Compounds for treatment of PI3K gamma mediated diseases and uses thereof

Abstract

The invention relates to a PI3K gamma kinase inhibitor which is a compound shown in a formula (I) or pharmaceutically acceptable salt, solvate, polymorphic substance, ester, acid, isomer, metabolite or prodrug thereof, and # imgabs0 # R1, R2 and R3 are defined in the specification. The invention further relates to application of the PI3K gamma kinase inhibitor in preparation of drugs for treating diseases related to PI3K gamma kinase and related signal path activity. # imgabs1 #

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to compounds for treating cancer, inflammatory diseases or autoimmune diseases and uses thereof. Background Art

[0002] Phosphatidylinositol 3-kinase (PI3K) plays an important role in cell growth, development, division, differentiation, and apoptosis, and is closely associated with the development and progression of tumors. Based on their structure and substrate specificity, PI3K can be divided into three types: type I, type II, and type III. Type I PI3K is the most extensively studied subtype and is most closely associated with tumors. Type I PI3K is further divided into types IA and IB. Type IA PI3K has three catalytic subunits: p110α, p110β, and p110δ. Type I PI3K has a single catalytic subunit: p110γ. Depending on the catalytic subunit, these PI3Ks are designated PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. 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, so the development of targeted p110γ inhibitors will become a research hotspot in the future.

[0003] The PI3Kγ signaling pathway of macrophages promotes immunosuppression by inhibiting the activation of T cells. Inhibiting PI3Kγ can activate the immune response and significantly inhibit the growth of transplanted tumors. Preclinical studies have shown that PI3Kγ plays a very important 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 anti-tumor macrophages (M1), downregulating immunosuppression, increasing immune activity, and ultimately leading to the activation and proliferation of cytotoxic T cells.

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

[0005] Therefore, the development of PI3Kγ inhibitors can change 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 dysfunction or neurological diseases. Summary of the Invention

[0006] The present disclosure aims 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 a subject.

[0007] In one aspect, the present 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, represents a fused heteroaryl group having 2 or 3 nitrogen atoms, preferably selected from: More preferably selected from

[0010] R1 is selected from H, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkyl, C 1-6 Alkylsulfonamide or C 3-6 Cycloalkylsulfonamide, preferably hydroxyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkylsulfonamide or C 3-6 a cycloalkylsulfonyl group, more preferably a methoxy group;

[0011] R2 is selected from H, halogen or C 1-6 Alkoxy, preferably C 1-3 an alkoxy group, more preferably a methoxy group;

[0012] R3 is selected from

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

[0014] W is selected from a 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 Halogenated alkyl, C 1-6 Alkylamino, C 3-6 Cycloalkylamino, C 1-6 Haloalkylamino, C 1-6 Hydroxyalkylamino, 5-7 membered heterocyclic group (such as morpholinyl, piperazinyl, piperidinyl, etc.), 5-7 membered heterocyclic group C 1-3 alkyl (e.g., morpholinomethyl, etc.), aryl (e.g., phenyl, etc.), heteroaryl (e.g., pyridyl, furyl, pyrimidinyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, tetrazolyl, etc.), 5-7 membered heterocycloalkylamino (e.g., tetrahydropyranylamino, morpholinylamino, piperidinylamino, piperazinylamino, etc.), or heteroarylamino (e.g., pyridinylamino, thiazolylamino, etc.), which are optionally substituted by 1-3 independently R x Group substitution, R x Independently selected from hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino;

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

[0017] R6 and R7 are each independently selected from hydroxy, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or aralkyl (such as benzyl, etc.), or R6 and R7 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl or 5-7 membered heterocyclic group (eg pyrrolidinyl, etc.), which is optionally substituted by 1-3 independently R y Group substitution, R y Independently selected from oxo, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 hydroxyalkyl or 5-7 membered heterocyclic group (e.g., morpholinyl, etc.).

[0018] In a preferred aspect, the present 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 as defined above,

[0021] Wherein, the heterocyclic group described in the present application is selected from oxetanyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyranyl, and the heteroaryl group is selected from pyridinyl, furanyl, pyrimidinyl, thienyl, 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 haloalkyl, morpholinyl, piperazinyl, phenyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl or tetrazolyl, which is optionally substituted by 1-3 independently R x Group substitution, R x Independently selected from C 1-6 R5 is a substituent on an alkylene group, wherein m is 0, 1 or 2, and R5 is independently selected from hydroxyl or halogen, or two R5 together with the carbon atom to which they are attached form C 3-6 cycloalkyl or oxetanyl.

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

[0024] In another embodiment, W is O; R4 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-3 alkyl, phenyl, pyridyl or pyrazolyl, which is optionally substituted by 1-3 independently R x Group substitution, R x independently selected from cyano, halogen, C 1-6 Alkyl or C 1-6 Alkoxy; 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 Haloalkylamino, C 1-6hydroxyalkylamino, tetrahydropyranylamino, morpholinylamino, piperidinylamino, piperazinylamino, pyridinylamino or thiazolylamino, which is optionally substituted by 1-3 independently R x Group substitution, R x Independently selected from C 1-6 Alkyl; 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 Halogenated alkyl, C 1-6 alkylamino, piperidinyl, morpholinomethyl, phenyl, furanyl, thienyl or imidazolyl, which is optionally substituted by 1-3 independently R x Group substitution, R x Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino; m is 0.

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

[0028] In another preferred aspect, the present 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] wherein 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, the present 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 as 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, or R6 and R7 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl or pyrrolidinyl, which is optionally substituted by 1-3 independently R y Group substitution, Ry Independently selected from oxo, hydroxy, amino, C 1-3 Alkyl, C 1-3 hydroxyalkyl or morpholinyl,

[0035] The heterocyclic group described in the present application is selected from oxetanyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyranyl, and the heteroaryl group is selected from pyridinyl, furanyl, pyrimidinyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, tetrazolyl or thiazolyl.

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

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

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

[0046] In other aspects, the present disclosure relates to the use of the aforementioned PI3Kγ kinase inhibitor in the preparation of a medicament for treating a PI3Kγ-mediated disease selected from cancer, inflammatory disease or autoimmune disease. wherein the cancer is selected from one or more of the following: blood cancer, brain cancer, gastrointestinal cancer, skin cancer, urinary system cancer, 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, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, leiomyosarcoma, cervical cancer, uterine cancer, endometrial cancer, bladder cancer, epithelial cancer, squamous cell carcinoma, adenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, bile duct cancer, neuroendocrine cancer, 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The results show the effect of the test compounds on the body weight of mice in the MC38 mouse autoimmune model.

[0048] Figure 2 The inhibitory effect of the tested compounds on tumors was shown in the MC38 mouse autoimmune model.

[0049] Figure 3 The results show the tumor inhibition rate of the tested compounds in the MC38 mouse autoimmune model. DETAILED DESCRIPTION

[0050] the term

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

[0052] Unless otherwise indicated, the present invention employs conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the skill of the art. Unless specific definitions are provided, the nomenclature and laboratory procedures and techniques associated with analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are those known to those skilled in the art. In general, the aforementioned techniques and steps can be implemented by conventional methods well known in the art and described in various general and more specific literature, which are cited and discussed in this specification.

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

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

[0055] The term "alkoxyalkyl" refers to an alkyl group, as defined herein, substituted by an alkoxy group, as defined herein.

[0056] The term "cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen. Cycloalkyl includes a group having 3-12 ring atoms. According to structure, cycloalkyl can be a monovalent group or a divalent group (e.g., cycloalkylidene). In the present invention, cycloalkyl is preferably a cycloalkyl having 3-8 carbon atoms, more preferably a "low cycloalkyl" having 3-6 carbon atoms. The example of cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and adamantyl.

[0057] The term "alkyl (cycloalkyl)" or "cycloalkylalkyl" refers to an alkyl group as defined herein substituted with a cycloalkyl group as defined herein. Non-limiting examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

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

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

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

[0061] The term "heteroaryl" refers to an aromatic group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The N-containing "heteroaryl" moiety refers to an aromatic group in which at least one skeletal atom on the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monovalent group or a divalent group (i.e., a heteroarylidene group). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindole, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, and furopyridinyl.

[0062] The term "alkyl (aryl)" or "aralkyl" refers to an alkyl group as defined herein substituted with an aryl group as defined herein. Non-limiting examples of alkyl (aryl) groups include benzyl, phenethyl, and the like.

[0063] The term "alkyl(heteroaryl)" or "heteroarylalkyl" means an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein.

[0064] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein where one or more of the backbone chain atoms is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or a combination thereof. The heteroatom(s) may be located at any position within the heteroalkyl group or at the position where the heteroalkyl group is attached to the rest of the molecule.

[0065] As used herein, the term "heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic ring in which one or more of the atoms forming the ring are heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring can be a monocyclic or polycyclic ring consisting of three, four, five, six, seven, eight, nine, or more than nine atoms. The heterocycloalkyl ring can be optionally substituted. Examples of heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiinane, 1,4-oxathiinane, 1,4-oxathiinane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbital Acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazolidine, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolane. Depending on the structure, the heterocycloalkyl group can be a monovalent group or a divalent group (i.e., a heterocycloalkylene group).

[0066] The term "alkyl(heterocycloalkyl)" or "heterocycloalkylalkyl" means an alkyl group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0067] The term "alkoxy(heterocycloalkyl)" or "heterocycloalkylalkoxy" means an alkoxy group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0068] The term "halo" 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 certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from one another.

[0070] The term "hydroxy" refers to an -OH group.

[0071] The term "cyano" refers to a -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 (attached through a ring carbon), and heterocyclyl (attached through a ring carbon).

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

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

[0075] The term "alkanoyl" refers to a -CO-NH-R group, wherein R is alkyl as defined herein.

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

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

[0078] The terms "arylamino" and "diarylamino" refer to amino substituents further substituted with one or two aryl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen, lower alkyl, or aryl, wherein N is attached to at least one or two aryl groups, respectively.

[0079] The term "cycloalkylamino" refers to an amino substituent further substituted with one or two cycloalkyl groups as defined herein.

[0080] The term "heteroalkylamino" refers to an amino substituent further substituted with one or two heteroalkyl groups as defined herein.

[0081] The term "aralkylamino" herein refers to the group -NRR' wherein R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.

