Cyclic compound as multi-target kinase inhibitor and preparation method thereof

Abstract

The invention discloses a cyclic compound serving as a multi-target kinase inhibitor and a preparation method of the cyclic compound. The multi-target kinase inhibitor disclosed by the invention is shown in a general formula I, and R1, R2, R3, R3a, L1, L2, L3, ring A and ring B are shown in the description and claims. The invention also discloses a preparation method of the general formula I and an activity inhibition test result of the general formula I for inhibiting various kinases. The compound as shown in the general formula I can be used for preparing medicines for treating neurodegenerative diseases such as cancer and Parkinson's disease. # imgabs0 #

Description

Cyclic compounds as multi-target kinase inhibitors and methods for their preparation Technical Field

[0001] The present invention provides a cyclic multi-target kinase inhibitor, specifically its preparation method and use in the treatment and prevention of kinase-mediated inflammatory diseases, cancer, and neurodegenerative diseases, such as cancer, Parkinson's disease, and Alzheimer's disease. The present invention also unexpectedly discovered that multiple cyclic compounds possess the ability to penetrate the blood-brain barrier. Background Art

[0002] Leucine-rich repeat kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson's disease (PD) (Monfrini, E. & Di Fonzo, A. Leucine-Rich Repeat Kinase (LRRK2) Genetics and Parkinson's Disease. Adv. Neurobiol. 14, 3–30 (2017)). LRRK2 gene mutations are also associated with primary PD (Di Maio, R. et al. LRRK2 activation in idiopathic Parkinson's disease. Sci. Transl. Med. 10, (2018)). Therefore, LRRK2 kinase inhibitors may be an effective therapeutic drug for PD. In addition, LRRK2 mutations are also associated with immune-related diseases, such as inflammatory bowel disease (IBD), and are also potential targets for the treatment of such diseases (Wallings RL, et al. LRRK2 at the Interface Between Peripheral and Central Immune Function in Mutations in tyrosine kinases such as FGFR and VEGFR are also clearly associated with the development of various cancers and developmental abnormalities. Therefore, inhibitors of these kinases may become effective therapeutic drugs for the treatment of cancer, Parkinson's disease, developmental abnormalities, Alzheimer's disease, and other neurodegenerative diseases.

[0003] Summary of the Invention

[0004] The present invention discloses a class of cyclic compounds capable of effectively inhibiting multiple kinases.

[0005] Another object of the present invention is to provide a method for preparing the compound.

[0006] The first aspect of the present invention provides a compound as shown in general formula I, or its various isomers and pharmaceutically acceptable salts:

[0007] Where:

[0008] Selected from the following ring structures:

[0009]

[0010] Selected from the following ring structures:

[0011] in:

[0012] R 1 Selected from hydrogen, halogen, cyano, SF5, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 3-10 Cycloalkyl, -NR 4 R 5 , 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; wherein R 1 Each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl group is optionally and independently substituted with one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkoxy and oxo (=O) group substitution;

[0013] R 2 Selected from hydrogen, halogen, cyano, C 1-12 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C(O)R 4 、C(O)OR 4 、-NR 4 R 5 、C(O)NR 4 R 5 , SO2R 4 、SO2NR 4 R 5 , where R 2 Each alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl group is optionally and independently replaced by one or more groups selected from halo, hydroxy, amino, cyano;

[0014] R 3a Selected from hydrogen, halogen, cyano, C 1-12 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C(O)R 4、C(O)OR 4 、-NR 4 R 5 、C(O)NR 4 R 5 , SO2R 4 、SO2NR 4 R 5 , where R 3a Each alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl group is optionally and independently replaced by one or more groups selected from halo, hydroxy, amino, cyano;

[0015] R 3 Independently selected from hydrogen, halogen, cyano, SF5, C 1-12 Alkyl, C 1-12 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, -C(O)R 4 、-C(O)OR 4 、-NR 4 R 5 、-C(O)NR 4 R 5 、SO2R 4 、SO2NR 4 R 5 , where R 3 The alkyl group is optionally replaced by one or more halo or C 1-3 Alkoxy substituted; R 3 and R 3a Can be connected to form N, NR 6 , NC 1-6 alkyl, O or S 5-membered heterocyclic or heteroaromatic ring; or two R 3 Together form = O;

[0016] R 4 and R 5 are each independently selected from hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein R 4 or R 5 Each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl group of R is independently and optionally substituted with one or more groups selected from halo, hydroxy, amino, nitro, cyano, (C1-6)alkoxy and oxo (=O); or R 4 and R5 together with the atoms to which they are attached, form an optionally substituted heterocyclyl;

[0017] Y is a carbon atom or a nitrogen atom, provided that the required covalent bonding requirements are met;

[0018] Z and W are independently CH, CH2, (CR 3 2) t 、(CR 3 ) t , NH, O, S or N; or Z and W together with the substituents to which they are connected form a 3-7 membered ring, including a cycloalkane ring, a cycloalkene ring, a heterocyclic ring or a heteroaromatic ring containing 1-3 heteroatoms, wherein the heteroatoms are selected from N, O or S; or when Z or W is (CR 3 2) t When any two R 3 Connected to a carbon atom to form =0 or a 3-6 membered ring, wherein the ring includes a cycloalkane ring or a cycloalkene ring;

[0019] represents a single bond or a double bond;

[0020] t is 1, 2, or 3.

[0021] Preferably, the compound of formula I Selected from the following ring structures:

[0022] 2 Rs 3 Together with the same carbon atom or different carbon atoms connected thereto, they form a 3- to 10-membered carbocyclic or heterocyclic ring, wherein the heteroatom is selected from N, NH, NC 1-6 Alkyl, O or S;

[0023] L 1 Selected from chemical bonds, -(CR a R b ) n NR 6 (CR a R b ) m -,-O(CR a R b ) n NR 6 (CR a R b ) m -,-(CR a R b ) n NR 6 C(O)-,-O(CR a R b ) n NR 6C(O)-,-(CR a R b ) n C(O)NR 6 -,-O(CR a R b ) n C(O)NR 6 -,-(CR a R b ) n NR 6 (CR a R b ) m NR 6 -、-(CR a R b ) n NR 6 (CR a R b ) m -、-(CR a R b ) n O(CR a R b ) m -、- NR 6 (CR a R b ) n O(CR a R b ) m -、-NR 6 (CR a R b ) m NR 6 -、-(CR a R b ) n O(CR a R b ) m NR 6 -、-(CR a R b ) n O(CR a R b ) m O-,-(CR a R b ) n S(CR a R b ) m -,-(CR a R b ) n S(CR a Rb ) m NR 6 -,-(CR a R b ) m -,-NR 6 (CR a R b ) m -,-(CR a R b ) m NR 6 -,-O(CR a R b ) m -,-(CR a R b ) m O-,-O(CR a R b ) m O-,-(CR a R b ) n NR 6 C 3-6 Cycloalkyl-,-(CR a R b ) n NR 6 C 3-6 Cycloalkyl-NR 6 -,-O(R a R b ) q CH=CH(R a R b ) r -,-(CR a R b ) q CH=CH(CR a R b ) r -,-O(R a R b ) q CH=CH(R a R b ) r NR 6 -,O(CR a R b ) q CH=CH(CR a R b ) r NR 6 C(O)-,-O(CR a R b ) qCH=CH(CR a R b ) r C(O)NR 6 -、-(CR a R b ) q CH=CH(CR a R b ) r NR 6 -、-(CR a R b ) q CH=CH(CR a R b ) r NR 6 CO-、-(CR a R b ) q CH=CH(CR a R b ) r C(O)NR 6 -、-O(R a R b ) n CH=CH(R a R b ) m O-、-NR 6 (R a R b ) n CH=CH(R a R b ) m -、-NR 6 (R a R b ) n CH=CH(R a R b ) m O-、-NR 6 (R a R b ) n CH=CH(R a R b ) m S-、-NR 6 (R a R b ) n CH=CH(R a R b ) m NR 6 -、-S(R a R b ) nCH=CH(R a R b ) m -、S(R a R b ) n CH=CH(R a R b ) m NR 6 -、-NR 6 (R a R b ) n CH=CH(R a R b ) m S-、-(R a R b ) n CH=CH(R a R b ) m S-、-O(R a R b ) n CH=CH(R a R b ) m S-、-S(R a R b ) n CH=CH(R a R b ) m O-, -phenyl-, -heterocyclyl-, -heteroaryl-, NR 6 (CR a R b ) n C≡C(CR a R b ) m -;

[0024] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0025] m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0026] L 2 Selected from-CR a R b -、-CR aa =CR bb -, -C(O)-, -C(O)C(O)-, -C(S)-, -S(O)2-, -C 3-6 Cycloalkyl-, -phenyl-, -5- or 6-membered heterocyclyl-, -5- or 6-membered heteroaryl-;

[0027] L3 Selected from chemical bonds, -(CR a R b ) q -、-(CR a R b ) q -NR 6 -、-NR 6 (CR a R b ) q -、-O(CR a R b ) q -NR 6 -、-NR 6 (CR a R b ) q O-、-O(CR a R b ) q -、-(CR a R b ) q O-、-(CR a R b ) q -C 3-6 Cycloalkyl-, 5-membered or 6-membered heterocyclic group, -(CR a R b ) q -CR aa =CR bb -、-C 3-6 Cycloalkyl-NR 6 -、-(CR a R b ) q NR 6 -、-(CR a R b ) q NR 6 C(O)-、-(CR a R b ) q NR 6 C(O)O-、-(CR a R b ) q C(O)NR 6 -、(CR a R b ) q OC(O)NR 6 -;

[0028] q is selected from 0, 1, 2, 3, 4, 5 or 6;

[0029] r is an integer from 1 to 4;

[0030] R 6 are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Aryl, -C(O)C 1- 6 heteroaryl, -C(O)C 3-6 Cycloalkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 1-6 Aryl, -S(O)2C 1-6 Heteroaryl, -S)O)2C 3-6 Cycloalkyl, -C(O)NR 7 C 1-6 Aryl, -C(O)NR 7 C 1-6 Heteroaryl, -C(O)NR 7 C 3-6 Cycloalkyl, -SO2NR 7 C 1-6 Alkyl, -S(O)2NR 7 C 1-6 Aryl, -S(O)2NR 7 C 1-6 Heteroaryl, -S(O)2NR 7 C 3-6 Cycloalkyl, -C(O)C(O)NR 7 C 1-6 Aryl, -C(O)C(O)NR 7 C 1-6 Heteroaryl, -C(O)C(O)NR 7 C 3-6 Cycloalkyl; wherein R 6 Each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl group is optionally and independently substituted with one or more groups selected from halo, hydroxy, amino, cyano, (C 1-6 ) alkoxy and oxo (=O) group substitution;

[0031] R 7 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein R 7 Each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is optionally and independently substituted with one or more groups selected from halo, hydroxy, amino, cyano, (C 1-6 ) alkoxy and oxo (=O) group substitution;

[0032] R a and Rb independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, hydroxy, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)2, C 1-6 Alkylsulfonyl, S(O)2NH2, S(O)2NHC 1-6 Alkyl, NHC(O)NH2, NHC(O)NHC 1-6 Alkyl, NHC(O)OC 1-6 Alkyl, C(O)-C 1-6 alkyl, 1-6 heteroalkyl, heterocyclyl or heterocyclylalkyl; or R a and R b The carbon atoms to which they are connected can form a three- to six-membered carbocyclic or heterocyclic ring, wherein the heteroatom in the heterocyclic ring is selected from NR 6 ,O,S;

[0033] R aa and R bb independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated cycloalkyl; or R aa and R bb The carbon atoms to which they are connected can form a three- to six-membered carbocyclic or heterocyclic ring, wherein the heteroatom in the heterocyclic ring is selected from NR 6 ,O,S.

[0034] In another preferred embodiment, R 1 and R 2 Each independently selected from hydrogen, halogen, cyano, SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0035] Preferably, the compound of general formula I is a compound represented by formula II:

[0036] where R 1 、R 2 、R 3、R 3a 、L 1 and L 3 The definition of is as described in formula I.

[0037] In another preferred embodiment, the compound of general formula I is a compound represented by formula III:

[0038] where R 1 、R 2 、R 3 、R 3a 、L 1 and L 3 The definition of is as described in formula I.

[0039] In another preferred embodiment, the compound of formula I is a compound represented by formula IV:

[0040] where R 1 、R 2 、R 3 、R 3a 、L 1 、L 2 and L 3 The definition of is as described in Formula I;

[0041] X is N or CR x ; R x Selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, where R x The alkyl group is optionally replaced by one or more halo or C 1-3 Alkoxy substitution;

[0042] In another preferred embodiment, the compound of general formula I is a compound represented by formula V:

[0043] where R 1 、R 2 、R 3a 、L 1 、L 2 and L 3 The definition of is as described in Formula I;

[0044] R 3b Selected from hydrogen, C 1-12 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -C(O)R 4 、-C(O)OR 4and -C(O)NR 4 R 5 , where R 3b The alkyl and cycloalkyl groups are optionally substituted by one or more halogen or C 1-3 Alkoxy substitution;

[0045] R 4 and R 5 are independently selected from hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl, where R 4 or R 5 Each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl group of R is independently and optionally substituted with one or more groups selected from halo, hydroxy, amino, nitro, cyano, (C1-6)alkoxy and oxo (=O); or R 4 and R 5 together with the atoms to which they are attached, form an optionally substituted heterocyclyl;

[0046] X is N or CR x ; R x Selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl;

[0047] In another preferred embodiment, the compound of formula I is a compound represented by formula VI:

[0048] where R 1 、R 2 、R 3 、R 3a 、L 1 、L 2 and L 3 The definition of is as described in Formula I;

[0049] X is N or CR x ; R x Selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl.

[0050] In another preferred embodiment, the compound of general formula I is a compound represented by formula VII:

[0051] where R 1 、R 2 、R 3a 、L 1 、L 2 and L 3 The definition of is as described in Formula I;

[0052] R 3b Selected from C 1-12 Alkyl, C 1-12 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -C(O)R 4 、-C(O)OR 4 and -C(O)NR 4 R 5 , where R 3b The alkyl group is optionally replaced by one or more halo or C 1-3 Alkoxy substitution;

[0053] R 4 and R 5 are independently selected from hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl, where R 4 or R 5 Each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl group of R is independently and optionally substituted with one or more groups selected from halo, hydroxy, amino, nitro, cyano, (C1-6)alkoxy and oxo (=O); or R 4 and R 5 together with the atoms to which they are attached, form an optionally substituted heterocyclyl;

[0054] X is N or CR x ; R x Selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl;

[0055] In another preferred embodiment, the compound of general formula I is a compound represented by formula VIII:

[0056] where R 1 、R 2 、R 3 、R3a 、L 1 、L 2 and L 3 The definition of is as described in formula I.

[0057] In another preferred embodiment, the compound of general formula I is a compound represented by formula IX:

[0058] where R 1 、R 2 、R 3a 、L 1 、L 2 and L 3 The definition of is as described in formula I.

[0059] In another preferred embodiment, the compound of general formula I is a compound represented by formula X:

[0060] where R 1 、R 2 、R 3a 、L 1 、L 2 and L 3 The definition of is as described in formula I.

[0061] R 3 Independently selected from hydrogen, halogen, cyano, SF5, C 1-12 Alkyl, C 1-12 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -C(O)R 4 、-C(O)OR 4 and -C(O)NR 4 R 5 , where R 3 The alkyl group is optionally replaced by one or more halo or C 1-3 Alkoxy substitution;

[0062] R 4 and R 5 are independently selected from hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl, where R 4 or R 5Each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl group of R is independently and optionally substituted with one or more groups selected from halo, hydroxy, amino, nitro, cyano, (C1-6)alkoxy and oxo (=O); or R 4 and R 5 together with the atoms to which they are attached, form an optionally substituted heterocyclyl;

[0063] In another preferred embodiment, the compound of general formula I is a compound represented by formula XI:

[0064] where R 1 、R 2 、R 3 、R 3a 、L 1 、L 2 and L 3 The definition of is as described in formula I.

[0065] In another preferred embodiment, the compound of general formula I is a compound represented by formula XII:

[0066] where R 1 、R 2 、R 3 、R 3a 、L 1 、L 2 and L 3 The definition of is as described in formula I.

[0067] In another preferred embodiment, the compound of general formula I is a compound represented by formula XIII:

[0068] where R 1 、R 2 、R 3a 、L 1 、L 2 and L 3 The definition of is as described in Formula I;

[0069] R 3 Independently selected from hydrogen, halogen, cyano, SF5, C 1-12 Alkyl, C 1-12 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -C(O)R 4 、-C(O)OR 4 and -C(O)NR 4 R 5 , where R 3The alkyl group is optionally replaced by one or more halo or C 1-3 Alkoxy substitution;

[0070] R 4 and R 5 are independently selected from hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl, where R 4 or R 5 Each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl group of R is independently and optionally substituted with one or more groups selected from halo, hydroxy, amino, nitro, cyano, (C1-6)alkoxy and oxo (=O); or R 4 and R 5 Together with the atoms to which they are attached, they form an optionally substituted heterocyclyl.

[0071] In another preferred embodiment, the compound of general formula I is a compound represented by formula XIV:

[0072] where R 1 、R 2 、R 3 、R 3a 、L 1 、L 2 and L 3 The definition of is as described in formula I.

[0073] In another preferred embodiment, the compound of general formula I is a compound represented by formula XV:

[0074] where R 1 、R 2 、R 3 、R 3a 、L 1 and L 3 The definition of is as described in formula I.

[0075] In another preferred embodiment, the compound of general formula I is a compound represented by formula XVI:

[0076] where R 1 、R 2 、R 3 、R 3a 、L 1 and L 3 The definition of is as described in formula I.

[0077] In another preferred embodiment, the compound of general formula I is a compound represented by formula XVII:

[0078] where R 1 、R 2 、R 3 、R 3a 、L 1 and L 3 The definition of is as described in formula I.

