Crystals of free bases of inhibitors containing bicyclic derivatives, methods for producing the same, and their use.

Abstract

This invention relates to crystalline free bases of inhibitors containing bicyclic derivatives, and methods for preparing and using the same. Specifically, this invention relates to crystalline compounds of general formula (I), methods for preparing the same, and pharmaceutical compositions containing therapeutically effective amounts of the crystalline compounds, as well as to their use as RET inhibitors in the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease, and related diseases such as AIDS. [Formula 1] TIFF2023550069000218.tif38164

Description

Detailed description of the invention

[0001] This application claims priority to Chinese patent application 2020112717256, filed on November 13, 2020, and Chinese patent application 202111333586X, filed on November 11, 2021. This application incorporates the full text of the above Chinese patent applications.

[0002] [Technical field] This invention belongs to the field of biomedical technology and, more specifically, relates to crystals of free bases of inhibitors containing bicyclic derivatives, as well as methods for producing and using the same.

[0003] [Background technology] The RET (rearranged during transfection) protein is encoded by the proto-oncogene RET located on chromosome 10 and is a receptor tyrosine kinase consisting of an extracellular domain, a transmembrane domain, and an intracellular kinase domain. RET ligands are glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), such as GDNF, neuroturin (NRTN), artemin (ARTN), and percefin (PSPN). Activation of the receptor requires the synergistic effect of the co-receptor GFRα family. GFLs dimerize with GFRα, bind to RET, and recruit it to cholesterol-rich membrane regions. The RET protein then dimerizes and undergoes autophosphorylation, thereby activating downstream signaling pathways such as RAS-MAPK, PI3K-AKT, and PKC. RET plays a crucial role in the development of the kidney and enteric nervous system during embryonic development; it is also important for homeostasis of tissues such as neuroendocrine, hematopoietic, and male germ cells.

[0004] Impairment of RET protein function leads to the development of various diseases. During development, a lack of RET protein function can lead to a range of congenital disorders, such as Hirschsprung's disease (HSCR) and congenital kidney and urinary tract disorders (CAKUT). Activating mutations of the RET protein, including RET protein fusions caused by point mutations and chromosomal rearrangements, are also associated with the development of many diseases. RET fusions occur mainly in 1-2% of non-small cell lung cancer (NSCLC) patients and 5-10% of papillary thyroid carcinoma, while RET mutations occur mainly in 60% of medullary thyroid carcinoma, and activating mutations of the RET protein are found in many other tumors, including breast cancer, gastric cancer, colon cancer, and chronic myelomonocytic leukemia.

[0005] Despite significant clinical needs, current treatments targeting RET (Reactive Emission Tomography) still have major limitations. Unlike the highly effective clinical efficacy of targeted drugs for ALK and EGFR, there are currently no approved targeted drugs for RET. Clinically, multi-kinase inhibitors (MKIs) such as vandetinib and cabozantinib are primarily used, but these MKIs suffer from low selectivity, significant side effects, and low efficacy, and the problem of drug resistance during the course of treatment remains unresolved.

[0006] Due to the demand for RET-targeted drugs, many pharmaceutical companies both domestically and internationally have begun developing RET-specific targeted drugs. Among these, two that stand out are Loxo-292 from Loxo Oncology, which has entered Phase I / II clinical trials, and BLU-667 from Blueprint, which has entered Phase I clinical trials. These two targeted drugs have shown excellent efficacy and safety in preclinical trials in patients with RET-activating mutations, and have overcome drug resistance mutations that can occur in preclinical activity screening. In the future, they are expected to bring more treatment options for cancers with RET-activating mutations.

[0007] Currently, there are no specific targeted drugs for RET targets, and there is a significant clinical demand. RET inhibitors, with their higher selectivity, superior activity, better safety, and ability to overcome drug-resistant mutations, have the potential to treat a variety of cancers and represent a broad market outlook.

[0008] In a PCT international application (application number: PCT / CN2020 / 090142) filed by Jiangsu Hansoh Pharmaceutical Group Co., Ltd., the structure of an inhibitor containing a bicyclic derivative is disclosed. Subsequent research and development has focused on simplifying the process manufacturing method and improving stability and bioavailability. The present invention has conducted a comprehensive study of the free base of the above-mentioned substance and is working to obtain stable crystals that are easy to process, easy to store, and have high bioavailability, making them suitable for future pharmaceutical development.

[0009] [Overview of the prefecture] All content contained in patent PCT / CN2020 / 090142 is incorporated by reference into this invention.

[0010] The object of the present invention is to provide crystals of a compound represented by general formula (I).

[0011] [ka]

[0012] however: L is selected from -CH2- or -NHC(O)-, M is selected from CR or N. R represents hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, and C. 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 Selected from aryl or 5- to 12-membered heteroaryl, X1 is CR a Or selected from N, X2 is CR b Or selected from N, R a And R b Are each independently hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 Selected from aryl or 5- to 12-membered heteroaryl, R1, R2 and R3 are each independently hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 Selected from aryl or 5- to 12-membered heteroaryl, R4 is C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic group, -O(CH2) m R5, -(CH2) m R5, -NR6(CH2) mR5, -NR6C(O)R5, -CH=CH-(CH2) m R5, -O(CH2) m S(O)R5, -O(CH2) m S(O)2R5 or -O(CH2) m S(O)(=NH)R5, C 2-6 Alkenil, C 2-6 Selected from alkynyl and 3- to 8-membered heterocyclic groups, and further optionally, deuterium, halogen, amino, nitro, hydroxy, cyano, and C 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Substituted with one or more substituents of aryl and 5-12 membered heteroaryl groups, R5 and R6 are independently hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, and C. 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Selected from aryl or 5-12 member heteroaryls, C 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenil, C2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 12-membered heteroaryl may further optionally be deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thiol, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl, 5- to 12-membered heteroaryl, =NH, -(CH2) t R7, -(CH2) t OR7 and -(CH2) t substituted by one or more substituents of C(O)NR7R8, R7 and R8 are each independently hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 [[ID=^41]]haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 selected from aryl or 5- to 12-membered heteroaryl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C It should be noted that there may be some inaccuracies in the original text, especially in the repeated and seemingly incomplete expressions. This translation is done as accurately as possible based on the given text.3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 member heteroaryls can be further optionally combined with deuterium, halogen, amino, nitro, hydroxy, cyano, or C. 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Substituted with one or more substituents of aryl and 5-12 membered heteroaryl groups, n is 0, 1, 2, or 3. m is 0, 1, 2 or 3, and t is 0, 1, 2, or 3.

[0013] In a more preferred embodiment of the present invention, M is selected from CR or N. R is hydrogen, amino acid, or C 1-3 Selected from alkyl groups, Preferably hydrogen, amino or methyl, X1 is CR a Or selected from N, X2 is CR b Or selected from N, R a and R b These are hydrogen, deuterium, halogen, and C, respectively, independently. 1-3 Alkyl or C 1-3 Selected from alkoxy, Preferably, hydrogen, fluorine, chlorine, methyl or methoxy, R1, R2, and R3 are independently hydrogen, deuterium, halogen, and C, respectively. 1-3 Alkyl or C 1-3 Selected from alkoxy, Preferably, it is hydrogen, fluorine, chlorine, methyl, or methoxy.

[0014] In a more preferred embodiment of the present invention, R4 is C 2-3 Alkinyl, C 2-3 Alkenyl, a heterocyclic group containing 3-8 nitrogen or oxygen atoms, -O(CH2) m R5, -(CH2) m R5, -NR6(CH2) m R5, -NHC(O)R5, -CH=CH-(CH2) m R5, -O(CH2) m S(O)R5, -O(CH2) m S(O)2R5 or -O(CH2) m Selected from S(O)(=NH)R5, the 3-8 member nitrogen or oxygen atom-containing heterocyclic group may further optionally contain deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, or C 1-3 Alkyl, C 1-3 Hydroxyalkyl or C 1-3 Substituted with one or more substituents of alkoxy, Preferably vinyl, ethinyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, 2-azaspiro[3.3]heptanyl, -OCH2R5, -O(CH2)2R5, -(CH2)2R5, -NR6(CH2) m R5, -NHC(O)R5, -CH=CH-(CH2) m R5, -O(CH2) m S(O)R5, -O(CH2) m S(O)2R5 or -O(CH2) m Selected from S(O)(=NH)R5, vinyl, ethinyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl and 2-azaspiro[3.3]heptanyl are further optionally substituted with one or more substituents of deuterium, hydroxy, cyano, methyl, hydroxyethyl, 2-hydroxyisopropyl, and 2-aminoisopropyl. R5 is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-3 Alkyl, C 1-3 Alkyl deuterated, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 2-3 Alkenil, C 2-3 Alkinyl, C 3-6 Selected from cycloalkyl or 3- to 8-membered heterocyclic groups, C 1-3 Alkyl, C 1-3 Alkyl deuterated, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 2-3 Alkenil, C 2-3 Alkinyl, C 3-6 Cycloalkyl and 3- to 8-membered heterocyclic groups may further optionally contain deuterium, halogen, amino, nitro, hydroxy, cyano, or C. 1-3 Alkyl, C 1-3 Alkyl deuterated, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 2-3 Alkenil, C 2-3 Alkinyl, C 3-6 Substituted with one or more substituents of a cycloalkyl group, a 3- to 8-membered heterocyclic group, -CH2R7, -CH2OR7, and -C(O)NR7R8, Preferably, the substituents are methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, ethynyl, oxethenyl, thietanyl, azetidinyl, tetrahydropyranyl, bicyclo[1.1.1]pentanyl, or tetrahydro-2H-thiopyran, and the substituents are further optionally substituted with one or more substituents of deuterium, hydroxy, amino, cyano, fluorine, chlorine, bromine, methoxy, ethynyl, cyclopropyl, hydroxyethyl, oxo, =NH, -CH2OCH3, -C(O)NH2, and -C(O)NHCH3. R6 is hydrogen, deuterium, halogen, amino, hydroxyl, or C 1-3 Selected from alkyl groups, Preferably hydrogen, deuterium, or methyl, R7 and R8 are independently hydrogen, deuterium, halogen, amino, hydroxyl, or C 1-3 Selected from alkyl groups, Preferably hydrogen, deuterium, or methyl, n is 0, 1, 2 or 3, and m is 0, 1, 2, or 3.

[0015] In a more preferred embodiment of the present invention, the compound is further represented by general formula (II).

[0016] [ka]

[0017] R2 is selected from hydrogen, fluorine, or chlorine. R4 is -O(CH2) m R5, -(CH2) m R5 or -NR6(CH2) m Selected from R5, R5 is C 2-3Selected from alkynyls, preferably further optionally deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-3 Alkyl, C 1-3 Alkyl deuterated, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl or C 3-6 It is substituted with one or more cycloalkyl substituents.

[0018] In a more preferred embodiment of the present invention, the compound is 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride, characterized in that the crystal is a type I, type II, type III, type IV, or type V crystal.

[0019] Most preferably, and in a more preferred embodiment of the present invention, Example 63 represents a type I crystal of the compound 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0020] The powder X-ray spectrum of the type I crystal has diffraction peaks at 2θ of 5.0±0.2°, or at 9.6±0.2°, or at 15.0±0.2°, or at 17.2±0.2°, or at 22.2±0.2°, or at 19.4±0.2°, or at 30.2±0.2°, or at 8.2±0.2°, or at 25.1±0.2°, or at 26.9±0.2°, preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably including any 6, 7, or 8 of them. The powder X-ray spectrum of the type I crystal has diffraction peaks at 2θ 5.0±0.2°, or at 8.2±0.2°, or at 9.6±0.2°, or at 12.9±0.2°, or at 15.0±0.2°, or at 17.2±0.2°, or at 15.4±0.2°, or at 16.6±0.2°, or at 17.7±0.2°, or at 18.5±0.2°, preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably including any 6, 7, or 8 of them. As a specific example, the powder X-ray spectrum of a type I crystal includes diffraction peaks located at one or more locations where 2θ is at least 5.0±0.2°, 9.6±0.2°, and 15.0±0.2°, preferably including two of these locations, more preferably three, and optionally including at least one more location where 2θ is at 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 30.2±0.2°, or 8.2±0.2°, preferably including two, three, four, or five of these locations. The diffraction peaks are located at 2θ of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, and 19.4±0.2°. Alternatively, the diffraction peaks located at 2θ 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, and 8.2±0.2° are included. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, and 8.2±0.2°. The powder X-ray spectrum of the type I crystal includes diffraction peaks located at one or more locations with 2θ of at least 5.0±0.2°, 8.2±0.2°, and 9.6±0.2°, preferably including two of these locations, more preferably three, and optionally including at least one more location with 2θ of 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, or 16.6±0.2°, preferably including two, three, four, or five of these locations. The diffraction peaks are located at 2θ of 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, and 17.2±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, and 15.4±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, and 16.6±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, and 15.4±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 8.2±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, and 16.6±0.2°. Preferably, the powder X-ray spectrum of the type I crystal further optionally includes diffraction peaks located at one or more locations where 2θ is 10.0±0.2°, 25.4±0.2°, 26.9±0.2°, 13.0±0.2°, 12.9±0.2°, or 20.0±0.2°, preferably including at least any 2-3, 4-5, or 6-7 of these locations, and more preferably including any 2, 3, 4, 5, 6, or 7 of these locations. The diffraction peaks are located at 2θ of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 26.9±0.2°, and 10.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 26.9±0.2°, and 25.4±0.2°. Preferably, the powder X-ray spectrum of the type I crystal further optionally includes diffraction peaks located at one or more locations where 2θ is 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, 19.3±0.2°, or 24.0±0.2°, preferably including at least any 2-3, 4-5, or 6 of these locations, and more preferably including any 2, 3, 4, 5, or 6 of these locations. The diffraction peaks are located at 2θ of 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, and 19.3±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, 19.3±0.2°, and 24.0±0.2°. More preferably, the powder X-ray spectrum of the type I crystal includes diffraction peaks located at one or more of the following locations with 2θ: 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 30.2±0.2°, 25.1±0.2°, 10.0±0.2°, 25.1±0.2°, 25.4±0.2°, 26.9±0.2°, 13.0±0.2°, 12.9±0.2°, or 20.0±0.2°, and preferably includes diffraction peaks located at any of the following locations: The powder X-ray spectrum of type I crystals is 2θ The locations at 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, and 17.2±0.2°, Alternatively, at the locations of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, and 22.2±0.2°, Alternatively, at the locations of 5.0±0.2°, 9.6±0.2°, 17.2±0.2°, and 22.2±0.2°, Alternatively, at the locations of 5.0±0.2°, 15.0±0.2°, 17.2±0.2° and 22.2±0.2°, Alternatively, at the locations of 9.6±0.2°, 15.0±0.2°, 17.2±0.2° and 22.2±0.2°, Alternatively, at the locations of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2° and 25.1±0.2°, Alternatively, at the locations of 8.2±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 19.4±0.2°, 22.2±0.2°, 25.1±0.2° and 25.4±0.2°, Alternatively, diffraction peaks are present at 5.0±0.2°, 10.0±0.2°, 15.0±0.2°, 17.2±0.2°, 19.4±0.2°, 22.2±0.2°, 25.1±0.2°, and 25.4±0.2°.

[0021] More preferably, the powder X-ray spectrum of the type I crystal includes diffraction peaks located at one or more of the following locations with 2θ: 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, 19.3±0.2°, or 24.0±0.2°, and preferably includes diffraction peaks located at any of the following locations: The powder X-ray spectrum of type I crystals is 2θ The locations at 5.0±0.2°, 8.2±0.2°, and 9.6±0.2°, Alternatively, at the points of 5.0±0.2°, 8.2±0.2°, 9.6±0.2° and 12.9±0.2°, Alternatively, at the points of 8.2±0.2°, 9.6±0.2°, 12.9±0.2° and 15.0±0.2°, Alternatively, at the locations of 9.6±0.2°, 12.9±0.2°, 15.0±0.2° and 17.2±0.2°, Alternatively, at the locations of 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, and 15.4±0.2°, Alternatively, at the points of 15.0±0.2°, 17.2±0.2°, 15.4±0.2° and 16.6±0.2°, Alternatively, at the locations of 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2° and 17.2±0.2°, Alternatively, at the locations of 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2° and 15.4±0.2°, Alternatively, at the locations of 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2° and 16.6±0.2°, Alternatively, at the locations of 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2° and 17.7±0.2°, Alternatively, at the following locations: 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2° and 18.5±0.2°, Alternatively, diffraction peaks are present at 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, and 19.3±0.2°.

[0022] The characteristic X-ray diffraction peaks, expressed using the Cu-Kα line and corresponding to the 2θ angle and the interplanar spacing d-value, are shown in Table 1.

[0023] [Table 1]

[0024] Example 63 of the present invention represents a type I crystal of compound 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, the powder X-ray spectrum is basically as shown in Figure 1, the DSC spectrum is basically as shown in Figure 2, the melting point of the type I crystal is 216.8~218.4°C, and the TGA spectrum is basically as shown in Figure 3.

[0025] In a more preferred embodiment of the present invention, Example 63 represents a type II crystal of the compound 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0026] The powder X-ray spectrum of the type II crystal includes diffraction peaks located at one or more locations with 2θ of at least 4.8±0.2°, 17.7±0.2°, and 16.6±0.2°, preferably including two of these locations, more preferably three, and optionally including at least one more location with 2θ of 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 17.0±0.2°, or 18.6±0.2°, preferably including two, three, four, or five of these locations. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, and 19.1±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, and 17.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, and 18.6±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, and 17.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, and 17.0±0.2°. Preferably, the powder X-ray spectrum of the type II crystal further optionally includes diffraction peaks located at one or more locations where 2θ is 4.5±0.2°, 15.4±0.2°, 14.6±0.2°, 24.0±0.2°, 21.5±0.2°, 20.5±0.2°, or 18.0±0.2°, preferably including at least any 2-3, 4-5, or 6-7 of these locations, and more preferably including any 2, 3, 4, 5, 6, or 7 of these locations. The diffraction peaks are located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 4.5±0.2°, and 15.4±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 4.5±0.2°, and 14.6±0.2°. More preferably, the powder X-ray spectrum of the type II crystal includes diffraction peaks located at one or more of the following 2θ values: 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 17.0±0.2°, 18.6±0.2°, 4.5±0.2°, 15.4±0.2°, 14.6±0.2°, 24.0±0.2°, 21.5±0.2°, 20.5±0.2°, or 18.0±0.2°, and preferably includes diffraction peaks located at four, five, six, eight, or ten of these values, optionally selected. The powder X-ray spectrum of type II crystals is 2θ The locations at 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, and 9.4±0.2°, The locations at 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, and 18.4±0.2°, The following locations are affected: 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, and 20.5±0.2°. The following locations are affected: 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 17.0±0.2°, and 18.6±0.2°. Diffraction peaks are observed at the following locations: 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 17.0±0.2°, 18.6±0.2°, 4.5±0.2°, and 14.6±0.2°.

[0027] More preferably, the powder X-ray spectra of the type II crystals have 2θ values ​​of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 17.0±0.2°, 18.6±0.2°, 4.5±0.2°, 15.4±0.2°, 14.6±0.2°, 24.0±0.2°, and 21.5±0. It includes diffraction peaks located at one or more of the following locations: 0.2°, 20.5±0.2°, 18.0±0.2°, 26.0±0.2°, 22.0±0.2°, 14.8±0.2°, 28.8±0.2°, or 25.4±0.2°, preferably including diffraction peaks located at 6, 8, 10, 11, or 12 of these locations, The characteristic X-ray diffraction peaks, expressed using the Cu-Kα line and corresponding to the 2θ angle and the interplanar spacing d-value, are shown in Table 2.

[0028] [Table 2]

[0029] Example 63 of the present invention represents a type II crystal of compound 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, the powder X-ray spectrum is basically as shown in Figure 4, the DSC spectrum is basically as shown in Figure 5, and the TGA spectrum is basically as shown in Figure 6.

[0030] In a more preferred embodiment of the present invention, Example 63 represents a type III crystal of the compound 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0031] The powder X-ray spectrum of the type III crystal has diffraction peaks at 2θ of 4.6±0.2°, or at 15.2±0.2°, or at 9.9±0.2°, or at 16.7±0.2°, or at 18.2±0.2°, or at 17.9±0.2°, or at 25.5±0.2°, or at 15.0±0.2°, or at 19.5±0.2°, or at 23.6±0.2°, preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably including any 6, 7, or 8 of them. The powder X-ray spectrum of a type III crystal includes diffraction peaks located at one or more locations where 2θ is at least 4.6±0.2°, 15.2±0.2°, or 9.9±0.2°, preferably including two of these locations, more preferably three, and optionally including at least one more location where 2θ is at 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 25.5±0.2°, or 15.0±0.2°, preferably including two, three, four, or five of these locations. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, and 17.9±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, and 25.5±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, and 15.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, and 25.5±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 18.2±0.2°, 17.9±0.2°, and 15.0±0.2°. The powder X-ray spectrum of the type III crystal further optionally includes diffraction peaks located at one or more locations where 2θ is 19.5±0.2°, 23.6±0.2°, 26.1±0.2°, 22.0±0.2°, 20.2±0.2°, 21.1±0.2°, or 27.4±0.2°, preferably including at least any 2-3, 4-5, or 6-7 of these locations, and more preferably including any 2, 3, 4, 5, 6, or 7 of these locations. The diffraction peaks are located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 19.5±0.2°, and 23.6±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 19.5±0.2°, and 26.1±0.2°. The powder X-ray spectrum of a type III crystal includes diffraction peaks located at one or more of the following 2θ values: 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 25.5±0.2°, 15.0±0.2°, 19.5±0.2°, 23.6±0.2°, 26.1±0.2°, 22.0±0.2°, 20.2±0.2°, 21.1±0.2°, or 27.4±0.2°, preferably including diffraction peaks located at four, five, six, eight, or ten of these values, which can be selected as needed. The powder X-ray spectrum of type III crystals is as follows: 2θ The locations at 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, and 16.7±0.2°, Alternatively, at the locations of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, and 18.2±0.2°, Alternatively, at the locations of 4.6±0.2°, 15.2±0.2°, 16.7±0.2° and 18.2±0.2°, Alternatively, at the locations of 4.6±0.2°, 9.9±0.2°, 16.7±0.2°, and 18.2±0.2°, Alternatively, at the locations of 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, and 18.2±0.2°, The following locations are affected: 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, and 17.9±0.2°. The following locations are affected: 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 26.1±0.2°, and 22.0±0.2°. Diffraction peaks are observed at 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 25.5±0.2°, 15.0±0.2°, 19.5±0.2°, and 23.6±0.2°.

[0032] The characteristic X-ray diffraction peaks, expressed using Cu-Kα rays and corresponding to the 2θ angle and the interplanar spacing d-value, are shown in Table 3.

[0033] [Table 3]

[0034] Example 63 of the present invention represents a type III crystal of compound 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, the powder X-ray spectrum is basically as shown in Figure 7, the DSC spectrum is basically as shown in Figure 8, and the TGA spectrum is basically as shown in Figure 9.

[0035] In a more preferred embodiment of the present invention, Example 63 represents the type IV crystal of compound 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0036] The powder X-ray spectrum of the type IV crystal has diffraction peaks at 2θ of 5.0±0.2°, or at 4.8±0.2°, or at 15.0±0.2°, or at 19.1±0.2°, or at 14.3±0.2°, or at 10.0±0.2°, or at 23.9±0.2°, or at 25.1±0.2°, or at 30.3±0.2°, or at 9.6±0.2°, preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably including any 6, 7, or 8 of them. The powder X-ray spectrum of the type IV crystal includes diffraction peaks located at one or more locations where 2θ is at least 5.0±0.2°, 4.8±0.2°, or 15.0±0.2°, preferably including two of these locations, more preferably three, and optionally including at least one more location where 2θ is at 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, or 25.1±0.2°, preferably including two, three, four, or five of these locations. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, and 10.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, and 23.9±0.2°. The powder X-ray spectrum of the type IV crystal further optionally includes diffraction peaks located at one or more locations where 2θ is 30.3±0.2° or 9.6±0.2°, preferably including at least any 2-3, 4-5, or 6-7 such peaks, and more preferably including any 2, 3, 4, 5, 6, or 7 such peaks. The diffraction peaks are located at 2θ of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, and 30.3±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, and 9.6±0.2°. The powder X-ray spectrum of type IV crystals includes diffraction peaks located at one or more of the following 2θ values: 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, 25.1±0.2°, 30.3±0.2°, or 9.6±0.2°, preferably including, optionally, 4, 5, 6, 8, or 10 diffraction peaks located at these values. The powder X-ray spectrum of type IV crystals shows that 2θ is It includes diffraction peaks located at 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, and 19.1±0.2°. Alternatively, at the locations of 5.0±0.2°, 4.8±0.2°, 15.0±0.2° and 14.3±0.2°, Alternatively, at the locations of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 23.9±0.2° and 25.1±0.2°, Alternatively, at the following locations: 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, and 25.1±0.2°. Alternatively, at the following locations: 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, 25.1±0.2°, and 30.3±0.2°. Alternatively, diffraction peaks are present at 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, 25.1±0.2°, 30.3±0.2°, and 9.6±0.2°.

[0037] Table 4 shows the characteristic X-ray diffraction peaks, expressed using the Cu-Kα line, based on the 2θ angle and the interplanar spacing d value.

[0038] [Table 4]

[0039] Example 63 of the present invention represents a type IV crystal of compound 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, the powder X-ray spectrum is basically as shown in Figure 10, the DSC spectrum is basically as shown in Figure 11, and the TGA spectrum is basically as shown in Figure 12.

[0040] In a more preferred embodiment of the present invention, Example 63 represents a V-type crystal of the compound 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0041] The powder X-ray spectrum of the V-type crystal has a diffraction peak at 2θ of 4.7±0.2°, or at 18.2±0.2°, or at 10.1±0.2°, or at 18.8±0.2°, or at 15.6±0.2°, or at 17.0±0.2°, or at 21.8±0.2°, or at 14.7±0.2°, or at 19.3±0.2°, or at 25.8±0.2°, preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably including any 6, 7, or 8 of them.