[0082] The term "heteroarylamino" refers to an amino substituent further substituted with one or two heteroaryl groups as defined herein.

[0083] The term "heterocycloalkylamino" refers to an amino group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0084] The term "alkylaminoalkyl" means an alkyl group, as defined herein, substituted with an alkylamino group, as defined herein.

[0085] The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups.

[0086] The term "aminoalkoxy" refers to an alkoxy substituent further substituted with one or more amino groups.

[0087] The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxy groups.

[0088] The term "cyanoalkyl" refers to an alkyl substituent further substituted with one or more cyano groups.

[0089] The term "acyl" refers to a monovalent atomic group remaining after removing a hydroxyl group from an organic or inorganic oxygen-containing acid, and has the general formula RM(O)-, where M is usually C.

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

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

[0092] The term "arylcarbonyl" means a carbonyl group, as defined herein, substituted with an aryl group, as defined herein.

[0093] The term "alkoxycarbonyl" refers to a carbonyl group further substituted with an alkoxy group.

[0094] The term "heterocycloalkylcarbonyl" refers to a carbonyl group further substituted with a heterocycloalkyl group.

[0095] The terms "alkylaminocarbonyl," "cycloalkylaminocarbonyl," "arylaminocarbonyl," "aralkylaminocarbonyl," and "heteroarylaminocarbonyl" refer to a carbonyl group, as defined herein, substituted with an alkylamino group, a cycloalkylamino group, an arylamino group, an aralkylamino group, or a heteroarylamino group, as defined herein, respectively.

[0096] The term "alkylcarbonylalkyl" or "alkanoylalkyl" refers to an alkyl group further substituted with an alkylcarbonyl group.

[0097] The term "alkylcarbonylalkoxy" or "alkanoylalkoxy" refers to an alkoxy group further substituted with an alkylcarbonyl group.

[0098] The term "heterocycloalkylcarbonylalkyl" refers to an alkyl group further substituted with a heterocycloalkylcarbonyl group.

[0099] The term "mercapto" refers to a -SH group. The term "alkylthio" refers to a mercapto group, as defined herein, substituted with an alkyl group, as defined herein.

[0100] The term "sulfone" or "sulfonyl" refers to the functional group of sulfonic acid after losing the hydroxyl group, specifically refers to the -S(=O)2- group.

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

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

[0103] The term "alkylsulfoxide" or "alkylsulfinyl" refers to an alkyl-S(=O)- group.

[0104] The term "alkylsulfonyl" or "alkylsulfonyl" refers to -S(=O)2-R, where R is alkyl.

[0105] The term "alkylaminosulfonyl" refers to a sulfone group, as defined herein, substituted with an alkylamino group, as defined herein.

[0106] The terms "alkylsulfonylamino" or "alkylsulfonamido", and "cycloalkylsulfonylamino" or "cycloalkylsulfonamido" refer to an amino group as defined herein substituted with an alkylsulfonyl or cycloalkylsulfonyl group as defined herein, i.e., -NH-S(=O)2-R, wherein 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 "optionally" refers to one or more events described later that may or may not occur, and includes both events that occur and events that do not occur. The term "optionally substituted" or "substituted" refers to that the group mentioned can be substituted by one or more additional groups, each of which is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methylsulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc. Among them, the amino protecting group is preferably selected from pivaloyl, tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl, etc.

[0109] As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, esters, acids, isomers, metabolites, prodrugs, and isotopically labeled derivatives of the disclosed compounds.

[0110] The term "pharmaceutically acceptable salt" herein refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesirable toxicological effects, i.e., is suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, and is 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 free acid or free base form of the purified compound with a suitable base or acid, respectively. 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 provided 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 by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionic acid salt, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, naphthalene-m,n-disulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0111] "Solvate" or "solvate" refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap fixed molar ratios of solvent molecules in their crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. "Hydrates" are formed by the association of one or more water molecules with one molecule of the substance, wherein the water remains in its molecular form as HO.

[0112] A "metabolite" of a compound disclosed herein is a derivative of the compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. The term "metabolized," as used herein, refers to the sum of processes by which a particular substance is altered by an organism (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Thus, an enzyme can produce a specific structural transformation into a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while diphosphoglucosyltransferase catalyzes 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 the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds. Both methods are known in the art. In some embodiments, metabolites of the compound are formed by an oxidation process and correspond to the corresponding hydroxyl-containing compound. In some embodiments, the compound is metabolized to a pharmaceutically active metabolite.

[0113] As used herein, the term "modulate" refers to interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0114] The term "prodrug" or "prodrug" refers to a derivative that may not be pharmacologically active but, in certain circumstances, can be administered orally or parenterally and thereafter metabolized in vivo to form a pharmacologically active compound of the present invention. Non-limiting examples of prodrugs include esters, carbonates, half-esters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals, and ketals, among others.

[0115] An "effective amount" refers to an amount of a drug or pharmaceutical formulation that will elicit the biological or medical response of a tissue, system, animal, or human being, for example, that is being studied by a researcher or physician. Furthermore, the term "therapeutically effective amount" refers to any amount that results in treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject that has not received that amount. Also included within the scope of the term is an amount effective to enhance normal physiological function.

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

[0117] As used herein, the term "prevention" includes both preventing or slowing the onset of clinically significant disease development or preventing or slowing the onset of a preclinically significant disease stage in an at-risk individual. This includes prophylactic treatment of individuals at risk of developing disease.

[0118] The term "subject" or "patient" includes organisms that can suffer from a disorder or a disorder associated with reduced or insufficient programmed cell death (apoptosis) or that can otherwise benefit from the administration of the compounds of the invention, such as humans and non-human animals. Preferred humans include human patients suffering from or prone to suffering from a disorder 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 paper 50 It refers to the drug concentration required to inhibit 50% of cell growth, that is, the drug concentration when the growth of 50% of cells (such as cancer cells) is inhibited or controlled.

[0120] IC used in this article 50 It refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of the maximal effect in the assay in which the effect is measured.

[0121] The EC used in this paper 50 It refers to the dose, concentration or amount of a test compound that elicits a dose-dependent response that elicits 50% of the maximal expression of a specific response induced, stimulated or potentiated by the particular test compound.

[0122] Kinase inhibitors

[0123] The present 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, represents a fused heteroaryl group having 2 or 3 nitrogen atoms, preferably selected from: More preferably selected from

[0126] R1 is selected from H, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkyl, C 1-6 Alkylsulfonamide or C 3-6 Cycloalkylsulfonamide, preferably hydroxyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkylsulfonamide or C 3-6 a cycloalkylsulfonyl group, more preferably a methoxy group;

[0127] R2 is selected from H, halogen or C 1-6 Alkoxy, preferably C 1-3 an alkoxy group, more preferably a methoxy group;

[0128] R3 is selected from

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

[0130] W is selected from a 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 Halogenated alkyl, C 1-6 Alkylamino, C 3-6 Cycloalkylamino, C 1-6 Haloalkylamino, C 1-6 Hydroxyalkylamino, 5-7 membered heterocyclic group (such as morpholinyl, piperazinyl, piperidinyl, etc.), 5-7 membered heterocyclic group C 1-3 alkyl (e.g., morpholinomethyl, etc.), aryl (e.g., phenyl, etc.), heteroaryl (e.g., pyridyl, furyl, pyrimidinyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, tetrazolyl, etc.), 5-7 membered heterocycloalkylamino (e.g., tetrahydropyranylamino, morpholinylamino, piperidinylamino, piperazinylamino, etc.), or heteroarylamino (e.g., pyridinylamino, thiazolylamino, etc.), which are optionally substituted by 1-3 independently Rx Group substitution, R x Independently selected from hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino;

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

[0133] R6 and R7 are each independently selected from hydroxy, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or aralkyl (such as benzyl, etc.), or R6 and R7 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl or 5-7 membered heterocyclic group (eg pyrrolidinyl, etc.), which is optionally substituted by 1-3 independently R y Group substitution, R y Independently selected from oxo, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 hydroxyalkyl or 5-7 membered heterocyclic group (e.g., morpholinyl, etc.).

[0134] In a preferred aspect, the present 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 as defined above,

[0137] Wherein, the heterocyclic group described in the present application is selected from oxetanyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyranyl, and the heteroaryl group is selected from pyridinyl, furanyl, pyrimidinyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, tetrazolyl or thiazolyl.

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

[0139] R1 is selected from H, hydroxy, halogen, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkyl, C 1-6 Alkylsulfonamide or C 3-6 Cycloalkylsulfonamide, preferably hydroxyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkylsulfonamide or C 3-6 a cycloalkylsulfonyl group, more preferably a methoxy group;

[0140] R2 is selected from H, halogen or C 1-6 Alkoxy, preferably C 1-3 an alkoxy group, more preferably a methoxy group;

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

[0142] W is selected from a 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 Halogenated alkyl, C 1-6 Alkylamino, C 3-6 Cycloalkylamino, C 1-6 Haloalkylamino, C 1-6 hydroxyalkylamino, morpholinyl, piperazinyl, piperidinyl, morpholinomethyl, phenyl, pyridinyl, furanyl, pyrimidinyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, tetrazolyl, tetrahydropyranylamino, morpholinylamino, piperidinylamino, piperazinylamino, pyridinylamino, or thiazolylamino, which is optionally substituted by 1-3 independently R x Group substitution, R x Independently selected from hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino;

[0144] R5 is a substituent on an alkylene group, wherein m is 0, 1 or 2, and R5 is independently selected from hydroxyl or halogen, or two R5 together with the carbon atom to which they are attached form C 3-6 cycloalkyl or oxetanyl.

[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 haloalkyl, morpholinyl, piperazinyl, phenyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl or tetrazolyl, which is optionally substituted by 1-3 independently R x Group substitution, R x Independently selected from C 1-6 R5 is a substituent on an alkylene group, wherein m is 0, 1 or 2, and R5 is independently selected from hydroxyl or halogen, or two R5 together with the carbon atom to which they are attached form C 3-6 cycloalkyl or oxetanyl.

