Inhibitors containing dicyclic derivatives, their preparation methods and applications

Abstract

This invention relates to inhibitors containing dicyclic derivatives, their preparation methods, and applications. In particular, this invention relates to compounds of general formula (II), their preparation methods, pharmaceutical compositions thereof, and their use as RET inhibitors in the treatment of related diseases such as cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease, and AIDS, wherein the substituents in general formula (II) are the same as defined in the specification.

Description

[0001] This application claims priority to Chinese patent applications CN201910400013.0 (filed May 14, 2019), CN201910615987.0 (filed July 9, 2019), CN201910816375.8 (filed August 30, 2019), CN201910895078.7 (filed September 20, 2019), and CN202010177893.2 (filed March 13, 2020). The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of drug synthesis, specifically relating to an inhibitor containing a dicyclic derivative, its preparation method, and its application. Background Technology

[0003] RET (rearranged during transfection) protein, encoded by the proto-oncogene RET located on chromosome 10, is a receptor tyrosine kinase composed of an extracellular domain, a transmembrane domain, and an intracellular kinase domain. RET ligands are glial cell-derived neurotrophic factor (GDNF) family ligands (GFLs), such as GDNF, neurturin (NRTN), artemin (ARTN), and persehin (PSPN). Activation of the receptor also requires the co-receptor GFRα family. GFLs and GFRα form a dimer, binding to RET and recruiting it to a cholesterol-rich membrane region. The RET protein dimers 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 kidneys and enteric nervous system during embryonic development; it is also important for the homeostasis of neuroendocrine, hematopoietic, and male germ cell tissues.

[0004] Disorders of RET protein function lead to a variety of diseases. During development, loss of RET protein function can result in a range of congenital diseases such as Hirschsprung's disease (HSCR) and congenital kidney and urinary tract malformations (CAKUT). Activating mutations in RET protein, including point mutations and RET protein fusions resulting from chromosomal rearrangements, are also associated with various diseases. RET fusions primarily occur in 1–2% of non-small cell lung cancer (NSCLC) patients and 5–10% of papillary thyroid carcinomas, while RET mutations mainly occur in 60% of medullary thyroid carcinomas. Furthermore, activating mutations of RET protein have been found in many other tumors such as breast cancer, gastric cancer, colorectal cancer, and chronic myeloid leukemia.

[0005] Despite significant clinical need, current treatments targeting RET remain extremely limited. Unlike targeted therapies for ALK and EGFR, which have achieved excellent clinical efficacy, there are currently no approved targeted therapies for RET. Current clinical treatments primarily utilize multi-kinase inhibitors (MKIs) such as vandetinib and cabozantinib. However, these MKIs suffer from poor selectivity, high side effects, and poor efficacy, and they also cannot overcome the drug resistance issues that arise during treatment.

[0006] The demand for RET-targeted therapies has attracted numerous domestic and international pharmaceutical companies to conduct research and development of RET-specific targeted drugs. Among the most prominent are Loxo Oncology's LOXO-292, which has entered Phase I / II clinical trials, and Blueprint's BLU-667, which has also entered Phase I clinical trials. Both of these targeted drugs have demonstrated very good efficacy and safety in patients with RET activating mutations in early clinical trials. Furthermore, they have overcome potential drug resistance mutations in preclinical activity screening, and are expected to provide more treatment options for cancers with RET activating mutations in the future.

[0007] Currently, there are no specific targeted drugs for RET, indicating a significant clinical need. RET inhibitors with higher selectivity, better activity, better safety profiles, and the ability to overcome drug resistance mutations have the potential to treat various cancers and possess broad market prospects. Summary of the Invention

[0008] The object of this invention is to provide a compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of general formula (I) has the following structure:

[0009]

[0010] in:

[0011] X1 to X6 are each independently selected from C, N, CR5, and CR aa R bb or NR aa ;

[0012] L is selected from the bond, -(CH2). n1 CR aa R bb -、-(CH2) n1 NR aa C(O)(CH2) n2 -、-(CH2) n1 C(O)(CH2) n2 (CR aa R bb ) m -、-(CH2)n1 C(O)(CR aa R bb ) m (CH2) n2 -、-(CH2) n1 C(O)NR cc (CR aa R bb ) n2 -、-(CH2) n1 (O)(CH2) n2 -or-(CH2) n1 NR aa (CH2) n2 -;

[0013] Ring A is selected from heterocyclic, aryl, or heteroaryl groups;

[0014] Ring B is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0015] R1 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 R aa -(C≡C) n1 (CR aa R bb ) m R cc -(C=C) n1 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 R aa -(CH2) n1 S(CH2) n2 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 S(O) m R aa -(CH2) n1 O(CH2) n2 S(O)(=NRaa (CH2) m R bb -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 S(O)(=NR aa (CH2) n2 R bb -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa (CH2) n2 R bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 NR aa S(O) m R bb The alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyanoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, oxo, thio, imino, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH2) n1 R dd -(CH2) n1 OR dd -(CH2) n1 S(CH2) n2 R dd -(CH2) n1 C(O)R dd -(CH2)n1 C(O)OR dd -(CH2) n1 S(O) m R dd -(CH2) n1 S(O)(=NR dd (CH2) n2 R ee -(CH2) n1 NR dd R ee -(CH2) n1 P(O)R dd R ee -(CH2) n1 C(O)NR dd R ee -(CH2) n1 NR dd C(O)R ee and -(CH2) n1 NR dd S(O) m R ee One or more substituents in it are replaced;

[0016] R2 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally further substituted by one or more substituents selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0017] R3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally further substituted by one or more substituents selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0018] Alternatively, any two adjacent or non-adjacent R3 links may form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further substituted with one or more substituents selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0019] R4 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 R aa -(CH2) n1 OR aa -(CH2) n1 S(CH2) n2 R aa -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 S(O)(=NR aa (CH2) n2 R bb -(CH2) n1 NR aa R bb -(CH2) n1P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 NR aa S(O) m R bb The alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyanoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH2) n1 R cc -(CH2) n1 OR cc -(CH2) n1 S(CH2) n2 R cc -(CH2) n1 C(O)R cc -(CH2) n1 C(O)OR cc -(CH2) n1 S(O) m R cc -(CH2) n1 S(O)(=NR cc (CH2) n2 R dd -(CH2) n1 NR cc R dd -(CH2) n1 P(O)R cc R dd -(CH2) n1 C(O)NR cc R dd -(CH2) n1 NR cc C(O)R dd Or -(CH2) n1 NR cc S(O)m R dd One or more substituents in it are replaced;

[0020] R5 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 R aa -(CH2) n1 OR aa -(CH2) n1 S(CH2) n2 R aa -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 S(O)(=NR aa (CH2) n2 R bb -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 NR aa S(O) m R bb ;

[0021] R aa R bb R cc R dd and R eeEach of the following is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl may optionally be further substituted by one or more substituents selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, oxo, imino, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

[0022] Or, R aa R bb R cc R dd and R ee Any two of them can be linked to form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl group may optionally be further substituted by one or more substituents selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, oxo, imino, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0023] x is 0, 1, 2, 3, 4 or 5;

[0024] y is 0, 1, 2, 3, 4 or 5;

[0025] z can be 0, 1, 2, 3, 4, 5, or 6;

[0026] m is 0, 1, or 2;

[0027] n1 is 0, 1, 2, or 3; and

[0028] n2 can be 0, 1, 2, or 3.

[0029] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, further comprises general formula (II):

[0030]

[0031] in:

[0032] The ring C is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0033] R6 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 R aa -(CH2) n1 OR aa -(CH2) n1 S(CH2) n2 R aa -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 S(O)(=NR aa (CH2) n2 R bb -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 NR aa S(O) m R bb ;

[0034] R7 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 R aa -(C≡C) n1 (CR aa R bb ) m R cc -(C=C) n1 (CR aa R bb ) mR cc 、-(CH2) n1 O(CH2) n2 (CR aa R bb ) m R cc 、-(CH2) n1 O(CH2) n2 R aa 、-(CH2) n1 S(CH2) n2 R aa 、-(CH2) n1 O(CH2) n2 S(O) m R aa 、-(CH2) n1 O(CH2) n2 S(O)(=NR aa (CH2) m R bb 、-(CH2) n1 C(O)R aa [[ID=...]] 、-(CH2) n1 C(O)OR aa 、-(CH2) n1 S(O) m R aa 、-(CH2) n1 S(O)(=NR aa (CH2) n2 R bb 、-(CH2)<== n1 NR aa R bb 、-(CH2) n1 P(O)R aa R bb 、-(CH2) n1 C(O)NR aa R bb 、-(CH2) n1 NR aa C(O)R bb 、-(CH2) n1 NR aa (CH2) n2 R bb 或-(CH2) n1 NR aa S(O) m R bb It should be noted that the content you provided contains some tags that may not be fully recognized in a general context. If this is part of a specific technical or formatted document, it's important to ensure the tags are properly interpreted within that system. Also, the text seems to be a chemical or molecular structure-related description with some incomplete or potentially incorrect notations in the original. If possible, it would be beneficial to double-check the source for accuracy.The alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyanoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, oxo, thio, imino, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH2) n1 R dd -(CH2) n1 OR dd -(CH2) n1 S(CH2) n2 R dd -(CH2) n1 C(O)R dd -(CH2) n1 C(O)OR dd -(CH2) n1 S(O) m R dd -(CH2) n1 S(O)(=NR dd (CH2) n2 R ee -(CH2) n1 NR dd R ee -(CH2) n1 P(O)R dd R ee -(CH2) n1 C(O)NR dd R ee -(CH2) n1 NR dd C(O)R ee and -(CH2) n1 NR dd S(O) m R ee One or more substituents in it are replaced;

[0035] p is 0, 1, 2 or 3;

[0036] w is 0, 1, 2, 3, 4, 5, or 6;

[0037] Ring A, Ring B, X1~X5, L, R2~R3, R aa ~R eey, z, n1, n2 and m are as described in general formula (I).

[0038] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, further comprises general formula (III):

[0039]

[0040] in:

[0041] X3 is selected from N or CR5;

[0042] R5 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 R aa -(CH2) n1 OR aa -(CH2) n1 S(CH2) n2 R aa -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 S(O)(=NR aa (CH2) n2 R bb -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 NR aa S(O) m R bb ;

[0043] Ring A, Ring B, Ring C, X3, L, R2, R3, R6~R7, R aa ~R bbp, y, z, w, n1, n2 and m are as described in general formula (II).

[0044] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof, further comprises general formula (IV):

[0045]

[0046] in:

[0047] R8 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0048] q can be 0, 1, 2, 3, or 4;

[0049] Rings B, C, X1 to X5, L, R3, R6 to R7, x, z, and w are as described in general formula (II).

[0050] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, further comprises general formula (V):

[0051]

[0052] in:

[0053] M1 and M2 are each independently selected from CR aa Or N;

[0054] R9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 R aa -(CH2) n1 OR aa -(CH2) n1 S(CH2) n2 R aa -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 S(O)(=NR aa (CH2) n2 Rbb -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 NR aa S(O) m R bb ;

[0055] s can be 0, 1, 2, 3, 4, or 5;

[0056] Ring A, Ring B, X1~X5, L, R2, R3, R7, R aa R bb p, y, z, n1, n2 and m are as described in general formula (II).

[0057] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, further comprises general formula (VI):

[0058]

[0059] in:

[0060] G1 and G2 are each independently selected from CR aa Or N;

[0061] R 10 Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0062] Or, any two adjacent or non-adjacent R 10The links form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl group is optionally further substituted by one or more substituents selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0063] t can be 0, 1, 2, 3, or 4;

[0064] Ring A, Ring C, X1~X5, L, R1, R2, R6~R7, R aa p, y and w are as described in general formula (II).

[0065] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof, further comprises general formula (VII):

[0066]

[0067] in:

[0068] Rings B, C, X3, L, R6, R7, p, and w are as described in general formula (III);

[0069] E, R3, R8, z, and q are as described in general formula (IV).

[0070] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof, further comprises general formula (VIII):

[0071]

[0072] in:

[0073] L is selected from the bond, -(CH2). n1 CR aa R bb -、-(CH2) n1 NR aa C(O)(CH2) n2 -、-(CH2) n1 C(O)(CH2) n2 (CR aa R bb ) m -、-(CH2) n1C(O)(CR aa R bb ) m (CH2) n2 -、-(CH2) n1 C(O)NR cc (CR aa R bb ) n2 -、-(CH2) n1 (O)(CH2) n2 -or-(CH2) n1 NR aa (CH2) n2 -;

[0074] G1 and G2 are each independently selected from CR aa Or N;

[0075] R4 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 R aa -(CH2) n1 OR aa -(CH2) n1 S(CH2) n2 R aa -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 S(O)(=NR aa (CH2) n2 R bb -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 NR aa S(O) m R bbThe alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyanoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH2) n1 R cc -(CH2) n1 OR cc -(CH2) n1 S(CH2) n2 R cc -(CH2) n1 C(O)R cc -(CH2) n1 C(O)OR cc -(CH2) n1 S(O) m R cc -(CH2) n1 S(O)(=NR cc (CH2) n2 R dd -(CH2) n1 NR cc R dd -(CH2) n1 P(O)R cc R dd -(CH2) n1 C(O)NR cc R dd -(CH2) n1 NR cc C(O)R dd Or -(CH2) n1 NR cc S(O) m R dd One or more substituents in it are replaced;

[0076] R7 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 R aa -(C≡C) n1 (CR aa Rbb ) m R cc ,-(C=C) n1 (CR aa R bb ) m R cc ,-(CH2) n1 O(CH2) n2 (CR a aR bb ) m R cc ,-(CH2) n1 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​m R bb The alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyanoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, oxo, thio, imino, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH2) n1 R dd -(CH2) n1 OR dd -(CH2) n1 S(CH2) n2 R dd -(CH2) n1 C(O)R dd -(CH2) n1 C(O)OR dd -(CH2) n1 S(O) m R dd -(CH2) n1 S(O)(=NR d d)(CH2) n2 R ee -(CH2) n1 NR dd R ee -(CH2) n1 P(O)R dd R ee -(CH2) n1 C(O)NR dd R ee -(CH2) n1 NR dd C(O)R ee and -(CH2) n1 NR dd S(O) m R ee One or more substituents in it are replaced;

[0077] R8 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0078] R9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 R aa -(CH2) n1 OR aa -(CH2) n1 S(CH2) n2 R aa -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 S(O)(=NR aa (CH2) n2 R bb -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 NR aa S(O) m R bb ;

[0079] R 10 Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0080] Or, any two adjacent or non-adjacent R 10The links form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl group is optionally further substituted by one or more substituents selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0081] R 11 Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2) n1 R aa -(CH2) n1 OR aa -(CH2) n1 SR aa -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 NR aa S(O) m R bb ;

[0082] t can be 0, 1, 2, or 3;

[0083] z can be 0, 1, 2, 3, 4, 5, or 6;

[0084] p is 0, 1, 2 or 3;

[0085] q is 0, 1, 2, 3, or 4; and

[0086] s can be 0, 1, 2, 3, 4 or 5.

[0087] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof, further comprises general formula (IX):

[0088]

[0089] in:

[0090] X3, L, R7 and p are as described in general formula (III);

[0091] R8 and q are as described in general formula (IV);

[0092] M1, M2, R9 and s are as described in general formula (V);

[0093] G1, G2, R 10 And t as described in general formula (VI).

[0094] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (IX), its stereoisomer, or a pharmaceutically acceptable salt thereof, further comprises general formula (X):

[0095]

[0096] in:

[0097] G2 is selected from CR aa Or N;

[0098] M2 is selected from CR aa Or N;

[0099] L is selected from the bond, -(CH2). n1 CR aa R bb -、-(CH2) n1 NR aa C(O)(CH2) n2 -、-(CH2) n1 C(O)(CH2) n2 (CR aa R bb ) m -、-(CH2) n1 C(O)(CR aa R bb ) m (CH2) n2 -、-(CH2) n1 C(O)NR cc (CR aa R bb )n2 -、-(CH2) n1 (O)(CH2) n2 -or-(CH2) n1 NR aa (CH2) n2 -;

[0100] R7 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 (CR aa R bb ) m R cc -(C≡C) n1 (CR aa R bb ) m R cc -(C=C) n1 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 R aa -(CH2) n1 S(CH2) n2 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 S(O) m R aa -(CH2) n1 O(CH2) n2 S(O)(=NR aa (CH2) m R bb -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 S(O)(=NRaa (CH2) n2 R bb -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb -(CH2) n1 NR aa (CH2) n2 R bb Or -(CH2) n1 NR aa S(O) m R bb The alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyanoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, oxo, thio, imino, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH2) n1 R dd -(CH2) n1 OR dd -(CH2) n1 S(CH2) n2 R dd -(CH2) n1 C(O)R dd -(CH2) n1 C(O)OR dd -(CH2) n1 S(O) m R dd -(CH2) n1 S(O)(=NR d d)(CH2) n2 R ee -(CH2) n1 NR dd R ee-(CH2) n1 P(O)R dd R ee -(CH2) n1 C(O)NR dd R ee -(CH2) n1 NR dd C(O)R ee and -(CH2) n1 NR dd S(O) m R ee One or more substituents in it are replaced;

[0101] R9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 R aa -(CH2) n1 OR aa -(CH2) n1 S(CH2) n2 R aa -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 S(O)(=NR aa (CH2) n2 R bb -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 NR aa S(O) m R bb ;

[0102] R 10Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0103] Or, any two adjacent or non-adjacent R 10 The links form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl group is optionally further substituted by one or more substituents selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0104] R11 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 R aa -(CH2) n1 OR aa -(CH2) n1 SR aa -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 NR aa S(O) m R bb ;

[0105] R aa R bb R cc Rdd and R ee Each of the following is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl may optionally be further substituted by one or more substituents selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, oxo, imino, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0106] Or, R aa R bb R cc R dd and R ee Any two of them can be linked to form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl group may optionally be further substituted by one or more substituents selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, oxo, imino, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0107] s can be 0, 1, 2, 3, 4, or 5;

[0108] t is 0, 1, 2, 3, or 4; and

[0109] p can be 0, 1, 2, or 4.

[0110] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (X), its stereoisomer, or a pharmaceutically acceptable salt thereof, further comprises general formulas (XI) and (XI-A):

[0111]

[0112] in:

[0113] R 12Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0114] R 13 Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2) n1 (CR aa R bb ) m R cc -(C≡C) n1 (CR aa R bb ) m R cc -(C=C) n1 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 (CR aa R bb ) m R cc -(CH2) n1 OR aa -(CH2) n1 O(CH2) n2 R aa -(CH2) n1 S(C H 2) n2 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 S(O) m R aa -(CH2) n1 O(CH2) n2 S(O)(=NR aa (CH2) m R bb -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2)n1 S(O)(=NR aa (CH2) n2 R bb -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb -(CH2) n1 NR aa (CH2) n2 R bb Or -(CH2) n1 NR aa S(O) m R bb The alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyanoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, oxo, thio, imino, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH2) n1 R dd -(CH2) n1 OR dd -(CH2) n1 S(CH2) n2 R dd -(CH2) n1 C(O)R dd -(CH2) n1 C(O)OR dd -(CH2) n1 S(O) m R dd -(CH2) n1 S(O)(=NR dd (CH2) n2 R ee -(CH2) n1 NR ddR ee -(CH2) n1 P(O)R dd R ee -(CH2) n1 C(O)NR dd R ee -(CH2) n1 NR dd C(O)R ee CH2 n1 NR dd S(O) m R ee One or more substituents in it are replaced;

[0115] R 12 The following groups are considered to be hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0116] R 15 and R 16 Each group is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or -(CH2). n1 OR aa 、;

[0117] L, R 11 R aa ~R ee n1, n2 and m are as described in the general formula (X).

[0118] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof, further comprises general formula (XII):

[0119]

[0120] in:

[0121] L is selected from the bond, -(CH2). n1 CR aa R bb -、-(CH2) n1 NR aa C(O)(CH2) n2 -、-(CH2) n1 C(O)(CH2) n2 (CR aa R bb ) m -、-(CH2)n1 C(O)(CR aa R bb ) m (CH2) n2 -、-(CH2) n1 C(O)NR cc (CR aa R bb ) n2 -、-(CH2) n1 (O)(CH2) n2 -or-(CH2) n1 NR aa (CH2) n2 -;

[0122] M1 and M2 are each independently selected from CR aa Or N;

[0123] X1 and X2 are each independently selected from C and CR. aa Or N;

[0124] R3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0125] R9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 R aa -(CH2) n1 OR aa -(CH2) n1 S(CH2) n2 R aa -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 S(O)(=NR aa (CH2) n2 R bb -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2)n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 NR aa S(O) m R bb ;

[0126] R 11 Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2) n1 R aa -(CH2) n1 OR aa -(CH2) n1 SR aa -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O) m R aa -(CH2) n1 NR aa R bb -(CH2) n1 P(O)R aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 NR aa S(O) m R bb ;

[0127] z can be 0, 1, 2, 3, 4 or 5;

[0128] s can be 0, 1, 2, 3, 4, or 5;

[0129] R 12 ~R 14 R aa ~R ee n1, n2 and m are as described in the general formula (XI).

[0130] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, further comprises general formula (IX-A):

[0131]

[0132] in:

[0133] L is selected from the bond, -(CH2). n1 CR aa R bb -、-(CH2) n1 NR aa C(O)(CH2) n2 -、-(CH2) n1 C(O)(CH2) n2 (CR aa R bb ) m -、-(CH2) n1 C(O)(CR aa R bb ) m (CH2) n2 -、-(CH2) n1 C(O)NR cc (CR aa R bb ) n2 -、-(CH2) n1 (O)(CH2) n2 -or-(CH2) n1 NR aa (CH2) n2 -,

[0134] Preferred ions are -CH2-, -CD2-, -O-, or -NHC(O)-.

[0135] G2 is selected from N or CR aa N, CH or CCH3 are preferred;

[0136] M1 is selected from N or CR aa N, CH or CCH3 are preferred;

[0137] M2 is selected from N or CR aa N or CH are preferred;

[0138] R9 is selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy,

[0139] C 1-6Deuterated alkoxy, C 1-6 Halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, or -(CH2) n1 OR aa ;

[0140] Preferred hydrogen, halogen, C 1-6 Alkoxy, C 1-6 deuterated alkoxy or -OR aa ;

[0141] The preferred compounds are hydrogen, fluorine, chlorine, methyl, methoxy, deuterated methyloxy, or cyclopropyloxy.

[0142] R 17 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkyne, 3-12 heterocyclic, 5-12 heteroaryl, or -(CH2) n1 (CR aa R bb )R cc The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 The alkynyl, 3-12 heterocyclic and 5-12 heteroaryl groups are optionally further selected from hydrogen, hydroxyl, cyano, oxo, thio, amino, imino, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 3-8 The alkyl group or one or more substituents of a cycloalkyl or 3-12 heterocyclic group are substituted;

[0143] R 24 and R 25 Each element is independently selected from hydrogen, deuterium, and 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 Halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10Aryl, 5-12 heteroaryl, or -(CH2) n1 OR aa Preferably hydrogen or methyl;

[0144] Or, R 24 and R 25 Together with the carbon atoms they are attached to and G2, they form a C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, preferably nitrogen-containing heterocyclic butyl groups;

[0145] R aa R bb and R cc Each is independently selected from hydrogen, deuterium, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, hydroxyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic or C 6-14 Aryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, hydroxyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups and C 6-14 The aryl group may be further selected from hydrogen, halogen, cyano, hydroxyl, oxo, imino, C 1-6 Alkyl and C 1-6 One or more substituents in the hydroxyalkyl group are substituted;

[0146] Or, R aa R bb and R cc Any two elements in a string can be linked to form a C. 3-8 Cycloalkyl or 3-12 membered heterocyclic group, wherein the C 3-8 Cycloalkyl and 3-12 membered heterocyclic groups may be further selected from hydrogen, amino, halogen, cyano, hydroxyl, oxo, imino, C 1-6 Alkyl and C 1-6 One or more substituents in the hydroxyalkyl group are substituted;

[0147] n1 is 0, 1, or 2;

[0148] n2 is 0, 1, or 2;

[0149] m is 0, 1, or 2; and

[0150] s can be 0, 1, 2 or 3.

[0151] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, further comprises general formula (IX-B):

[0152]

[0153] in:

[0154] M3 is selected from the following: -O-, -S-, -NH-, or -NCH3-.

[0155] R 18 and R 19 Each element is independently selected from hydrogen, deuterium, and 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 Halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, preferably hydrogen or methyl;

[0156] Or, R 18 and R 19 Together with the carbon atoms they are attached to, they form a C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, preferably C 3-6 Cycloalkyl or a 3-7 membered heterocyclic group containing 1-2 oxygen, nitrogen, or sulfur atoms, more preferably cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, aziridine, bicyclo[1,1,1]pentane, or 1-aminoethylene-1-oxothiran, wherein the C 3-8 Cycloalkyl or 3-12-membered heterocyclic groups may be further selected from hydrogen, C 1-6 Alkyl, hydroxyl, cyano and C 1-6 One or more substituents in the hydroxyalkyl group are substituted;

[0157] R 20 Selected from hydrogen, deuterium, and 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 Halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl,

[0158] Hydrogen, cyano or amino groups are preferred;

[0159] R 24 and R 25 Each element is independently selected from hydrogen, deuterium, and 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 Halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, or -(CH2) n1 OR aa Preferably hydrogen or methyl;

[0160] Or, R 24 and R 25 Together with the carbon atoms they are attached to and G2, they form a C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, preferably nitrogen-containing heterocyclic butyl groups;

[0161] r is 0, 1, or 2;

[0162] L, G2, M1, M2, R9, and s are as described in the general formula (IX-A).

[0163] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R in general formula (IX-B) 18 and R 19 Each element is independently selected from hydrogen, deuterium, and 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 Halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, preferably hydrogen, methyl, ethynyl, amino, cyano or hydroxyl;

[0164] Or, R 18 and R 19 Together with the carbon atoms they are attached to, they form a C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, preferably C 3-6Cycloalkyl or a 3-7 membered heterocyclic group containing 1-2 oxygen, nitrogen, or sulfur atoms, more preferably cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, aziridine, tetrahydropyran, bicyclo[1,1,1]pentane, or 1-aminoethylene-1-oxothiran, wherein the C 3-8 Cycloalkyl or 3-12-membered heterocyclic groups, optionally further selected from hydrogen, C 1-6 Alkyl, halogen, hydroxyl, cyano, C 1-6 Hydroxyalkyl and -(CH2) n1 C(O)NR aa R bb One or more substituents in it are replaced;

[0165] R 20 Selected from hydrogen, deuterium, and 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 Halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups, preferably hydrogen, methyl, ethynyl, amino, cyano or hydroxyl.