[0042] The powder X-ray spectrum of the V-type crystal includes diffraction peaks located at one or more locations where 2θ is at least 4.7±0.2°, 18.2±0.2°, or 10.1±0.2°, preferably including two of these locations, more preferably three, and optionally including at least one more location where 2θ is at 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 21.8±0.2°, or 14.7±0.2°, preferably including two, three, four, or five of these locations. Alternatively, the diffraction peaks include those located at 2θ of 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, and 17.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, and 21.8±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, and 14.7±0.2°.

[0043] The powder X-ray spectrum of the V-type crystal further optionally includes diffraction peaks located at one or more locations where 2θ is 19.3±0.2°, 25.8±0.2°, 15.2±0.2°, 17.8±0.2°, 20.4±0.2°, 23.5±0.2°, or 25.6±0.2°, preferably including at least any 2-3, 4-5, or 6-7 of these locations, and more preferably including any 2, 3, 4, 5, 6, or 7 of these locations. It includes diffraction peaks located at 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 19.3±0.2° and 25.8±0.2°. Alternatively, it includes diffraction peaks located at 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 19.3±0.2°, and 15.2±0.2°.

[0044] The powder X-ray spectrum of the V-type crystal includes diffraction peaks located at one or more of the following 2θ values: 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 21.8±0.2°, 14.7±0.2°, 19.3±0.2°, 25.8±0.2°, 15.2±0.2°, 17.8±0.2°, 20.4±0.2°, 23.5±0.2°, or 25.6±0.2°, preferably including diffraction peaks located at four, five, six, eight, or ten of these values, which can be selected as needed. The powder X-ray spectrum of a V-type crystal shows that 2θ is It includes diffraction peaks located at 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, and 18.8±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.7±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, and 21.8±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 21.8±0.2°, and 14.7±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 21.8±0.2°, 14.7±0.2°, 19.3±0.2°, and 15.2±0.2°.

[0045] The characteristic X-ray diffraction peaks, expressed using the Cu-Kα line and corresponding to the 2θ angle and the interplanar spacing d-value, are shown in Table 5.

[0046] [Table 5]

[0047] Example 63 of the present invention represents a V-type crystal of compound 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, the powder X-ray spectrum is basically as shown in Figure 13, the DSC spectrum is basically as shown in Figure 14, and the TGA spectrum is basically as shown in Figure 15.

[0048] The crystal described in the present invention is characterized in that the 2θ error between the position of the diffraction peak with the top 10 relative peak intensities in its powder X-ray spectrum and the diffraction peak at the corresponding position in the corresponding figure is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0049] In a preferred embodiment of the present invention, the crystals of any compound represented by general formula (I) are either solvent-containing or solvent-free, where the solvent is selected from one or more of the following: water, methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, n-heptane, heptane, ethyl formate, isopropyl acetate, cyclohexane, methyl tert-butyl ether, or isopropyl ether.

[0050] In a preferred embodiment of the present invention, the number of solvents in the crystals of any compound represented by general formula (I) is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5, or 3, and more preferably 0.5, 1, 2, or 3.

[0051] In a preferred embodiment of the present invention, the crystals of the compound represented by general formula (I) are non-solvent crystals, and preferably anhydrous crystals. In a preferred embodiment of the present invention, the crystals of the compound represented by general formula (I) are aqueous crystals, with the number of water molecules being 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5, or 3, and more preferably 0.5, 1, 2, or 3.

[0052] In a more preferred embodiment of the present invention, the crystals of compound 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile are non-solvent compounds, preferably anhydrous or aqueous compounds.

[0053] In a more preferred embodiment of the present invention, the number of water molecules in the aqueous crystal of compound 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5, or 3, and more preferably 0.5, 1, 2, or 3.

[0054] Those skilled in the art are well aware that XRPDs can exhibit predetermined displacements and intensity deviations due to detection methods, conditions, and equipment. As a specific example of the crystal of the present invention, its XRPD is shown in Figure X, and those skilled in the art know that when the deviation of the displacement 2θ of the main characteristic peak is ±0.5, particularly about ±0.2, they can all be identified as the same crystal.

[0055] The present invention also provides a method for producing crystals of a compound represented by general formula (I), which specifically includes the following steps. 1) Weigh an appropriate amount of free base, suspend it in a poor solvent, and the suspension density is preferably 50-200 mg / mL. 2) Shake the suspension obtained above, preferably at a temperature of 0 to 50°C, and preferably for a period of 4 hours to 10 days. 3) The above suspension is quickly centrifuged, the supernatant is removed, and the remaining solid is placed in a vacuum dryer at 50°C and dried until the weight is constant to obtain the target product. however: The poor solvent is selected from methanol, acetone, ethyl acetate, tetrahydrofuran, acetonitrile, ethanol, 88% acetone, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, methyl tert-butyl ether, n-heptane, benzene, toluene, chlorobenzene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, ethyl formate, isopropyl acetate, tert-butanol, 2-butanone, or 3-pentanone, and is preferably acetonitrile, acetone, ethyl acetate, methanol, or ethanol.

[0056] The present invention also provides a method for producing crystals of a compound represented by general formula (I), which specifically includes the following steps. 1) Weigh out an appropriate amount of free base and dissolve it in a good solvent. 2) Optionally, add the reverse solvent to the solution obtained above. 3) Stir until a solid precipitates, preferably at a crystallization temperature of 0-50°C. 4) Optionally, quickly centrifuge the above suspension, 5) Remove the supernatant and dry the remaining solid to obtain the target product. however: Good solvents are selected from methanol, acetone, ethyl acetate, tetrahydrofuran, acetonitrile, ethanol, 88% acetone, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, chlorobenzene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, ethyl formate, isopropyl acetate, tert-butanol, 2-butanone, or 3-pentanone, and preferably dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, acetonitrile, or 2-butanone.

[0057] The poor solvent is selected from methanol, ethanol, ethyl acetate, acetone, isopropanol, toluene, n-heptane, water, isopropyl acetate, cyclohexane, methyl tert-butyl ether, and isopropyl ether, and is preferably water, n-heptane, cyclohexane, and methyl tert-butyl ether.

[0058] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a crystalline general formula compound represented by formula (I), and one or more pharmaceutically acceptable carriers or excipients. The object of the present invention is also to provide the use of crystals of the compound 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, represented by formula (I), and pharmaceutical compositions thereof, in the production of RET inhibitors.

[0059] The object of the present invention is to provide the use of crystalline compounds and pharmaceutical compositions of a compound represented by general formula (I) in the manufacture of a pharmacopoeia for the treatment and / or prevention of tumors, wherein the tumor is preferably selected from non-small cell lung cancer, fibrosarcoma, pancreatic tumor, medullary thyroid cancer, papillary thyroid tumor, soft tissue sarcoma, high-grade solid tumor, breast tumor, and colon tumor.

[0060] Crystals can be identified by powder X-ray spectroscopy. However, those skilled in the art know that the peak intensity and / or peak characteristics of powder X-ray diffraction may vary depending on different experimental conditions, such as different diffraction test conditions and / or preferred orientation. At the same time, because different instruments have different accuracies, the measured 2θ values ​​may have an error of about ±0.2, and individual peaks may have an error of about ±0.3 or ±0.4. However, it is known that the relative intensity values ​​of peaks depend more on the characteristics of the sample being measured, such as the size of the crystals in the sample, the crystal orientation effect, and the purity of the analyte, than on the position of the peaks, and the expressed peak intensity deviation can be about ±20% or more.

[0061] [Detailed description of the invention] Unless otherwise stated, the terms used in the specification and claims of this invention have the following meanings: The term "alkyl" refers to a linear or branched saturated hydrocarbon group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, This includes 3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof.More preferably, it is a lower alkyl containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available connection point. The substituent is preferably one or more of the following groups, which are independently alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carbamate group. In the present invention, it is preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

[0062] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl; polycyclic cycloalkyls include spiro, condensed, and crosslinked cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl, more preferably cyclopropyl, cyclobutyl, and cyclopentyl.

[0063] The term "heterocyclic group" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents, which contain 3 to 20 ring atoms, one or more of which are nitrogen, oxygen, or S(O). m The heteroatoms are selected from (where m is an integer from 0 to 2) but do not include the -OO-, -OS-, or -SS- ring portion, and the remaining ring atoms are carbon. Preferably, the group contains 3 to 12 ring atoms, where 1 to 4 are heteroatoms, more preferably 3 to 8 ring atoms, and most preferably 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietanyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, and preferably oxetanyl, pyrrolidonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl. Polycyclic heterocyclic groups include heterocyclic groups of spiro rings, fused rings, and bridging rings; where the relevant polycyclic groups of spiro rings, fused rings, and bridging rings are optionally linked to other groups through single bonds, or further linked to other cycloalkyl, heterocyclic groups, aryl, and heteroaryl groups through any two or more atoms on the ring.

[0064] The multiple ring groups may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carbamate.

[0065] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above. "Haloalkoxy" refers to an alkoxy substituted with one or more halogens, where alkoxy is as defined above.

[0066] "Hydroxyalkyl" refers to an alkyl group substituted with hydroxyl, where the alkyl group is as defined above. "Alkenyl" refers to an alkenyl group, also called an alkenyl, where alkenyl can be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carbamate.

[0067] "Alkynyl" refers to (CH≡C-), where alkynyl can be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carbamate.

[0068] "Hydroxy" refers to the -OH group. "Halogen" refers to fluorine, chlorine, bromine, or iodine. "Amino" refers to -NH2.

[0069] "Cyano" refers to -CN. "Nitro" refers to -NO2. "Carboxyl" refers to -C(O)OH.

[0070] "THF" refers to tetrahydrofuran. ",'' ,'' refers to ethyl acetate. "MeOH" refers to methanol.

[0071] "DMF" refers to N,N-dimethylacetamide. "DIPEA" refers to diisopropylethylamine. "TFA" refers to trifluoroacetic acid.

[0072] "MeCN" refers to acetonitrile. "DMA" refers to N,N-dimethylacetamide. "Et2O" refers to diethyl ether.

[0073] "DCE" refers to 1,2-dichloroethylene. "DIPEA" refers to N,N-diisopropylethylamine. "NBS" refers to N-bromosuccinimide.

[0074] "NIS" refers to N-iodobromosuccinimide. "Cbz-Cl" refers to benzyl chloroformate. "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0075] "Dppf" refers to 1,1'-bis(diphenylphosphin)ferrocene. "HATU" refers to 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0076] "KHMDS" refers to potassium hexamethyldisilazide. "LiHMDS" refers to lithium bis(trimethylsilyl)amide. "MeLi" refers to methyllithium.

[0077] "n-BuLi" refers to n-butyllithium. "NaBH(OAc)3" refers to sodium triacetoxyborohydride. "DMAP" refers to 4-dimethylaminopyridine.

[0078] "SEM-Cl" refers to chloromethyltrimethylsilylethyl ether. "Xantphos" refers to 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene.

[0079] "DCM" refers to dichloromethane. Different terms such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all express the same meaning, i.e., X can be any one or more of A, B, and C.

[0080] Any hydrogen atom in the present invention can be replaced with its isotope, deuterium, and any hydrogen atom in the example compounds according to the present invention can also be replaced with a deuterium atom. "Optional" or "optionally" means that the following matters or circumstances may occur but are not necessarily expected to occur, and the description includes both cases where the matters or circumstances described therein occur and cases where they do not occur. For example, "optionally alkyl-substituted multiple ring groups" means that alkyl groups may be present but are not necessarily required, and the description includes both cases where multiple ring groups are substituted with alkyl groups and cases where multiple ring groups are not substituted with alkyl groups.

[0081] "Substituting" means that one or more hydrogen atoms of a group, preferably up to five, and more preferably one to three, are independently substituted with a corresponding number of substituents. Needless to say, substituents are only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions with little effort (through experiment and theory). For example, when an amino or hydroxyl group containing free hydrogen is bonded to a carbon atom having an unsaturated (e.g., olefin) bond, it can be unstable.

[0082] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs with other chemical components, as well as other components such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of the "pharmaceutical composition" is to facilitate administration to a living organism, to facilitate the absorption of the active ingredient, and thereby to exert biological activity.

[0083] "Pharmacologically acceptable salt" refers to a salt of the compound of the present invention, which, when used in mammals, is safe and effective and possesses the desired biological activity. [Brief explanation of the drawing]

[0084] [Figure 1]XRPD spectrum of Form I crystal of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxo)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 2] DSC spectrum of Form I crystal of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxo)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 3] TGA spectrum of Form I crystal of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxo)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 4] XRPD spectrum of Form II crystal of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxo)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 5] DSC spectrum of Form II crystal of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxo)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 6]It is the TGA spectrum of the type II crystal of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxo)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 7] It is the XRPD spectrum of the type III crystal of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxo)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 8] It is the DSC spectrum of the type III crystal of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxo)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 9] It is the TGA spectrum of the type III crystal of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxo)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 10] It is the XRPD spectrum of the type IV crystal of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxo)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 11]This is the DSC spectrum of the type IV crystal of 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 12] This is the TGA spectrum of the type IV crystal of 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 13] This is the XRPD spectrum of the V-type crystal of 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 14] This is the DSC spectrum of the V-type crystal of 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 15] This is the TGA spectrum of the V-type crystal of 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Figure 16]This is the DVS spectrum of the type I crystal of 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. [Modes for carrying out the invention]

[0085] The present invention will be further described below based on examples, but the present invention is not limited to the scope of these examples. 1. Manufacturing of the compound Examples The structure of the compounds of the present invention can be identified by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is recorded in parts per million (ppm). A Bruker AVANCE-400 nuclear magnetic resonance spectrometer is used for NMR measurements, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0086] For liquid chromatography-mass spectrometry (LC-MS) measurements, an Agilent 1200 Infinity Series mass spectrometer is used. For HPLC measurements, an Agilent 1200DAD high-performance liquid chromatography system (column: Sunfire C18 150×4.6mm) and a Waters 2695-2996 high-performance liquid chromatography system (column: Gimini C18 150×4.6mm) are used.

[0087] Thin-layer chromatography uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. TLC uses plates with a thickness of 0.15 mm to 0.20 mm, while thin-layer chromatography for product separation and purification uses plates with a thickness of 0.4 mm to 0.5 mm. Column chromatography typically uses Yantai Huanghai silica gel with a thickness of 200 to 300 mesh as the support.

[0088] The starting materials used in the embodiments of this invention are known and commercially available, or can be synthesized according to methods known in the art. Unless otherwise specified, all reactions of the present invention are carried out under a continuous magnetic stirrer, in an atmosphere of dry nitrogen or argon gas, the solvent is a dry solvent, and the reaction temperature is in °C.

[0089] Example 1 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(methylsulfinyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0090] [ka]

[0091] Step 1: 2-(methylthio)ethane-1-ol

[0092] [ka]

[0093] Ethyl 2-(methylthio)acetate (500 mg, 3.7 mmol) was dissolved in 20 mL of MeOH, and NaBH4 (562 mg, 14.8 mmol) was added at 0 °C. The mixture was stirred at room temperature for 0.5 h. 10 mL of NH4Cl solution was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. It was filtered and spin-dried to obtain 2-(methylthio)ethan-1-ol (240 mg, colorless liquid, yield: 70%).

[0094] Step 2: 4-Bromo-6-(2-(methylthio)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0095]

Chemical formula

[0096] 4-Bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.42 mmol) was dissolved in 10 mL of THF, and 2-(methylthio)ethan-1-ol (16 mg, 0.5 mmol), triphenylphosphine (165 mg, 0.63 mmol) and DIAD (127 mg, 0.63 mmol) were added. The mixture was stirred at room temperature overnight. 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. It was filtered and spin-dried, and the crude product was separated by column chromatography (eluted with dichloromethane / methanol = 10 / 1) to obtain 4-bromo-6-(2-(methylthio)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (69 mg, white solid, yield: 53%).

[0097] MS m / z (ESI): 311.9 [M+H] + . Step 3: 4-Bromo-6-(2-(methylsulfinyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0098]

Chemical formula

[0099] 4-Bromo-6-(2-(methylthio)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg, 0.64 mmol) was dissolved in 20 mL of DCM, m-chloroperoxybenzoic acid (110 mg, 0.64 mmol) was added, and the mixture was stirred at room temperature for 4 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration and spin drying, the crude product was separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to obtain 4-bromo-6-(2-(methylsulfinyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (189 mg, white solid, yield: 90%).

[0100] MS m / z (ESI): 327.9 [M+H] + . Step 4: tert-butyl3-(5-bromopyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0101] [ka]

[0102] 5-bromo-2-fluoropyridine (500 mg, 2.5 mmol) was dissolved in 20 mL of DMSO, and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (489 mg, 2.8 mmol) and potassium carbonate (1.7 g, 12.5 mmol) were added. The mixture was stirred overnight at 90°C. 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, spin-dried, and the crude product was separated by column chromatography (washed with petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl 3-(5-bromopyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (650 mg, white solid, yield: 73%).

[0103] MS m / z (ESI): 354.0 [M+H] + . Step 5: 3-(5-bromopyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane

[0104] [ka]

[0105] 100 mg, 0.28 mmol of tert-butyl 3-(5-bromopyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate was dissolved in 3 mL of DCM, 1 mL of TFA was added, and the mixture was stirred at room temperature for 2 hours. The mixture was spin-dried, and the pH was adjusted to basic by adding aqueous sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (20 mL x 3). The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and spin-dried to obtain 3-(5-bromopyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane (70 mg, white solid, yield: 99%).

[0106] MS m / z (ESI): 254.0 [M+H] + . Step 6: 3-(5-bromopyridine-2-yl)-6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane

[0107] [ka]

[0108] 3-(5-bromopyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane (70 mg, 0.28 mmol) and 6-methoxynicotinaldehyde (113 mg, 0.83 mmol) were dissolved in 10 mL of DCE, and NaBH(OAc)3 (176 mg, 0.83 mmol) was added. The mixture was stirred overnight at room temperature. 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 × 3). The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, spin-dried, and the crude product was separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to obtain 3-(5-bromopyridine-2-yl)-6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (60 mg, white solid, yield: 57%).

[0109] MS m / z (ESI): 375.0 [M+H] + . Step 7: 6-(2-(methylsulfinyl<sulfinyl>)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0110] [ka]

[0111] 4-Bromo-6-(2-(methylsulfinyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg, 0.6 mmol), bis(pinacolate)diborone (232 mg, 0.91 mmol), Pd(dppf)Cl2 (44 mg, 0.06 mmol), and KOAc (176 mg, 1.8 mmol) were dissolved in dioxane / H2O (20 mL, v / v=10:1) and stirred overnight at 90°C under nitrogen gas protection. 10 mL of water was added and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, spin-dried, and the crude product was separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to obtain 6-(2-(methylsulfinyl<sulfinyl>)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (117 mg, white solid, yield: 52%).

[0112] MS m / z (ESI): 376.1 [M+H] + . Step 8: 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(methylsulfinyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0113] [ka]

[0114] 6-(2-(methylsulfinyl<sulfinyl>)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (60 mg, 0.16 mmol), 3-(5-bromopyridine-2-yl)-6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (72 mg, 0.19 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), and KOAc (44 mg, 0.5 mmol) were dissolved in dioxane / H2O (20 mL, v / v=10:1) and stirred overnight at 90°C under nitrogen gas protection. 10 mL of water was added and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration and spin-drying, the crude product was purified by prep-HPLC to obtain the product 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(methylsulfinyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (41 mg, white solid, yield 48%).

[0115] MS m / z (ESI): 544.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 8.82 (d, J = 1.9 Hz, 1H), 8.62 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.85 (dd, J = 8.8, 2.4 Hz, 1H), 7.68 (dd, J = 8.5, 2.2 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 6.78 (t, J = 9.4 Hz, 2H), 4.62 - 4.44 (m, 2H), 3.82 (s, 3H), 3.73 (d, J = 11.6 Hz, 2H), 3.67 (d, J = 5.7 Hz, 2H), 3.58 - 3.52 (m, 2H), 3.50 (s, 2H), 3.13 (dt, J = 13.6, 4.4 Hz, 1H), 2.67 (s, 3H), 2.59 - 2.52 (m, 2H), 1.59 (d, J = 8.5 Hz, 1H). Example 2 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(methylsulfonyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0116] [ka]

[0117] Using 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(methylsulfinyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(methylsulfonyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel (45 mg, white solid, 70% yield) was obtained by referring to step 3 of Example 1.

[0118] MS m / z (ESI): 560.2 [M+H] + . Example 3 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(S-methylsulfonimidoyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0119] [ka]

[0120] 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(methylsulfonyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (60 mg, 0.11 mmol) was dissolved in 5 mL of methanol, and ammonium carbamate (17 mg, 0.22 mmol) and iodobenzene diacetate (70 mg, 0.22 mmol) were added. The mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 × 3). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The product was filtered, spin-dried, and the crude product was purified by prep-HPLC to obtain the product 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(S-methylsulfonimidoyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (25 mg, white solid, 45% yield).

[0121] MS m / z (ESI): 559.2 [M+H] + . Example 4 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-(methylsulfinyl<sulfinyl>)propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0122] [ka]

[0123] Using ethyl 3-(methylthio)propionate as a starting material, the title compound (35 mg, white solid, 40%) was obtained by referring to Example 1. MS m / z (ESI): 558.2 [M+H] + . Example 5 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-(methylsulfonyl)propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0124] [ka]

[0125] Using 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-(methylsulfinyl<sulfinyl>)propoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-(methylsulfonyl)propoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel (32 mg, white solid, yield 56%) was obtained by referring to Example 2.

[0126] MS m / z (ESI): 574.2 [M+H] + . Example 6 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-(S-methylsulfonimidoyl)propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0127] [ka]

[0128] Using 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-(methylsulfonimidoyl)propoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-(S-methylsulfonimidoyl)propoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel (28 mg, white solid, yield 44%) was obtained by referring to Example 3.

[0129] MS m / z (ESI): 573.2 [M+H] + . Example 7 6-(3-(2-hydroxypropane-2-yl)azetidine-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0130] [ka]

[0131] Step 1: 6-Bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate

[0132] [ka]

[0133] 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitride, dichloromethane, and pyridine were sequentially added to a 25 mL neck flask. The reaction solution was stirred for 2 minutes, and then trifluoromethanesulfonic anhydride was slowly added dropwise. The reaction solution was stirred at room temperature for 12 hours to concentrate it, and after dissolving it in ethyl acetate, it was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated and purified by column chromatography to obtain the product 6-bromo-3-cyanopyrazolo[1,5-a]pyridine-6-yltrifluoromethanesulfonate.

[0134] MS m / z (ESI): 370.0[M+H] + , 372.0[M+H+2] + . Step 2: 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0135] [ka]

[0136] 6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate, 6-((6-methoxypyridine-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane, tetrakis(triphenylphosphine)palladium, sodium carbonate, and dioxane and water were added sequentially to a 25 mL three-necked flask, and the reaction solution was purged with nitrogen gas five times. The reaction solution was heated to 85°C under nitrogen gas protection and stirred for 5 hours, then cooled to room temperature, concentrated, dissolved in ethyl acetate, washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by prep-HPLC to obtain 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride, as described in step 2 of Example 7.

[0137] MS m / z (ESI): 516.1[M+H] + , 518.1[M+H+2] + . Step 3: 6-(3-(2-hydroxypropan-2-yl)azetidine-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0138] [ka]

[0139] A mixture of 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (80 mg, 0.15 mmol), 2-(azetidine-3-yl)propan-2-ol (36 mg, 0.30 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 0.0075 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (4 mg, 0.0075 mmol), cesium carbonate (146 mg, 0.45 mmol), and toluene (4 mL) was purged with nitrogen gas and stirred at 130°C for 2 hours under microwave conditions. After the reaction was complete, the mixture was cooled to room temperature, the reaction solution was concentrated and dissolved in ethyl acetate (20 mL), washed with saturated brine (15 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and spin-dried, and then separated and purified by preparative chromatography (18 mg, white solid, yield: 21%).

[0140] MS m / z (ESI): 551.2[M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.32 (d, J = 2.1 Hz, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.85 - 7.79 (m, 2H), 7.71 (dd, J = 8.5, 2.3 Hz, 1H), 6.92 (d, J = 1.7 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 3.97 (t, J = 7.8 Hz, 2H), 3.92 - 3.84 (m, 7H), 3.78 (d, J = 5.6 Hz, 2H), 3.65 (s, 1H), 3.62 (s, 3H), 2.95 - 2.81 (m, 1H), 2.70 (d, J = 7.0 Hz, 1H), 1.70 (d, J = 8.8 Hz, 1H), 1.21 (s, 6H). Example 8 6-(3-hydroxy-3-methylbuto-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0141] [ka]

[0142] Step 1: 6-Bromo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0143] [ka]

[0144] Using 6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate as a starting material, 6-bromo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (620 mg, white solid, yield 56%) was obtained by referring to step 7 of Example 1.

[0145] MS m / z (ESI): 348.0 [M+H] + . Step 2: 6-(3-hydroxy-3-methylbuto-1-in-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonil

[0146] [ka]

[0147] 6-Bromo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (300 mg, 0.86 mmol) was dissolved in 20 mL of triethylamine, and 2-methylbuto-3-in-2-ol (108 mg, 1.3 mmol), Pd2(PPh3)2Cl2 (120 mg, 0.17 mmol), and CuI (17 mg, 0.09 mmol) were added. The mixture was reacted overnight at 65°C under nitrogen gas protection. 10 mL of aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, spin-dried, and the crude organisms were separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to obtain 6-(3-hydroxy-3-methylbuto-1-in-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (197 mg, white solid, yield: 65%).

[0148] MS m / z (ESI): 352.1 [M+H] + . Step 3: 6-(3-hydroxy-3-methylbuto-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0149] [ka]

[0150] Using 6-(3-hydroxy-3-methylbuto-1-in-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and 3-(5-bromopyridine-2-yl)-6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane as starting materials, 6-(3-hydroxy-3-methylbuto-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride (25 mg, white solid, yield 43%) was obtained by referring to step 8 of Example 1.

