.6H z,1H),6.79(s,1H),6.61(s,1H),4.90(d,J=4.8Hz,1H),4.63(t,J=5.6Hz,1H),4.00(s,3H),3. 56(dd,J=10.8,5.4Hz,1H), 3.40(dd,J=10.5,5.0Hz,2H), 3.36–3.30(m,1H), 3.09–3.02(m,1H). MS m / z(ESI):424.14[M+H] + .

[0629] Example 137 Synthesis of compound 137 (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-hydroxypropyl)urea

[0630]

[0631] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (R)-1-(2-hydroxypropyl)urea (11 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 26 mg of the yellow product (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-hydroxypropyl)urea (compound 137), with a yield of 53%. 1 HNMR(500MHz,DMSO-d6)δ9.23(s,1H),8.53(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.03(d,J=2 .0Hz,1H),7.89(d,J=1.4Hz,1H),7.46(s,0.25H),7.32(s,0.5H),7.17(s,0.25H),7.12(dd,J=7 .3,2.1Hz,1H),6.83(s,1H),6.60(s,1H),4.80(d,J=4.7Hz,1H),3.99(s,3H),3.71(ddd,J=11.1 ,6.3,4.7Hz,1H),3.19(ddd,J=13.2,6.1,4.7Hz,1H),3.05–2.98(m,1H),1.08(d,J=6.2Hz,3H). MS m / z(ESI):408.15[M+H] + .

[0632] Example 138 Synthesis of compound 138 (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-hydroxypropyl)urea

[0633]

[0634] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (S)-1-(2-hydroxypropyl)urea (11 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 24 mg of the yellow product (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-hydroxypropyl)urea (compound 138), with a yield of 49%. 1 H NMR (500MHz, DMSO-d6) δ9.24(s,1H),8.53(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.03(d,J=2 .0Hz,1H),7.89(d,J=1.4Hz,1H),7.47(s,0.25H),7.32(s,0.5H),7.17(s,0.25H),7.12(dd,J=7 .3,2.1Hz,1H),6.84(s,1H),6.61(s,1H),4.81(d,J=4.7Hz,1H),3.99(s,3H),3.71(ddd,J=11.1 ,6.3,4.7Hz,1H),3.19(ddd,J=13.2,6.1,4.7Hz,1H),3.05–2.98(m,1H),1.08(d,J=6.2Hz,3H). MS m / z(ESI):408.15[M+H] + .

[0635] Example 139 Synthesis of compound 139: 1-(1-cyanochloropropyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea

[0636]

[0637] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), 1-amino-1-cyclopropyl cyanide hydrochloride (17 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 24 mg of the yellow product 1-(1-cyanochloropropyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (compound 139), with a yield of 48%. 1 H NMR(500MHz,DMSO-d6)δ9.58(s,1H),8.56(d,J=7.2Hz,1H),8.51(d,J=2.1H z,1H),8.05(d,J=2.0Hz,1H),7.93(d,J=1.5Hz,1H),7.92(s,1H),7.47(s,0 .25H),7.33(s,0.5H),7.18(s,0.25H),7.16(dd,J=7.3,2.0Hz,1H),6.67(s ,1H),4.00(s,3H),1.50(dd,J=8.1,5.4Hz,2H),1.24(dd,J=8.2,5.5Hz,2H). MS m / z(ESI):415.13[M+H] + .

[0638] Example 140 Synthesis of compound 140: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-a]pyridin-2-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)urea

[0639]

[0640] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), 3-amino-1,1,1-trifluoropropane-2-ol (18 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 27 mg of the yellow product 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-a]pyridin-2-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)urea (compound 140), with a yield of 49%. 1 H NMR(500MHz,DMSO-d6)δ9.47(s,1H),8.54(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H), 8.04(d,J=2.0Hz,1H),7.90(d,J=1.5Hz,1H),7.48(s,0.25H),7.33(s,0.5H),7.19( s,0.25H),7.14(dd,J=7.3,2.1Hz,1H),7.09(s,1H),6.61(d,J=6.3Hz,2H),4.10(d ,J=4.1Hz,1H),3.99(s,3H),3.58(ddd,J=13.8,6.5,4.0Hz,1H),3.24–3.17(m,1H). MS m / z(ESI):462.12[M+H] + .

[0641] Example 141 Synthesis of compound 141 (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-fluoro-3-hydroxypropyl)urea

[0642]

[0643] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (R)-3-amino-2-fluoropropane-1-ol (13 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 28 mg of the yellow product (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-fluoro-3-hydroxypropyl)urea (compound 141), with a yield of 55%. 1 H NMR(500MHz,DMSO-d6)δ9.24(s,1H),8.54(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.03(d ,J=2.0Hz,1H),7.90(d,J=1.4Hz,1H),7.45(s,0.25H),7.31(s,0.5H),7.16(s,0.25H),7. 13(dd,J=7.3,2.0Hz,1H),6.91(s,1H),6.60(s,1H),5.01(t,J=5.7Hz,1H),4.66–4.61(m, 0.5H), 4.56–4.51 (m, 0.5H), 4.00 (s, 3H), 3.67–3.47 (m, 3H), 3.40 (dd, J = 10.7, 3.6Hz, 1H). MS m / z(ESI):426.14[M+H] + .