[0079] In another preferred embodiment, the compound of general formula I is a compound represented by formula XVIII:

[0080] where R 1 、R 2 、R 3 、R 3a 、L 1 and L 3 The definition of is as described in formula I.

[0081] In another preferred embodiment, the compound of general formula I is a compound represented by formula XIX:

[0082] where R 1 、R 2 、R 3 、R 3a 、L 1 and L 3 The definition of is as described in formula I.

[0083] In another preferred embodiment, the compound of general formula I is a compound represented by formula XX:

[0084] where R 1 、R 2 、R 3 、R 3a 、L 1 and L 3 The definition of is as described in formula I.

[0085] In another preferred embodiment, the compound of general formula I is a compound represented by formula XXI:

[0086] where R 1 、R 2 、R 3 、R 3a 、L 1 and L 3 The definition of is as described in formula I.

[0087] In another preferred embodiment, the compound of general formula I is a compound represented by formula XXII:

[0088] where R 1 、R 2 、R 3 、R 3a 、L 1 and L 3 The definition of is as described in formula I.

[0089] In another preferred embodiment, in all general formulas, R 1 and R 2 independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl;

[0090] R 3 Selected from hydrogen, halogen, NR 4 R 5 , CF3, SF5, CN;

[0091] R 3a Selected from hydrogen, halogen, CF, CN, NR 4 R 5 , SO2Me, SO2cyclopropane, SO2NR 4 R 5 ;

[0092] L 3 Selected from:

[0093] where R a and R b independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, hydroxy; or R a and R b The carbon atoms to which they are connected can form a three- to six-membered carbocyclic or heterocyclic ring, wherein the heteroatom in the heterocyclic ring is selected from NR 6 ,O,S;R 6 As defined above.

[0094] In another preferred embodiment, L in the compound of formula I 2 Selected from -C(O)- or the following heterocyclic structures:

[0095] The above heterocycle may be substituted by one or two halogens, -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0096] In another preferred embodiment, the compounds of Formula I to Formula XXII are:

[0097] In another preferred embodiment, the compounds of Formula I to Formula XXII include all stereoisomers.

[0098] In another preferred embodiment, the compounds of Formula I to Formula XXII include all atropisomers.

[0099] In another preferred embodiment, the stereoisomers of the compounds of Formula I to Formula XXII are cis-trans isomers.

[0100] In another preferred embodiment, the compounds of Formula I to Formula XXII are optically pure isomers.

[0101] In another preferred embodiment, the compounds of Formula I to Formula XXII are racemates.

[0102] In another preferred embodiment, the compounds of Formula I to Formula XXII are enantiomers.

[0103] In another preferred embodiment, any one or more hydrogen atoms in the compounds of Formula I to Formula XXII may be replaced by a deuterium atom.

[0104] In another preferred embodiment, the compounds of Formula I to Formula XXII include prodrugs thereof.

[0105] In another preferred embodiment, the pharmaceutically acceptable salts of Formula I to Formula XXII are selected from the following group: hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate (toluenesulfonate), 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, and mandelate.

[0106] definition

[0107] The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, including straight-chain and branched hydrocarbon groups, such as methyl (i.e., CH3-), ethyl (i.e., CH3CH2-), n-propyl (i.e., CH3CH2CH2-), isopropyl (i.e., (CH3)2CH-), n-butyl (i.e., CH3CH2CH2CH2-), isobutyl (i.e., (CH3)2CHCH2-), sec-butyl (i.e., (CH3)(CH3CH2)CH-), tert-butyl (i.e., (CH3)3C-), n-pentyl (i.e., CH3CH2CH2CH2CH2-), and neopentyl (i.e., (CH3)3CCH2-).

[0108] As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6 to 14) carbon atoms, which may have a single ring (e.g., phenyl) or a fused ring (e.g., naphthyl or anthracenyl). If the point of attachment is at an aromatic carbon atom, the fused ring may be non-aromatic (e.g., 2-benzoxazolone, 2H-1,4-benzoxazin-3(4H)-on-7-yl, etc.). Preferred aryl groups include phenyl and naphthyl.

[0109] As used herein, the term "alkenyl" refers to an alkenyl group having 2 to 10 (such as 2 to 6 or 2 to 4) carbon atoms and having at least 1 (such as 1 to 2) unsaturated olefinic bonds (>C=C<). Examples of such groups include vinyl, allyl, and but-3-enyl. As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms and having a single or multiple rings (including fused systems, bridged ring systems, and spiro ring systems). In a fused ring system, one or more rings may be cycloalkyl, heterocyclic, aryl, or heteroaryl, as long as the connection point is through the ring of the cycloalkyl group. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

[0110] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0111] As used herein, the term "heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can be monocyclic (e.g., pyridyl or furanyl) or fused rings (e.g., indolizinyl or benzothienyl), wherein the fused rings can be non-aromatic and / or contain one heteroatom, as long as the point of attachment is through an aromatic heteroaryl atom. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to N-oxide (NO), sulfinyl, or sulfonyl. Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, thienyl, and furanyl.

[0112] As used herein, the term "substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the same substituents as defined for substituted aryl.

[0113] As used herein, the term "heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated, partially saturated or unsaturated group (but not aromatic) having a single ring or fused rings (including bridged and spiro ring systems) with 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen within the ring. In a fused ring system, one or more rings can be cycloalkyl, aryl or heteroaryl, as long as the point of attachment is through the non-aromatic ring. In one embodiment, the nitrogen atom and / or sulfur atom of the heterocyclic group is optionally oxidized to provide N-oxide, sulfinyl and sulfonyl moieties.

[0114] As used herein, the term "substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclic group substituted with 1 to 5 (e.g., 1 to 3) substituents, the substituents being the same as those defined for substituted cycloalkyl.

[0115] When not otherwise specified, each cycloalkyl group is C 3-6 Cycloalkyl, each heterocyclic group is a 3-10 membered heterocyclic group, each aryl is C 6-10 Aryl, each heteroaryl is a 5-10 membered heteroaryl.

[0116] The substituents are selected from, but not limited to, the following chemical groups: halogen, -C 1-6 Alkyl, -C 3-8 Cycloalkyl, -C 1-6 Haloalkyl, -C 3-8 Halogenated cycloalkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkoxy, -C 1-6 Alkylthio, -C 0-6 Alkylene-OH, nitro, aldehyde, -SF5, -C 0-6 Alkylene-NR a R b 、-C 0-6 Alkylene-carboxyl, -C 0-6 Alkylene-COR a 、-C 0-6 Alkylene-CO2R a 、-C 0-6 Alkylene-CONR d R e 、-C 0-6 Alkylene-SO2R a 、-C 0-6 Alkylene-SO2NR d R e , carbonyl, -C 0-6 Alkylene-CN,-C3-8cycloalkyl-OH,-C 2-6 Alkenyl, C 2-6 Alkynyl, -C0-6 Alkylene-S(O)(NH)C 1-6 alkyl,-C 0-6 Alkylene-S(O)(NCN)C 1-6 alkyl,-C 0-6 Alkylene-NR c S(O)2R b ,-C 0-6 Alkylene-NR c S(O)2NR c R b ,-C 0-6 Alkylene-NR c C(O)NH2,-C 0-6 Alkylene-NR c C(O)R b ,-C 0-6 Alkylene-NR c C(O)NR d R e ,-C 0-6 Alkylene-NR c C(O)OR b ,-C 0-6 Alkylene-NRSO2R b C(O)-R b ,-C 0-6 Alkylene-P(O)R c R b ,-C 0-6 Alkylene-P(O)(OR c )(OR b ),-C 0-6 Alkylene-C(O)C 1-6 Alkyleneamino, C 1-6 Heteroalkyl, C 5-10 Carbon ring, C 5-10 Aryl, C 2-10 Heterocyclic, C 2-10 Heteroaromatic ring.

[0117] In this application, C 0-6 Alkylene refers to a group having no alkylene or having C 1-6 Alkylene.

[0118] As used herein, the term "stereoisomer" refers to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

[0119] As used herein, the term "tautomer" refers to alternative forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups that contain ring atoms attached to an -NH- portion of the ring and an =N- portion of the ring, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0120] "Prodrug" refers to any derivative of a compound of the Examples that, when administered to a subject, is capable of providing, directly or indirectly, a compound of the Examples or its active metabolite or residue. Particularly preferred derivatives and prodrugs are those that, when administered to a subject, increase the bioavailability of a compound of the Examples (e.g., an orally administered compound is more readily absorbed into the bloodstream) or increase the delivery of the parent compound to biological compartments (e.g., the brain or lymphatic system) relative to the parent species. Prodrugs include ester forms of the compounds of the invention.

[0121] When the compounds described in the present invention exist as stereoisomers, the present invention includes all stereoisomers of the compounds.

[0122] When the compounds described in the present invention exist as tautomers, the present invention includes all tautomers of the compounds.

[0123] In the case where the compounds described in the present invention exist as tautomers, the present invention includes all atropisomers of the compounds.

[0124] The present invention also includes deuterated compounds in which any one or more hydrogen atoms in the compounds are replaced by its stable isotope deuterium.

[0125] The present invention also provides active ingredients within a safe and effective amount of the compounds of formula I and formula XXII, and pharmaceutically acceptable carriers.

[0126] The "active ingredient" described in the present invention refers to the compounds of Formula I to Formula XXII described in the present invention.

[0127] The "active ingredient" and pharmaceutical composition of the present invention can be used to treat diseases such as neurodegenerative diseases (including Parkinson's disease) and cancer.

[0128] A "safe and effective amount" refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, a pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one tablet or capsule.

[0129] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gels suitable for human use and of sufficient purity and low toxicity. "Compatibility" as used herein refers to the ability of the components of the composition to be compatible with the active ingredient of the present invention, and with each other, without significantly reducing the efficacy of the active ingredient.

[0130] Typically, the compounds of the preferred embodiments will be administered in a therapeutically effective amount, via any acceptable mode of administration for similarly acting agents. The actual dosage of the compounds (i.e., active ingredients) of the preferred embodiments will be determined based on a number of factors, such as the severity of the disease to be treated, the age and relative health of the patient, the efficacy of the compound being used, the route and form of administration, and other factors. The drug may be administered multiple times a day, preferably once or twice a day. All of these factors are within the consideration of the attending physician.

[0131] For the purposes of the preferred embodiments, a therapeutically effective dose can generally be a total daily dose administered to a patient in a single or divided dose, for example, from about 0.001 to about 1000 mg / kg body weight per day, preferably from about 1.0 to about 30 mg / kg body weight per day. A dosage unit composition may contain a dosage factor thereof to form a daily dose. The choice of dosage form depends on various factors, such as the mode of administration and the bioavailability of the drug substance. Generally, the compounds of the preferred embodiments can be administered as pharmaceutical compositions by any of the following routes: oral, systemic (e.g., transdermal, intranasal, or via suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). The preferred route of administration is oral, and a convenient daily dose can be adjusted based on the degree of bitterness. The composition can take the form of a tablet, pill, capsule, semisolid, powder, sustained-release formulation, solution, suspension, elixir, aerosol, or any other suitable composition. Another preferred method of administering the compounds of the preferred embodiments is by inhalation. This is an effective method for delivering therapeutic agents directly to the respiratory tract (see, e.g., U.S. Patent No. 5,607,915).

[0132] Suitable pharmaceutically acceptable carriers or excipients include, for example, treating agents and drug delivery modifiers and accelerators, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting point waxes, ion exchange resins, and combinations of any two or more thereof. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including petroleum, animal oils, vegetable oils, or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous glucose solutions, and ethylene glycol. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0133] As used herein, the term "pharmaceutically acceptable salt" refers to non-toxic acid or alkaline earth metal salts of compounds of Formula I to Formula XXII. These salts can be prepared in situ during the final isolation and purification of the compounds of Formula I to Formula XXII, or by reacting a suitable organic or inorganic acid or base with a basic or acidic functional group, respectively. Representative salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, gluconate heptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthylsulfonate, oxalate, pamoate, pectinate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, and undecanoate. In addition, nitrogen-containing basic groups can be quaternized with the following reagents: alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long-chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides, etc. This results in water-soluble, oil-soluble, or dispersible products. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, and citric acid. Base addition salts can be prepared in situ during the final isolation and purification of the compounds of Formulas I to XXII, or by reacting the carboxylic acid moiety with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate), ammonia, or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, salts based on alkali and alkaline earth metal cations, such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0134] The second aspect of the present invention provides a method for preparing the compounds of Formula I to Formula XXII described in the first aspect, wherein the method is selected from one of the following schemes.

[0135] Compound IA is reacted with the corresponding bromide using a base to give I-1, followed by reduction of the nitro group to amine I-2 (reduction conditions include but are not limited to Zn / AcOH, Fe / NH4Cl / EtOH, Zn / NH4Cl / EtOH, Pd / C / H2 / MeOH), amine I-2 is reacted with a suitably substituted 2,4-dichloropyrimidine under acid catalysis to give I-3 (acid catalysis conditions include but are not limited to pTsOH, ZnCl2), and then reacted with mono-Boc diamine under alkaline conditions to give I-4 (alkaline conditions include but are not limited to D IPEA, TEA), and the ester is hydrolyzed under alkaline conditions to obtain I-5 (alkaline conditions such as but not limited to KOH / H2O, NaOH / H2O, LiOH / H2O), followed by removal of Boc under acidic conditions to obtain I-6 (acidic conditions such as but not limited to TFA / DCM, HCl / 1,4-dioxane), and finally intramolecular condensation using a condensation reagent to obtain the final product I (condensation reagent such as but not limited to HOAT, HOBT, HATU, EDCI, BOP, TCFH / NMI).

[0136] (Boc)2NH reacts with the corresponding dibromoalkane under alkaline conditions to obtain II-1 (alkaline conditions such as but not limited to K2CO3, Cs2CO3), and then reacts with the corresponding azido alcohol or azidothiol under alkaline conditions to obtain II-2 (alkaline conditions such as but not limited to nBuLi, NaH), and then reacts under acidic conditions to obtain II-3 (acidic conditions such as but not limited to TFA / DCM, HCl / 1,4-dioxane). Compound II-3 reacts with intermediate I-3 under alkaline conditions to obtain II-4 (alkaline conditions such as but not limited to DIPEA, TEA), and then the azide group is reduced to amine II-5 (reduction conditions such as but not limited to Pd / C / H2 / EA, PtO2 / MeOH, Raney-Ni / N2H4 H2O / TEA / MeOH), and the ester is hydrolyzed under alkaline conditions to obtain II-6 (alkaline conditions such as but not limited to KOH / H2O, NaOH / H2O, LiOH / H2O), and intramolecular condensation is carried out using a condensation reagent to obtain the final product II (condensation reagents such as but not limited to HOAT, HOBT, HATU, EDCI, BOP, TCFH / NMI).

[0137] The corresponding mono-Boc diamine reacts with a suitably substituted 2,4-dichloropyrimidine under alkaline conditions to give III-1 and III-2 (basic conditions such as but not limited to DIPEA, TEA), and a suitably substituted 1-hydropyrazole is nitrated under acidic conditions to give III-3 (nitration conditions such as but not limited to 98% H2SO4 / 68% HNO3, 98% H2SO4 / KNO3, Ac2O / 68% HNO3), which reacts with 1,2-dichloroethane under alkaline conditions to give intermediate III-4, which is then reacted with a suitably substituted ethyl diazoacetate to give III-5, and the nitro group is subsequently reduced to amine III-6 (reduction conditions such as but not limited to Zn / AcOH, Fe / NH4Cl / EtOH, Zn / NH4 Cl / EtOH, Pd / C / H2 / MeOH), amine III-6 reacts with compound III-1 under acid catalysis to obtain III-7 (acid catalysis conditions such as but not limited to pTsOH, ZnCl2), and the ester is hydrolyzed under alkaline conditions to obtain III-8 (alkaline conditions such as but not limited to KOH / H2O, NaOH / H2O, LiOH / H2O), followed by reaction under acidic conditions to obtain III-9 (acidic conditions such as but not limited to TFA / DCM, HCl / 1,4-dioxane), and intramolecular condensation is carried out using a condensation reagent to obtain the final product III (condensation reagents such as but not limited to HOAT, HOBT, HATU, EDCI, BOP, TCFH / NMI).

[0138] Starting from IX-1, chlorination with a chlorination reagent such as NCS yields product IX-2, which is then substituted with a haloamine compound under alkaline conditions to yield product IX-3. Under acidic conditions, such as CF3COOH, IX-3 undergoes substitution with I-2 to yield IX-4. This is followed by ester hydrolysis and removal of the BOC protecting group under acidic conditions, followed by ring closure with an amide condensation reagent such as HATU to yield the target product IX.

[0139] Starting from X-1, an acid-catalyzed reaction with I-2 yields X-2. Halogenation is then performed using a suitable halogenating agent such as NIS or NBS, followed by protection with a suitable protecting group such as BOC or Ts to yield X-3. X-3 undergoes a Sonogashira reaction with a suitable alkynylamine to yield X-4, which is then reduced using Ranney Ni to yield X-5. X-5 undergoes ester hydrolysis and acid-catalyzed deprotection, followed by ring closure using an amide condensation reagent to yield X-8. Substitution is then performed on X-8 under appropriate conditions to yield the final product, X.

[0140] Starting from intermediate I-1, the ester is hydrolyzed under basic conditions (e.g., but not limited to, KOH / H2O, NaOH / H2O, or LiOH / H2O) to yield XI-1. Subsequently, the carboxyl group is reduced to an alcohol using a reducing agent, such as borane dimethyl sulfide, to yield XI-2. The alcohol is then oxidized using a suitable oxidizing agent to yield aldehyde XI-3 (e.g., but not limited to, DMP, PCC, or PDC). Intermediate XI-3 is alkynylated using a suitable reagent, such as the Bestmann-Ohira reagent, to yield XI-4. This is then subjected to a click reaction with a suitable azide-substituted Boc amine to yield intermediate XI-5. XI-5 is then deprotected under suitable conditions (e.g., but not limited to, TFA / DCM, HCl / 1,4-dioaxane) to yield XI-6. Then, under alkaline conditions (such as but not limited to TEA and DIPEA), the intermediate XI-7 is reacted with a suitable substituted 2,4-dichloropyrimidine to obtain the intermediate XI-7; finally, a reduction reaction is carried out in the presence of a suitable metal (such as but not limited to Zn and Fe), and the final product XI is obtained by one-step ring closure.