[0151] MS m / z (ESI): 520.2 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.83 (s, 1H), 8.47 (s, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.09 (s, 1H), 7.84 (dd, J = 8.8, 2.3 Hz, 1H), 7.72 (dd, J = 8.4, 2.1 Hz, 1H), 7.41 (s, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 3.91 (s, 1H), 3.88 (s, 4H), 3.79 (d, J = 5.7 Hz, 2H), 3.66 (s, 1H), 3.63 (s, 3H), 2.74 - 2.62 (m, 1H), 1.70 (d, J = 8.9 Hz, 1H), 1.59 (s, 6H). Example 9 6-(2-cyano-2-methylpropoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0152] [ka]

[0153] Step 1: 4-Bromo-6-(2-cyano-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0154] [ka]

[0155] 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg, 0.84 mmol) and 3-hydroxy-2,2-dimethylpropionitrile (83 mg, 0.84 mmol) were dissolved in 5 mL of anhydrous tetrahydrofuran solution. Then, triphenylphosphine (330 mg, 1.26 mmol) and diisopropyl azodicarboxylic acid (202 mg, 1 mmol) were added, and the reaction solution was stirred at 0°C for 12 hours under nitrogen gas protection. The reaction solution was concentrated, dissolved in ethyl acetate (10 mL), washed three times with water (5 mL x 3), and the organic layer was concentrated. The organic layer was then separated by column chromatography (dichloromethane / methanol: 30 / 1) and purified to obtain the product 4-bromo-6-(2-cyano-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (180 mg, yellow solid, yield: 67.1%).

[0156] MS m / z (ESI): 319.0 [M+H] + . 321.0 [M+H+2] + . Step 2: 6-(2-cyano-2-methylpropoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0157] [ka]

[0158] Using 4-bromo-6-(2-cyano-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, the product 6-(2-cyano-2-methylpropoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel was obtained by referring to step 2 of Example 7.

[0159] MS m / z (ESI): 535.2[M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J = 2.5 Hz, 1H), 8.23 ​​(s, 1H), 8.16 (d, J = 2.1 Hz, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.81-7.75 (m, 2H), 7.19 (d, J = 2.1 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 3.97 (s, 3H), 3.96 - 3.86 (m, 6H), 3.78 - 3.64 (m, 4H), 2.94 - 2.80 (m, 1H), 1.78 - 1.72 (m, 1H), 1.55 (s, 6H). Example 10 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(methylsulfonyl)ethyl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0160] [ka]

[0161] Step 1: 3-Bromo-5-(2-(methylsulfonyl)ethyl)pyridine

[0162] [ka]

[0163] DMSO (780 mg, 10 mmol) was dissolved in 10 mL of THF, n-BuLi (4 mL, 10 mmol) was added at -78°C, and the mixture was stirred at -78°C for 0.5 hours. 3-bromo-5-(bromomethyl)pyridine (500 mg, 2 mmol) was added at -78°C, the mixture was slowly raised to room temperature, stirred for 2 hours, and 10 mL of aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, spin-dried, and the crude product was separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to obtain 3-bromo-5-(2-(methylsulfonyl)ethyl)pyridine (252 mg, yield: 48%).

[0164] MS m / z (ESI): 263.9 [M+H] + . Step 2: 4-Bromo-6-(2-(methylsulfonyl)ethyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0165] [ka]

[0166] 1,8-diazabicyclo[5.4.0]undeca-7-ene was added in batches to a dichloromethane solution of 3-bromo-5-(2-(methylsulfonyl)ethyl)pyridine and 2-chloroacrylonitrile, then the mixture was heated to room temperature and stirred for 24 hours. Methyl tert-butyl ether was added to the reaction solution, and the mixture was allowed to slurry at room temperature for 15 minutes. After filtration, the cake was dried to obtain 4-bromo-6-(2-(methylsulfonyl)ethyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (350 mg, white solid).

[0167] MS m / z (ESI): 327.9 [M+H] + . Step 3: 6-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0168] [ka]

[0169] Using 4-bromo-6-(2-(methylsulfonyl)ethyl)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 6-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel (230 mg, white solid, 68%) was obtained by referring to step 7 of Example 1.

[0170] MS m / z (ESI): 376.1 [M+H] + . Step 4: 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(methylsulfonyl)ethyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0171] [ka]

[0172] Using 6-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(methylsulfonyl)ethyl)pyrazolo[1,5-a]pyridine-3-carbonitriel (30 mg, white solid, 48%) was obtained by referring to step 8 of Example 1.

[0173] MS m / z (ESI): 544.2 [M+H] + . Example 11 6-(3-hydroxy-3-methylbutyl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0174] [ka]

[0175] Referencing Example 10, the product 6-(3-hydroxy-3-methylbutyl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (33 mg, white solid) was obtained.

[0176] MS m / z (ESI): 524.2 [M+H] + . Example 12 6-((1-imino-1-hydroxy-1l6-thietan-3-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0177] [ka]

[0178] Step 1: Thiethane-3-yl methanol

[0179] [ka]

[0180] Thiethane-3-carboxylic acid (500 mg, 4.2 mmol) was dissolved in 10 mL of THF, LiAlH4 (8.4 mL, 8.4 mmol) was added at -78°C, the mixture was stirred at -78°C for 2 hours, the temperature was slowly raised to room temperature and stirred for 2 hours, 10 mL of aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and spin-dried to obtain the crude product thietan-3-ylmethanol (314 mg, yield: 72%).

[0181] Step 2: 4-Bromo-6-(thietan-3-ylmethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0182] [ka]

[0183] Using 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitride and thietan-3-ylmethanol as starting materials, 4-bromo-6-(thietan-3-ylmethoxy)pyrazolo[1,5-a]pyridine-3-carbonitride (210 mg, white solid, 67%) was obtained by referring to step 2 of Example 1.

[0184] MS m / z (ESI): 323.9 [M+H] + . Step 3: 4-Bromo-6-((1-hydroxythiethane-3-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0185] [ka]

[0186] Using 4-bromo-6-(thietan-3-ylmethoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 4-bromo-6-((1-hydroxythietan-3-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel (180 mg, white solid, 85%) was obtained by referring to step 3 of Example 1.

[0187] MS m / z (ESI): 339.9 [M+H] + . Step 4: 4-Bromo-6-((1-imino-1-hydroxy-1l6-thietan-3-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitri

[0188] [ka]

[0189] Using 4-bromo-6-((1-hydroxythiethane-3-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 4-bromo-6-((1-imino-1-hydroxy-1l6-thiethane-3-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel (150 mg, white solid, 79%) was obtained by referring to Example 3.

[0190] MS m / z (ESI): 354.9 [M+H] + . Step 5: 6-((1-imino-1-hydroxy-1l6-thietan-3-yl)methoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0191] [ka]

[0192] Using 4-bromo-6-((1-imino-1-hydroxy-116-thietan-3-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 6-((1-imino-1-hydroxy-116-thietan-3-yl)methoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel (96 mg, white solid, 64%) was obtained by referring to step 7 of Example 1.

[0193] MS m / z (ESI): 403.1 [M+H] + . Step 6: 6-((1-imino-1-hydroxy-1l6-thietan-3-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0194] [ka]

[0195] Using 6-((1-imino-1-hydroxy-116-thietan-3-yl)methoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 6-((1-imino-1-hydroxy-116-thietan-3-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel (30 mg, white solid, 34%) was obtained by referring to step 8 of Example 1.

[0196] MS m / z (ESI): 571.2 [M+H] + . 1H NMR (400 MHz, MeOD) δ 8.53 (s, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.32 (s, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 4.43 - 4.22 (m, 4H), 4.21 - 4.05 (m, 4H), 4.06 - 3.94 (m, 5H), 3.91 (s, 3H), 3.67 - 3.59 (m, 1H), 3.22 - 3.11 (m, 1H), 2.25 - 1.88 (m, 2H). Example 13 6-(2-(1-imino-1-hydroxy-116-thietan-3-yl)ethoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0197] [ka]

[0198] Using 2-(thietan-3-yl)ethane-1-ol as a starting material, 6-(2-(1-imino-1-hydroxy-116-thietan-3-yl)ethoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (35 mg, white solid) was obtained by referring to Example 12. MS m / z (ESI): 585.2 [M+H] + . Example 14 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(1-hydroxytetrahydro-2H-thiopyran-4-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0199] [ka]

[0200] Using 2-(tetrahydro-2H-thiopyran-4-yl)ethane-1-ol as a starting material, 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(1-hydroxytetrahydro-2H-thiopyran-4-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (29 mg, white solid) was obtained by referring to Example 12. MS m / z (ESI): 598.2 [M+H] + . Example 15 6-(2-(1-imino-1-hydroxyhexahydro-1l6-thiopyran-4-yl)ethoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0201] [ka]

[0202] Using 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-(1-hydroxytetrahydro-2H-thiopyran-4-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 6-(2-(1-imino-1-hydroxyhexahydro-1l6-thiopyran-4-yl)ethoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel (18 mg, white solid) was obtained by referring to Example 3.

[0203] MS m / z (ESI): 613.2 [M+H] + . Example 16 6-((1-imino-1-hydroxyhexahydro-1l6-thiopyran-4-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0204] [ka]

[0205] Step 1: Preparation of 4-bromo-6-((tetrahydro-2H-thiopyran-4-yl)oxo)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0206] [ka]

[0207] 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (10 g, 42.0 mmol) was dissolved in tetrahydrofuran (100 ml), and tetrahydro-2H-thiopyran-4-ol (6 g, 50.4 mmol) and triphenylphosphine (22 g, 84.0 mmol) were added. DEAD (14.6 g, 84.0 mmol) was slowly added dropwise to the reaction solution. The reaction was stirred overnight at room temperature. Water was added to quench the reaction, and then ethyl acetate was added for extraction. After drying the organic phase, it was spin-dried. The crude product was purified by column chromatography to obtain 4-bromo-6-((tetrahydro-2H-thiopyran-4-yl)oxo)pyrazolo[1,5-a]pyridine-3-carbonitrile (7 g, yield: 49%).

[0208] MS m / z (ESI): 337.9[M+H] + . Step 2: Preparation of 4-bromo-6-((1-imino-1-hydroxyhexahydro-1l6-thiopyran-4-yl)oxo)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0209] [ka]

[0210] 4-bromo-6-((tetrahydro-2H-thiopyran-4-yl)oxo)pyrazolo[1,5-a]pyridine-3-carbonitrile (3 g, 8.9 mmol) was dissolved in methanol (40 ml), and ammonium carbonate (1.6 g, 16.9 mmol) and (diacetoxyiodo)benzene (5.7 g, 17.8 mmol) were added. The reaction was stirred overnight at room temperature. The reaction solution was spin-dried. The crude product was purified by column chromatography to obtain 4-bromo-6-((1-imino-1-hydroxyhexahydro-116-thiopyran-4-yl)oxo)pyrazolo[1,5-a]pyridine-3-carbonitrile (350 mg, yield: 11%).

[0211] MS m / z (ESI): 368.9[M+H] + . Step 3: Preparation of 6-((1-imino-1-hydroxyhexahydro-1l6-thiopyran-4-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0212] [ka]

[0213] 4-bromo-6-((1-imino-1-hydroxyhexahydro-1l6-thiopyran-4-yl)oxo)pyrazolo[1,5-a]pyridine-3-carbonitride and 6-((6-methoxypyridine-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane As a raw material, 6-((1-imino-1-hydroxyhexahydro-1l6-thiopyran-4-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (35 mg, yield: 36%) was obtained by referring to step 8 of Example 1.

[0214] MS m / z (ESI): 585.2[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.89 (dd, J = 7.6, 2.0 Hz, 1H), 8.62 (s, 1H), 8.42 (t, J = 2.4 Hz, 1H), 8.07 (s, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.72 - 7.60 (m, 1H), 7.51 - 7.40 (m, 1H), 6.78 (t, J = 9.4 Hz, 2H), 4.90 - 4.78 (m, 1H), 3.82 (s, 3H), 3.79 - 3.61 (m, 4H), 3.60 - 3.45 (m, 4H), 3.27 - 3.13 (m, 2H), 3.13 - 2.98 (m, 2H), 2.65 - 2.53 (m, 1H),2.31 - 2.14 (m, 3H), 2.13 - 1.92 (m, 1H), 1.59 (d, J = 8.4 Hz, 1H), 0.84 - 0.69 (m, 1H). Example 17 6-(3-amino-3-methylbuto-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0215] [ka]

[0216] Using 2-methylbuto-3-in-2-amine as a starting material, and referring to Example 7, 6-(3-amino-3-methylbuto-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile was obtained.

[0217] MS m / z (ESI): 519.2 [M+H] + . 1H NMR (400 MHz, Methanol-d4) δ 8.82 (d, J = 1.3 Hz, 1H), 8.46 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.84 (dd, J = 8.9, 2.5 Hz, 1H), 7.72 (dd, J = 8.5, 2.5 Hz, 1H), 7.41 (d, J = 1.4 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 4.01 - 3.83 (m, 5H), 3.84 - 3.73 (m, 2H), 3.72 - 3.56 (m, 4H), 2.78 - 2.65 (m, 1H), 1.71 (d, J = 9.0 Hz, 1H), 1.52 (s, 6H). Example 18 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-hydroxy-3-methylbuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0218] [ka]

[0219] Step 1: 6-Bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate

[0220] [ka]

[0221] 6-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrilate (5 g, 21 mmol) and triethylamine (4.2 g, 42 mmol) were dissolved in dichloromethane (500 mL). Trifluoromethanesulfonic acid anhydride (8.9 g, 31.5 mmol) was added under ice bath, and the mixture was stirred at room temperature for 12 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate (5 g, white solid, yield: 64%).

[0222] 1 H NMR (400 MHz, DMSO) δ 9.60 (d, J = 0.9 Hz, 1H), 8.85 (s, 1H), 8.23 ​​(s, 1H). Step 2: 6-bromo-4-(6-fluoropyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0223] [ka]

[0224] A mixed solution of 6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate (5g, 13.51 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.3g, 14.86 mmol), potassium carbonate (3.7g, 27 mmol), and dioxane (100 mL) is mixed with [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichlorophosphate. Lido-dichloromethane complex (494 mg, 0.68 mmol) was added, and the mixture was purged three times with nitrogen gas. The mixture was then stirred at 70°C for 16 hours under nitrogen gas protection. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure and dried. The filtrate was separated by column chromatography (dichloromethane / methanol = 10:1) to obtain 6-bromo-4-(6-fluoropyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (3 g, yield: 70%), a white solid.

[0225] 1 H NMR (400 MHz, DMSO) δ 9.49 (d, J = 1.3 Hz, 1H), 8.73 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.27 (td, J = 8.2, 2.5 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.40 (dd, J = 8.5, 2.5 Hz, 1H). MS m / z (ESI): 317.0 [M+H] + . Step 3: tert-butyl3-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate

[0226] [ka]

[0227] Using 6-bromo-4-(6-fluoropyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbonitride as a starting material, tert-butyl3-(5-(6-bromo-3-cyanopyrazole[1,5-a]pyridine-4-yl)pyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate was obtained by referring to step 7 of Example 11.

[0228] MS m / z (ESI): 495.1 [M+H] + . Step 4: 4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitriel

[0229] [ka]

[0230] Using tert-butyl3-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate as a starting material, 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-bromopyrazolo[1,5-a]pyridin-3-carbonitride was obtained by referring to step 8 of Example 11.

[0231] MS m / z (ESI): 395.1 [M+H] + . Step 5: 6-bromo-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0232] [ka]

[0233] Using 4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitriel and 5-fluoro-6-methoxynicotinaldehyde as raw materials, 6-bromo-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel was obtained by referring to step 9 of Example 11.

[0234] MS m / z (ESI): 534.1 [M+H] + . Step 6: 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-hydroxy-3-methylbuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitri

[0235] [ka]

[0236] Using 2-methylbuto-3-in-2-ol and 6-bromo-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride as raw materials, 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-hydroxy-3-methylbuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 2 of Example 8.

[0237] MS m / z (ESI): 538.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.76 (dd, J = 8.8, 2.4 Hz, 1H), 7.47 (d, J = 11.1 Hz, 1H), 7.30 (s, 1H), 6.68 (d, J = 8.7 Hz, 1H), 4.01 (s, 3H), 3.80 (s, 4H), 3.59 (s, 4H), 2.78 - 2.53 (m, 2H), 1.65 (s, 6H). Example 19 6-(3-cyclopropyl-3-hydroxyprop-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0238] [ka]

[0239] 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (50 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-cyclopropylprop-2-yn-1-ol (47 mg, 0.5 mmol), triethylamine (50 mg, 0.5 mmol), Pd2(PPh3)2Cl2 (7 mg, 0.01 mmol), and CuI (1 mg, 0.01 mmol) were added. The mixture was reacted overnight at 65°C under nitrogen gas protection. 5 mL of aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (3 mL x 3). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, spin-dried, and the crude organisms were separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to obtain 6-(3-cyclopropyl-3-hydroxyprop-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (15 mg, white solid, yield: 29%).

[0240] MS m / z (ESI): 532.2 [M+H] + . Example 20 6-((1-cyanocyclopentyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0241] [ka]

[0242] Using 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and (1-cyanocyclopentyl)methyl 4-methylbenzene sulfonate as raw materials, 6-((1-cyanocyclopentyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrideride was obtained by referring to step 2 of Example 27.

[0243] MS m / z (ESI): 561.2 [M+H] + . Example 21 6-((S)-3-hydroxybuto-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0244] [ka]

[0245] Using 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and (S)-buto-3-in-2-ol as raw materials, 6-((S)-3-hydroxybuto-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride (white solid) was obtained by referring to step 2 of Example 20.

[0246] MS m / z (ESI): 506.2 [M+H] + . 1 H NMR (400 MHz, Methanol-d4) δ 8.85 (s, 1H), 8.47 (s, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.08 (d, J = 2.5 Hz, 1H), 7.84 (dd, J = 8.9, 2.6 Hz, 1H), 7.72 (dd, J = 8.5, 2.5 Hz, 1H), 7.42 (s, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 4.72 (q, J = 6.6 Hz, 1H), 3.96 - 3.84 (m, 5H), 3.83 - 3.74 (m, 2H), 3.69 - 3.56 (m, 4H), 2.76 - 2.64 (m, 1H), 1.70 (d, J = 8.9 Hz, 1H), 1.51 (d, J = 6.6 Hz, 3H). Example 22 6-((R)-3-hydroxybuto-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0247] [ka]

[0248] Using 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and (R)-buto-3-in-2-ol as raw materials, 6-((R)-3-hydroxybuto-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride (white solid) was obtained by referring to step 2 of Example 20.

[0249] MS m / z (ESI): 506.2 [M+H] + . 1 H NMR (400 MHz, Methanol-d4) δ 8.85 (d, J = 1.4 Hz, 1H), 8.47 (s, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.09 (s, 1H), 7.84 (dd, J = 8.8, 2.5 Hz, 1H), 7.72 (dd, J = 8.5, 2.5 Hz, 1H), 7.42 (d, J = 1.4 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 4.75 - 4.70 (m, 1H), 3.92 - 3.85 (m, 5H), 3.84 - 3.75 (m, 2H), 3.68 - 3.58 (m, 4H), 2.74 - 2.67 (m, 1H), 1.71 (d, J = 9.0 Hz, 1H), 1.51 (d, J = 6.7 Hz, 3H). Example 23 6-(3-amino-3-methylbuto-1-in-1-yl)-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0250] [ka]

[0251] Step 1: Preparation of 6-bromo-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0252] [ka]

[0253] Using 4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 6-bromo-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel (yellow solid) was obtained by referring to step 6 of Example 1. MS m / z (ESI): 519.1 [M+H] + . Step 2: Preparation of 6-(3-amino-3-methylbuto-1-in-1-yl)-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0254] [ka]

[0255] Using 6-bromo-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 6-(3-amino-3-methylbuto-1-in-1-yl)-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel (white solid) was obtained by referring to step 2 of Example 20.

[0256] MS m / z (ESI): 522.2 [M+H] + . Example 24 6-(3-amino-3-methylbuto-1-in-1-yl)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0257] [ka]

[0258] Using 6-bromo-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and 2-methylbuto-3-in-2-amine as raw materials, 6-(3-amino-3-methylbuto-1-in-1-yl)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride (white solid) was obtained by referring to step 2 of Example 20.

[0259] MS m / z (ESI): 537.2 [M+H] + . Example 25 6-(3-hydroxy-3-methylbuto-1-in-1-yl)-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0260] [ka]

[0261] Using 6-bromo-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 6-(3-hydroxy-3-methylbuto-1-in-1-yl)-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel (white solid) was obtained by referring to step 2 of Example 20.

[0262] MS m / z (ESI): 523.3 [M+H] + . Example 26 4-(6-(6-((6-cyclopropoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-hydroxy-3-methylbuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0263] [ka]

[0264] Step 1: 5-(chloromethyl)-2-cyclopropoxypyridine

[0265] [ka]

[0266] 5-(chloromethyl)-2-fluoropyridine (900 mg, 6.2 mmol) was dissolved in 30 mL of THF, and cyclopropanol (539 mg, 9.3 mmol) was added. Tert-butyl potassium (1.04 g, 9.3 mmol) was slowly added to the reaction solution in batches. The reaction was stirred at room temperature for 4 hours. Water was added to the reaction solution to quench the reaction, and then ethyl acetate was added for extraction. After drying the organic phase, it was spin-dried. The crude product was purified by column chromatography to obtain 5-(chloromethyl)-2-cyclopropoxypyridine (0.6 g, yield: 52%).

[0267] MS m / z (ESI): 184.2 [M+H] + . Step 2: 6-bromo-4-(6-(6-((6-cyclopropoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0268] [ka]

[0269] 4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile (500 mg, 1.26 mmol) was dissolved in DMAc (15 mL), and 5-(chloromethyl)-2-cyclopropoxypyridine (279 mg, 1.52 mmol) and potassium tert-butoxide (284 mg, 2.53 mmol) were added. The reaction solution was stirred at 90°C for 4 hours. Water was added to quench the reaction, and then ethyl acetate was added for extraction. After drying the organic phase, it was spin-dried. The crude product was purified by column chromatography to obtain 6-bromo-4-(6-(6-((6-cyclopropoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (300 mg, yield: 44%).

[0270] MS m / z (ESI): 542.2 [M+H] + . Step 3: 4-(6-(6-((6-cyclopropoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-hydroxy-3-methylbuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitri

[0271] [ka]

[0272] Using 2-methylbuto-3-in-2-ol and 6-bromo-4-(6-(6-((6-cyclopropoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride as raw materials, 4-(6-(6-((6-cyclopropoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-hydroxy-3-methylbuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to Example 8.

[0273] MS m / z (ESI): 546.2 [M+H] + . Example 27 6-((1-cyanocyclopropyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0274] [ka]

[0275] Step 1: 6-Hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0276] [ka]

[0277] (6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)boronic acid and 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitride were used as raw materials, and 6-hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride (500 mg, white solid, yield 80%) was obtained by referring to step 8 of Example 1.

[0278] MS m / z (ESI): 454.1 [M+H] + . Step 2: 6-((1-cyanocyclopropyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0279] [ka]

[0280] 6-Hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (50 mg, 0.11 mmol) was dissolved in 2 mL of DMF, and (1-cyanocyclopropyl)methyl-4-methylbenzenesulfonate (28 mg, 0.11 mmol) and potassium carbonate (42 mg, 0.3 mmol) were added. The mixture was stirred overnight at 90°C. 10 mL of water was added, and the mixture was extracted with ethyl acetate (2 mL x 3). The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, spin-dried, and the crude product was separated by preparative prep-HPLC to obtain 6-((1-cyanocyclopropyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (23 mg, white solid, yield: 39%).

[0281] MS m / z (ESI): 533.2 [M+H] + . 1 H NMR (400 MHz, Methanol-d4) δ 8.47 (d, J = 2.1 Hz, 1H), 8.39 - 8.33 (m, 2H), 8.09 (s, 1H), 7.86 (dd, J = 8.8, 2.5 Hz, 1H), 7.72 (dd, J = 8.5, 2.5 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 4.15 (s, 2H), 3.93 - 3.87 (m, 5H), 3.82 - 3.77 (m, 2H), 3.69 - 3.60 (m, 4H), 2.74 - 2.65 (m, 1H), 1.75 - 1.66 (m, 1H), 1.47 - 1.40 (m, 2H), 1.28 - 1.24 (m, 2H). Example 28 6-((1-cyanocyclopropyl)methoxy)-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0282] [ka]

[0283] Step 1: 3-(5-bromopyridine-2-yl)-6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane

[0284] [ka]

[0285] Using 3-(5-bromopyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane and 6-(methoxy-d3)nicotinaldehyde as starting materials, 3-(5-bromopyridine-2-yl)-6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane was obtained by referring to step 6 of Example 1.

[0286] MS m / z (ESI): 378.0 [M+H] + . Step 2: 6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane

[0287] [ka]

[0288] Using 3-(5-bromopyridine-2-yl)-6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane as a starting material, 6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane was obtained by referring to step 7 of Example 1.

[0289] MS m / z (ESI): 426.2 [M+H] + . Step 3: 6-Hydroxy-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0290] [ka]

[0291] Using 6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane and 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitride as raw materials, 6-hydroxy-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 8 of Example 1.

[0292] MS m / z (ESI): 457.2 [M+H] + . Step 4: 6-((1-cyanocyclopropyl)methoxy)-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0293] [ka]

[0294] Using 6-hydroxy-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and (1-cyanocyclopropyl)methyl-4-methylbenzenesulfonate as raw materials, 6-((1-cyanocyclopropyl)methoxy)-4-(6-((6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrideride was obtained by referring to step 2 of Example 27.

[0295] MS m / z (ESI): 536.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.42 (d, J = 2.5 Hz, 1H), 8.23 ​​(s, 1H), 8.13 (d, J = 2.2 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.91 - 7.74 (m, 2H), 7.19 (d, J = 2.1 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 4.09 - 3.99 (m, 4H), 3.98 - 3.89 (m, 2H), 3.84 - 3.64 (m, 4H), 2.05 - 1.97 (m, 1H), 1.79 - 1.71 (m, 1H), 1.53 - 1.48 (m, 2H), 1.21 - 1.15 (m, 2H). Example 29 6-((1-hydroxycyclopropyl)ethynyl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0296] [ka]

[0297] Using 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and 1-ethynylcyclopropane-1-ol as raw materials, 6-((1-hydroxycyclopropyl)ethynyl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride (white solid) was obtained by referring to step 2 of Example 20.