[0644] Example 142 Synthesis of (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-fluoro-3-hydroxypropyl)urea compound 142

[0645]

[0646] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), (S)-3-amino-2-fluoropropane-1-ol (13 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 23 mg of the yellow product (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-fluoro-3-hydroxypropyl)urea (compound 142), with a yield of 45%. 1 H NMR (500MHz, DMSO-d6) δ9.24(s,1H),8.54(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.03(d,J=1 .9Hz,1H),7.90(d,J=1.4Hz,1H),7.45(s,0.25H),7.31(s,0.5H),7.16(s,0.25H),7.13(dd,J= 7.3,2.0Hz,1H),6.90(s,1H),6.60(s,1H),5.01(t,J=5.7Hz,1H),4.63(dd,J=6.8,5.1Hz,0.5H ), 4.53 (dd, J = 6.8, 5.2 Hz, 0.5H), 3.99 (s, 3H), 3.66–3.45 (m, 3H), 3.39 (dd, J = 12.9, 5.8 Hz, 1H). MS m / z(ESI):426.14[M+H] + .

[0647] Example 143 Synthesis of compound 143: 1-(2,2-difluoro-3-hydroxypropyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea

[0648]

[0649] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirring at room temperature, phenyl(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), 3-amino-2,2-difluoroprop-1-ol (16 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added. The reaction mixture was incubated at 60 °C for 1 hour. After the reaction was complete, the mixture was neutralized with 10 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na₂SO₄. After vacuum distillation of the organic phase, a crude product was obtained. The crude product was then subjected to silica gel column chromatography to obtain 40 mg of the yellow product 1-(2,2-difluoro-3-hydroxypropyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)urea (compound 143), with a yield of 75%. 1 H NMR(500MHz,DMSO-d6)δ9.30(s,1H),8.55(d,J=7.2Hz,1H),8.51(d,J=2.1H z,1H),8.03(d,J=2.0Hz,1H),7.91(d,J=1.4Hz,1H),7.45(s,0.25H),7.30(s ,0.5H),7.16(s,0.25H),7.14(dd,J=7.3,2.1Hz,1H),6.98(s,1H),6.61(s,1 H), 5.57 (t, J = 6.3Hz, 1H), 3.99 (s, 3H), 3.68 (ddt, J = 20.2, 13.5, 6.7Hz, 4H). MS m / z(ESI): 444.13 [M+H] + .

[0650] Example 144 Synthesis of compound 144: 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((3-(hydroxymethyl)oxetane-3-yl)methyl)urea

[0651]

[0652] In a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Then, under stirrin...

Claims

1. A PI3Kγ kinase inhibitor selected from the following compounds or pharmaceutically acceptable salts thereof: Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Compound 7 Compound 8 Compound 9 Compound 10 Compound 11 Compound 12 Compound 13 Compound 14 Compound 15 Compound 16 Compound 18 Compound 19 Compound 20 Compound 21 Compound 22 Compound 23 Compound 24 Compound 28 Compound 29 Compound 33 Compound 34 Compound 35 Compound 36 Compound 37 Compound 38 Compound 39 Compound 40 Compound 41 Compound 42 Compound 43 Compound 44 Compound 45 Compound 46 Compound 47 Compound 48 Compound 49 Compound 50 Compound 51 Compound 52 Compound 53 Compound 54 Compound 55 Compound 56 Compound 58 Compound 59 Compound 60 Compound 62 Compound 63 Compound 64 Compound 65 Compound 71 Compound 73 Compound 74 Compound 75 Compound 76 Compound 77 Compound 79 Compound 80 Compound 83 Compound 85 Compound 86 Compound 88 Compound 89 Compound 90 Compound 91 Compound 92 Compound 93 Compound 95 Compound 98 Compound 99 Compound 100 Compound 101 Compound 106 Compound 107 Compound 108 Compound 109 Compound 111 Compound 112 Compound 135 Compound 136 Compound 141 Compound 142 Compound 143 Compound 146 Compound 147 Compound 148 Compound 149 Compound 150 Compound 151 Compound 152 Compound 154 Compound 155 Compound 156 Compound 157 Compound 158 Compound 159 Compound 160 Compound 161 Compound 162 Compound 163 Compound 164 Compound 166 Compound 167 Compound 168 Compound 169 Compound 170 Compound 171 Compound 172 Compound 173 Compound 174 Compound 175 Compound 176 Compound 177 Compound 178 Compound 179 Compound 180 Compound 181 Compound 182 Compound 186 Compound 189 Compound 190 Compound 191 Compound 192 Compound 195 Compound 196 Compound 199 Compound 200 Compound 201 Compound 202, Compound 203, Compound 204.

2. A pharmaceutical composition comprising the PI3Kγ kinase inhibitor as claimed in claim 1, and a pharmaceutically acceptable carrier or excipient, or optionally other therapeutic agents.

3. Use of the PI3Kγ kinase inhibitor of claim 1 in the preparation of a medicament for treating PI3Kγ-mediated diseases selected from cancer, inflammatory diseases or autoimmune diseases.

4. The use as described in claim 3, wherein the cancer is selected from one or more of the following: blood cancer, brain cancer, gastrointestinal cancer, skin cancer, urinary system cancer, head and neck cancer, uterine cancer, or adenocarcinoma.

5. The use as described in claim 3, wherein the inflammatory disease or autoimmune disease is selected from one or more of the following: asthma, emphysema, allergy, dermatitis, arthritis, psoriasis, lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, eczema, scleroderma, or multiple sclerosis.

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