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

[0147] In another embodiment, W is O; R4 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-3 alkyl, phenyl, pyridyl or pyrazolyl, which is optionally substituted by 1-3 independently R x Group substitution, R x independently selected from cyano, halogen, C 1-6 Alkyl or C 1-6 Alkoxy; 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 Haloalkylamino, C 1-6 hydroxyalkylamino, tetrahydropyranylamino, morpholinylamino, piperidinylamino, piperazinylamino, pyridinylamino or thiazolylamino, which is optionally substituted by 1-3 independently R x Group substitution, R x Independently selected from C 1-6 Alkyl; 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 Halogenated alkyl, C 1-6 alkylamino, piperidinyl, morpholinomethyl, phenyl, furanyl, thienyl or imidazolyl, which is optionally substituted by 1-3 independently R x Group substitution, R x Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino; m is 0.

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

[0151] In another preferred aspect, the present 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] wherein 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, the present 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 as defined above.

[0157] Specifically, Selected from: More preferably selected from

[0158] R1 is selected from H, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkyl, C 1-6 Alkylsulfonamide or C 3-6 Cycloalkylsulfonamide, preferably hydroxyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkylsulfonamide or C 3-6 a cycloalkylsulfonyl group, more preferably a methoxy group;

[0159] R2 is selected from H, halogen or C 1-6 Alkoxy, preferably C 1-3 an alkoxy group, more preferably a methoxy group;

[0160] R6 and R7 are each independently selected from hydroxy, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6Halogenated alkyl, C 3-6 Cycloalkyl or benzyl, or R6 and R7 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl or pyrrolidinyl, which is optionally substituted by 1-3 independently R y Group substitution, R y Independently selected from oxo, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 hydroxyalkyl or morpholinyl.

[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, or R6 and R7 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl or pyrrolidinyl, which is optionally substituted by 1-3 independently R y Group substitution, R y Independently selected from oxo, hydroxy, amino, C 1-3 Alkyl, C 1-3 hydroxyalkyl or morpholinyl.

[0162] For each variable, any combination of the above groups is also contemplated herein. It will be appreciated that substituents and substitution patterns on the compounds provided herein can be selected by one skilled in the art to provide chemically stable compounds that can be synthesized using techniques known in the art and those described herein.

[0163] Also described herein are pharmaceutically acceptable salts, solvates, polymorphs, esters, acids, isomers, metabolites, or prodrugs of this compound.

[0164] In particular, the compounds described herein can be made 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, or the like; or 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, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthoic acid, stearic acid, muconic 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 (such as lithium, sodium, potassium), alkaline earth metal ions (such as magnesium or calcium) or aluminum ions; or coordinated with organic bases or inorganic bases, acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, etc.; acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0165] The corresponding counter ion of the pharmaceutically acceptable salt can be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, 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, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization.

[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, elemental analysis. The various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state). Various microscopic techniques include, but are not limited to, IR microscopy and Raman microscopy.

[0168] Drug uses

[0169] The PI3Kγ kinase inhibitors of the present disclosure can be used in medicaments for treating PI3Kγ-mediated diseases selected from cancer, inflammatory diseases, or autoimmune diseases. wherein the cancer is selected from one or more of the following: blood cancer, brain cancer, gastrointestinal cancer, skin cancer, urinary system cancer, 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, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, leiomyosarcoma, cervical cancer, uterine cancer, endometrial cancer, bladder cancer, epithelial cancer, squamous cell carcinoma, adenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, bile duct cancer, neuroendocrine cancer, 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 disorder 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 tumor (e.g., a heme malignancy) or metastatic lesion, a lymphoma or metastatic lesion, such as a metastatic lesion of any cancer or tumor disclosed herein. In one embodiment, the cancer is 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 selected from one or more of the following cancers or tumors: head and neck cancer, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, oral cancer, oropharyngeal cancer, laryngeal cancer, hypopharyngeal cancer, salivary gland cancer, paraganglioma, pancreatic cancer, gastric cancer, skin cancer, esophageal cancer, endometrial cancer, liver cancer and bile duct cancer, bone cancer, intestinal cancer, colon cancer, rectal cancer, ovarian cancer, prostate cancer, lung cancer, breast cancer, lymphatic system tumors, blood cancer, myeloma, central nervous system tumors, brain cancer or its metastatic lesions. In some embodiments, the cancer treated by the methods or compounds disclosed herein is a solid tumor (e.g., carcinoid, carcinoma or sarcoma) or its metastatic lesions. 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 metastases thereof. In one embodiment, the solid tumor is prostate cancer, breast cancer, or glioblastoma, or metastases thereof.

[0173] In some embodiments, the cancer or tumor 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 cancer), gastric cancer, head and neck cancer, kidney cancer, brain cancer, or metastases thereof.

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

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

[0176] In some embodiments, the disorder 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 disorder is rheumatoid arthritis. In one embodiment, the disorder is rheumatoid arthritis, and the amount of the compound is effective to improve one or more symptoms associated with rheumatoid arthritis, wherein the symptoms associated with rheumatoid arthritis are independently reduced joint swelling, reduced serum anti-collagen levels, reduced joint pathology, reduced bone resorption, reduced cartilage destruction, reduced pannus, and / or reduced inflammation.

[0177] In some embodiments, the disorder 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 disorder is asthma.

[0178] In an embodiment of the present invention, the medicine comprising the compounds of this invention can be administered to the patient by at least one of injection, oral administration, inhalation, rectal administration and transdermal administration. When the patient is treated according to the present invention, the amount of a given drug depends on many factors, such as specific dosage regimen, disease or disease type and severity thereof, the uniqueness (such as body weight) of the patient or host for treatment, but, according to specific surrounding circumstances, including, for example, the specific drug, route of administration, disease for treatment and the patient or host for treatment, the dosage can be conventionally determined by methods known in the art. Usually, for the dosage used in adult treatment, the dosage is typically 0.02-5000mg / days, such as the scope of about 1-1500mg / days. The desired dose can be conveniently expressed as a dose or simultaneously administered (or in a short time) or at appropriate intervals, such as two, three, four or more doses per day. It will be appreciated by those skilled in the art that, although the above-mentioned dosage range has been given, specific effective amount can be appropriately adjusted according to the patient's situation and in conjunction with a physician's diagnosis.

[0179] In some embodiments of the methods or uses disclosed herein, a compound as described herein, any one of the compounds, is administered to a subject at a dosage (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 dosage (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 dosage is about 1-10 mg. In some embodiments, the dosage is about 1-50 mg. In some embodiments, the dosage is about 1-100 mg.

[0180] Preparation of compounds

[0181] The compounds disclosed herein, including salts thereof, 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 one skilled in the art of organic synthesis.

[0183] The choice of appropriate protecting groups can be readily determined by one skilled in the art.

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

[0185] Compounds 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'-tetramethyluronium hexafluorophosphate

[0188] DIPEA: N,N-diisopropylethylamine

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

[0190]

[0191] To a 100-mL round-bottom flask, 6 mL of methanol was added. With stirring at room temperature, a solution of N-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)acetamide (1.0 g, 3.2 mmol, 1.0 eq) and 2 mL of hydrochloric acid in ethyl acetate were added. The reaction system was allowed to react at room temperature for 24 hours. After completion of the reaction, the crude product was obtained by vacuum distillation. The reaction was neutralized with saturated sodium bicarbonate (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 sodium chloride, respectively, and then dried over anhydrous sodium sulfate (Na₂SO₄). The crude product was obtained by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain 820 mg of the yellow product, 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine, in a yield of 95%. MS m / z (ESI): 272.11 [M+H]. + .

[0192] To a 100 mL round-bottom flask, add 30 mL of tetrahydrofuran and, with stirring at 0°C, add 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 704 mg of a yellow product, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)carbamate, in a 60% yield. MS m / z (ESI): 392.14 [M+H]. + .

[0193] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 18 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea Compound 2

[0195]

[0196] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 20 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (Compound 2), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(2-fluorophenoxy)ethyl)urea Compound 3

[0198]

[0199] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 20 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(2-fluorophenoxy)ethyl)urea (Compound 3), in 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 1-(2-(2-chlorophenoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)urea Compound 4

[0201]

[0202] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 18 mg of a yellow product, 1-(2-(2-chlorophenoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)urea (Compound 4), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea Compound 5

[0204]

[0205] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-((1-methyl-1H-pyrazol-4-yl)oxy)ethan-1-amine (30 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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 30 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea (Compound 5), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-methoxyethyl)urea Compound 6

[0207]

[0208] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 27 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-methoxyethyl)urea (Compound 6), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-ethoxyethyl)urea Compound 7

[0210]

[0211] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 25 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-ethoxyethyl)urea (Compound 7), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-isopropoxyethyl)urea Compound 8

[0213]

[0214] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 20 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-isopropoxyethyl)urea (Compound 8), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-propoxyethyl)urea Compound 9

[0216]

[0217] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 17 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-propoxyethyl)urea (Compound 9), in 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 1-(2-(cyclopropylmethoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)urea Compound 10

[0219]

[0220] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 23 mg of a yellow product, 1-(2-(cyclopropylmethoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)urea (Compound 10), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(3-methoxypropyl)urea Compound 11

[0222]

[0223] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 18 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(3-methoxypropyl)urea (Compound 11), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(3-ethoxypropyl)urea Compound 12

[0225]

[0226] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 15 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(3-ethoxypropyl)urea (Compound 12), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(3-isopropoxypropyl)urea Compound 13

[0228]

[0229] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 22 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(3-isopropoxypropyl)urea (Compound 13), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(3-isobutoxypropyl)urea Compound 14

[0231]

[0232] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 24 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(3-isobutoxypropyl)urea (Compound 14), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-morpholinoethyl)urea Compound 15

[0234]

[0235] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 23 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-morpholinoethyl)urea (Compound 15), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)urea Compound 16

[0237]

[0238] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 20 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)urea (Compound 16), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(thiophen-3-yl)ethyl)urea Compound 17

[0240]

[0241] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 25 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(thiophen-3-yl)ethyl)urea (Compound 17), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(1-methyl-1H-imidazol-4-yl)ethyl)urea Compound 18

[0243]

[0244] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 20 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(1-methyl-1H-imidazol-4-yl)ethyl)urea (Compound 18), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(1-propyl-1H-imidazol-4-yl)ethyl)urea Compound 19

[0246]

[0247] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), 2-(1-propyl-1H-imidazol-4-yl)ethan-1-amine (21 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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 20 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(1-propyl-1H-imidazol-4-yl)ethyl)urea (Compound 19), in a 36% yield. MS m / z (ESI): 451.22 [M+H]. + .