[0141] Intermediate XI-4 is reacted with TMSN3 in a click reaction to yield intermediate XII-1. This is then substituted with a suitable bromo-substituted Boc amine under basic conditions, such as cesium carbonate, to yield XII-2. The Boc protecting group of XII-2 is removed under suitable conditions (such as, but not limited to, TFA / DCM, HCl / 1,4-dioaxane) to yield XII-3. This is then reacted with a suitable substituted 2,4-dichloropyrimidine under basic conditions (such as, but not limited to, TEA or DIPEA) to yield intermediate XII-4. Finally, reduction in the presence of a suitable metal (such as, but not limited to, Zn or Fe) results in a one-step ring closure to yield the final product XII.

[0142] Intermediate XI-2 is reacted with TsCl under basic conditions, such as TEA, to produce XIII-1, which is then reacted with sodium azide to produce intermediate XIII-2. Intermediate XIII-2 undergoes a click reaction with a suitable Boc aminoalkyne to produce intermediate XIII-3. The Boc protecting group is then removed under suitable conditions (such as, but not limited to, TFA / DCM, HCl / 1,4-dioaxane) to produce XIII-4. Intermediate XIII-4 is reacted with a suitable substituted 2,4-dichloropyrimidine under basic conditions (such as, but not limited to, TEA or DIPEA) to produce intermediate XIII-5. Finally, reduction in the presence of a suitable metal (such as, but not limited to, Zn or Fe) results in a one-step ring closure to yield the final product XIII.

[0143] Starting from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine, a halogen is removed by reduction with NaBH4, followed by halogenation with a halogenating agent such as NBS to afford XIV-2. XIV-2 undergoes a Sonogashira coupling reaction with an alkynamine, followed by reduction of the alkynyl group to an alkyl group with PtO2 to afford XIV-4. XIV-4 undergoes a Buchwald coupling reaction with an aminopyrazole to afford XIV-5, followed by ester hydrolysis and BOC removal to afford XIV-6. XIV-6 is condensed with an amide condensation reagent such as COMU, followed by chlorination with a halogenating agent such as NCS to afford XIV.

[0144] The third aspect of the present invention provides the use of the compounds of formula I to formula XXII described in the first aspect for:

[0145] (i) preparing multi-kinase inhibitors for the treatment of neurodegenerative diseases, inflammatory diseases (such as IBD) and cancer;

[0146] (ii) preparing drugs for preventing and / or treating LRRK2-mediated diseases, especially Parkinson's disease;

[0147] (iii) Preparation of combination drugs for tumor treatment comprising compounds of Formula I to Formula XXII and other tumor drugs: PD-1 antibodies, CTLA-4 antibodies, PD-L1 antibodies, PD-L2 antibodies, adoptive cell transplantation therapy, cancer vaccines, IDO (indoleamine 2,3-dioxygenase) inhibitors, TDO (tryptophan dioxygenase) inhibitors, IDO / TDO dual inhibitors, EP4 antagonists, HDAC (histone deacetylase) inhibitors, STING (stimulator of interferon genes) activators, kinase inhibitors, any other chemotherapy drugs or targeted therapy drugs, radiotherapy drugs.

[0148] (iv) Preparation of methods for preventing and / or treating diseases mediated by FGFR, VEGFR, RET, DYRK2, TYRO3, etc., such as cancer and chondrodysplasia.

[0149] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0150] The following abbreviations have the indicated meanings: BETAC: benzyltriethylammonium chloride; EA: ethyl acetate; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM: dichloromethane; DIBAL: diisobutylaluminum hydride; DIPEA: diisopropylethylamine; DMAP: N,N-dimethylaminopyridine; DME: 1,2-dimethoxyethane; DMF: N,N-dimethylformamide; DMPE: 1, 2-Bis(dimethylphosphino)ethane; DMSO: dimethyl sulfoxide; DPPB: 1,4-bis(diphenylphosphino)butane; DPPE: 1,2-bis(diphenylphosphino)ethane; DPPF: 1,1'-bis(diphenylphosphino)ferrocene; DPPM: 1,1'-bis(diphenylphosphino)methane; DIAD: diisopropyl azodicarboxylate; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; HATU: O- (7-Azobenzotriazole)-1,1,3,3-tetramethyluronium hexafluorophosphate; HMPA: hexamethylphosphoramide; HOAT: N-hydroxy-7-azobenzotriazole; IPA: isopropyl alcohol; LDA: lithium diisopropylamide; LHMDS: lithium bis(hexamethyldisilazide); LAH: lithium aluminum hydride; NCS: N-chlorosuccinimide; PE: petroleum ether; PyBOP: benzotriazol-1-yloxytripyrrolidino hexafluorophosphate phosphate; TDA: tris[2-(2-methoxyethoxy)ethyl]amine; DCM: dichloromethane; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; NCS: N-chlorosuccinimide; NMM: N-methylmorpholine; NMP: N-methylpyrrolidone; PPh3: triphenylphosphine; RT: room temperature; T3P: propylphosphonic anhydride; TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate.

[0151] Reversed-Phase HPLC Purification Conditions: HPLC-MS analysis was performed on a Waters HPLC 2790 using a Waters micromass ZQ 4000 (MAA050) mass detector and a Waters 2487 UV detector. The column used was a Phenomenex OOB-4605-E0 (5U-XB-C18-100A, 50 x 4.6 mm). The mobile phase consisted of eluent A (water, 0.05% TFA) and eluent B (CH3CN, 0.05% TFA), with an elution rate of 1 mL / min. Initial conditions were 90% A for 1 minute, followed by a linear decrease from 90% A to 10% A over 5 minutes, and then a return to 90% A over 1 minute. The total run time was 7 minutes. The mobile phase gradient and run time can be adjusted appropriately based on the properties of the compound.

[0152] Chiral HPLC separation conditions: An Agilent Technologies 1200 Infinity LC system was used, with a Daicel CHIRALPAK IG column (Cat. No. IG00EE-AT002). The mobile phase consisted of eluent A (n-hexane) and eluent B (ethanol), with an elution rate of 3 ml / min and a constant ethanol ratio. The ethanol ratio in the mobile phase and run time can be adjusted based on the compound properties and chiral column type. DETAILED DESCRIPTION

[0153] With reference to the following examples, it is easier to understand the content of the present invention, which are provided to illustrate the present invention rather than to limit its scope. Unless otherwise indicated, percentages and parts are all calculated by weight, and units are parts by weight.

[0154] Unless otherwise stated, the materials and reagents used in the examples of the present invention are commercially available products.

[0155] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0156] Example 1: T-1

[0157] (E)-3 3 ,4,4-trimethyl-15-(trifluoromethyl)-3 1 H-2,6,10-Triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclodecane-5-one

[0158] Step 1: Preparation of Z-1

[0159] 3-Methyl-4-nitropyrazole (7.34 g, 1.0 eq) was dissolved in DMF and stirred in an ice bath. Potassium carbonate (12 g, 1.5 eq) was added portionwise and stirred at room temperature for 10 minutes. Methyl 2-bromoisobutyrate (15.68 g, 1.5 eq) was added dropwise in an ice bath and allowed to react at room temperature for 15-20 hours. Upon completion, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The organic phase was isolated and purified by flash column chromatography (100% PE-10% EA:PE) to obtain Intermediate Z-1 (12.77 g, a colorless oil).

[0160] MS ESI: m / z = 228.1, [M+H] + .

[0161] Step 2: Preparation of Z-2

[0162] Intermediate Z-1 (4.62 g) was dissolved in methanol, stirred at room temperature, and the atmosphere was purged with nitrogen. 10% Pd / C (454 mg) was added, the atmosphere was purged with hydrogen, and the reaction was allowed to proceed at room temperature for 18 h. After the reaction was completed, the atmosphere was purged with nitrogen, and the product was filtered through Celite. The filtrate was concentrated and purified by flash column chromatography (50% EA:PE-100% EA) to afford Intermediate Z-2 (3.92 g, brown oil).

[0163] MS ESI: m / z = 198.1, [M+H] + .

[0164] Step 3: Preparation of Z-3

[0165] Intermediate Z-2 (1.97 g, 1.0 eq) was dissolved in isopropanol (30 mL) and stirred at room temperature. Zinc chloride (1.64 g, 1.2 eq) was added and allowed to react at room temperature for 2 h. 2,4-Dichloro-5-trifluoromethylpyrimidine (2.39 g, 1.1 eq) was dissolved in dichloromethane (64 mL) and stirred in an ice bath. Z-7 was added dropwise. After addition, the mixture was allowed to react in an ice bath for 1 h. Triethylamine (1.1 g, 1.1 eq) was then added dropwise in an ice bath and stirred for 1 h. Upon completion of the reaction, 5% sodium bicarbonate solution (48 mL) was added to quench the reaction. The mixture was diluted with dichloromethane and filtered through celite. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated and purified by flash column chromatography (100% PE-20% EA:PE) to obtain intermediate Z-3 (3.6 g, creamy yellow solid).

[0166] MS ESI: m / z = 378.1, [M+H] + .

[0167] Step 4: Preparation of Z-4

[0168] Intermediate Z-3 (1.1 g, 1.0 eq) was dissolved in acetonitrile (20 mL) and stirred at room temperature. N-Boc-1,3-propylenediamine (608 mg, 1.2 eq) and triethylamine (587 mg, 2 eq) were added and reacted at room temperature for 16 h. After the reaction, the system was concentrated and purified by flash column chromatography (100% PE-50% EA:PE) to obtain intermediate Z-4 ​​(1.2 g).

[0169] MS ESI: m / z = 516.1, [M+H] + .

[0170] Step 5: Preparation of Z-5

[0171] Intermediate Z-4 ​​(270 mg, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and stirred at room temperature. Water (0.5 mL) and lithium hydroxide monohydrate (26.4 mg, 1.2 eq) were added and allowed to react at room temperature for 2 h. Upon completion of the reaction, water and ethyl acetate were added. The pH of the system was adjusted to 4 with 1 M hydrochloric acid. The product was extracted twice with ethyl acetate. The organic phases were combined, concentrated, and purified by flash column chromatography (100% DCM-20% MeOH:DCM) to obtain intermediate Z-5.

[0172] Step 6: Preparation of Z-6

[0173] Intermediate Z-5 (50 mg, 1.0 eq) was dissolved in dichloromethane (1 mL, 0.1 M) and stirred at room temperature. TFA (205 mg, 18.0 eq) was added and allowed to react at room temperature for 1 h. Upon completion of the reaction, the system was concentrated and toluene (2 mL) was added to obtain the crude product Z-6, which was then used for the next ring-closure reaction.

[0174] Step 7: Preparation of T-1

[0175] The crude product Z-6 from step 7 was dissolved in ultra-dry DMF (2.5 mL, 0.04 M). HATU (42 mg, 1.1 eq) and DIPEA (65 mg, 5.0 eq) were added with stirring at room temperature and allowed to react for 1 h. After the reaction, water and ethyl acetate were added. Extraction was performed with ethyl acetate, and the organic phase was washed five times with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by flash column chromatography (100% DCM-5% MeOH:DCM) to yield 30 mg of a white solid, T-1.

[0176] MS ESI: m / z = 384.2, [M+H] + .

[0177] 1 H NMR (400 MHz, CDCl3) δ8.11(s,1H),7.74(s,1H),6.76(s,1H),5.40(s,1H),4.68(s,1H),3.30(q,J=7.4 Hz,2H),3.16(q,J=5.7,5.3 Hz,2H),2.24(s,3H),1.88(s,6H),1.52–1.42(m,2H).

[0178] Example 2: T-2

[0179] (E)-3 3 ,4,4-trimethyl-1 5 -(trifluoromethyl)-3 1 H-9-oxa-2,6,13-triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclotridecan-5-one

[0180] Step 1: Preparation of Z-7

[0181] Using M-5 (21 mg, 1.0 eq) and Z-3 (66 mg, 1.2 eq) as raw materials, the intermediate Z-7 (52.6 mg, colorless oil) was obtained under the same conditions as the preparation of Z-4 in the fourth step of Example 1.

[0182] MS ESI: m / z = 486.2, [M+H] + .

[0183] Step 2: Preparation of Z-8

[0184] The intermediate Z-7 (31 mg) was dissolved in ethyl acetate (1.5 mL), stirred at room temperature, replaced with nitrogen, and 10% Pd / C (5 mg) was added, replaced with hydrogen, and reacted at room temperature for 2 h. The reaction solution was filtered through celite, rinsed with methanol, and the filtrate was concentrated to obtain the crude product Z-8 (28 mg).

[0185] MS ESI: m / z = 460.2, [M+H] + .

[0186] Step 3: Preparation of Z-9

[0187] Using Z-8 (14.4 mg) as the starting material, the intermediate Z-9 was obtained using the same conditions as those used in the preparation of Z-5 in the fifth step of Example 1.

[0188] MS ESI: m / z = 446.2, [M+H] + .

[0189] Step 4: Preparation of T-2

[0190] Using the crude product Z-9 as the starting material, 10 mg of white solid T-2 was obtained under the same conditions as in step 7 of Example 1.

[0191] MS ESI: m / z = 428.2, [M+H] + .

[0192] 1H NMR (400 MHz, CDCl3) δ8.12–8.09(m,1H),7.74(s,1H),6.42(s,1H),5.87(s,1H),5.10(s,1H),3.59(dt,J=10.9,6.1 Hz,2H),3.42(t,J=5.2 Hz, 4H), 3.37 (t, J = 5.2 Hz, 2H), 2.22 (s, 3H), 1.84 (s, 6H), 1.76 (dq, J = 10.6, 5.5 Hz, 2H).

[0193] Example 3: T-3

[0194] (±)-(1 1 R,1 2 S,2 1 R,E)-2 3 -cyclopropyl-4- 5 -(trifluoromethyl)-2 1 H-3,5,9-Triaza-4(2,4)-pyrimidin-2(1,4)-pyrazol-1(1,2)-cyclopropylcyclodecane-10-one

[0195] Step 1: Preparation of Z-10

[0196] Place concentrated sulfuric acid (29 mL) in a 250 mL single-necked flask, keep warm in an ice bath, and slowly add 3-cyclopropyl-pyrazole (5 g, 1.0 eq) dropwise. Stir in an ice bath for 5 minutes after addition. Continue to add concentrated nitric acid (3.5 mL, 1.1 eq) dropwise. Incubate in an ice bath for 1 hour. Upon completion of the reaction, add the system to 300 mL of ice water and extract three times with ethyl acetate. Combine the organic phases, wash with saturated sodium bicarbonate solution until neutral, then with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate to yield crude product Z-10 (5.6 g, brownish-red solid).

[0197] MS ESI: m / z = 154.2, [M+H] + .

[0198] Step 2: Preparation of Z-11

[0199] Dissolve Z-10 (5.6 g, 1.0 eq) in 1,2-dichloroethane (50 mL) and stir at room temperature. Add benzyltriethylammonium chloride (833.7 mg, 0.1 eq). Stir in an ice bath, then add NaOH solution (7.3 g, 5 eq, 10 mL). Replace the atmosphere with nitrogen and react at 80°C for 8 hours before cooling to room temperature. Filter the reaction mixture, concentrate the filtrate, and purify it by flash column chromatography (100% PE-20% EA:PE) to obtain Z-11 (2.6 g, white solid).

[0200] MS ESI: m / z = 180.1, [M+H] + .

[0201] Step 3: Preparation of Z-12 and Z-13

[0202] Z-11 (2.59 g, 1.0 eq) and bis((α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)rhodium) (110 mg, 0.01 eq) were dissolved in dichloromethane (55 mL) and stirred at room temperature. A solution of ethyl diazoacetate (9.9 g, 6.0 eq) in dichloromethane (16.5 mL) was slowly added dropwise (approximately 2 h) in an ice bath. The mixture was allowed to react at room temperature for 12 h. The reaction solution was concentrated and purified by flash column chromatography (100% PE-5% EA:PE-20% EA:PE) to afford Z-13 (1.53 g Rf: 0.5 ± 20% EA:PE) as a blue solid and Z-12 (1.13 g Rf: 0.3 ± 20% EA:PE) as a brown solid.

[0203] MS ESI: m / z = 266.1, [M+H] + .

[0204] Step 4: Preparation of Z-14

[0205] Z-12 (265.3 mg, 1.0 eq) was dissolved in ethanol (5.5 mL), and water (1.5 mL) was added. The mixture was stirred at room temperature, and ammonium chloride (230 mg, 4.3 eq) and reduced iron powder (240 mg, 4.3 eq) were added. After reacting at 80°C for 2 hours, the mixture was cooled to room temperature. After the reaction, the mixture was filtered through celite and rinsed with ethanol. The filtrate was concentrated and purified by flash column chromatography (100% DCM-10% MeOH:DCM) to obtain Z-14 (150 mg, a brown oil).

[0206] MS ESI: m / z = 236.1, [M+H] + .

[0207] Step 5: Preparation of Z-15

[0208] Z-14 (118 mg, 1.0 eq) was dissolved in 1,4-dioxane (5 mL) and stirred at room temperature. M-1 (177 mg, 1.0 eq) and p-toluenesulfonic acid monohydrate (28.8 mg, 0.3 eq) were added. The atmosphere was purged with nitrogen and the mixture was reacted at 90°C for 2 hours before cooling to room temperature. After the reaction, water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The organic phase was then purified by flash column chromatography (100% PE-70% EA:PE) to afford Z-15 (100 mg, pink solid).

[0209] MS ESI: m / z = 554.3, [M+H] + .

[0210] Step 6: Preparation of Z-16

[0211] Using Z-15 (56 mg) as the starting material, the intermediate Z-16 was obtained under the same conditions as those used in the preparation of Z-5 in the fifth step of Example 1.

