Polycyclic compound for treating nervous system diseases and tumors

Abstract

The invention discloses a polycyclic compound as a tubulin stabilizer and a preparation method thereof, the structure of the polycyclic compound is shown in a general formula (I), and the definitions of Ar, W, Z, X, Y and heterocyclic ring A are shown in the specification. The invention also discloses a preparation method of the compound. The compound shown in the general formula (I) can be used for preparing medicines for preventing and / or treating tumors and neurodegenerative diseases. # imgabs0 #

Description

A polycyclic compound for the treatment of neurological diseases and tumors

[0001] The present invention belongs to the technical field of medicinal chemistry, and specifically relates to a compound containing spirocyclic and cyclocyclic structures that can be used to treat nervous system diseases and tumors (including brain gliomas) and a preparation method thereof.

[0002] Microtubules are essential components of the cytoskeleton, responsible for crucial physiological functions such as cell proliferation, maintaining cell morphology, and transporting intracellular substances. In the central nervous system, neurons, the primary functional cells, are a specialized cell type that no longer undergo mitosis and instead possess a polarized morphology. Axons, which transmit neural signals outward, rely on rapid transport pathways formed by microtubules and other cytoskeletal proteins to rapidly transport intracellular substances between the cell body and nerve endings. Under pathological conditions, microtubule composition and function change, contributing to the pathogenesis of many important diseases. For example, Alzheimer's disease (AD) is characterized by two characteristic pathological features: the aggregation of amyloid-β (Aβ) and Tau protein. Hyperphosphorylation of Tau causes it to lose its ability to bind to tubulin and deposits as neurofibrillary tangles, impairing microtubule-mediated axonal transport and leading to distal axonal degeneration. Tubulin stabilizers can promote the binding of Tau protein to tubulin, improve the transport and function of vesicles involved in the protein quality control system in cells, and reduce the formation of neurofibrillary tangle deposition by tau. Therefore, they can be used to treat Alzheimer's disease and other neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, multiple sclerosis and traumatic nerve injury.

[0003] On the other hand, there are also a class of malignant tumors in the central nervous system that are highly aggressive and poorly treated, such as gliomas. These diseases typically arise in proliferating glial cells in the brain. Like most tumor cells, disordered cell proliferation causes diseased glial cells to develop into malignant cancer cells. Therefore, microtubule stabilizers that can cross the blood-brain barrier, specifically inhibit malignant glial cell proliferation while being relatively harmless to neurons, hold great promise for treating these central nervous system diseases.

[0004] The present invention discovered a new class of compounds containing spirocyclic and fused ring structures with unexpectedly high tubulin stability

[0005]

[0006] The object of the present invention is to provide a novel compound containing a spirocyclic and cyclocyclic structure with high tubulin stabilizing activity.

[0007] Another object of the present invention is to provide a method for preparing the compound.

[0008] The first aspect of the present invention provides a compound of formula (I) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt or prodrug thereof:

[0009] Where,

[0010] Ar is:

[0011] X 1 Cl, CN, vinyl, -CH=CHC 1-6 Alkyl, -CH=CHC 3-6 Cycloalkyl, -C≡CH, -C≡C 1-6 Alkyl, -C≡CC 3-6 Cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, SC 1-6 alkyl;

[0012] R 1 C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic, C3-C 10 Halogenated cycloalkyl or R 1 for:

[0013] R 1a and R 1b Independently hydrogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, C3-C 10 Halogenated cycloalkyl, C7-C 11 Spiroalkanes, C5-C 10 Heterocyclic spirocyclic, aryl, heteroaryl;

[0014] R 2 is hydrogen;

[0015] R 3 and R 4 independently hydrogen, F, Cl, Br;

[0016] W is a chemical bond, -O(CR a R b) n -、-(CR a R b ) n O-、-S(CR a R b ) n -、-(CR a R b ) n S-、-(CR a R b ) n -NR e -、-N(R e )-(CR a R b ) n -、-C(O)N(R e )-(CR a R b ) n -、-N(R e )C(O)-(CR a R b ) n -、-(CR a R b ) n -、-C(O)(CR a R b ) n -、-(CR a R b ) n C(O)-, arylene, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, C 6-10 Arylene, C5-C9 fused heteroaromatic, 5-membered or 6-membered heteroaromatic;

[0017] R a and each R b are independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Alkenyl, substituted or unsubstituted C6-C 20 Aryl, or substituted or unsubstituted C3-C 14 Heteroaryl; R a and R b Together with the carbon atoms to which they are attached, they can form a three- to eight-membered ring or a four- to eight-membered heterocyclic ring, wherein the heteroatom can be sulfur, oxygen, NH or NR e ;