[0298] MS m / z (ESI): 518.2 [M+H] + . Example 30 6-(4-fluoro-3-(fluoromethyl)-3-hydroxybuto-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0299] [ka]

[0300] Using 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and 1-fluoro-2-(fluoromethyl)buto-3-in-2-ol as raw materials, 6-(4-fluoro-3-(fluoromethyl)-3-hydroxybuto-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride (white solid) was obtained by referring to step 2 of Example 20.

[0301] MS m / z (ESI): 556.2 [M+H] + . Example 31 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-(2-hydroxypropan-2-yl)azetidine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0302] [ka]

[0303] Step 1: 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-(2-hydroxypropan-2-yl)azetidine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0304] [ka]

[0305] A mixture of 6-bromo-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (50 mg, 0.094 mmol), 2-(azetidine-3-yl)propan-2-ol (16 mg, 0.14 mmol), cesium carbonate (122 mg, 0.376 mmol), and toluene (3 mL) is mixed with tris(dibenzylideneacetone)dipalladium (5 mg, 0.005 mmol) and 4,5-bis(diphenylphosphin)-9 ,9-dimethylxanthene (3 mg, 0.005 mmol) was added, the mixture was purged with nitrogen gas, and stirred at 130°C with microwaves for 2 hours. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure and dried. Separation by preparative chromatography yielded a white solid 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-(2-hydroxypropan-2-yl)azetidine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (15 mg, yield: 28%).

[0306] MS m / z (ESI): 569.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 2.1 Hz, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 7.79 (dd, J = 8.8, 2.3 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.57 (s, 1H), 6.75 (d, J = 1.7 Hz, 1H), 6.69 (d, J = 8.7 Hz, 1H), 4.01 (s, 3H), 3.99 - 3.93 (m, 2H), 3.91 - 3.83 (m, 4H), 3.66 (s, 4H), 2.91 - 2.79 (m, 2H), 1.25 (s, 6H). Example 32 6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0307] [ka]

[0308] Step 1: 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0309] [ka]

[0310] Using 4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile and 6-methoxynicotinaldehyde as raw materials, 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile was obtained by referring to step 9 of Example 11.

[0311] MS m / z (ESI): 516.1 [M+H] + . Step 2: 6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0312] [ka]

[0313] Using 6-methyl-2-azaspiro[3.3]heptan-6-ol as a starting material, 6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile was obtained by referring to step 1 of Example 31.

[0314] MS m / z (ESI): 563.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 6.8 Hz, 2H), 7.89 (s, 1H), 7.80 (dd, J = 8.7, 2.3 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 6.71 (t, J = 5.9 Hz, 2H),4.01- 3.93 (m, 10H), 3.74 (s, 4H), 2.96 (s, 1H), 2.39 (s, 4H), 1.40 (s, 3H). Example 33 6-(3-hydroxy-3-methylazetidine-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0315] [ka]

[0316] Using 3-methylazetidine-3-ol as a starting material, 6-(3-hydroxy-3-methylazetidine-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 1 of Example 31.

[0317] MS m / z (ESI): 523.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.15 (s, 3H), 7.82 (d, J = 7.4 Hz, 1H), 7.74 (s, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 1.7 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 4.21 (s, 2H), 4.01 (s, 2H), 3.93-3.92 (m, 7H), 3.84 (d, J = 7.3 Hz, 4H), 1.68 (s, 3H). Example 34 6-(3-hydroxy-3-methylpyrrolidine-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0318] [ka]

[0319] Using 3-methylpyrrolidine-3-ol as a starting material, 6-(3-hydroxy-3-methylpyrrolidine-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile was obtained by referring to step 1 of Example 31.

[0320] MS m / z (ESI): 537.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 2H), 8.16 (m, 2H), 7.88 (d, J = 6.7 Hz, 1H), 7.80 (s, 1H), 6.93 (s, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 4.18-4.13 (m, 2H), 4.07-4.03(m, 2H), 3.93 (s, 3H), 3.65-3.61 (m, 2H), 3.46-3.41 (m, 2H), 2.24 - 2.12 (m, 3H), 2.0-1.96 (m, 3H), 1.31 (s, 3H). Example 35 6-(4-hydroxy-4-methylpiperidine-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0321] [ka]

[0322] Using 4-methylpiperidine-4-ol as a starting material, 6-(4-hydroxy-4-methylpiperidine-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 1 of Example 31.

[0323] MS m / z (ESI): 551.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 8.07 (s, 2H), 7.82 (d, J = 6.7 Hz, 1H), 7.22 (d, J = 1.6 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 6.71 (d, J = 8.7 Hz, 1H), 3.99 (s, 2H), 3.93 (s, 3H), 3.85 (s, 4H), 3.36-3.32 (m, 2H), 3.23 - 3.15 (m, 2H), 1.85 - 1.74 (m, 6H), 1.35 (s, 3H). Example 36 6-((1-cyanocyclobutyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0324] [ka]

[0325] Referring to Example 27, 6-((1-cyanocyclobutyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (white solid) was obtained.

[0326] MS m / z (ESI): 547.2 [M+H] + . Example 37 6-((3-cyanooxetane-3-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0327] [ka]

[0328] Referring to Example 27, 6-((3-cyanooxetane-3-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (12 mg, white solid, 29%) was obtained.

[0329] MS m / z (ESI): 549.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.83 (d, J = 2.0 Hz, 1H), 8.64 (s, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.06 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 6.9 Hz, 1H), 7.40 (s, 1H), 6.81 - 6.76 (m, 2H), 4.93 (d, J = 6.5 Hz, 2H), 4.70 (s, 2H), 4.68 (d, J = 6.5 Hz, 2H), 3.82 (s, 3H), 3.67 (d, J = 5.3 Hz, 2H), 3.53-3.47 (m, 6H), 2.01 - 1.99 (m, 2H). Example 38 6-(((1-hydroxycyclopropyl)methyl)(methyl)amino)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0330] [ka]

[0331] Using 1-((methylamino)methyl)cyclopropan-1-ol as a starting material, 6-(((1-hydroxycyclopropyl)methyl)(methyl)amino)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 1 of Example 31.

[0332] MS m / z (ESI): 537.3 [M+H] + . Example 39 6-(((1-cyanocyclopropyl)methyl)amino)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0333] [ka]

[0334] Using 1-(aminomethyl)cyclopropane-1-carbonitride as a starting material, 6-(((1-cyanocyclopropyl)methyl)amino)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 1 of Example 31.

[0335] MS m / z (ESI): 532.3 [M+H] + . Example 40 4-(6-(6-((6-cyclopropoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-(2-hydroxypropan-2-yl)azetidine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0336] [ka]

[0337] Using 6-bromo-4-(6-(6-((6-cyclopropoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride as a starting material, the product 4-(6-(6-((6-cyclopropoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-(2-hydroxypropan-2-yl)azetidine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 2 of Example 31.

[0338] MS m / z (ESI): 577.2[M+H] + . Example 41 6-(3-(2-hydroxypropan-2-yl)azetidine-1-yl)-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0339] [ka]

[0340] Using 6-bromo-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 6-(3-(2-hydroxypropan-2-yl)azetidine-1-yl)-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel (20 mg, yellow solid, 30%) was obtained by referring to step 1 of Example 31.

[0341] MS m / z (ESI): 554.3 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.32 (d, J = 2.1 Hz, 1H), 8.24 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 8.8, 2.4 Hz, 1H), 7.71 (dd, J = 8.6, 2.3 Hz, 1H), 6.92 (d, J = 1.7 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 3.97 (t, J = 7.8 Hz, 2H), 3.91 - 3.85 (m, 4H), 3.79 (d, J = 5.7 Hz, 2H), 3.65 (s, 1H), 3.62 (s, 3H), 2.92 - 2.84 (m, 1H), 2.71 (s, 1H), 1.70 (d, J = 8.9 Hz, 1H), 1.21 (s, 6H). Example 42 N-(3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)-2-hydroxy-2-methylpropanamide

[0342] [ka]

[0343] Step 1: tert-butyl(3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)carbamate

[0344] [ka]

[0345] Using tert-butylcarbamate as a starting material, tert-butyl(3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)carbamate was obtained by referring to step 1 of Example 31.

[0346] MS m / z (ESI): 553.3 [M+H] + . Step 2: 6-amino-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0347] [ka]

[0348] Using tert-butyl(3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)carbamate as a starting material, 6-amino-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonilicate was obtained by referring to step 1 of Example 31.

[0349] MS m / z (ESI): 453.3 [M+H] + . Step 3: N-(3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)-2-hydroxy-2-methylpropanamide

[0350] [ka]

[0351] A mixture of 6-amino-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride, 2-hydroxy-2-methylpropionic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, triethylamine, N,N-dimethylamine hydrochloride, and dichloromethane was stirred at room temperature for 16 hours. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried. Separation by column chromatography yielded N-(3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)-2-hydroxy-2-methylpropanamide.

[0352] MS m / z (ESI): 539.2 [M+H] + . Example 43 6-((1-aminocyclopropyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0353] [ka]

[0354] Step 1: Preparation of tert-butyl(1-(((3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)oxo)methyl)cyclopropyl)carbamate

[0355] [ka]

[0356] Tert-butyl(1-(bromomethyl)cyclopropyl)carbamate and 6-hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile were dissolved in DMAc, and tert-butyl(1-(bromomethyl)cyclopropyl)carbamate and cesium carbonate were added. The reaction solution was stirred overnight at 100°C. Water was added to the reaction solution, and then ethyl acetate was added for extraction. After drying the organic phase, it was spin-dried. The crude product was purified by prep-HPLC to obtain (tert-butyl(1-(((3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)oxo)methyl)cyclopropyl)carbamate.

[0357] MS m / z (ESI): 623.3 [M+H] + . Step 2: Preparation of 6-((1-aminocyclopropyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0358] [ka]

[0359] Tert-butyl(1-(((3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)oxo)methyl)cyclopropyl)carbamate was dissolved in a 25% trifluoroacetic acid / dichloromethane solution. The reaction solution was stirred at room temperature for 2 hours. After spin-drying the reaction solution, dichloromethane was added. An aqueous solution of NaHCO3 was slowly added to adjust the pH to 7-8. After drying the organic layer, it was spin-dried to obtain 6-((1-aminocyclopropyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride.

[0360] MS m / z (ESI): 523.3 [M+H] + . Example 44 6-((cis-3-hydroxy-3-methylcyclobutyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0361] [ka]

[0362] Step 1: cis-3-(hydroxymethyl)-1-methylcyclobutan-1-ol

[0363] [ka]

[0364] To a solution of cis-3-hydroxy-3-methylcyclobutan-1-carboxylic acid (1 g, 7.68 mmol) in tetrahydrofuran (10 mL) at 0°C, borane-tetrahydrofuran solution (7.5 mL, 15 mmol, 2 M) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, methanol was added to quench the reaction, and then the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain cis-3-(hydroxymethyl)-1-methylcyclobutan-1-ol (600 mg, crude product), a colorless oily substance.

[0365] Step 2: (cis-3-hydroxy-3-methylcyclobutyl)methyl-4-methylbenzenesulfonate

[0366] [ka]

[0367] A mixture of cis-3-(hydroxymethyl)-1-methylcyclobutan-1-ol (600 mg, 5.17 mmol), triethylamine (1.04 g, 10.34 mmol), and dichloromethane (10 mL) was mixed with p-toluenesulfonyl chloride (987 mg, 5.17 mmol). The mixture was stirred at room temperature for 16 hours. After the reaction was complete, water was added to quench the reaction, followed by extraction with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried. The mixture was then separated by column chromatography to obtain a colorless oily substance, (cis-3-hydroxy-3-methylcyclobutyl)methyl-4-methylbenzenesulfonate (800 mg, yield: 57%).

[0368] Step 3: 6-((cis-3-hydroxy-3-methylcyclobutyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0369] [ka]

[0370] Using 6-hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and (cis-3-hydroxy-3-methylcyclobutyl)methyl-4-methylbenzenesulfonate as raw materials, 6-((cis-3-hydroxy-3-methylcyclobutyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrideride was obtained by referring to step 2 of Example 27.

[0371] MS m / z (ESI): 552.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 1.9 Hz, 1H), 8.21 (s, 1H), 8.13 (s, 2H), 7.87 - 7.73 (m, 2H), 7.13 (d, J = 1.6 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 4.03 (d, J = 5.8 Hz, 2H), 3.92 (s, 7H), 3.70 (s, 4H), 2.89 (s, 1H), 2.41-2.36(m, 1H), 2.32-2.27(m, 2H), 2.05-2.00(m, 3H), 1.45 (s, 3H). Example 45 6-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0372] [ka]

[0373] Step 1: Bicyclo[1.1.1]pentane-1,3-diyldimethanol

[0374] [ka]

[0375] To a solution of 3-(methyl ester <methoxycarbonyl>)bicyclo[1.1.1]pentane-1-carboxylic acid (1 g, 5.88 mmol) in tetrahydrofuran (10 mL) at 0°C, lithium aluminum hydride (670 mg, 17.63 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, sodium sulfate decahydrate was added to quench the mixture, and the solution was filtered. The filtrate was concentrated under reduced pressure and dried to obtain a colorless oily substance, bicyclo[1.1.1]pentane-1,3-diyldimethanol (640 mg, 85%).

[0376] 1 H NMR (400 MHz, DMSO) δ 4.39 (t, J = 5.5 Hz, 2H), 3.35 (d, J = 5.5 Hz, 4H), 1.45 (s, 6H). Step 2: (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzene sulfonate

[0377] [ka]

[0378] Using bicyclo[1.1.1]pentan-1,3-diyldimethanol as a starting material, (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzenesulfonate was obtained by referring to step 2 of Example 44.

[0379] Step 3: 6-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0380] [ka]

[0381] Using 6-hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl4-methylbenzenesulfonate as raw materials, 6-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrideride was obtained by referring to step 2 of Example 27.

[0382] MS m / z (ESI): 564.3 [M+H] + . Example 46 (E)-6-(3-hydroxy-3-methylbutato-1-en-1-yl)-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0383] [ka]

[0384] 6-bromo-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and (E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)buto-3-en-2-ol are used as raw materials. Referring to step 8 of Example 1, (E)-6-(3-hydroxy-3-methylbutato-1-en-1-yl)-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (10 mg, white solid, 30%) was obtained.

[0385] MS m / z (ESI): 522.3 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.71 (s, 1H), 8.40 (s, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.09 (s, 1H), 7.86 (dd, J = 8.8, 2.3 Hz, 1H), 7.72 (dd, J = 8.5, 2.3 Hz, 1H), 7.64 (s, 1H), 6.89 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 6.65 (q, J = 16.1 Hz, 2H), 3.91 (s, 1H), 3.88 (s, 4H), 3.79 (d, J = 5.5 Hz, 2H), 3.67 - 3.62 (m, 4H), 2.71 (s, 1H), 1.71 (d, J = 9.0 Hz, 1H), 1.40 (s, 6H). Example 47 6-((3-hydroxybicyclo[1.1.1]pentan-1-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0386] [ka]

[0387] Step 1: 6-((3-hydroxybicyclo[1.1.1]pentan-1-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0388] [ka]

[0389] A mixture of 6-hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (50 mg, 0.11 mmol), 3-(bromomethyl)bicyclo[1.1.1]pentan-1-ol (29 mg, 0.17 mmol), potassium carbonate (46 mg, 0.33 mmol), and acetonitrile (5 mL). After stirring at 70°C for 2 hours, the mixture was cooled to room temperature, filtered, concentrated under reduced pressure, dried, and separated by preparative chromatography to obtain 6-((3-hydroxybicyclo[1.1.1]pentan-1-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (10 mg, yield: 17%).

[0390] MS m / z (ESI): 550.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.25 - 8.15 (m, 3H), 7.85 (d, J = 4.0 Hz, 1H), 7.17 (s, 1H), 6.84 (d, J = 9.2 Hz, 1H), 6.74 (d, J = 7.8 Hz, 2H), 4.09 (s, 2H), 4.02 (s, 2H), 3.94 (s, 3H), 3.24-3.19 (m, 2H), 2.93-2.88(m, 2H), 2.24 - 2.20 (m, 2H), 1.58 (s, 6H). Example 48 6-(4-hydroxy-4-methylpento-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0391] [ka]

[0392] Using 2-methylpento-4-in-2-ol as a starting material, 6-(4-hydroxy-4-methylpento-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 2 of Example 8.

[0393] MS m / z (ESI): 534.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.78 (dd, J = 8.8, 2.4 Hz, 2H), 7.31 (s, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 3.98-3.93 (m, 7H), 3.72 (s, 4H), 2.66 (s, 2H), 1.41 (s, 6H). Example 49 6-((1-aminocyclopropyl)ethynyl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0394] [ka]

[0395] Using 1-ethynylcyclopropane-1-amine as a starting material, 6-((1-aminocyclopropyl)ethynyl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile was obtained by referring to step 2 of Example 8.

[0396] MS m / z (ESI): 517.2 [M+H] + . Example 50 4-(6-(6-((6-cyclopropoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0397] [ka]

[0398] 5-(chloromethyl)-2-cyclopropoxypyridine (91 mg, 0.495 mmol) and 4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg, 0.495 mmol) were dissolved in DMSO (15 mL), and cesium carbonate (322 mg, 0.989 mmol) was added. The reaction was stirred at 90°C for 2 hours. Water was added to the reaction solution, and then ethyl acetate was added for extraction. After drying the organic phase, it was spin-dried. The crude product was purified by prep-HPLC to obtain 4-(6-(6-((6-cyclopropoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (33.6 mg, yield: 12%).

[0399] MS m / z (ESI): 552.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 2.0 Hz, 1H), 8.59 (s, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.85 (dd, J = 8.8, 2.6 Hz, 1H), 7.70 (dd, J = 8.5, 2.4 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 6.80 (dd, J = 8.7, 3.9 Hz, 2H), 4.72 (s, 1H), 4.21 - 4.11 (m, 1H), 3.88 (s, 2H), 3.80 - 3.64 (m, 4H), 3.62 - 3.47 (m, 4H), 2.55 - 2.53 (m, 1H), 1.59 (d, J = 8.4 Hz, 1H), 1.23 (s, 6H), 0.79 - 0.71 (m, 2H), 0.68 - 0.59 (m, 2H). Example 51 6-((3-hydroxybicyclo[1.1.1]pentan-1-yl)methoxy)-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0400] [ka]

[0401] Using 6-hydroxy-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and 3-(bromomethyl)bicyclo[1.1.1]pentan-1-ol as raw materials, 6-((3-hydroxybicyclo[1.1.1]pentan-1-yl)methoxy)-4-(6-(6-((6-(methoxy-d3)pyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride were obtained by referring to step 1 of Example 37.

[0402] MS m / z (ESI): 553.3 [M+H] + . Example 52 6-((3-cyano-3-methylcyclobutyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0403] [ka]

[0404] Using 6-hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and (3-cyano-3-methylcyclobutyl)methyl-4-methylbenzenesulfonate as raw materials, 6-((3-cyano-3-methylcyclobutyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrideride was obtained by referring to step 2 of Example 27.

[0405] MS m / z (ESI): 561.2 [M+H] + . Example 53 6-((3-cyanobicyclo[1.1.1]pentan-1-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0406] [ka]

[0407] Using (3-cyanobicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzene sulfonate as a starting material, 6-((3-cyanobicyclo[1.1.1]pentan-1-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile was obtained by referring to step 2 of Example 27.

[0408] MS m / z (ESI): 559.3.[M+H] + . Example 54 6-((1-imino-1-hydroxyhexahydro-1l6-thiopyran-4-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0409] [ka]

[0410] Using (tetrahydro-2H-thiopyran-4-yl)methanol as a starting material, and referring to Example 16, 6-((1-imino-1-hydroxyhexahydro-1l6-thiopyran-4-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile was obtained.

[0411] MS m / z (ESI): 599.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 2.1 Hz, 1H), 8.60 (s, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 8.8, 2.5 Hz, 1H), 7.68 (dd, J = 8.5, 2.4 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 6.78 (t, J = 8.5 Hz, 2H), 4.16 (t, J = 6.5 Hz, 1H), 4.09 - 3.98 (m, 1H), 3.89 (d, J = 17.8 Hz, 1H), 3.82 (s, 3H), 3.77 - 3.64 (m, 4H), 3.60 - 3.45 (m, 4H), 3.32 - 3.26 (m, 1H), 3.20 - 3.09 (m, 1H), 3.08 - 2.97 (m, 1H), 2.79 (q, J = 11.3 Hz, 1H), 2.65 - 2.53 (m, 1H), 2.38 - 2.25 (m, 1H), 2.19 - 2.05 (m, 1H), 2.02 - 1.93 (m, 1H), 1.92 - 1.73 (m, 1H), 1.58 (d, J = 8.4 Hz, 1H). Example 55 6-((1-cyanocyclopropyl)methoxy)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0412] [ka]

[0413] Using 6-bromo-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and (1-cyanocyclopropyl)methyl 4-methylbenzene sulfonate as raw materials, 6-((1-cyanocyclopropyl)methoxy)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrideride was obtained by referring to step 2 of Example 27.

[0414] MS m / z (ESI): 551.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 2.1 Hz, 1H), 8.62 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.86 (dd, J = 8.8, 2.6 Hz, 1H), 7.64 (dd, J = 11.6, 1.9 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.21 (s, 2H), 3.92 (s, 3H), 3.84 - 3.65 (m, 4H), 3.63 - 3.48 (m, 4H), 2.61 - 2.53 (m, 1H), 1.59 (d, J = 8.4 Hz, 1H), 1.51 - 1.33 (m, 2H), 1.31 - 1.16 (m, 2H). Example 56 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((3-hydroxybicyclo[1.1.1]pentan-1-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0415] [ka]

[0416] Using 3-(bromomethyl)bicyclo[1.1.1]pentan-1-ol and 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitride as raw materials, 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((3-hydroxybicyclo[1.1.1]pentan-1-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 1 of Example 47.

[0417] MS m / z (ESI): 568.2 [M+H] + . Example 57 6-((1-cyano-3,3-difluorocyclobutyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0418] [ka]

[0419] Step 1: 1-(chloromethyl)-3,3-difluorocyclobutane-1-carbonitrile

[0420] [ka]

[0421] 3,3-difluorocyclobutane-1-carbonitrile (200 mg, 1.7 mmol) was dissolved in 10 mL of THF, and LDA (1 mL, 2 M) was added at -78°C. The mixture was stirred at -78°C for 1 hour. Bromochloromethane (441 mg, 3.4 mmol) was added at -78°C, and the mixture was stirred from -78°C to room temperature for 3 hours. Water (20 mL) was added to the reaction solution, and then ethyl acetate (20 mL x 3) was added for extraction. After drying the organic phase, it was spin-dried to obtain the crude product 1-(chloromethyl)-3,3-difluorocyclobutane-1-carbonitrile (280 mg, yield: 99%).

[0422] Step 2: 6-((1-cyano-3,3-difluorocyclobutyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0423] [ka]

[0424] 6-hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (50 mg, 0.13 mmol) was dissolved in 5 mL of DMF, and 1-(chloromethyl)-3,3-difluorocyclobutane-1-carbonitrile (280 mg) and potassium carbonate (55 mg, 0.4 mmol) were added, and the mixture was stirred at 80°C for 5 hours. The product was spin-dried, and the crude product was purified by prep-HPLC to obtain 6-((1-cyano-3,3-difluorocyclobutyl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (3.4 mg, yield: 4.5%).

[0425] MS m / z (ESI): 583.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 2.4 Hz, 1H), 8.26 (s, 1H), 8.23 ​​(d, J = 1.3 Hz, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.86 (d, J = 4.5 Hz, 1H), 7.22 - 7.19 (m, 1H), 6.90 - 6.83 (m, 1H), 6.77 (s, 1H), 4.28 (s, 2H), 3.94 (s, 3H), 3.34 - 3.22 (m, 3H), 3.07 - 2.97 (m, 3H), 2.96 - 2.88 (m, 2H), 2.25 - 2.19 (m, 2H), 2.06 - 1.93 (m, 4H). Example 58 6-((3-cyanooxetane-3-yl)methoxy)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0426] [ka]

[0427] Using 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 6-((3-cyanooxetane-3-yl)methoxy)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriel was obtained by referring to Example 31.

[0428] MS m / z (ESI): 567.2 [M+H] + . Example 59 6-((4-cyanotetrahydro-2H-pyran-4-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0429] [ka]

[0430] Using 6-hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and (4-cyanotetrahydro-2H-pyran-4-yl)methyl 4-methylbenzene sulfonate as raw materials, 6-((4-cyanotetrahydro-2H-pyran-4-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrideride was obtained by referring to step 2 of Example 31.

[0431] MS m / z (ESI): 577.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.42 (d, J = 2.5 Hz, 1H), 8.24 (s, 1H), 8.17 (d, J = 2.1 Hz, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.90-7.78 (m, 2H), 7.18 (d, J = 2.1 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 4.14 - 4.02 (m, 4H), 3.99-3.88 (m, 6H), 3.86 - 3.61 (m, 6H), 2.12-2.05 (m, 2H), 1.90 - 1.78 (m, 3H), 1.78 - 1.64 (m, 2H). Example 60 6-((4-cyanotetrahydro-2H-pyran-4-yl)methoxy)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0432] [ka]

[0433] Using 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitride and (4-cyanotetrahydro-2H-pyran-4-yl)methyl 4-methylbenzene sulfonate as raw materials, 6-((4-cyanotetrahydro-2H-pyran-4-yl)methoxy)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrideride was obtained by referring to step 2 of Example 31.

[0434] MS m / z (ESI): 595.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.42 (d, J = 2.5 Hz, 1H), 8.24 (s, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J = 8.8, 2.6 Hz, 1H), 7.55 (d, J = 19.9 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 4.09 (d, J = 4.0 Hz, 1H), 4.06 (s, 3H), 4.01 (s, 3H), 3.91 - 3.78 (m, 6H), 3.70 - 3.62 (m, 3H), 2.90 - 2.73 (m, 1H), 2.11 - 2.05 (m, 2H), 1.89 - 1.77 (m, 3H), 1.73 - 1.69 (m, 1H). Example 61 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-hydroxy-4-methoxy-3-methylbuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitri

[0435] [ka]

[0436] Using 6-bromo-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and 1-methoxy-2-methylbuto-3-in-2-ol as raw materials, 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-hydroxy-4-methoxy-3-methylbuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 2 of Example 31.