[0248] Example 20 Synthesis of 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

[0249]

[0250] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)propan-1-amine (25 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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 22 mg of a 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), in a 39% yield. MS m / z (ESI): 438.19 [M+H]. +.

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

[0252]

[0253] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 separately with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 30 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(phenylamino)ethyl)urea (Compound 21), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea Compound 22

[0255]

[0256] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 28 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea (Compound 22), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea Compound 23

[0258]

[0259] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), N-(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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 34 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (Compound 23), in 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)ureido)pyrazolo[1,5-A]pyrimidin-5-yl)pyridin-3-yl)methanesulfonamide Compound 24

[0261]

[0262] To a 100-mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. 5-Chloropyrazolo[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-dioxybenzaldehyde-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 tetrakistriphenylphosphine palladium (34 mg, 0.03 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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 phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous NaSO. The organic phase was distilled under reduced pressure to obtain a crude product. Silica gel column chromatography afforded 168 mg of the yellow product, N-(5-(2-aminopyrazolo[1,5-A]pyrimidin-5-yl)-2-methoxypyridin-3-yl)methanesulfonamide, in an 85% yield. MS m / z (ESI): 335.09 [M+H]. + .

[0263] To a 100 mL round-bottom flask, add 30 mL of tetrahydrofuran and, with stirring at 0°C, 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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 34 mg of a yellow product, phenyl(5-(6-methoxy-5-(methylsulfonamido)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)carbamate, in a 50% yield. MS m / z (ESI): 455.11 [M+H]. + .

[0264] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(6-methoxy-5-(methylsulfonamido)pyridin-3-yl)pyrazolo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 15 mg of a yellow product, N-(2-methoxy-5-(2-(3-(2-phenoxyethyl)ureido)pyrazolo[1,5-A]pyrimidin-5-yl)pyridin-3-yl)methanesulfonamide (Compound 24), in 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 1-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)-3-(2-phenoxyethyl)urea Compound 25

[0266]

[0267] To a 100-mL round-bottom flask, 15 mL of 1,4-dioxane and 3 mL of water were added. 6-Bromo-[1,2,4]triazolo[1,5-A]pyridin-2-amine (500 mg, 2.35 mmol, 1.0 eq), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)pyridine (747 mg, 2.82 mmol, 1.2 eq), potassium carbonate (648 mg, 4.7 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (139 mg, 0.12 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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 phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous NaSO. The organic phase was distilled under reduced pressure to obtain a crude product. Silica gel column chromatography afforded 568 mg of the yellow product, 6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-amine, in an 89% yield. MS m / z (ESI): 272.11 [M+H]. + .

[0268] To a 100 mL round-bottom flask, add 25 mL of tetrahydrofuran and, with stirring at 0°C, add 6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 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 a 50% yield. MS m / z (ESI): 392.14 [M+H]. + .

[0269] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to yield 20 mg of a 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 36% yield. MS m / z (ESI): 435.18 [M+H]. + .

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

[0271]

[0272] To a 100-mL round-bottom flask, 15 mL of 1,4-dioxane and 3 mL of water were added. 6-Chloromidazo[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-dioxybenzaldehyde-2-yl)pyridine (944 mg, 3.56 mmol, 1.2 eq), potassium carbonate (819 mg, 5.94 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (173 mg, 0.15 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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 purified by silica gel column chromatography to yield 700 mg of a yellow product, 6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-amine, in an 87% yield. MS m / z (ESI): 272.11 [M+H] + .

[0273] To a 100 mL round-bottom flask, add 25 mL of tetrahydrofuran and, with stirring at 0°C, 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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 438 mg of a yellow product, phenyl (6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)carbamate, in a 56% yield. MS m / z (ESI): 392.14 [M+H]. + .

[0274] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 18 mg of a yellow product, 1-(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)-3-(2-phenoxyethyl)urea (Compound 26), in a 32% yield. MS m / z (ESI): 435.18 [M+H]. + .

[0275] Example 27 Synthesis of 1-(6-(5,6-dimethoxypyridin-3-yl)-1H-benzo[D]imidazol-2-yl)-3-(2-phenoxyethyl)urea Compound 27

[0276]

[0277] To a 100-mL round-bottom flask, 15 mL of 1,4-dioxane and 3 mL of water were added. 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-dioxybenzaldehyde-2-yl)pyridine (750 mg, 2.83 mmol, 1.2 eq), potassium carbonate (651 mg, 4.72 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (139 mg, 0.12 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion, the reaction 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. The crude product was purified by silica gel column chromatography to obtain 549 mg of a yellow product, 6-(5,6-dimethoxypyridin-3-yl)-1H-benzo[D]imidazol-2-amine, in an 86% yield. MS m / z (ESI): 271.12 [M+H]. + .

[0278] To a 100 mL round-bottom flask, add 25 mL of tetrahydrofuran and, with stirring at 0°C, add 6-(5,6-dimethoxypyridin-3-yl)-1H-benzo[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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 325 mg of a yellow product, phenyl (6-(5,6-dimethoxypyridin-3-yl)-1H-benzo[D]imidazol-2-yl)carbamate, in a 45% yield. MS m / z (ESI): 391.14 [M+H]. + .

[0279] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (6-(5,6-dimethoxypyridin-3-yl)-1H-benzo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to yield 17 mg of a yellow product, 1-(6-(5,6-dimethoxypyridin-3-yl)-1H-benzo[D]imidazol-2-yl)-3-(2-phenoxyethyl)urea (Compound 27), in a 30% yield. MS m / z (ESI): 434.18 [M+H]. + .

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

[0281]

[0282] To a 100-mL round-bottom flask, 15 mL of 1,4-dioxane and 3 mL of water were added. 7-Bromo-[1,2,4]triazolo[1,5-A]pyridin-2-amine (500 mg, 2.35 mmol, 1.0 eq), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)pyridine (748 mg, 2.82 mmol, 1.2 eq), potassium carbonate (648 mg, 4.7 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (139 mg, 0.12 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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 phase was 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. Silica gel column chromatography afforded 536 mg of the yellow product, 7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-amine, in an 84% yield. MS m / z (ESI): 272.11 [M+H]. + .

[0283] To a 100 mL round-bottom flask, add 25 mL of tetrahydrofuran and, with stirring at 0°C, add 7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 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 a 52% yield. MS m / z (ESI): 392.14 [M+H]. + .

[0284] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 16 mg of a 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), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-phenoxyethyl)urea Compound 29

[0286]

[0287] To a 100 mL round-bottom flask, add 20 mL of dichloromethane. 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 while stirring at room temperature. The reaction system was allowed to react at room temperature for 14 hours. After the reaction, the filtered yellow product was dissolved in 15 mL of methanol, and potassium carbonate (1.38 g, 10 mmol, 2.0 eq) was added while stirring at room temperature. The reaction system was allowed to react for an additional 8 hours at room temperature. After the reaction, 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 purified by silica gel column chromatography to yield 550 mg of a yellow product, 5-bromopyrazolo[1,5-A]pyridin-2-amine, in a yield of 52%. MS m / z (ESI): 211.98 [M+H] + .

[0288] To a 100-mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. 5-Bromopyrazolo[1,5-A]pyridin-2-amine (550 mg, 2.61 mmol, 1.0 eq), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)pyridine (1.37 g, 5.2 mmol, 2.0 eq), potassium carbonate (718 mg, 5.2 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (151 mg, 0.13 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was allowed to react at 90°C for 4 hours. After completion of the reaction, 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. The crude product was purified by silica gel column chromatography to obtain 675 mg of a yellow product, 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-amine, in an 88% yield. MS m / z (ESI): 271.12 [M+H] + .

[0289] To a 100 mL round-bottom flask, add 30 mL of tetrahydrofuran and, with stirring at 0°C, add 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 600 mg of a yellow product, phenyl(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in a 60% yield. MS m / z (ESI): 391.14 [M+H] + .

[0290] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 22 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-phenoxyethyl)urea (Compound 29), in 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 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea Compound 30

[0292]

[0293] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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]oxadiazol-5-yl)ethylamine (41 mg, 0.25 mmol, 1.2 eq), and triethylamine (58 μL, 0.42 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 32 mg of a yellow product, 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea (Compound 30), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(2-fluorophenoxy)ethyl)urea Compound 31

[0295]

[0296] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)ethanamine (22 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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 30 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(2-fluorophenoxy)ethyl)urea (Compound 31), in 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 1-(2-(2-chlorophenoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea Compound 32

[0298]

[0299] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 25 mg of a yellow product, 1-(2-(2-chlorophenoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 32), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea Compound 33

[0301]

[0302] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 28 mg of a 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), in 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 1-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-yloxy)ethyl)urea Compound 34

[0304]

[0305] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 28 mg of a yellow product, 1-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-yloxy)ethyl)urea (Compound 34), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-4-yloxy)ethyl)urea Compound 35

[0307]

[0308] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)ethanamine (19 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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 30 mg of a 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), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(4-methoxyphenoxy)ethyl)urea Compound 36

[0310]

[0311] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 28 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(4-methoxyphenoxy)ethyl)urea (Compound 36), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(2-methoxyphenoxy)ethyl)urea Compound 37

[0313]

[0314] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 30 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(2-methoxyphenoxy)ethyl)urea (Compound 37), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(3-fluorophenoxy)ethyl)urea Compound 38

[0316]

[0317] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)ethanamine (22 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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 25 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(3-fluorophenoxy)ethyl)urea (Compound 38), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(4-fluorophenoxy)ethyl)urea Compound 39

[0319]

[0320] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)ethanamine (22 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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 27 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(4-fluorophenoxy)ethyl)urea (Compound 39), in 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 1-(2-(3-cyanophenoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea Compound 40

[0322]

[0323] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 30 mg of a yellow product, 1-(2-(3-cyanophenoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 40), in a yield of 50%. 1 HNMR(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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea Compound 41

[0325]

[0326] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)ethan-1-amine (30 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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 26 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea (Compound 41), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-phenoxypropyl)urea Compound 42

[0328]