[0212] MS ESI: m / z = 526.2, [M+H] + .

[0213] Step 7: Preparation of Z-17

[0214] Using Z-16 as raw material, the intermediate Z-17 was obtained under the same conditions as the preparation of Z-6 in the sixth step of Example 1.

[0215] MS ESI: m / z = 426.2, [M+H] + .

[0216] Step 8: Preparation of T-3

[0217] Using Z-17 as the starting material, 21 mg of white solid T-3 was obtained under the same conditions as those used in the preparation of T-1 in the seventh step of Example 1.

[0218] MS ESI: m / z = 408.2, [M+H] + .

[0219] 1 H NMR (400 MHz, DMSO-d6) δ9.05(s,1H),8.56(s,1H),8.09(s,1H),7.81(s,1H),7.22(s,1H),3.78(s,1H),3.58(d,J=5.0 Hz,2H),3.03(s,1H),2.66(d,J=12.7 Hz,1H),2.15(s,2H),2.06(q,J=7.8 Hz,1H),1.59(d,J=6.4 Hz,1H),1.25(d,J=5.1 Hz,1H),1.12(s,1H),0.85–0.61(m,4H).

[0220] Example 4 and Example 5 (T4 and T5)

[0221] Example 3 (13 mg) was subjected to chiral separation using the following conditions:

[0222] Chiral column: CHIRALPAK IG (5 μm; 10 mm × 250 mm);

[0223] Mobile phase: 25% EtOH / 75% n-hexane;

[0224] Flow rate: 2 mL / min;

[0225] Example 4: Retention time was 11.1 minutes (6 mg).

[0226] Example 5: Retention time was 15.2 minutes (4 mg).

[0227] Example 6: T-6

[0228] (E)-1 5 -Chloro-3 3 ,4,4-trimethyl-1 7 H, 3 1 H-2,6-diaza-1(2,7)-pyrrolo[2,3-d]pyrimidin-3(4,1)-pyrazolocyclononan-5-one

[0229] Step 1: Preparation of Y-1

[0230] 2-Chloro-7H-pyrrolo[2,3-d]pyrimidine (5 g) was dissolved in MeCN (70 ml), followed by the addition of NaH (1.56 g, 1.2 eq, 60% in petroleum ether). After stirring for 5 minutes, tert-butyl (3-bromopropyl)carbamate (7.98 g, 1.02 eq) was added. After stirring overnight, the reaction was quenched by the addition of saturated NH4Cl solution, extracted with EA, and washed twice with saturated NaCl solution. The organic phase was spin-dried to yield the product Y-1 in quantitative yield.

[0231] MS ESI: m / z = 311, [M+1] + .

[0232] Step 2: Preparation of Y-2

[0233] Y-1 (6 g) was dissolved in THF (50 ml), followed by the addition of NCS (2.83 g, 1.1 eq). After stirring at room temperature for 4 h, the reaction was quenched by the addition of a saturated solution of NH4Cl. The mixture was extracted with EA and then washed three times with a saturated solution of NaCl. The organic phase was spin-dried to give 4.45 g of Y-2.

[0234] MS ESI: m / z = 345, [M+1] + .

[0235] Step 3: Preparation of Y-3

[0236] Y-2 (500mg) is dissolved in NMP (7ml), then 2-(4-amino-3-methyl-1H-pyrazole-1-yl)-2-methylpropionic acid methyl ester (342.6mg, 1.2eq) and CF3COOH (0.55ml, 5eq) are added. After the air in the reaction flask is replaced with nitrogen, 100 ℃ are heated overnight, then NaHCO3 saturated solution is added to quench the reaction, and EA is extracted. After the organic phase is spin-dried, 406mg khaki crude product Y-3 is obtained by rapid silica gel column chromatography.

[0237] MS ESI: m / z = 406, [M+1] + .

[0238] Step 4: Preparation of Y-4

[0239] 100 mg of crude product Y-3 was dissolved in THF (2 ml) and water (0.2 ml), and then lithium hydroxide monohydrate (54.7 mg, 5 eq) was added. After stirring at room temperature overnight, 2N HCl was added to adjust the pH to acidic, and the mixture was directly spin-dried and used in the next reaction.

[0240] MS ESI: m / z = 391, [M+1] + .

[0241] Step 5: Preparation of T-6

[0242] Y-4 obtained in the previous step was dissolved in DMF (3 ml), followed by the addition of HATU (103 mg, 1.1 eq) and DIPEA (0.21 ml, 5 eq). After stirring at room temperature for 2 h, the reaction was quenched by the addition of saturated NH4Cl solution and extracted with EA. The organic phase was dried and purified by flash silica gel column chromatography and reverse-phase C18 preparative chromatography to yield 12 mg of T-6 as a white solid.

[0243] MS ESI: m / z = 374, [M+1] + .

[0244] 1 H NMR(400 MHz, CDCl3)δ8.49(s,1H),8.42–8.20(bs,1H),7.83(s,1H),6.96(s,1H),5.20( s,1H),3.95–3.90(m,2H),3.19(m,2H),2.24(s,3H),1.92(s,6H),1.82(m,2H).

[0245] Example 7: T-7

[0246] (E)-1 5 -Chloro-3 3,4,4,6-tetramethyl-1 7 H, 3 1 H-2,6-diaza-1(2,7)-pyrrolo[2,3-d]pyrimidin-3(4,1)-pyrazolocyclononan-5-one

[0247] Step 1: Preparation of Y-5

[0248] Y-2 (200 mg) was dissolved in THF (4 ml), followed by the addition of NaH (34.78 mg, 1.5 eq, 60%). After stirring for several minutes, MeI (43 μl, 1.2 eq) was added. After stirring overnight, additional NaH (60 mg, 60%) and MeI (50 μl) were added. After stirring for 6 h, the reaction was quenched by the addition of saturated NH4Cl solution and extracted with EA. The organic phase was dried and purified by flash silica gel column chromatography to yield 153 mg of Y-5 as a colorless oil.

[0249] MS ESI: m / z = 359, [M+1] + .

[0250] Step 2: Preparation of Y-6

[0251] Y-5 (153 mg) was dissolved in n-BuOH (3 ml), and methyl 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanoate (100 mg, 1.2 eq) and CF3COOH (0.16 ml, 5 eq) were added. The air in the reaction flask was replaced with nitrogen, and the mixture was heated at 100°C for 4 h. A saturated solution of NaHCO3 was then added to quench the reaction, and the mixture was extracted with EA. The organic phase was spin-dried and purified by flash silica gel column chromatography to give 34 mg of Y-6.

[0252] MS ESI: m / z = 520, [M+1] + .

[0253] Step 3: Preparation of Y-7

[0254] 34mg Y-6 is dissolved in THF (2ml) and water (0.2ml), then lithium hydroxide monohydrate (13.7mg, 5eq) is added. After stirring at room temperature overnight, a little NaCl saturated solution is added to dilute, then 2N HCl is added and pH is adjusted to acidic, EA extraction. The solid obtained after being spin-dried for organic phase is directly used for next step.

[0255] MS ESI: m / z = 506, [M+1] + .

[0256] Step 4: Preparation of Y-8

[0257] HCl dioxane (2 ml, 4N) was added to Y-7 obtained in the previous step, and the mixture was stirred at room temperature for 2 h, and then spin-dried to dryness. The obtained solid was directly used in the next step.

[0258] MS ESI: m / z = 406, [M+1] + .

[0259] Step 5: Preparation of T-7

[0260] Using Y-8 obtained in the previous step as a raw material, 15 mg of white solid T-7 was prepared under the same conditions as in the fifth step of Example 6.

[0261] MS ESI: m / z = 388, [M+1] + .

[0262] 1 H NMR(400 MHz, CDCl3)δ8.47(s,1H),8.40(bs,1H),8.13(s,1H),6.96(s,1H),4.65–4.52(m,1H),4.23(m,1H),3. 94(m,1H),2.55(m,1H),2.36(s,3H),2.33(s,3H),2.00(m,1H),1.98(s,3H),1.80(s,3H),1.73(m,1H).

[0263] Example 8: T-8

[0264] (E)-1 3 -Chloro-3 3 ,4,4-trimethyl-1 1 H, 3 1 H-2,6-diaza-1(6,1)pyrazolo[3,4-d]pyrimidin-3(4,1)-pyrazolocyclononan-5-one

[0265] Step 1: Preparation of Y-9

[0266] 6-Chloro-1H-pyrazolo[3,4-d]pyrimidine (2 g) was dissolved in DMF (30 ml), followed by the addition of NCS (1.91 g, 1.1 eq). The air in the reaction flask was replaced with nitrogen, and the mixture was heated at 70°C overnight. The reaction was quenched by the addition of a saturated solution of NH4Cl, and extracted with EA. The organic phase was washed twice with a saturated solution of NaCl, dried, and purified by flash silica gel column chromatography to yield 1.37 g of Y-9.

[0267] MS ESI: m / z = 189, [M+1] + .

[0268] Step 2: Preparation of Y-10

[0269] Y-9 (1.37 g) was dissolved in DMF (20 ml), and KCO (3.34 mg, 2 eq) and tert-butyl (3-bromopropyl)carbamate (2.07 g, 1.2 eq) were then added. After stirring at room temperature overnight, NHCl saturated solution was added to quench the reaction, and EA was extracted. The organic phase was washed twice with NaCl saturated solution, then spin-dried, and 1.26 g of Y-10 as a white solid was obtained by rapid silica gel column chromatography.

[0270] MS ESI: m / z = 346, [M+1] + .

[0271] Step 3: Preparation of Y-11

[0272] Y-10 (200 mg) was dissolved in n-BuOH (4 ml), and methyl 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanoate (160 mg, 1.4 eq) and CF3COOH (0.22 ml, 5 eq) were added. The air in the reaction flask was replaced with nitrogen and heated at 100°C overnight. A saturated NaHCO3 solution was then added to make the solution alkaline. THF (4 ml) and BOC2O (1.2 eq, 0.16 ml) were then added. After stirring for 3 h, the mixture was extracted with EA. The organic phase was spin-dried and purified by flash silica gel column chromatography to yield 270 mg of Y-11 as a pale yellow solid.

[0273] MS ESI: m / z = 507, [M+1] + .

[0274] Step 4: Preparation of Y-12

[0275] Y-12 was prepared using Y-11 (270 mg) as the starting material under the same conditions as in the third step of Example 7.

[0276] MS ESI: m / z = 493, [M+1] + .

[0277] Step 5: Preparation of Y-13

[0278] Y-12 obtained in the above step was used as a raw material, and Y-13 was prepared under the same conditions as in the fourth step of Example 7.

[0279] MS ESI: m / z = 393, [M+1] + .

[0280] Step 6: Preparation of T-8

[0281] Using Y-13 obtained in the previous step as raw material, 23 mg of white solid T-8 was prepared under the same conditions as in the fifth step of Example 6.

[0282] MS ESI: m / z = 375, [M+1] + .

[0283] 1 H NMR (400 MHz, CDCl3) δ8.74(s,1H),7.89(s,1H),7.13(s,1H),5.55(s,1H),4.15(t,J=7.1 Hz,2H),3.16(m,2H),2.23(s,3H),1.93(s,6H),1.91(m,2H).

[0284] Example 9: T-9

[0285] (E)-3 3 ,4,4-trimethyl-1 1 H, 3 1 H-2,6-diaza-1(5,3)pyrazolo[4,3-d]pyrimidin-3(4,1)-pyrazolocyclononan-5-one

[0286] Step 1: Preparation of Y-14

[0287] Using 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (1.5 g) and NIS (4.38 mg, 2 eq) as raw materials, the reaction temperature was set to 80°C, and the same operation as the second step of Example 8 was used to obtain 2.97 g of a light yellow crude product Y-14.

[0288] MS ESI: m / z = 281, [M+1] + .

[0289] Step 2: Preparation of Y-15

[0290] Using Y-14 (300 mg) as the starting material, 300 mg of yellow solid Y-15 was obtained under the same conditions as in the third step of Example 8.

[0291] MS ESI: m / z = 442, [M+1] + .

[0292] Step 3: Preparation of Y-16

[0293] Y-15 (300 mg) was dissolved in THF (3 ml), and then BOC2O (0.17 ml, 1.1 eq), DMAP (8.3 mg, 0.1 eq) and NEt3 (0.14 ml, 1.5 eq) were added. After stirring at room temperature for 20 min, the mixture was spin-dried and used directly in the next step.

[0294] MS ESI: m / z = 542, [M+1]+ .

[0295] Step 4: Preparation of Y-17

[0296] The product from the previous step (320 mg) was dissolved in DMF (3 ml) and NEt (3 ml), and N-Boc-aminopropyne (110 mg, 1.2 eq), Pd(PPh)Cl (41.5 mg, 0.1 eq), and CuI (22.5 mg, 0.2 eq) were added. The air in the reaction flask was replaced with nitrogen, and the mixture was heated at 80°C for 1 h. The reaction was quenched by adding a saturated solution of NH4Cl, and extracted with EA. The organic phase was dried and purified by flash silica gel column chromatography to yield 267 mg of a yellow crude product, Y-17.

[0297] MS ESI: m / z = 569, [M+1] + .

[0298] Step 5: Preparation of Y-18

[0299] Y-17 (267 mg) was dissolved in a mixture of methanol (9 ml) and EA (5 ml), and an appropriate amount of Ranney Ni was added. The mixture was reduced with hydrogen gas at standard atmospheric pressure for 16 h, then filtered, dried, and purified by flash silica gel column chromatography to obtain 118 mg of a yellow solid Y-18.

[0300] MS ESI: m / z = 573, [M+1] + .

[0301] Step 6: Preparation of Y-19

[0302] Y-19 was prepared using Y-18 (118 mg) as the starting material under the same conditions as in the third and fourth steps of Example 7.

[0303] MS ESI: m / z = 359, [M+1] + .

[0304] Step 7: Preparation of T-9

[0305] Y-19 obtained in the previous step was dissolved in DMF (5 ml), followed by the addition of HATU (121.8 mg, 1.5 eq) and DIPEA (0.18 ml, 5 eq). After stirring at room temperature for 2 h, 4 ml of 2N NaOH solution was added. After stirring for 1 h, the mixture was diluted with NaHCO₃ solution and extracted with EA. The organic phase was dried and purified by flash silica gel column chromatography and reverse-phase C₁₈ preparative chromatography to yield 28 mg of T-9 as a pale yellow solid.

[0306] MS ESI: m / z = 341, [M+1] + .

[0307] 1 H NMR (400 MHz, CDCl3) δ8.85(s,1H),7.93(s,1H),6.71(s,1H),5.88(s,1H),3.20(m,2H),2.91(t,J=7.1 Hz,2H),2.22(s,3H),1.95(s,6H),1.81(m,2H).

[0308] Example 10: T-10

[0309] (1 1 R,1 2 S,2 1 R,E)-2 3 -cyclopropyl-9-methyl-4 5 -(trifluoromethyl)-2 1 H-3,5,9-Triaza-4(2,4)-pyrimidin-2(1,4)-pyrazol-1(1,2)-cyclopropylcyclodecane-10-one

[0310] Step 1: Preparation of Z-18

[0311] Using Z-14 (100 mg, 1 eq) and M-6 (160 mg, 1 eq) as starting materials, the same conditions as those used in the preparation of Z-15 in the fifth step of Example 3 were used to obtain intermediate Z-18 (70 mg).

[0312] MS ESI: m / z = 568.2, [M+H] + .

[0313] Step 2: Preparation of Z-19

[0314] Using Z-18 (70 mg) as the starting material, the intermediate Z-19 was obtained under the same conditions as those used in the preparation of Z-5 in the fifth step of Example 1.

[0315] MS ESI: m / z = 540.2, [M+H] + .

[0316] Step 3: Preparation of Z-20

[0317] Using Z-19 as the raw material, the intermediate Z-20 was obtained under the same conditions as those used in the preparation of Z-6 in the sixth step of Example 1.

[0318] MS ESI: m / z = 440.2, [M+H] + .

[0319] Step 4: Preparation of T-10

[0320] Using Z-20 as the raw material, 15 mg of white solid T-10 was obtained under the same conditions as the preparation of T-1 in the seventh step of Example 1.

[0321] MS ESI: m / z = 422.2, [M+H] + .

[0322] 1 H NMR (400 MHz, Chloroform-d) δ8.08(s,1H),7.54(s,1H),7.13(s,1H),5.51(s,1H),4.29–4.19(m,1H),3.87(td,J=7.8,5.2 Hz,1H),3.79(dt,J=13.2,7.3 Hz,1H),3.47(m,J=7.1,3.3 Hz,1H),3.31(s,3H),2.74–2.62(m,1H),2.45–2.34(m,1H),2.23(q,J=7.9 Hz,1H),2.02(q,J=5.9 Hz,1H),1.70(ddd,J=10.3,8.0,5.5 Hz,1H),1.58–1.42(m,2H),0.90(dd,J=7.4,3.4Hz,3H),0.82–0.74(m,1H).

[0323] Example 11: T-11

[0324] (1 1 R,1 2 R,2 1 S,E)-2 3 -cyclopropyl-4- 5 -(trifluoromethyl)-2 1 H-3,5,9-Triaza-4(2,4)-pyrimidin-2(1,4)-pyrazol-1(1,2)-cyclopropylcyclodecane-10-one

[0325] Step 1: Preparation of Z-21

[0326] Starting from Z-13 (265 mg), the intermediate Z-21 (170 mg) was obtained using the same conditions as those used in the preparation of Z-14 in the fourth step of Example 3.

[0327] MS ESI: m / z = 236.1, [M+H] + .

[0328] Step 2: Preparation of Z-22

[0329] Using Z-21 (47 mg, 1 eq) and M-1 (70.8 mg, 1 eq) as starting materials, the same conditions as those used in the preparation of Z-15 in the fifth step of Example 3 were used to obtain intermediate Z-22 (71 mg).

[0330] MS ESI: m / z = 554.3, [M+H] + .

[0331] Step 3: Preparation of Z-23

[0332] Using Z-22 (55 mg) as the starting material, the intermediate Z-23 was obtained under the same conditions as those used in the preparation of Z-5 in the fifth step of Example 1.