[0437] MS m / z (ESI): 568.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.31 (s, 1H), 7.90 (s, 1H), 7.78 (dd, J = 8.8, 2.4 Hz, 1H), 7.67 (dd, J = 11.8, 7.1 Hz, 1H), 7.32 (s, 1H), 6.70 (d, J = 8.7 Hz, 1H), 4.02 (s, 3H), 3.89 (s, 3H), 3.72 (s, 5H), 3.60 (d, J = 9.1 Hz, 1H), 3.52 (s, 3H), 3.45 (d, J = 9.1 Hz, 1H), 2.97 (m, 2H), 1.58 (s, 3H). Example 62 6-(2-hydroxy-2-methylbuto-3-in-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0438] [ka]

[0439] Step 1: 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0440] [ka]

[0441] 6-hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg, 0.441 mmol) was dissolved in DMF (20 mL), and bromoacetone (121 mg, 0.882 mmol), cesium carbonate (431 mg, 1.32 mmol), and sodium iodide (66 mg, 0.441 mmol) were added, respectively. The reaction was stirred overnight at room temperature. Water was added to the reaction solution, and then ethyl acetate was added for extraction. After drying the organic phase, it was spin-dried. The crude product was purified by column chromatography to obtain 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (160 mg, yield: 71%).

[0442] MS m / z (ESI): 510.1 [M+H] + . Step 2: 6-((2-hydroxy-2-methylbuto-3-in-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0443] [ka]

[0444] 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (160 mg, 0.314 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), and ethinyl magnesium chloride (6.28 mL, 3.14 mmol, 0.5 M) was slowly added. After the addition was complete, the reaction solution was stirred for 1 hour. The reaction was quenched with aqueous ammonium chloride, and then extracted with ethyl acetate. The organic phase was dried and then spin-dried. The crude product was purified by column chromatography to obtain 6-((2-hydroxy-2-methylbuto-3-in-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (48 mg, yield: 28%).

[0445] MS m / z (ESI): 536.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 2.1 Hz, 1H), 8.60 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.85 (dd, J = 8.8, 2.6 Hz, 1H), 7.68 (dd, J = 8.5, 2.4 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 6.78 (dd, J = 10.8, 8.6 Hz, 2H), 5.84 (s, 1H), 4.08 (s, 2H), 3.82 (s, 3H), 3.78 - 3.70 (m, 2H), 3.70 - 3.65 (m, 2H), 3.61 - 3.52 (m, 2H), 3.50 (s, 2H), 3.40 (s, 1H), 2.57 - 2.53 (m, 1H), 1.59 (d, J = 8.5 Hz, 1H), 1.49 (s, 3H). Example 63 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0446] [ka]

[0447] Step 1: 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0448] [ka]

[0449] 6-hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg, 0.441 mmol) was dissolved in DMF (20 mL), and bromoacetone (121 mg, 0.882 mmol), cesium carbonate (431 mg, 1.32 mmol), and sodium iodide (66 mg, 0.441 mmol) were added, respectively. The reaction was stirred overnight at room temperature. Water was added to the reaction solution, and then ethyl acetate was added for extraction. After drying the organic phase, it was spin-dried. The crude product was purified by column chromatography to obtain 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (160 mg, yield: 71%).

[0450] MS m / z (ESI): 510.1 [M+H] + . Step 2: 6-((2-hydroxy-2-methylbuto-3-in-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0451] [ka]

[0452] 4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (160 mg, 0.314 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), and ethinyl magnesium chloride (6.28 mL, 3.14 mmol, 0.5 M) was slowly added. After the addition was complete, the reaction solution was stirred for 1 hour. The reaction was quenched with aqueous ammonium chloride, and then extracted with ethyl acetate. The organic phase was dried and then spin-dried. The crude product was purified by column chromatography to obtain 6-((2-hydroxy-2-methylbuto-3-in-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (48 mg, yield: 28%).

[0453] MS m / z (ESI): 536.1 [M+H] + . Step 3: 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0454] [ka]

[0455] 6-((2-hydroxy-2-methylbuto-3-in-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (48.2 mg, 0.09 mmol) was subjected to chiral separation to obtain 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (16 mg).

[0456] [Table 6]

[0457] t R =9.002 minutes MS m / z (ESI): 536.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 2.1 Hz, 1H), 8.60 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.85 (dd, J = 8.8, 2.6 Hz, 1H), 7.68 (dd, J = 8.5, 2.4 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 6.78 (m, 2H), 5.84 (s, 1H), 4.08 (s, 2H), 3.82 (s, 3H), 3.78 - 3.63 (m, 4H), 3.61 - 3.46 (m, 4H), 3.40 (s, 1H), 2.57 - 2.53 (m, 1H), 1.59 (d, J = 8.5 Hz, 1H), 1.49 (s, 3H). Example 64 6-(((S)-2-hydroxy-2-methylbuto-3-in-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0458] [ka]

[0459] Step 1: 6-(((S)-2-hydroxy-2-methylbuto-3-in-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0460] [ka]

[0461] 6-((2-hydroxy-2-methylbuto-3-in-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (48.2 mg, 0.09 mmol) was subjected to chiral separation to obtain 6-(((S)-2-hydroxy-2-methylbuto-3-in-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (18 mg).

[0462] [Table 7]

[0463] t R =7.431 minutes MS m / z (ESI): 536.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 2.1 Hz, 1H), 8.60 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.85 (dd, J = 8.8, 2.6 Hz, 1H), 7.68 (dd, J = 8.5, 2.4 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 6.78 (m, 2H), 5.84 (s, 1H), 4.08 (s, 2H), 3.82 (s, 3H), 3.78 - 3.63 (m, 4H), 3.61 - 3.46 (m, 4H), 3.40 (s, 1H), 2.57 - 2.53 (m, 1H), 1.59 (d, J = 8.5 Hz, 1H), 1.49 (s, 3H). Example 65 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(((S)-2-hydroxy-2-methylbuto-3-in-1-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0464] [ka]

[0465] Step 1: 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0466] [ka]

[0467] Using 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel (190 mg, yield 84%) was obtained by referring to step 1 of Example 63.

[0468] MS m / z (ESI): 528.1 [M+H] + . Step 2: 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(((S)-2-hydroxy-2-methylbuto-3-in-1-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitri

[0469] [ka]

[0470] Using 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel as a starting material, 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(((S)-2-hydroxy-2-methylbuto-3-in-1-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitriel (40 mg, yield 22%) was obtained by referring to step 2 of Example 63.

[0471] MS m / z (ESI): 554.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 2.1 Hz, 1H), 8.60 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.85 (dd, J = 8.8, 2.6 Hz, 1H), 7.64 (dd, J = 11.5, 1.9 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.84 (s, 1H), 4.08 (s, 2H), 3.92 (s, 3H), 3.81 - 3.65 (m, 4H), 3.64 - 3.48 (m, 4H), 3.40 (s, 1H), 2.59 - 2.53 (m, 1H), 1.59 (d, J = 8.4 Hz, 1H), 1.49 (s, 3H). Example 66 3-(((3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)oxo)methyl)bicyclo[1.1.1]pentan-1-formamide

[0472] [ka]

[0473] (3-Carbamoylbicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzene sulfonate and 6-hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride were used as raw materials, and 3-(((3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)oxo)methyl)bicyclo[1.1.1]pentan-1-formamide was obtained by referring to step 2 of Example 27.

[0474] MS m / z (ESI): 577.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 9.70 - 9.62 (m, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.21 (s, 1H), 8.16 - 8.08 (m, 2H), 7.93 - 7.77 (m, 2H), 7.13 (d, J = 1.9 Hz, 1H), 6.73 (dd, J = 22.6, 8.7 Hz, 2H), 5.52 (s, 1H), 5.39 (s, 1H), 4.07 (s, 2H), 3.93 (s, 5H), 3.72 (s, 4H), 2.96 (s, 1H), 2.88 (s, 1H), 2.15 (s, 6H). Example 67 3-(((3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)oxo)methyl)-N-methylbicyclo[1.1.1]pentan-1-formamide

[0475] [ka]

[0476] (3-(methylcarbamoyl)bicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzene sulfonate and 6-hydroxy-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride were used as raw materials, and 3-(((3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)oxo)methyl)-N-methylbicyclo[1.1.1]pentan-1-formamide was obtained by referring to step 2 of Example 27.

[0477] MS m / z (ESI): 591.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 2.2 Hz, 1H), 8.21 (s, 1H), 8.14 - 8.05 (m, 2H), 7.78 (dd, J = 8.8, 2.4 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 1.9 Hz, 1H), 6.70 (dd, J = 15.4, 8.7 Hz, 2H), 5.58 (d, J = 4.5 Hz, 1H), 4.05 (s, 2H), 3.92 (s, 3H), 3.83 (dd, J = 17.6, 8.8 Hz, 4H), 3.60 (s, 4H), 2.83 (d, J = 4.9 Hz, 3H), 2.72 (d, J = 5.8 Hz, 1H), 2.11 (s, 6H), 1.67 (d, J = 8.7 Hz, 1H). Example 68 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((R)-3-hydroxybuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0478] [ka]

[0479] (R)-buto-3-in-2-ol and 6-bromo-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride were used as raw materials, and 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((R)-3-hydroxybuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitride were obtained by referring to step 2 of Example 8.

[0480] MS m / z (ESI): 524.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 1.0 Hz, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.31 (s, 1H), 7.89 (s, 1H), 7.78 (dd, J = 8.8, 2.4 Hz, 1H), 7.62 (s, 1H), 7.30 (d, J = 1.2 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 4.80 (q, J = 6.6 Hz, 1H), 4.01 (s, 3H), 3.97 - 3.82 (m, 3H), 3.71 (s, 4H), 2.87 (s, 2H), 1.74 (d, J = 8.2 Hz, 1H), 1.59 (d, J = 6.6 Hz, 3H). Example 69 6-((3-cyanobicyclo[1.1.1]pentan-1-yl)methoxy)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0481] [ka]

[0482] (3-cyanobicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzene sulfonate and 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitride were used as raw materials, and 6-((3-cyanobicyclo[1.1.1]pentan-1-yl)methoxy)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride were obtained by referring to step 2 of Example 31.

[0483] MS m / z (ESI): 577.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 1.9 Hz, 1H), 8.22 (s, 1H), 8.07 (s, 1H), 7.88 (s, 1H), 7.79 (dd, J = 8.7, 2.0 Hz, 1H), 7.60 (s, 1H), 7.11 (s, 1H), 6.70 (d, J = 8.8 Hz, 1H), 4.01 (s, 5H), 3.88 (m, 4H), 3.68 (s, 4H), 2.85 (s, 1H), 2.37 (s, 6H), 1.76 - 1.69 (m, 1H). Example 70 6-((3-cyano-3-methylcyclobutyl)methoxy)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0484] [ka]

[0485] (3-cyano-3-methylcyclobutyl)methyl 4-methylbenzene sulfonate and 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitride were used as raw materials, and 6-((3-cyano-3-methylcyclobutyl)methoxy)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride were obtained by referring to step 2 of Example 31.

[0486] MS m / z (ESI): 579.3 [M+H] + . Example 71 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0487] [ka]

[0488] (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzene sulfonate and 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitride were used as raw materials, and 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitride were obtained by referring to step 2 of Example 27.

[0489] MS m / z (ESI): 582.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 2.1 Hz, 1H), 8.21 (s, 1H), 8.11 (d, J = 1.9 Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J = 8.8, 2.4 Hz, 1H), 7.54 (d, J = 10.8 Hz, 1H), 7.14 (d, J = 1.9 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 4.05 (s, 2H), 4.01 (s, 3H), 3.85 (d, J = 11.3 Hz, 4H), 3.66 (s, 6H), 2.79 (s, 1H), 1.82 (s, 6H), 1.70 (d, J = 8.8 Hz, 1H). Example 72 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((cis-3-hydroxy-3-methylcyclobutyl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0490] [ka]

[0491] (cis-3-hydroxy-3-methylcyclobutyl)methyl 4-methylbenzene sulfonate and 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitride were used as raw materials, and 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((cis-3-hydroxy-3-methylcyclobutyl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitride were obtained by referring to step 2 of Example 27.

[0492] MS m / z (ESI): 570.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 2.1 Hz, 1H), 8.21 (s, 1H), 8.13 (d, J = 1.9 Hz, 1H), 7.92 (s, 1H), 7.81 (dd, J = 8.7, 2.2 Hz, 1H), 7.75 (s, 1H), 7.14 (d, J = 1.9 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 4.14 - 3.99 (m, 7H), 3.93 (s, 2H), 3.77 (s, 4H), 3.00 (s, 1H), 2.38 (dd, J = 15.0, 7.6 Hz, 1H), 2.29 (dd, J = 12.5, 7.4 Hz, 2H), 2.02 (t, J = 10.2 Hz, 2H), 1.78 (s, 2H), 1.45 (s, 3H). Example 73 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-hydroxy-3-methylazetidine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0493] [ka]

[0494] Using 3-methylazetidine-3-ol and 6-bromo-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride as raw materials, 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-(3-hydroxy-3-methylazetidine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 1 of Example 31.

[0495] MS m / z (ESI): 541.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.15 (s, 1H), 7.95 (s, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 6.74 (dd, J = 11.8, 5.2 Hz, 2H), 4.25 (s, 2H), 4.02 (s, 3H), 3.88 (dd, J = 36.0, 7.4 Hz, 7H), 3.22 (s, 1H), 2.25 - 2.18 (m, 1H), 2.01 (s, 1H), 1.85 (s, 2H), 1.68 (s, 3H). Example 74 1-Cyano-N-(3-Cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)cyclopropane-1-formamide

[0496] [ka]

[0497] Step 1: 1-Cyano-N-(3-Cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)cyclopropane-1-formamide

[0498] [ka]

[0499] 6-amino-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was dissolved in DMF, and 1-cyanocyclopropane-1-carboxylic acid, HATU, and DIEA were added. The reaction was stirred overnight at room temperature. Water was added, and then ethyl acetate was added for extraction. After washing with saturated sodium chloride solution for the organic phase, the mixture was dried and spin-dried. The crude product was purified by column chromatography to obtain 1-cyano-N-(3-cyano-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)cyclopropane-1-formamide (off-white solid).

[0500] MS m / z (ESI): 546.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.43 (br., s, 1H), 9.26 (d, J = 1.7 Hz, 1H), 8.65 (s, 1H), 8.40 (d, J = 2.6 Hz, 1H), 8.07 (d, J = 2.3 Hz, 1H), 7.83 (dd, J = 8.8, 2.6 Hz, 1H), 7.74 - 7.64 (m, 2H), 6.82 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 3.82 (s, 3H), 3.80 - 3.65 (m, 4H), 3.61 - 3.49 (m, 4H), 1.79 - 1.70 (m, 3H), 1.59 (d, J = 8.4 Hz, 1H), 1.26 - 1.13 (m, 2H). Example 75 6-(3-hydroxy-4-methoxy-3-methylbuto-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0501] [ka]

[0502] 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbonitride and 1-methoxy-2-methylbuto-3-in-2-ol yielded 6-(3-hydroxy-4-methoxy-3-methylbuto-1-in-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbonitride (off-white solid).

[0503] MS m / z (ESI): 550.3 [M+H]+ . 1 H NMR (400 MHz, DMSO) δ 9.09 (s, 1H), 8.76 (s, 1H), 8.42 (s, 1H), 8.09 (s, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 7.40 (s, 1H), 6.80 (s, 1H), 5.72 (s, 1H), 3.79 (m, 14H), 3.15 - 2.98 (m, 4H), 1.47 (s, 3H). Example 76 6-(3-cyano-3-methylazetidine-1-yl)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0504] [ka]

[0505] Using 6-bromo-4-(6-(6-(5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and 3-methylazetidine-3-carbonitride as raw materials, 6-(3-cyano-3-methylazetidine-1-yl)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 1 of Example 31.

[0506] MS m / z (ESI): 550.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.79 (dd, J = 8.8, 2.4 Hz, 1H), 7.73 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 10.5 Hz, 1H), 6.70 (dd, J = 5.2, 3.4 Hz, 2H), 4.29 (d, J = 7.0 Hz, 2H), 4.01 (s, 3H), 3.91-3.85 (m, 6H), 3.67-3.64 (m, 4H), 2.80 (s, 1H), 1.83 (s, 3H), 1.70 (d, J = 8.7 Hz, 1H). Example 77 6-(3-cyano-3-methylazetidine-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0507] [ka]

[0508] Step 1: Preparation of 6-(3-cyano-3-methylazetidine-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0509] [ka]

[0510] A mixture of 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.19 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.0095 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5 mg, 0.011 mmol), cesium carbonate (123 mg, 0.38 mmol), 3-methylazetidine-3-carbonitrile (28 mg, 0.29 mmol), and toluene (5 mL) was purged with nitrogen gas and stirred at 130°C for 2 hours under microwave conditions. After the reaction was complete, the mixture was cooled to room temperature, the reaction solution was concentrated and dissolved in ethyl acetate, washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and spin-dried. The mixture was then separated and purified by preparative chromatography to obtain 6-(3-cyano-3-methylazetidine-1-yl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile (45 mg, white solid, yield: 45%).

[0511] MS m / z (ESI): 532.3 [M+H] + . 1H NMR (400 MHz, DMSO) δ 8.53 (s, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 1.5 Hz, 1H), 8.07 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 1.7 Hz, 1H), 6.78 (t, J = 9.3 Hz, 2H), 4.27 (d, J = 7.7 Hz, 2H), 3.91 (d, J = 7.7 Hz, 2H), 3.82 (s, 3H), 3.76-3.67 (m, 4H), 3.56-3.50 (m, 4H), 2.04 - 1.93 (m, 1H), 1.67 (s, 3H), 1.59 (d, J = 7.9 Hz, 1H). Example 78 6-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0512] [ka]

[0513] Using 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and 4-ethynyltetrahydro-2H-pyran-4-ol as raw materials, 6-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 2 of Example 8.

[0514] MS m / z (ESI): 562.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.31 (s, 1H), 6.79 (d, J = 8.6 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 4.12 (d, J = 7.1 Hz, 2H), 4.04 - 3.90 (m, 7H), 3.88 - 3.68 (m, 6H), 2.32 (s, 1H), 2.13 - 2.03 (m, 3H), 1.96-1.90 (m, 2H). Example 79 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((4-hydroxytetrahydro-2H-pyran-4-yl)ethinyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0515] [ka]

[0516] Using 6-bromo-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and 4-ethynyltetrahydro-2H-pyran-4-ol as raw materials, 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)pyrazolo[1,5-a]pyridine-3-carbonitride were obtained by referring to step 2 of Example 8.

[0517] MS m / z (ESI): 580.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 7.97 - 7.75 (m, 3H), 7.31 (s, 1H), 6.72 (d, J = 8.6 Hz, 1H), 4.20 - 4.08 (m, 2H), 4.05 - 3.93 (m, 7H), 3.84-3.70 (m, 6H), 2.13 - 2.03 (m, 3H), 1.97 - 1.88 (m, 3H). Example 80 6-((3-hydroxyoxetane-3-yl)ethynyl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0518] [ka]

[0519] Referring to step 2 of Example 8, 6-((3-hydroxyoxetane-3-yl)ethynyl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (white solid) was obtained.

[0520] MS m / z (ESI): 534.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 10.6 Hz, 1H), 6.72 (dd, J = 16.3, 8.5 Hz, 2H), 4.95 (d, J = 6.7 Hz, 2H), 4.83 (d, J = 6.7 Hz, 2H), 3.92 (s, 3H), 3.89 (s, 4H), 3.67 (s, 4H), 2.82 (s, 1H), 1.72 (d, J = 8.2 Hz, 2H). Example 81 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((3-hydroxyoxetan-3-yl)ethinyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0521] [ka]

[0522] Referring to step 2 of Example 8, 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((3-hydroxyoxobutan-3-yl)ethynyl)pyrazolo[1,5-a]pyridine-3-carbonitride (white solid) was obtained.

[0523] MS m / z (ESI): 552.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 7.89 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.54 (s, 1H), 7.30 (s, 1H), 6.70 (d, J = 8.7 Hz, 1H), 4.95 (d, J = 6.7 Hz, 2H), 4.83 (d, J = 6.8 Hz, 2H), 4.01 (s, 3H), 3.88 (s, 4H), 3.66 (s, 4H), 2.81 (s, 1H), 1.71 (d, J = 6.8 Hz, 2H). Example 82 6-((1-hydroxycyclobutyl)ethynyl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride

[0524] [ka]

[0525] Using 6-bromo-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and 1-ethynylcyclobutan-1-ol as raw materials, 6-((1-hydroxycyclobutyl)ethynyl)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 2 of Example 31.

[0526] MS m / z (ESI): 532.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 1.3 Hz, 1H), 8.75 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.07 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 8.8, 2.5 Hz, 1H), 7.68 (dd, J = 8.5, 2.4 Hz, 1H), 7.46 (d, J = 1.4 Hz, 1H), 6.83 - 6.73 (m, 2H), 6.00 (s, 1H), 3.82 (s, 3H), 3.79 - 3.67 (m, 4H), 3.60 - 3.50 (m, 4H), 2.58 - 2.56 (m, 1H), 2.47 - 2.39 (m, 2H), 2.29 - 2.19 (m, 2H), 1.85 - 1.78 (m, 2H), 1.62 - 1.57 (m, 1H). Example 83 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((1-hydroxycyclobutyl)ethynyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0527] [ka]

[0528] Using 6-bromo-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and 1-ethynylcyclobutan-1-ol as raw materials, 4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)-6-((1-hydroxycyclobutyl)ethynyl)pyrazolo[1,5-a]pyridine-3-carbonitride was obtained by referring to step 2 of Example 8.

[0529] MS m / z (ESI): 550.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.75 (s, 1H), 8.42 (s, 1H), 7.91 (s, 1H), 7.86 (dd, J = 8.7, 2.6 Hz, 1H), 7.64 (d, J = 11.4 Hz, 1H), 7.45 (d, J = 1.3 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 5.99 (s, 1H), 3.92 (s, 3H), 3.76 - 3.68 (m, 4H), 3.60 - 3.51 (m, 4H), 2.58 - 2.56 (m, 1H), 2.45 - 2.35 (m, 2H), 2.27 - 2.23 (m, 2H), 1.83 - 1.78 (m, 2H), 1.59 (d, J = 8.2 Hz, 1H). Example 84 N-(1-(5-(3-cyano-6-(3-hydroxy-3-methylbuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-5-fluoro-2-methylbenzamide

[0530] [ka]

[0531] Using 6-(3-hydroxy-3-methylbuto-1-in-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitride and N-(1-(5-bromopyridine-2-yl)-4-methylpiperidine-4-yl)-5-fluoro-2-methylbenzamide as starting materials, N-(1-(5-(3-cyano-6-(3-hydroxy-3-methylbuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-5-fluoro-2-methylbenzamide (30 mg, white solid, yield 45%) was obtained by referring to step 8 of Example 1.

[0532] MS m / z (ESI): 551.2 [M+H] + . 1 H NMR (400 MHz, Methanol-d4) δ 8.82 (d, J = 1.3 Hz, 1H), 8.46 (s, 1H), 8.29 (d, J = 2.5 Hz, 1H), 7.76 (dd, J = 9.0, 2.5 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.28 - 7.21 (m, 1H), 7.09 - 7.02 (m, 2H), 6.98 (d, J = 8.9 Hz, 1H), 4.10 - 4.00 (m, 2H), 3.44 - 3.39 (m, 2H), 2.44 - 2.38 (m, 2H), 2.38 (s, 3H), 1.77 - 1.69 (m, 2H), 1.58 (s, 6H), 1.54 (s, 3H). Example 85 3-Chloro-N-(1-(5-(3-cyano-6-(3-hydroxy-3-methylbuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide

[0533] [ka]

[0534] Step 1: tert-butyl(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)carbamate

[0535] [ka]

[0536] Using 6-bromo-4-(6-fluoropyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbonitriel as a starting material, tert-butyl(1-(5-(6-bromo-3-cyanopyrazole[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)carbamate was obtained by referring to step 4 of Example 1.

[0537] MS m / z (ESI): 511.1 [M+H] + . Step 2: 4-(6-(4-amino-4-methylpiperidine-1-yl)pyridine-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonil

[0538] [ka]

[0539] Using tert-butyl(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)carbamate as a starting material, 4-(6-(4-amino-4-methylpiperidine-1-yl)pyridine-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile (white solid) was obtained by referring to step 5 of Example 1.

[0540] MS m / z (ESI): 411.1 [M+H] + . Step 3: N-(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-3-chloropicorinamide

[0541] [ka]

[0542] Using 4-(6-(4-amino-4-methylpiperidine-1-yl)pyridine-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile as a starting material, N-(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolinamide (white solid) was obtained by referring to step 1 of Example 20.

[0543] MS m / z (ESI): 550.0 [M+H] + . Step 4: 3-Chloro-N-(1-(5-(3-cyano-6-(3-hydroxy-3-methylbuto-1-in-1-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide

[0544] [ka]

[0545] Using N-(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolinamide as a starting material, 3-chloro-N-(1-(5-(3-cyano-6-(3-hydroxy-3-methylbuto-1-in-1-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)picolinamide (white solid) was obtained by referring to step 2 of Example 20.

[0546] MS m / z (ESI): 554.2 [M+H] + . 1 H NMR (400 MHz, Methanol-d4) δ 8.81 (d, J = 1.3 Hz, 1H), 8.50 (dd, J = 4.7, 1.3 Hz, 1H), 8.45 (s, 1H), 8.28 (d, J = 2.6 Hz, 1H), 7.96 (dd, J = 8.2, 1.4 Hz, 1H), 7.75 (dd, J = 8.8, 2.6 Hz, 1H), 7.48 (dd, J = 8.2, 4.7 Hz, 1H), 7.38 (d, J = 1.3 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H), 4.18 - 4.03 (m, 2H), 3.48 - 3.37 (m, 2H), 2.54 - 2.34 (m, 2H), 1.80 - 1.68 (m, 2H), 1.58 (s, 6H), 1.56 (s, 3H). Example 86 N-(1-(5-(6-(3-amino-3-methylbuto-1-in-1-yl)-3-cyanopyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolinamide

[0547] [ka]

[0548] Using N-(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolinamide and 2-methylbuto-3-in-2-amine as starting materials, N-(1-(5-(6-(3-amino-3-methylbuto-1-in-1-yl)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolinamide (white solid) was obtained by referring to step 2 of Example 20.