[0166] The present invention also provides a preferred embodiment, wherein the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, further comprises the general formula (X) shown in general formula (XIII):

[0167]

[0168] in:

[0169] R 11 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, 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 Halogenated alkoxy groups, C 2-6 alkenyl or C 2-6 alkynyl group;

[0170] R 13 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 Alkyne group, -O(CH2) n1 (CR aa R bb ) m R cc or

[0171] R aa R bb and R cc Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, 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 Halogenated alkoxy groups, C 2-6 alkenyl or C 2-6 alkynyl group;

[0172] R c and R d Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, 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 Halogenated alkoxy groups, C 2-6 alkenyl or C 2-6 alkynyl group,

[0173] Or, R c and R d It forms C with adjacent carbon atoms. 3-8 Cycloalkyl, optionally prefixed with deuterium, halogen, amino, nitro, hydroxyl, 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 Halogenated alkoxy groups, C 2-6 alkenyl or C 2-6 One or more substituents in the alkynyl group are substituted;

[0174] M1 and M2 are each independently selected from -N- or -CH-;

[0175] R16 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, 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 Halogenated alkoxy groups, C 2-6 alkenyl or C 2-6 alkynyl group;

[0176] R a and R b Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, 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 Halogenated alkoxy groups, C 2-6 alkenyl or C 2-6 alkynyl group;

[0177] K is an integer of 0, 1, or 2;

[0178] n1 is an integer of 1, 2, or 3;

[0179] m is an integer of 1, 2, or 3.

[0180] The present invention also provides a preferred embodiment, wherein the compound of general formula (XIII), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0181] R 11 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, or C 1-3 alkyl;

[0182] R 13 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, -OCH2CR aa R bb R cc or

[0183] R aa R bb and Rcc Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl or C 2-4 alkynyl group;

[0184] R c and R d Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 Halogenated alkoxy groups,

[0185] Or, R c and R d It forms C with adjacent carbon atoms. 3-6 Cycloalkyl, optionally prefixed with deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 One or more substituents in the haloalkoxy group are substituted;

[0186] M1 is -N- and M2 is -CH-, or M1 is -CH- and M2 is -N-;

[0187] R 16 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 Halogenated alkoxy groups;

[0188] R a and R b Each is independently selected from hydrogen, deuterium, or halogen.

[0189] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, further comprises general formula (X):

[0190]

[0191] In a preferred embodiment of the present invention, R 18 and R 19 Each element is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6-membered heteroaryl, preferably hydroxyl or methyl;

[0192] R9 is selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-4 alkenyl or C 2-4 alkynyl group;

[0193] s can be 0, 1, 2 or 3.

[0194] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, in general formula (IX-B) Selected from

[0195] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomer, or its pharmaceutically acceptable salt is further represented by general formula (IX-C):

[0196]

[0197] in:

[0198] R 21 and R 22 Each element is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Deuterated alkoxy, C 1-6 Halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C2-6 ynyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, --(CH2) n1 C(O)R aa Or -(CH2) n1 R aa ;

[0199] Or, R 21 and R 22 Together with the carbon atoms they are attached to, they form a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally further selected from hydrogen, amino, halogen, cyano, hydroxyl, oxo, C 1-6 Alkyl and C 1-6 One or more substituents in the hydroxyalkyl group are substituted;

[0200] Preferably, the azacyclobutane, pyrrolidinyl, 2-azaspiro[3.3]heptane, or piperidinyl is used, wherein the azacyclobutane, pyrrolidinyl, 2-azaspiro[3.3]heptane, or piperidinyl is optionally further hydrogenated or C-dimethylamineized. 1-6 Substituted by one or more substituents of alkyl, hydroxy, or hydroxyalkyl groups;

[0201] R 24 and R 25 Each element is independently selected from hydrogen, deuterium, and 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 Halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, or -(CH2) n1 OR aa Preferably hydrogen or methyl;

[0202] Or, R 24 and R 25 Together with the carbon atoms they are attached to and G2, they form a C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, preferably nitrogen-containing heterocyclic butyl groups;

[0203] L, G2, M1, M2, R9, R aa, s and n1 are as described in the general formula (IX-A).

[0204] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R in general formula (IX-C) 21 and R 22 Each element is independently selected from hydrogen, deuterium, and 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 Halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n1 C(O)R aa Or -(CH2) n1 R aa ;

[0205] Or, R 21 and R 22 Together with the carbon atoms they are attached to, they form a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally further selected from hydrogen, amino, halogen, cyano, hydroxyl, oxo, C 1-6 Alkyl and C 1-6 One or more substituents in the hydroxyalkyl group are substituted;

[0206] Preferred are aziridine, pyrrolidinyl, 2-azispiro[3.3]heptane or piperidinyl, wherein the aziridine, pyrrolidinyl, 2-azispiro[3.3]heptane or piperidinyl may optionally be further substituted with one or more substituents selected from hydrogen, C1-3 alkyl, cyano, hydroxy or hydroxyalkyl.

[0207] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, in general formula (IX-C) Selected from

[0208] Among them, R 26 and R 27 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0209] Preferred groups include hydrogen, hydroxyl, cyano, and C. 1-3 Alkyl or C 1-3 Hydroxyalkyl;

[0210] More preferably, hydrogen, hydroxyl, cyano, methyl or hydroxyisopropyl.

[0211] In a preferred embodiment of the present invention, L is selected from -CH2-, -CD2-, -O-, -S-, -C(O)NH-, or -NHC(O)-;

[0212] G2 is selected from -N-, -CH-, or -CCH3-;

[0213] M1 is selected from -N-, -CH-, or -CCH3-;

[0214] M2 is selected from -N- or -CH-.

[0215] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, is further represented by general formula (IX-D):

[0216]

[0217] in:

[0218] R 23 Selected from hydrogen, deuterium, and 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 Halogenated alkoxy groups, C 1-6 Hydroxyl alkyl, halogen, amino, nitro, hydroxy, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n1 C(O)R aa Or -(CH2) n1 R aa ,

[0219] Preferably hydroxyl, cyano or C 1-6 Hydroxyalkyl;

[0220] L, G2, M1, M2, M3, R9, R aa , s and n1 are as described in the general formula (IX-A).

[0221] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R in general formula (IX-D) 23 Selected from hydroxyl, cyano, C 1-6 Hydroxyalkyl or -(CH2) n1 C(O)NR aa R bb .

[0222] The present invention also provides a preferred embodiment, wherein the compounds represented by the general formulas, their stereoisomers, or their pharmaceutically acceptable salts are:

[0223] Ring A is selected from the following groups:

[0224]

[0225] Ring B is selected from the following groups:

[0226]

[0227] The ring C is selected from the following groups:

[0228]

[0229] The present invention also provides a preferred embodiment, wherein the compounds represented by the general formulas, their stereoisomers, or their pharmaceutically acceptable salts are:

[0230] L is selected from the bond, -(CH2). n1 CR aa R bb -、-(CH2) n1 NR aa C(O)(CH2) n2 -、-(CH2) n1 C(O)(CR aa R bb ) m (CH2) n2 -、-(CH2) n1 C(O)(CH2) m (CR aa R bb ) n2 -、-(CH2) n1 C(O)NR cc (CRaa R bb ) n2 -、-(CH2) n1 (O)(CH2) n2 -or-(CH2) n1 NR aa (CH2) n2 -;

[0231] Preferred octets are -(CH2)2-, -(CD2)2-, -O-, -C(O)NH-, -C(O)N(CH3)-, -NHC(O)-, or -O(CH2)2-.

[0232] R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, oxo, C 2-6 Alkyne group, 3-12 membered heterocyclic group, 5-12 membered heteroaryl group, -(C≡C) n1 (CR aa R bb ) m R cc -(C=C) n1 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 (CR aa R bb ) m C(O)NHR cc -(CH2) n1 S(CH2) n2 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 S(O) m R aa -(CH2) n1 O(CH2) n2 S(O)(=NR aa (CH2) m R bb -(CH2) n1 O(CH2)n2 R aa -(CH2) n1 NR aa (CH2) n2 CR bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 S(O)(=NR aa (CH2) n2 R bb The C mentioned therein 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkyne, 3-12 heterocyclic and 5-12 heteroaryl, optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkoxy, halogen, hydroxyl, amino, cyano, oxo, thio, imino, C 3-8 The alkyl group is replaced by one or more substituents in the cycloalkyl group and the 3-12 membered heterocyclic group;

[0233] R2 is selected from hydrogen or halogen;

[0234] R3 is selected from hydrogen, C 1-6 Alkyl or amino; or, any two adjacent or non-adjacent R3 links form a C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0235] R4 is selected from C 1-6 Alkyl, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 6-10 aryl and 5-12 heteroaryl groups, optionally further selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Alkyl groups, halogens, -(CH2) n1 OR aa -(CH2) n1 C(O)NR aa R bb Or -(CH2) n1 NR aa C(O)R bb One or more substituents in it are replaced;

[0236] R5 is selected from cyano, -C(O)NR aa R bb Or -(CH2)n1 P(O)R aa R bb ;

[0237] R6 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkyl groups, halogens, amino groups, -(CH2) n1 OR aa -(CH2) n1 C(O)NR aa R bb Or -(CH2) n1 NR aa C(O)R bb ;

[0238] R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, oxo, C 2-6 Alkyne group, 3-12 membered heterocyclic group, 5-12 membered heteroaryl group, -(C≡C) n1 (CR aa R bb ) m R cc -(C=C) n1 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 (CR aa R bb ) m C(O)NHR cc -(CH2) n1 S(CH2) n2 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 S(O) m R aa -(CH2) n1 O(CH2) n2 S(O)(=NR aa (CH2) m R bbb -(CH2) n1O(CH2) n2 R aa -(CH2) n1 NR aa (CH2) n2 CR bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 S(O)(=NR aa (CH2) n2 R bb The C mentioned therein 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkyne, 3-12 heterocyclic and 5-12 heteroaryl, optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkoxy, halogen, hydroxyl, amino, cyano, oxo, thio, imino, C 3-8 The cyclic alkyl group or one or more substituents in a 3-12 membered heterocyclic group are substituted;

[0239] R8 is selected from hydrogen or halogen;

[0240] R9 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or -OR aa ;

[0241] R 10 Selected from hydrogen, C 1-6 Alkyl or amino;

[0242] Or, any two adjacent or non-adjacent R 10 Links form a C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0243] R 11 Selected from cyano, -(CH2) n1 P(O)R aa R bb Or -(CH2) n1 C(O)NR aa R bb ;

[0244] R 12 Selected from hydrogen, C 1-6 Alkyl or halogen;

[0245] R 13 Selected from C1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkyne group, 3-12 membered heterocyclic group, 5-12 membered heteroaryl group, -(C≡C) n1 (CR aa R bb ) m R cc -(C=C) n1 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 (CR aa R bb ) m C(O)NHR cc -(CH2) n1 S(CH2) n2 (CR aa R bb ) m R cc -(CH2) n1 O(CH2) n2 S(O) m R aa -(CH2) n1 O(CH2) n2 S(O)(=NR aa (CH2) m R bb -(CH2) n1 O(CH2) n2 R aa -(CH2) n1 NR aa (CH2) n2 CR bb -(CH2) n1 NR aa C(O)R bb Or -(CH2) n1 S(O)(=NR aa (CH2) n2 R bb The C mentioned therein 1-6 Alkyl, C 1-6 Alkoxy, C 2-6Alkyne, 3-12 heterocyclic and 5-12 heteroaryl, optionally further selected from hydrogen, C 1-6 Alkyl, hydroxyl, thiol, imino, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 3-8 The cyclic alkyl group or one or more substituents in a 3-12 membered heterocyclic group are substituted;

[0246] R 14 Selected from hydrogen or halogen;

[0247] R 15 Selected from hydrogen or halogen;

[0248] R 16 Selected from hydrogen, alkoxy, or -OR aa ;

[0249] R aa R bb and R cc Each is independently selected from hydrogen, deuterium, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, hydroxyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic or C 6-14 Aryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, hydroxyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups and C 6-14 aryl, optionally further selected from hydrogen, halogen, cyano, hydroxyl, oxo, imino, C 1-6 Alkyl and C 1-6 One or more substituents in the hydroxyalkyl group are substituted;

[0250] Or, R aa R bb and R cc Any two elements in a string can be linked to form a C. 3-8 Cycloalkyl or 3-12 membered heterocyclic group, wherein the C 3-8 Cycloalkyl and 3-12 membered heterocyclic groups may optionally be further selected from hydrogen, halogen, cyano, hydroxyl, oxo, imino, C 1-6 Alkyl and C 1-6 It is substituted by one or more substituents in the hydroxyalkyl group.

[0251] The present invention also relates to a method for preparing compounds of general formula (IX-A) or their stereoisomers and pharmaceutically acceptable salts thereof, comprising the following steps:

[0252]

[0253] The coupling reaction of general formula (IX-A1) and general formula (IX-A2) yields the compound of general formula (IX-A) or its stereoisomer and its pharmaceutically acceptable salt;

[0254] in:

[0255] X1 is selected from halogens; preferably fluorine, chlorine, bromine or iodine; more preferably bromine.

[0256] The present invention also relates to a method for preparing compounds of general formula (IX-B) or their stereoisomers and pharmaceutically acceptable salts thereof, comprising the following steps:

[0257]

[0258] The reaction of general formula (IX-B1) with general formula (IX-B2) yields the compound of general formula (IX-B) or its stereoisomer and its pharmaceutically acceptable salt;

[0259] in:

[0260] R 28 Selected from halogens, -B(OH)2, or borate esters; preferably fluorine, chlorine, bromine, iodine, -B(OH)2, or...

[0261] R 29 Selected from halogens, boric acids, or borate esters; preferably fluorine, chlorine, bromine, iodine, -B(OH)2, or...

[0262] When R 28 When it is halogen, R 29 Selected from boric acid or borate esters;

[0263] When R 28 When selected from boric acid or borate ester, R 29 It is a halogen.

[0264] The present invention also relates to a method for preparing compounds of general formula (IX-B) or their stereoisomers and pharmaceutically acceptable salts thereof, comprising the following steps:

[0265]

[0266] The reaction of general formula (IX-B3) with general formula (IX-B4) yields the compound of general formula (IX-B) or its stereoisomer and its pharmaceutically acceptable salt;

[0267] in:

[0268] M3 is selected from the following: -O-, -S-, -NH-, or -NCH3-.

[0269] R 30 Selected from halogens and hydroxyl groups; preferably fluorine, chlorine, bromine, iodine, or hydroxyl groups; more preferably bromine and hydroxyl groups;

[0270] Pg is selected from hydrogen, halogens or hydroxyl protecting groups, wherein the halogens are preferably fluorine, chlorine, bromine or iodine;

[0271] When Pg is a hydroxyl protecting group, it is selected from methyl, tert-butyl, triphenyl, methyl thiomethyl ether, 2-methoxyethoxymethyl ether, methoxymethyl ether, p-methoxybenzyl ether, tert-valeryl, benzyl ether, methoxymethyl, trimethylsilyl, tetrahydrofuranyl, tert-butyldimethylsilyl, acetyl, benzoyl or p-toluenesulfonyl; preferably p-toluenesulfonyl.

[0272] When M3 is -O-, Pg is selected from hydrogen or hydroxyl protecting groups.

[0273] The present invention also relates to a method for preparing compounds of general formula (IX-C) or their stereoisomers and pharmaceutically acceptable salts thereof, comprising the following steps:

[0274]

[0275] The reaction of general formula (IX-C1) with general formula (IX-C2) yields the compound shown in general formula (IX-B) or its stereoisomer and its pharmaceutically acceptable salt;

[0276] in:

[0277] X2 is selected from halogens; preferably fluorine, chlorine, bromine or iodine; more preferably bromine.

[0278] The present invention also relates to a method for preparing a compound of general formula (X) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, comprising the following steps:

[0279]

[0280]

[0281] in:

[0282] R 18 and R 19 Each element is independently selected from hydrogen, deuterium, and 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 Halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl,

[0283] Or, R 18 and R 19 Together with the carbon atoms they are attached to, they form a C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, preferably C 3-6 Cycloalkyl or a 3-7 membered heterocyclic group containing 1-2 oxygen, nitrogen, or sulfur atoms, more preferably cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, aziridine, bicyclo[1,1,1]pentane, or 1-aminoethylene-1-oxothiran, wherein the C 3-8 Cycloalkyl or 3-12-membered heterocyclic groups may be further selected from hydrogen, C 1-6 Alkyl, hydroxyl, cyano and C 1-6 One or more substituents in the hydroxyalkyl group are substituted;

[0284] Preferred, R 18 and R 19 Each is independently selected from hydrogen, methyl, or hydroxyl.

[0285] The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of each of the general formula compounds shown, their stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0286] The present invention also provides a preferred embodiment, and relates to the use of the general formula compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of RET inhibitor-related drugs.

[0287] The present invention also provides a preferred embodiment, which also relates to the use of the compound of general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof, in the preparation of medicaments for the treatment and / or prevention of diseases such as non-small cell lung cancer, fibrosarcoma, pancreatic tumors, medullary thyroid carcinoma, papillary thyroid carcinoma, soft tissue sarcoma, high-grade solid tumors, breast tumors and colon tumors.

[0288] The present invention further relates to a method for preparing a medicament for treating and / or preventing diseases such as non-small cell lung cancer, fibrosarcoma, pancreatic tumors, medullary thyroid carcinoma, papillary thyroid carcinoma, soft tissue sarcoma, high-grade solid tumors, breast tumors, and colon tumors, using compounds of general formula (I), stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0289] This invention also relates to methods for treating and / or preventing diseases such as non-small cell lung cancer, fibrosarcoma, pancreatic tumors, medullary thyroid carcinoma, papillary thyroid carcinoma, soft tissue sarcoma, high-grade solid tumors, breast tumors, and colon tumors, comprising administering to the said mammals a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

[0290] In some implementations, this method relates to the treatment and / or prevention of conditions such as non-small cell lung cancer, fibrosarcoma, pancreatic tumors, medullary thyroid carcinoma, papillary thyroid carcinoma, soft tissue sarcoma, high-grade solid tumors, breast tumors, and colon tumors.

[0291] The treatment methods provided herein include administering a therapeutically effective amount of the compound of the present invention to a subject. In one embodiment, the present invention provides a method for treating menopausal hot flash-related disorders in mammals. The method includes administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof, to said mammal.

[0292] Detailed description of the invention

[0293] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0294] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched 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, 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 their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. 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. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0295] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0296] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0297] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 4-quintile, 4-quintile, 4-quintile, 5-quintile, or 5-quintile / 6-quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0298]

[0299] It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

[0300]

[0301] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0302]

[0303] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0304]

[0305] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0306] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, C(O), S(O) (=NH), or S(O). m(where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetane, thiobutane, azirone, tetrahydropyranyl, azironeheptyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolidinyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetane, thiobutane, azirone, tetrahydrofuranyl, tetrahydropyranyl, 1-aminomethylene-1-oxothiran, azironeheptyl, piperidinyl, and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups via single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups via any two or more atoms on the ring. The heterocyclic group can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from hydrogen, alkyl, hydroxyalkyl, amino, imino, cyano, oxo, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl.

[0307] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, S(O) (=NH) or S(O). m The ring atoms are (where m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of shared spiroatoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0308]

[0309] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m(where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0310]

[0311] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0312]

[0313] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0314]

[0315] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0316] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0317]

[0318] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0319] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrrololyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, pyridazinyl, and oxadiazole, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, thiazolyl, pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrololyl, thiophene, thiazolyl, pyrimidinyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazole, pyridinyl, pyridazinyl, and oxadiazole. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0320]

[0321] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0322] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0323] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0324] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0325] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0326] "Alkenyl" refers to alkenyl groups, also known as olefin groups. The alkenyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0327] "Alkyne" refers to (CH≡C- or -C≡C-), wherein the alkynyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0328] "Hydroxy" refers to the -OH group.

[0329] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0330] "Amino" refers to -NH2.

[0331] “Cyano” refers to -CN.

[0332] "Nitro" refers to -NO2.

[0333] "Carboxyl group" refers to -C(O)OH.

[0334] "THF" refers to tetrahydrofuran.

[0335] “EtOAc” refers to ethyl acetate.

[0336] “MeOH” refers to methanol.

[0337] "DMF" refers to N,N-dimethylformamide.

[0338] "DIPEA" refers to diisopropylethylamine.

[0339] "TFA" refers to trifluoroacetic acid.

[0340] “MeCN” refers to acetonitrile.

[0341] “DMA” stands for N,N-dimethylacetamide.

[0342] “Et2O” refers to diethyl ether.

[0343] “DCE” refers to 1,2-dichloroethane.

[0344] "DIPEA" refers to N,N-diisopropylethylamine.

[0345] “NBS” refers to N-bromosuccinimide.

[0346] “NIS” refers to N-iodosuccinimide.

[0347] “Cbz-Cl” refers to benzyl chloroformate.

[0348] “Pd2(dba)3” refers to tris(dibenzylacetone)dipalladium.

[0349] “Dppf” refers to 1,1'-bis(diphenylphosphine)ferrocene.

[0350] “HATU” refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0351] "KHMDS" refers to potassium hexamethyldisilamide.

[0352] "LiHMDS" refers to lithium bis(trimethylsilyl)amine.

[0353] “MeLi” refers to methyl lithium.

[0354] “n-BuLi” refers to n-butyllithium.

[0355] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0356] The 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, that is, X can be any one or more of A, B, and C.

[0357] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by deuterium atoms.

[0358] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0359] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0360] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0361] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity. Detailed Implementation

[0362] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0363] Example

[0364] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0365] LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0366] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0367] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0368] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0369] Example 1

[0370] 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(methylthionyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0371]

[0372] Step 1: 2-(methylthio)ethane-1-ol

[0373]

[0374] 2-(methylthio)ethyl 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 x 3). The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and evaporated to dryness to give 2-(methylthio)ethane-1-ol (240 mg, colorless liquid, 70% yield).

[0375] Step 2: 4-Bromo-6-(2-(methylthio)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0376]

[0377] 4-Bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylonitrile (100 mg, 0.42 mmol) was dissolved in 10 mL of THF, and 2-(methylthio)ethane-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 overnight at room temperature. 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the crude product was separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to give 4-bromo-6-(2-(methylthio)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (69 mg, white solid, 53% yield).

[0378] MS m / z (ESI): 311.9 [M+H] + .

[0379] Step 3: 4-Bromo-6-(2-(methylthionyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0380]

[0381] 4-Bromo-6-(2-(methylthio)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (200 mg, 0.64 mmol) was dissolved in 20 mL of DCM, and m-chloroperoxybenzoic acid (110 mg, 0.64 mmol) was added. The mixture was stirred at room temperature for 4 h, and then extracted with 10 mL of water and ethyl acetate (20 mL * 3). The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the crude product was separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to give 4-Bromo-6-(2-(methylthionyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (189 mg, white solid, 90% yield).

[0382] MS m / z (ESI): 327.9 [M+H] + .

[0383] Step 4: Tert-butyl-3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester

[0384]

[0385] 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-carboxylic acid ester (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 * 3). The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the crude product was separated by column chromatography (washed with petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl-3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester (650 mg, white solid, 73% yield).

[0386] MS m / z (ESI): 354.0 [M+H] + .

[0387] Step 5: 3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane

[0388]

[0389] 100 mg (0.28 mmol) of tert-butyl-3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester was dissolved in 3 mL of DCM, and 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The solution was evaporated to dryness, and the pH was adjusted to alkaline with sodium bicarbonate solution. The solution was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solution was filtered and evaporated to dryness to give 70 mg (white solid, 99% yield) of 3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane.

[0390] MS m / z (ESI): 254.0 [M+H] + .

[0391] Step 6: 3-(5-bromopyridin-2-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane

[0392]

[0393] 3-(5-bromopyridin-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 mL * 3). The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the crude product was separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to give 3-(5-bromopyridin-2-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (60 mg, white solid, 57% yield).

[0394] MS m / z (ESI): 375.0 [M+H] + .

[0395] Step 7: 6-(2-(methylthionyl<sulfinyl>)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0396]

[0397] 4-Bromo-6-(2-(methylthionyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylon (200 mg, 0.6 mmol), pinacol diboronate (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 protection. Extraction was performed with 10 mL of water and ethyl acetate (20 mL * 3). The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The product was filtered, evaporated to dryness, and the crude product was separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to give 6-(2-(methylthionyl<sulfinyl>)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile (117 mg, white solid, yield 52%).

[0398] MS m / z (ESI): 376.1 [M+H] + .

[0399] Step 8: 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(methylthionyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0400]

[0401] 6-(2-(methylthionyl<sulfinyl>)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (60 mg, 0.16 mmol), 3-(5-bromopyridin-2-yl)-6-((6-methoxypyridin-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 protection. Extraction was performed with 10 mL of water and ethyl acetate (20 mL * 3). The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The crude product was filtered, evaporated to dryness, and prepared by prep-HPLC to obtain the product 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(methylthionyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (41 mg, white solid, yield 48%).

[0402] MS m / z (ESI): 544.2 [M+H] + .

[0403] 1 H NMR (400MHz, DMSO) δ8.82 (d, J=1.9Hz, 1H), 8.62 (s, 1H), 8.41 (d, J=2.3Hz, 1H), 8.07 (d, J=1.9Hz, 1H ), 7.85 (dd, J=8.8, 2.4Hz, 1H), 7.68 (dd, J=8.5, 2.2Hz, 1H), 7.32 (d, J=2.0Hz, 1H), 6.78 (t, J=9.4Hz, 2H), 4.62-4.44(m, 2H), 3.82(s, 3H), 3.73(d, J=11.6Hz, 2H), 3.67(d, J=5.7Hz, 2H), 3.58-3.52(m, 2H ), 3.50 (s, 2H), 3.13 (dt, J = 13.6, 4.4Hz, 1H), 2.67 (s, 3H), 2.59-2.52 (m, 2H), 1.59 (d, J = 8.5Hz, 1H).

[0404] Example 2

[0405] 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(methanesulfonyl)ethoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0406]

[0407] Using 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(methylthionyl<sulfinyl>)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, 4-(6-(6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(methanesulfonyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (45 mg, white solid, yield 70%) was obtained by referring to the third step of Example 1.

[0408] MS m / z (ESI): 560.2 [M+H] + .

[0409] Example 3

[0410] 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(S-methylsulfonamide)ethoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0411]

[0412] 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3-1,1]heptane-3-yl)pyridin-3-yl)-6-(2-(methanesulfonyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile (60 mg, 0.11 mmol) was dissolved in 5 mL of methanol, and ammonium carbamate (17 mg, 0.22 mmol) and iodophenyl diacetic acid (70 mg, 0.22 mmol) were added. The mixture was reacted at room temperature for 2 h. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The product was filtered, evaporated to dryness, and the crude product was prepared by prep-HPLC to obtain 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(S-methylsulfonamide)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile (25 mg, white solid, yield 45%).

[0413] MS m / z (ESI): 559.2 [M+H] + .

[0414] Example 4

[0415] 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(3-(methylthionyl<sulfinyl>)propoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0416]

[0417] The title compound (35 mg, white solid, 40%) was obtained from ethyl 3-(methylthio)propionate as the starting material, referring to Example 1.

[0418] MS m / z (ESI): 558.2 [M+H] + .

[0419] Example 5

[0420] 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(3-(methanesulfonyl)propoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0421]

[0422] Using 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(3-(methylthionyl<sulfinyl>)propoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile as a starting material, 4-(6-(6-(6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(3-(methanesulfonyl)propoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (32 mg, white solid, 56%) was obtained with reference to Example 2.

[0423] MS m / z (ESI): 574.2 [M+H] + .

[0424] Example 6

[0425] 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(3-(S-methylsulfonamide)propoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0426]

[0427] Using 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(3-(3-(methylthionyl<sulfinyl>)propoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, 4-(6-(6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(3-(S-methylsulfonyl)propoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (28 mg, white solid, 44%) was obtained with reference to Example 3.

[0428] MS m / z (ESI): 573.2 [M+H] + .