[0333] MS ESI: m / z = 526.2, [M+H] + .

[0334] Step 4: Preparation of Z-24

[0335] Z-23 (0.1 mmol) was added to a 4 M solution of hydrogen chloride in dioxane (2 mL) and stirred at room temperature for 2 hours. Upon completion of the reaction, the system was directly spin-dried to obtain intermediate Z-24, which was then used for the next ring-closure reaction.

[0336] MS ESI: m / z = 426.2, [M+H] + .

[0337] Step 5: Preparation of T-11

[0338] Z-24 (0.1 mmol) was used as the starting material, and the same conditions as those for the preparation of T-1 in the seventh step of Example 1 were used, followed by purification by reverse phase C18 preparative chromatography to obtain 10 mg of a white solid T-11.

[0339] MS ESI: m / z = 408.2, [M+H] + .

[0340] 1H NMR (400 MHz, DMSO-d6) δ9.31 (s, 0.20H), 9.03 (s, 0.66H), 8.34 (s, 0.18H), 8.14 (s, 0.22H), 8.10 (d, J = 5.6 Hz, 1.28H), 7.86 (d, J = 9.1 Hz,0.21H),7.67–7.58(m,0.76H),7.14(t,J=5.8 Hz,0.72H),6.93(d,J=8.2 Hz,0.21H),3.61(dt,J=7.7,3.8 Hz,0.96H),3.51(s,0.96H),2.89(qd,J=12.5,6.7 Hz,2H),2.06(ddd,J=9.4,6.0,2.8 Hz,1.06H),1.98(m,J=12.9,7.6,6.1 Hz,1.81H),1.83–1.59(m,2H),1.55–1.46(m,1.13H),1.24(s,0.98H),0.86–0.66(m,3.54H).

[0341] Example 12: T-12

[0342] (E)-3 3 ,4,4-trimethyl-1 5 -(trifluoromethyl)-3 1 H-2,6,9-Triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclononane-5-one

[0343] Step 1: Preparation of Z-25

[0344] Using Z-3 (189 mg, 1 eq) and mono-Boc ethylenediamine (120 mg, 1.5 eq) as starting materials, the same conditions as those used in the preparation of Z-4 in the fourth step of Example 1 were used to obtain the intermediate light yellow oil Z-25 (244 mg).

[0345] MS ESI: m / z = 502.2, [M+H] + .

[0346] Step 2: Preparation of Z-26

[0347] Using Z-25 (200 mg, 1 eq) as the starting material, the same conditions as those used in the preparation of Z-5 in the fifth step of Example 1 were used to obtain the intermediate white solid Z-26 (189 mg).

[0348] MS ESI: m / z = 488.2, [M+H] + .

[0349] Step 3: Preparation of Z-27

[0350] Using Z-26 (0.38 mmol) as the starting material, the intermediate Z-27 was obtained under the same conditions as those used in the preparation of Z-24 in the fourth step of Example 11.

[0351] MS ESI: m / z = 388.2, [M+H] + .

[0352] Step 4: Preparation of T-12

[0353] Z-27 (0.38 mmol) was used as the starting material, and the same conditions as those for the preparation of T-1 in the seventh step of Example 1 were used, followed by purification by reverse phase C18 preparative chromatography to obtain 24 mg of white solid T-12.

[0354] MS ESI: m / z = 370.2, [M+H] + .

[0355] 1 H NMR (400 MHz, Chloroform-d) δ8.14(s,1H),7.71(s,1H),6.55(s,1H),6.14(s,1H),5.43(s,1H),3.33(s,4H),2.25(s,3H),1.89(s,6H).

[0356] Example 13: T-13

[0357] (E)-3 3 ,4,4-trimethyl-1 5 -(trifluoromethyl)-3 1 H-2,6,11-Triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocycloundecan-5-one

[0358] Step 1: Preparation of Z-28

[0359] Using Z-3 (189 mg, 1 eq) and 1,4-monoBoc butanediamine (141 mg, 1.5 eq) as starting materials, the same conditions as those used in the preparation of Z-4 in the fourth step of Example 1 were used to obtain the intermediate light yellow oil Z-28 (263 mg).

[0360] MS ESI: m / z = 530.2, [M+H] + .

[0361] Step 2: Preparation of Z-29

[0362] Using Z-28 (212 mg, 1 eq) as starting material, the same conditions as those used in the preparation of Z-5 in the fifth step of Example 1 were used to obtain the intermediate white solid Z-29 (208 mg).

[0363] MS ESI: m / z = 516.2, [M+H] + .

[0364] Step 3: Preparation of Z-30

[0365] Using Z-29 (0.38 mmol) as the starting material, the intermediate Z-30 was obtained under the same conditions as those used in the preparation of Z-24 in the fourth step of Example 11.

[0366] MS ESI: m / z = 416.2, [M+H] + .

[0367] Step 4: Preparation of T-13

[0368] Using Z-30 (0.38 mmol) as the starting material, the same conditions as those for the preparation of T-1 in the seventh step of Example 1 were used, and then purified by reverse phase C18 preparative chromatography to obtain 27.5 mg of white solid T-13.

[0369] MS ESI: m / z = 398.2, [M+H] + .

[0370] 1 H NMR (400 MHz, Chloroform-d) δ8.09(s,1H),7.64(s,1H),6.51(s,1H),5.38(s,1H),5.33(s,1H),3.14(h,J=5.3 Hz, 4H), 2.24 (s, 2H), 1.85 (s, 5H), 1.58 (t, J = 8.5 Hz, 2H), 1.47 (t, J = 6.1 Hz, 2H).

[0371] Example 14: T-14

[0372] (E)-3 3 -methyl-1 5 -(trifluoromethyl)-3 1 H-2,6,10-Triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclodecane-5-one

[0373] Step 1: Preparation of Z-31

[0374] Intermediate Z-31 was obtained using intermediate M-12 (105 mg, 1 eq) and 1,3-monoBoc propylenediamine (78.4 mg, 1.5 eq) as raw materials under the same conditions as those used in the preparation of step Z-4 in Example 1.

[0375] MS ESI: m / z = 488.2, [M+H] + .

[0376] Step 2: Preparation of Z-32

[0377] Using Z-31 (0.3 mmol) as the starting material, the same conditions as those used in the preparation of Z-5 in the fifth step of Example 1 were used to obtain the intermediate white solid Z-32.

[0378] MS ESI: m / z = 474.2, [M+H] + .

[0379] Step 3: Preparation of Z-33

[0380] Using Z-32 (0.3 mmol) as the starting material, the intermediate Z-33 was obtained under the same conditions as those used in the preparation of Z-24 in the fourth step of Example 11.

[0381] MS ESI: m / z = 374.2, [M+H] + .

[0382] Step 4: Preparation of T-14

[0383] Using Z-33 (0.3 mmol) as the starting material, the same conditions as those used in the preparation of T-1 in the seventh step of Example 1 were used to obtain 16.4 mg of white solid T-14.

[0384] MS ESI: m / z = 356.1, [M+H] + .

[0385] 1 H NMR (400 MHz, Chloroform-d) δ8.14–8.09(m,1H),7.60(s,1H),6.56(s,1H),5.41(s,1H),4.81(s,3H),3.33(q,J=7.4 Hz,2H),3.21(q,J=5.1 Hz,2H),2.23(s,3H),1.25(s,2H).

[0386] Example 15: T-15

[0387] (E)-3 3 -methyl-1 5 -(trifluoromethyl)-3 1H-2,6,9-Triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclononane-5-one

[0388] Step 1: Preparation of Z-34

[0389] Intermediate Z-34 was obtained using intermediate M-12 (105 mg, 1 eq) and mono-Boc ethylenediamine (72.2 mg, 1.5 eq) as starting materials under the same conditions as those used in the preparation of step Z-4 in Example 1.

[0390] MS ESI: m / z = 474.2, [M+H] + .

[0391] Step 2: Preparation of Z-35

[0392] Using Z-34 (0.3 mmol) as the starting material, the same conditions as those used in the preparation of Z-5 in the fifth step of Example 1 were used to obtain the intermediate white solid Z-35.

[0393] MS ESI: m / z = 460.2, [M+H] + .

[0394] Step 3: Preparation of Z-36

[0395] Using Z-35 (0.3 mmol) as the starting material, the same conditions as those used in the preparation of Z-24 in the fourth step of Example 11 were used to obtain the intermediate Z-36.

[0396] MS ESI: m / z = 360.2, [M+H] + .

[0397] Step 4: Preparation of T-15

[0398] Using Z-36 (0.3 mmol) as the starting material, the same conditions as those used in the preparation of T-1 in the seventh step of Example 1 were used to obtain 5.4 mg of white solid T-15.

[0399] MS ESI: m / z = 342.1, [M+H] + .

[0400] 1 H NMR (400 MHz, Chloroform-d) δ8.15(s,1H),7.54(s,1H),6.53(s,1H),6.48(s,1H),5.46(s,1H),4.77(d,J=23.7 Hz,2H),3.63(s,1H),3.35(s,2H),2.97(s,1H),2.25(s,3H).

[0401] Example 16: T-16

[0402] (3 4 E,5 4 Z)-3 3 ,4,4-trimethyl-1 5 -(trifluoromethyl)-3 1 H,5 1 H-2,9-diaza-1(2,4)-pyrimidine-5(4,1)-triazole-3(4,1)-pyrazolecyclononane

[0403] Step 1: Preparation of E-1

[0404] Intermediate M-17 (193 mg, 1.0 eq) was dissolved in MeOH (0.5 mL) and DMF (4 mL). N-BOC-3-azido-propylamine (300 mg, 1.5 eq) and CuI (19 mg, 0.12 eq) were added sequentially. The atmosphere was purged with nitrogen and the reaction was continued at 110°C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, and sodium chloride solution and ethyl acetate were added. The mixture was then dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by flash column chromatography (100% PE-50% EA / PE) to afford E-1 (350 mg), a yellow oil.

[0405] MS ESI: m / z = 394.1, [M+H] + .

[0406] Step 2: Preparation of E-2

[0407] Intermediate E-1 (0.657 mmol) was used as a starting material and the same conditions as those used in the preparation of Z-24 in the fourth step of Example 11 were used to obtain intermediate E-2 as a white solid.

[0408] MS ESI: m / z = 294.1, [M+H] + .

[0409] Step 3: Preparation of E-3

[0410] To intermediate E-2 (0.657 mmol, 1.0 eq), add isopropanol (5 mL), then add DIPEA (340 mg, 4 eq) and stir at room temperature until dissolved. Add a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (157 mg, 1.1 eq) in isopropanol (2 mL) dropwise in an ice bath. After addition, allow to react at room temperature for 1-2 hours. After the reaction is complete, concentrate the mixture and purify it by flash column chromatography (100% PE-50% EA / PE) to afford intermediate E-3 (140 mg) as a pale yellow oil.

[0411] MS ESI: m / z = 474.1, [M+H]+ .

[0412] Step 4: Preparation of T-16

[0413] Intermediate E-3 (70 mg, 1.0 eq) was dissolved in ethanol (4 mL), and water (1.5 mL) was added. The mixture was stirred at room temperature, and ammonium chloride (144 mg, 18 eq) and reduced iron powder (75 mg, 9 eq) were added. The atmosphere was replaced with nitrogen, and the mixture was reacted at 90°C for 12 hours before cooling to room temperature. After the reaction was complete, the mixture was filtered through celite and rinsed with ethyl acetate. Sodium chloride solution and sodium bicarbonate solution were added, and the aqueous phase was extracted twice with ethyl acetate and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by flash column chromatography (100% PE-100% EA) to obtain T-16 (40 mg) as a white solid.

[0414] MS ESI: m / z = 408.1, [M+H] + .

[0415] 1 H NMR(400 MHz,Chloroform-d)δ8.08(s,1H),7.34(s,1H),7.17(s,1H),6.58(s,1H),5.20(s, 1H),4.58–4.48(m,2H),3.33–3.20(m,2H),2.26(s,3H),2.07(s,6H),2.05(s,2H).

[0416] Example 17: T-17

[0417] (3 4 E,5 3 Z)-3 3 ,4,4-trimethyl-1 5 -(trifluoromethyl)-3 1 H,5 2 H-2,9-diaza-1(2,4)-pyrimidine-5(4,2)-triazole-3(4,1)-pyrazolecyclononane

[0418] Step 1: Preparation of E-4

[0419] TMSN3 (172.8 mg, 1.5 eq) was dissolved in MeOH (0.5 mL) and DMF (4 mL). Intermediate M-17 (193 mg, 1.0 eq) and CuI (19 mg, 0.12 eq) were added sequentially. The atmosphere was purged with nitrogen and the reaction was continued at 110°C for 16 h. After completion of the reaction, the mixture was cooled to room temperature and poured into 20 g of ice. Ethyl acetate was added and the mixture was filtered through Celite. The aqueous phase was extracted twice with EA. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by flash column chromatography (100% PE-50% EA / PE) to afford E-4 (159 mg), a yellow oil.

[0420] MS ESI: m / z = 237.1, [M+H] + .

[0421] Step 2: Preparation of E-5

[0422] Intermediate E-4 (159 mg, 1.0 eq) was dissolved in methanol (3.5 mL) and stirred at room temperature. N-Boc-3-aminopropyl bromide (797.6 mg, 5.0 eq) and Cs2CO3 (873 mg, 4.0 eq) were added. The atmosphere was replaced with nitrogen and the reaction was continued at 50°C for 36 h. After the reaction was completed, the mixture was cooled to room temperature and filtered through celite. The organic phase was concentrated and purified by flash column chromatography (100% PE-50% EA / PE) to afford E-5 (160 mg).

[0423] MS ESI: m / z = 394.2, [M+H] + .

[0424] Step 3: Preparation of E-6

[0425] Intermediate E-5 (0.4 mmol) was used as the starting material and the same conditions as those used in the preparation of Z-24 in the fourth step of Example 11 were used to obtain intermediate yellow oil E-6.

[0426] MS ESI: m / z = 294.1, [M+H] + .

[0427] Step 4: Preparation of E-7

[0428] Using intermediate E-6 (0.4 mmol) as starting material, the same conditions as those used in the preparation of E-3 in the third step of Example 16 were used to obtain intermediate E-7 (75 mg) as a light yellow oil.

[0429] MS ESI: m / z = 474.1, [M+H] + .

[0430] Step 5: Preparation of T-17

[0431] Using intermediate E-7 (0.07 mmol) as starting material, the same conditions as those used in the preparation of T-16 in the fourth step of Example 16 were used, and then purified by reverse phase C18 preparative chromatography to obtain white solid T-17 (10 mg).

[0432] MS ESI: m / z = 408.1, [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ8.06(s,1H),7.60(s,1H),7.57(s,1H),6.80(s,1H),5.26(s,1H),4.65–4.57(m,2H),3.41(dd,J=17.3,6.6 Hz,2H),2.26(s,3H),2.24–2.16(m,2H),2.02(s,6H).

[0433] Example 18: T-18

[0434] (E)-3 3 ,4,4-trimethyl-1 5 H,3 1 H-2,6-diaza-1(2,7)-pyrrolo[3,2-d]pyrimidin-3(4,1)-pyrazolocyclononan-5-one

[0435] Step 1: Preparation of Y-20

[0436] 2,4-Dichloropyrrolo[3,2-D]pyrimidine (6.7 g) was dissolved in MeOH (100 ml), followed by the addition of zinc powder (9.32 g) and CH3COOH (13.45 ml). The reaction was completed after heating at 70°C for approximately 5 h. The reaction solution was filtered and dried, and then purified by flash silica gel column chromatography to yield 3.37 g of Y-20 as a white solid.

[0437] MS ESI: m / z = 154, [M+H] + .

[0438] Step 2: Preparation of Y-21

[0439] Using Y-20 (1 g) as starting material, 1.17 g of crude compound Y-21 was prepared under the same conditions as in the second step of Example 9.

[0440] MS ESI: m / z = 315, [M+H] + .

[0441] Step 3: Preparation of Y-22

[0442] 1.17g crude product Y-21 was dissolved in DMF (30ml), and then NIS (1617.6mg) was added. After stirring for 30min, the reaction was completed, and the reaction solution was quenched with a saturated Na2S2O4 aqueous solution and then extracted with EA. The organic phase was washed with a saturated aqueous solution of NaCl, then spin-dried, and the intermediate compound was obtained by rapid silica gel column chromatography. The intermediate was dissolved in THF (15ml), and then Boc2O (1.03ml), DMAP (45.47mg) and NEt3 (0.77ml) were added. After stirring for about 30min, the reaction solution was spin-dried, and then 1.27g Y-22 was obtained by silica gel column chromatography.

[0443] MS ESI: m / z = 541, [M+H] + .

[0444] Step 4: Preparation of Y-23

[0445] Using Y-22 (1.27 g) as starting material, 1.57 g of Y-23 was prepared under the same conditions as in the fourth step of Example 9.

[0446] MS ESI: m / z = 567, [M+H] + .

[0447] Step 5: Preparation of Y-24

[0448] Y-24 (720 mg) was prepared using Y-23 (1.57 g) as a starting material under the same conditions as in the fifth step of Example 9.

[0449] MS ESI: m / z = 572, [M+H] + .

[0450] Step 6: Preparation of Y-25

[0451] Y-24 (720 mg) was used as the starting material and the same conditions as in the sixth step of Example 9 were used to prepare 450 mg of Y-25.

[0452] MS ESI: m / z = 358, [M+H] + .

[0453] Step 7: Preparation of T-18

[0454] Y-25 (720 mg) was dissolved in MeCN (20 ml), followed by the addition of TCFH (424 mg) and NMI (0.5 ml). After stirring at room temperature for 2 h, the reaction was complete. The reaction solution was quenched with a saturated NH4Cl aqueous solution and then extracted with EA. The organic phase was spin-dried and purified by rapid silica gel column chromatography to yield 100 mg of T-18.

[0455] MS ESI: m / z = 340, [M+H] + .