[0549] MS m / z (ESI): 553.2 [M+H] + . 1 H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J = 1.4 Hz, 1H), 8.50 (d, J = 4.8 Hz, 1H), 8.45 (s, 1H), 8.28 (d, J = 2.5 Hz, 1H), 7.99 - 7.94 (m, 1H), 7.78 - 7.73 (m, 1H), 7.51 - 7.46 (m, 1H), 7.38 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H), 4.15 - 4.05 (m, 2H), 3.50 - 3.45 (m, 2H), 2.44 - 2.38 (m, 2H), 1.78 - 1.72 (m, 2H), 1.56 (s, 3H), 1.52 (s, 6H). Example 87 N-(1-(5-(6-(3-amino-3-methylbuto-1-in-1-yl)-3-cyanopyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-5-fluoro-2-methylbenzamide

[0550] [ka]

[0551] Step 1: N-(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)-5-fluoro-2-methylbenzamide

[0552] [ka]

[0553] Using 4-(6-(4-amino-4-methylpiperidine-1-yl)pyridine-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile and 5-fluoro-2-methylbenzoic acid as raw materials, N-(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-5-fluoro-2-methylbenzamide (white solid) was obtained by referring to step 2 of Example 20.

[0554] MS m / z (ESI): 547.1 [M+H] + . Step 2: N-(1-(5-(6-(3-amino-3-methylbuto-1-in-1-yl)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)-5-fluoro-2-methylbenzamide

[0555] [ka]

[0556] Using N-(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)-5-fluoro-2-methylbenzamide and 2-methylbuto-3-in-2-amine as starting materials, N-(1-(5-(6-(3-amino-3-methylbuto-1-in-1-yl)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)-5-fluoro-2-methylbenzamide (white solid) was obtained by referring to step 2 of Example 20.

[0557] MS m / z (ESI): 550.2 [M+H] + . 1H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J = 1.3 Hz, 1H), 8.45 (s, 1H), 8.28 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 8.9, 2.6 Hz, 1H), 7.38 (d, J = 1.2 Hz, 1H), 7.28 - 7.21 (m, 1H), 7.11 - 7.02 (m, 2H), 6.98 (d, J = 8.9 Hz, 1H), 4.08 - 4.00 (m, 2H), 3.43 - 3.38 (m, 2H), 2.46 - 2.39 (m, 2H), 2.38 (s, 3H), 1.75 - 1.69 (m, 2H), 1.54 (s, 3H), 1.52 (s, 6H). Example 88 3-Chloro-N-(1-(5-(3-cyano-6-(3-(2-hydroxypropane-2-yl)azetidine-1-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide

[0558] [ka]

[0559] Using 2-(azetidine-3-yl)propan-2-ol and N-(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolinamide as raw materials, 3-chloro-N-(1-(5-(3-cyano-6-(3-(2-hydroxypropan-2-yl)azetidine-1-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)picolinamide was obtained by referring to step 1 of Example 31.

[0560] MS m / z (ESI): 585.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 3.9 Hz, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 7.94 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.71 (s, 1H), 7.38 (dd, J = 8.1, 4.5 Hz, 1H), 6.77 (s, 1H), 4.14 (s, 2H), 3.96 (t, J = 7.6 Hz, 2H), 3.85 (t, J = 6.6 Hz, 2H), 3.48 (s, 2H), 2.48 (s, 2H), 1.89 - 1.80 (m, 2H), 1.25 (s, 3H), 1.24 (s, 6H). Example 89 3-Chloro-N-(1-(5-(3-cyano-6-(6-hydroxy-6-methyl-2-azaspiro[3,3]heptan-2-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide

[0561] [ka]

[0562] Using 6-methyl-2-azaspiro[3.3]heptan-6-ol as a starting material, 3-chloro-N-(1-(5-(3-cyano-6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide was obtained by referring to step 1 of Example 31.

[0563] MS m / z (ESI): 597.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 7.94 (s, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.39 (d, J = 4.6 Hz, 1H), 6.89 (s, 1H), 6.71 (s, 1H), 4.15 (s, 2H), 3.94 (d, J = 5.8 Hz, 4H), 3.47 (s, 2H), 2.48 (s, 2H), 2.38 (s, 4H), 1.84 (s, 2H), 1.39 (s, 3H), 1.25 (s, 3H). Example 90 N-(1-(5-(6-((1-aminocyclopropyl)ethinyl)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolinamide

[0564] [ka]

[0565] Using 1-ethynylcyclopropane-1-amine as a starting material, N-(1-(5-(6-((1-aminocyclopropyl)ethynyl)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolinamide was obtained by referring to step 2 of Example 31.

[0566] MS m / z (ESI): 551.2[M+H] + . Example 91 N-(1-(5-(6-((1-aminocyclopropyl)methoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolinamide

[0567] [ka]

[0568] Step 1: tert-butyl(1-(((4-(6-(4-(3-chloropicolineamino)-4-methylpiperidine-1-yl)pyridine-3-yl)-3-cyanopyrazolo[1,5-a]pyridine-6-yl)oxo)methyl)cyclopropyl)carbamate

[0569] [ka]

[0570] N-(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolinamide (100 mg, 0.182 mmol) was dissolved in NMP (2 mL), and tert-butyl(1-(hydroxy)cyclopropyl)carbamate (51 mg, 0.272 mmol) and cesium carbonate (177 mg, 0.545 mmol) were added. The reaction was stirred with microwaves at 160°C for 1 hour to directly produce tert-butyl(1-(((4-(6-(4-(3-chloropicolinamino)-4-methylpiperidine-1-yl)pyridine-3-yl)-3-cyanopyrazolo[1,5-a]pyridine-6-yl)oxo)methyl)cyclopropyl)carbamate.

[0571] MS m / z (ESI): 657.2 [M+H] + . Step 2: N-(1-(5-(6-((1-aminocyclopropyl)methoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)-3-chloropicorinamide

[0572] [ka]

[0573] Using tert-butyl(1-(((4-(6-(4-(3-chloropicolineamino)-4-methylpiperidine-1-yl)pyridine-3-yl)-3-cyanopyrazolo[1,5-a]pyridine-6-yl)oxo)methyl)cyclopropyl)carbamate as a starting material, N-(1-(5-(6-((1-aminocyclopropyl)methoxy)-3-cyanopyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolineamide was obtained by referring to step 5 of Example 1.

[0574] MS m / z (ESI): 557.2 [M+H] + . Example 92 3-Chloro-N-(1-(5-(3-cyano-6-((1-cyanocyclopropyl)methoxy)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide

[0575] [ka]

[0576] Step 1: 3-Chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide

[0577] [ka]

[0578] Using 4-(6-fluoropyridine-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile as a starting material, 3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide was obtained by referring to steps 1-3 of Example 85.

[0579] MS m / z (ESI): 488.1 [M+H] + . Step 2: 3-Chloro-N-(1-(5-(3-cyano-6-((1-cyanocyclopropyl)methoxy)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide

[0580] [ka]

[0581] Using 3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide and (1-cyanocyclopropyl)methyl 4-methylbenzene sulfonate as raw materials, 3-chloro-N-(1-(5-(3-cyano-6-((1-cyanocyclopropyl)methoxy)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide was obtained by referring to step 2 of Example 27.

[0582] MS m / z (ESI): 567.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 2.3 Hz, 1H), 8.60 (s, 1H), 8.53 (d, J = 4.7 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H), 8.28 (s, 1H), 8.03 - 7.98 (m, 1H), 7.82 - 7.74 (m, 1H), 7.52 - 7.48 (m, 1H), 7.39 (d, J = 1.9 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 4.20 (s, 2H), 4.10 - 4.01 (m, 2H), 3.40 - 3.34 (m, 2H), 2.34 - 2.30 (m, 2H), 1.63 - 1.54 (m, 2H), 1.45 (s, 3H), 1.44 - 1.39 (m, 2H), 1.22 - 1.16 (m, 2H). Example 93 N-(1-(5-(3-cyano-6-((1-cyanocyclopropyl)methoxy)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-3-fluoropicolinamide

[0583] [ka]

[0584] Step 1: N-(1-(5-(3-3-cyano-6-hydroxypyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-3-fluoropicolinamide

[0585] [ka]

[0586] Using 4-(6-fluoropyridine-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile as a starting material, N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-3-fluoropicolinamide was obtained by referring to steps 1-3 of Example 85.

[0587] MS m / z (ESI): 472.1 [M+H] + . Step 2: N-(1-(5-(3-cyano-6-((1-cyanocyclopropyl)methoxy)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-3-fluopicolinamide

[0588] [ka]

[0589] N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-3-fluoropicolinamide and (1-cyanocyclopropyl)methyl 4-methylbenzene sulfonate were used as raw materials, and N-(1-(5-(3-cyano-6-((1-cyanocyclopropyl)methoxy)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-3-fluoropicolinamide was obtained by referring to step 2 of Example 31.

[0590] MS m / z (ESI): 551.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 2.1 Hz, 1H), 8.60 (s, 1H), 8.51 - 8.43 (m, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.21 (s, 1H), 7.89 - 7.81 (m, 1H), 7.78 (dd, J = 8.8, 2.6 Hz, 1H), 7.68 - 7.58 (m, 1H), 7.39 (d, J = 2.1 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 4.20 (s, 2H), 4.10 - 3.98 (m, 2H), 3.31 - 3.24 (m, 2H), 2.40 - 2.27 (m, 2H), 1.69 - 1.56 (m, 2H), 1.46 (s, 3H), 1.45 - 1.40 (m, 2H), 1.24 - 1.16 (m, 2H). Example 94 3-Chloro-N-(1-(5-(3-cyano-6-((3-cyanooxetane-3-yl)methoxy)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide

[0591] [ka]

[0592] Using 3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide as a starting material, and referring to Example 31, 6-((3-cyanooxetane-3-yl)methoxy)-4-(6-(6-((5-fluoro-6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile was obtained.

[0593] MS m / z (ESI): 583.2 [M+H] + . Example 95 3-Chloro-N-(1-(5-(3-cyano-6-(3-hydroxy-3-methylazetidine-1-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide

[0594] [ka]

[0595] Using 3-methylazetidine-3-ol and N-(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolinamide as starting materials, 3-chloro-N-(1-(5-(3-cyano-6-(3-hydroxy-3-methylazetidine-1-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide was obtained by referring to step 1 of Example 31.

[0596] MS m / z (ESI): 557.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 3.7 Hz, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.72 (s, 1H), 7.38 (dd, J = 8.1, 4.5 Hz, 1H), 6.92 (d, J = 9.6 Hz, 1H), 6.75 (s, 1H), 4.15 (s, 2H), 3.91 (d, J = 7.3 Hz, 2H), 3.82 (d, J = 7.2 Hz, 2H), 3.49 (s, 2H), 2.49 (s, 2H), 2.24 - 2.18 (m, 1H), 1.88 - 1.80 (m, 2H), 1.68 - 1.65 (m, 3H), 1.25 (s, 3H). Example 96 3-Chloro-N-(1-(5-(3-cyano-6-(3-cyano-3-methylazetidine-1-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide

[0597] [ka]

[0598] Using 3-methylazetidine-3-carbonitride and N-(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolinamide as starting materials, 3-chloro-N-(1-(5-(3-cyano-6-(3-cyano-3-methylazetidine-1-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide was obtained by referring to step 1 of Example 31.

[0599] MS m / z (ESI): 566.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.46 (dd, J = 4.5, 1.3 Hz, 1H), 8.31 (d, J = 2.3 Hz, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.83 (dd, J = 8.1, 1.3 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.37 (dd, J = 8.1, 4.5 Hz, 1H), 6.82 (d, J = 8.9 Hz, 1H), 6.67 (d, J = 1.9 Hz, 1H), 4.28 (d, J = 7.0 Hz, 2H), 4.09 (d, J = 13.6 Hz, 2H), 3.88 (d, J = 7.0 Hz, 2H), 3.39 (t, J = 11.1 Hz, 2H), 2.43 (d, J = 13.8 Hz, 2H), 1.84 (d, J = 4.3 Hz, 1H), 1.82 (s, 3H), 1.78 (d, J = 4.1 Hz, 1H), 1.60 (s, 3H). Example 97 3-Chloro-N-(1-(5-(3-cyano-6-((3-hydroxyoxetane-3-yl)ethinyl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-4-methylpiperidine-4-yl)picolinamide

[0600] [ka]

[0601] Using 3-ethynyloxetan-3-ol and N-(1-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)-3-chloropicolinamide as starting materials, 3-chloro-N-(1-(5-(3-cyano-6-((3-hydroxyoxetan-3-yl)ethynyl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-yl)picolinamide was obtained by referring to step 2 of Example 8.

[0602] MS m / z (ESI): 568.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.39 (d, J = 3.9 Hz, 1H), 8.24 (s, 2H), 7.84 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.31 (dd, J = 7.8, 4.6 Hz, 1H), 7.23 (s, 1H), 6.77 (d, J = 9.0 Hz, 1H), 4.87 (d, J = 6.6 Hz, 2H), 4.64 (d, J = 6.7 Hz, 2H), 3.99 (d, J = 13.6 Hz, 2H), 3.34 (t, J = 11.0 Hz, 2H), 2.36 (d, J = 14.0 Hz, 2H), 1.73 (d, J = 3.8 Hz, 2H), 1.53 (s, 3H). 2. Evaluation of compound biological tests The present invention will be further described below based on test examples, but these examples are not intended to limit the scope of the present invention.

[0603] 1. Enzyme Test Experiment Test Example 1. Detection of the inhibitory effect of the compound of the present invention on the activity of RET wild-type and mutant kinases. 1. Experimental Objective: The purpose of this experiment is to detect the inhibitory effect of the compound of the present invention on the activity of RET wild-type and mutant kinases.

[0604] 2.1 Experimental equipment: Centrifuge (Eppendorf 5810R); Microplate reader (BioTek Synergy H1); Pipette (Eppendorf & Rainin).

[0605] 2.2 Experimental Reagents: RET enzyme was purchased from Carna, and the product number is 08-159. The RET M918T enzyme was purchased from Carna, and its product number is 08-508. KIF5B-RET was purchased from SignalChem, and its product number is R02-19FG-05. CCDC6-RET was purchased from SignalChem, Inc., with product number R02-19BG-05. RET V804M enzyme was purchased from Thermofisher, product number PV6223. RET V804L enzyme was purchased from Thermofisher, product number PV4397. The HTRF KinEASE-TK kit was purchased from Cisbio, and the product number is 62TK0PEC. The ATP was purchased from Thermofisher, and its product number is PV3227. The 384-well plate was purchased from PerkinElmer, and its product number is 6007290.

[0606] 2.3 Test compound: This is a compound used in the examples of the present invention, and it is a compound I created myself. 3. Experimental method: In this experiment, the activity of compounds against RET kinases was detected using homogeneous time-resolved fluorescence (HTRF). The experiment was performed in a 384-well plate, and compound solutions of different concentrations were prepared using experimental buffer (25 mM HEPES, 10 mM MgCl2, 0.01% TritonX-100). These solutions were added to the 384-well plate, along with diluted RET, RET M918T, CCDC6-RET, KIF5B-RET, RET V804M, or RET V804L kinase solutions (0.01-2 nM) and the TK-substrate. ATP solutions containing biotin (500 nM to 1 μM) and Km (0.19 to 200 μM) were added to a total reaction system of 10 μL. The mixture was centrifuged at 1000 rpm for 1 minute to ensure homogeneity, and then reacted at room temperature for 45 minutes. After that, a mixed solution of Sa-XL665 and TK-ab-Cryptate prepared using 10 μL of detection solution was added, centrifuged at 1000 rpm for 1 minute to ensure homogeneity, and reacted at room temperature for 1 hour. Finally, data was read using a BioTek Synergy H1 meter, and readings at 665 nm and 620 nm were recorded.

[0607] 4. Experimental data processing method: Data was read using a BioTek Synergy H1 meter, readings at 665nm and 620nm were recorded, the ratio (665nm / 620nm) was calculated, the inhibition rate was calculated, and nonlinear regression curve fitting of concentration and inhibition rate was performed using Graphpad Prism software. 50 The value was retrieved.

[0608] 5. Experimental results: Through the aforementioned testing methods, the specific example compound test data for various mutant kinases of RET are shown in Table 8.

[0609] [Table 8]

[0610] 6. Experimental conclusion: The compounds of the present invention's examples showed good inhibitory activity against various mutant kinases of RET, with significant activity observed against drug-resistant mutant RET M918T, KIF5B-RET, and RET V804L.

[0611] Test Example 2. Detection of the inhibitory effect of the compound of the present invention on KDR kinase activity. 1. Experimental Objective: The purpose of this experiment is to detect the inhibitory ability of compounds on KDR kinase activity.

[0612] 2.1 Experimental equipment: Centrifuge (Eppendorf 5810R); Microplate reader (BioTek Synergy H1); Pipette (Eppendorf & Rainin).

[0613] 2.2 Experimental Reagents: KDR kinase was purchased from Carna, Inc., with product number 08-191. The HTRF KinEASE-TK kit was purchased from Cisbio, and the product number is 62TK0PEC. The ATP was purchased from Thermofisher, and its product number is PV3227. The 384-well plate was purchased from PerkinElmer, and its product number is 6007290.

[0614] 2.3 Test compound: The compound in the embodiment of the present invention is a compound that I manufactured myself. 3. Experimental method: In this experiment, the activity of compounds against KDR kinase was detected using homogeneous time-resolved fluorescence (HTRF). This experiment was conducted in a 384-well plate. Compound solutions of different concentrations were prepared using experimental buffer (25 mM HEPES, 10 mM MgCl2, 0.01% TritonX-100), added to the 384-well plate, and further diluted KDR kinase solution (0.05 nM), substrate TK-substrate biotin (500 nM to 1 μM), and Km concentration (0.19 to 200 μM) ATP solution were added. The total reaction system volume was 10 μL. The mixture was centrifuged at 1000 rpm for 1 minute to ensure uniform mixing, and reacted at room temperature for 45 minutes. Then, a mixed solution of Sa-XL665 and TK-ab-Cryptate prepared using 10 μL of detection solution was added, centrifuged at 1000 rpm for 1 minute to ensure uniform mixing, and reacted at room temperature for 1 hour. Finally, data was read using a BioTek Synergy H1 microplate reader, and readings at 665 nm and 620 nm were recorded.

[0615] 4. Experimental data processing method: Data was read using a BioTek Synergy H1 meter, readings at 665nm and 620nm were recorded, the ratio (665nm / 620nm) was calculated, the inhibition rate was calculated, and nonlinear regression curve fitting of concentration and inhibition rate was performed using Graphpad Prism software. 50 The value was retrieved.

[0616] 5. Experimental results: Through the above test method, test data for specific examples was obtained, as shown in Table 9.

[0617] [Table 9]

[0618] 6. Experimental conclusion: The above data indicates that the compounds of the examples shown in the present invention have a strong inhibitory effect on RET kinase activity, but a relatively weak inhibitory effect on KDR kinase activity. Comparing the data from the two groups, it can be seen that the series of compounds of the present invention have high selectivity for inhibiting KDR / RET kinase activity.

[0619] II. Cell Biology Experiment Test Test Example 1. Detection of the inhibitory effect of the compound of the present invention on the proliferative activity of TT cells. 1. Experimental Objective: The purpose of this experiment is to detect the inhibitory effect of compounds on the proliferative activity of TT cells.

[0620] 2.1 Experimental equipment: Microplate reader (BioTek Synergy H1); Pipette (Eppendorf & Rainin).

[0621] 2.2 Experimental Reagents: TT cells were purchased from the Chinese Academy of Sciences' cell bank. Cell Titer-Glo cells were purchased from Promega, Inc., under product number G7573.

[0622] 2.3 Test compound: The compound in the embodiment of the present invention is a compound that I manufactured myself. 3. Experimental method: After culturing TT cells to appropriate confluence, the TT cells were collected, adjusted to appropriate cell concentration in complete medium, and the cell suspension was spread into 96-well plates at 90 μL per well. The plates were incubated overnight at 37°C with 5% CO2. Compound solutions of various concentrations were prepared using DMSO and culture medium to establish solvent controls. 10 μL of the compound solution was added per well to the 96-well plates and incubated at 37°C with 5% CO2 for 72 hours. CellTiter-Glo solution was then added, shaken to mix uniformly, and incubated in the dark for 10 minutes. Data was read using a BioTek Synergy H1 microplate reader.

[0623] 4. Experimental data processing method: The inhibition rate is calculated using the emission signal value, and nonlinear regression curve fitting of concentration and inhibition rate is performed using Graphpad Prism software, and IC 50 The value was retrieved.

[0624] 5. Experimental results:

[0625] [Table 10]

[0626] 6. Experimental conclusion: The above data demonstrates that the compounds of the present invention have a good inhibitory effect on the proliferation of TT cells.

[0627] Test Example 2: Detection of the inhibitory effect of the compound of the present invention on the proliferative activity of Ba / F3 KIF5B-RET cells. 1. Experimental Objective: The objective is to detect the inhibitory effect of the compound of the present invention on the proliferative activity of Ba / F3 KIF5B-RET cells.

[0628] 2. Equipment and reagents: 2.1 Experimental equipment: Microplate reader (BioTek Synergy H1); Pipette (Eppendorf & Rainin).

[0629] 2.2 Experimental Reagents: Ba / F3 KIF5B-RET is provided by Kang Yuan Bo Chuang Biotechnology (Beijing) Co., Ltd., its cell number is CVCL_UE86, and can be looked up on the cell information site https: / / web.expasy.org / cellosaurus / . This stable cell line does not require IL-3-dependent growth. Cell Titer-Glo cells were purchased from Promega, Inc., under product number G7573.

[0630] 2.3 Test compound: The compound in the embodiment of the present invention is a compound that I manufactured myself. 3. Experimental method: When Ba / F3 KIF5B-RET cells were cultured to appropriate confluence, the cells were collected, adjusted to appropriate cell concentration in complete medium, spread the cell suspension in a 96-well plate at 90 μL per well, and allowed to adhere overnight in a 37°C, 5% CO2 incubator. Compound solutions of various concentrations were prepared using DMSO and culture medium to set up solvent controls. 10 μL of the compound solution was added per well to the 96-well plate and placed in a 37°C, 5% CO2 incubator, followed by incubation for 72 to 144 hours. Then, CellTiter-Glo solution was added, shaken to mix uniformly, and then incubated in the dark for 10 minutes. Data was read using a BioTek Synergy H1 microplate reader.

[0631] 4. Experimental data processing method: The inhibition rate is calculated using the emission signal value, and nonlinear regression curve fitting of concentration and inhibition rate is performed using Graphpad Prism software, and IC 50 The value was retrieved.

[0632] 5. Experimental results:

[0633] [Table 11]

[0634] 6. Experimental conclusion: The above data demonstrates that the compounds of the present invention have a good inhibitory effect on the proliferation of Ba / F3 KIF5B-RET cells.

[0635] Test Example 3. Inhibitory effect of the compound of the present invention on the phosphorylation of ERK, a downstream signaling factor of TT cells. 1. Experimental Objective: The objective is to detect the inhibitory effect of compounds on the phosphorylation of ERK, a downstream signaling factor of TT cells.

[0636] 2. Laboratory equipment and reagents: 2.1 Experimental equipment: Imager (Biorad ChemiDoc) TM MP); Pipette (Eppendorf & Rainin).

[0637] 2.2 Experimental Reagents: The pERK antibody was purchased from Cell Signaling Technology, Inc., with product number 4370S. The total ERK antibody was purchased from Cell Signaling Technology, Inc., under product number 4696S. The internal reference GAPDH was purchased from Cell Signaling Technology, Inc., with product number 5174S. The fluorescent secondary antibodies were purchased from LI-COR, with product numbers P / N 925-68071 and P / N 926-32210.

[0638] 2.3 Test compound: The compound in the embodiment of the present invention is a compound that I manufactured myself. 3. Experimental method: This experiment uses the Western blot method to detect the inhibitory effect of the compound of the present invention on the phosphorylation of ERK, a downstream signaling factor of TT cells. After culturing TT cells to the appropriate confluence, the cells were collected, adjusted to the appropriate cell concentration in complete medium, spread the cell suspension in a 96-well plate, and allowed to adhere overnight in an incubator at 37°C and 5% CO2 with 1 mL per well. Diluted solutions of the compound at different concentrations (3.7 nM, 11.1 nM, 33.3 nM, 100 nM, 300 nM) were added, and the mixture was incubated at 37°C for 2 hours. The cell supernatant was aspirated, washed once with PBS, and proteins were collected from the lysate. After protein denaturation, the following Western blot experiment was performed. Protein electrophoresis was performed at 120V for approximately 75 minutes, then the membrane was transferred to a PVDF membrane at 10V for 45 minutes using a semi-dry transfer machine, blocked with 5% BSA at room temperature for 1 hour, the PVDF membrane was cut into appropriately sized strips, incubated overnight at 4°C in each prepared antibody diluent, washed the membranes 6 times with TBST, incubated with goat anti-mouse secondary antibody and goat anti-rabbit secondary antibody at room temperature for 1 hour, washed the membranes 6 times with TBST, and then transferred to BioradChemiDoc TM Imaging was performed using an MP imaging system.

[0639] 4. Experimental data processing method: By detecting protein strip bands, we determined the inhibitory effect of compounds on ERK phosphorylation levels in TT cells at different concentrations.

[0640] 5. Experimental results: Both Examples 63 and 64 significantly inhibited ERK phosphorylation levels in TT cells and showed dose-dependent effects. After culturing the compounds with TT cells at 37°C for 2 hours, Example 63 nearly completely inhibited ERK phosphorylation at 300 nM, 100 nM, 33.3 nM, and 11.1 nM, and inhibited about half of ERK phosphorylation at 3.7 nM. On the other hand, Example 64 completely inhibited ERK phosphorylation at 300 nM and 100 nM, the degree of inhibition decreased slightly at 33.3 nM, inhibited half of the ERK phosphorylation level at 11.1 nM, and showed weak inhibition at 3.7 nM.