[0018] R c and each R dEach is independently hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C2-C 10 Alkenyl, C6-C 20 Aryl, C3-C 14 Heteroaryl; R c and R d It may be substituted by one or more groups selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, aldehyde, carboxyl, alkoxy, -CF3, -SF5. c and R d Together with the nitrogen atom to which they are attached, they can form a three- to eight-membered ring or a four- to eight-membered heterocyclic ring, wherein the heteroatom can be sulfur, oxygen, NH or NR e ;

[0019] R e is hydrogen, C1-C6 alkyl, -(CR a R b ) n -C3-C6 cycloalkyl, -(CR a R b ) n -aryl, -(CR a R b ) n -heteroaryl; R e It may be substituted by one or more groups selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, aldehyde, carboxyl, alkoxy, -CF3, and -SF5.

[0020] Y is H, halogen, OR e 、-(CR a R b ) m -CO2H、-(CR a R b ) m -CO(CR a R b ) n -NR a R b 、C1-C6 alkyl、-(CR a R b ) n -C3-C6 cycloalkyl, -(CR a R b ) n -aryl, -(CR a R b ) n -heteroaryl, -(CR a R b ) n -NR c Rd 、-O(CR a R b ) n -NR c R d 、-S(CR a R b ) n -NR c R d 、-NR e (CR a R b ) n -NR c R d 、-(CR a R b ) n -P(O)Me2、-(CR a R b ) n -SO2R a 、-(CR a R b ) n -SO2NR c R d 、-(CR a R b ) n -NR e CONR c R d 、-(CR a R b ) n -CONR c R d .

[0021] m and n are independently 0 or an integer from 1 to 6;

[0022] is a monocyclic hydrocarbon group, a spirocyclic hydrocarbon group, a condensed hydrocarbon group, a bridged hydrocarbon group, a monocyclic heterocyclic group, a spirocyclic heterocyclic group, a condensed heterocyclic group or a bridged heterocyclic group structure;

[0023] X and Z are independently C(R 5 ), N;

[0024] R 5 For hydrogen, OH, CN, halogen, NR c R d 、C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, -(CR a R b ) n -C3-C10 Cycloalkyl, -(CR a R b ) n -C3-C 10 Halogenated cycloalkyl, -(CR a R b ) n -CO2H、-(CR a R b ) n -CONR c R d ;

[0025] In another preferred embodiment, Ar is:

[0026] In another preferred embodiment, in the general formula (I)

[0027] for:

[0028] In another preferred embodiment, W in the general formula (I) is a chemical bond or O.

[0029] In another preferred embodiment, W in the general formula (I) is -C≡C-.

[0030] In another preferred embodiment, X in the general formula (I) is N or CH.

[0031] In another preferred embodiment, Y in the general formula (I) is H, C1-C6 alkyl, C1-C6 fluoroalkyl, -C3-C6 cycloalkane, -(CR a R b ) n -NR c R d 、-SO2R a 、-SO2NR c R d 、-CONR c R d , aryl or heteroaryl.

[0032] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (II):

[0033] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, and W, Z, X, Y are defined as in the general formula (I).

[0034] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (III):

[0035] Where, X 1 is Cl, methyl, ethyl or cyclopropyl, and the heterocyclic rings A, W, Z, X and Y are as defined in the general formula (I);

[0036] R 1a CF3,

[0037] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (IV):

[0038] wherein X1 is Cl, methyl, CF3, ethyl or cyclopropyl, R1a, Ra, Rb, Rc, Rd and Re are defined as in the general formula (I); W is a chemical bond, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, -O(CRaRb)n-, -(CRaRb)nO-, -(CRaRb)nS-, -S(CRaRb)n-, -(CRaRb)nNRa- or -NRe(CRaRb)n-; and n is 0 or an integer from 1 to 3.

[0039] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (V):

[0040] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, R 1a 、R a 、R b 、R c 、R d and R e The definitions are as described in the general formula (I); W is a chemical bond, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, -O(CR a R b ) n -、-(CR a R b ) n O-、-(CR a R b ) n S-、-S(CR a R b ) n -、-(CR a R b ) nNR a -or-NR e (CR a R b ) n -; n is 0 or an integer from 1 to 3.

[0041] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (VI):

[0042] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, R 1a 、R a 、R b 、R c 、R d and R e The definitions are as described in the general formula (I); W is a chemical bond, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, -O(CR a R b ) n -、-(CR a R b ) n O-、-(CR a R b ) n S-、-S(CR a R b ) n -、-(CR a R b ) n NR a -or-NR e (CR a R b ) n -; n is 0 or an integer from 1 to 3.