[0429] Example 7

[0430] 6-((2-hydroxy-2-methylpropyl)thio)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0431]

[0432] Step 1: 4-Bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yltrifluoromethanesulfonate

[0433]

[0434] In a 25 mL single-necked flask, 200 mg of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylonitrile (0.84 mmol), 5 mL of dichloromethane, and 1 mL of pyridine were added sequentially. After stirring the reaction mixture for 2 minutes, trifluoromethanesulfonic anhydride (355 mg, 1.26 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated, dissolved in 10 mL of ethyl acetate, and washed with saturated brine (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 1 / 1) to give 280 mg of 4-bromo-3-cyanopyrazolo[1,5-a]pyridine-6-yl trifluoromethanesulfonate (pale yellow solid, yield: 90.0%).

[0435] MS m / z (ESI): 370.0 [M+H] + 372.0[M+H+2] + .

[0436] Step 2: 4-Bromo-6-((2-hydroxy-2-methylpropyl)thio)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0437]

[0438] In a 25 mL three-necked flask, 4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yltrifluoromethanesulfonate (280 mg, 0.75 mmol), 1-mercapto-2-methylpropane-2-ol (80 mg, 0.75 mmol), tris(dibenzylacetone)dipalladium (68 mg, 0.075 mmol), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (71 mg, 0.15 mmol), diisopropylethylamine (193 mg, 1.5 mmol), and dioxane (10 mL) were added sequentially. The reaction solution was purged with nitrogen five times. The reaction solution was heated to 85 °C under nitrogen protection and stirred for 5 hours, then cooled to room temperature. The reaction solution was concentrated, dissolved in ethyl acetate (10 mL), washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography (dichloromethane / methanol: 30 / 1) to give the product 4-bromo-6-((2-hydroxy-2-methylpropyl)thio)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (140 mg, white solid, yield: 56.6%).

[0439] MS m / z (ESI): 326.0 [M+H] + 328.0 [M+H+2] + .

[0440] Step 3: 6-((2-hydroxy-2-methylpropyl)thio)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0441]

[0442] In a 25 mL three-necked flask, 4-bromo-6-((2-hydroxy-2-methylpropyl)thio)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (50 mg, 0.15 mmol), 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (64 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol), sodium carbonate (48 mg, 0.45 mmol), dioxane (5 mL), and water (1 mL) were added sequentially. The reaction solution was purged with nitrogen five times. The reaction solution was heated to 85°C under nitrogen protection and stirred for 5 hours. After cooling to room temperature, the reaction solution was concentrated, dissolved in ethyl acetate (10 mL), and washed with saturated brine (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by prep-HPLC to give 6-((2-hydroxy-2-methylpropyl)thio)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (25 mg, white solid, yield: 30.1%).

[0443] MS m / z (ESI): 542.2 [M+H] + .

[0444] Example 8

[0445] 6-((2-hydroxy-2-methylpropyl)thio)-4-(6-(4-((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0446]

[0447] Step 1: 4-(6-fluoropyridin-3-yl)-6-((2-hydroxy-2-methylpropyl)thio)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0448]

[0449] In a 25 mL three-necked flask, 4-bromo-6-((2-hydroxy-2-methylpropyl)thio)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (100 mg, 0.30 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (68 mg, 0.30 mmol), tetrakis(triphenylphosphine)palladium (27 mg, 0.03 mmol), sodium carbonate (97 mg, 0.09 mmol), dioxane (5 mL), and water (1 mL) were added sequentially. The reaction solution was purged with nitrogen five times. The reaction solution was heated to 85 °C under nitrogen protection and stirred for 5 hours, then cooled to room temperature. The reaction solution was concentrated, dissolved in ethyl acetate (10 mL), and washed with saturated brine (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography (dichloromethane / methanol: 30 / 1) to give 4-(6-fluoropyridin-3-yl)-6-((2-hydroxy-2-methylpropyl)thio)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (85 mg, pale yellow solid, yield: 80.9%).

[0450] MS m / z (ESI): 343.1 [M+H] + .

[0451] Step 2: 6-((2-hydroxy-2-methylpropyl)thio)-4-(6-(4-((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0452]

[0453] In a 25 mL three-necked flask, 4-(6-fluoropyridin-3-yl)-6-((2-hydroxy-2-methylpropyl)thio)pyrazolo[1,5-a]pyridine-3-carboxynitrile (85 mg, 0.25 mmol), 2-methoxy-5-(piperidin-4-oxy)pyridine (52 mg, 0.25 mmol), diisopropylethylamine (65 mg, 0.50 mmol), and dimethyl sulfoxide (2 mL) were added sequentially. The reaction solution was heated to 90 °C under nitrogen protection and stirred for 48 hours. After cooling to room temperature, the reaction solution was concentrated, dissolved in ethyl acetate (10 mL), washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by prep-HPLC to give the product 6-((2-hydroxy-2-methylpropyl)thio)-4-(6-(4-((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (60 mg, white solid, yield: 45.5%).

[0454] MS m / z (ESI): 531.2 [M+H]+ .

[0455] Example 9

[0456] 6-(2-hydroxy-2-methylpropylsulfonamide)-4-(6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0457]

[0458] Step 1: 4-Bromo-6-((2-hydroxy-2-methylpropyl)thionyl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0459]

[0460] 4-Bromo-6-((2-hydroxy-2-methylpropyl)thio)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (100 mg, 0.30 mmol) was dissolved in dichloromethane (5 mL), cooled to -20 °C in a dry ice / ethyl acetate bath, and m-chloroperoxybenzoic acid (51 mg, 0.3 mmol) was added in portions. After the addition was complete, the ice bath was removed and the mixture was allowed to rise naturally to room temperature, followed by stirring for 30 minutes. Saturated sodium carbonate solution (5 mL) was added to the reaction solution, followed by extraction with ethyl acetate (5 mL x 2). The organic phase was mixed, washed with saturated sodium chloride solution (5 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-bromo-6-((2-hydroxy-2-methylpropyl)thionyl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (95 mg, 90.5%).

[0461] MS m / z (ESI): 342.0 [M+H] + 344.0[M+2+H] + .

[0462] Step 2: 4-Bromo-6-(2-hydroxy-2-methylpropylsulfonyl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0463]

[0464] 4-Bromo-6-((2-hydroxy-2-methylpropyl)thionyl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (95 mg, 0.28 mmol) was dissolved in methanol (5 mL), and ammonium carbamate (108 mg, 1.39 mmol) and diacetic acid iodobenzene (268 mg, 0.83 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. The reaction was stopped, and water (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (5 mL x 2), and the organic phases were combined. The organic phases were washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-bromo-6-(2-hydroxy-2-methylpropylsulfonyl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (90 mg, 90.7%).

[0465] MS m / z (ESI): 357.0 [M+H] + 359.0[M+2+H] + .

[0466] Step 3: 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropylsulfonamide)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0467]

[0468] Using 4-bromo-6-(2-hydroxy-2-methylpropylsulfonamide)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, the product 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropylsulfonamide)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (95 mg, white solid, yield 95.6%) was obtained in the first step of Reference Example 8.

[0469] MS m / z (ESI): 374.1 [M+H] + .

[0470] Step 4: 6-(2-hydroxy-2-methylpropylsulfonamide)-4-(6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0471]

[0472] Using 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropylsulfonamide)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, the product 6-(2-hydroxy-2-methylpropylsulfonamide)-4-(6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (30 mg, white solid, yield 22.0%) was obtained in step 2 of Example 8.

[0473] MS m / z (ESI): 532.2 [M+H] + .

[0474] Example 10

[0475] 6-(ethylsulfonamide)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0476]

[0477] Step 1: 4-Bromo-6-(ethylthio)pyrazolo[1,5-a]pyridine-3-carboxylonitrile

[0478]

[0479] 4-Bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate (200 mg, 0.54 mmol), sodium ethyl mercaptan (90 mg, 1.08 mmol), and dioxane (5 mL) were added sequentially to a 25 mL three-necked flask. The reaction mixture was heated to 85 °C under nitrogen protection and stirred for 5 hours. After cooling to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate (10 mL), and washed with saturated brine (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography (dichloromethane / methanol: 30 / 1) to obtain the product 4-bromo-6-(ethylthio)pyrazolo[1,5-a]pyridin-3-carboxynitrile (120 mg, white solid, yield: 78.7%).

[0480] MS m / z (ESI): 282.0 [M+H] + 284.0[M+H+2] + .

[0481] Step 2: 4-Bromo-6-(ethylthionyl<sulfinyl>)pyrazolo[1,5-a]pyridine-3-carboxylon

[0482]

[0483] Using 4-bromo-6-(ethylthio)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a raw material, the product 4-bromo-6-(ethylthionyl<sulfinyl>)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (120 mg, white solid, yield 96.6%) was obtained in the first step of Reference Example 9.

[0484] MS m / z (ESI): 298.0 [M+H] +300.0[M+H+2] + .

[0485] Step 3: 4-Bromo-6-(ethylsulfonyl)pyrazolo[1,5-a]pyridine-3-carboxylon

[0486]

[0487] Using 4-bromo-6-(ethylsulfonyl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a raw material, the product 4-bromo-6-(ethylsulfonyl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (120 mg, white solid, yield 95.9%) was obtained in step 2 of Example 9.

[0488] MS m / z (ESI): 313.0 [M+H] + 315.0[M+H+2] + .

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

[0490]

[0491] Using 4-bromo-6-(ethylsulfonamide)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, the product 6-(ethylsulfonamide)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (45 mg, white solid, yield 22.2%) was obtained in step 3 of Example 7.

[0492] MS m / z (ESI): 529.2 [M+H] + .

[0493] Example 11

[0494] 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-7-methylpyrazolo[1,5-a]pyridin-3-carboxynitrile

[0495]

[0496] Step 1: 5-Bromo-3-methoxy-2-methylpyridine

[0497]

[0498] 5-Bromo-2-methylpyridine-3-phenol (10 g, 53.2 mmol) was dissolved in acetonitrile (50 mL), then potassium carbonate (14.7 g, 106.4 mmol) was added, followed by dropwise addition of iodomethane (22.66 g, 160 mmol). The mixture was stirred at 80 °C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by stepwise separation (petroleum ether / ethyl acetate = 15:1) to give a pale yellow solid 5-bromo-3-methoxy-2-methylpyridine (5 g, yield: 46.7%).

[0499] 1 H NMR (400MHz, CDCl3) δ8.14 (d, J=1.6Hz, 1H), 7.22 (d, J=1.4Hz, 1H), 3.84 (s, 3H), 2.42 (s, 3H).

[0500] MS m / z (ESI): 202.0 [M+H] + .

[0501] Step 2: 2,4,6-Trimethylbenzenesulfonic acid 1-amino-5-bromo-3-methoxy-2-methylpyridine-1-cation

[0502]

[0503] 5-bromo-3-methoxy-2-methylpyridine (5 g, 24.75 mmol) was added in portions to a solution of 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (5.32 g, 24.75 mmol) in dichloromethane (50 mL) at 0 °C. The mixture was stirred at 0 °C for 1.5 h. Methyl tert-butyl ether (30 mL) was added to the reaction mixture, and the mixture was stirred for 15 min. The mixture was then filtered, and the filter cake was dried to give a white solid 2,4,6-trimethylbenzenesulfonic acid 1-amino-5-bromo-3-methoxy-2-methylpyridine-1-cation (9 g, yield: 87.3%).

[0504] Step 3: 4-Bromo-6-methoxy-7-methylpyrazolo[1,5va]pyridine-3-carboxynitrile

[0505]

[0506] 1,8-diazabicyclo[5.4.0]undecane-7-ene (6.6 g, 43.2 mmol) was added in portions to a solution of 1-amino-5-bromo-3-methoxy-2-methylpyridin-1-cation (9 g, 21.6 mmol) of 2,4,6-trimethylbenzenesulfonic acid (2.8 g, 32.37 mmol) in dichloromethane (100 mL) at 0 °C. The mixture was then heated to room temperature and stirred for 24 hours. Methyl tert-butyl ether (50 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The mixture was then filtered, and the filter cake was dried to give a pale yellow solid 4-bromo-6-methoxy-7-methylpyrazolo[1,5-a]pyridin-3-carboxylonitrile (2 g, yield: 35%).

[0507] MS m / z (ESI): 266.0 [M+H] + .

[0508] Step 4: 4-Bromo-6-hydroxy-7-methylpyrazolo[1,5-a]pyridine-3-carboxynitrile

[0509]

[0510] Aluminum trichloride (2 g, 15.1 mmol) was added in portions to a 1,2-dichloroethane solution (2 g, 7.55 mmol) of 4-bromo-6-methoxy-7-methylpyrazolo[1,5-a]pyridine-3-carboxylonitrile (2 g, 7.55 mmol). The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, quenched with sodium sulfate decahydrate, filtered, and the filter cake was washed with dichloromethane. The filtrate was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to give a black solid 4-bromo-6-hydroxy-7-methylpyrazolo[1,5-a]pyridine-3-carboxylonitrile (1.5 g, yield: 79%).

[0511] MS m / z (ESI): 249.7 [MH] + .

[0512] Step 5: 4-Bromo-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridine-3-carboxynitrile

[0513]

[0514] 2,2-Dimethylethylene oxide (857 mg, 11.9 mmol) was added to a solution of 4-bromo-6-hydroxy-7-methylpyrazolo[1,5-a]pyridine-3-carboxylonitrile (1.5 g, 5.95 mmol), potassium carbonate (1.6 g, 11.9 mmol), and acetonitrile (10 mL). The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure and separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily substance 4-bromo-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridine-3-carboxylonitrile (1.4 g, yield: 74%).

[0515] MS m / z (ESI): 324.0 [M+H] + .

[0516] Step 6: 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridin-3-carboxynitrile

[0517]

[0518] Add 1,1-bis(diphenylphosphine)ferrocene to a mixed solution of 4-bromo-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridine-3-carboxylonitrile (1.4 g, 4.32 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (1.15 g, 5.18 mmol), potassium acetate (847 mg, 8.64 mmol), and dioxane (15 mL). The palladium(II) dichloromethane complex (178 mg, 0.22 mmol) was purged with nitrogen three times and stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled and filtered. The filtrate was concentrated to dryness under reduced pressure and separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily substance 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridin-3-carboxylonitrile (1.2 g, yield: 82%).

[0519] MS m / z (ESI): 341.1 [M+H] + .

[0520] Step 7: tert-butyl 3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester

[0521]

[0522] A mixture of 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridin-3-carboxylonitrile (1.2 g, 3.52 mmol), tert-butyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.4 g, 7.04 mmol), N,N-diisopropylethylamine (1.36 g, 10.56 mmol), and dimethyl sulfoxide (10 mL) was stirred at 100 °C for 24 hours. After the reaction was complete, water was added to quench the reaction. Extracted with ethyl acetate (50 mL * 3), the combined organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily tert-butyl 3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester (800 mg, yield: 44%).

[0523] MS m / z (ESI): 519.2 [M+H] + .

[0524] Step 8: 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridin-3-carboxynitrile

[0525]

[0526] tert-Butyl 3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3-1.1]heptane-6-carboxylic acid ester (800 mg, 1.54 mmol)) was dissolved in dichloromethane (9 mL), and then trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and dried. The product was used directly in the next step without purification to obtain a pale yellow oily substance 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridin-3-carboxylonitrile (1 g, crude product).

[0527] MS m / z (ESI): 419.2 [M+H] + .

[0528] Step 9: 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-7-methylpyrazolo[1,5-a]pyridin-3-carboxynitrile

[0529]

[0530] Sodium cyanoborohydride (45 mg, 0.72 mmol) was added to a solution of 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridin-3-carboxynitrile (100 mg, 0.24 mmol), 6-methoxynicotinaldehyde (66 mg, 0.48 mmol), and 1,2-dichloroethane (3 mL). The mixture was then stirred at room temperature for 24 hours. After the reaction was complete, sodium cyanoborohydride was added. The solution was quenched in water, extracted with ethyl acetate (20 mL * 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. After preparative chromatography, a white solid 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-7-methylpyrazolo[1,5-a]pyridin-3-carboxylonitrile (10 mg, yield: 8%) was obtained.

[0531] MS m / z (ESI): 540.2 [M+H] + .

[0532] Example 12

[0533] 3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenyl-3-diazabicyclo[3.1.1]heptane-6-carboxamide

[0534]

[0535]

[0536] Carbonyl diimidazole (58 mg, 0.36 mmol) was added to a solution of 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridin-3-carboxynitrile (100 mg, 0.24 mmol), triethylamine (48 mg, 0.48 mmol), and dichloromethane (3 mL), and the mixture was stirred at room temperature for 1 hour. Then aniline (33 mg, 0.36 mmol) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. After preparative chromatography, a white solid 3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenyl-3-diazabicyclo[3.1.1]heptane-6-carboxamide (15 mg, yield: 12%) was obtained.

[0537] MS m / z (ESI): 538.2 [M+H] + .

[0538] Example 13

[0539] 6-(2-hydroxy-2-methylpropoxy)-7-methyl-4-(6-(4-(pyridin-3-oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0540]

[0541] A mixture of 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridine-3-carboxylonitrile (100 mg, 0.24 mmol), 3-(piperidin-4-yloxy)pyridine (85 mg, 0.48 mmol), potassium carbonate (99 mg, 0.72 mmol), and acetonitrile (3 mL) was stirred at 100 °C for 16 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. After preparative chromatography, a white solid 6-(2-hydroxy-2-methylpropoxy)-7-methyl-4-(6-(4-(pyridin-3-oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (15 mg, yield: 13%) was obtained.

[0542] MS m / z (ESI): 499.2 [M+H] + .

[0543] Example 14

[0544] 4-(6-(6-((6-ethoxy-5-fluoropyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0545]

[0546] Step 1: 5-Bromo-2-fluoro-3-methoxypyridine

[0547]

[0548] 5-Bromo-2-fluoropyridine-3-phenol (5 g, 26.18 mmol) was dissolved in acetonitrile (50 mL), then potassium carbonate (7.2 g, 52.36 mmol) was added, followed by dropwise addition of iodomethane (11.2 g, 78.54 mmol). The mixture was stirred at 80 °C for 16 hours. The reaction solution was cooled to room temperature, concentrated to dryness under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a pale yellow solid 5-bromo-2-fluoro-3-methoxypyridine (4.5 g, yield: 83%).

[0549] 1 H NMR (400MHz, CDCl3) δ7.80 (d, J=1.8Hz, 1H), 7.38 (dd, J=8.8, 1.9Hz, 1H), 3.91 (s, 3H).

[0550] MS m / z (ESI): 206.0 [M+H] + .

[0551] Step 2: 2,4,6-Trimethylbenzenesulfonic acid 1-amino-5-bromo-2-fluoro-3-methoxypyridine-1-cation

[0552]

[0553] 5-bromo-2-fluoro-3-methoxypyridine (5 g, 21.84 mmol) was added in portions to a solution of 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (4.7 g, 21.84 mmol) in dichloromethane (50 mL) at 0 °C. The mixture was stirred at 0 °C for 1.5 h. Methyl tert-butyl ether (100 mL) was added to the reaction mixture, and the mixture was stirred for 15 min. The mixture was then filtered, and the filter cake was dried to give a pale yellow solid 2,4,6-trimethylbenzenesulfonic acid 1-amino-5-bromo-2-fluoro-3-methoxypyridine-1-cation (8 g, yield: 87%).

[0554] Step 3: 4-Bromo-7-fluoro-6-methoxypyrazolo[1,5-a]pyridine-3-carboxynitrile

[0555]

[0556] 1,8-diazabicyclo[5.4.0]undecane-7-ene (5.8 g, 38 mmol) was added in portions to a solution of 1-amino-5-bromo-2-fluoro-3-methoxypyridin-1-cation of 2,4,6-trimethylbenzenesulfonic acid (8 g, 19 mmol) and 2-chloroacrylonitrile (2.5 g, 28.5 mmol) in dichloromethane (80 mL) at 0 °C. The mixture was then heated to room temperature and stirred for 24 hours. Methyl tert-butyl ether (100 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The mixture was then filtered, and the filter cake was dried to give a pale yellow solid 4-bromo-7-fluoro-6-methoxypyrazolo[1,5-a]pyridin-3-carboxylonitrile (3 g, yield: 58%).

[0557] MS m / z (ESI): 270.0 [M+H] + .

[0558] Step 4: 4-Bromo-7-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylonitrile

[0559]

[0560] Aluminum trichloride (3 g, 22.22 mmol) was added in portions to a 1,2-dichloroethane solution (3 g, 11.11 mmol) of 4-bromo-7-fluoro-6-methoxypyrazolo[1,5-a]pyridine-3-carboxynitrile (3 g, 11.11 mmol). The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, quenched with sodium sulfate decahydrate, filtered, and the filter cake was washed with dichloromethane. The filtrate was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to give a white solid 4-bromo-7-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxynitrile (2.2 g, yield: 77%).

[0561] MS m / z (ESI): 255.0 [MH] + .

[0562] Step 5: 4-Bromo-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0563]

[0564] 2,2-Dimethylethylene oxide (1.24 g, 17.2 mmol) was added to a solution of 4-bromo-7-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylonitrile (2.2 g, 8.6 mmol), potassium carbonate (2.37 g, 17.2 mmol), and acetonitrile (25 mL). The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure and separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily substance 4-bromo-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (2 g, yield: 71%).

[0565] MS m / z (ESI): 328.0 [M+H] + .

[0566] Step 6: 7-Fluoro-4-(6-Fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0567]

[0568] Add 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (50 mg, 0.061 mg) to a mixture of 4-bromo-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (2 g, 6.1 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (1.63 g, 7.32 mmol), potassium acetate (1.2 g, 12.2 mmol), and dioxane (30 mL) to a solution of 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (50 mg, 0.061 mg). After purging with nitrogen three times, the mixture was stirred at 100°C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and then separated by column chromatography (dichloromethane / methanol = 10:1) to obtain a colorless oily substance 7-fluoro-4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (1.4 g, yield: 67%).

[0569] MS m / z (ESI): 345.1 [M+H] + .

[0570] Step 7: tert-butyl 3-(5-(3-cyano-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester

[0571]

[0572] A mixture of 7-fluoro-4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (1.4 g, 4.06 mmol), tert-butyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.61 g, 8.12 mmol), N,N-diisopropylethylamine (1.57 g, 12.18 mmol), and dimethyl sulfoxide (15 mL) was stirred at 100 °C for 24 hours. After the reaction was complete, water was added to quench the reaction. Extracted with ethyl acetate (50 mL * 3), the combined organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily tert-butyl 3-(5-(3-cyano-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester (1.05 g, yield: 50%).

[0573] MS m / z (ESI): 523.2 [M+H] + .

[0574] Step 8: 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0575]

[0576] 1.05 g (2.01 mmol) of tert-butyl 3-(5-(3-cyano-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester was dissolved in dichloromethane (9 mL), and then trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and dried. The solution was used directly in the next step without purification to obtain a pale yellow oily substance 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (1.2 g, crude product).

[0577] MS m / z (ESI): 423.2 [M+H] + .

[0578] Step 9: 4-(6-(6-((6-ethoxy-5-fluoropyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0579]

[0580] Sodium cyanoborohydride (54 mg, 0.85 mmol) was added to a solution of 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile (120 mg, 0.28 mmol), 6-ethoxy-5-fluoronicotinaldehyde (73 g, 0.43 mmol), and 1,2-dichloroethane (5 mL). The mixture was then stirred at room temperature for 24 hours. After the reaction was complete, sodium cyanoborohydride was added. The solution was quenched in water, extracted with ethyl acetate (50 mL * 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. After preparative chromatography, a white solid 4-(6-(6-((6-ethoxy-5-fluoropyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (15 mg, yield: 9%) was obtained.

[0581] MS m / z (ESI): 576.2 [M+H] + .

[0582] Example 15

[0583] 7-Fluoro-6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0584]

[0585] The title compound was synthesized using 7-fluoro-4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile as the starting material, following the synthetic method described in Example 13.

[0586] MS m / z (ESI): 503.2 [M+H] + .

[0587] Example 16

[0588] 7-Fluoro-6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methylpyridazin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0589]

[0590] Step 1: tert-butyl-4-((6-methylpyridazin-3-yl)oxo)piperidine-1-carboxylic acid ester

[0591]

[0592] 2 g (9.95 mmol) of tert-butyl-4-hydroxypiperidine-1-carboxylic acid ester was added to 20 mL of anhydrous N,N-dimethylformamide at 0 °C. Then, sodium hydrogen hydrate (796 mg, 19.9 mmol) was added at 0 °C and the mixture was stirred at room temperature for 30 minutes. 3-chloro-6-methylpyridazine (1.9 g, 14.93 mmol) was then added. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was separated by column chromatography to give a white solid tert-butyl-4-((6-methylpyridazine-3-yl)oxo)piperidine-1-carboxylic acid ester (1.2 g, yield: 41%).

[0593] MS m / z (ESI): 294.1 [M+H] + .

[0594] Step 2: 3-Methyl-6-(piperidin-4-oxy)pyridazine

[0595]

[0596] Trifluoroacetic acid (3 mL) was added dropwise to a solution of tert-butyl-4-((6-methylpyridin-3-yl)oxo)piperidine-1-carboxylic acid ester (1.2 g, 4.1 mmol) in dichloromethane (9 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated to dryness under reduced pressure to obtain a pale yellow solid, 3-methyl-6-(piperidine-4-oxy)pyridazine (1.5 g, crude product).

[0597] MS m / z (ESI): 194.1 [M+H] + .

[0598] Step 3: 7-Fluoro-6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methylpyridazin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0599]

[0600] The title compound was obtained from 4-(6-methylpyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridine-3-carboxylonitrile and 3-methyl-6-(piperidin-4-oxy)pyridazine using the method of Example 13.

[0601] MS m / z (ESI): 518.2 [M+H] + .

[0602] Example 17

[0603] 3-(5-(3-cyano-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[0604]

[0605] The title compound was obtained using 7-fluoro-4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as the starting material, with reference to Example 13.

[0606] MS m / z (ESI): 533.2 [M+H] + .

[0607] Example 18

[0608] 3-(5-(3-cyano-7-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenyl-3,6-azabicyclo[3.1.1]heptane-6-carboxamide

[0609]

[0610] The title compound was obtained by referring to Example 12, using 7-fluoro-4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as the starting material.

[0611] MS m / z (ESI): 542.2 [M+H] + .

[0612] Example 19

[0613] 7-Chloro-6-((R)-2-hydroxypropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0614]

[0615] Referring to Example 14, 5-bromo-2-chloropyridine-3-phenol in the first step was replaced with 5-bromo-2-fluoropyridine-3-phenol, and (R)-2-methyloxapropane in the fifth step was replaced with 2,2-dimethylethylene oxide, to obtain the title compound.

[0616] MS m / z (ESI): 546.2 [M+H] + .

[0617] Example 20

[0618] 5-Chloro-6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0619]

[0620] Step 1: 2,4,6-Trimethylbenzenesulfonic acid 1-amino-3-bromo-4-chloro-5-methoxypyridine-1-cation

[0621]

[0622] 3-bromo-4-chloro-5-methoxypyridine (5 g, 22.52 mmol) was added in portions to a solution of 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (4.8 g, 22.52 mmol) in dichloromethane (100 mL) at 0 °C. The mixture was stirred at 0 °C for 1.5 hours. Methyl tert-butyl ether (30 mL) was added to the reaction mixture, and the mixture was stirred for 15 minutes. The mixture was then filtered, and the filter cake was dried to obtain a pale yellow solid, 2,4,6-trimethylbenzenesulfonic acid 1-amino-3-bromo-4-chloro-5-methoxypyridine-1-cation (9 g, crude product).