[0456] 1 H NMR(400 MHz, CDCl3)δ8.95(s,1H),8.64(s,1H),7.94(s,1H),7.39(s,1H),7.01(s,1H), 5.78(s,1H),3.14(m,2H),2.63(m,2H),2.23(s,3H),1.94(s,6H),1.66(m,2H).

[0457] Example 19: T-19 and T-20

[0458] (E)-1 1 ,3 3 ,4,4-tetramethyl-1 1 H,3 1 H-2,6-diaza-1(5,3)-pyrazolo[4,3-d]pyrimidine-3(4,1)-pyrazinocyclononanone-5-one (T-19)

[0459] (1 3 E,1 4 Z,3 4 E)-1 2 ,3 3 ,4,4-tetramethyl-1 2 H, 3 1 H-2,6-diaza-1(5,3)-pyrazolo[4,3-d]pyrimidin-3(4,1)-pyrazinocyclononane-5-one (T-20)

[0460] T-9 (30 mg) was dissolved in DMF (2 ml) under ice, followed by the addition of KCO (14.6 mg) and MeI (8 μl). The mixture was stirred overnight at room temperature, quenched with saturated aqueous NHCl, and extracted with EA. The organic phase was dried and purified by flash silica gel column chromatography and reverse-phase C18 preparative chromatography to yield 5.2 mg of T-19 and 6.7 mg of T-20.

[0461] MS ESI: m / z = 355, [M+H] + .

[0462] 1H NMR(400 MHz, CDCl3)δ8.73(s,1H),7.92(s,1H),6.55(s,1H),5.95(s,1H),4.03(s,3H),3.17(m,2H),2.87(m,2H),2.21(s,3H),1.84(s,6H),1.79(m,2H). (T-19)

[0463] 1 H NMR(400 MHz, CDCl3) δ9.07(s,1H),7.95(s,1H),6.46(s,1H),6.35(s,1H),4.08(s,2H),3.06(m,2H),2.92(m,2H),2.21(s,3H),1.94(s,6H),1.83(m,2H). (T-20)

[0464] Example 20: T-21

[0465] (E)-1 5 ,3 3 ,4,4-tetramethyl-1 5 H, 3 1 H-2,6-diaza-1(2,7)-pyrrolo[3,2-d]pyrimidin-3(4,1)-pyrazolocyclononan-5-one

[0466] 30 mg of T-18 was dissolved in 2 ml of DMF, followed by the addition of KOH (20 mg) and MeI (8 μl). The mixture was stirred at room temperature overnight, quenched with saturated aqueous NH4Cl, and extracted with EA. The organic phase was dried and purified by flash silica gel column chromatography and reverse-phase C18 preparative chromatography to yield 10.7 mg of T-21.

[0467] MS ESI: m / z = 355, [M+H] + .

[0468] 1 H NMR(400 MHz, CDCl3)δ8.43(s,1H),7.93(s,1H),7.08(s,1H),6.70(s,1H),5.91(s,1H), 3.77(s,3H),3.12(m,2H),2.59(m,2H),2.21(s,3H),1.93(s,6H),1.65(m,2H).

[0469] Example 21: T-22

[0470] (E)-1 5 -Chloro-3 3 ,4,4-trimethyl 17 H,3 1 H-2,6-diaza-1(2,7)-pyrrolo[2,3-d]pyrimidin-3(4,1)-pyrazolocyclodecane-5-one

[0471] Compound T-22 was prepared using conditions similar to those in Example 6.

[0472] MS ESI: m / z = 391, [M+H] + .

[0473] 1 H NMR (400 MHz, CDCl3) δ8.57(s,1H),7.79(s,1H),6.75(s,1H),6.55(s,1H),5.55(s,1H),3.88–3.67(m,2H),3.29(dd,J=11.2,5.7 Hz, 2H), 2.26 (s, 3H), 2.10–1.91 (m, 2H), 1.86 (s, 5H), 1.62 (dd, J = 11.9, 6.5 Hz, 3H).

[0474] Example 22: T-23

[0475] (E)-1 5 -Chloro-3 3 ,4,4,6-tetramethyl-1 7 H, 3 1 H-2,6-diaza-1(2,7)-pyrrolo[2,3-d]pyrimidin-3(4,1)-pyrazolocyclodecane-5-one

[0476] Compound T-23 was prepared using conditions similar to those in Example 7.

[0477] MS ESI: m / z = 405, [M+H] + .

[0478] Example 23: T-24 and T-25

[0479] (1 1 Z,3 4 E)-3 3 ,4,4-trimethyl 3 1 H-2,6-diaza-1(2,7)-pyrrolo[2,1-f][1,2,4]triazine-3(4,1)-pyrazolocyclononane-5-one (T-24)

[0480] (1 1 Z,3 4 E)-1 5 -Chloro-33 ,4,4-trimethyl 3 1 H-2,6-diaza-1(2,7)-pyrrolo[2,1-f][1,2,4]triazine-3(4,1)-pyrazolocyclononane-5-one (T-25)

[0481] Step 1: Preparation of Y-26

[0482] 2,4-Dichloropyrrolo[2,1-f][1,2,4]triazine (25 g) was dissolved in isopropanol (50 ml) and tetrahydrofuran (300 ml), followed by the addition of NaBH4 (8.04 g). After stirring at room temperature for 2 h, the mixture was filtered and dried. The resulting solid was dissolved in DCM (350 ml), followed by the addition of DDQ (36.22 g). After stirring for 1.5 h, the mixture was washed twice with a saturated aqueous NaHCO3 solution. The organic phase was dried and dissolved in EA, then filtered through a silica gel pad. The organic phase was dried to give 20.38 g of yellow Y-26.

[0483] MS ESI: m / z = 154, [M+H] + .

[0484] Step 2: Preparation of Y-27

[0485] Y-26 (20.38 g) was dissolved in MeCN (500 ml) under ice-cooling, and then NBS (23.62 g) was added. After stirring at room temperature for 2 h, the reaction solution was quenched with water, and the solid product was collected by filtration. The MeCN in the liquid phase was removed by vortexing, and then the product was extracted with EA. After spin-drying, the resulting solids were combined. The solid was purified by silica gel column chromatography to obtain 28.69 g of crude Y-27.

[0486] MS ESI: m / z = 232, [M+H] + .

[0487] Step 3: Preparation of Y-28

[0488] Y-27 (28.69 g) was dissolved in DMF (300 ml) and NEt (300 ml), followed by the addition of N-Boc-aminopropyne (20.08 g), Pd(PPh)Cl (4.33 g), and CuI (4.7 g). The air in the flask was replaced with nitrogen, and the reaction was completed after heating at 80°C for 3 h. The reaction was quenched with NH4Cl solution, extracted with EA, and the organic phase was washed with a saturated NaCl solution, dried, and filtered to yield 29.6 g of crude product Y-28.

[0489] MS ESI: m / z = 307, [M+H] + .

[0490] Step 4: Preparation of Y-29

[0491] Y-28 (29.6 g) was dissolved in MeOH (400 ml), followed by the addition of PtO2 (1.1 g). The air was replaced with H2, and the mixture was stirred at room temperature overnight. PtO2 (1.1 g) was then added. After stirring for approximately 2 days, the reaction was stopped, filtered, and dried. Impurities were removed by rapid silica gel column chromatography. The resulting product was dissolved in MeOH (300 ml), and PtO2 (500 mg) was added. The air was replaced with H2, and the mixture was stirred overnight. The reaction was complete. After filtration and drying, 19.31 g of the over-reduction product was obtained by rapid silica gel column chromatography. The resulting over-reduction product was dissolved in DCM (400 ml), and DDQ (14.02 g, 1 eq) was added. The reaction was stirred at room temperature for 2 hours, and the reaction was completed. The product was washed twice with a saturated aqueous NaHCO3 solution. The organic phase was dried and then purified by rapid silica gel column chromatography to obtain 19.2 g of Y-29.

[0492] MS ESI: m / z = 311, [M+H] + .

[0493] Step 5: Preparation of Y-30

[0494] Y-29 (19.2 g) was dissolved in 1,4-dioxane (300 ml), and methyl 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanoate (14.62 g), Pd(OAc)2 (1.03 g), ±BINAP (3.85 g), and Cs2CO3 (40.26 g) were added. The atmosphere was replaced with nitrogen, and the mixture was heated at 100°C for 2 h. After the reaction was complete, the mixture was quenched with a saturated solution of NH4Cl, and then extracted with EA. The organic phase was dried and purified by flash silica gel column chromatography to yield 25.74 g of Y-30.

[0495] MS ESI: m / z = 472, [M+H] + .

[0496] Step 6: Preparation of Y-31

[0497] Y-30 (25.74 g) was dissolved in MeOH (100 ml) and water (10 ml), followed by the addition of lithium hydroxide monohydrate (9.17 g). After stirring overnight at room temperature, the MeOH was removed by vortexing, and an appropriate amount of saturated aqueous NaCl solution was added. The mixture was acidified with 2N HCl and extracted with EA. The organic phase was dried by vortexing, and 100 ml of 4N HCl dioxane was added. After stirring at room temperature for 2.5 h, the mixture was dried by vortexing to obtain an excess of the theoretical amount of Y-31, which was then used in the next step.

[0498] MS ESI: m / z = 358, [M+H]+ .

[0499] Step 7: Preparation of T-24

[0500] Y-31 (19.5 g) was dissolved in DMF (800 ml), NEt (15.14 ml) was added, and then COMU (28 g) was slowly added dropwise to a solution of COMU (800 ml) in DMF. After stirring overnight at room temperature, COMU (3 g) was added. After stirring for 2 h, the reaction was quenched by addition of H2O, followed by extraction with EA. The organic phase was dried and purified by flash silica gel column chromatography to yield 9.17 g of T-24.

[0501] MS ESI: m / z = 340, [M+H] + .

[0502] 1 H NMR (400 MHz, CDCl3) δ8.61 (s, 1H), 7.91 (s, 1H), 6.67 (d, J = 4.5 Hz, 1H), 6.49 (d, J = 4.5 Hz,1H),6.08(s,1H),5.05(s,1H),3.22(m,2H),2.81–2.71(m,8H),2.25(s,11H),1.92(s,22H),1.62–1.52(m,8H).

[0503] Step 8: Preparation of T-25

[0504] T-24 was dissolved in THF (90 ml) and MeOH (30 ml), and NCS (3.176 g) was added. After stirring at room temperature for 1 day, NCS (600 mg) was added. After stirring overnight, the reaction solution was quenched with a saturated solution of Na2S2O3, extracted with EA, and the organic phase was washed with a saturated aqueous solution of NaCl. The organic phase was spin-dried and purified by flash silica gel column chromatography to yield 7.2 g of T-25.

[0505] MS ESI: m / z = 374, [M+H] + .

[0506] 1 H NMR(400 MHz, CDCl3)δ8.64(s,1H),7.89(s,1H),6.43(s,1H),6.16(s,1H),4.96(s,1 H),3.21(m,2H),2.78–2.65(m,2H),2.25(s,3H),1.89(s,6H),1.57(m,2H).

[0507] Example 24: T-26

[0508] (1 1Z, 3 4 E)-1 5 -Chloro-3 3 ,4,4-trimethyl 3 1 H-2,6-diaza-1(2,7)-pyrrolo[2,1-f][1,2,4]triazine-3(4,1)-pyrazolocyclodecane-5-one

[0509] Using Y-27 as the raw material, replacing N-Boc-aminopropyne in Example 23 with N-BOC-3-butyn-1-amine, and adopting the same other conditions, T-26 was prepared.

[0510] MS ESI: m / z = 391, [M+H] + .

[0511] 1 H NMR (400 MHz, CDCl3) δ8.61(s,1H),7.76(s,1H),6.39(s,1H),6.19(s,1H),5.45(s,1H),3.27(dd,J=10.6,5.4 Hz,2H),2.65(dt,J=11.7,6.2 Hz,2H),2.27(s,3H),1.85(s,6H),1.77–1.67(m,2H),1.65–1.48(m,2H).

[0512] Example 25: T-27

[0513] (1 1 Z, 3 4 E)-1 5 ,3 3 -Dichloro-4,4-dimethyl-3 1 H-2,6-diaza-1(2,7)-pyrrolo[2,1-f][1,2,4]triazine-3(4,1)-pyrazolocyclononane-5-one

[0514] Using Y-29 as the raw material, 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropionic acid methyl ester was replaced with 2-(4-amino-3-chloro-1H-pyrazol-1-yl)-2-methylpropionic acid methyl ester, and T-27 was prepared under the same conditions as in Example 23.

[0515] MS ESI: m / z = 394, [M+H] + .

[0516] 1H NMR(400 MHz, CDCl3)δ8.66(s,1H),7.99(s,1H),6.45(s,1H),6.24(s,1H),5.02(s,1H),3.38–3.16(m,2H),2.85–2.67(m,2H),1.91(s,6H),1.59(m,2H).

[0517] Example 26: T-28

[0518] (1 1 Z, 3 4 E)-1 5 -Chloro-3 3 -cyclopropyl-4,4-dimethyl-3 1 H-2,6-diaza-1(2,7)-pyrrolo[2,1-f][1,2,4]triazine-3(4,1)-pyrazolocyclononane-5-one

[0519] Using Y-29 as raw material, 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropionic acid methyl ester was replaced with 2-(4-amino-3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropionic acid methyl ester, and T-28 was prepared under the same conditions as Example 23.

[0520] MS ESI: m / z = 403, [M+H] + .

[0521] 1 H NMR (400 MHz, CDCl3) δ8.65(s,1H),7.84(s,1H),6.44(s,1H),6.24(s,1H),4.93(s,1H),3.20(d,J=5.2 Hz,2H),2.81–2.65(m,2H),1.88(s,5H),1.85–1.76(m,2H),1.53(d,J=39.7 Hz,5H),0.90–0.81(m,4H).

[0522] Example 27: T-29

[0523] (1 1 Z, 3 4 E)-3 3 ,4,4-trimethyl-1 5 -(trifluoromethyl)-3 1 H-2,6-diaza-1(2,7)-pyrrolo[2,1-f][1,2,4]triazine-3(4,1)-pyrazolocyclononane-5-one

[0524] Step 1: Preparation of Y-32

[0525] T-24 (100 mg) was dissolved in DMF (2 ml), and NIS (70 mg) was added. After stirring at room temperature for 2 h, the mixture was quenched with a saturated aqueous solution of Na2S2O3 and extracted with EA. The organic phase was dried and purified by flash silica gel column chromatography to yield 135 mg of Y-32.

[0526] Step 2: Preparation of T-29

[0527] T-29 (40 mg) was dissolved in DMF (2 ml), and methyl fluorosulfonyldifluoroacetate (25 mg) and CuI (18 mg) were added. After replacing the air with nitrogen, the mixture was heated at 80°C for approximately 2 h. Methyl fluorosulfonyldifluoroacetate (50 mg) was added and heated at 80°C for approximately 15 h. The mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EA. The organic phase was dried and purified by flash silica gel column chromatography and C18 preparative column chromatography to yield 9 mg of T-29.

[0528] MS ESI: m / z = 408, [M+H] + .

[0529] 1 H NMR(400 MHz, CDCl3)δ8.83(s,1H),7.85(s,1H),6.80(s,1H),6.59(s,1H),4.91(s,1 H),3.25(m,2H),2.86–2.71(m,2H),2.26(s,3H),1.92(s,6H),1.59(m,2H).

[0530] Example 28: T-30

[0531] (1 1 Z, 3 4 E)-3 3 ,4,4-trimethyl-5-oxo-3 1 H-2,6-diaza-1(2,7)-pyrrolo[2,1-f][1,2,4]triazine-3(4,1)-pyrazolocyclononane-1 5 -Nitrile

[0532] Y-32 (30 mg) was dissolved in DMF (2 ml), and Zn(CN)2 (15 mg), Pd(dppf)2Cl2 in DCM (26 mg), and zinc powder (2 mg) were added. The atmosphere was replaced with nitrogen, and the mixture was heated at 100°C for approximately 3 h. The mixture was then quenched with a saturated aqueous solution of NH4Cl and extracted with EA. The organic phase was dried and purified by flash silica gel column chromatography and C18 preparative column chromatography to yield 18 mg of T-30.

[0533] MS ESI: m / z = 365, [M+H] + .

[0534] 1 H NMR(400 MHz, CDCl3)δ8.89(s,1H),7.91(s,1H),6.84(s,1H),6.37(s,1H),4.93(s,1 H),3.25(m,2H),2.85–2.72(m,2H),2.28(s,3H),1.93(s,6H),1.58(m,2H).

[0535] Example 29: T-31

[0536] (E)-3 3 ,4,4,6,10-pentamethyl-1 5 -(trifluoromethyl)-3 1 H-2,6,10-Triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclodecane-5-one

[0537] T-31 was prepared using Z-3 and tert-butyl methyl (3-(methylamino)propyl)carbamate as raw materials under the same conditions as in Example 1.

[0538] MS ESI: m / z = 412, [M+H] + .

[0539] 1 H NMR (400 MHz, DMSO-d6) δ9.27(s,1H),8.28(s,1H),7.85(s,1H),4.24(s,1H),4.07(s,1H),3.06(s,4H),2.67(s,2H),2.19(d,J=12.5 Hz,5H),1.81(s,4H),1.59(s,4H).

[0540] Example 30: T-32

[0541] (E)-3 3 ,4,4,10-tetramethyl-1 5 -(trifluoromethyl)-3 1 H-2,6,10-Triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclodecane-5-one

[0542] T-32 was prepared using Z-3 and tert-butyl 2-(methylamino)propylcarbamate as raw materials under the same conditions as in Example 1.

[0543] MS ESI: m / z = 398, [M+H] + .

[0544] 1 H NMR (400 MHz, Chloroform-d) δ8.28(s,1H),7.69(s,1H),6.52(s,1H),4.61(s,1H),3.44–3.37(m,2H),3.19(d,J=4.7 Hz, 2H), 3.09 (s, 3H), 2.24 (s, 3H), 1.87 (s, 6H), 1.55 (d, J = 7.4 Hz, 2H).