[0641] 6. Experimental conclusion: The above protocol demonstrates that the compound of the present invention exhibits a dose-dependent inhibitory effect on the phosphorylation of ERK, a downstream signaling factor of TT cells.

[0642] 3. Detection of pharmacokinetics in Balb / C mice 1. Research purpose: Using Balb / C mice as test animals, we will study the following compounds in their application and investigate the pharmacokinetic behavior of plasma in mice after oral administration at a dose of 5 mg / kg.

[0643] 2. Test protocol: 2.1 Test drug: This is an embodiment of the present invention, and the compound was manufactured by myself.

[0644] 2.2 Test animals: Six Balb / C mice / example, male, Shanghai Jiesijie Laboratory Animal Co., Ltd., Animal Production Permit Number (SCXK(Shanghai)2013-0006 N0.311620400001794).

[0645] 2.3 Administration: Balb / C mice, male; after overnight fasting, each was administered via po, with a dose of 5 mg / kg and a volume of 10 mL / kg.

[0646] 2.4 Sample preparation: 0.5% CMC-Na (1% Tween80) was dissolved using ultrasound to produce a clear solution or a homogeneous suspension.

[0647] 2.5 Sample Collection: Before and after administration, and at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours, 0.1 mL of blood was collected from the orbit of the mice, placed in an EDTA-K2 test tube, the plasma was centrifuged at 4°C and 6000 rpm for 6 minutes, and stored at -80°C.

[0648] 2.5 Sample Processing: 1) A 40 μL plasma sample was added to 160 μL of acetonitrile and allowed to precipitate. After mixing, the mixture was centrifuged at 3500 × g for 5 to 20 minutes.

[0649] 2) After processing, 100 μL of the supernatant solution was taken and the concentration of the test compound was analyzed by LC / MS / MS. 2.6 Liquid phase analysis • Liquid phase conditions: Shimadzu LC-20AD pump ·Mass spectrometry conditions: AB Sciex API4000 mass spectrometer • Column: Phenomenex Gemiu 5um C18 50×4.6mm Mobile phase: Solution A: 0.1% formic acid aqueous solution, Solution B: acetonitrile • Flow rate: 0.8 mL / min • Elution time: 0-4.0 minutes, the eluent is as follows:

[0650] [Table 12]

[0651] 3. Test Results and Analysis The main pharmacokinetic parameters were calculated using WinNonlin 6.1, and the results of the mouse pharmacokinetic experiments are shown in Table 13 below.

[0652] [Table 13]

[0653] 4. Experimental conclusion: The results of the mouse pharmacokinetic experiments shown in the table indicate that the compounds of the present invention exhibit good metabolic properties, with high exposure AUC and high maximum blood drug concentration C. max All of them appear to be in good condition.

[0654] IV. Tumor suppression experiments in a Ba / F3 KIF5B-RET transplanted tumor model 1. Experimental Objective: The objective is to evaluate the antitumor activity of the test compound against subcutaneously transplanted tumors of Ba / F3 KIF5B-RET cells in nude mice.

[0655] 2. Laboratory equipment and reagents: 2.1 Equipment: Ultra-clean workbench (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Device Factory); CO2 incubator (311, Thermo); Centrifuge (Centrifuge 5720R, Eppendorf); Fully automatic cell counter (Countess II, Life); Pipette (10-20 μL, Eppendorf); Microscope (TS100, Nikon); Vernier caliper (500-196mm, Mitutoyo, Japan); Cell culture flasks (T25 / T75 / T225, Corning).

[0656] 2.2 Reagents: RPMI1640 (22400-089, Gibco); Fetal bovine serum (FBS) (10099-141, Gibco); Phosphate buffer (PBS) (10010-023, Gibco).

[0657] 2.3 Test compound: The compound in the embodiment of the present invention is a compound that I manufactured myself. 3. Experimental Procedure: Ba / F3 KIF5B-RET cells were extracted from the cell bank, resuscitated, and then added to RPMI1640 medium (RPMI1640 + 10% FBS + 1% Glu + 1% P / S). They were cultured in a CO2 incubator (incubator temperature 37°C, CO2 concentration 5%), and when the cell count increased to the number required for in vivo inoculation, the Ba / F3 KIF5B-RET cells were collected. The cells were counted using a fully automated cell counter, and according to the count result, the cells were resuspended in PBS to form a cell suspension (density: 2 × 10⁶). 7 A solution ( / mL) was prepared and placed in an icebox for later use.

[0658] Six-to-eight-week-old female BALB / c nude mice were used, weighing approximately 18-22g. The mice were housed in SPF-grade animal rooms, in single cages with five mice per cage. All cages, bedding, and water were disinfected before use, and all animals had free access to food and water. Before the experiment, mouse and rat ear tags were attached, and the skin at the inoculation site was disinfected with 75% medical alcohol before inoculation. 0.1 mL of Ba / F3 KIF5B-RET cells (2 × 10⁶) was administered to the right posterior dorsal region of each mouse. 6 Subcutaneous inoculation was performed (containing [number] cells). Tumor volume was 60-200 mm². 3 When the target was reached, group administration was initiated, with 5 mice per group. Each test compound was administered orally twice daily for 14 days. Tumor volume was measured twice a week, the body weight of the mice was measured, and tumor TGI (%) was calculated.

[0659] 4. Data processing: Tumor volume (mm 3 The formula for calculating ) is: V = V = 0.5 × D × d × d, where D and d represent the long and short diameters of the tumor, respectively.

[0660] Calculation of TGI (%): If the tumor has not regressed, TGI (%) = [(1 - (average tumor volume at the end of treatment in a specific treatment group - average tumor volume at the start of treatment in that treatment group)) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100% If the tumor regresses, TGI (%) = [(1 - (average tumor volume at the end of administration for a specific treatment group - average tumor volume at the start of administration for that treatment group) / average tumor volume at the start of administration for that treatment group)] × 100%.

[0661] 5. Experimental results:

[0662] [Table 14]

[0663] 6. Experimental conclusion: The above data demonstrate that, after 14 days of continuous oral administration, the example compounds of the present invention can significantly inhibit the proliferation of xenograft tumors in Ba / F3 KIF5B-RET nude mice.

[0664] 5. Pharmacodynamic experiments on a subcutaneous xenograft tumor model of human bone marrow-like thyroid cancer cells (TT). 1. Experimental Objective: The objective is to evaluate the antitumor effect of the test compound by performing in vivo pharmacodynamic experiments using a human bone marrow-like thyroid cancer cell xenograft tumor model (TT) with BALB / c nude mice as the test animal.

[0665] 2. Laboratory equipment and reagents: 2.1 Equipment: CO2 incubator (311, Thermo); High-speed refrigerated centrifugal separator (Multifuge X3R, Thermo); Automatic cell counter (Mini-006-0484, Cellometer); Bio-cabinet (1300 SERIES A2, Thermo); Electronic balance (JJ300Y, Changshu Shuangjie); Vernier caliper (0-150mm / 0.01mm, Mitutoyo, Japan).

[0666] 2.2 Reagents: F-12K (21127-022, Gibco); Fetal bovine serum (FBS) (10099-141, Gibco); Streptomycin biantibody (PS) (SV30010, Hyclone).

[0667] 3. Laboratory animals: BALB / c nude mice, female, 6-8 weeks old, weighing 18-22g, provided by Shanghai Lingchang Biotechnology Co., Ltd.

[0668] 4. Test compound: The compound in the embodiment of the present invention is a compound that I manufactured myself. 5. Experimental Procedure: 5.1 Cell Culture: TT cells were cultured in vitro in a monolayer under the following conditions: 20% heat-inactivated fetal bovine serum and 1% penicillin-streptomycin biantibody were added to F-12K culture medium at 37°C and 5% CO2. Digestion with trypsin-EDTA was performed twice a week, and the cells were subcultured. When the cells were in the exponential growth phase, they were collected, counted, and inoculated.

[0669] 5.2 Tumor Inoculation: When TT cells were in the logarithmic growth phase, they were collected after full growth, ensuring a survival rate of over 90%. Approximately 1 × 10⁻⁶ 7 A 0.2 mL cell suspension containing TT cells (cells suspended in basic F-12K medium with 50% Matrigel added) was subcutaneously inoculated into the right posterior dorsal region of each mouse, with an average tumor volume of approximately 150-200 mm². 3 When the target was reached, group-based administration was initiated.

[0670] 5.3 Experimental group assignments and dosage: 1. The day of group assignment was designated as Day 0 (D0). The interval between BID administrations was 6-8 hours / 18-16 hours. The first dose was administered in the afternoon of Day 0, and the last dose was administered in the morning of Day 21.

[0671] 2. Dosage volume: 10 L / g depending on the body weight of nude mice. Animal feed: After the animals arrived, they were raised in the experimental environment for 7 days before the experiment began. The animals were housed in SPF-grade IVC (Independent Air Supply System) cages (5 animals per cage).

[0672] Animal grouping: Before administration, the weight of the animals was measured, and the volume of the tumors was also measured. The animals were randomly divided into groups according to tumor volume (random grouping design), with 5 animals per group. Observation: The health and mortality of the animals were monitored daily, and the effects of the drug on the animals' daily behavior, such as activity, food and water intake, changes in body weight (measured twice a week or every other day), physical signs, or other abnormalities, were observed regularly. Based on the number of animals in each group, the number of deaths and adverse events in the animals within each group were recorded.

[0673] Experimental indicators: Tumor diameter was measured twice a week using calipers. The formula for calculating tumor volume was: V = a × b 2 The formula is / 2, where a and b represent the long and short diameters of the tumor, respectively. The antitumor effect of the compound was evaluated by TGI(%). TGI(%) = (1-(TV Treatment / Dx -TV Treatment / D1 ) / (TV Control / Dx -TV Control / D1 )) × 100%. The tumor inhibitory effect is TGI = (1 - (TW control -TW treatment ) / TW control Calculated using a multiplier of 100%. A TGI ≥ 58% indicates that the test substance can effectively inhibit tumor growth, and a TGI ≥ 90% indicates that the test substance can very effectively inhibit tumor growth.

[0674] 5.4 Data Analysis: The t-test is used for comparing two groups. For comparisons between three or more groups, one-way ANOVA is used. If there are significant differences in the F-scores, multiple comparisons must be performed after the ANOVA analysis. All data were analyzed using GraphPadPrism 5.0.

[0675] 6. Experimental results:

[0676] [Table 15]

[0677] 7. Experimental conclusion: The above data demonstrate that, after 21 days of continuous oral administration, the example compounds of the present invention can significantly inhibit the proliferation of thyroid cancer cell (TT) transplant tumors in nude mice.

[0678] 6. Effect of the compound of the present invention on hERG current 1. Experimental Objective: The objective is to evaluate the effect of compounds on hERG current in HEK293 cells using manual patch-clamp whole-cell recording technology.

[0679] 2. Laboratory equipment and reagents: 2.1 Reagents: Terfenadine (Sigma-Aldrich, MKBX6318V); HEK293-hERG cell line (human fetal kidney cells that stably express hERG channels), source: Academy of Military Medical Sciences.

[0680] 2.2 Equipment: Patch clamp amplifier (700B, Axon Instruments, USA); Digital-to-analog converter (DigiData 1440A, Axon Instruments, USA); Inverted microscope (Ti-S, Nikon, Japan); Micro-manipulator (MP-225, Sutter Instrument, USA); Microelectrode puller (P-97, Sutter Instrument, USA); Microelectrode (Borosilicate glass, Sutter Instrument, USA); Peristaltic pump (BT100-2J, Longerpump, China); Impact-resistant table and shielding net (TMC, USA); Data acquisition software (Clampex 10.3, Axon Instruments, USA); Data analysis software (Clampfit 10.3, Axon Instruments, USA); Ultrapure water system (Synergy UV, Merck).

[0681] 3. Experimental method: Cell culture: Human embryonic kidney cells (HEK293) that stably express the hERG channel were cultured in DMEM medium (DMEM, HyClone) placed in a cell incubator containing 5% CO2 at 37°C. Approximately 10% fetal bovine serum (FBS, Gibco) was added to the cell medium.

[0682] The composition of the cell culture medium is as shown in the table below.

[0683] [Table 16]

[0684] The study used human embryonic kidney cells (HEK293-hERG) that stably express hERG channels. HEK293 cells were clamped using a Multi Clamp 700B manual patch-clamp system to form a whole-cell voltage clamp pattern, and hERG currents were induced at the corresponding voltages. Cells were administered terfenadine, the positive control product, at concentrations of 0.1, 1, 3, 10, and 30 μmol / L via a 6-channel perfusion system, respectively. The tail currents of the hERG channels were recorded, and the peak values ​​of the tail currents at each concentration were acquired using Clampex 10.3 software, with data analyzed using Clampfit 10.3 software. The peak values ​​of the tail currents recorded with the solvent control were set to 100%, and data for the positive control and target reagents were standardized. Curve fitting and IC were performed using the standard Hill formula in GraphPad Prism 5.00 software. 50 The calculation was performed.

[0685] 4. Experimental results: In this study, the actual concentration was lower than the theoretical concentration due to adsorption of the test substance to the walls of the drug delivery system; therefore, the actual concentration was used for statistics. The actual concentrations of Example 63, whose prepared concentrations were 0.1, 1, 3, 10, and 30 μmol / L, were 0.07, 0.58, 2.17, 6.14, and 28.61 μmol / L, respectively. Under the conditions of this study, the mean inhibition rates of Example 63 against HEK293 cell hERG current were 3.24%±5.14%, 8.39%±3.51%, 12.69%±5.67%, 35.40%±2.15%, and 58.84%±3.92%, respectively. 50 The concentration was 16.89 μmol / L. Under the same test conditions, a positive control terfenadine at 10 μmol / L also inhibited the hERG current, with an average inhibition rate of 97.45% ± 1.07%.

[0686] 7. Research on Crystals 1. Experimental equipment: 1.1 Laboratory Equipment - Several Parameters of Physicochemical Detection Equipment

[0687] [Table 17]

[0688] 2. Crystal Manufacturing 2.1 Preparation of crystals of the free base of the compound from Example 63 2.1.1 Preparation of Type I Crystals of Free Bases 10 mg of the compound (amorphous) was weighed, 10 mL of methanol was added, and the mixture was heated to 50°C to dissolve it. The mixture was filtered while still hot and left overnight in a refrigerator (2-8°C). Precipitation was observed, and the mixture was quickly centrifuged to remove the supernatant. The solid was vacuum-dried at 40°C to obtain type I crystals. Detection analysis revealed the XRPD figure shown in Figure 1, the DSC figure shown in Figure 2, and the TGA figure shown in Figure 3.

[0689] 2.1.2 Preparation of Type II Crystals of Free Bases 15 mg of the compound (Type I crystal) was weighed and placed in a 2 mL glass vial. 200 μL of 2-methyltetrahydrofuran was added to obtain a suspension. The suspension was placed in a magnetic stirrer and slurryed at 50°C for 2-3 days. The suspension was separated, the supernatant was removed, and the solid was further dried overnight in a vacuum dryer (vacuum drying under reduced pressure at 50°C) to obtain Type II crystals. Detection analysis revealed the XRPD figure shown in Figure 4, the DSC figure shown in Figure 5, and the TGA figure shown in Figure 6.

[0690] 2.1.3 Preparation of Type III Crystals of Free Bases 15 mg of the compound (Type I crystal) was weighed and placed in a 2 mL glass vial. 200 μL of dibutanone was added to obtain a suspension. The suspension was placed in a magnetic stirrer and allowed to slurry at 50°C for 2-3 days. The suspension was then centrifuged, the supernatant was removed, and the solid was further dried overnight in a vacuum dryer (vacuum drying under reduced pressure at 50°C) to obtain Type III crystals. Detection analysis revealed the XRPD plot shown in Figure 7, the DSC plot shown in Figure 8, and the TGA plot shown in Figure 9.

[0691] 2.1.4 Preparation of Type IV Crystals of Free Bases 20 mg of the compound (Type I crystal) was weighed, 3.5 mL of 88% acetone was added, and the mixture was heated to 50°C to completely dissolve it. The mixture was filtered while still hot, and the filtrate was vacuum-dried at 50°C to allow rapid volatilization, thereby obtaining Type IV crystals. Detection analysis revealed the XRPD figure shown in Figure 10, the DSC figure shown in Figure 11, and the TGA figure shown in Figure 12.

[0692] 2.1.5 Preparation of V-type crystals of free bases 10 mg of the compound (Type I crystal) was weighed, 500 μL of tetrahydrofuran was added, and the mixture was heated to 50°C to dissolve it. 700 μL of cyclohexane was added to precipitate the solid, which was stirred overnight. The mixture was then quickly centrifuged, the supernatant was removed, and the solid was vacuum-dried at 50°C to obtain Type V crystals. Detection analysis revealed the XRPD figure shown in Figure 13, the DSC figure shown in Figure 14, and the TGA figure shown in Figure 15.

[0693] 3. Experiments on the solid stability of free base compounds 3.1 Compound Stability Experiment of Example 63 3.1.1 Experimental Objective: The purpose of this study is to investigate the physicochemical stability of the compound under conditions of light irradiation at 5000 lx, high temperature at 60°C, high humidity at 92.5% RH, and high temperature and high humidity at 50°C / 75% RH, in order to provide a basis for the storage of the compound.

[0694] 3.1.2 Equipment and Liquid-Phase Analysis Conditions

[0695] [Table 18]

[0696] 3.1.3 Experimental Protocol: Approximately 1 mg of type I crystals were taken and observed for 5 and 10 days under conditions of light irradiation at 5000 lx, high temperature at 60°C, high humidity at 92.5% RH, and high temperature and high humidity at 50°C / 75% RH. The content was measured by HPLC and external standard method, and the changes in related substances were calculated by chromatographic peak area normalization.

[0697] 3.1.4 Experimental Results: The results for the physical and chemical stability of the free base type I crystals are shown in Table 19.

[0698] [Table 19]

[0699] 3.1.5 Experimental Conclusion: The data above indicates that type I crystals of free bases exhibit good stability under conditions of high temperature, high humidity, high temperature and high humidity, and light irradiation.

[0700] 4. Hygroscopicity experiment 4.1 Hygroscopicity experiment of compound in Example 63 4.1.1 Experimental Objective: The purpose is to investigate the hygroscopicity of type I crystals of free base compounds under different relative humidity conditions, thereby providing a basis for the storage of these compounds.

[0701] 4.1.2 Experimental equipment and parameters:

[0702] [Table 20]

[0703] 4.1.3 Experimental Protocol: Type I crystals of the compound's free base were placed in saturated water vapor at the same relative humidity, and the compound and water vapor were allowed to reach a dynamic equilibrium state. The rate of increase in the compound's weight due to moisture absorption after equilibrium was then calculated.

[0704] 4.1.4 Experimental Results: The free base type I crystals showed an increase in weight due to moisture absorption of approximately 0.43% under RH 80%, indicating slight hygroscopicity. Under relative humidity conditions of 0-95%, moisture absorption and desorption were repeated twice, and the XRPD spectrum of the free base type I crystals remained unchanged, meaning the crystals did not deform. The specific isotherms are shown in Figure 16.

[0705] 4.1.5 Experimental Conclusion: Free base type I crystals are slightly hygroscopic, and the crystals are stable under high humidity conditions. 5. Solubility experiments in different media 5.1 Solubility experiment of compound 63 in Example 63 5.1.1 Experimental Objective: The purpose is to provide evidence for drug discovery potential by comparing the solubility of free base type I crystals in pH 1-8 USP buffer, artificial gastric fluid (FaSSGF), fasting artificial intestinal fluid (FaSSIF), non-fasting artificial intestinal fluid (FeSSIF), and pure water.

[0706] 5.1.2 Experimental Protocol: Approximately 1 mg of free base type I crystals were suspended in different media for 4 hours, and the thermodynamic solubility of the compound at 37°C was measured by HPLC and external standard method.

[0707] 5.1.3 Experimental Results: The results of the solubility experiments for type I crystals of bases are shown in Table 21 below.

[0708] [Table 21]

[0709] 6. Experiment to confirm thermodynamically stable crystals 6.1 Competitive slurrying experiment of the compound from Example 63. 6.1.1 Experimental Objective: The purpose is to confirm thermodynamically stable crystals through competitive slurrying experiments.

[0710] 6.1.2 Experimental Protocol: Equal amounts of type I to type V crystals were weighed and mixed in pairs. Ethyl acetate was added, and the mixture was stirred at 50°C for 3 days. After rapid centrifugation, the supernatant was removed, and the solid precipitate was vacuum-dried in an oven at 40°C before performing XRPD characterization.

[0711] 6.1.3 Experimental Results:

[0712] [Table 22]

[0713] 7. Screening experiment for crystalline polymorphism 7.1 Screening of crystalline polymorphisms in Example 63: 7.1.1 Experimental Objective: The purpose is to obtain more crystals by performing screening experiments for crystalline polymorphism using various methods.

[0714] 7.1.2 Experimental Protocol: 7.1.2.1 Method for suspension and slurry preparation: 15 mg of the compound was weighed into 2 mL glass vials, 200 μL of solvent was added to obtain a suspension, the suspension was placed in a magnetic stirrer and slurryed at 50°C for 2-3 days, centrifuged, the supernatant was removed, and the solid was further dried overnight in a vacuum dryer (vacuum drying under reduced pressure at 50°C). XRPD was detected, and if any changes were observed, DSC detection was performed. The results of the screening and characterization are shown in Table 23.

[0715] [Table 23]

[0716] 7.1.2.2 Rapid cooling method: 10 mg of the compound was weighed, the corresponding solvent was added, and the mixture was heated to 50°C. If it did not dissolve, more solvent was added until it dissolved. The mixture was filtered while still hot, cooled to -25°C, and the presence or absence of precipitation was observed. If precipitation was present, the mixture was quickly centrifuged, the supernatant was removed, and the solid was vacuum-dried overnight at 40°C. The solid XRPD was then measured and compared with the initial XRPD. The results are shown in Table 24 below.

[0717] [Table 24]

[0718] 7.1.2.3 Rapid volatilization method: 10 mg of the compound was weighed, the corresponding solvent was added, and the mixture was heated to 50°C. If it did not dissolve, more solvent was added until it dissolved. The mixture was filtered while still hot, and then placed overnight in a vacuum dryer at 50°C to rapidly volatilize it. The solid XRPD was then measured and compared with the initial XRPD. The results are shown in Table 25 below.

[0719] [Table 25]

[0720] 7.1.2.4 Reverse solvent crystallization method: Appropriate amounts of each compound were weighed, a predetermined volume of good solvent was added, and the mixture was dissolved at high temperature. The mixture was filtered, divided into equal 1 mL portions, and the reverse solvent was added. If a solid precipitate formed, the mixture was stirred overnight, then quickly centrifuged, the supernatant was removed, and the solid was vacuum-dried overnight at 50°C. Next, the solid XRPD was measured and compared with the initial XRPD. A total of four crystalline polymorphs were identified, and the results are shown in Table 26 below.

[0721] [Table 26]

[0722] 8. Detection of water content in crystals 8.1 Elemental analysis The C, H, and N content in the compound was measured using an Elementar Vario ELIII elemental analyzer.

[0723] [Table 27]

[0724] The moisture content measurement further indicated that the sample did not contain water of crystallization.

Claims

1. A crystal of a compound, wherein the compound has the following specific structure. 【Chemistry 1】

2. The crystal is a type I, type II, type III, type IV, or type V crystal of 6-(((R)-2-hydroxy-2-methylbuto-3-in-1-yl)oxo)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile, provided that: The powder X-ray spectrum of type I crystals has diffraction peaks at 2θ of 5.0±0.2°, or at 9.6±0.2°, or at 15.0±0.2°, or at 17.2±0.2°, or at 22.2±0.2°, or at 19.4±0.2°, or at 30.2±0.2°, or at 8.2±0.2°, or at 25.1±0.2°, or at 26.9±0.2°, or The powder X-ray spectrum of the type I crystal has diffraction peaks at 2θ of 5.0±0.2°, or at 8.2±0.2°, or at 9.6±0.2°, or at 12.9±0.2°, or at 15.0±0.2°, or at 17.2±0.2°, or at 15.4±0.2°, or at 16.6±0.2°, or at 17.7±0.2°, or at 18.5±0.2°. The powder X-ray spectrum of the type II crystal shows diffraction peaks at 2θ of 4.8±0.2°, or at 17.7±0.2°, or at 16.6±0.2°, or at 9.4±0.2°, or at 18.4±0.2°, or at 19.1±0.2°, or at 17.0±0.2°, or at 18.6±0.2°, or at 4.5±0.2°, or at 15.4±0.2°. The powder X-ray spectrum of the type III crystal has diffraction peaks at 2θ of 4.6±0.2°, or at 15.2±0.2°, or at 9.9±0.2°, or at 16.7±0.2°, or at 18.2±0.2°, or at 17.9±0.2°, or at 25.5±0.2°, or at 15.0±0.2°, or at 19.5±0.2°, or at 23.6±0.2°. The powder X-ray spectrum of the type IV crystal has diffraction peaks at 2θ of 5.0±0.2°, or at 4.8±0.2°, or at 15.0±0.2°, or at 19.1±0.2°, or at 14.3±0.2°, or at 10.0±0.2°, or at 23.9±0.2°, or at 25.1±0.2°, or at 30.3±0.2°, or at 9.6±0.2°. The crystal of the compound according to claim 1, characterized in that the powder X-ray spectrum of the V-type crystal has a diffraction peak at 2θ of 4.7±0.2°, or at 18.2±0.2°, or at 10.1±0.2°, or at 18.8±0.2°, or at 15.6±0.2°, or at 17.0±0.2°, or at 21.8±0.2°, or at 14.7±0.2°, or at 19.3±0.2°, or at 25.8±0.2°.