[0623] Step 2: 4-Bromo-5-chloro-6-methoxypyrazolo[1,5-a]pyridine-3-carboxynitrile

[0624]

[0625] 1,8-diazabicyclo[5.4.0]undecane-7-ene (6.3 g, 41.2 mmol) was added in portions to a solution of 1-amino-3-bromo-4-chloro-5-methoxypyridin-1-cation of 2,4,6-trimethylbenzenesulfonic acid (9 g, 20.6 mmol) and 2-chloroacrylonitrile (2.7 g, 30.9 mmol) in dichloromethane (100 mL) at 0 °C. The mixture was then heated to room temperature and stirred for 24 hours. Methyl tert-butyl ether (50 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The mixture was then filtered, and the filter cake was dried to give a pale yellow solid 4-bromo-5-chloro-6-methoxypyrazolo[1,5-a]pyridin-3-carboxylonitrile (3 g, yield: 51%).

[0626] MS m / z (ESI): 286.0 [M+H] + .

[0627] Step 3: 4-Bromo-5-chloro-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylon

[0628]

[0629] Aluminum trichloride (7 g, 52.63 mmol) was added in portions to a 1,2-dichloroethane solution (3 g, 10.53 mmol) of 4-bromo-5-chloro-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylonitrile (3 g, 10.53 mmol), and the mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the mixture was quenched with sodium sulfate decahydrate, filtered, and the filter cake was washed with dichloromethane. The filtrate was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to give a white solid 4-bromo-5-chloro-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylonitrile (2.1 g, yield: 74%).

[0630] MS m / z (ESI): 269.9 [MH] + .

[0631] Step 4: 4-Bromo-5-chloro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0632]

[0633] 2,2-Dimethylethylene oxide (1.1 g, 15.5 mmol) was added to a solution of 4-bromo-5-chloro-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylonitrile (2.1 g, 7.75 mmol), potassium carbonate (2.14 g, 15.5 mmol), and acetonitrile (25 mL). The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure and separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily substance 4-bromo-5-chloro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (1.4 g, yield: 53%).

[0634] MS m / z (ESI): 344.0 [M+H] + .

[0635] Step 5: 5-Chloro-4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0636]

[0637] Add 1,1-bis(diphenylphosphine)ferrocene to a mixed solution of 4-bromo-5-chloro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (1.4 g, 4.08 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (1.1 g, 4.9 mmol), potassium acetate (800 mg, 8.16 mmol), and dioxane (20 mL). The palladium(II) dichloromethane complex (330 mg, 0.4 mmol) was purged with nitrogen three times and stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled and filtered. The filtrate was concentrated to dryness under reduced pressure and separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily substance 5-chloro-4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (1 g, yield: 68%).

[0638] MS m / z (ESI): 361.1 [M+H] + .

[0639] Step 6: 5-Chloro-6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-one]pyridin-3-carboxynitrile

[0640]

[0641] The synthesis of Example 22 is based on Example 13.

[0642] MS m / z (ESI): 519.2 [M+H] + .

[0643] Example 21

[0644] 5-Fluoro-6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0645]

[0646] Replacing 3-bromo-4-fluoro-5-methoxypyridine with 3-bromo-4-chloro-5-methoxypyridine, the reaction was carried out according to steps one through five of Example 20, followed by steps seven through nine of Example 14 to obtain the title compound.

[0647] MS m / z (ESI): 544.2 [M+H] + .

[0648] Example 22

[0649] 5-Fluoro-6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-one]pyridin-3-carboxynitrile

[0650]

[0651] The title compound was obtained by replacing 3-bromo-4-fluoro-5-methoxypyridine with 3-bromo-4-chloro-5-methoxypyridine, as described in Example 20.

[0652] MS m / z (ESI): 503.2 [M+H] + .

[0653] Example 23

[0654] 6-(3-(2-hydroxypropane-2-yl)acridin-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0655]

[0656] Step 1: 6-Bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate

[0657]

[0658] Using 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carboxylonitrile as a raw material, the product 6-bromo-3-cyanopyrazolo[1,5-a]pyridine-4-yl trifluoromethanesulfonate was obtained in the first step of Reference Example 7.

[0659] MS m / z (ESI): 370.0 [M+H] + 372.0[M+H+2] + .

[0660] Step 2: 6-bromo-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0661]

[0662] Using 6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate as a raw material, refer to Example 7, step 3 to obtain the product 6-bromo-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile.

[0663] MS m / z (ESI): 516.1 [M+H] + 518.1[M+H+2] + .

[0664] Step 3: 6-(3-(2-hydroxypropane-2-yl)acridin-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0665]

[0666] A mixture of 6-bromo-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile (80 mg, 0.15 mmol), 2-(acetidin-3-yl)propane-2-ol (36 mg, 0.30 mmol), tris(dibenzylideneacetone)palladium (7 mg, 0.0075 mmol), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (4 mg, 0.0075 mmol), cesium carbonate (146 mg, 0.45 mmol), and toluene (4 mL) was purged with nitrogen and stirred in a microwave at 130 °C for 2 hours. After the reaction was completed and cooled to room temperature, the reaction solution was concentrated, dissolved in ethyl acetate (20 mL), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and then purified by chromatographic separation (18 mg, white solid, yield: 21%).

[0667] MS m / z (ESI): 551.2 [M+H] + .

[0668] 1 H NMR (400MHz, MeOD) δ8.32 (d, J=2.1Hz, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.85-7.79 (m, 2H), 7.71 (dd, J=8.5, 2.3Hz, 1H), 6.92 (d, J=1.7Hz, 1H), 6.86 (d, J=8.8Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 3.97 (t, J=7.8Hz, 2H), 3.92-3.84 (m, 7H), 3.78 (d, J=5.6Hz, 2H), 3.65 (s, 1H), 3. 62 (s, 3H), 2.95-2.81 (m, 1H), 2.70 (d, J = 7.0Hz, 1H), 1.70 (d, J = 8.8Hz, 1H), 1.21 (s, 6H).

[0669] Example 24

[0670] 6-(3-(2-hydroxypropane-2-yl)acridin-1-yl)-4-(6-(4-((6-methoxypyridazin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0671]

[0672] Step 1: 6-Bromo-4-(6-Fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile

[0673]

[0674] Using 6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate as a raw material, the product 6-bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile was obtained by referring to the third step of Example 7.

[0675] MS m / z (ESI): 317.0 [M+H] + 319.0[M+H+2] + .

[0676] Step 2: 6-Bromo-4-(6-(4-((6-methoxypyridazin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0677]

[0678] Using 6-bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a raw material, the product 6-bromo-4-(6-(4-((6-methoxypyridazin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile was obtained in the second step of Example 8.

[0679] MS m / z (ESI): 506.1 [M+H] + 508.1[M+H+2] + .

[0680] Step 3: 6-(3-(2-hydroxypropane-2-yl)acetin-1-yl)-4-(6-(4-((6-methoxypyridazin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0681]

[0682] Using 6-bromo-4-(6-(4-((6-methoxypyridazin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile as a raw material, the product 6-(3-(2-hydroxypropane-2-yl)acetidin-1-yl)-4-(6-(4-((6-methoxypyridazin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile was obtained in the second step of Example 7.

[0683] MS m / z (ESI): 541.2 [M+H] + .

[0684] Example 25

[0685] (6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-yl)dimethylphosphine oxide

[0686]

[0687] Step 1: 4-Bromo-3-iodopyrazolo[1,5-a]pyridine-6-phenol

[0688]

[0689] 4-Bromopyrazolo[1,5-a]pyridine-6-phenol (500 mg, 2.3 mmol) was dissolved in 20 mL of THF, and N-iodosuccinimide (792 mg, 3.5 mmol) was added. The reaction was carried out at room temperature for 6 h. 10 mL of ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the crude product was separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to give 4-bromo-3-iodopyrazolo[1,5-a]pyridine-6-phenol (404 mg, white solid, 52% yield).

[0690] MS m / z (ESI): 338.8 [M+H] + .

[0691] Step 2: 1-((4-bromo-3-iodopyrazolo[1,5-a]pyridin-6-yl)oxo)-2-methylpropane-2-ol

[0692]

[0693] 4-Bromo-3-iodopyrazolo[1,5-a]pyridin-6-phenol (300 mg, 0.89 mmol) was dissolved in 20 mL of DMF, and 2,2-dimethyloxapropane (641 mg, 8.9 mmol) and K₂CO₃ (368 mg, 2.7 mmol) were added. The mixture was reacted overnight at 85 °C. 10 mL of ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the crude product was separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to give 1-((4-bromo-3-iodopyrazolo[1,5-a]pyridin-6-yl)oxo)-2-methylpropane-2-ol (262 mg, white solid, 72% yield).

[0694] MS m / z (ESI): 410.9 [M+H] + .

[0695] Step 3: Oxidation of (4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-yl)dimethylphosphine

[0696]

[0697] 1-((4-bromo-3-iodopyrazolo[1,5-a]pyridin-6-yl)oxo)-2-methylpropane-2-ol (300 mg, 0.89 mmol) was dissolved in 20 mL of dioxane, and dimethylphosphine oxide (104 mg, 1.3 mmol), Pd2(dba)3 (82 mg, 0.09 mmol), Xantphos (103 mg, 0.18 mmol), and TEA (270 mg, 2.7 mmol) were added. The mixture was reacted overnight at 85 °C. 10 mL of ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filter, evaporate to dryness, and separate the crude product by column chromatography (washing with dichloromethane / methanol = 10 / 1) to give (4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-yl)dimethylphosphine oxidation (180 mg, white solid, yield 56%).

[0698] MS m / z (ESI): 361.0 [M+H] + .

[0699] Step 4: Oxidation of (6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridin-3-yl)dimethylphosphine

[0700]

[0701] Using (4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-yl)dimethylphosphine oxidation as a starting material, (6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridin-3-yl)dimethylphosphine oxidation (120 mg, white solid, 65%) was obtained by referring to step 7 of Example 1.

[0702] MS m / z (ESI): 409.2 [M+H] + .

[0703] Step 5: Oxidation of (6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-yl)dimethylphosphine

[0704]

[0705] Using (6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridin-3-yl)dimethylphosphine oxidation and 3-(5-bromopyridin-2-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane as a starting material, (6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-yl)dimethylphosphine oxidation (35 mg, white solid, 53%) was obtained by referring to step 8 of Example 1.

[0706] MS m / z (ESI): 577.2 [M+H] + .

[0707] Example 26

[0708] 4-(6-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-yl)dimethylphosphine oxide

[0709]

[0710] Using (6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyrazolo[1,5-a]pyridin-3-yl)dimethylphosphine oxidation and 3-(5-bromopyridin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane as a starting material, 4-(6-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-yl)dimethylphosphine oxidation (28 mg, white solid, 49%) was obtained by referring to step 8 of Example 1.

[0711] MS m / z (ESI): 595.2 [M+H] + .

[0712] Example 27

[0713] 3-(5-(3-(dimethylphospho)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[0714]

[0715] Using (6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridin-3-yl)dimethylphosphine oxidation and 3-(5-bromopyridin-2-yl)-N-phenyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide as a starting material, 3-(5-(3-(dimethylphospho)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (38 mg, white solid, 56%) was obtained by referring to step 8 of Example 1.

[0716] MS m / z (ESI): 575.2 [M+H] + .

[0717] Example 28

[0718] 4-(6-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide

[0719]

[0720] Step 1: 2,4,6-Trimethylbenzenesulfonic acid 1-amino-5-bromo-3-methoxy-2-methylpyridine-1-cation

[0721]

[0722] 3-bromo-5-methoxypyridine (10 g, 57.8 mmol) was added in portions to a solution of 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (12.4 g, 57.8 mmol) in dichloromethane (100 mL) at 0 °C. The mixture was stirred at 0 °C for 1.5 h. Methyl tert-butyl ether (150 mL) was added to the reaction mixture and stirred for 15 min. The mixture was then filtered, and the filter cake was dried to give a crude white solid of 2,4,6-trimethylbenzenesulfonic acid 1-amino-5-bromo-3-methoxy-2-methylpyridine-1-cation (15 g, yield: 62%).

[0723] Step 2: Ethyl 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid ester

[0724]

[0725] Ethyl propargyl ester (7.05 g, 71.94 mmol) was added dropwise to a solution of 1-amino-5-bromo-3-methoxy-2-methylpyridin-1-cation of 2,4,6-trimethylbenzenesulfonic acid (15 g, 35.97 mmol), triethylamine (10.9 g, 107.91 mmol), and anhydrous N,N-dimethylformamide (100 mL). The mixture was stirred at room temperature for 16 hours. The reaction solution was then added to ice water and slurried for 15 minutes. The mixture was then filtered, the filter cake was dried, and then separated by column chromatography to obtain a pale yellow solid, ethyl 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (1 g, yield: 9%).

[0726] MS m / z (ESI): 299.0 [M+H] + .

[0727] Step 3: 4-Bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid

[0728]

[0729] Lithium hydroxide monohydrate (281 mg, 6.68 mmol) was added to a solution of ethyl 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid ester (1 g, 3.34 mmol) in methanol (10 mL) and water (10 mL). The mixture was stirred at room temperature for 16 hours. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH to 2, and a white solid precipitated. The solid was filtered, the filter cake was washed with water, and the filter cake was dried to obtain a white solid 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (800 mg, crude product).

[0730] MS m / z (ESI): 271.0 [M+H] + .

[0731] Step 4: 4-Bromo-6-methoxy-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide

[0732]

[0733] A mixture of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (800 mg, 2.96 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (1.35 g, 3.55 mmol), triethylamine (897 mg, 8.88 mmol), N,N-dimethylamine hydrochloride (485 mg, 5.92 mmol), and dichloromethane (15 mL) was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily substance 4-bromo-6-methoxy-N,N-dimethylpyrazolo[1,5va]pyridine-3-carboxamide (700 mg, yield: 80%).

[0734] MS m / z (ESI): 298.0 [M+H] + .

[0735] Step 5: 4-Bromo-6-hydroxy-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide

[0736]

[0737] Aluminum trichloride (1.57 g, 11.8 mmol) was added in portions to a 10 mL solution of 4-bromo-6-methoxy-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide (700 mg, 2.36 mmol) in 1,2-dichloroethane. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, quenched with sodium sulfate decahydrate, filtered, the filter cake was washed with dichloromethane, the filtrate was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a brown solid 4-bromo-6-hydroxy-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide (620 mg, crude product).

[0738] MS m / z (ESI): 282.0 [MH] + .

[0739] Step 6: 4-Bromo-6-(2-hydroxy-2-methylpropoxy)-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide

[0740]

[0741] 2,2-Dimethylethylene oxide (317 mg, 4.4 mmol) was added to a solution of 4-bromo-6-methoxy-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide (620 mg, 2.2 mmol), potassium carbonate (605 mg, 4.4 mmol), and acetonitrile (10 mL). The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure and separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily substance 4-bromo-6-(2-hydroxy-2-methylpropoxy)-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide (520 mg, yield: 67%).

[0742] MS m / z (ESI): 356.2 [M+H] + .

[0743] Step 7: 4-(6-Fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide

[0744]

[0745] Add 1,1-bis(diphenylphosphine)ferrocene to a mixture of 4-bromo-6-(2-hydroxy-2-methylpropoxy)-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide (520 mg, 1.46 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (391 mg, 1.75 mmol), potassium acetate (286 mg, 2.92 mmol), and dioxane (10 mL). The palladium(II) dichloromethane complex (60 mg, 0.07 mmol) was purged with nitrogen three times and stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was cooled and filtered. The filtrate was concentrated to dryness under reduced pressure and separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily substance 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide (405 mg, yield: 75%).

[0746] MS m / z (ESI): 373.2 [M+H] + .

[0747] Step 8: tert-butyl 3-(5-(3-(dimethylcarbamoyl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester

[0748]

[0749] A mixed solution of 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide (405 mg, 1.09 mmol), tert-butyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester (432 mg, 2.18 mmol), N,N-diisopropylethylamine (422 mg, 3.27 mmol), and dimethyl sulfoxide (8 mL) was stirred at 100 °C for 24 hours. After the reaction was completed, water was added to quench the reaction. Extracted with ethyl acetate (50 mL * 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily tert-butyl 3-(5-(3-(dimethylcarbamoyl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester (280 mg, yield: 47%).

[0750] MS m / z (ESI): 551.2 [M+H] + .

[0751] Step 9: 4-(6-Fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide

[0752]

[0753] 280 mg (0.51 mmol) of tert-butyl-3-(5-(3-(dimethylcarbamoyl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester was dissolved in dichloromethane (9 mL), and then trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was concentrated to dryness under reduced pressure and used directly in the next step without purification to obtain a pale yellow oily substance, 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-N,N-dimethylpyrazolo[1,5-a]pyridin-3-carboxamide (300 mg, crude product).

[0754] MS m / z (ESI): 451.2 [M+H] + .

[0755] Step 10: 4-(6-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-N,N-dimethylpyrazolo[1,5-a]pyridin-3-carboxamide

[0756]

[0757] Referring to step nine of Example 14, the title compound was obtained using 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide as a reactant.

[0758] MS m / z (ESI): 590.3 [M+H] + .

[0759] Example 29

[0760] 6-(2-methoxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide

[0761]

[0762] Step 1: 8-Bromo-6-(2-methoxyethoxy)-N,N-dimethylindene-1-carboxamide

[0763]

[0764] To a mixture of 4-bromo-6-hydroxy-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide (1.2 g, 4-24 mmol), 2-methoxyethane-1-ol (322 mg, 5.09 mmol), triphenylphosphine (1.67 g, 6.36 mmol), and tetrahydrofuran (15 mL) at 0°C, diisopropyl azodicarbonate (1.28 g, 6.36 mmol) was added dropwise. The mixture was then stirred at room temperature for 16 hours under nitrogen protection. After the reaction was complete, the mixture was cooled and concentrated under reduced pressure to dryness. The solution was separated by column chromatography to obtain a colorless oily substance, 8-bromo-6-(2-methoxyethoxy)-N,N-dimethylindene-1-carboxamide (1.3 g, yield: 90%).

[0765] MS m / z (ESI): 341.0 [M+H] +

[0766] The reactions in steps two through five, as described in steps seven through ten of Example 28, yield 6-(2-methoxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide.

[0767] MS m / z (ESI): 558.3 ​​[M+H] + .

[0768] Example 30

[0769] N-Cyclopropyl-6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0770]

[0771] Referring to the synthesis in Example 28, the N,N-dimethylamine hydrochloride was replaced with cyclopropylamine hydrochloride in step four to obtain the title compound.

[0772] MS m / z (ESI): 584.3 [M+H] + .

[0773] Example 31

[0774] 6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0775]

[0776] Step 1: 6-Bromo-4-(4,4,5,5-Tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0777]

[0778] Using 6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate as a raw material, 6-bromo-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (620 mg, white solid, 56%) was obtained by referring to step 7 of Example 1.

[0779] MS m / z (ESI): 348.0 [M+H] + .

[0780] Step 2: 6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0781]

[0782] 6-Bromo-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylon (300 mg, 0.86 mmol) was dissolved in 20 mL of triethylamine, and 2-methylbut-3-yn-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 reaction was carried out overnight at 65 °C under nitrogen protection. 10 mL of ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filter, evaporate to dryness, and separate the crude product by column chromatography (washing with dichloromethane / methanol = 10 / 1) to give 6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (197 mg, white solid, yield 65%).

[0783] MS m / z (ESI): 352.1 [M+H] + .

[0784] Step 3: 6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0785]

[0786] Using 6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile and 3-(5-bromopyridin-2-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane as raw materials, 6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (25 mg, white solid, 43%) was obtained by referring to step 8 of Example 1.

[0787] MS m / z (ESI): 520.2 [M+H] + .

[0788] 1 H NMR (400MHz, MeOD) δ8.83 (s, 1H), 8.47 (s, 1H), 8.35 (d, J=2.1Hz, 1H), 8.09 (s, 1H) , 7.84 (dd, J=8.8, 2.3Hz, 1H), 7.72 (dd, J=8.4, 2.1Hz, 1H), 7.41 (s, 1H), 6.88 (d, J= 8.9Hz, 1H), 6.78 (d, J=8.5Hz, 1H), 3.91 (s, 1H), 3.88 (s, 4H), 3.79 (d, J=5.7Hz, 2H) , 3.66 (s, 1H), 3.63 (s, 3H), 2.74-2.62 (m, 1H), 1.70 (d, J=8.9Hz, 1H), 1.59 (s, 6H).

[0789] Example 32

[0790] 6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-(6-(4-((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0791]

[0792]

[0793] Using 6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile and 5-bromo-2-(4-((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)pyridine as raw materials, 6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-(6-(4-((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)pyridine[1,5-a]pyridine-3-carboxylonitrile (33 mg, white solid, 49%) was obtained by referring to step 8 of Example 1.

[0794] MS m / z (ESI): 509.2 [M+H] + .

[0795] 1 H NMR (400MHz, MeOD) δ8.82 (s, 1H), 8.45 (s, 1H), 8.29 (d, J=2.2Hz, 1H), 7.84 (d, J=2. 9Hz, 1H), 7.76 (dd, J=8.8, 2.4Hz, 1H), 7.43 (dd, J=8.9, 3.0Hz, 1H), 7.39 (s, 1H), 6. 99 (d, J=9.0Hz, 1H), 6.76 (d, J=8.9Hz, 1H), 4.67-4.47 (m, 2H), 4.10-3.98 (m, 2H), 3 .86(s, 3H), 3.60-3.49(m, 2H), 2.11-2.04(m, 2H), 1.84-1.76(m, 2H), 1.58(s, 6H).

[0796] Example 33

[0797] N-(1-(5-(3-cyano-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

[0798]

[0799] Using 6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile and N-(1-(5-bromopyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide as raw materials, refer to step 8 of Example 1 to obtain N-(1-(5-(3-cyano-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide (30 mg, white solid, 45%).

[0800] MS m / z (ESI): 551.2 [M+H] + .

[0801] 1 H NMR (400MHz, Methanol-d4) δ8.82 (d, J=1.3Hz, 1H), 8.46 (s, 1H), 8.29 (d, J=2. 5Hz, 1H), 7.76 (dd, J=9.0, 2.5Hz, 1H), 7.41-7.36 (m, 1H), 7.28-7.21 (m, 1H), 7 .09-7.02(m, 2H), 6.98(d, J=8.9Hz, 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).

[0802] Example 34

[0803] 6-(2-cyano-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0804]

[0805] Step 1: 4-Bromo-6-(2-cyano-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0806]

[0807] 4-Bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylonitrile (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 azodicarboxylate (202 mg, 1 mmol) were added. The reaction solution was stirred at 0 °C for 12 hours under nitrogen protection. The reaction solution was concentrated, dissolved in ethyl acetate (10 mL), and washed three times with water (5 mL * 3). The organic phase was concentrated and purified by column chromatography (dichloromethane / methanol: 30 / 1) to obtain the product 4-bromo-6-(2-cyano-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (180 mg, yellow solid, yield 67.1%).

[0808] MS m / z (ESI): 319.0 [M+H] + .321.0[M+H+2] + .

[0809] Step 2: 6-(2-cyano-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0810]

[0811] Using 4-bromo-6-(2-cyano-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a raw material, the product 6-(2-cyano-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile was obtained in step 3 of Example 7.

[0812] MS m / z (ESI): 535.2 [M+H] + .

[0813] 1H NMR (400MHz, Chloroform-d) δ8.43 (d, J=2.5Hz, 1H), 8.23 ​​(s, 1H), 8.16 (d, J=2.1Hz, 1H), 8.13 (d, J=2.4Hz, 1H), 7.81-7.75 (m, 2H), 7.19 (d, J=2.1Hz, 1H ), 6.75 (d, J=8.5Hz, 1H), 6.70 (d, J=8.8Hz, 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).

[0814] Example 35

[0815] 6-(2-cyano-2-methylpropoxy)-4-(6-(4-((6-methylpyridazin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0816]

[0817] Step 1: 6-(2-cyano-2-methylpropoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0818]

[0819] Using 4-bromo-6-(2-cyano-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a raw material, the product 6-(2-cyano-2-methylpropoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile was obtained in step 3 of Example 7.

[0820] MS m / z (ESI): 336.1 [M+H] + .

[0821] Step 2: 6-(2-cyano-2-methylpropoxy)-4-(6-(4-((6-methylpyridazin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0822]

[0823] Using 6-(2-cyano-2-methylpropoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a raw material, the product 6-(2-cyano-2-methylpropoxy)-4-(6-(4-((6-methylpyridazin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile was obtained in the second step of Example 8.

[0824] MS m / z (ESI): 509.2 [M+H] + .

[0825] Example 36

[0826] 6-((1-cyanocyclopropyl)methoxy)-4-(6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0827]

[0828] Step 1: 4-Bromo-6-((1-cyanocyclopropyl)methoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[0829]

[0830] Using 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, the product 4-bromo-6-((1-cyanocyclopropyl)methoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile was obtained in the first step of Reference Example 34. MS m / z (ESI): 317.0 [M+H] + 319.0[M+H+2] + .

[0831] Step 2: 6-((1-cyanocyclopropyl)methoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0832]

[0833] Using 4-bromo-6-((1-cyanocyclopropyl)methoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a raw material, the product 6-((1-cyanocyclopropyl)methoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile was obtained in step 3 of Example 7.

[0834] MS m / z (ESI): 334.1 [M+H] + .

[0835] Step 3: 6-((1-cyanocyclopropyl)methoxy)-4-(6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0836]

[0837] Using 6-((1-cyanocyclopropyl)methoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a raw material, the product 6-((1-cyanocyclopropyl)methoxy)-4-(6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile was obtained in the second step of Example 8.

[0838] MS m / z (ESI): 492.2 [M+H] + .

[0839] Example 37

[0840] 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(6-((1-methylacetidin-3-yl)methoxy)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane

[0841]

[0842] Step 1: Preparation of N-(3,5-dibromopyridin-2-yl)-N′-hydroxyformamidin

[0843]

[0844] 3,5-Dibromopyridin-2-amine (10 g, 39.7 mmol) was dissolved in isopropanol (100 mL), and DMFDMA (6.15 g, 51.6 mmol) was added. The reaction mixture was stirred at 100 °C for 2 hours. The reaction was then cooled to 50 °C, and hydroxylamine hydrochloride (3.59 g, 51.6 mmol) was added, followed by stirring overnight. The reaction mixture was directly evaporated to dryness. The crude product was purified by column chromatography to give the target molecule N-(3,5-dibromopyridin-2-yl)-N′-hydroxyformamidinium (11 g, yield: 94%).

[0845] MS m / z (ESI): 293.8 [M+H] + .

[0846] Step 2: Preparation of 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyridine

[0847]

[0848] N-(3,5-dibromopyridin-2-yl)-N′-hydroxyformamidinium (11 g, 37.3 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and TFAA (8.62 g, 41.0 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the reaction mixture was slowly brought to room temperature and stirred for 3 hours. NaHCO3 aqueous solution was slowly added to the reaction mixture to quench the reaction, followed by extraction with methyl tert-butyl ether. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyridine (8.2 g, yield: 79%).

[0849] MS m / z (ESI): 275.8 [M+H] + .