[0329] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 30 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-phenoxypropyl)urea (Compound 42), in 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 1-(2-(cyclopropylmethoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea Compound 43

[0331]

[0332] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 25 mg of a yellow product, 1-(2-(cyclopropylmethoxy)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 43), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-ethoxypropyl)urea Compound 44

[0334]

[0335] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 20 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-ethoxypropyl)urea (Compound 44), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-isopropoxy)urea Compound 45

[0337]

[0338] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 22 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-isopropoxy)urea (Compound 45), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-morpholinoethyl)urea Compound 46

[0340]

[0341] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 20 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-morpholinoethyl)urea (Compound 46), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-morpholinopropyl)urea Compound 47

[0343]

[0344] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 23 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-morpholinopropyl)urea (Compound 47), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-(piperazin-1-yl)propyl)urea Compound 48

[0346]

[0347] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), tert-butyl 4-(3-aminopropyl)piperazine-1-carboxylate (34 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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to obtain 15 mg of a 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), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(phenylamino)ethyl)urea Compound 49

[0349]

[0350] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 separately with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 30 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(phenylamino)ethyl)urea (Compound 49), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea Compound 50

[0352]

[0353] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 28 mg of a 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), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-ylamino)ethyl)urea Compound 51

[0355]

[0356] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 30 mg of a 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), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea Compound 52

[0358]

[0359] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.13 mmol, 1.0 eq), N-(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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 34 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (Compound 52), in 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 1-(2-(1H-pyrazol-1-yl)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea Compound 53

[0361]

[0362] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 28 mg of a yellow product, 1-(2-(1H-pyrazol-1-yl)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 53), in 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 1-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea Compound 54

[0364]

[0365] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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]triazole-1-ethylamine (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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 33 mg of a yellow product, 1-(2-(1H-1,2,4-triazol-1-yl)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 54), in 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 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

[0367]

[0368] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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]oxadiazol-5-yl)ethylamine (28 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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 28 mg of a 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), in a 44% yield. MS m / z (ESI): 424.17 [M+H]. + .

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

[0370]

[0371] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 30 mg of a yellow product, 1-(2-(2H-tetrazol-5-yl)ethyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 56), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-phenylpropyl)urea Compound 57

[0373]

[0374] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to obtain a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridine-2-yl)pyridine-3-ylpyridine-4-ol.

[0375] 28 mg of 3-(3-phenylpropyl)urea (Compound 57), yield 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-(1-methyl-1H-pyrazol-4-yl)propyl)urea Compound 58

[0377]

[0378] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 25 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(3-(1-methyl-1H-pyrazol-4-yl)propyl)urea (Compound 58), in 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 1-(3-(1H-pyrazol-1-yl)propyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea Compound 59

[0380]

[0381] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)propan-1-amine (18 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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 28 mg of a yellow product, 1-(3-(1H-pyrazol-1-yl)propyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 59), in 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 1-(3-(1H-1,2,4-triazol-1-yl)propyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea Compound 60

[0383]

[0384] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 24 mg of a yellow product, 1-(3-(1H-1,2,4-triazol-1-yl)propyl)-3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 60), in a 44% yield. MS m / z (ESI): 423.19 [M+H] + .

[0385] Example 61 Synthesis of N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)-2-morpholinoacetamide Compound 61

[0386]

[0387] To a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added. 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-morpholineacetic acid 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 with stirring at room temperature. The reaction system was allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was neutralized with 10 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 purified by silica gel column chromatography to afford 28 mg of a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)-2-morpholinoacetamide (Compound 61), in a 41% yield. MS m / z (ESI): 484.54 [M+H]. + .

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

[0389]

[0390] To a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added. 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-methylpiperidine-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 with stirring at room temperature. The reaction system was allowed to react at room temperature for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 25 mg of a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)-1-methylpiperidine-4-carboxamide (Compound 62), in a 37% yield. MS m / z (ESI): 482.57 [M+H]. + .

[0391] Example 63 Synthesis of N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)cyclopropanecarboxamide Compound 63

[0392]

[0393] To a 25 mL round-bottom flask, add 2 mL of tetrahydrofuran. 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), cyclopropylcarbonyl chloride (18 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was neutralized with 10 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 purified by silica gel column chromatography to afford 25 mg of a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)cyclopropanecarboxamide (Compound 63), in a 42% yield. 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)ureido)ethyl)cyclobutanecarboxamide Compound 64

[0395]

[0396] To a 25 mL round-bottom flask, add 2 mL of tetrahydrofuran. 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), cyclobutylcarbonyl chloride (20 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was neutralized with 10 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 purified by silica gel column chromatography to afford 32 mg of a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)cyclobutanecarboxamide (Compound 64), in a 52% yield. MS m / z (ESI): 439.50 [M+H]. + .

[0397] Example 65 Synthesis of 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-methyl-2-oxopyrrolidin-3-yl)urea Compound 65

[0398]

[0399] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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-methylpyrrolidin-2-one tosylate (40 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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 25 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-methyl-2-oxopyrrolidin-3-yl)urea (Compound 65), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,4S)-4-hydroxy-4-methylcyclohexyl)urea Compound 66

[0401]

[0402] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 20 mg of a 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), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-hydroxy-4-methylcyclohexyl)urea Compound 67

[0404]

[0405] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 20 mg of a 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), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-morpholinocyclohexyl)urea Compound 68

[0407]

[0408] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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-(morpholin-4-yl)-cyclohexane (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 system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to yield 22 mg of a 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 37% yield. MS m / z (ESI): 481.26 [M+H] + .

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

[0410]

[0411] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 22 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-hydroxycyclohexyl)urea (Compound 69), in 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 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,4S)-4-hydroxycyclohexyl)urea Compound 70

[0413]

[0414] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 20 mg of a yellow product, 1-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,4S)-4-hydroxycyclohexyl)urea (Compound 70), in 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 1-(5-(5-hydroxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-phenoxyethyl)urea Compound 71

[0416]

[0417] To a 100-mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. 5-Bromopyrazolo[1,5-A]pyridin-2-amine (430 mg, 2.04 mmol, 1.0 eq), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)pyridin-3-ol (615 mg, 2.45 mmol, 1.2 eq), potassium carbonate (563 mg, 4.08 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (116 mg, 0.1 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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 purified by silica gel column chromatography to yield 340 mg of a yellow product, 5-(2-aminopyrazolo[1,5-A]pyridin-5-yl)-2-methoxypyridin-3-ol, in a 67% yield. MS m / z (ESI): 257.10 [M+H] + .

[0418] To a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran and, with stirring at 0°C, add 5-(2-aminopyrazolo[1,5-A]pyridin-5-yl)-2-methoxypyridin-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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 290 mg of a yellow product, phenyl(5-(5-hydroxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in a 58% yield. MS m / z (ESI): 377.12 [M+H] + .

[0419] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 90 mg of a yellow product, 1-(5-(5-hydroxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-phenoxyethyl)urea (Compound 71), in a 54% yield. MS m / z (ESI): 420.17 [M+H]. + .

[0420] Example 72 Synthesis of 2-methoxy-N-methyl-5-(2-(3-(2-phenoxyethyl)ureido)pyrazolo[1,5-A]pyridin-5-yl)nicotinamide Compound 72

[0421]

[0422] To a 25 mL round-bottom flask, 1 mL of tetrahydrofuran was added. 2-methoxy-5-(2-(3-(2-phenoxyethyl)ureido)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) were added with stirring at room temperature. The reaction system was allowed to react at room temperature for 14 hours. After completion of the reaction, the reaction system was diluted with 10 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 purified by silica gel column chromatography to give 6 mg of a yellow product, 2-methoxy-N-methyl-5-(2-(3-(2-phenoxyethyl)ureido)pyrazolo[1,5-A]pyridin-5-yl)nicotinamide (Compound 72), in 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 1-(5-(5-hydroxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea Compound 73

[0424]

[0425] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5-hydroxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (150 mg, 0.4 mmol, 1.0 eq), N-(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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 43 mg of a yellow product, 1-(5-(5-hydroxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (Compound 73), in 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)ureido)pyrazolo[1,5-A]pyridin-5-yl)pyridin-3-yl)methanesulfonamide Compound 74

[0427]

[0428] To a 100-mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. 5-Bromopyrazolo[1,5-A]pyridin-2-amine (306 mg, 1.45 mmol, 1.0 eq), N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-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 tetrakistriphenylphosphine palladium (81 mg, 0.07 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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 phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous NaSO. The organic phase was distilled under reduced pressure to obtain a crude product. Silica gel column chromatography afforded 410 mg of the yellow product, N-(5-(2-aminopyrazolo[1,5-A]pyridin-5-yl)-2-methoxypyridin-3-yl)methanesulfonamide, in an 85% yield. MS m / z (ESI): 334.10 [M+H]. + .

[0429] To a 100-mL round-bottom flask, add 10 mL of tetrahydrofuran and, with stirring at 0°C, add 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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 260 mg of a yellow product, phenyl(5-(6-methoxy-5-(methylsulfonamido)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in a 64% yield. MS m / z (ESI): 454.12 [M+H]. + .

[0430] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was allowed to react at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 33 mg of a yellow product, N-(2-methoxy-5-(2-(3-(2-(pyrimidin-2-ylamino)ethyl)ureido)pyrazolo[1,5-A]pyridin-5-yl)pyridin-3-yl)methanesulfonamide (Compound 74), in 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 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea Compound 75

[0432]

[0433] To a 100-mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. 5-Bromopyrazolo[1,5-A]pyridin-2-amine (200 mg, 0.95 mmol, 1.0 eq), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-3-(trifluoromethyl)pyridine (346 mg, 1.14 mmol, 1.2 eq), potassium carbonate (262 mg, 1.9 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (58 mg, 0.05 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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. Silica gel column chromatography afforded 200 mg of a yellow product, 5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-amine, in a 68% yield. MS m / z (ESI): 309.10 [M+H]. + .

[0434] To a 100 mL round-bottom flask, add 10 mL of tetrahydrofuran and, with stirring at 0°C, add 5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 125 mg of a yellow product, phenyl(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in a 56% yield. MS m / z (ESI): 429.12 [M+H]. + .