3. The powder X-ray spectrum of the type I crystal has a diffraction peak at 2θ 5.0±0.2°, or at 9.6±0.2°, or at 15.0±0.2°, or at 17.2±0.2°, or at 22.2±0.2°, or at 19.4±0.2°, or at 30.2±0.2°, or at 8.2±0.2°, or at 25.1±0.2°, or at 26.9±0.2°, and includes any 2 to 5 locations, or 3 to 5 locations, or 3 to 6 locations, or 3 to 8 locations, or 5 to 8 locations, or The powder X-ray spectrum of the type I crystal has diffraction peaks at 2θ of 5.0±0.2°, or at 8.2±0.2°, or at 9.6±0.2°, or at 12.9±0.2°, or at 15.0±0.2°, or at 17.2±0.2°, or at 15.4±0.2°, or at 16.6±0.2°, or at 17.7±0.2°, or at 18.5±0.2°, and includes any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 locations of the above diffraction peaks. The powder X-ray spectrum of the type II crystal has diffraction peaks at 2θ of 4.8±0.2°, or at 17.7±0.2°, or at 16.6±0.2°, or at 9.4±0.2°, or at 18.4±0.2°, or at 19.1±0.2°, or at 17.0±0.2°, or at 18.6±0.2°, or at 4.5±0.2°, or at 15.4±0.2°, and includes any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 locations of the above diffraction peaks. The powder X-ray spectrum of the type III crystal has diffraction peaks at 2θ of 4.6±0.2°, or at 15.2±0.2°, or at 9.9±0.2°, or at 16.7±0.2°, or at 18.2±0.2°, or at 17.9±0.2°, or at 25.5±0.2°, or at 15.0±0.2°, or at 19.5±0.2°, or at 23.6±0.2°, and includes any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks. The powder X-ray spectrum of the type IV crystal has diffraction peaks at 2θ of 5.0±0.2°, or at 4.8±0.2°, or at 15.0±0.2°, or at 19.1±0.2°, or at 14.3±0.2°, or at 10.0±0.2°, or at 23.9±0.2°, or at 25.1±0.2°, or at 30.3±0.2°, or at 9.6±0.2°, and includes any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks. The powder X-ray spectrum of the V-type crystal is characterized in that it has diffraction peaks at 4.7±0.2°, or at 18.2±0.2°, or at 10.1±0.2°, or at 18.8±0.2°, or at 15.6±0.2°, or at 17.0±0.2°, or at 21.8±0.2°, or at 14.7±0.2°, or at 19.3±0.2°, or at 25.8±0.2°, and contains any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 diffraction peaks, as described in claim 2.

4. The powder X-ray spectrum of the type I crystal has diffraction peaks at 2θ 5.0±0.2°, or at 9.6±0.2°, or at 15.0±0.2°, or at 17.2±0.2°, or at 22.2±0.2°, or at 19.4±0.2°, or at 30.2±0.2°, or at 8.2±0.2°, or at 25.1±0.2°, or at 26.9±0.2°, including any 6, 7, or 8 of these locations, or The powder X-ray spectrum of the type I crystal has diffraction peaks at 2θ of 5.0±0.2°, or at 8.2±0.2°, or at 9.6±0.2°, or at 12.9±0.2°, or at 15.0±0.2°, or at 17.2±0.2°, or at 15.4±0.2°, or at 16.6±0.2°, or at 17.7±0.2°, or at 18.5±0.2°, including any 6, 7, or 8 of these locations. The powder X-ray spectrum of the type II crystal has diffraction peaks at 2θ of 4.8±0.2°, or at 17.7±0.2°, or at 16.6±0.2°, or at 9.4±0.2°, or at 18.4±0.2°, or at 19.1±0.2°, or at 17.0±0.2°, or at 18.6±0.2°, or at 4.5±0.2°, or at 15.4±0.2°, including any 6, 7, or 8 of these locations. The powder X-ray spectrum of the type III crystal has diffraction peaks at 2θ of 4.6±0.2°, or at 15.2±0.2°, or at 9.9±0.2°, or at 16.7±0.2°, or at 18.2±0.2°, or at 17.9±0.2°, or at 25.5±0.2°, or at 15.0±0.2°, or at 19.5±0.2°, or at 23.6±0.2°, including any 6, 7, or 8 of these locations. The powder X-ray spectrum of the type IV crystal has diffraction peaks at 2θ of 5.0±0.2°, or at 4.8±0.2°, or at 15.0±0.2°, or at 19.1±0.2°, or at 14.3±0.2°, or at 10.0±0.2°, or at 23.9±0.2°, or at 25.1±0.2°, or at 30.3±0.2°, or at 9.6±0.2°, including any 6, 7, or 8 of these locations. The powder X-ray spectrum of the V-type crystal is characterized in that it has diffraction peaks at 2θ of 4.7±0.2°, or at 18.2±0.2°, or at 10.1±0.2°, or at 18.8±0.2°, or at 15.6±0.2°, or at 17.0±0.2°, or at 21.8±0.2°, or at 14.7±0.2°, or at 19.3±0.2°, or at 25.8±0.2°, and includes any six, seven, or eight of these positions, as is the case with the crystal of the compound according to claim 2.

5. The powder X-ray spectrum of the type I crystal includes diffraction peaks located at 2θ of 5.0±0.2°, 9.6±0.2°, and 15.0±0.2°, and optionally includes at least one more peak at 2θ of 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 30.2±0.2°, or 8.2±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, and 19.4±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, and 8.2±0.2°. Alternatively, the powder X-ray spectrum of the type I crystal may include diffraction peaks located at 2θ 5.0±0.2°, 8.2±0.2°, and 9.6±0.2°, and optionally further include at least one location at 2θ 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, or 16.6±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, and 17.2±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, and 15.4±0.2°. The powder X-ray spectrum of the type II crystal includes diffraction peaks located at 2θ of 4.8±0.2°, 17.7±0.2°, and 16.6±0.2°, and optionally includes at least one more peak at 2θ of 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 17.0±0.2°, or 18.6±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, and 19.1±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, and 17.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, and 18.6±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, and 17.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, and 17.0±0.2°. The powder X-ray spectrum of the type III crystal includes diffraction peaks located at 2θ of 4.6±0.2°, 15.2±0.2°, and 9.9±0.2°, and optionally further includes at least one more location at 2θ of 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 25.5±0.2°, or 15.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, and 17.9±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, and 25.5±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, and 15.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, and 25.5±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 18.2±0.2°, 17.9±0.2°, and 15.0±0.2°. The powder X-ray spectrum of the type IV crystal includes diffraction peaks located at 2θ of 5.0±0.2°, 4.8±0.2°, and 15.0±0.2°, and optionally includes at least one more peak at 2θ of 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, or 25.1±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, and 10.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, and 23.9±0.2°. The powder X-ray spectrum of the V-type crystal includes diffraction peaks located at 2θ of 4.7±0.2°, 18.2±0.2°, and 10.1±0.2°, and optionally further includes at least one more location at 2θ of 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 21.8±0.2°, or 14.7±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, and 17.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, and 21.8±0.2°. Alternatively, the crystal of the compound according to claim 2, characterized in that it contains diffraction peaks located at 2θ of 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, and 14.7±0.2°.

6. The powder X-ray spectrum of the type I crystal includes diffraction peaks located at 2θ of 5.0±0.2°, 9.6±0.2°, and 15.0±0.2°, and optionally further includes two, three, four, or five locations among 2θ of 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 30.2±0.2°, or 8.2±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, and 19.4±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, and 8.2±0.2°. Alternatively, the powder X-ray spectrum of the type I crystal may include diffraction peaks located at 2θ 5.0±0.2°, 8.2±0.2°, and 9.6±0.2°, and optionally include two, three, four, or five more peaks at 2θ 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, or 16.6±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, and 17.2±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, and 15.4±0.2°. The powder X-ray spectrum of the type II crystal includes diffraction peaks located at 2θ of 4.8±0.2°, 17.7±0.2°, and 16.6±0.2°, and optionally includes two, three, four, or five more peaks at 2θ of 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 17.0±0.2°, or 18.6±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, and 19.1±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, and 17.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, and 18.6±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, and 17.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, and 17.0±0.2°. The powder X-ray spectrum of the type III crystal includes diffraction peaks located at 2θ of 4.6±0.2°, 15.2±0.2°, and 9.9±0.2°, and optionally includes two, three, four, or five more peaks at 2θ of 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 25.5±0.2°, or 15.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, and 17.9±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, and 25.5±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, and 15.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, and 25.5±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 18.2±0.2°, 17.9±0.2°, and 15.0±0.2°. The powder X-ray spectrum of the type IV crystal includes diffraction peaks located at 2θ of 5.0±0.2°, 4.8±0.2°, and 15.0±0.2°, and optionally includes two, three, four, or five more peaks at 2θ of 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, or 25.1±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, and 10.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, and 23.9±0.2°. The powder X-ray spectrum of the V-type crystal includes diffraction peaks located at 2θ of 4.7±0.2°, 18.2±0.2°, and 10.1±0.2°, and optionally includes two, three, four, or five more peaks at 2θ of 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 21.8±0.2°, or 14.7±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, and 17.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, and 21.8±0.2°. Alternatively, the crystal of the compound according to claim 5, characterized in that it contains diffraction peaks located at 2θ of 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, and 14.7±0.2°.

7. The powder X-ray spectrum of type I crystals further includes diffraction peaks located at one or more of the following arbitrary 2θ values: 10.0±0.2°, 25.4±0.2°, 26.9±0.2°, 13.0±0.2°, 12.9±0.2°, or 20.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 26.9±0.2°, and 10.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 26.9±0.2°, and 25.4±0.2°. Alternatively, the powder X-ray spectrum of a type I crystal may further optionally include diffraction peaks located at one or more points where 2θ is 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, 19.3±0.2°, or 24.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, and 19.3±0.2°. Alternatively, the diffraction peaks include those located at 2θ 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, 19.3±0.2°, and 24.0±0.2°. The powder X-ray spectrum of type II crystals further includes diffraction peaks located at one or more of the following arbitrary 2θ values: 4.5±0.2°, 15.4±0.2°, 14.6±0.2°, 24.0±0.2°, 21.5±0.2°, 20.5±0.2°, or 18.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 4.5±0.2°, and 15.4±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 4.5±0.2°, and 14.6±0.2°. The powder X-ray spectrum of the type III crystal further includes diffraction peaks located at one or more of the following arbitrary 2θ values: 19.5±0.2°, 23.6±0.2°, 26.1±0.2°, 22.0±0.2°, 20.2±0.2°, 21.1±0.2°, or 27.4±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 19.5±0.2°, and 23.6±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 19.5±0.2°, and 26.1±0.2°. The powder X-ray spectrum of type IV crystals further includes diffraction peaks located at one or more locations where 2θ is 30.3 ± 0.2° or 9.6 ± 0.2°, which can be optionally selected. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, and 30.3±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, and 9.6±0.2°. The powder X-ray spectrum of the V-type crystal further includes diffraction peaks located at one or more of the following arbitrary 2θ values: 19.3±0.2°, 25.8±0.2°, 15.2±0.2°, 17.8±0.2°, 20.4±0.2°, 23.5±0.2°, or 25.6±0.2°. Alternatively, it includes diffraction peaks located at 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 19.3±0.2° and 25.8±0.2°. Alternatively, a crystal of the compound according to any one of claims 2 to 6, characterized in that it includes diffraction peaks located at 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 19.3±0.2°, and 15.2±0.2°.

8. The powder X-ray spectrum of the type I crystal further optionally includes diffraction peaks located at any two, three, four, five, or six locations where 2θ is 10.0±0.2°, 25.4±0.2°, 26.9±0.2°, 13.0±0.2°, 12.9±0.2°, or 20.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 26.9±0.2°, and 10.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 26.9±0.2°, and 25.4±0.2°. Alternatively, the powder X-ray spectrum of a type I crystal may further optionally include diffraction peaks located at any two, three, four, five, or six points on the list of 2θ values ​​of 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, 19.3±0.2°, or 24.0±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, and 19.3±0.2°. Alternatively, the diffraction peaks include those located at 2θ 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, 19.3±0.2°, and 24.0±0.2°. The powder X-ray spectrum of type II crystals further includes diffraction peaks located at any two, three, four, five, six, or seven points where 2θ is 4.5±0.2°, 15.4±0.2°, 14.6±0.2°, 24.0±0.2°, 21.5±0.2°, 20.5±0.2°, or 18.0±0.2°, which can be optionally selected. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 4.5±0.2°, and 15.4±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 4.5±0.2°, and 14.6±0.2°. The powder X-ray spectrum of the type III crystal further includes diffraction peaks located at any two, three, four, five, six, or seven points where 2θ is 19.5±0.2°, 23.6±0.2°, 26.1±0.2°, 22.0±0.2°, 20.2±0.2°, 21.1±0.2°, or 27.4±0.2°, which can be optionally selected. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 19.5±0.2°, and 23.6±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 19.5±0.2°, and 26.1±0.2°. The powder X-ray spectrum of type IV crystals further includes diffraction peaks located at any one or two points where 2θ is 30.3 ± 0.2° or 9.6 ± 0.2°, which can be optionally selected. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, and 30.3±0.2°. Alternatively, the diffraction peaks include those located at 2θ of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, and 9.6±0.2°. The powder X-ray spectrum of the V-type crystal further includes, optionally, diffraction peaks located at any two, three, four, five, six, or seven points among 2θ of 19.3±0.2°, 25.8±0.2°, 15.2±0.2°, 17.8±0.2°, 20.4±0.2°, 23.5±0.2°, or 25.6±0.2°. Alternatively, it includes diffraction peaks located at 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 19.3±0.2° and 25.8±0.2°. Alternatively, a crystal of the compound according to any one of claims 2 to 6, characterized in that it includes diffraction peaks located at 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 19.3±0.2°, and 15.2±0.2°.

9. The powder X-ray spectrum of type I crystals includes diffraction peaks located at one or more of the following positions with 2θ: 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 30.2±0.2°, 25.1±0.2°, 10.0±0.2°, 25.4±0.2°, 26.9±0.2°, 13.0±0.2°, 12.9±0.2°, or 20.0±0.2°. The powder X-ray spectrum of type I crystals shows that 2θ is The locations at 9.6±0.2°, 15.0±0.2°, and 17.2±0.2°, Alternatively, at the locations of 5.0±0.2°, 9.6±0.2°, 15.0±0.2° and 17.2±0.2°, Alternatively, at the locations of 5.0±0.2°, 9.6±0.2°, 15.0±0.2° and 22.2±0.2°, Alternatively, it has diffraction peaks located at 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, and 25.1±0.2°. Alternatively, the powder X-ray spectrum of a type I crystal includes diffraction peaks located at one or more of the following positions in 2θ: 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, 19.3±0.2°, or 24.0±0.2°. The powder X-ray spectrum of type I crystals shows that 2θ is The following locations are affected: 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2°, and 17.7±0.2°. Alternatively, at the following locations: 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2° and 18.5±0.2°, Alternatively, it has diffraction peaks located at 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2° and 19.3±0.2°, The powder X-ray spectrum of type II crystals includes diffraction peaks located at one or more of the following 2θ values: 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 17.0±0.2°, 18.6±0.2°, 4.5±0.2°, 15.4±0.2°, 14.6±0.2°, 24.0±0.2°, 21.5±0.2°, 20.5±0.2°, or 18.0±0.2°. The powder X-ray spectrum of type II crystals shows that 2θ is 4.8±0.2°, 17.7±0.2°, 16.6±0.2° and 9.4±0.2°, Alternatively, at the locations of 4.8±0.2°, 17.7±0.2°, 16.6±0.2° and 18.4±0.2°, Alternatively, at the locations of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2° and 20.5±0.2°, Alternatively, at the locations of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 17.0±0.2° and 18.6±0.2°, Alternatively, it has diffraction peaks located at 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 17.0±0.2°, 18.6±0.2°, 4.5±0.2°, and 14.6±0.2°. The powder X-ray spectrum of type III crystals includes diffraction peaks located at one or more of the following 2θ values: 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 25.5±0.2°, 15.0±0.2°, 19.5±0.2°, 23.6±0.2°, 26.1±0.2°, 22.0±0.2°, 20.2±0.2°, 21.1±0.2°, or 27.4±0.2°. The powder X-ray spectrum of type III crystals shows that 2θ is 4.6±0.2°, 15.2±0.2°, 9.9±0.2° and 16.7±0.2°, Alternatively, at the locations of 4.6±0.2°, 15.2±0.2°, 9.9±0.2° and 18.2±0.2°, Alternatively, at the locations of 4.6±0.2°, 15.2±0.2°, 16.7±0.2° and 18.2±0.2°, Alternatively, at the locations of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2° and 17.9±0.2°, Alternatively, at the following locations: 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 26.1±0.2° and 22.0±0.2°, Alternatively, it has diffraction peaks located at 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 25.5±0.2°, 15.0±0.2°, 19.5±0.2° and 23.6±0.2°, The powder X-ray spectrum of type IV crystals includes diffraction peaks located at one or more of the following positions in 2θ: 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, 25.1±0.2°, 30.3±0.2°, or 9.6±0.2°. The powder X-ray spectrum of type IV crystals shows that 2θ is It includes diffraction peaks located at 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, and 19.1±0.2°. Alternatively, at the locations of 5.0±0.2°, 4.8±0.2°, 15.0±0.2° and 14.3±0.2°, Alternatively, at the locations of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 23.9±0.2° and 25.1±0.2°, Alternatively, at the following locations: 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, and 25.1±0.2°, Alternatively, at the following locations: 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, 25.1±0.2°, and 30.3±0.2°, Alternatively, it has diffraction peaks located at 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, 25.1±0.2°, 30.3±0.2° and 9.6±0.2°. The powder X-ray spectrum of the V-type crystal includes diffraction peaks located at one or more of the following 2θ values: 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 21.8±0.2°, 14.7±0.2°, 19.3±0.2°, 25.8±0.2°, 15.2±0.2°, 17.8±0.2°, 20.4±0.2°, 23.5±0.2°, or 25.6±0.2°. The powder X-ray spectrum of a V-type crystal shows that 2θ is 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, and 18.8±0.2°; Alternatively, at the locations of 4.7±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2° and 21.8±0.2°, Alternatively, at the following locations: 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 21.8±0.2° and 14.7±0.2°, Alternatively, the crystal of the compound according to claim 2, characterized by having diffraction peaks located at 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 21.8±0.2°, 14.7±0.2°, 19.3±0.2°, and 15.2±0.2°.

10. The powder X-ray spectrum of a type I crystal includes diffraction peaks located at 4, 5, 6, 8, or 10 locations among 2θ of 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 30.2±0.2°, 25.1±0.2°, 10.0±0.2°, 25.4±0.2°, 26.9±0.2°, 13.0±0.2°, 12.9±0.2°, or 20.0±0.2°, The powder X-ray spectrum of type I crystals shows that 2θ is The locations at 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, and 17.2±0.2°, Alternatively, at the locations of 5.0±0.2°, 9.6±0.2°, 15.0±0.2° and 22.2±0.2°, Alternatively, it has diffraction peaks located at 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, and 25.1±0.2°. Alternatively, the powder X-ray spectrum of a type I crystal may contain diffraction peaks located at 4, 5, 6, 8, or 10 points among 2θ at 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, 19.3±0.2°, or 24.0±0.2°. The powder X-ray spectrum of type I crystals shows that 2θ is The following locations are affected: 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2°, and 17.7±0.2°. Alternatively, at the following locations: 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2° and 18.5±0.2°, Alternatively, it has diffraction peaks located at 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2° and 19.3±0.2°, The powder X-ray spectrum of type II crystals includes diffraction peaks located at 4, 5, 6, 8, or 10 points among 2θ values ​​of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 17.0±0.2°, 18.6±0.2°, 4.5±0.2°, 15.4±0.2°, 14.6±0.2°, 24.0±0.2°, 21.5±0.2°, 20.5±0.2°, or 18.0±0.2°. The powder X-ray spectrum of type II crystals shows that 2θ is 4.8±0.2°, 17.7±0.2°, 16.6±0.2° and 9.4±0.2°, Alternatively, at the locations of 4.8±0.2°, 17.7±0.2°, 16.6±0.2° and 18.4±0.2°, Alternatively, at the locations of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2° and 20.5±0.2°, Alternatively, at the locations of 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 17.0±0.2° and 18.6±0.2°, Alternatively, it has diffraction peaks located at 4.8±0.2°, 17.7±0.2°, 16.6±0.2°, 9.4±0.2°, 18.4±0.2°, 19.1±0.2°, 17.0±0.2°, 18.6±0.2°, 4.5±0.2°, and 14.6±0.2°. The powder X-ray spectrum of type III crystals includes diffraction peaks located at 4, 5, 6, 8, or 10 points among 2θ values ​​of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 25.5±0.2°, 15.0±0.2°, 19.5±0.2°, 23.6±0.2°, 26.1±0.2°, 22.0±0.2°, 20.2±0.2°, 21.1±0.2°, or 27.4±0.2°. The powder X-ray spectrum of type III crystals shows that 2θ is 4.6±0.2°, 15.2±0.2°, 9.9±0.2° and 16.7±0.2°, Alternatively, at the locations of 4.6±0.2°, 15.2±0.2°, 9.9±0.2° and 18.2±0.2°, Alternatively, at the locations of 4.6±0.2°, 15.2±0.2°, 16.7±0.2° and 18.2±0.2°, Alternatively, at the locations of 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2° and 17.9±0.2°, Alternatively, at the following locations: 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 26.1±0.2° and 22.0±0.2°, Alternatively, it has diffraction peaks located at 4.6±0.2°, 15.2±0.2°, 9.9±0.2°, 16.7±0.2°, 18.2±0.2°, 17.9±0.2°, 25.5±0.2°, 15.0±0.2°, 19.5±0.2° and 23.6±0.2°, The powder X-ray spectrum of type IV crystals includes diffraction peaks located at 4, 5, 6, 8, or 10 points among 2θ values ​​of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, 25.1±0.2°, 30.3±0.2°, or 9.6±0.2°. The powder X-ray spectrum of type IV crystals shows that 2θ is It includes diffraction peaks located at 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, and 19.1±0.2°. Alternatively, at the locations of 5.0±0.2°, 4.8±0.2°, 15.0±0.2° and 14.3±0.2°, Alternatively, at the locations of 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 23.9±0.2° and 25.1±0.2°, Alternatively, at the following locations: 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, and 25.1±0.2°, Alternatively, at the following locations: 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, 25.1±0.2°, and 30.3±0.2°, Alternatively, it has diffraction peaks located at 5.0±0.2°, 4.8±0.2°, 15.0±0.2°, 19.1±0.2°, 14.3±0.2°, 10.0±0.2°, 23.9±0.2°, 25.1±0.2°, 30.3±0.2° and 9.6±0.2°. The powder X-ray spectrum of the V-type crystal contains diffraction peaks located at 4, 5, 6, 8, or 10 points among 2θ values ​​of 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 21.8±0.2°, 14.7±0.2°, 19.3±0.2°, 25.8±0.2°, 15.2±0.2°, 17.8±0.2°, 20.4±0.2°, 23.5±0.2°, or 25.6±0.2°. The powder X-ray spectrum of a V-type crystal shows that 2θ is 4.7±0.2°, 18.2±0.2°, 10.1±0.2° and 18.8±0.2°, Alternatively, at the locations of 4.7±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2° and 21.8±0.2°, Alternatively, at the following locations: 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 21.8±0.2° and 14.7±0.2°, Alternatively, the crystal of the compound according to claim 9, characterized by having diffraction peaks located at 4.7±0.2°, 18.2±0.2°, 10.1±0.2°, 18.8±0.2°, 15.6±0.2°, 17.0±0.2°, 21.8±0.2°, 14.7±0.2°, 19.3±0.2°, and 15.2±0.2°.

11. The powder X-ray spectrum of a type I crystal is such that 2θ is The following locations are affected: 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 26.9±0.2°, and 10.0±0.2°. Alternatively, at the following locations: 5.0±0.2°, 9.6±0.2°, 15.0±0.2°, 17.2±0.2°, 22.2±0.2°, 19.4±0.2°, 26.9±0.2° and 25.4±0.2°, Alternatively, at the locations of 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2° and 19.3±0.2°, Alternatively, at the following locations: 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, 19.3±0.2° and 24.0±0.2°, Alternatively, at the locations of 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2° and 17.7±0.2°, Alternatively, at the following locations: 5.0±0.2°, 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2° and 18.5±0.2°, Alternatively, the crystal of the compound according to claim 2, characterized by having diffraction peaks located at 8.2±0.2°, 9.6±0.2°, 12.9±0.2°, 15.0±0.2°, 17.2±0.2°, 15.4±0.2°, 16.6±0.2°, 17.7±0.2°, 18.5±0.2°, and 19.3±0.2°.

12. The crystal of the compound according to any one of claims 1 to 11, characterized in that the crystal is an anhydrous crystal.

13. 1) Weigh an appropriate amount of free base, suspend it in a poor solvent, and the suspension density is 50-200 mg / mL. 2) Shake the suspension obtained above, at a temperature of 0 to 50°C. 3) A method for producing crystals of the compound according to any one of claims 1 to 12, comprising the step of rapidly centrifuging the above suspension, removing the supernatant, and drying the remaining solid to obtain the target product. (however: The poor solvent is selected from one or more of acetonitrile, 2-methyltetrahydrofuran, or 2-butanone.

14. 1) Weigh an appropriate amount of free base and dissolve it in a good solvent. 2) Optionally, add a poor solvent to the solution obtained above. 3) Stir until a solid precipitates, with a crystallization temperature of 0-50°C. 4) Optionally, quickly centrifuge the above suspension, 5) A method for producing crystals of a compound according to any one of claims 1 to 12, comprising the step of removing the supernatant and drying the remaining solid to obtain a target product. (however: A good solvent is selected from one or more of methanol, tetrahydrofuran, 88% acetone, or dichloromethane. The poor solvent is selected from one or more of the following: ethanol, ethyl acetate, isopropanol, toluene, n-heptane, water, isopropyl acetate, cyclohexane, methyl tert-butyl ether, or isopropyl ether.

15. A pharmaceutical composition comprising a therapeutically effective amount of crystals of the compound described in claims 1 to 12 and one or more pharmaceutically acceptable carriers and excipients.

16. Use of a crystalline compound according to any one of claims 1 to 12, or the pharmaceutical composition according to claim 15, in the production of a RET inhibitor.

17. Use of a crystalline compound according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 15, in the manufacture of a pharmaceutical for treating and / or preventing a tumor, wherein the tumor is selected from non-small cell lung cancer, fibrosarcoma, pancreatic tumor, medullary thyroid cancer, papillary thyroid tumor, soft tissue sarcoma, high-grade solid tumor, breast tumor, and colon tumor.

Images