[0850] Step 3: Preparation of 3-(5-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)pyridin-2-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane

[0851]

[0852] 6,8-Dibromo-[1,2,4]triazolo[1,5-a]pyridine (4 g, 14.4 mmol) was dissolved in DMF (50 mL), and 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (7.3 g, 17.3 mmol) and saturated sodium carbonate aqueous solution (15 mL) were added. Under nitrogen protection, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (1.05 g, 1.44 mmol) was added. The reaction was stirred at 90 °C for 3 hours. Water (50 mL) was added, followed by extraction with ethyl acetate (100 mL). The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to obtain the target molecule 3-(5-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)pyridin-2-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (3.5 g, yield: 49%).

[0853] MS m / z (ESI): 492.1 [M+H] + .

[0854] Step 4: Preparation of 8-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-phenol

[0855]

[0856] 3-(5-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)pyridin-2-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (3.5 g, 7.1 mmol) was dissolved in dioxane (40 mL), and KOH (0.6 g, 10.7 mmol) and water (20 mL) were added. Under nitrogen protection, tris(dibenzylacetone)dipalladium (0.65 g, 0.71 mmol) and tBu-Xphos (0.6 g, 1.42 mmol) were added. The reaction mixture was stirred overnight at 90 °C. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to obtain 8-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-phenol (2 g, yield: 65%).

[0857] MS m / z (ESI): 430.2 [M+H] + .

[0858] Step 5: Preparation of 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(6-((1-methylacetidin-3-yl)methoxy)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane

[0859]

[0860] 8-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-phenol (300 mg, 0.699 mmol) was dissolved in DMAc (10 mL), and 3-(bromomethyl)-1-methylacetidine (172 mg, 1.05 mmol) and cesium carbonate (569 mg, 1.75 mmol) were added. The reaction mixture was stirred overnight at 100 °C. Water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL). The organic phase was dried and then evaporated to dryness. The crude product was purified by prep-HPLC to obtain 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(6-((1-methylacetidin-3-yl)methoxy)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (50 mg. Yield: 14%).

[0861] MS m / z (ESI): 513.2 [M+H] + .

[0862] Example 38

[0863] 3-(((8-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxo)methyl)cyclobutane-1-ol

[0864]

[0865] Using 8-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-phenol and 3-(bromomethyl)cyclobutane-1-ol as raw materials, 3-(((8-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxo)methyl)cyclobutane-1-ol (40 mg, yield: 11%) was obtained in step 5 of Example 37.

[0866] MS m / z (ESI): 514.2 [M+H] + .

[0867] Example 39

[0868] (R)-1-((8-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxo)propane-2-ol

[0869]

[0870] Step 1: Preparation of 6-bromo-8-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine

[0871]

[0872] Using 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyridine and 1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)piperazine as raw materials, 6-bromo-8-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazine-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine (1 g, yield: 70%) was obtained in step 3 of Example 37.

[0873] MS m / z (ESI): 480.2 [M+H] + .

[0874] Step 2: Preparation of 8-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-phenol

[0875]

[0876] Using 6-bromo-8-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine as a starting material, 8-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-phenol (400 mg, yield: 57%) was obtained in step four of Example 37.

[0877] MS m / z (ESI): 418.2 [M+H] + .

[0878] Step 3: Preparation of (R)-1-((8-(6-(4-(((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxo)propane-2-ol

[0879]

[0880] 8-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-phenol (300 mg, 0.719 mmol) was dissolved in DMF (5 mL), and (R)-2-methyloxapropylcyclohexane (835 mg, 14.4 mmol) and potassium carbonate (497 mg, 3.59 mmol) were added. The reaction mixture was stirred at 50 °C for 3 days. Water (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL). The organic phase was dried and then evaporated to dryness. The crude product was purified by prep-HPLC to (R)-1-((8-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxo)propane-2-ol (100 mg, yield: 29%).

[0881] MS m / z (ESI): 476.2 [M+H] + .

[0882] Example 40

[0883] 7-(2-hydroxy-2-methylpropoxy)-5-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-carboxynitrile

[0884]

[0885] Step 1: Preparation of ethyl 5-bromo-7-methoxyimidazo[1,2-a]pyridine-3-carboxylate

[0886]

[0887] 6-Bromo-4-methoxypyridine-2-amine (10 g, 49.2 mmol) was dissolved in ethanol (100 mL), and ethyl 2-chloro-3-carbonylpropionate (7.42 g, 49.2 mmol) was added. The reaction mixture was refluxed overnight. The reaction solution was evaporated to dryness and then purified by direct column chromatography to give the target molecule, ethyl 5-bromo-7-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid (3.0 g, yield: 20%).

[0888] MS m / z (ESI): 299.2 [M+H] + .

[0889] Step 2: Preparation of 5-bromo-7-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid

[0890]

[0891] Ethyl 5-bromo-7-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid (3.0 g, 10.0 mmol) was dissolved in THF (20 mL), and 2N LiOH (10 mL) was added. The reaction mixture was stirred overnight at room temperature. Ethyl acetate (20 mL) was added for extraction. After collecting the aqueous phase, 1N HCl was added to adjust the pH to 3-4, and ethyl acetate (50 mL) was added to extract. The organic phase was collected, dried, and then evaporated to dryness to obtain 5-bromo-7-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid (2.5 g, yield: 92%).

[0892] MS m / z (ESI): 270.8 [M+H] + .

[0893] Step 3: Preparation of 5-bromo-7-methoxyimidazo[1,2-a]pyridine-3-carboxamide

[0894]

[0895] 5-Bromo-7-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid (2.5 g, 9.2 mmol) was dissolved in DMF (30 mL), and NH4Cl (0.99 g, 18.5 mmol), HATU (5.3 g, 13.8 mmol), and DIEA (3.6 g, 27.7 mmol) were added. The reaction mixture was stirred overnight at room temperature. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The organic phase was washed with saturated sodium chloride, dried, and then evaporated to dryness. The crude product was purified by column chromatography to give 5-bromo-7-methoxyimidazo[1,2-a]pyridine-3-carboxamide (2 g, yield: 80%).

[0896] MS m / z (ESI): 269.8 [M+H] + .

[0897] Step 4: Preparation of 5-bromo-7-methoxyimidazo[1,2-a]pyridine-3-carboxylonitrile

[0898]

[0899] 5-Bromo-7-methoxyimidazo[1,2-a]pyridine-3-carboxamide (2 g, 7.4 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and pyridine (1.46 g, 18.5 mmol) was added. TFAA (3.9 g, 18.5 mmol) was added slowly dropwise. After the addition was complete, the reaction was stirred at room temperature for 3 hours. Water (50 mL) was added, followed by extraction with ethyl acetate (100 mL). The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 5-bromo-7-methoxyimidazo[1,2-a]pyridine-3-carboxynitrile (1.5 g, yield: 80%).

[0900] MS m / z (ESI): 251.8 [M+H] + .

[0901] Step 5: Preparation of 5-bromo-7-hydroxyimidazo[1,2-a]pyridine-3-carboxylonitrile

[0902]

[0903] 5-Bromo-7-methoxyimidazo[1,2-a]pyridine-3-carboxylonitrile (1.5 g, 6.0 mmol) was dissolved in DCE (20 mL). AlCl3 (2.4 g, 17.9 mmol) was slowly added to the reaction solution. After the addition was complete, the reaction was refluxed overnight under nitrogen protection. Tetrahydrofuran (100 mL) was added to the reaction solution, followed by excess sodium sulfate decahydrate (20 g), and the mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was evaporated to dryness. The crude product was subjected to column chromatography to give 5-bromo-7-hydroxyimidazo[1,2-a]pyridine-3-carboxylonitrile (1.2 g, yield: 85%).

[0904] MS m / z (ESI): 237.8 [M+H] + .

[0905] Step 6: Preparation of 5-bromo-7-(2-hydroxy-2-methylpropoxy)imidazo[1,2-a]pyridine-3-carboxylonitrile

[0906]

[0907] 5-Bromo-7-hydroxyimidazo[1,2-a]pyridine-3-carboxylonitrile (1.2 g, 5.0 mmol) was dissolved in DMF (20 mL), and 2,2-dimethyloxapropane (3.6 g, 50.4 mmol) and potassium carbonate (2.1 g, 15.1 mmol) were added. The reaction mixture was stirred overnight at 85 °C. Water (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried, and evaporated to dryness. The crude product was purified by column chromatography to give 5-bromo-7-(2-hydroxy-2-methylpropoxy)imidazo[1,2-a]pyridine-3-carboxylonitrile (1.3 g, yield: 83%).

[0908] MS m / z (ESI): 310.2 [M+H] + .

[0909] Step 7: Preparation of 7-(2-hydroxy-2-methylpropoxy)-5-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylonitrile

[0910]

[0911] Using 5-bromo-7-(2-hydroxy-2-methylpropoxy)imidazo[1,2-a]pyridine-3-carboxylonitrile and 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane as raw materials, 7-(2-hydroxy-2-methylpropoxy)-5-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylonitrile (100 g, yield: 55%) was obtained in step 3 of Example 37.

[0912] MS m / z (ESI): 526.2 [M+H] + .

[0913] Example 41

[0914] 7-(2-hydroxy-2-methylpropoxy)-5-(6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-carboxynitrile

[0915]

[0916] Using 5-bromo-7-(2-hydroxy-2-methylpropoxy)imidazo[1,2-a]pyridine-3-carboxylonitrile and 2-(4-(pyridine-3-oxy)piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine as starting materials, 7-(2-hydroxy-2-methylpropoxy)-5-(6-(4-(pyridine-2-oxy)piperidin-1-yl)pyridine-3-yl)imidazo[1,2-a]pyridine-3-carboxylonitrile (85 mg, yield: 65%) was obtained in step 3 of Example 37.

[0917] MS m / z (ESI): 485.2 [M+H] + .

[0918] Example 42

[0919] N-(1-(5-(3-cyano-7-(2-hydroxy-2-methylpropoxy)imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2,6-difluorobenzamide

[0920]

[0921] Step 1: Preparation of benzyl 4-((tert-butylthionyl(sulfinyl)amino)-4-methylpiperidine-1-carboxylic acid ester

[0922]

[0923] Benzyl 4-((tert-butylthionylsulfinyl)imino)piperidine-1-carboxylic acid ester (5 g, 14.9 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to 0 °C. Methyl magnesium bromide (17.9 mL, 17.9 mmol) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction was slowly heated to room temperature and stirred for 3 hours. An aqueous solution of ammonium chloride (10 mL) was slowly added dropwise to quench the reaction, followed by extraction with ethyl acetate (100 mL). The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give benzyl 4-((tert-butylthionyl)imino)-4-methylpiperidine-1-carboxylic acid ester (4.2 g, yield: 80%).

[0924] MS m / z (ESI): 353.2 [M+H] + .

[0925] Step 2: Preparation of benzyl 4-amino-4-methylpiperidine-1-carboxylic acid ester

[0926]

[0927] 4.2 g (11.9 mmol) of benzyl 4-((tert-butylthionyl(sulfinyl)amino)-4-methylpiperidine-1-carboxylic acid ester was dissolved in 50 mL of 25% trifluoroacetic acid / dichloromethane solution. The reaction mixture was stirred at room temperature for 2 hours. After the reaction mixture was evaporated to dryness, 100 mL of dichloromethane was added. NaHCO3 aqueous solution was slowly added to adjust the pH to 7–8. After drying the organic phase, the mixture was evaporated to dryness to give 2.8 g (yield: 95%) of benzyl 4-amino-4-methylpiperidine-1-carboxylic acid ester.

[0928] MS m / z (ESI): 249.2 [M+H] + .

[0929] Step 3: Preparation of benzyl 4-(2,6-difluorobenzoylamino)-4-methylpiperidine-1-carboxylic acid ester

[0930]

[0931] Using benzyl 4-amino-4-methylpiperidine-1-carboxylic acid ester and 2,6-difluorobenzoic acid as raw materials, benzyl 4-(2,6-difluorobenzoamide)-4-methylpiperidine-1-carboxylic acid ester (1.5 g, yield: 84%) was obtained in step 3 of Reference Example 40.

[0932] MS m / z (ESI): 389.2 [M+H] + .

[0933] Step 4: Preparation of 2,6-difluoro-N-(4-methylpiperidin-4-yl)benzamide

[0934]

[0935] Methyl 4-(2,6-difluorobenzoamide)-4-methylpiperidin-1-carboxylic acid ester (1.5 g, 3.9 mmol) was dissolved in methanol (50 mL), and palladium / carbon (200 mg) was added. The reaction was stirred under hydrogen atmosphere for 6 hours. The reaction solution was filtered. The filtrate was evaporated to dryness to give 2,6-difluoro-N-(4-methylpiperidin-4-yl)benzamide (900 mg, yield: 92%).

[0936] MS m / z (ESI): 255.2 [M+H] + .

[0937] Step 5: Preparation of 5-(6-fluoropyridin-3-yl)-7-(2-hydroxy-2-methylpropoxy)imidazo[1,2-a]pyridine-3-carboxylonitrile

[0938]

[0939] Using 5-bromo-7-(2-hydroxy-2-methylpropoxy)imidazo[1,2-a]pyridine-3-carboxylonitrile and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine as raw materials, 5-(6-fluoropyridin-3-yl)-7-(2-hydroxy-2-methylpropoxy)imidazo[1,2-a]pyridine-3-carboxylonitrile (200 mg, yield: 72%) was obtained in step 3 of Example 37.

[0940] MS m / z (ESI): 327.2 [M+H] + .

[0941] Step 6: Preparation of N-(1-(5-(3-cyano-7-(2-hydroxy-2-methylpropoxy)imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2,6-difluorobenzamide

[0942]

[0943] 5-(6-fluoropyridin-3-yl)-7-(2-hydroxy-2-methylpropoxy)imidazo[1,2-a]pyridine-3-carboxynitrile (100 mg, 0.306 mmol) was dissolved in DMSO (10 mL), and 2,6-difluoro-N-(4-methylpiperidin-4-yl)benzamide (78 mg, 0.306 mmol) and DIEA (119 mg, 0.92 mmol) were added. The reaction mixture was stirred at 90 °C for 2 days. Water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried, and then evaporated to dryness. The crude product was purified by prep-HPLC to obtain N-(1-(5-(3-cyano-7-(2-hydroxy-2-methylpropoxy)imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2,6-difluorobenzamide (70 mg, yield: 41%).

[0944] MS m / z (ESI): 561.2 [M+H] + .

[0945] Example 43

[0946] (R)-5-(6-(4-(3-hydroxy-3-phenylpropionyl)piperazin-1-yl)pyridin-3-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-carboxynitrile

[0947]

[0948] Step 1: Preparation of tert-butyl 4-(5-(3-cyano-7-hydroxyimidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate

[0949]

[0950] Using 5-bromo-7-hydroxyimidazo[1,2-a]pyridine-3-carboxylonitrile and tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyridin-2-yl)piperazine-1-carboxylate as raw materials, refer to Example 37, step 3 to obtain tert-butyl4-(5-(3-cyano-7-hydroxyimidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (1 g, yield: 72%).

[0951] MS m / z (ESI): 421.2 [M+H] + .

[0952] Step 2: Preparation of tert-butyl 4-(5-(3-cyano-7-(((trifluoromethyl)sulfonyl)oxo)imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylic acid ester

[0953]

[0954] 1 g (2.4 mmol) of tert-butyl 4-(5-(3-cyano-7-hydroxyimidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylic acid ester was dissolved in anhydrous dichloromethane (20 mL) and cooled to 0 °C. DIEA (0.46 g, 3.6 mmol) was added to the reaction mixture. Trifluoromethanesulfonic anhydride (0.74 g, 2.6 mmol) was slowly added. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 3 hours. Water (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (20 mL). The organic phase was dried and then evaporated to dryness to obtain 1.2 g (yield: 91%) of tert-butyl 4-(5-(3-cyano-7-(((trifluoromethyl)sulfonyl)oxo)imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylic acid ester.

[0955] MS m / z (ESI): 553.2 [M+H] + .

[0956] Step 3: Preparation of tert-butyl 4-(5-(3-cyano-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylic acid ester

[0957]

[0958] Using tert-butyl 4-(5-(3-cyano-7-((((trifluoromethyl)sulfonyl)oxo)imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-pyrazole as raw materials, tert-butyl 4-(5-(3-cyano-7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (0.8 g, yield: 76%) was obtained in step 3 of Example 37.

[0959] MS m / z (ESI): 485.2 [M+H] + .

[0960] Step 4: Preparation of 7-(1-methyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylonitrile

[0961]

[0962] 0.8 g (1.7 mmol) of tert-butyl-4-(5-(3-cyano-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylic acid ester was dissolved in 25% trifluoroacetic acid / dichloromethane solution (20 mL). The reaction solution was stirred at room temperature for 2 hours. After the reaction solution was evaporated to dryness, dichloromethane (30 mL) was added. NaHCO3 aqueous solution was slowly added to adjust the pH to 7-8. After drying the organic phase, it was evaporated to dryness to give 7-(1-methyl-1H-pyrazol-4-yl)-5-(6-(piperazine-1-yl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-carboxylonitrile (0.6 g, yield: 95%).

[0963] MS m / z (ESI): 385.2 [M+H] + .

[0964] Step 5: Preparation of (R)-5-(6-(4-(3-hydroxy-3-phenylpropionyl)piperazin-1-yl)pyridin-3-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxylonitrile

[0965]

[0966] Using 7-(1-methyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-carboxylonitrile and (R)-3-hydroxy-3-phenylpropionic acid as starting materials, (R)-5-(6-(4-(3-hydroxy-3-phenylpropionyl)piperazin-1-yl)pyridin-3-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-carboxylonitrile (70 mg, yield: 62%) was obtained in step 3 of Example 40. MS m / z (ESI): 533.2 [M+H] + .

[0967] Example 44

[0968] (R)-5-(6-(4-(2-hydroxy-3-phenylpropionyl)piperazin-1-yl)pyridin-3-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-carboxynitrile

[0969]

[0970] Using 7-(1-methyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-carboxylonitrile and (R)-2-hydroxy-3-phenylpropionic acid as raw materials, (R)-5-(6-(4-(2-hydroxy-3-phenylpropionyl)piperazin-1-yl)pyridin-3-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-carboxylonitrile (65 mg, yield: 66%) was obtained in step 3 of Example 40.

[0971] MS m / z (ESI): 533.2 [M+H] + .

[0972] Example 45

[0973] 4-(5-(3-cyano-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)-N-isobutylpiperazine-1-carboxamide

[0974]

[0975] 7-(1-methyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxynitrile (0.1 g, 0.26 mmol) was dissolved in dichloromethane (5 mL), and DIEA (168 mg, 1.3 mmol) and CDI (84 mg, 0.52 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, and then 2-methylpropane-1-amine (38 mg, 0.52 mmol) was added. The reaction mixture was stirred for 2 days. Water (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (20 mL). The organic phase was dried and then evaporated to dryness. The crude product was purified by prep-HPLC to obtain 4-(5-(3-cyano-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)-N-isobutylpiperazine-1-carboxamide (30 mg, yield: 24%).

[0976] MS m / z (ESI): 484.2 [M+H] + .

[0977] Example 46

[0978] 6-((R)-2-hydroxypropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-1-methyl-1H-indazole-3-carboxynitrile

[0979]

[0980] Step 1: 2-Bromo-6-fluoro-4-methoxybenzaldehyde

[0981]

[0982] Diisopropylaminolithium (73.17 mmol, 36.6 mL, 2M tetrahydrofuran) was added dropwise to a tetrahydrofuran (100 mL) solution of 1-bromo-3-fluoro-5-methoxybenzene (10 g, 48.78 mmol) at -78 °C. The mixture was stirred at -78 °C for 1 hour, followed by the addition of anhydrous N,N-dimethylformamide (7.12 g, 97.56 mmol). The mixture was stirred at -78 °C for 2 hours, quenched with saturated ammonium chloride solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to give crude 2-bromo-6-fluoro-4-methoxybenzaldehyde (6.2 g, yield: 55%).

[0983] MS m / z (ESI): 232.9 [M+H] + .

[0984] Step 2: 4-Bromo-6-methoxy-1H-indazole

[0985]

[0986] A mixed solution of 2-bromo-6-fluoro-4-methoxybenzaldehyde (6.2 g, 26.84 mmol), hydrazine hydrate (2.7 g, 53.68 mmol, 98%), and dimethyl sulfoxide (50 mL) was stirred at 130 °C for 2 hours. After cooling to room temperature, water was added and the mixture was stirred until a solid precipitated. The solid was filtered, the filter cake was washed with water, and then dried to give a pale yellow solid, 4-bromo-6-methoxy-1H-indazole (5.3 g, yield: 87%).

[0987] MS m / z (ESI): 227.0 [M+H] + .

[0988] Step 3: 4-Bromo-6-methoxy-1-methyl-1H-indazole

[0989]

[0990] Sodium hydroxide (1.8 g, 46.9 mmol) was added to a tetrahydrofuran (50 mL) solution of 4-bromo-6-methoxy-1H-indazole (5.3 g, 23.45 mmol) at 0 °C. The mixture was stirred for 30 minutes, and iodomethane (5 g, 35.17 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours, quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily substance, 4-bromo-6-methoxy-1-methyl-1H-indazole (2.8 g, yield: 50%).

[0991] MS m / z (ESI): 241.0 [M+H] + .

[0992] Step 4: 4-Bromo-3-iodo-6-methoxy-1-methyl-1H-indazole

[0993]

[0994] Iodine (4.4 g, 17.5 mmol) was added to a mixed solution of 4-bromo-6-methoxy-1-methyl-1H-indazole (2.8 g, 11.67 mmol), potassium hydroxide (1.3 g, 23.34 mmol), and N,N-dimethylformamide (30 mL). The mixture was stirred at room temperature for 3 hours. After the reaction was complete, saturated sodium bisulfite solution was added, and a solid precipitated. The solid was filtered, the filter cake was washed with water, and the filter cake was dried to give a pale yellow solid 4-bromo-3-iodo-6-methoxy-1-methyl-1H-indazole (3.1 g, yield: 73%).

[0995] MS m / z (ESI): 366.8 [M+H] + .

[0996] Step 5: 4-Bromo-6-methoxy-1-methyl-1H-indazole-3-carboxynitrile

[0997]

[0998] To a mixture of 4-bromo-3-iodo-6-methoxy-1-methyl-1H-indazole (3.1 g, 8.47 mmol), zinc cyanide (2 g, 16.94 mmol), and anhydrous N,N-dimethylformamide (50 mL), tris(dibenzylacetone)dipalladium (388 mg, 0.42 mmol) was added. The mixture was then purged three times with nitrogen and stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was extracted with water and dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The crude product was directly used in the next step to obtain a black solid, 4-bromo-6-methoxy-1-methyl-1H-indazole-3-carboxynitrile (3.5 g, crude product).

[0999] MS m / z (ESI): 266.0 [M+H] + .

[1000] Step 6: 4-Bromo-6-hydroxy-1-methyl-1H-indazole-3-carboxynitrile

[1001]

[1002] Aluminum trichloride (8.8 g, 66.05 mmol) was added in portions to a 1,2-dichloroethane solution (40 mL) of 4-bromo-6-methoxy-1-methyl-1H-indazole-3-carboxynitrile (3.5 g, 13.21 mmol). The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, quenched with sodium sulfate decahydrate, filtered, and the filter cake was washed with dichloromethane. The filtrate was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a brown solid, 4-bromo-6-hydroxy-1-methyl-1H-indazole-3-carboxynitrile (3.2 g, crude product).

[1003] MS m / z (ESI): 250.9 [MH]-.

[1004] Step 7: 4-Bromo-6-(2-hydroxypropoxy)-1-methyl-1H-indazole-3-carboxynitrile

[1005]

[1006] 2-methylethylene oxide (835 mg, 14.16 mmol) was added to a solution of 4-bromo-6-hydroxy-1-methyl-1H-indazole-3-carboxynitrile (1.5 g, 7.08 mmol), potassium carbonate (2.93 g, 21.23 mmol), and acetonitrile (15 mL). The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure and separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily substance 4-bromo-6-(2-hydroxypropoxy)-1-methyl-1H-indazole-3-carboxynitrile (900 mg, yield: 41%).

[1007] MS m / z (ESI): 310.0 [M+H] + .

[1008] Step 8: (R)-4-(6-fluoropyridin-3-yl)-6-(2-hydroxypropoxy)-1-methyl-1H-indazole-3-carboxynitrile

[1009]

[1010] To 4-bromo-6-(2-hydroxypropoxy)-1-methyl-1H-indazole-3-carboxynitrile (900 mg, 2.91 mg / L) A mixture of 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (120 mg, 0.15 mmol) was added to a mixed solution of 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (778 mg, 3.49 mmol), potassium acetate (570 mg, 5.82 mmol), and dioxane (10 mL). After three nitrogen purgings, the mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled and filtered. The filtrate was concentrated to dryness under reduced pressure and separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oil (R)-4-(6-fluoropyridin-3-yl)-6-(2-hydroxypropoxy)-1-methyl-1H-indazole-3-carboxylonitrile (650 mg, yield: 69%).

[1011] MS m / z (ESI): 327.1 [M+H] + .

[1012] Step 9: 3-(5-(3-cyano-6-((R)-2-hydroxypropoxy)-1-methyl-1H-indazol-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3]3.1.1]heptan-6-carboxylic acid ethyl ester

[1013]

[1014] A mixed solution of (R)-4-(6-fluoropyridin-3-yl)-6-(2-hydroxypropoxy)-1-methyl-1H-indazole-3-carboxylonitrile (650 mg, 1.99 mmol), tert-butyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester (788 mg, 3.98 mmol), N,N-diisopropylethylamine (770 mg, 5.97 mmol), and dimethyl sulfoxide (8 mL) was stirred at 100 °C for 24 hours. After the reaction was completed, water was added to quench the reaction. Extracted with ethyl ester (50 mL * 3), the combined organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and separated by column chromatography (dichloromethane / methanol = 10:1) to obtain colorless oily 3-(5-(3-cyano-6-((R)-2-hydroxypropoxy)-1-methyl-1H-indazol-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3]3.1.1]heptane-6-carboxylic acid ethyl ester (410 mg, yield: 41%).

[1015] MS m / z (ESI): 505.2 [M+H] + .

[1016] Step 10: 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-((R)-2-hydroxypropoxy)-1-methyl-1H-indazole-3-nitrile

[1017]

[1018] Ethyl 3-(5-(3-cyano-6-((R)-2-hydroxypropoxy)-1-methyl-1H-indazol-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3]3.1.1]heptane-6-carboxylate (410 mg, 0.81 mmol) was dissolved in dichloromethane (6 mL), and then trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and used directly in the next step without purification to obtain a pale yellow oily substance 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-((R)-2-hydroxypropoxy)-1-methyl-1H-indazol-3-onitrile (520 mg, crude product).

[1019] MS m / z (ESI): 405.2 [M+H] + .

[1020] Step 11: 6-((R)-2-hydroxypropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridinpyridin-3-yl)-1-methyl-1H-indazole-3-carboxylonitrile

[1021]

[1022] Sodium cyanoborohydride (47 mg, 0.75 mmol) was added to a solution of 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-((R)-2-hydroxypropoxy)-1-methyl-1H-indazole-3-onitrile (100 mg, 0.25 mmol), 6-methoxynicotinaldehyde (51 mg, 0.37 mmol), and 1,2-dichloroethane (3 mL). The mixture was then stirred at room temperature for 24 hours. After the reaction was complete, water was added. Quenching, extraction with ethyl acetate (20 mL * 3), combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. After preparative chromatography, a white solid 6-((R)-2-hydroxypropoxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1-1]heptane-3-yl)pyridinpyridin-3-yl)-1-methyl-1H-indazole-3-carboxylonitrile (12 mg, yield: 9%) was obtained.