[0545] Example 31: T-33

[0546] (E)-3 3 ,4,4,6-tetramethyl-1 5 -(trifluoromethyl)-3 1 H-2,6,10-Triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclodecane-5-one

[0547] T-33 was prepared using Z-3 and tert-butyl 3-aminopropyl(methyl)carbamate as raw materials under the same conditions as in Example 1.

[0548] MS ESI: m / z = 398, [M+H] + .

[0549] 1 H NMR (400 MHz, Chloroform-d) δ8.10(s,1H),7.99(s,1H),7.52(s,1H),5.62(s,1H),4.48(s,1H),3.84(s,1H),3.21(s,1H),2.53(d,J=14.2 Hz,1H),2.31(s,3H),2.29(s,3H),1.96(s,3H),1.76(s,3H),1.72(s,2H).

[0550] Example 32: T-34

[0551] (E)-3 3 ,4,4,6-tetramethyl-1 5 -(trifluoromethyl)-3 1 H-2,6,10-Triaza-1(2,4)-pyrimidine-3(4,1)-pyrazolocyclodecane

[0552] Dissolve T-33 (80 mg) in THF (2 mL) and add a 2M solution of borane dimethyl sulfide in THF (0.4 mL, 0.8 mmol, 4.0 eq). After reacting at 65°C for 36 hours, cool to room temperature. Add 2 mL of methanol and stir until the solution becomes clear. Directly spin dry the solution and purify it by flash column chromatography (100% PE-30% EA / PE) to obtain 6 mg of solid compound T-34.

[0553] MS ESI: m / z = 384, [M+H] + .

[0554] 1 H NMR(400 MHz,Chloroform-d)δ8.17(s,1H),7.52(s,2H),5.78(s,1H),3.02(s,2H),2. 56(s,2H),2.26(s,3H),2.19(s,3H),1.61(s,2H),1.54(s,6H),1.26(s,2H).

[0555] Example 33: T-35

[0556] (3 4 E, 6 4 Z)-3 3 ,4,4-trimethyl-1 5 -(trifluoromethyl)-3 1 H, 6 1 H-2,9-diaza-1(2,4)-pyrimidine-6(4,1)-triazole-3(4,1)-pyrazolecyclononane

[0557] T-35 was prepared using M-21 and N-BOC-2-azidoethylamine as raw materials under the same conditions as in Example 16.

[0558] MS ESI: m / z = 408, [M+H] + .

[0559] 1 H NMR (400 MHz, Chloroform-d) δ8.16(s,1H),7.16(s,1H),6.79(s,1H),5.88(s,1H),5.66(s,1H),4.32(s,2H),3.67(q,J=6.8 Hz,2H),3.27(s,2H),2.29(s,3H),1.55(s,6H).

[0560] Example 34: T-36

[0561] (3 4E, 6 3 Z)-3 3 ,4,4-trimethyl-1 5 -(trifluoromethyl)-3 1 H, 6 2 H-2,9-diaza-1(2,4)-pyrimidine-6(4,2)-triazole-3(4,1)-pyrazolecyclononane

[0562] T-36 was prepared using M-21 and N-Boc-bromoethylamine as raw materials under the same conditions as Example 17.

[0563] MS ESI: m / z = 408, [M+H] + .

[0564] 1 H NMR (400 MHz, Chloroform-d) δ8.09(s,1H),7.18(s,1H),7.14(s,1H),7.05(s,1H),5.62(s,1H),4.45(t,J=6.2 Hz,2H),3.88(q,J=6.3 Hz,2H),3.08(s,2H),2.23(s,3H),1.68(s,6H).

[0565] Example 35: T-37

[0566] (E)-3 3 ,4,4-trimethyl-1 5 -(trifluoromethyl)-3 1 H-6-Oxa-2,10-diaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclodecane-5-one

[0567] Step 1: Preparation of Y-33

[0568] Using Z-3 (75.6 mg) and 3-amino-1-propanol as raw materials, the same conditions as in the fourth step of Example 1 were used to prepare 77.5 mg of Y-3.

[0569] MS ESI: m / z = 417, [M+H] + .

[0570] Step 2: Preparation of Y-34

[0571] Y-34 (60 mg) was prepared using Y-33 (70 mg) as a starting material under the same conditions as in the fifth step of Example 1.

[0572] MS ESI: m / z = 403, [M+H] + .

[0573] Step 3: Preparation of T-37

[0574] Y-33 (40 mg) was dissolved in 2 ml of ultra-dry THF, and a solution of DIPEA (155 mg) and TCBC (49 mg) in THF (2 ml) was added. The reaction was stirred at room temperature for 19 hours, and a solution of TCBC (25 mg) in THF (0.5 ml) was added. After further stirring at room temperature for 10 hours, 30 ml of dry toluene was added to the system, and a solution of DMAP (73 mg, 0.6 mmol, 6 eq) in toluene (10 ml) was added dropwise at room temperature with stirring. The reaction was stirred at room temperature for 18 hours, and the system was directly spin-dried. The reaction was purified by flash silica gel column chromatography and C18 preparative chromatography to yield 19 mg of T-37 as a white solid.

[0575] MS ESI: m / z = 385, [M+H] + .

[0576] 1 H NMR(400 MHz,Chloroform-d)δ8.12(s,1H),7.91(s,1H),6.53(s,1H),5.37(s,1H),4 .14–4.08(m,2H),3.49(s,2H),2.20(s,3H),1.88(s,6H),1.82–1.73(m,2H).

[0577] Example 36: T-38

[0578] (E)-3 3 ,4,4,7-tetramethyl-1 5 -(trifluoromethyl)-3 1 H-2,6,10-Triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclodecane-5-one

[0579] T-38 was prepared using Z-3 and 3-BOC-aminobutylamine as raw materials under the same conditions as in Example 1.

[0580] MS ESI: m / z = 398, [M+H] + .

[0581] 1H NMR (400 MHz, DMSO-d6) δ9.00 (s, 1H), 8.11 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 6.0 Hz, 1H), 5.71 (d, J = 7.9 Hz, 1H), 3.67 (d, J = 8.3 Hz,1H),3.46(s,1H),3.14–3.03(m,1H),2.14(s,3H),1.74(s,3H),1.63(s,3H),1.57–1.45(m,1H),1.28(q,J=11.4 Hz,1H),0.97(d,J=6.6 Hz,3H).

[0582] Example 37: T-39

[0583] (E)-3 3 ,4,4,7,7-pentamethyl-1 5 -(trifluoromethyl)-3 1 H-2,6,10-Triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclodecane-5-one

[0584] T-39 was prepared using Z-3 and tert-butyl (4-amino-2-methylbutan-2-yl)carbamate hydrochloride as raw materials under the same conditions as in Example 1.

[0585] MS ESI: m / z = 412, [M+H] + .

[0586] 1 H NMR (400 MHz, CDCl3) δ8.10(s,1H),7.76(s,1H),6.97(s,1H),5.38(s,1H),4.85(s,1H),3.35(dd,J=13.2,9.3 Hz,2H),2.20(s,3H),1.87(s,6H),1.50–1.41(m,2H),1.30(s,6H).

[0587] Example 38: T-40

[0588] (3 4 E, 8E)-3 3 ,4,4-trimethyl-1 5 -(trifluoromethyl)-3 1 H-2,6,11-Triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocycloundecanoocten-5-one

[0589] T-40 was prepared using Z-3 and tert-butyl (E)-(4-aminobut-2-en-1-yl)carbamate as raw materials under the same conditions as in Example 1.

[0590] MS ESI: m / z = 396, [M+H] + .

[0591] 1 H NMR (400 MHz, DMSO-d6) δ8.52(s,1H),8.01(s,1H),7.67(s,1H),7.33(s,1H),7.12(s,1H),5.52(d,J=15.4 Hz,1H),5.37(d,J=15.7 Hz, 1H), 3.51 (s, 4H), 2.01 (d, J = 3.9 Hz, 3H), 1.62 (s, 6H).

[0592] Example 39: T-41

[0593] (5 1 s, 5 4 s, E)-1 3 ,8,8-trimethyl-3 5 -(trifluoromethyl)-1 1 H-2,4,6-Triaza-3(2,4)-pyrimidin-1(4,1)-pyrazol-5(1,4)-cyclohexylcyclooctan-7-one

[0594] T-41 was prepared using Z-3 and 1-N-Boc-cis-1,4-cyclohexanediamine as raw materials under the same conditions as in Example 1.

[0595] MS ESI: m / z = 424, [M+H] + .

[0596] 1 H NMR(400 MHz,Chloroform-d)δ8.09(s,1H),7.67(s,1H),6.29(s,1H),5.55(s,1H),5.10(s,1H), 3.93(s,1H),3.04(s,1H),2.37–2.23(m,2H),2.19(s,2H),1.88(s,4H),1.77(d,J=13.5 Hz,2H),1.52–1.23(m,7H).

[0597] Example 40: T-42

[0598] (5 3 R, E)-1 3 ,8,8-trimethyl-35 -(trifluoromethyl)-1 1 H-2,4,6-Triaza-3(2,4)-pyrimidin-1(4,1)-pyrazol-5(1,3)-cyclohexylcyclooctan-7-one

[0599] T-42 was prepared using Z-3 and tert-butyl ((1S,3R)-3-aminocyclohexyl)carbamate as raw materials under the same conditions as in Example 1.

[0600] MS ESI: m / z = 424, [M+H] + .

[0601] 1 H NMR (400 MHz, Chloroform-d) δ8.08 (s, 1H), 7.63 (s, 1H), 6.62 (d, J = 84.3 Hz, 1H), 5.36 (d, J = 64.0 Hz,1H),4.98(s,1H),3.91(s,1H),3.38–2.97(m,2H),2.54(s,1H),2.18(s,3H),2.01(s,2H),1.97–1.79(m,8H).

[0602] Example 41: T-43

[0603] (E)-8,8-difluoro-3 3 ,4,4-trimethyl-1 5 -(trifluoromethyl)-3 1 H-6-Oxa-2,10-diaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclodecane-5-one

[0604] T-43 was prepared using Z-3 and 3-amino-2,2-difluoropropan-1-ol as raw materials under the same conditions as Example 35.

[0605] MS ESI: m / z = 421, [M+H] + .

[0606] 1 H NMR (400 MHz, Chloroform-d) δ8.18(s,1H),7.64(s,1H),6.51(s,1H),5.38(s,1H),4.32(t,J=10.1 Hz,2H),3.99(t,J=14.4 Hz,2H),2.19(s,3H),1.89(s,6H).

[0607] Example 42: T-44

[0608] (E)-3',4',4'-Trimethyl-5'-(trifluoromethyl)spiro[cyclopropane-8'-2,6,10-triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclodecane]-5'-one

[0609] T-44 was prepared using Z-3 and tert-butyl ((1-(aminomethyl)cyclopropyl)) as raw materials under the same conditions as in Example 1.

[0610] MS ESI: m / z = 410, [M+H] + .

[0611] 1 H NMR(400 MHz,Chloroform-d)δ8.11(s,1H),7.74(s,1H),6.86(s,1H),5.13(s,1H),4.9 8(s,1H),3.50(s,2H),3.01(s,2H),2.23(s,3H),1.89(s,6H),0.23(d,J=22.4 Hz,4H).

[0612] Example 43: T-45

[0613] (E)-3 3 ,4,4,9,9-pentamethyl-1 5 -(trifluoromethyl)-3 1 H-2,6,10-Triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclodecane-5-one

[0614] Step 1: Preparation of Y-35

[0615] Y-35 was prepared using M-14 and tert-butyl (4-amino-2-methylbutan-2-yl)carbamate hydrochloride as raw materials under the same conditions as in step 7 of Example 1.

[0616] Step 2: Preparation of T-45

[0617] T-45 was prepared using Y-35 as the raw material under the same conditions as in Example 16.

[0618] MS ESI: m / z = 412, [M+H] + .

[0619] 1H NMR(400 MHz,Chloroform-d)δ8.06(s,1H),7.65(s,1H),7.42(s,1H),5.25(s,1H),4.63(s,1H),3.22–3.09(m,2H),2.22(s,3H),1.86(s,8H),1.31(s,6H).

[0620] Example 44: T-46

[0621] (E)-3 3 ,4,4,9-tetramethyl-1 5 -(trifluoromethyl)-3 1 H-2,6,10-Triaza-1(2,4)-pyrimidin-3(4,1)-pyrazolocyclodecane-5-one

[0622] Compound T-46 was prepared using M-14 and 3-BOC-aminobutylamine as raw materials under the same conditions as Example 43.

[0623] MS ESI: m / z = 398, [M+H] + .

[0624] 1 H NMR (400 MHz, Chloroform-d) δ8.09(s,1H),7.73(s,1H),6.94(s,1H),4.98(d,J=6.0Hz,1H),4.64(s,1H),3.85(dt,J=11.4,6.7 Hz,1H),3.37(td,J=13.5,7.4 Hz,1H),3.03(d,J=11.3 Hz,1H),2.23(s,3H),1.89(s,3H),1.86(s,3H),1.61(t,J=13.6 Hz,1H),1.36(t,J=12.3 Hz, 1H), 1.25 (d, J = 6.6 Hz, 3H).

[0625] Preparation of intermediate M-1

[0626] 1.4 g of 2,4-dichloro-5-trifluoromethylpyrimidine was dissolved in 24 mL of acetonitrile, and N-Boc-1,3-propylenediamine (1.24 mg) and TEA (1.3 g) were added at room temperature and reacted for 18 h. The reaction solution was concentrated and subjected to column chromatography (100% PE-10% EA:PE) to obtain intermediates M-1 (0.99 g Rf: 0.4 20% EA:PE) and M-2 (1.1 g Rf: 0.3 20% EA:PE).

[0627] MS ESI: m / z = 355.2, [M+H] + .

[0628] Preparation of intermediate M-5

[0629] Step 1: Preparation of M-3

[0630] Dissolve 3.3 g of bis-Boc ammonia in 165 mL of DMF. Add 9.9 g of cesium carbonate in portions at room temperature and allow to react for 1 hour. Then, add 1,3-dibromopropane dropwise and stir at room temperature for 12 hours. The reaction mixture is filtered, concentrated, and purified by column chromatography (100% PE-10% EA:PE) to afford intermediate Z-3 (4.39 g).

[0631] Step 2: Preparation of M-4

[0632] Dissolve ethanol azido (87.1 mg) in ultra-dry DMSO (3 mL) and stir in an ice bath. Add 60% NaH under nitrogen, then add a solution of M-3 (338.2 mg) in DMSO (6 mL) dropwise in an ice bath. Allow to react at room temperature for 2 h. After addition, quench the reaction with 2 mL of saturated ammonium chloride solution, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate to yield crude product M-4 (243 mg, pale yellow oil).

[0633] Step 3: Preparation of M-5

[0634] Intermediate M-4 (240 mg, 1 eq) was dissolved in 1,4-dioxane (2.5 mL, 0.3 M), kept warm in an ice bath, and 4 M hydrogen chloride solution in dioxane (1 mL, 5.7 eq) was added dropwise. After addition, the mixture was stirred at room temperature for 16 h. The reaction mixture was directly concentrated and purified by flash column chromatography (100% DCM-10% MeOH:DCM) to obtain intermediate M-5 (21 mg, colorless oil).

[0635] MS ESI: m / z = 145.2, [M+H] + .

[0636] Preparation of intermediate M-6

[0637] Intermediate M-6 was obtained using 2,4-dichloro-5-trifluoromethylpyrimidine and N-methyl-N-Boc-1,3-propylenediamine as raw materials under the same conditions as those for preparing intermediate M-1 in Example 6.

[0638] MS ESI: m / z = 369.2, [M+H] + .

[0639] Preparation of intermediates M-12 and M-13

[0640] Step 1: Preparation of M-8 and M-9

[0641] Using 3-methyl-4-nitropyrazole (2.54 g, 1.0 eq) and methyl 2-bromoacetate (4.59 g, 1.5 eq) as raw materials, the same conditions as those for the preparation of the first step Z-1 in Example 1 were used to obtain a mixture of intermediate light yellow oils M-8 and M-9 (3.7 g).

[0642] MS ESI: m / z = 200.1, [M+H] + .

[0643] Step 2: Preparation of M-10 and M-11

[0644] Using a mixture of M-8 and M-9 (1.99 g) as the starting material, the same conditions as those used in the preparation of Z-2 in the second step of Example 1 were used to obtain a mixture of intermediate brown oils M-10 and M-11 (1.21 g).

[0645] Step 3: Preparation of M-12 and M-13

[0646] Using a mixture of M-10 and M-11 (1.11 g) as the starting material, the same conditions as those used in the preparation of Z-3 in the third step of Example 1 were used to obtain intermediates M-12 as a white solid (850 mg Rf: 0.15 20% EA / PE) and M-13 (Rf: 0.320% EA / PE).

[0647] MS ESI: m / z = 350.2, [M+H] + .

[0648] Preparation of intermediate M-17

[0649] Step 1: Preparation of M-14

[0650] Using Z-1 (4 g, 1.0 eq) as the starting material, the same conditions as those used in the preparation of Z-5 in the fifth step of Example 1 were used to obtain the intermediate white solid M-14 (3.4 g).

[0651] MS ESI: m / z = 212.2, [MH] + .

[0652] Step 2: Preparation of M-15

[0653] Intermediate M-14 (2.2 g, 1.0 eq) was dissolved in THF (40 mL) in a 100 mL sealed tube and stirred at room temperature. A 2 M solution of borane dimethyl sulfide in THF (10 mL, 2.0 eq) was added. After reacting at 65°C for 48 hours, the mixture was cooled to room temperature. Upon completion of the reaction, methanol and ammonium chloride solution were added to quench the reaction. Most of the THF was removed by rotary evaporation, and the mixture was diluted with ethyl acetate. Saturated brine was added, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting mixture was purified by flash column chromatography (100% PE-30% EA / PE) to afford M-15 (2 g) as a solid.

[0654] MS ESI: m / z = 200.1, [M+H] + .