[0435] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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), N-(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 with stirring at room temperature. The reaction system was allowed to react at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to obtain 28 mg of a yellow product, 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (Compound 75), in 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 1-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea Compound 76

[0437]

[0438] To a 100-mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. 5-Bromopyrazolo[1,5-A]pyridin-2-amine (350 mg, 1.66 mmol, 1.0 eq), 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)pyridine (546 mg, 2.16 mmol, 1.3 eq), potassium carbonate (458 mg, 3.32 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (92 mg, 0.08 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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. The crude product was purified by silica gel column chromatography to obtain 380 mg of a yellow product, 5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-amine, in an 89% yield. MS m / z (ESI): 259.10 [M+H] + .

[0439] To a 100 mL round-bottom flask, add 10 mL of tetrahydrofuran and, with stirring at 0°C, add 5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 175 mg of a yellow product, phenyl (5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in a 60% yield. MS m / z (ESI): 379.12 [M+H]. + .

[0440] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (80 mg, 0.21 mmol, 1.0 eq), N-(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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 50 mg of a yellow product, 1-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (Compound 76), in 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)ureido)pyrazolo[1,5-A]pyridin-5-yl)pyridin-3-yl)cyclopropanesulfonamide Compound 77

[0442]

[0443] To a 100-mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. 5-Bromopyrazolo[1,5-A]pyridin-2-amine (263 mg, 1.2 mmol, 1.0 eq), N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzoic 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 tetrakistriphenylphosphine palladium (69 mg, 0.06 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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. Silica gel column chromatography afforded 375 mg of a yellow product, N-(5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)cyclopropanesulfonamide, in an 87% yield. MS m / z (ESI): 360.11 [M+H]. + .

[0444] To a 100-mL round-bottom flask, add 10 mL of tetrahydrofuran and, with stirring at 0°C, add 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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 150 mg of a yellow product, phenyl(5-(5-(cyclopropanesulfonamido)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in a 56% yield. MS m / z (ESI): 480.13 [M+H]. + .

[0445] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5-(cyclopropanesulfonamido)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.1 mmol, 1.0 eq), N-(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 with stirring at room temperature. The reaction system was allowed to react at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 28 mg of a yellow product, N-(2-methoxy-5-(2-(3-(2-(pyrimidin-2-ylamino)ethyl)ureido)pyrazolo[1,5-A]pyridin-5-yl)pyridin-3-yl)cyclopropanesulfonamide (Compound 77), in 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 1-(5-(6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea Compound 78

[0447]

[0448] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (60 mg, 0.17 mmol, 1.0 eq), N-(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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 30 mg of a yellow product, 1-(5-(6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (Compound 78), in 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 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea Compound 79

[0450]

[0451] To a 100-mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. 5-Bromopyrazolo[1,5-A]pyridin-2-amine (420 mg, 2.0 mmol, 1.0 eq), 3-(difluoromethoxy)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)pyridine (780 mg, 2.6 mmol, 1.3 eq), potassium carbonate (552 mg, 4.0 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (116 mg, 0.1 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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. Silica gel column chromatography afforded 552 mg of a yellow product, 5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-amine, in a 90% yield. MS m / z (ESI): 307.10 [M+H]. + .

[0452] To a 100-mL round-bottom flask, add 10 mL of tetrahydrofuran and, with stirring at 0°C, add 5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 100 mg of a yellow product, phenyl (5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in a yield of 71%. MS m / z (ESI): 427.12 [M+H]. + .

[0453] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (50 mg, 0.12 mmol, 1.0 eq), N-(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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 23 mg of a yellow product, 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyrimidin-2-ylamino)ethyl)urea (Compound 79), in 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 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea Compound 80

[0455]

[0456] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 25 mg of a yellow product, 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea (Compound 80), in 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 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea Compound 81

[0458]

[0459] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 separately with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 35 mg of a yellow product, 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-2-ylamino)ethyl)urea (Compound 81), in 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)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea Compound 82

[0461]

[0462] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (60 mg, 0.17 mmol, 1.0 eq), 2-(3-methyl-[1,2,4]oxadiazol-5-yl)ethylamine (33 mg, 0.2 mmol, 1.2 eq), and triethylamine (47 μL, 0.34 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 28 mg of a yellow product, 1-(5-(6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea (Compound 82), in 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 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea Compound 83

[0464]

[0465] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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]oxadiazol-5-yl)-ethanamine (46 mg, 0.28 mmol, 1.2 eq), and triethylamine (65 μL, 0.48 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 28 mg of a yellow product, 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)urea (Compound 83), in 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)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea Compound 84

[0467]

[0468] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (60 mg, 0.17 mmol, 1.0 eq), 2-((1-methyl-1H-pyrazol-4-yl)oxy)ethan-1-amine (28 mg, 0.2 mmol, 1.2 eq), and triethylamine (47 μL, 0.34 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 8 mg of a yellow product, 1-(5-(6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea (Compound 84), in 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 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea Compound 85

[0470]

[0471] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)ethan-1-amine (22 mg, 0.15 mmol, 1.1 eq), and triethylamine (39 μL, 0.28 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 30 mg of a yellow product, 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea (Compound 85), in 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 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(2-(1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea Compound 86

[0473]

[0474] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)ethan-1-amine (40 mg, 0.28 mmol, 1.2 eq), and triethylamine (65 μL, 0.47 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 30 mg of a yellow product, 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(2-(1-methyl-1H-pyrazol-4-yl)oxy)ethyl)urea (Compound 86), in 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 1-(2-(1H-pyrazol-1-yl)ethyl)-3-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea Compound 87

[0476]

[0477] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 35 mg of a yellow product, 1-(2-(1H-pyrazol-1-yl)ethyl)-3-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 87), in 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 1-(2-(1H-pyrazol-1-yl)ethyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)urea Compound 88

[0479]

[0480] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 27 mg of a yellow product, 1-(2-(1H-pyrazol-1-yl)ethyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)urea (Compound 88), in 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)ureido)ethyl)cyclopentanecarboxamide Compound 89

[0482]

[0483] To a 25 mL round-bottom flask, add 2 mL of tetrahydrofuran. 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), cyclopentylcarbonyl chloride (23 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was neutralized with 10 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 purified by silica gel column chromatography to afford 28 mg of a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)cyclopentanecarboxamide (Compound 89), in a 44% yield. MS m / z (ESI): 453.52 [M+H]. + .

[0484] Example 90 Synthesis of N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)cyclohexanecarboxamide Compound 90

[0485]

[0486] To a 25 mL round-bottom flask, add 2 mL of tetrahydrofuran. 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), cyclohexylcarbonyl chloride (25 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was neutralized with 10 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 purified by silica gel column chromatography to afford 31 mg of a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)cyclohexanecarboxamide (Compound 90), in a 48% yield. MS m / z (ESI): 467.55 [M+H]. + .

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

[0488]

[0489] To a 25 mL round-bottom flask, add 2 mL of tetrahydrofuran. 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 with stirring at room temperature. The reaction system was allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was neutralized with 10 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 purified by silica gel column chromatography to afford 30 mg of a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)benzamide (Compound 91), in a 47% yield. MS m / z (ESI): 461.50 [M+H]. + .

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

[0491]

[0492] To a 25 mL round-bottom flask, add 2 mL of tetrahydrofuran and, with stirring at room temperature, add 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-thiophenecarbonyl chloride (25 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq). The reaction system was allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was neutralized with 10 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 purified by silica gel column chromatography to afford 27 mg of a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)thiophene-2-carboxamide (Compound 92), in a 41% yield. MS m / z (ESI): 467.52 [M+H]. + .

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

[0494]

[0495] To a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. 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-dioxaborolan-2-yl)pyridine (33 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (8 mg, 0.007 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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 phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous NaSO. The organic phase was distilled under reduced pressure to obtain a crude product. Silica gel column chromatography afforded 20 mg of the yellow product, 1-(5-(pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (Compound 93), in a 41% yield. MS m / z (ESI): 375.41 [M+H]. + .

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

[0497]

[0498] To a 100-mL round-bottom flask, 20 mL of 1,4-dioxane and 4 mL of water were added. 5-Bromopyrazolo[1,5-A]pyridin-2-amine (400 mg, 1.9 mmol, 1.0 eq), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)pyridine (536 mg, 2.3 mmol, 1.2 eq), potassium carbonate (524 mg, 3.8 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (116 mg, 0.10 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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. Silica gel column chromatography afforded 393 mg of a yellow product, 5-(6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-amine, in an 86% yield. MS m / z (ESI): 241.11 [M+H]. + .

[0499] To a 100 mL round-bottom flask, add 10 mL of tetrahydrofuran and, with stirring at 0°C, add 5-(6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 440 mg of a yellow product, phenyl(5-(6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate, in a yield of 76%. MS m / z (ESI): 361.13 [M+H]. + .

[0500] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (5-(6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)carbamate (60 mg, 0.17 mmol, 1.0 eq), 2-(pyridin-3-yloxy)ethanamine (28 mg, 0.2 mmol, 1.2 eq), and triethylamine (47 μL, 0.34 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 25 mg of a yellow product, 1-(5-(6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (Compound 94), in 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 1-(5-(5-ethoxy-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea Compound 95

[0502]

[0503] To a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. 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-dioxaborolan-2-yl)pyridine (45 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (8 mg, 0.007 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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 phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous NaSO. The organic phase was distilled under reduced pressure to obtain a crude product. Silica gel column chromatography afforded 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), in a 34% yield. MS m / z (ESI): 449.49 [M+H]. + .

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

[0505]

[0506] To a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. 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-dioxaborol-2-yl)pyridine (47 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (8 mg, 0.007 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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 phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous NaSO. The organic phase was distilled under reduced pressure to obtain a crude product. Silica gel column chromatography afforded 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), in a 46% yield. MS m / z (ESI): 463.52 [M+H]. + .

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

[0508]

[0509] To a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. 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-dioxaborolan-2-yl)pyridine (47 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (8 mg, 0.007 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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 phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous NaSO. The organic phase was distilled under reduced pressure to obtain a crude product. Silica gel column chromatography afforded 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), in a 42% yield. MS m / z (ESI): 463.52 [M+H]. + .