[1023] MS m / z (ESI): 526.2 [M+H] + .

[1024] Example 47

[1025] 4-(6-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-hydroxyethoxy)-1-methyl-1H-indazole-3-carboxynitrile

[1026]

[1027] Referring to steps 1 through 8 of Example 46, wherein the 2-methylethylene oxide in step 7 is replaced with ethylene oxide, the title compound is obtained.

[1028] MS m / z (ESI): 530.2 [M+H] + .

[1029] Example 48

[1030] 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-1-methyl-1H-indazole-3-carboxynitrile

[1031]

[1032] Referring to Example 46, the 2-methylethylene oxide in step 7 was replaced with 2,2-dimethylethylene oxide, and then, referring to Example 13, the title compound was obtained.

[1033] MS m / z (ESI): 529.2 [M+H] + .

[1034] Example 49

[1035] 6-(2-hydroxy-2-methylpropoxy)-4-(2-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)thiazolyl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1036]

[1037] Step 1: tert-butyl-3-(5-bromothiazolyl-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester

[1038]

[1039] 300 mg (1.5 mmol) of tert-butyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester was dissolved in 20 mL of LDM, and 2,5-dibromothiazole (547 mg, 2.2 mmol), K₂CO₃ (621 mg, 4.5 mmol), and KI (25 mg, 0.15 mmol) were added. The mixture was reacted overnight at 90 °C under nitrogen protection. 10 mL of ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the crude product was separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to give 230 mg (white solid, 42% yield) of tert-butyl-3-(5-bromothiazole-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester.

[1040] MS m / z (ESI): 360.0 [M+H] + .

[1041] Step 2: 2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-5-bromothiazole

[1042]

[1043] Using tert-butyl 3-(5-bromothiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester as a raw material, 2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-5-bromothiazol (210 mg, white solid, 99%) was obtained by referring to step 5 of Example 1.

[1044] MS m / z (ESI): 259.9 [M+H] + .

[1045] Step 3: 5-Bromo-2-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)thiazole

[1046]

[1047] Using 2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-bromothiazole as a starting material, 5-bromo-2-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)thiazole (100 mg, white solid, 52%) was obtained by referring to step 6 of Example 1.

[1048] MS m / z (ESI): 381.0 [M+H] + .

[1049] Step 4: 6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1050]

[1051] Using 4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, 6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (130 mg, white solid, 61%) was obtained by referring to step 7 of Example 1.

[1052] MS m / z (ESI): 358.1 [M+H] + .

[1053] Step 5: 6-(2-hydroxy-2-methylpropoxy)-4-(2-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)thiazolyl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1054]

[1055] Using 6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile and 5-bromo-2-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)thiazole as raw materials, 6-(2-hydroxy-2-methylpropoxy)-4-(2-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)thiazole-5-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (33 mg, white solid, 47%) was obtained by referring to step 8 of Example 1.

[1056] MS m / z (ESI): 532.2 [M+H] + .

[1057] Example 50

[1058] 4-(2-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)thiazolyl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1059]

[1060] Step 1: 5-Bromo-2-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)thiazole

[1061]

[1062] Using 2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-bromothiazole and 5-fluoro-6-methoxynicotinaldehyde as raw materials, 5-bromo-2-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)thiazole (220 mg, white solid, 62%) was obtained by referring to step 6 of Example 1.

[1063] MS m / z (ESI): 399.0 [M+H] + .

[1064] Step 2: 4-(2-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)thiazolyl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1065]

[1066] Using 6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile and 5-bromo-2-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)thiazole as raw materials, 4-(2-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)thiazole was obtained by referring to step 8 of Example 1.

[1067] MS m / z (ESI): 550.2 [M+H] + .

[1068] Example 51

[1069] 3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)thiazolyl)-N-phenyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[1070]

[1071] Step 1: 3-(5-bromothiazol-2-yl)-N-phenyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[1072]

[1073] 2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-5-bromothiazole (300 mg, 1.2 mmol) was dissolved in 20 mL of LCM, and CDI (280 mg, 1.7 mmol) and TEA (245 mg, 2.4 mmol) were added. The mixture was reacted at room temperature for 2 h. Aniline (223 mg, 2.4 mmol) was added, and the mixture was reacted at room temperature overnight. 10 mL of ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the crude product was separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to give 3-(5-bromothiazole-2-yl)-N-phenyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (223 mg, white solid, 49% yield).

[1074] MS m / z (ESI): 379.0 [M+H] + .

[1075] Step 2: 3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)thiazolyl)-N-phenyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[1076]

[1077] Using 6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile and 3-(5-bromothiazol-2-yl)-N-phenyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide as raw materials, 3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)thiazol-2-yl)-N-phenyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (29 mg, white solid, 39%) was obtained by referring to step 8 of Example 1.

[1078] MS m / z (ESI): 530.1 [M+H] + .

[1079] Example 52

[1080] 6-(2-hydroxyethoxy)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1,3,4-thiadiazol-2-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1081]

[1082] Step 1: tert-butyl-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester

[1083]

[1084] Using 2,5-dibromo-1,3,4-thiadiazole as a raw material, the first step of Example 49 yielded tert-butyl 3-(5-bromo-1,3,4-thiadiazole-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester (530 mg, white solid, 67%).

[1085] MS m / z (ESI): 361.0 [M+H] + .

[1086] Step 2: 2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-5-bromo-1,3,4-thiadiazole

[1087]

[1088] Using tert-butyl 3-(5-bromo-1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester as a raw material, 2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-5-bromo-1,3,4-thiadiazole (350 mg, white solid, 99%) was obtained by referring to step 5 of Example 1.

[1089] MS m / z (ESI): 260.9 [M+H] + .

[1090] Step 3: 2-Bromo-5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1,3,4-thiadiazole

[1091]

[1092] Using 2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-bromo-1,3,4-thiadiazole as a starting material, 2-bromo-5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazole (120 mg, white solid, 56%) was obtained by referring to step 6 of Example 1.

[1093] MS m / z (ESI): 382.0 [M+H] + .

[1094] Step 4: 6-(2-hydroxyethoxy)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1,3,4-thiadiazol-2-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1095]

[1096] Using 6-(2-hydroxyethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile and 2-bromo-5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazole as raw materials, 6-(2-hydroxyethoxy)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazole-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (25 mg, white solid, 38%) was obtained by referring to step 8 of Example 1.

[1097] MS m / z (ESI): 505.1 [M+H] + .

[1098] Example 53

[1099] 4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1,3,4-thiadiazol-2-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1100]

[1101] Step 1: 2-Bromo-5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1,3,4-thiadiazole

[1102]

[1103] Using 2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-bromo-1,3,4-thiadiazole as a starting material, 2-bromo-5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazole (150 mg, white solid, 59%) was obtained by referring to step 6 of Example 1.

[1104] MS m / z (ESI): 400.0 [M+H] + .

[1105] Step 2: 4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1,3,4-thiadiazol-2-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1106]

[1107] Using 6-(2-hydroxyethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile and 2-bromo-5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazole as raw materials, 4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazole-2-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (32 mg, white solid, 41%) was obtained by referring to step 8 of Example 1.

[1108] MS m / z (ESI): 523.1 [M+H] + .

[1109] Example 54

[1110] 6-(2-hydroxy-2-methylpropoxy)-4-(3-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1111]

[1112] Step 1: Preparation of tert-butyl 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester

[1113]

[1114] 3-Bromo-1-(4-methoxybenzyl)-1H-pyrazole (5 g, 18.7 mmol) was dissolved in DMF (30 mL), and tert-butyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester (4.45 g, 22.5 mmol) and sodium tert-butoxide (2.7 g, 28.1 mmol) were added separately under nitrogen protection. The reaction mixture was stirred overnight at 90 °C. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to obtain tert-butyl 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester (5 g, yield: 69%).

[1115] MS m / z (ESI): 385.2 [M+H] + .

[1116] Step 2: Preparation of 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane

[1117]

[1118] Using tert-butyl 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester as a raw material, 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane was obtained in step four of Example 43.

[1119] MS m / z (ESI): 285.2 [M+H] + .

[1120] Step 3: 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane

[1121]

[1122] 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane (2 g, 7.0 mmol) was dissolved in DCE (30 mL), and 6-methoxynicotinaldehyde (1.9 g, 14.1 mmol) and sodium triacetoxyborohydride (4.5 g, 21.0 mmol) were added. The reaction mixture was stirred overnight at room temperature. Water (60 mL) was added to the reaction mixture, followed by extraction with dichloromethane (50 mL). The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (2.1 g, yield: 75%).

[1123] MS m / z (ESI): 406.2 [M+H] + .

[1124] Step 4: 6-((6-methoxypyridin-3-yl)methyl)-3-(1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane

[1125]

[1126] Using 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane as a starting material, 6-((6-methoxypyridin-3-yl)methyl)-3-(1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane (yield: 80%) was obtained in step four of Example 42.

[1127] MS m / z (ESI): 286.2 [M+H] + .

[1128] Step 5: Preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(3-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1129]

[1130] Using 6-((6-methoxypyridin-3-yl)methyl)-3-(1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane and 4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as raw materials, 6-(2-hydroxy-2-methylpropoxy)-4-(3-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile was obtained in step four of Example 42.

[1131] MS m / z (ESI): 515.2 [M+H] + .

[1132] Example 55

[1133] 4-(3-(6-((6-ethoxy-5-fluoropyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1H-pyrazol-1-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1134]

[1135] Step 1: Preparation of tert-butyl 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester

[1136]

[1137] 3-Bromo-1-(4-methoxybenzyl)-1H-pyrazole (5 g, 18.7 mmol) was dissolved in DMF (30 mL), and tert-butyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester (4.45 g, 22.5 mmol) and sodium tert-butoxide (2.7 g, 28.1 mmol) were added separately under nitrogen protection. The reaction mixture was stirred overnight at 90 °C. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to obtain tert-butyl 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester (5 g, yield: 69%).

[1138] MS m / z (ESI): 385.2 [M+H] + .

[1139] Step 2: Preparation of 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane

[1140]

[1141] Using tert-butyl 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester as the starting material, 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane (3.5 g, yield: 95%) was obtained in step four of Example 43.

[1142] MS m / z (ESI): 285.2 [M+H] + .

[1143] Step 3: Preparation of 6-((6-ethoxy-5-fluoropyridin-3-yl)methyl)-3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane

[1144]

[1145] 3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane (2 g, 7.0 mmol) was dissolved in DCE (30 mL), and 6-ethoxy-5-fluoronicotinaldehyde (2.4 g, 14.1 mmol) and sodium triacetoxyborohydride (4.5 g, 21.0 mmol) were added. The reaction mixture was stirred overnight at room temperature. Water (60 mL) was added to the reaction mixture, followed by extraction with dichloromethane (50 mL). The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 6-((6-ethoxy-5-fluoropyridin-3-yl)methyl)-3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane (2.5 g, yield: 81%).

[1146] MS m / z (ESI): 438.2 [M+H] + .

[1147] Step 4: Preparation of 6-((6-ethoxy-5-fluoropyridin-3-yl)methyl)-3-(1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane

[1148]

[1149] Using 6-((6-ethoxy-5-fluoropyridin-3-yl)methyl)-3-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane as a starting material, 6-((6-ethoxy-5-fluoropyridin-3-yl)methyl)-3-(1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane (500 mg, yield: 86%) was obtained in step four of Example 42.

[1150] MS m / z (ESI): 318.2 [M+H] + .

[1151] Step 5: Preparation of 4-(3-(6-((6-ethoxy-5-fluoropyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1H-pyrazol-1-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile

[1152]

[1153] Using 6-((6-ethoxy-5-fluoropyridin-3-yl)methyl)-3-(1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane and 4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as raw materials, 4-(3-(6-((6-ethoxy-5-fluoropyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1H-pyrazol-1-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (80 mg, yield: 32%) was obtained in step four of Example 42.

[1154] MS m / z (ESI): 547.2 [M+H] + .

[1155] Example 56

[1156] 6-(2-hydroxy-2-methylpropoxy)-4-(3-(4-((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1157]

[1158] Step 1: Preparation of 2-methoxy-5-(piperidin-4-oxy)pyridine

[1159]

[1160] Using tert-butyl 4-((6-methoxypyridin-3-yl)oxo)piperidine-1-carboxylic acid ester as a starting material, 2-methoxy-5-(piperidine-4-oxy)pyridine (2 g, yield: 90%) was obtained in step 4 of Example 43.

[1161] MS m / z (ESI): 209.2 [M+H] + .

[1162] Step 2: Preparation of tert-butyl 3-(4-((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)-1H-pyrazole-1-carboxylic acid ester

[1163]

[1164] Using 2-methoxy-5-(piperidin-4-oxy)pyridine and tert-butyl-3-bromo-1H-pyrazole-1-carboxylic acid ester as raw materials, in the first step of Reference Example 55, tert-butyl-3-(4-((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)-1H-pyrazole-1-carboxylic acid ester (yield: 68%) was obtained.

[1165] MS m / z (ESI): 375.2 [M+H] + .

[1166] Step 3: Preparation of 5-((1-(1H-pyrazol-3-yl)piperidin-4-yl)oxo)-2-methoxypyridine

[1167]

[1168] Using tert-butyl 3-(4-(((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)-1H-pyrazole-1-carboxylic acid ester as a starting material, 5-((1-(1H-pyrazole-3-yl)piperidin-4-yl)oxo)-2-methoxypyridine (yield: 88%) was obtained in step four of Example 43.

[1169] MS m / z (ESI): 275.2 [M+H] + .

[1170] Step 4: Preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(3-(4-((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1171]

[1172] Using 5-((1-(1H-pyrazol-3-yl)piperidin-4-yl)oxo)-2-methoxypyridine and 4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as raw materials, 6-(2-hydroxy-2-methylpropoxy)-4-(3-(4-((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (75 mg, yield: 30%) was obtained in step four of Example 42.

[1173] MS m / z (ESI): 504.2 [M+H] + .

[1174] Example 57

[1175] 4-(4-chloro-6-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1176]

[1177] Step 1: tert-butyl-3-(5-bromo-4-chloropyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester

[1178]

[1179] Using 5-bromo-4-chloro-2-fluoropyridine as a raw material, the product tert-butyl-3-(5-bromo-4-chloropyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester was obtained in the second step of Example 8.

[1180] MS m / z (ESI): 388.0 [M+H] + 390.0[M+H+2] + .

[1181] Step 2: 3-(5-bromo-4-chloropyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane

[1182]

[1183] 300 mg (0.78 mmol) of tert-butyl-3-(5-bromo-4-chloropyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was slowly added dropwise. The reaction mixture was then stirred at room temperature for 3 hours. The reaction mixture was concentrated, dissolved in ethyl acetate (10 mL), and saturated sodium carbonate solution (5 mL) was added to the reaction solution. The mixture was washed with saturated sodium chloride solution (5 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 230 mg (3-(5-bromo-4-chloropyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane).

[1184] MS m / z (ESI): 288.0 [M+H] + 290.0[M+2+H] + .

[1185] Step 3: 3-(5-bromo-4-chloropyridin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane

[1186]

[1187] 3-(5-bromo-4-chloropyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (230 mg, 0.78 mmol) and 5-fluoro-6-methoxynicotinaldehyde (120 mg, 0.78 mmol) were dissolved in dichloroethane (5 mL), and sodium borohydride acetate (248 mg, 1.17 mmol) was added with stirring. The reaction mixture was then stirred at room temperature for 12 hours. Add saturated sodium carbonate solution (5 mL) to the reaction solution, extract with ethyl acetate (10 mL), wash with saturated sodium chloride solution (5 mL x 2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure and separate by column chromatography (dichloromethane / methanol: 30 / 1) to obtain 3-(5-bromo-4-chloropyridin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (200 mg, white solid, 58.1%).

[1188] MS m / z (ESI): 427.0 [M+H] + 429.0 [M+2+H] + .

[1189] Step 4: 3-(4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane

[1190]

[1191] In a 25 mL three-necked flask, 3-(5-bromo-4-chloropyridin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (200 mg, 0.47 mmol), bis-pinacol borate (142 mg, 0.56 mmol), 1,1′-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (19 mg, 0.023 mmol), potassium acetate (91 mg, 0.93 mmol), and dioxane (5 mL) were added sequentially. The reaction solution was purged with nitrogen five times. The reaction solution was heated to 85 °C under nitrogen protection and stirred for 5 hours, then cooled to room temperature. The reaction solution was concentrated, dissolved in ethyl acetate (10 mL), and washed with saturated brine (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by prep-HPLC to give 3-(4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (160 mg, yield: 72.2%).

[1192] MS m / z (ESI): 475.2 [M+H] + .

[1193] Step 5: 4-(4-chloro-6-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1194]

[1195] Using 3-(4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyridin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane as a raw material, refer to Example 7, step 3 to obtain the product 4-(4-chloro-6-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile.

[1196] MS m / z (ESI): 578.2 [M+H] + .

[1197] Example 58

[1198] 4-(4-chloro-6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1199]

[1200] Step 1: 5-Bromo-4-chloro-2-(4-(pyridin-2-oxy)piperidin-1-yl)pyridine

[1201]

[1202] Using 5-bromo-4-chloro-2-fluoropyridine as a raw material, the product 5-bromo-4-chloro-2-(4-(pyridin-2-oxy)piperidin-1-yl)pyridine was obtained in the second step of Example 8.

[1203] MS m / z (ESI): 368.0 [M+H] + 370.0 [M+H+2] + .

[1204] Step 2: 4-Chloro-2-(4-(pyridin-2-oxy)piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine

[1205]

[1206] Using 5-bromo-4-chloro-2-(4-(pyridin-2-oxy)piperidin-1-yl)pyridine as a raw material, the product 4-chloro-2-(4-(pyridin-2-oxy)piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine was obtained in step four of Example 57.

[1207] MS m / z (ESI): 416.2 [M+H] + ,

[1208] Step 3: 4-(4-chloro-6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1209]

[1210] Using 4-chloro-2-(4-(pyridin-2-oxy)piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine as a raw material, the product 4-(4-chloro-6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile was obtained in step 3 of Example 7.

[1211] MS m / z (ESI): 519.1 [M+H] + .

[1212] Example 59

[1213] 4-(6-(4-amino-4-((6-methoxypyridin-3-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1214]

[1215] Step 1: Preparation of 1-(tert-butyl)4-ethyl 4-((6-methoxypyridin-3-yl)methyl)piperidine-1,4-dicarboxylic acid ester

[1216]

[1217] 1-(tert-butyl)-4-ethylpiperidine-1,4-dicarboxylic acid ester (10 g, 38.9 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and the solution was cooled to -76 °C under nitrogen protection. LDA (29.2 mL, 58.4 mmol) was slowly added dropwise to the reaction solution, keeping the temperature below -70 °C. After the addition was complete, the reaction solution was slowly heated to 0 °C, stirred for half an hour, and then cooled to -76 °C. 5-(bromomethyl)-2-methoxypyridine (9.4 g, 46.6 mmol) was slowly added to the reaction solution. After the addition was complete, the reaction solution was heated to room temperature and stirred for 4 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution, followed by extraction with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 1-(tert-butyl)4-ethyl 4-((6-methoxypyridin-3-yl)methyl)piperidine-1,4-dicarboxylic acid ester (3.5 g, yield: 24%).

[1218] MS m / z (ESI): 379.2 [M+H] + .

[1219] Step 2: Preparation of 1-(tert-butoxycarbonyl)-4-((6-methoxypyridin-3-yl)methyl)piperidine-4-carboxylic acid

[1220]

[1221] Using 51-(tert-butyl)4-ethyl 4-((6-methoxypyridin-3-yl)methyl)piperidine-1,4-dicarboxylic acid ester as a starting material, 1-(tert-butoxycarbonyl)-4-((6-methoxypyridin-3-yl)methyl)piperidine-4-carboxylic acid (2 g, yield: 80%) was obtained in step 2 of Example 40.

[1222] MS m / z (ESI): 351.2 [M+H] + .

[1223] Step 3: Preparation of tert-butyl-4-((tert-butoxycarbonyl)amino)-4-((6-methoxypyridin-3-yl)methyl)piperidine-1-carboxylic acid ester

[1224]

[1225] 1-(tert-butoxycarbonyl)-4-((6-methoxypyridin-3-yl)methyl)piperidine-4-carboxylic acid (2 g, 5.7 mmol) was dissolved in tert-butanol (50 mL), and DIEA (1.1 g, 8.6 mmol) and diphenyl azide phosphate (1.7 g, 6.3 mmol) were added. The reaction mixture was stirred at 80 °C for 6 hours. The reaction mixture was then evaporated to dryness. The crude product was purified by column chromatography to give tert-butyl-4-((tert-butoxycarbonyl)amino)-4-((6-methoxypyridin-3-yl)methyl)piperidine-1-carboxylic acid ester (1.6 g, yield: 67%).

[1226] MS m / z (ESI): 422.2 [M+H] + .

[1227] Step 3: Preparation of 4-((6-methoxypyridin-3-yl)methyl)piperidine-4-amine

[1228]

[1229] Using tert-butyl-4-((tert-butoxycarbonyl)amino)-4-((6-methoxypyridin-3-yl)methyl)piperidine-1-carboxylic acid ester as a starting material, refer to Example 43, step four to obtain 4-((6-methoxypyridin-3-yl)methyl)piperidine-4-amine (0.8 g, yield: 70%).

[1230] MS m / z (ESI): 222.2 [M+H] + .

[1231] Step 4: Preparation of 4-(6-(4-amino-4-((6-methoxypyridin-3-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile

[1232]

[1233] Using 4-((6-methoxypyridin-3-yl)methyl)piperidin-4-amine and 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile as raw materials, 4-(6-amino-4-((6-methoxypyridin-3-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (55 mg, yield: 46%) was obtained in step 6 of Example 42.

[1234] MS m / z (ESI): 528.2 [M+H] + .

[1235] Example 60

[1236] 4-(6-(4-amino-4-(pyridin-3-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1237]

[1238] Step 1: Preparation of 1-(tert-butyl)4-ethyl-4-(pyridin-3-ylmethyl)piperidine-1,4-dicarboxylic acid ester

[1239]

[1240] Using 1-(tert-butyl)4-ethylpiperidine-1,4-dicarboxylic acid ester and 3-(bromomethyl)pyridine as raw materials, 1-(tert-butyl)4-ethyl-4-(pyridin-3-ylmethyl)piperidine-1,4-dicarboxylic acid ester (3 g, yield: 68%) was obtained in the first step of Reference Example 59.

[1241] MS m / z (ESI): 349.2 [M+H] + .

[1242] Step 2: Preparation of 1-(tert-butoxycarbonyl)-4-(pyridin-3-ylmethyl)piperidine-4-carboxylic acid

[1243]

[1244] Using 1-(tert-butyl)4-ethyl-4-(pyridin-3-ylmethyl)piperidine-1,4-dicarboxylic acid ester as a starting material, 1-(tert-butoxycarbonyl)-4-(pyridin-3-ylmethyl)piperidine-4-carboxylic acid (2.2 g, yield: 78%) was obtained in step 2 of Reference Example 40.

[1245] MS m / z (ESI): 321.2 [M+H] + .

[1246] Step 3: Preparation of tert-butyl-4-((tert-butoxycarbonyl)amino)-4-(pyridin-3-ylmethyl)piperidine-1-carboxylic acid ester

[1247]

[1248] Using 1-(tert-butoxycarbonyl)-4-(pyridin-3-ylmethyl)piperidine-4-carboxylic acid as a starting material, tert-butyl 4-((tert-butoxycarbonyl)amino)-4-(pyridin-3-ylmethyl)piperidine-1-carboxylic acid ester (1.2 g, yield: 48%) was obtained in step 3 of Example 59.

[1249] MS m / z (ESI): 392.2 [M+H] + .

[1250] Step 4: Preparation of 4-(pyridin-3-ylmethyl)piperidine-4-amine

[1251]

[1252] Using tert-butyl-4-((tert-butoxycarbonyl)amino)-4-(pyridin-3-ylmethyl)piperidine-1-carboxylic acid ester as a starting material, 4-(pyridin-3-ylmethyl)piperidine-4-amine (0.6 g, yield: 73%) was obtained in step four of Example 43.

[1253] MS m / z (ESI): 192.2 [M+H] + .

[1254] Step 5: Preparation of 4-(6-(4-amino-4-(pyridin-3-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile

[1255]

[1256] Using 4-(pyridin-3-ylmethyl)piperidin-4-amine and 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile as raw materials, 4-(6-(4-amino-4-(pyridin-3-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (65 mg, yield: 44%) was obtained in step 6 of Example 42.

[1257] MS m / z (ESI): 498.2 [M+H] + .

[1258] Example 61

[1259] 4-(4-(4-amino-1-((6-methoxypyridin-3-yl)methyl)piperidin-4-yl)phenyl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1260]

[1261] Step 1: Preparation of benzyl 4-((tert-butylthionyl(sulfinyl)amino)-4-(4-chlorophenyl)piperidine-1-carboxylic acid ester

[1262]

[1263] Using benzyl 4-((tert-butylthionyl<sulfinyl>)imino)piperidine-1-carboxylate and magnesium bromide (4-chlorophenyl) as raw materials, in the first step of Example 42, benzyl 4-((tert-butylthionyl<sulfinyl>)amino)-4-(4-chlorophenyl)piperidine-1-carboxylate (2 g, yield: 33%) was obtained.

[1264] MS m / z (ESI): 449.2 [M+H] + .

[1265] Step 2: Preparation of benzyl 4-((tert-butylthionyl<sulfinyl>)amino)-4-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperidine-1-carboxylic acid ester

[1266]

[1267] Using benzyl 4-((tert-butylthionyl<sulfinyl>)amino)-4-(4-chlorophenyl)piperidine-1-carboxylate and 6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile as raw materials, in step 3 of Example 37, benzyl 4-((tert-butylthionyl<sulfinyl>)amino)-4-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperidine-1-carboxylate (1.2 g, yield: 66%) was obtained.

[1268] MS m / z (ESI): 644.2 [M+H] + .

[1269] Step 3: Preparation of N-(4-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperidin-4-yl)-2-methylpropane-2-sulfinamide

[1270]

[1271] Using benzyl 4-((tert-butylthionyl<sulfinyl>)amino)-4-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperidine-1-carboxylic acid ester as a starting material, refer to Example 42, step four to obtain N-(4-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperidine-4-yl)-2-methylpropane-2-sulfinamide (0.8 g, yield: 80%).

[1272] MS m / z (ESI): 510.2 [M+H] + .

[1273] Step 4: Preparation of N-(4-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)-1-((6-methoxypyridin-3-yl)methyl)piperidin-4-yl)-2-methylpropane-2-sulfinamide)

[1274]

[1275] Using N-(4-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperidin-4-yl)-2-methylpropane-2-sulfinamide and 6-methoxynicotinaldehyde as raw materials, in the third step of Reference Example 55, N-(4-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)-1-((6-methoxypyridin-3-yl)methyl)piperidin-4-yl)-2-methylpropane-2-sulfinamide (0.3 g, yield: 56%) was obtained.