[0043] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (VII):

[0044] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, R 1a 、R a 、R b 、R c 、R d and R e The definitions are as described in the general formula (I); W is a chemical bond, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, -O(CR a Rb ) n -、-(CR a R b ) n O-、-(CR a R b ) n S-、-S(CR a R b ) n -、-(CR a R b ) n NR a -or-NR e (CR a R b ) n -; n is 0 or an integer from 1 to 3.

[0045] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (VIII):

[0046] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, R 1a 、R a 、R b 、R c 、R d and R e The definitions are as described in the general formula (I); W is a chemical bond, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, -O(CR a R b ) n -、-(CR a R b ) n O-、-(CR a R b ) n S-、-S(CR a R b ) n -、-(CR a R b ) n NR a -or-NR e (CR a R b ) n -; n is 0 or an integer from 1 to 3.

[0047] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (IX):

[0048] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, R 1a 、R a 、R b 、R c 、R d and R e The definitions are as described in the general formula (I); W is a chemical bond, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, -O(CR a R b ) n -、-(CR a R b ) n O-、-(CR a R b ) n S-、-S(CR a R b ) n -、-(CR a R b ) n NR a -or-NR e (CR a R b ) n -; n is 0 or an integer from 1 to 3.

[0049] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (X):

[0050] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, R a 、R b 、R c 、R d and R e The definitions are as described in the general formula (I); W is a chemical bond, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, -O(CR a R b ) n -、-(CR a R b ) n O-、-(CR a R b ) n S-、-S(CR a R b ) n -、-(CR a Rb ) n NR a -or-NR e (CR a R b ) n -; n is 0 or an integer from 1 to 3.

[0051] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (XI):

[0052] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, R a 、R b 、R c 、R d and R e The definitions are as described in the general formula (I); W is a chemical bond, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, -O(CR a R b ) n -、-(CR a R b ) n O-、-(CR a R b ) n S-、-S(CR a R b ) n -、-(CR a R b ) n NR a -or-NR e (CR a R b ) n -; n is 0 or an integer from 1 to 3.

[0053] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (XII):

[0054] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, R a 、R b 、R c 、R d and R e The definitions are as described in the general formula (I); W is a chemical bond, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, -O(CR a R b )n -、-(CR a R b ) n O-、-(CR a R b ) n S-、-S(CR a R b ) n -、-(CR a R b ) n NR a -or-NR e (CR a R b ) n -; n is 0 or an integer from 1 to 3.

[0055] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (XIII):

[0056] Where R a 、R b 、R c 、R d and R e The definitions are as described in the general formula (I); W is a chemical bond, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, -O(CR a R b ) n -、-(CR a R b ) n O-、-(CR a R b ) n S-、-S(CR a R b ) n -、-(CR a R b ) n NR a -or-NR e (CR a R b ) n -; n is 0 or an integer from 1 to 3.

[0057] In another preferred embodiment, the compound of general formula (I) is represented by general formula (VIV):

[0058] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, Ra 、R b 、R c 、R d and R e The definitions are as described in the general formula (I); W is a chemical bond, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, -O(CR a R b ) n -、-(CR a R b ) n O-、-(CR a R b ) n S-、-S(CR a R b ) n -、-(CR a R b ) n NR a -or-NR e (CR a R b ) n -; n is 0 or an integer from 1 to 3.

[0059] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (XV):

[0060] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, R a 、R b 、R c 、R d and R e The definitions are as described in the general formula (I); W is a chemical bond, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, -O(CR a R b ) n -、-(CR a R b ) n O-、-(CR a R b ) n S-、-S(CR a R b ) n -、-(CR a R b ) n NR a -or-NR e (CR a Rb ) n -; n is 0 or an integer from 1 to 3.

[0061] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (XVI):

[0062] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, W is a chemical bond, -O(CR a R b ) n -、-(CR a R b ) n O-、-S(CR a R b ) n -、-(CR a R b ) n S-、-NR e -(CR a R b ) n -、-(CR a R b ) n NR e -, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-; R a 、R b , Y and R e The definition of is as described in general formula (I), and n is 0, or an integer from 1 to 6.

[0063] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (XVII):

[0064] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, W is a chemical bond, -O(CR a R b ) n -、-(CR a R b ) n O-、-S(CR a R b ) n -、-(CR a R b ) n S-、-NR e -(CR a R b )n -、-(CR a R b ) n NR e -, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-; R a 、R b , Y and R e The definition of is as described in general formula (I), and n is 0, or an integer from 1 to 6.