[0510] Example 98 Synthesis of N-(2-methoxy-5-(2-(3-(2-(pyridin-3-yloxy)ethyl)ureido)pyrazolo[1,5-A]pyridin-5-yl)pyridin-3-yl)methanesulfonamide Compound 98

[0511]

[0512] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)ethanamine (18 mg, 0.13 mmol, 1.2 eq), and triethylamine (30 μL, 0.22 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 33 mg of a yellow product, N-(2-methoxy-5-(2-(3-(2-(pyridin-3-yloxy)ethyl))ureido)pyrazolo[1,5-A]pyridin-5-yl)pyridin-3-yl)methanesulfonamide (Compound 98), in 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)ureido)pyrazolo[1,5-A]pyridin-5-yl)pyridin-3-yl)cyclopropanesulfonamide Compound 99

[0514]

[0515] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)ethanamine (17 mg, 0.12 mmol, 1.2 eq), and triethylamine (28 μL, 0.2 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 30 mg of a yellow product, N-(2-methoxy-5-(2-(3-(2-(pyridin-3-oxy)ethyl)ureido)pyrazolo[1,5-A]pyridin-5-yl)pyridin-3-yl)cyclopropanesulfonamide (Compound 99), in a 58% yield. MS m / z (ESI): 524.17 [M+H]. + .

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

[0517]

[0518] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 23 mg of a yellow product, 1-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (Compound 100), in 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 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea Compound 101

[0520]

[0521] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)ethanamine (39 mg, 0.28 mmol, 1.2 eq), and triethylamine (65 μL, 0.47 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 25 mg of a yellow product, 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea (Compound 101), in 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 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-oxy)ethyl)urea Compound 102

[0523]

[0524] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)ethanamine (35 mg, 0.25 mmol, 1.2 eq), and triethylamine (58 μL, 0.42 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 31 mg of a yellow product, 1-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-oxy)ethyl)urea (Compound 102), in 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 1-(5-(6-chloro-5-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-yloxy)ethyl)urea Compound 103

[0526]

[0527] To a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. 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-methoxypyridine-5-boronic acid pinacol ester (43 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (8 mg, 0.007 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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 purified by silica gel column chromatography to afford 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 a 21% yield. MS m / z (ESI): 439.88 [M+H]. + .

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

[0529]

[0530] To a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. 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-methylpyridine-5-boronic acid pinacol ester (35 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (8 mg, 0.007 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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 purified by silica gel column chromatography to afford 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 a 50% yield. MS m / z (ESI): 389.44 [M+H]. + .

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

[0532]

[0533] To a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. 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 xanaxol ester (36 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (8 mg, 0.007 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was allowed to react at 90°C for 4 hours. After completion of the reaction, 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 purified by silica gel column chromatography to afford 24 mg of a 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 47% yield. MS m / z (ESI): 393.40 [M+H]. + .

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

[0535]

[0536] To a 25 mL round-bottom flask, 5 mL of 1,4-dioxane and 1 mL of water were added. 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-dioxaborol-2-yl)pyridine (30 mg, 0.16 mmol, 1.2 eq), potassium carbonate (36 mg, 0.26 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (8 mg, 0.007 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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 phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous NaSO. The organic phase was distilled under reduced pressure to obtain a crude product. Silica gel column chromatography afforded 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), in a 47% yield. MS m / z (ESI): 441.42 [M+H]. + .

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

[0538]

[0539] To a 25 mL round-bottom flask, add 2 mL of tetrahydrofuran. 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), furoyl chloride (22 mg, 0.17 mmol, 1.2 eq), and DIPEA (49 μL, 0.28 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was neutralized with 10 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 purified by silica gel column chromatography to afford 20 mg of a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)furan-2-carboxamide (Compound 107), in a 32% yield. MS m / z (ESI): 451.46 [M+H]. + .

[0540] Example 108 Synthesis of 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

[0541]

[0542] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 27 mg of a 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), in a 47% yield. MS m / z (ESI): 436.45 [M+H]. + .

[0543] Example 109 Synthesis of 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

[0544]

[0545] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 30 mg of a 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 a 53% yield. MS m / z (ESI): 436.45 [M+H]. + .

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

[0547]

[0548] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. Phenyl (6-(5,6-dimethoxypyridin-3-yl)-1H-benzo[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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 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 an 18% yield. MS m / z (ESI): 435.46 [M+H]. + .

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

[0550]

[0551] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 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 26% yield. MS m / z (ESI): 436.45 [M+H]. + .

[0552] Example 112 Synthesis of N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)-1-methyl-1H-imidazole-4-carboxamide Compound 112

[0553]

[0554] To a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added. 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-imidazolecarboxylic 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 with stirring at room temperature. The reaction system was allowed to react at room temperature for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 22 mg of a yellow product, N-(2-(3-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)ethyl)-1-methyl-1H-imidazole-4-carboxamide (Compound 112), in a 34% yield. MS m / z (ESI): 465.49 [M+H]. + .

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

[0556]

[0557] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)ethanamine (18 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 20 mg of a yellow product, 1-(6-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)-3-(2-(pyridin-3-oxy)ethyl)urea (Compound 113), in 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 1-(6-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)-3-(2-(pyridin-3-oxy)ethyl)urea Compound 114

[0559]

[0560] To a 100-mL round-bottom flask, 15 mL of 1,4-dioxane and 3 mL of water were added. 6-Chloromidazo[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-dioxybenzaldehyde-2-yl)pyridine (1084 mg, 3.6 mmol, 1.2 eq), potassium carbonate (828 mg, 6.0 mmol, 2.0 eq), and tetrakistriphenylphosphine palladium (173 mg, 0.15 mmol, 0.05 eq) were added with stirring at room temperature. The reaction system was incubated at 90°C for 4 hours. After completion of the reaction, 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. Silica gel column chromatography afforded 506 mg of a yellow product, 6-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-amine, in a 55% yield. MS m / z (ESI): 308.10 [M+H]. + .

[0561] To a 100 mL round-bottom flask, add 25 mL of tetrahydrofuran and, with stirring at 0°C, 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). The reaction system was allowed to react at 0°C for 1 hour. After completion of the reaction, 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. Silica gel column chromatography afforded 181 mg of a yellow product, phenyl (6-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)carbamate, in a 65% yield. MS m / z (ESI): 428.12 [M+H]. + .

[0562] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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)ethanamine (18 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 20 mg of a 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), in 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 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-morpholinocyclohexyl)urea Compound 115

[0564]

[0565] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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-(morpholin-4-yl)-cyclohexane (24 mg, 0.13 mmol, 1.1 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to afford 25 mg of a 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 a 40% yield. MS m / z (ESI): 517.24 [M+H]. + .

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

[0567]

[0568] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 20 mg of a 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), in 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 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-hydroxycyclohexyl)urea Compound 117

[0570]

[0571] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 23 mg of a 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), in 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 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1S,3S)-3-hydroxycyclopentyl)urea Compound 118

[0573]

[0574] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 20 mg of a 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), in 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 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)urea Compound 119

[0576]

[0577] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 22 mg of a yellow product, 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)urea (Compound 119), in 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 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

[0579]

[0580] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 24 mg of a 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), in 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 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-hydroxy-4-methylcyclohexyl)urea Compound 121

[0582]

[0583] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 25 mg of a yellow product, 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1R,4R)-4-hydroxy-4-methylcyclohexyl)urea (Compound 121), in 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 1-((1S,4S)-4-aminocyclohexyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea Compound 122

[0585]

[0586] To a 100 mL round-bottom flask, add 2 mL of dichloromethane. Tert-butyl ((1S,4S)-4-(3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)cyclohexyl)carbamate (50 mg, 0.09 mmol, 1.0 eq) and 2 mL of trifluoroacetic acid while stirring at room temperature. The reaction system was allowed to react at room temperature for 2 hours. After completion of the reaction, the crude product was obtained by distillation under reduced pressure. The reaction 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. The organic phase was distilled under reduced pressure to obtain a crude product. Silica gel column chromatography yielded 10 mg of the yellow product, 1-((1S,4S)-4-aminocyclohexyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 122), in a 25% yield. MS m / z (ESI): 447.20 [M+H]. + .

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

[0588]

[0589] To a 100 mL round-bottom flask, add 2 mL of dichloromethane. Tert-butyl ((1R,4R)-4-(3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)cyclohexyl)carbamate (50 mg, 0.09 mmol, 1.0 eq) and 2 mL of trifluoroacetic acid while stirring at room temperature. The reaction system was allowed to react at room temperature for 2 hours. After completion of the reaction, the crude product was obtained by distillation under reduced pressure. The reaction 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. The organic phase was distilled under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography to afford 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 a 33% yield. MS m / z (ESI): 447.20 [M+H]. + .

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

[0591]

[0592] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 15 mg of a 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), in 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 (R)-1-(1-cyclopropyl-2-hydroxyethyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea Compound 125

[0594]

[0595] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 17 mg of a yellow product, (R)-1-(1-cyclopropyl-2-hydroxyethyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 125), in 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-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea Compound 126

[0597]

[0598] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 16 mg of a yellow product, (S)-1-(1-cyclopropyl-2-hydroxyethyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 126), in 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 (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxypropane-2-yl)urea Compound 127

[0600]

[0601] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 16 mg of a 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), in 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 (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxybutane-2-yl)urea Compound 128

[0603]

[0604] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 23 mg of a 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), in 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] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 25 mg of a 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), in 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 (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-phenylpropane-2-yl)urea Compound 130

[0609]

[0610] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 30 mg of a 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), in 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 (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-phenylpropane-2-yl)urea Compound 131

[0612]

[0613] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 27 mg of a 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), in 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 (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-methylbutan-2-yl)urea Compound 132

[0615]

[0616] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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-methylbutan-2-yl)urea (15 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 20 mg of a yellow product, (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-methylbutan-2-yl)urea (Compound 132), in 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 (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-methylbutan-2-yl)urea Compound 133

[0618]

[0619] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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-methylbutan-2-yl)urea (15 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 22 mg of a yellow product, (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(1-hydroxy-3-methylbutan-2-yl)urea (Compound 133), in 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 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((1-(hydroxymethyl)cyclopropyl)methyl)urea Compound 134

[0621]

[0622] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 25 mg of a 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), in 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 (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2,3-dihydroxypropyl)urea Compound 135