[1276] MS m / z (ESI): 631.3 [M+H] + .

[1277] Step 5: Preparation of 4-(4-(4-amino-1-((6-methoxypyridin-3-yl)methyl)piperidin-4-yl)phenyl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile

[1278]

[1279] Using N-(4-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)-1-((6-methoxypyridin-3-yl)methyl)piperidin-4-yl)-2-methylpropane-2-sulfinamide as a starting material, in the second step of Reference Example 42, 4-(4-(4-amino-1-((6-methoxypyridin-3-yl)methyl)piperidin-4-yl)phenyl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile (yield: 85%) was obtained.

[1280] MS m / z (ESI): 527.3 [M+H] + .

[1281] Example 62

[1282] 4-(6-(4-amino-4-(dihydroindole-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1283]

[1284] Step 1: 4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylic acid ethyl ester

[1285]

[1286] A mixture of 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (3 g, 9.2 mmol), ethyl 4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylate (3.0 g, 11.04 mmol), N,N-diisopropylethylamine (3.6 g, 27.6 mmol), and acetonitrile (30 mL) was prepared at 8... Stirred at 0℃ for 16 hours, and after the reaction was completed, concentrated under reduced pressure with silica gel until dry. Separated by column chromatography (dichloromethane / methanol = 10:1), a colorless oily substance 4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylic acid ethyl ester (800 mg, yield: 15%) was obtained.

[1287] MS m / z (ESI): 579.3 [M+H] + .

[1288] Step 2: 4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylic acid

[1289]

[1290] Lithium hydroxide monohydrate (116 mg, 2.76 mmol) was added to a solution of ethyl 4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylic acid ester (800 mg, 1.38 mmol) in methanol (10 mL) and water (10 mL). The mixture was stirred at room temperature for 16 hours. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH to 2, and a white solid precipitated. The mixture was filtered, the filter cake was washed with water, and the filter cake was dried to obtain a white solid 4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylic acid (600 mg, yield: 79%).

[1291] MS m / z (ESI): 551.2 [M+H] + .

[1292] Step 3: Tert-butyl (1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(dihydroindole)-1-carbonyl)piperidin-4-yl)tert-butyl carbamate

[1293]

[1294] The following substances were added: 4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylic acid (100 mg, 0.18 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (82.91 mg, 0.22 mmol), triethylamine (36 mg, 0.36 mmol), dihydroindole (32 mg, 0.27 mmol), and dichloromethane (5 The mixture (mL) 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 phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then separated by column chromatography (dichloromethane / methanol = 10:1) to give a colorless oily tert-butyl (1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(dihydroindole)-1-carbonyl)piperidin-4-yl)carbamate (30 mg, yield: 26%).

[1295] MS m / z (ESI): 652.3 [M+H] + .

[1296] Step 4: 4-(6-(4-amino-4-(dihydroindole-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-one]pyridine-3-carboxynitrile

[1297]

[1298] 30 mg (0.046 mmol) of tert-butyl (1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(dihydroindole)-1-carbonyl)piperidin-4-yl)carbamate was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and separated by preparative chromatography to obtain a pale yellow oily substance, 4-(6-(4-amino-4-(dihydroindole-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (12 mg, yield: 47%).

[1299] 1H NMR (400MHz, CDCl3) δ8.34 (s, 1H), 8.26-8.18 (m, 2H), 8.16 (s, 1H), 7.70 (d, J = 6.6Hz, 1H), 7.18 (m, 3H), 7.07-7.03 (m, 1H), 6.83 (d, J = 8.7Hz, 1 H), 4.42-4.39 (m, 2H), 4.11-4.07 (m, 2H), 3.85-3.81 (m, 4H), 3.13-3.0 9(t, J=7.7Hz, 2H), 2.51-2.47(m, 2H), 1.92-1.89(m, 4H), 1.40(s, 6H).

[1300] MS m / z (ESI): 552.3 [M+H] + .

[1301] Example 63

[1302] 4-Amino-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(6-methoxypyridin-3-yl)piperidine-4-carboxamide

[1303]

[1304] The synthesis of Example 63 is based on Example 62.

[1305] MS m / z (ESI): 557.2 [M+H] + .

[1306] Example 64

[1307] 4-Amino-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-methyl-N-phenylpiperidin-4-carboxamide

[1308]

[1309] The synthesis of Example 64 is based on Example 62.

[1310] MS m / z (ESI): 540.2 [M+H] + .

[1311] Example 65

[1312] 4-(6-(4-amino-4-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1313]

[1314] The synthesis of Example 65 is based on Example 62.

[1315] MS m / z (ESI): 553.2 [M+H] +

[1316] Example 66

[1317] 4-(6-(3-((1H-pyrazol-1-yl)methyl)-3-aminoacetidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1318]

[1319] Step 1: Preparation of 1-(tert-butyl)3-methyl-3-((tert-butoxycarbonyl)amino)acetidine-1,3-dicarboxylic acid ester

[1320]

[1321] 1-(tert-butyl)-3-methyl-3-aminoacetidine-1,3-dicarboxylic acid ester (10 g, 43.4 mmol) was dissolved in dichloromethane (100 mL), and di-tert-butyl dicarbonate (10 g, 45.6 mmol) and DIEA (8.4 g, 65.1 mmol) were added. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 1-(tert-butyl)-3-methyl-3-((tert-butoxycarbonyl)amino)acetidine-1,3-dicarboxylic acid ester (13 g, yield: 91%).

[1322] MS m / z (ESI): 331.2 [M+H] + .

[1323] Step 2: Preparation of tert-butyl-3-((tert-butoxycarbonyl)amino)-3-(hydroxymethyl)acetidine-1-carboxylic acid ester

[1324]

[1325] 1-(tert-butyl)3-methyl 3-((tert-butoxycarbonyl)amino)acetidine-1,3-dicarboxylic acid ester (5 g, 15.1 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and lithium aluminum hydride (0.86 g, 22.7 mmol) was added. The reaction mixture was stirred overnight at 70 °C. The reaction was quenched with water, followed by extraction with ethyl acetate. The mixture was filtered. The filtrate was dried and then evaporated to dryness. The crude product was purified by column chromatography to give tert-butyl 3-((tert-butoxycarbonyl)amino)-3-(hydroxymethyl)acetidine-1-carboxylic acid ester (2.3 g, yield: 50%).

[1326] MS m / z (ESI): 303.2 [M+H] + .

[1327] Step 3: Preparation of tert-butyl-3-((tert-butoxycarbonyl)amino)-3-(((methanesulfonyl)oxo)methyl)acetidine-1-carboxylic acid ester

[1328]

[1329] 2.3 g (7.6 mmol) of tert-butyl 3-((tert-butoxycarbonyl)amino)-3-(hydroxymethyl)acetidine-1-carboxylic acid ester was dissolved in anhydrous dichloromethane (30 mL), and DIEA (2 g, 15.2 mmol) was added. MsCl (1.1 g, 9.1 mmol) was slowly added dropwise to the reaction solution at 0 °C. After the addition was complete, the reaction solution was heated to room temperature and stirred for 4 hours. Water was added to the reaction, followed by extraction with dichloromethane. The organic phase was evaporated to dryness to give 2.8 g (yield: 97%) of tert-butyl 3-((tert-butoxycarbonyl)amino)-3-(((methanesulfonyl)oxy)methyl)acetidine-1-carboxylic acid ester.

[1330] MS m / z (ESI): 381.2 [M+H] + .

[1331] Step 4: Preparation of tert-butyl-3-((1H-pyrazol-1-yl)methyl)-3-((tert-butoxycarbonyl)amino)acetidine-1-carboxylic acid ester

[1332]

[1333] Using tert-butyl 3-((tert-butoxycarbonyl)amino)-3-(((methanesulfonyl)oxy)methyl)acetidine-1-carboxylic acid ester and 1H-pyrazole as raw materials, refer to Example 37, step 5 to obtain tert-butyl 3-((1H-pyrazole-1-yl)methyl)-3-((tert-butoxycarbonyl)amino)acetidine-1-carboxylic acid ester (1.5 g, yield: 45%).

[1334] MS m / z (ESI): 353.2 [M+H]+ .

[1335] Step 5: Preparation of 3-((1H-pyrazol-1-yl)methyl)acetidine-3-amine

[1336]

[1337] Using tert-butyl 3-((1H-pyrazol-1-yl)methyl)-3-((tert-butoxycarbonyl)amino)acetidine-1-carboxylic acid ester as a starting material, refer to Example 43, step four to obtain 3-((1H-pyrazol-1-yl)methyl)acetidine-3-amine (0.7 g, yield: 90%).

[1338] MS m / z (ESI): 153.1 [M+H] + .

[1339] Step 5: Preparation of 4-(6-(3-((1H-pyrazol-1-yl)methyl)-3-aminoacetidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile

[1340]

[1341] Using 3-((1H-pyrazol-1-yl)methyl)acetidine-3-amine and 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as raw materials, 4-(6-(3-((1H-pyrazol-1-yl)methyl)-3-aminoacetidine-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (63 mg, yield: 69%) was obtained in step 6 of Example 42.

[1342] MS m / z (ESI): 459.2 [M+H] + .

[1343] Example 67

[1344] 4-(6-(3-amino-3-((6-methoxypyridin-3-yl)methyl)acetidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1345]

[1346] Step 1: Preparation of 1-(tert-butyl)-3-methyl-3-((6-methoxypyridin-3-yl)methyl)acetidine-1,3-dicarboxylic acid ester

[1347]

[1348] Using 1-(tert-butyl)3-methylacetidine-1,3-dicarboxylic acid ester and 5-(bromomethyl)-2-methoxypyridine as raw materials, 1-(tert-butyl)3-methyl-3-((6-methoxypyridin-3-yl)methyl)acetidine-1,3-dicarboxylic acid ester (5 g, yield: 63%) was obtained in the first step of Reference Example 59.

[1349] MS m / z (ESI): 337.2 [M+H] + .

[1350] Step 2: Preparation of 1-(tert-butoxycarbonyl)-3-((6-methoxypyridin-3-yl)methyl)acetidine-3-carboxylic acid

[1351]

[1352] Using 1-(tert-butyl)3-methyl-3-((6-methoxypyridin-3-yl)methyl)acetidine-1,3-dicarboxylic acid ester as a starting material, 1-(tert-butoxycarbonyl)-3-((6-methoxypyridin-3-yl)methyl)acetidine-3-carboxylic acid (2.5 g, yield: 76%) was obtained in step 2 of Reference Example 40.

[1353] MS m / z (ESI): 323.2 [M+H] + .

[1354] Step 3: Preparation of tert-butyl-3-((tert-butoxycarbonyl)amino)-3-((6-methoxypyridin-3-yl)methyl)acetidine-1-carboxylic acid ester

[1355]

[1356] Using 1-(tert-butoxycarbonyl)-3-((6-methoxypyridin-3-yl)methyl)acetidine-3-carboxylic acid as a starting material, see Reference Example 59

[1357] The third step yielded tert-butyl 3-((tert-butoxycarbonyl)amino)-3-((6-methoxypyridin-3-yl)methyl)acetidine-1-carboxylic acid ester (1.5 g, yield: 67%).

[1358] MS m / z (ESI): 394.2 [M+H] + .

[1359] Step 4: Preparation of 3-((6-methoxypyridin-3-yl)methyl)acetidine-3-amine

[1360]

[1361] Using tert-butyl-3-((tert-butoxycarbonyl)amino)-3-((6-methoxypyridin-3-yl)methyl)acetidine-1-carboxylic acid ester as a starting material, refer to Example 43, step four to obtain 3-((6-methoxypyridin-3-yl)methyl)acetidine-3-amine (0.7 g, yield: 91%).

[1362] MS m / z (ESI): 194.1 [M+H] + .

[1363] Step 5: Preparation of 4-(6-(3-amino-3-((6-methoxypyridin-3-yl)methyl)acetidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile

[1364]

[1365] Using 3-((6-methoxypyridin-3-yl)methyl)acetidine-3-amine and 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile as raw materials, 4-(6-(3-amino-3-((6-methoxypyridin-3-yl)methyl)acetidine-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (53 mg, yield: 59%) was obtained in step 6 of Example 42.

[1366] MS m / z (ESI): 500.2 [M+H] + .

[1367] Example 68

[1368] 4-(4-(3-amino-1-((6-methoxypyridin-3-yl)methyl)acetidin-3-yl)phenyl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1369]

[1370] Step 1: Preparation of benzyl 3-((tert-butylthionyl(sulfinyl)amino)-3-(4-chlorophenyl)acetidine-1-carboxylic acid ester

[1371]

[1372] Using benzyl 3-((tert-butylthionyl<sulfinyl>)imino)acetidine-1-carboxylic acid ester and magnesium bromide (4-chlorophenyl) as raw materials, in the first step of Example 42, benzyl 3-((tert-butylthionyl<sulfinyl>)amino)-3-(4-chlorophenyl)acetidine-1-carboxylic acid ester (2.2 g, yield: 35%) was obtained.

[1373] MS m / z (ESI): 421.2 [M+H] + .

[1374] Step 2: Preparation of benzyl 3-((tert-butylthionyl<sulfinyl>)amino)-3-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)acetidine-1-carboxylic acid ester

[1375]

[1376] Using benzyl 3-((tert-butylthionyl<sulfinyl>)amino)-3-(4-chlorophenyl)acetidine-1-carboxylic acid ester and 6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile as raw materials, reference Example 37, step 3 yielded benzyl 3-((tert-butylthionyl<sulfinyl>)amino)-3-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)acetidine-1-carboxylic acid ester (1.3 g, yield: 68%).

[1377] MS m / z (ESI): 616.2 [M+H] + .

[1378] Step 3: Preparation of N-(3-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)acetidin-3-yl)-2-methylpropane-2-sulfinamide

[1379]

[1380] Using benzyl 3-((tert-butylthionyl<sulfinyl>)amino)-3-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)acetidine-1-carboxylic acid ester as a starting material, refer to Example 42, step four to obtain N-(3-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)acetidine-3-yl)-2-methylpropane-2-sulfinamide (0.9 g, yield: 82%).

[1381] MS m / z (ESI): 482.2 [M+H] + .

[1382] Step 4: Preparation of N-(3-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)-1-((6-methoxypyridin-3-yl)methyl)acetidin-3-yl)-2-methylpropane-2-sulfinamide

[1383]

[1384] Using N-(3-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)acetidin-3-yl)-2-methylpropane-2-sulfinamide and 6-methoxynicotinaldehyde as raw materials, refer to Example 55. In step 3, N-(3-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)-1-((6-methoxypyridin-3-yl)methyl)acetidin-3-yl)-2-methylpropane-2-sulfinamide (0.4 g, yield: 62%) was obtained.

[1385] MS m / z (ESI): 603.3 [M+H] + .

[1386] Step 5: Preparation of 4-(4-(3-amino-1-((6-methoxypyridin-3-yl)methyl)acetidin-3-yl)phenyl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile

[1387]

[1388] Using N-(3-(4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)-1-((6-methoxypyridin-3-yl)methyl)acetidin-3-yl)-2-methylpropane-2-sulfinamide as a starting material, in the second step of Reference Example 42, 4-(4-(3-amino-1-((6-methoxypyridin-3-yl)methyl)acetidin-3-yl)phenyl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile (150 mg, yield: 84%) was obtained.

[1389] MS m / z (ESI): 499.2 [M+H] + .

[1390] Example 69

[1391] 4-(6-(3-(3-amino-1H-pyrazol-1-yl)acetidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1392]

[1393] Step 1: Preparation of tert-butyl-3-(3-nitro-1H-pyrazole-1-yl)acetidine-1-carboxylic acid ester

[1394]

[1395] 3-Nitro-1H-pyrazole (10 g, 88.4 mmol) was dissolved in anhydrous DMF (120 mL), and tert-butyl-3-iodoaceridine-1-carboxylic acid ester (30 g, 106.1 mmol) and potassium carbonate (24.4 g, 176.9 mmol) were added. The reaction mixture was stirred overnight at 60 °C. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give tert-butyl-3-(3-nitro-1H-pyrazole-1-yl)aceridine-1-carboxylic acid ester (20 g, yield: 84%).

[1396] MS m / z (ESI): 269.1 [M+H] + .

[1397] Step 2: Preparation of 1-(acetidin-3-yl)-3-nitro-1H-pyrazole

[1398]

[1399] Using tert-butyl-3-(3-nitro-1H-pyrazole-1-yl)acetidine-1-carboxylic acid ester as a starting material, 1-(acetidine-3-yl)-3-nitro-1H-pyrazole (5 g, yield: 93%) was obtained in step four of Example 43. MS m / z (ESI): 169.1 [M+H] + .

[1400] Step 3: Preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(3-nitro-1H-pyrazol-1-yl)acetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile

[1401]

[1402] Using 1-(acridin-3-yl)-3-nitro-1H-pyrazole and 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as raw materials, 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(3-nitro-1H-pyrazole-1-yl)acridin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (500 mg, yield: 68%) was obtained in step 6 of Example 42.

[1403] MS m / z (ESI): 475.2 [M+H] + .

[1404] Step 4: Preparation of 4-(6-(3-(3-amino-1H-pyrazol-1-yl)acetidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile

[1405]

[1406] 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(3-nitro-1H-pyrazol-1-yl)acetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile (200 mg, 0.42 mmol) was dissolved in tetrahydrofuran (20 mL), and iron powder (235 mg, 4.22 mmol), ammonium chloride (225 mg, 4.22 mmol), and water (10 mL) were added. The reaction mixture was stirred at 80 °C for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was filtered. The filtrate was dried and then evaporated to dryness. The crude product was purified by prep-HPLC to obtain 4-(6-(3-(3-amino-1H-pyrazol-1-yl)acetidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (75 mg, yield: 40%).

[1407] MS m / z (ESI): 445.2 [M+H] + .

[1408] Example 70

[1409] N-(1-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acetidin-3-yl)-1H-pyrazol-3-yl)cyclopropylformamide

[1410]

[1411] N-(1-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acridin-3-yl)-1H-pyrazol-3-yl)cyclopropylcarboxamide (85 mg, yield: 72%) was obtained in step 3 using 4-(6-(3-(3-amino-1H-pyrazol-1-yl)acridin-1-yl)pyridin-3-yl)acridin-3-yl)cyclopropylcarboxamide as a starting material, as per Example 40.

[1412] MS m / z (ESI): 513.2 [M+H] + .

[1413] Example 71

[1414] 1-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acetidin-3-yl)-N-cyclopropyl-1H-pyrazol-3-carboxamide

[1415]

[1416] Step 1: Preparation of 1-diphenylmethylacrylidine-3-ylmethanesulfonate

[1417]

[1418] Using 1-diphenylmethylacetidine-3-ol as a starting material, 1-diphenylmethylacetidine-3-yl methanesulfonate (10 g, yield: 95%) was obtained in step 3 of Example 66.

[1419] MS m / z (ESI): 318.2 [M+H] + .

[1420] Step 2: Preparation of methyl 1-(1-diphenylmethylacrylidine-3-yl)-1H-pyrazole-3-carboxylic acid ester

[1421]

[1422] Using 1-diphenylmethylacrylidine-3-yl methanesulfonate and methyl 1H-pyrazole-3-carboxylate as raw materials, methyl 1-(1-diphenylmethylacrylidine-3-yl)-1H-pyrazole-3-carboxylate (3.5 g, yield: 40%) was obtained in step 5 of Example 37.

[1423] MS m / z (ESI): 348.2 [M+H] + .

[1424] Step 3: Preparation of 1-(1-diphenylmethylacetidin-3-yl)-1H-pyrazole-3-carboxylic acid

[1425]

[1426] Using methyl 1-(1-diphenylmethylacrylidine-3-yl)-1H-pyrazole-3-carboxylic acid ester as a starting material, 1-(1-diphenylmethylacrylidine-3-yl)-1H-pyrazole-3-carboxylic acid (2.0 g, yield: 75%) was obtained in step 2 of Reference Example 40.

[1427] MS m / z (ESI): 334.2 [M+H] + .

[1428] Step 4: Preparation of 1-(1-diphenylmethylacetidin-3-yl)-N-cyclopropyl-1H-pyrazole-3-carboxamide

[1429]

[1430] Using 1-(1-diphenylmethylacrylidine-3-yl)-1H-pyrazole-3-carboxylic acid and cyclopropylamine as raw materials, 1-(1-diphenylmethylacrylidine-3-yl)-N-cyclopropyl-1H-pyrazole-3-carboxamide (500 mg, yield: 71%) was obtained in step 3 of Example 40.

[1431] MS m / z (ESI): 373.2 [M+H] + .

[1432] Step 5: Preparation of 1-(acetidin-3-yl)-N-cyclopropyl-1H-pyrazole-3-carboxamide

[1433]

[1434] Using 1-(1-diphenylmethylacetidin-3-yl)-N-cyclopropyl-1H-pyrazole-3-carboxamide as a starting material, 1-(acetidin-3-yl)-N-cyclopropyl-1H-pyrazole-3-carboxamide (250 mg, yield: 72%) was obtained in step four of Example 42.

[1435] MS m / z (ESI): 207.2 [M+H] + .

[1436] Step 6: Preparation of 1-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acetidin-3-yl)-N-cyclopropyl-1H-pyrazol-3-carboxamide)

[1437]

[1438] Using 1-(acidil-3-yl)-N-cyclopropyl-1H-pyrazole-3-carboxamide and 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as raw materials, 1-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acidil-3-yl)-N-cyclopropyl-1H-pyrazole-3-carboxamide (80 mg, yield: 66%) was obtained in step 6 of Example 42.

[1439] MS m / z (ESI): 513.2 [M+H] + .

[1440] Example 72

[1441] 6-(2-hydroxy-2-methylpropoxy)-4-(6-(5-((6-methoxypyridin-3-yl)oxo)hexahydrocyclopentadien[c]pyrrolo-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1442]

[1443] Step 1: Tert-butyl 5-((6-methoxypyridin-3-yl)oxo)hexahydrocyclopentadien[c]pyrrole-2(1H)-carboxylic acid ester

[1444]

[1445] Using 6-methoxypyridine-3-phenol and tert-butyl-5-hydroxyhexahydrocyclopentadien[c]pyrrole-2(1H)-carboxylic acid ester as raw materials, the product tert-butyl-5-((6-methoxypyridine-3-yl)oxo)hexahydrocyclopentadien[c]pyrrole-2(1H)-carboxylic acid ester was obtained in the first step of Reference Example 34.

[1446] MS m / z (ESI): 335.2 [M+H] + .

[1447] Step 2: 5-((6-methoxypyridin-3-yl)oxo)octahydrocyclopentadien[c]pyrrole

[1448]

[1449] Using tert-butyl 5-((6-methoxypyridin-3-yl)oxo)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid ester as a starting material, the product 5-((6-methoxypyridin-3-yl)oxo)octahydrocyclopentadieno[c]pyrrole was obtained in step 2 of Example 57.

[1450] MS m / z (ESI): 235.1 [M+H] + .

[1451] Step 3: 6-(2-hydroxy-2-methylpropoxy)-4-(6-(5-((6-methoxypyridin-3-yl)oxo)hexahydrocyclopentadieno[c]pyrrolo-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1452]

[1453] Using 5-((6-methoxypyridin-3-yl)oxo)octahydrocyclopentadieno[c]pyrrole as a raw material, the product 6-(2-hydroxy-2-methylpropoxy)-4-(6-(5-((6-methoxypyridin-3-yl)oxo)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile was obtained in the second step of Example 8.

[1454] MS m / z (ESI) 541.2 [M+H] + .

[1455] Example 73

[1456] 6-(2-hydroxy-2-methylpropoxy)-4-(6-(5-(pyridin-3-ylmethoxy)hexahydrocyclopentadien[c]pyrrolo-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1457]

[1458] Step 1: tert-butyl-5-(pyridin-3-ylmethoxy)hexahydrocyclopentadien[c]pyrrole-2(1H)-carboxylic acid ester

[1459]

[1460] 660 mg (2.9 mmol) of tert-butyl-5-hydroxyhexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid ester was dissolved in tetrahydrofuran (10 mL), and sodium hydride (140 mg, 3.5 mmol, 60%) was added with stirring. The reaction mixture was then stirred at room temperature for 1 hour. 3-(bromomethyl)pyridine (500 mg, 2.9 mmol) was then added to the reaction mixture, and stirring continued for 12 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL). The extract was washed with saturated sodium chloride solution (5 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol: 30 / 1) to give tert-butyl-5-(pyridin-3-ylmethoxy)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid ester (550 mg, white solid, 59.5%).

[1461] MS m / z (ESI): 319.2 [M+H] + .

[1462] Step 2: 5-(pyridin-3-ylmethoxy)octahydrocyclopentadien[c]pyrrole

[1463]

[1464] Using tert-butyl 5-(pyridin-3-ylmethoxy)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid ester as a raw material, the product 5-(pyridin-3-ylmethoxy)octahydrocyclopentadieno[c]pyrrole was obtained in step 2 of Example 57.

[1465] MS m / z(ESI) 219.2 [M+H] + .

[1466] Step 3: 6-(2-hydroxy-2-methylpropoxy)-4-(6-(5-(pyridin-3-ylmethoxy)hexahydrocyclopentadien[c]pyrrolo-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1467]

[1468] Using 5-(pyridin-3-ylmethoxy)octahydrocyclopentadien[c]pyrrole as a raw material, the product 6-(2-hydroxy-2-methylpropoxy)-4-(6-(5-(pyridin-3-ylmethoxy)hexahydrocyclopentadien[c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile was obtained in step 2 of Example 8.

[1469] MS m / z (ESI) 525.2 [M+H] + .

[1470] Example 74

[1471] 6-(2-hydroxy-2-methylpropoxy)-4-(6-(5-(((6-methoxypyridin-3-yl)methyl)amino)-5-methylhexahydrocyclopentadieno[c]pyrrolo-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1472]

[1473] Step 1: 2-(5-bromopyridin-2-yl)hexahydrocyclopentadien[c]pyrrole-5(1H)-one

[1474]

[1475] Using 5-bromo-2-fluoropyridine and hexahydrocyclopentadieno[c]pyrrole-5(1H)-one as raw materials, the product 2-(5-bromopyridin-2-yl)hexahydrocyclopentadieno[c]pyrrole-5(1H)-one was obtained in the second step of Reference Example 8.

[1476] MS m / z(ESI) 281.0 [M+H] + .

[1477] Step 2: 2-(5-bromopyridin-2-yl)-5-methyleneoctahydrocyclopentadiene[c]pyrrole

[1478]

[1479] Methyltriphenylphosphine bromide (870 mg, 2.45 mmol) was dissolved in tetrahydrofuran (10 mL), N2 was substituted, and the mixture was cooled to 0 °C. Potassium tert-butoxide (330 mg, 2.93 mmol) was added, and the reaction was stirred at room temperature for 2 hours. After cooling to 0 °C, a tetrahydrofuran solution (10 mL) of 2-(5-bromopyridin-2-yl)hexahydrocyclopentadieno[c]pyrrole-5(1H)-one (450 mg, 1.60 mmol) was added. The reaction was stirred at room temperature for 2 hours, and then stirred overnight at 50 °C. The reaction was quenched with water (10 mL), and the aqueous phase was extracted with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate: 1 / 1) to give 2-(5-bromopyridin-2-yl)-5-methyleneoctahydrocyclopentadieno[c]pyrrole (300 mg, yield: 67%).