[0655] Step 3: Preparation of M-16

[0656] Intermediate M-15 (1.59 g, 1.0 eq) was dissolved in DCM (110 mL) and stirred in an ice bath. A suspension of Dess-Martin reagent (3.8 g, 1.1 eq) in DCM (15 mL) was added dropwise. The reaction was allowed to react at room temperature for 12 h. Upon completion of the reaction, saturated sodium bicarbonate solution and sodium thiosulfate solution were added to the system and stirred until the upper layer became clear. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography (100% PE-30% EA / PE) to afford M-16 (1.34 g) as a white solid.

[0657] Step 3: Preparation of M-17

[0658] Intermediate M-16 (985 mg, 1.0 eq) was dissolved in MeOH (30 mL). Dimethyl (1-diazo-2-oxopropyl)phosphonate (1.92 g, 2.0 eq) and potassium carbonate (1.38 g, 2.0 eq) were added all at once with stirring at room temperature. The reaction was stirred at room temperature for 14 h. Upon completion of the reaction, the mixture was added to 30 g of ice, extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by flash column chromatography (100% PE-10% EA / PE) to afford M-17 (854 mg) as a pale yellow solid.

[0659] MS ESI: m / z = 194.1, [M+H] + .

[0660] Preparation of intermediate M-19

[0661] Step 1: Preparation of M-18

[0662] M-18 was prepared using 3-cyclopropyl-4-nitro-1H-pyrazole as the starting material under the same conditions as in the first step of Example 1.

[0663] Step 2: Preparation of M-19

[0664] M-19 (500 mg) was dissolved in MeOH (10 ml), and then iron powder (553.4 mg) and NH4Cl (1057 mg) were added. The air was replaced with N2, and the mixture was stirred at 80°C for 4 h, filtered, and dried to obtain M-19.

[0665] MS ESI: m / z = 224, [M+H] + .

[0666] Preparation of intermediate M-21

[0667] Step 1: Preparation of M-20

[0668] Dissolve 3-methyl-4-nitropyrazole (20 g) in DMF (100 mL). Add methyl 3,3-dimethacrylate (53.8 g) and DBU (62 g) sequentially at room temperature. React at room temperature for 20 h. Add water and ethyl acetate, stir, and separate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate. Purify the organic phase by flash column chromatography to obtain 10.69 g of intermediate M-20 as a light yellow oil.

[0669] Step 2: Preparation of M-21

[0670] M-21 was prepared from M-20 using the same preparation method as intermediate M-17.

[0671] Kinase activity inhibition assay

[0672] Kinase activity inhibition test was completed by Aisiyipu Co., Ltd. (Beijing) using ADP-Glo ​​and HTRF

[0673] 1. Kinase Reaction Reagent Formula

[0674] 1.1. Kinase reaction buffer (1X)

[0675] Table 1.1-1 ADP-Glo ​​Buffer

[0676] 2 mM DTT, prepared fresh for use.

[0677] Table 1.1-2 HTRF buffer

[0678] 1.2. Kinase formula

[0679] Table 1.2-1 ADP-Glo ​​Kinase and Substrate Formula

[0680] Table 1.2-2 HTRF kinase and substrate formula

[0681] 2. Experimental Procedure

[0682] ADP-Glo&&HTRF method

[0683] 1) Prepare 2× ATP / substrate solution and 2× kinase / metal ion solution using kinase reaction buffer.

[0684] 2) Transfer 20 nL (ADP-GLo) or 40 nL (HTRF) of the compound dilution to a 384-well plate using an Echo 655. After centrifugation, add 2 μL of the 2× kinase and metal ion solution to the plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes.

[0685] 3) Add 2 μL of 2× substrate and ATP solution to the 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 60 minutes.

[0686] 4) Transfer 4 μL of ADP-Glo ​​to a 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes.

[0687] 5) Transfer 8 μL of the detection solution to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes.

[0688] 6) Read the luminescence signal using a multifunctional microplate reader.

[0689] 3. Data processing methods

[0690] The reading value of the negative control was set as 0% inhibition rate, and the reading value of the positive control was set as 100% inhibition rate, and the inhibition rate of each test solution was calculated.

[0691] Average value of positive control well ratio

[0692] Average value of negative control well ratio

[0693] The IC of the compound was obtained using the following nonlinear fitting formula: 50 (half inhibitory concentration): Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0694] X: log value of compound concentration

[0695] Y: Compound inhibition rate (%inh)

[0696] Z' factor calculation equation: Z'=1-3(SDmin+SDmax) / (AVEmax-AVEmin)

[0697] in:

[0698] Min is the positive control Data value, and max is the negative control DMSO Data value.

[0699] SD is standard error, and AVE is mean.

[0700] Table 2-1 LRRK2 activity inhibition test results

[0701] Table 2-2 Results of other kinase activity inhibition tests

[0702] Oral pharmacokinetic study in rats:

[0703] Two male SD rats were used as experimental animals and administered orally at a dose of 5 mg / kg. Drug preparation: 1% MC was added to the compound and ground and shaken until uniform. Samples were collected at 5, 15, 30 minutes, 1, 2, 4, and 8 hours after administration and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0704] Table 3 PK data of some compounds

[0705] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a prodrug thereof: Where: Selected from the following ring structures: Selected from the following ring structures: R 1 Selected from hydrogen, halogen, cyano, SF5, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, C(O)R 4 、C(O)OR 4 、-NR 4 R 5 、C(O)NR 4 R 5 , SO2R 4 、SO2NR 4 R 5 ,in, R 1 Each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl group is optionally and independently substituted with one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkoxy and oxo (=O) group substitution; R 2 Selected from hydrogen, halogen, cyano, C 1-12 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C(O)R 4 、C(O)OR 4 、-NR 4 R 5 、C(O)NR 4 R 5 , SO2R 4 、SO2NR 4 R 5 , where R 2 Each alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl group is optionally and independently replaced by one or more groups selected from halo, hydroxy, amino, cyano; R 3a Selected from hydrogen, halogen, cyano, C 1-12 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C(O)R 4 、C(O)OR 4 、-NR 4 R 5 、C(O)NR 4 R 5 、SO2R 4 、SO2NR 4 R 5 , where R 3a Each alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl group is optionally and independently replaced by one or more groups selected from halo, hydroxy, amino, cyano; R 3 Independently selected from hydrogen, halogen, cyano, SF5, C 1-12 Alkyl, C 1-12 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, -NR 4 R 5 、-C(O)R 4 、SO2R 4 、SO2NR 4 R 5 ,-C(O)OR 4 and -C(O)NR 4 R 5 , where R 3 The alkyl group is optionally replaced by one or more halo or C 1-3 Alkoxy substituted; R 3 and R 3a Can be connected to form N, NR 6 , NC 1-6 alkyl, O or S 5-membered heterocyclic or heteroaromatic ring; or two R 3 Together form = O; R 4 and R 5 are each independently selected from hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein R 4 or R 5 Each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl group of R is independently and optionally substituted with one or more groups selected from halo, hydroxy, amino, nitro, cyano, (C1-6)alkoxy and oxo (=O); or R 4 and R 5 together with the atoms to which they are attached, form an optionally substituted heterocyclyl; Y is a carbon atom or a nitrogen atom, provided that the required covalent bonding requirements are met; Z and W are independently CH, CH2, (CR 3 2) t 、(CR 3 ) t , NH, O, S or N; or Z and W together with the substituents to which they are connected form a 3-7 membered ring, including a cycloalkane ring, a cycloalkene ring, a heterocyclic ring or a heteroaromatic ring containing 1-3 heteroatoms, wherein the heteroatoms are selected from N, O or S; or when Z or W is (CR 3 2) t When any two R 3 Connected to a carbon atom to form =0 or a 3-6 membered ring, wherein the ring includes a cycloalkane ring or a cycloalkene ring; represents a single bond or a double bond, preferably, It is an aromatic ring; t is 1, 2, or 3; Preferably, the compound of formula I Selected from the following ring structures: Among them, 2 R 3 It can optionally form a 3- to 10-membered carbocyclic or heterocyclic ring with the same carbon atom or different carbon atoms to which it is attached, wherein the heteroatom is selected from N, NH, NC 1-6 Alkyl, O or S; L 1 Selected from chemical bonds, -(CR a R b ) n NR 6 (CR a R b ) m -, -O(CR a R b ) n NR 6 (CR a R b ) m -, -(CR a R b ) n NR 6 C(O)-, -O(CR a R b ) n NR 6 C(O)-, -NR 6 (CR a R b ) n NR 6 C(O)-C 3-6 cycloalkyl, -(CR a R b ) n NR 6 C(O)-(CR a R b ) m , -(CR a R b ) n C(O)NR 6 -, -O(CR a R b ) n C(O)NR 6 -, -(CR a R b ) n NR 6 (CR a R b ) m NR 6 -, -(CR a R b ) n O(CR a R b ) m -, -NR 6 (CR a R b ) n O(CR a R b ) m -,-(CR a R b ) n O(CR a R b ) m NR 6 -、-(CR a R b ) n O(CR a R b ) m O-,-(CR a R b ) n S(CR a R b ) m -,-(CR a R b ) n S(CR a R b ) m NR 6 -,-(CR a R b ) m -、-NR 6 (CR a R<o000191>) m -、-(CR a R<o000194>) m NR 6 -、-O(CR a R b ) m -、-(CR a R b ) m O-、-O(CR<00o0203>R b ) m O-、-(CR a R b ) n NR 6 C 3-6 Cycloalkyl-、-(CR a R b ) n NR 6 C 3-6 Cycloalkyl-NR 6 -、-O(CR a R b ) q CH=CH(CR a R b ) It should be noted that there may be some inaccuracies in the original text with some unclear or potentially incorrect notations (such as <o000191> and <o000194> which might be errors). This translation is done based on the best understanding of the provided text. r -、-(CR a R b ) q CH=CH(CR a R b ) r -、-O(CR a R b ) q CH=CH(CR a R b ) r NR 6 -、-O(CR a R b ) q CH=CH(CR a R b ) r NR 6 C(O)-、-O(CR a R b ) q CH=CH(CR a R b ) r C(O)NR 6 -、-(CR a R b ) q CH=CH(CR a R b ) r NR 6 -、-(CR a R b ) q CH=CH(CR a R b ) r NR 6 CO-、-(CR a R b ) q CH=CH(CR a R b ) r C(O)NR 6 -、-O(CR a R b ) n CH=CH(CR a R b ) m O-、-NR 6 (CR a R b ) n CH=CH(CR a R b ) m -, -NR 6 (CR a R b ) n CH=CH(CR a R b ) m O-, -NR 6 (CR a R b ) n CH=CH(CR a R b ) m S-, -NR 6 (CR a R b ) n CH=CH(CR a R b ) m NR 6 -, -S(CR a R<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ a R b ) n C≡C(CR a R b ) m -; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; L 2 Selected from-CR a R b -、-CR aa =CR bb -, -C(O)-, -C(O)C(O)-, -C(S)-, -S(O)2-, -C 3-6 Cycloalkyl-, -phenyl-, -5- or 6-membered heterocyclyl-, -5- or 6-membered heteroaryl-; L 3 Selected from chemical bonds, -(CR a R b ) q -、-(CR a R b ) q -NR 6 -、-NR 6 (CR a R b ) q -、-O(CR a R b ) q -NR 6 -、-NR 6 (CR a R b ) q O-、-O(CR a R b ) q -、-(CR a R b ) q O-、-(CR a R b ) q -C 3-6 Cycloalkyl-, 5-membered or 6-membered heterocyclic group, -(CR a R b ) q -CR aa =CR bb -、-C 3-6 Cycloalkyl-NR 6 -、-(CR a R b ) q NR 6 -、-(CR a R b ) q NR 6 C(O)-、-(CR a R b ) q NR 6 C(O)O-、-(CR a R b ) q C(O)NR 6 -、(CR a R b ) q OC(O)NR 6 -; q is selected from 0, 1, 2, 3, 4, 5 or 6; r is 1, 2, 3, or 4; Each R 6 are independently selected from the group consisting of hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Aryl, -C(O)C 1-6 Heteroaryl, -C(O)C 3-6 Cycloalkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 1-6 Aryl, -S(O)2C 1-6 Heteroaryl, -S)O)2C 3-6 Cycloalkyl, -C(O)NR 7 C 1-6 Aryl, -C(O)NR 7 C 1-6 Heteroaryl, -C(O)NR 7 C 3-6 Cycloalkyl, -SO2NR 7 C 1-6 Alkyl, -S(O)2NR 7 C 1-6 Aryl, -S(O)2NR 7 C 1-6 Heteroaryl, -S(O)2NR 7 C 3-6 Cycloalkyl, -C(O)C(O)NR 7 C 1-6 Aryl, -C(O)C(O)NR 7 C 1-6 Heteroaryl, -C(O)C(O)NR 7 C 3-6 Cycloalkyl; wherein R 6 Each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl group is optionally and independently substituted with one or more radicals selected from halogen, hydroxy, amino, cyano, (C 1-6 ) alkoxy and oxo (=O) group substitution; R 7 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein R 7 Each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is optionally and independently substituted with one or more groups selected from halo, hydroxy, amino, cyano, (C 1-6 ) alkoxy and oxo (=O) group substitution; R a and R b independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, hydroxy, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)2, C 1-6 Alkylsulfonyl, S(O)2NH2, S(O)2NHC 1-6 Alkyl, NHC(O)NH2, NHC(O)NHC 1-6 Alkyl, NHC(O)OC 1-6 Alkyl, C(O)-C 1-6 alkyl, 1-6 heteroalkyl, heterocyclyl or heterocyclylalkyl; or R a and R b The carbon atoms to which they are connected can form a three- to six-membered carbocyclic or heterocyclic ring, wherein the heteroatom in the heterocyclic ring is selected from NR 6 ,O,S; R aa and R bb independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated cycloalkyl; or R aa and R bb The carbon atoms to which they are connected can form a three- to six-membered carbocyclic or heterocyclic ring, wherein the heteroatom in the heterocyclic ring is selected from NR 6 ,O,S; When not otherwise specified, each cycloalkyl or cycloalkane ring is C 3-6 The cycloalkyl, each cycloalkenyl or cycloalkene ring is C 3-6 Cycloalkenyl, each heterocyclic group is a 3-10 membered heterocyclic group, each aryl is C 6-10 Aryl, each heteroaryl is a 5-10 membered heteroaryl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a prodrug thereof, characterized in that: The compound has a structure represented by a general formula selected from the group consisting of: The definitions of the groups are as described in claim 1.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, a stereoisomer or a tautomer thereof, or a prodrug thereof, wherein: The compound has the structure shown in the following formula, in R 1 、R 2 、R 3 、R 3a 、L 1 、L 3 , and Ring B as described in claim 1.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a prodrug thereof, wherein: The compound has a structure shown in the following formula: in R 1 、R 2 、R 3 、R 3a 、L 1 、L 3 , and Ring B as described in claim 1.

5. The compound according to claim 1, or a pharmaceutically acceptable salt, a stereoisomer or a tautomer thereof, or a prodrug thereof, wherein: The R1 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl; R 2 is selected from hydrogen, halogen or methyl; R 3 Selected from hydrogen, halogen, CF3, SF5, CN.

6. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a prodrug thereof, wherein: The L 1 Selected from:-NR 6 (CR a R b ) m -,-NR 6 C(O)-,-NR 6 (CR a R b ) m NR 6 -、-NR 6 (CR a R b ) n O(CR a R b ) m -、-NR 6 C 3-6 Cycloalkyl-, -NR 6 C 3-6 Cycloalkyl-NR 6 -、-NR 6 (CR a R b ) n CH=CH(CR a R b ) m -、-NR 6 (CR a R b ) n CH=CH(CR a R b ) m O-、-NR 6 (CR a R b ) n CH=CH(CR a R b ) m S-、-NR 6 (CR a R b ) n CH=CH(CR a R b ) m NR 6 -、-NR 6 (CR a R b ) n CH=CH(CR a R b ) m S-, -phenyl-, -heterocyclyl-, -heteroaryl-, NR 6 (CR a R b ) n C≡C(CR a R b ) m -。 7. The compound according to claim 1, or a pharmaceutically acceptable salt, a stereoisomer or a tautomer thereof, or a prodrug thereof, wherein: The L 3 Selected from: where R a and R b are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, hydroxy; or R a and R b The carbon atoms to which they are connected can form a three- to six-membered carbocyclic or heterocyclic ring, wherein the heteroatom in the heterocyclic ring is selected from NR 6 ,O,S;R 6 As defined above.

8. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a prodrug thereof, wherein: The L 2 Selected from -C(O)- or the following heterocyclic structures: The above heterocyclic ring may be substituted by one or two halogens, -CN, C1-C6 alkyl or C1-C6 haloalkyl.

9. The compound according to claim 1, wherein The compound is selected from all compounds described in the Examples and Summary of the Invention.

10. The compound according to claim 1, wherein The compound is selected from the group consisting of:

11. The use of the compound according to any one of claims 1 to 10, characterized in that Used for: (i) preparing kinase inhibitors; (ii) preparing a medicament for treating a kinase-mediated disease; (iii) preparing drugs for the treatment of Parkinson's disease, cancer and other neurodegenerative diseases; (iv) combined with immune checkpoint protein inhibitors or antibodies for the treatment of cancer; (v) Preparation of methods for preventing and / or treating diseases mediated by FGFR, VEGFR, RET, DYRK2, TYRO3, etc., such as cancer and chondrodysplasia.

12. The use according to claim 11, characterized in that The kinase-mediated disease is selected from the group consisting of cancer, inflammatory bowel disease (IBD), tuberculosis, leprosy, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, Injury, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, multiple sclerosis, diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, periodontitis, achondroplasia, lethal bone dysplasia, Crouzon syndrome with acanthosis nigricans, CATSHL syndrome, LADD syndrome, Muenke syndrome and SADDAN syndrome, etc.

13. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: a therapeutically effective amount of the compound according to any one of claims 1 to 10, and a pharmaceutically acceptable carrier.

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