[0624]

[0625] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 25 mg of a 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), in 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 (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2,3-dihydroxypropyl)urea Compound 136

[0627]

[0628] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 23 mg of a 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), in 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 (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-hydroxypropyl)urea Compound 137

[0630]

[0631] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 26 mg of a yellow product, (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-hydroxypropyl)urea (Compound 137), in 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 (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-hydroxypropyl)urea Compound 138

[0633]

[0634] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 24 mg of a yellow product, (S)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-hydroxypropyl)urea (Compound 138), in 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 1-(1-cyanochloropropyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea Compound 139

[0636]

[0637] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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-cyclopropylcyanide hydrochloride (17 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 24 mg of a yellow product, 1-(1-cyanochloropropyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 139), in 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 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)urea Compound 140

[0639]

[0640] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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 with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 27 mg of a yellow product, 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)urea (Compound 140), in 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 (R)-1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-(2-fluoro-3-hydroxypropyl)urea Compound 141

[0642]

[0643] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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-fluoropropan-1-ol (13 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 28 mg of a 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), in 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] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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-fluoropropan-1-ol (13 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 chromatographed on a silica gel column to give 23 mg of a 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), in 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 1-(2,2-difluoro-3-hydroxypropyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea Compound 143

[0648]

[0649] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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-difluoropropan-1-ol (16 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 40 mg of a yellow product, 1-(2,2-difluoro-3-hydroxypropyl)-3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea (Compound 143), in 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 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((3-(hydroxymethyl)oxetane-3-yl)methyl)urea Compound 144

[0651]

[0652] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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-aminomethyl-3-hydroxymethyloxetane (16 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 35 mg of a yellow product, 1-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)-3-((3-(hydroxymethyl)oxetane-3-yl)methyl)urea (Compound 144), in a yield of 65%. 1 H NMR (500MHz, DMSO-d6) δ9.22(s,1H),8.54(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8. 03(d,J=1.9Hz,1H),7.89(d,J=1.3Hz,1H),7.45(s,0.25H),7.30(s,0.5H),7.16(s,0. 25H),7.13(dd,J=7.3,2.0Hz,1H),6.97(s,1H),6.59(s,1H),4.98(t,J=5.3Hz,1H),4. 33 (dd, J = 13.0, 5.9 Hz, 4H), 3.99 (s, 3H), 3.62 (d, J = 5.4 Hz, 2H), 3.46 (d, J = 6.0 Hz, 2H). MS m / z(ESI):450.16[M+H] + .

[0653] Example 145 Synthesis of 2-(3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea)-N-(2,2,2-trifluoroethyl)acetamide Compound 145

[0654]

[0655] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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-amino-N-(2,2,2-trifluoroethyl)acetamide (22 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the reaction, 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 purified by silica gel column chromatography to give 18 mg of a yellow product, 2-(3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)urea)-N-(2,2,2-trifluoroethyl)acetamide (Compound 145), in a yield of 31%. 1 H NMR (500MHz, DMSO-d6) δ9.50(s,1H),8.72(t,J=6.3Hz,1H),8.55(d,J=7.2Hz,1H),8.50(d,J=2.1Hz,1H),8.04(d,J=1.9Hz,1H),7.91(d,J=1.3H z,1H),7.48(s,0.25H),7.34(s,0.5H),7.19(s,0.25H),7.15–7.07(m,2 H), 6.61 (s, 1H), 3.99 (s, 3H), 3.97–3.91 (m, 2H), 3.89 (d, J = 5.6Hz, 2H). MS m / z(ESI):489.13[M+H] + .

[0656] Example 146 Synthesis of N-(2,2-difluoroethyl)-2-(3-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)ureido)acetamide Compound 146

[0657]

[0658] To a 25 mL round-bottom flask, 2 mL of dimethyl sulfoxide was added. 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-amino-N-(2,2-difluoroethyl)acetamide (20 mg, 0.14 mmol, 1.2 eq), and triethylamine (33 μL, 0.24 mmol, 2.0 eq) were added with stirring at room temperature. The reaction system was incubated at 60°C for 1 hour. After completion of the re...

Claims

1. 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, in, represents a fused heteroaryl group having 2 or 3 nitrogen atoms, preferably selected from: More preferably selected from R1 is selected from H, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkyl, C 1-6 Alkylsulfonamide or C 3-6 Cycloalkylsulfonamide, preferably hydroxyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkylsulfonamide or C 3-6 Cycloalkylsulfonylamide, more preferably methoxy; R2 is selected from H, halogen or C 1-6 Alkoxy, preferably C 1-3 Alkoxy, more preferably methoxy; R3 is selected from Where n is 1, 2 or 3; W is selected from a direct bond, NH, O, -(C=O)- or -NH-(C=O)-; 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 Haloalkylamino, C 1-6 Hydroxyalkylamino, 5-7 membered heterocyclic group, 5-7 membered heterocyclic group C 1-3 alkyl, aryl, heteroaryl, 5-7 membered heterocycloalkylamino, or heteroarylamino, which is optionally substituted by 1-3 independently R x Group substitution, R x are independently selected from hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino; R5 is a substituent on an alkylene group, wherein m is 0, 1 or 2, and R5 is independently selected from hydroxyl or halogen, or two R5 together with the carbon atom to which they are attached form a C 3-6 Cycloalkyl or 4-7 membered heterocyclic group; 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, or R6 and R7 together with the carbon atom to which they are attached form a C 3-6 Cycloalkyl or 5-7 membered heterocyclic group, which is optionally substituted by 1-3 independently R y Group substitution, R y Independently selected from oxo, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or 5-7 membered heterocyclic group.

2. The PI3Kγ kinase inhibitor according to claim 1, which is a compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof, in, W, R1, R2, R4, R5, m and n are as defined in the preceding claims, The heterocyclic group is selected from oxetanyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyranyl, and the heteroaryl is selected from pyridinyl, furanyl, pyrimidinyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, tetrazolyl or thiazolyl.

3. The PI3Kγ kinase inhibitor according to claim 2, wherein W is a direct key; R4 is selected from hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 haloalkyl, morpholinyl, piperazinyl, phenyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl or tetrazolyl, which is optionally substituted by 1-3 independently R x Group substitution, R x Independently selected from C 1-6 alkyl; R5 is a substituent on an alkylene group, wherein m is 0, 1 or 2, and R5 is independently selected from hydroxyl or halogen, or two R5 together with the carbon atom to which they are attached form a C 3-6 Cycloalkyl or oxetanyl.

4. The PI3Kγ kinase inhibitor according to claim 2, wherein W is NH; R4 is selected from phenyl, pyridyl or pyrimidinyl; m is 0.

5. The PI3Kγ kinase inhibitor according to claim 2, wherein W is O; R4 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-3 alkyl, phenyl, pyridyl or pyrazolyl, which is optionally substituted by 1-3 independently R x Group substitution, R x are independently selected from cyano, halogen, C 1-6 Alkyl or C 1-6 Alkoxy; m is 0.

6. The PI3Kγ kinase inhibitor according to claim 2, wherein W is -(C=O)-; R4 is selected from C 1-6 Alkylamino, C 3-6 Cycloalkylamino, C 1-6 Haloalkylamino, C 1-6 hydroxyalkylamino, tetrahydropyranylamino, morpholinylamino, piperidinylamino, piperazinylamino, pyridinylamino or thiazolylamino, which is optionally substituted by 1-3 independently R x Group substitution, R x Independently selected from C 1-6 alkyl; m is 0.

7. The PI3Kγ kinase inhibitor according to claim 2, wherein 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, morpholinylmethyl, phenyl, furanyl, thienyl or imidazolyl, which is optionally substituted by 1-3 independently R x Group substitution, R x Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino; m is 0.

8. The PI3Kγ kinase inhibitor according to any one of claims 2 to 7, wherein n is 2.

9. The PI3Kγ kinase inhibitor according to any one of claims 1 to 7, which is a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof, wherein Q is selected from N or CH, and W, R1, R2, R4, R5, m and n are as defined in any one of the preceding claims.

10. The PI3Kγ kinase inhibitor according to claim 1, which is a compound of formula (III) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof, in, R1 and R2 are as defined in any of the preceding claims, R6 and R7 are each independently selected from C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl or benzyl, or R6 and R7 together with the carbon atom to which they are attached form a C 3-6 Cycloalkyl or pyrrolidinyl, which is optionally substituted by 1-3 independently R y Group substitution, R y Independently selected from oxo, hydroxy, amino, C 1-3 Alkyl, C 1-3 Hydroxyalkyl or morpholinyl, The heterocyclic group is selected from oxetanyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyranyl, and the heteroaryl is selected from pyridinyl, furanyl, pyrimidinyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, tetrazolyl or thiazolyl.

11. The PI3Kγ kinase inhibitor according to claim 1, which is selected from the following compounds or pharmaceutically acceptable salts, solvates, polymorphs, esters, acids, isomers, metabolites or prodrugs thereof: 。 12. A pharmaceutical composition comprising the PI3Kγ kinase inhibitor according to any one of claims 1 to 11, and a pharmaceutically acceptable carrier or excipient, or optionally other therapeutic agents.

13. Use of the PI3Kγ kinase inhibitor according to any one of claims 1 to 11 in the preparation of a medicament for treating a PI3Kγ-mediated disease selected from cancer, inflammatory disease or autoimmune disease.

14. The method of claim 13, wherein the cancer is selected from one or more of the following: blood cancer, brain cancer, gastrointestinal cancer, skin cancer, urinary system cancer, pancreatic cancer, lung cancer, medulloblastoma, basal cell carcinoma, glioma, breast cancer, prostate cancer, testicular cancer, esophageal cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor, colon cancer, colorectal cancer, ovarian cancer, melanoma, neuroectodermal tumor, head and neck cancer, soft tissue sarcoma, fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, leiomyosarcoma, cervical cancer, uterine cancer, endometrial cancer, bladder cancer, epithelial cancer, squamous cell carcinoma, adenocarcinoma, bronchial carcinoma, renal cell carcinoma, bile duct cancer, neuroendocrine carcinoma, carcinoid tumor, diffuse giant cell tumor, glioblastoma or solid tumor.

15. The use of claim 13, 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, Crohn's disease or multiple sclerosis.

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