[1480] MS m / z(ESI) 279.0 [M+H] + .

[1481] Step 3: N-(2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrolo-5-yl)formamide

[1482]

[1483] 2-(5-bromopyridin-2-yl)-5-methyleneoctahydrocyclopentadien[c]pyrrole (300 mg, 1.07 mmol) was dissolved in dichloromethane (30 mL), and acetic acid (180 mg, 3.0 mmol) was added. The mixture was cooled to 0 °C, and trimethylcyanosilicon (200 mg, 2.0 mmol) was added dropwise. The reaction was stirred at 0 °C for half an hour. Then, a mixture of acetic acid (180 mg, 3.0 mmol) and concentrated sulfuric acid (400 mg, 4.0 mmol) was slowly added dropwise, and the reaction was stirred overnight at 0 °C to room temperature. At 0 °C, an aqueous solution of 3 M sodium hydroxide was added until the pH was > 12. The aqueous phase was extracted with ethyl acetate (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give N-(2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-yl)carboxamide (230 mg, yield: 66.0%).

[1484] MS m / z (ESI): 324.0 [M+H] + .

[1485] Step 4: 2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-amine

[1486]

[1487] N-(2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadieno[c]pyrrole-5-yl)carboxamide (230 mg, 0.7 mmol) was dissolved in ethanol (5 mL), sodium hydroxide (80 mg, 2.1 mmol) and water (2 mL) were added, and the reaction was stirred overnight at 70 °C. The solvent was evaporated to dryness, water (5 mL) was added, the aqueous phase was extracted with ethyl acetate (5 mL x 2), the organic phase was washed with 1 M hydrochloric acid aqueous solution (5 mL), the pH of the aqueous phase was adjusted to >12 with 3 M sodium hydroxide aqueous solution, the aqueous phase was extracted with ethyl acetate (5 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadieno[c]pyrrole-5-amine (150 mg, yield: 71%).

[1488] MS m / z (ESI): 296.0 [M+H] + .

[1489] Step 5: 2-(5-bromopyridin-2-yl)-N-((6-methoxypyridin-3-yl)methyl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-amine

[1490]

[1491] Using 2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-amine as a raw material, the product 2-(5-bromopyridin-2-yl)-N-((6-methoxypyridin-3-yl)methyl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-amine was obtained in step 3 of Example 57.

[1492] MS m / z (ESI): 417.1 [M+H] + .

[1493] Step 6: N-((6-methoxypyridin-3-yl)methyl)-5-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)octahydrocyclopentadien[c]pyrrole-5-amine

[1494]

[1495] Using 2-(5-bromopyridin-2-yl)-N-((6-methoxypyridin-3-yl)methyl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-amine as a starting material, refer to Example 57, step four to obtain the product N-((6-methoxypyridin-3-yl)methyl)-5-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyridin-2-yl)octahydrocyclopentadien[c]pyrrole-5-amine.

[1496] MS m / z (ESI): 465.3 [M+H] + .

[1497] Step 7: 6-(2-hydroxy-2-methylpropoxy)-4-(6-(5-(((6-methoxypyridin-3-yl)methyl)amino)-5-methylhexahydrocyclopentadien[c]pyrrolo-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1498]

[1499] Using N-((6-methoxypyridin-3-yl)methyl)-5-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)octahydrocyclopentadieno[c]pyrrole-5-amine as a starting material, refer to Example 7, step 3 to obtain the product 6-(2-hydroxy-2-methylpropoxy)-4-(6-(5-(((6-methoxypyridin-3-yl)methyl)amino)-5-methylhexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile.

[1500] MS m / z (ESI): 568.3 [M+H] + .

[1501] Example 75

[1502] N-(2-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-methyloctahydrocyclopentadieno[c]pyrrolo-5-yl)-5-fluoro-2-methylbenzamide

[1503]

[1504] Step 1: N-(2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrolo-5-yl)-5-fluoro-2-methylbenzamide

[1505]

[1506] In a 25 mL three-necked flask, 2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-amine (300 mg, 1.0 mmol), 5-fluoro-2-methylbenzoic acid (156 mg, 1.0 mmol), 2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethylurea hexafluorophosphate (380 mg, 1.0 mmol), diisopropylethylamine (390 mg, 3 mmol), and dimethylformamide (5 mL) were added sequentially. After stirring at room temperature for 5 hours, the reaction mixture was dissolved in ethyl acetate (10 mL), washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography to give N-(2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrolo-5-yl)-5-fluoro-2-methylbenzamide (260 mg, yield: 59.3%).

[1507] MS m / z (ESI): 432.1 [M+H] + .

[1508] Step 2: 5-Fluoro-2-methyl-N-(5-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)octahydrocyclopentadien[c]pyrrole-5-yl)benzamide

[1509]

[1510] Using N-(2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrolo-5-yl)-5-fluoro-2-methylbenzamide as a raw material, refer to Example 57, step four to obtain the product 5-fluoro-2-methyl-N-(5-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyridin-2-yl)octahydrocyclopentadien[c]pyrrolo-5-yl)benzamide.

[1511] MS m / z (ESI): 480.2 [M+H] + .

[1512] Step 3: N-(2-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-methyloctahydrocyclopentadieno[c]pyrrolo-5-yl)-5-fluoro-2-methylbenzamide

[1513]

[1514] Using 5-fluoro-2-methyl-N-(5-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)octahydrocyclopentadieno[c]pyrrole-5-yl)benzamide as a raw material, refer to Example 7, step 3 to obtain the product N-(2-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-methyloctahydrocyclopentadieno[c]pyrrole-5-yl)-5-fluoro-2-methylbenzamide.

[1515] MS m / z (ESI): 583.2 [M+H] +

[1516] Example 76

[1517] 2-Chloro-N-(2-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-yl)benzamide

[1518]

[1519] Step 1: N-(2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrolo-5-yl)-2-chlorobenzamide

[1520]

[1521] Using 2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-amine as the raw material and 2-chlorobenzoic acid as the starting material, the product N-(2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-yl)-2-chlorobenzamide was obtained in the first step of Example 75.

[1522] MS m / z (ESI): 434.0 [M+H] + .

[1523] Step 2: 2-Chloro-N-(5-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)octahydrocyclopentadien[c]pyrrole-5-yl)benzamide

[1524]

[1525] Using N-(2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-yl)-2-chlorobenzamide as a raw material, refer to Example 57, step four to obtain the product 2-chloro-N-(5-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyridin-2-yl)octahydrocyclopentadien[c]pyrrole-5-yl)benzamide.

[1526] MS m / z (ESI): 482.2 [M+H] + .

[1527] Step 3: 2-Chloro-N-(2-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-methyloctahydrocyclopentadieno[c]pyrrole-5-yl)benzamide

[1528]

[1529] Using 2-chloro-N-(5-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)octahydrocyclopentadien[c]pyrrole-5-yl)benzamide as a raw material, the product 2-chloro-N-(2-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-yl)benzamide was obtained by referring to the third step of Example 7.

[1530] MS m / z (ESI): 585.2 [M+H] + .

[1531] Example 77

[1532] N-(2-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-methyloctahydrocyclopentadieno[c]pyrrolo-5-yl)-3-fluoro-6-methylmethylpyridinamide

[1533]

[1534] Step 1: N-(2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrolo-5-yl)-3-fluoro-6-methylmethylpyridinamide

[1535]

[1536] Using 2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-amine as the raw material and 3-fluoro-6-methylo-opyridinecarboxylic acid as the starting material, the product N-(2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-yl)-3-fluoro-6-methylmethylpyridine amide was obtained in the first step of Example 75.

[1537] MS m / z (ESI): 433.0 [M+H] + .

[1538] Step 2: 3-Fluoro-6-methyl-N-(5-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)octahydrocyclopentadien[c]pyrrole-5-yl)methylpyridinamide

[1539]

[1540] Using N-(2-(5-bromopyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrolo-5-yl)-3-fluoro-6-methylmethylpyridine amide as a raw material, refer to Example 57, step four to obtain the product 3-fluoro-6-methyl-N-(5-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyridin-2-yl)octahydrocyclopentadien[c]pyrrolo-5-yl)methylpyridine amide.

[1541] MS m / z (ESI): 481.2 [M+H] + .

[1542] Step 3: N-(2-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-methyloctahydrocyclopentadieno[c]pyrrolo-5-yl)-3-fluoro-6-methylmethylpyridinamide

[1543]

[1544] Using 3-fluoro-6-methyl-N-(5-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)octahydrocyclopentadien[c]pyrrole-5-yl)methylpyridine amide as a raw material, refer to Example 7, step 3 to obtain the product N-(2-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-methyloctahydrocyclopentadien[c]pyrrole-5-yl)-3-fluoro-6-methylmethylpyridine amide.

[1545] MS m / z (ESI): 584.2 [M+H] + .

[1546] Example 78

[1547] 6-(2-hydroxy-2-methylpropoxy)-4-(6-((1R,5S)-3-((6-methoxypyridin-3-yl)oxo)-8-azabicyclo[3.2.1]octane-8-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile

[1548]

[1549] Step 1: tert-butyl(1R,5S)-3-((6-methoxypyridin-3-yl)oxo)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[1550]

[1551] Using 6-methoxypyridine-3-phenol and tert-butyl(1R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester as raw materials, the product tert-butyl(1R,5S)-3-((6-methoxypyridine-3-yl)oxo)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was obtained in the first step of Reference Example 34.

[1552] MS m / z (ESI): 335.1 [M+H] + .

[1553] Step 2: (1R,5S)-3-((6-methoxypyridin-3-yl)oxo)-8-azabicyclo[3.2.1]octane

[1554]

[1555] Using tert-butyl(1R,5S)-3-((6-methoxypyridin-3-yl)oxo)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester as a raw material, the product (1R,5S)-3-((6-methoxypyridin-3-yl)oxo)-8-azabicyclo[3.2.1]octane was obtained in the second step of Reference Example 57.

[1556] MS m / z (ESI): 235.1 [M+H] + .

[1557] Step 3: 6-(2-hydroxy-2-methylpropoxy)-4-(6-((1R,5S)-3-((6-methoxypyridin-3-yl)oxo)-8-azabicyclo[3.2.1]octane-8-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile

[1558]

[1559] Using (1R,5S)-3-((6-methoxypyridin-3-yl)oxo)-8-azabicyclo[3.2.1]octane and 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as raw materials, the product 6-(2-hydroxy-2-methylpropoxy)-4-(6-((1R,5S)-3-((6-methoxypyridin-3-yl)oxo)-8-azabicyclo[3.2.1]octane-8-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile was obtained in the second step of Example 8.

[1560] MS m / z (ESI): 541.2 [M+H] + .

[1561] Example 79

[1562] 4-(6-(1-((5-fluoro-6-methoxypyridin-3-yl)methyl)-2,5-dihydro-1H-pyrrolo-3-yl)pyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1563]

[1564] Step 1: tert-Butyl-3-hydroxy-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)pyrrolidine-1-carboxylic acid ester

[1565]

[1566] 2-Bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (500 mg, 1.7 mmol) was dissolved in 20 mL of THF. n-BuLi (1 mL, 2.6 mmol) was added at -78 °C, and the mixture was stirred at -78 °C for half an hour. Tert-butyl-3-carbonylpyrrolidine-1-carboxylic acid ester was then added at -78 °C, and the mixture was stirred at room temperature for 2 hours. 10 mL of ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filter, evaporate to dryness, and separate the crude product by column chromatography (washing with petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl-3-hydroxy-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)pyrrolidine-1-carboxylate (379 mg, white solid, yield 57%).

[1567] MS m / z (ESI): 391.2 [M+H] + .

[1568] Step 2: Tert-butyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid ester

[1569]

[1570] 300 mg (0.76 mmol) of tert-butyl-3-hydroxy-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)pyrrolidine-1-carboxylic acid ester was dissolved in 20 mL of DCM. SOCl2 (1 mL) was added at room temperature, and the mixture was stirred for 2 h at room temperature. Then, 10 mL of ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the crude product was separated by column chromatography (washed with petroleum ether / ethyl acetate = 3 / 1) to give 197 mg (white solid, 70% yield) of tert-butyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid ester.

[1571] MS m / z (ESI): 373.2 [M+H] + .

[1572] Step 3: Tert-butyl-3-(5-(3-cyano-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid ester

[1573]

[1574] Using 4-bromo-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile and tert-butyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid ester as raw materials, tert-butyl 3-(5-(3-cyano-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid ester (180 mg, white solid, 72%) was obtained by referring to step 8 of Example 1.

[1575] MS m / z (ESI): 448.1 [M+H] + .

[1576] Step 4: 4-(6-(2,5-dihydro-1H-pyrrolo-3-yl)pyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1577]

[1578] Using tert-butyl 3-(5-(3-cyano-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid ester as a starting material, 4-(6-(2,5-dihydro-1H-pyrrole-3-yl)pyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (120 mg, white solid, 99%) was obtained by referring to step 5 of Example 1.

[1579] MS m / z (ESI): 348.1 [M+H] + .

[1580] Step 5: 4-(6-(1-((5-fluoro-6-methoxypyridin-3-yl)methyl)-2,5-dihydro-1H-pyrrolo-3-yl)pyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1581]

[1582] Using 4-(6-(2,5-dihydro-1H-pyrrolo-3-yl)pyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, 4-(6-(1-((5-fluoro-6-methoxypyridin-3-yl)methyl)-2,5-dihydro-1H-pyrrolo-3-yl)pyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (34 mg, white solid, 62%) was obtained by referring to step 6 of Example 1. MS m / z (ESI): 487.1 [M+H] + .

[1583] Example 80

[1584] 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-((6-methoxypyridin-3-yl)methyl)-2,5-dihydro-1H-pyrrolo-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1585]

[1586] Step 1: tert-butyl 3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid ester

[1587]

[1588] Using 4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile and tert-butyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid ester as raw materials, tert-butyl 3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid ester (165 mg, white solid, 65%) was obtained by referring to step 8 of Example 1.

[1589] MS m / z (ESI): 476.2 [M+H] + .

[1590] Step 2: 4-(6-(2,5-dihydro-1H-pyrrolo-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1591]

[1592] Using tert-butyl 3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid ester as a starting material, 4-(6-(2,5-dihydro-1H-pyrrole-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (82 mg, white solid, 67%) was obtained by referring to step 5 of Example 1.

[1593] MS m / z (ESI): 376.1 [M+H] + .

[1594] Step 3: 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-((6-methoxypyridin-3-yl)methyl)-2,5-dihydro-1H-pyrrolo-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1595]

[1596] Using 4-(6-(2,5-dihydro-1H-pyrrolo-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-((6-methoxypyridin-3-yl)methyl)-2,5-dihydro-1H-pyrrolo-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (23 mg, white solid, 42%) was obtained by referring to step 6 of Example 1.

[1597] MS m / z (ESI): 497.2 [M+H] + .

[1598] Example 81

[1599] 6-(3-hydroxy-3-methylbutyl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-7-carbonyl-6,7-dihydropyrazolo[1,5-c]pyrimidin-3-carboxynitrile

[1600]

[1601] MS m / z (ESI): 541.2 [M+H] + .

[1602] Example 82

[1603] 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(methanesulfonyl)ethyl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1604]

[1605] Step 1: 3-Bromo-5-(2-(methanesulfonyl)ethyl)pyridine

[1606]

[1607] 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 h. Then, 3-bromo-5-(bromomethyl)pyridine (500 mg, 2 mmol) was added at -78 °C, and the mixture was slowly brought to room temperature and stirred for 2 h. 10 mL of ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the crude product was separated by column chromatography (washed with dichloromethane / methanol = 10 / 1) to give 3-bromo-5-(2-(methanesulfonyl)ethyl)pyridine (252 mg, yield 48%).

[1608] MS m / z (ESI): 263.9 [M+H] + .

[1609] Step 2: 4-Bromo-6-(2-(methanesulfonyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxylon

[1610]

[1611] Using 3-bromo-5-(2-(methanesulfonyl)ethyl)pyridine as a starting material, 4-bromo-6-(2-(methanesulfonyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (350 mg, white solid) was obtained with reference to Example 11.

[1612] MS m / z (ESI): 327.9 [M+H] + .

[1613] Step 3: 6-(2-(methanesulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1614]

[1615] Using 4-bromo-6-(2-(methanesulfonyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, 6-(2-(methanesulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile was obtained by referring to step 7 of Example 1.

[1616] (230 mg, white solid, 68%).

[1617] MS m / z (ESI): 376.1 [M+H] + .

[1618] Step 4: 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(methanesulfonyl)ethyl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1619]

[1620] Using 6-(2-(methanesulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(methanesulfonyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (30 mg, white solid, 48%) was obtained by referring to step 8 of Example 1.

[1621] MS m / z (ESI): 544.2 [M+H] + .

[1622] Example 83

[1623] 6-(3-hydroxy-3-methylbutyl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1624]

[1625] Referring to Example 82, the product 6-(3-hydroxy-3-methylbutyl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (33 mg, white solid) was obtained.

[1626] MS m / z (ESI): 524.2 [M+H] + .

[1627] Example 84

[1628] 6-(3-hydroxy-3-methylbutyl)-4-(6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1629]

[1630] Referring to Example 82, the product 6-(3-hydroxy-3-methylbutyl)-4-(6-(4-(pyridin-2-oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile (38 mg, white solid) was obtained.

[1631] MS m / z (ESI): 483.2 [M+H] + .

[1632] Example 85

[1633] 6-((1-imino-1-hydroxy-1l6-thiobutane-3-yl)methoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1634]

[1635] Step 1: Thiobutyron-3-ylmethanol

[1636]

[1637] Thiobutyron-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, and the mixture was stirred at -78 °C for 2 h. The mixture was then slowly brought to room temperature and stirred for another 2 h. 10 mL of ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and evaporated to dryness to give the crude product, thiobutyron-3-ylmethanol (314 mg, 72% yield).

[1638] Step 2: 4-Bromo-6-(thiobutan-3-ylmethoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1639]

[1640] Using 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylonitrile and thiobutane-3-ylmethanol as raw materials, 4-bromo-6-(thiobutane-3-ylmethoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (210 mg, white solid, 67%) was obtained in step 2 of Example 1.

[1641] MS m / z (ESI): 323.9 [M+H] + .

[1642] Step 3: 4-Bromo-6-((1-hydroxythiobutyron-3-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1643]

[1644] Using 4-bromo-6-((1-hydroxythiobutyron-3-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, 4-bromo-6-((1-hydroxythiobutyron-3-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (180 mg, white solid, 85%) was obtained by referring to the third step of Example 1.

[1645] MS m / z (ESI): 339.9 [M+H] + .

[1646] Step 4: 4-Bromo-6-((1-imino-1-hydroxy-116-thiobutyron-3-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1647]

[1648] Using 4-bromo-6-((1-hydroxythiobutyron-3-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, 4-bromo-6-((1-imino-1-hydroxy-116-thiobutyron-3-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (150 mg, white solid, 79%) was obtained with reference to Example 3.

[1649] MS m / z (ESI): 354.9 [M+H] + .

[1650] Step 5: 6-((1-imino-1-hydroxy-116-thiobutyron-3-yl)methoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1651]

[1652] Using 4-bromo-6-((1-imino-1-hydroxy-116-thiobutyron-3-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, 6-((1-imino-1-hydroxy-116-thiobutyron-3-yl)methoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (96 mg, white solid, 64%) was obtained by referring to step 7 of Example 1.

[1653] MS m / z (ESI): 403.1 [M+H] + .

[1654] Step 6: 6-((1-imino-1-hydroxy-116-thiobutane-3-yl)methoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1655]

[1656] Using 6-((1-imino-1-hydroxy-116-thiobutyron-3-yl)methoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, 6-((1-imino-1-hydroxy-116-thiobutyron-3-yl)methoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (30 mg, white solid, 34%) was obtained by referring to step 8 of Example 1.

[1657] MS m / z (ESI): 571.2 [M+H] + .

[1658] 1 H NMR (400MHz, MeOD) δ8.53 (s, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 7. 87 (d, J=8.8Hz, 1H), 7.77 (d, J=8.7Hz, 1H), 7.32 (s, 1H), 6.90 (d, J=8.7Hz, 1H ), 6.83(d, J=8.7Hz, 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).

[1659] Example 86

[1660] 6-((1-imino-1-hydroxy-1l6-thiobutyron-3-yl)methoxy)-4-(6-(4-((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1661]

[1662] Using 6-((1-imino-1-hydroxy-116-thiobutyron-3-yl)methoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, 6-((1-imino-1-hydroxy-116-thiobutyron-3-yl)methoxy)-4-(6-(4-((6-methoxypyridin-3-yl)oxo)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (34 mg, white solid, 36%) was obtained by referring to step 8 of Example 1.

[1663] MS m / z (ESI): 560.2 [M+H] + .

[1664] Example 87

[1665] 6-(2-(1-imino-1-hydroxy-1l6-thiobutyron-3-yl)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1666]

[1667] Using 2-(thiobutan-3-yl)ethane-1-ol as a starting material, 6-(2-(1-imino-1-hydroxy-116-thiobutan-3-yl)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (35 mg, white solid) was obtained by referring to Example 85.

[1668] MS m / z (ESI): 585.2 [M+H] + .

[1669] Example 88

[1670] 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(1-hydroxytetrahydro-2H-thiaran-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1671]

[1672] Using 2-(tetrahydro-2H-thiaran-4-yl)ethane-1-ol as a starting material, 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(1-hydroxytetrahydro-2H-thiaran-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile (29 mg, white solid) was obtained by referring to Example 85.

[1673] MS m / z (ESI): 598.2 [M+H] + .

[1674] Example 89

[1675] 6-(2-(1-imino-1-hydroxyhexahydro-1]6-thiaran-4-yl)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1676]

[1677] Using 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-(1-hydroxytetrahydro-2H-thiaran-4-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile as a starting material, 6-(2-(1-imino-1-hydroxyhexahydro-116-thiaran-4-yl)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (18 mg, white solid) was obtained by referring to Example 3.

[1678] MS m / z (ESI): 613.2 [M+H] + .

[1679] Example 90

[1680] 6-((1-imino-1-hydroxyhexahydro-1l6-thiaran-4-yl)oxo)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[1681]

[1682] Step 1: Preparation of 4-bromo-6-((tetrahydro-2H-thiaran-4-yl)oxo)pyrazolo[1,5-a]pyridine-3-carboxylonitrile

[1683]

[1684] 4-Bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylonitrile (10 g, 42.0 mmol) was dissolved in tetrahydrofuran (100 mL), and tetrahydro-2H-thiaran-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 mixture. The reaction was stirred overnight at room temperature. The reaction was quenched by adding water, followed by extraction with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 4-bromo-6-((tetrahydro-2H-thiaran-4-yl)oxo)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (7 g, yield: 49%).

[1685] MS m / z (ESI): 337.9 [M+H] + .

[1686] Step 2: Preparation of 4-bromo-6-((1-imino-1-hydroxyhexahydro-116-thiaran-4-yl)oxo)pyrazolo[1,5-a]pyridine-3-carboxynitrile

[1687]

[1688] 4-Bromo-6-((tetrahydro-2H-thiaran-4-yl)oxo)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (3 g, 8.9 mmol) was dissolved in methanol (40 mL), and ammonium carbonate (1.6 g, 16.9 mmol) and (diacetoxyiodine)benzene (5.7 g, 17.8 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction solution was evaporated to dryness. The crude product was purified by column chromatography to give 4-bromo-6-((1-imino-1-hydroxyhexa...

Claims

1. Compounds represented by general formula (IX-C), their stereoisomers, or pharmaceutically acceptable salts thereof: in: L is selected from -CH2- or -NHC(O)-; G2 is selected from N or CR aa ; M1 is selected from N or CH; M2 is selected from N or CH; R9 is selected from hydrogen, halogens, and C. 1-3 Alkoxy or C 1-3 Deuterated alkoxy groups; R aa Selected from hydrogen or methyl; R 21 and R 22 Together with the nitrogen atoms they are attached to, they form a nitrogen-containing heterocyclic butyl group, wherein the nitrogen-containing heterocyclic butyl group is optionally further selected from hydrogen, halogen, cyano, hydroxyl, C. 1-3 Alkyl and C 1-3 One or more substituents in the hydroxyalkyl group are substituted; R 24 and R 25 Each is independently selected from hydrogen or methyl; Or, R 24 and R 25 Together with the carbon atoms they are attached to and G2, they form a nitrogen-containing heterocyclic butyl group; s can be 0, 1, or 2.

2. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, L is selected from -CH2- or -NHC(O)-; G2 is selected from N, CH or CCH3; M1 is CH; M2 is N; R9 is selected from hydrogen, fluorine, chlorine, methoxy, or deuterated methoxy. R 21 and R 22 Together with the nitrogen atoms to which they are attached, they form a nitrogen-containing heterocyclic butyl group, wherein the nitrogen-containing heterocyclic butyl group may optionally be further substituted with one or more substituents selected from fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, hydroxy, hydroxymethyl, hydroxyethyl or -C(CH3)2OH; R 24 and R 25 It is hydrogen; Or, R 24 and R 25 Together with the carbon atoms they are attached to and G2, they form a nitrogen-containing heterocyclic butyl group.

3. The compound according to claim 2, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, L stands for -CH2; G2 is N; R9 is selected from fluorine, chlorine, methoxy, or deuterated methoxy. R 21 and R 22 Together with the nitrogen atoms to which they are attached, they form an azahexacyclobutane, wherein the azahexacyclobutane may optionally be further substituted with one or more substituents selected from fluorine, chlorine, cyano, methyl, hydroxy, or hydroxymethyl.

4. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, L is selected from -CH2- or -NHC(O)-; G2 is selected from N, CH or CCH3; M1 is selected from N or CH; M2 is selected from N or CH; R9 is selected from methoxy or deuterated methyloxy; R 21 and R 22 Together with the nitrogen atoms they are attached to, they form a nitrogen-containing heterocyclic butyl group, wherein the nitrogen-containing heterocyclic butyl group is optionally further modified by hydrogen, C, or other hydrogen atoms. 1-3 Replaced by one or more substituents in the alkyl or hydroxyl group; R 24 and R 25 Each is independently selected from hydrogen or methyl; Or, R 24 and R 25 Together with the carbon atoms they are attached to and G2, they form a nitrogen-containing heterocyclic butyl group.

5. Of the following compounds, their stereoisomers, or pharmaceutically acceptable salts, wherein, The specific structure of the compound is as follows: or .

6. Of the following compounds, their stereoisomers, or pharmaceutically acceptable salts, wherein, The specific structure of the compound is as follows: 。 7. A method for preparing a compound of the general formula (IX-C) of claim 1, or a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein, Includes the following steps: The reaction of general formula (IX-C1) with general formula (IX-C2) yields the compound shown in general formula (IX-C) or its stereoisomer and its pharmaceutically acceptable salt; in: X2 is a halogen.

8. The method for preparing compounds of general formula (IX-C) or their stereoisomers and pharmaceutically acceptable salts according to claim 7, wherein, X2 is selected from fluorine, chlorine, bromine or iodine.

9. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1 to 6, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers.

10. The use of a compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of a RET inhibitor-related medicament.

11. The application according to claim 10, wherein, The drug is used to treat and / or prevent diseases related to non-small cell lung cancer, fibrosarcoma, pancreatic tumors, medullary thyroid carcinoma, papillary thyroid carcinoma, soft tissue sarcoma, breast tumors, or colon tumors.

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