[0065] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (XVIII):

[0066] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, Y is as defined in the general formula (I); W is a chemical bond, -O(CR a R b ) n -、-(CR a R b ) n O-、-S(CR a R b ) n -、-(CR a R b ) n S-、-NR e -(CR a R b ) n -、-(CR a R b ) n NR e -, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-; R a 、R b , Y and R e The definition of is as described in general formula (I), n is 0, or an integer from 1 to 6; R a 、R b , Y and R e The definition of is as described in general formula (I), and n is 0, or an integer from 1 to 6.

[0067] In another preferred embodiment, the compound of general formula (I) is represented by general formula (XIX):

[0068] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, Y is as defined in the general formula (I); W is a chemical bond, -O(CRa R b ) n -、-(CR a R b ) n O-、-S(CR a R b ) n -、-(CR a R b ) n S-、-NR e -(CR a R b ) n -、-(CR a R b ) n NR e -, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-; R a 、R b , Y and R e The definition of is as described in general formula (I), n is 0 or an integer from 1 to 6; n is 0 or an integer from 1 to 6.

[0069] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (XX):

[0070] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, Y is as defined in the general formula (I); W is a chemical bond, -O(CR a R b ) n -、-(CR a R b ) n O-、-S(CR a R b ) n -、-(CR a R b ) n S-、-NR e -(CR a R b ) n -、-(CR a R b ) n NR e -, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-; R a 、R b , Y and R e The definition of is as described in general formula (I); n is 0, or an integer from 1 to 6;

[0071] R 1a CF3,

[0072] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (XXI):

[0073] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, Y is as defined in the general formula (I); W is a chemical bond, -O(CR a R b ) n -、-(CR a R b ) n O-、-S(CR a R b ) n -、-(CR a R b ) n S-、-NR e -(CR a R b ) n -、-(CR a R b ) n NR e -, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-; n is 0 or an integer from 1 to 6;

[0074] R 1a CF3,

[0075] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (XXII):

[0076] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, Y is as defined in the general formula (I); W is a chemical bond, -O(CR a R b ) n -、-(CR a R b ) n O-、-S(CR a R b ) n -、-(CR a R b )n S-、-NR e -(CR a R b ) n -、-(CR a R b ) n NR e -, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-; n is 0 or an integer from 1 to 6;

[0077] R 1a For CF,

[0078] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (XXIII):

[0079] Where, X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, Y is as defined in the general formula (I); W is a chemical bond, -O(CR a R b ) n -、-(CR a R b ) n O-、-S(CR a R b ) n -、-(CR a R b ) n S-、-NR e -(CR a R b ) n -、-(CR a R b ) n NR e -, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-; n is 0 or an integer from 1 to 3;

[0080] R 1a CF3,

[0081] In another preferred embodiment, the compounds of the above general formulas (I) to (XXIII) are:

[0082] In another preferred embodiment, the stereoisomers are cis-trans isomers.

[0083] In another preferred embodiment, the compound is a racemate.

[0084] In another preferred embodiment, the stereoisomers are enantiomers.

[0085] In another preferred embodiment, any one or more hydrogen atoms in the compound may be replaced by deuterium.

[0086] In another preferred embodiment, the pharmaceutically acceptable salt is 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.

[0087] The compound of general formula (I) of the present invention can be obtained by the following preparation method, comprising the following steps:

[0088] Route 1

[0089] In the formula, R is C1-C6 alkyl or C1-C6 haloalkyl; Ar, X, W, Z, and Y are the same as defined above.

[0090] Route 2

[0091] Wherein, R is OH or (RO)2 is (OCMe2CMe2O); Ar, R 1 、R 2 、X, W, Z, Y are defined as above. Route 3

[0092] Where Ar, R 1 、R 2 , X, W, Z, Y are defined as before.

[0093] Route 4

[0094] Where Ar, R 1 、R 2 , X, W, Z, Y are defined as before.

[0095] Route 5

[0096] Where Ar, R 1 、R 2 , X, W, Z, Y are defined as before.

[0097] In the above method,

[0098] The base can be selected from the following group: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal hydride, alkaline earth metal hydride, alkali metal carbonate (hydrogen) salt, alkaline earth metal carbonate, bis (trimethylsilyl) amino alkali metal salt, pyridine, triethylamine, diisopropylethylamine and the like.

[0099] The acid can be selected from the following group: hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid and the like.

[0100] The reducing agent can be selected from the following group: lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, lithium borohydride, borane, sodium acetate borohydride, etc.

[0101] The palladium catalyst can be selected from the following group: tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, and the like.

[0102] The copper salt can be selected from the following group: cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide and the like.

[0103] The chlorinating agent can be selected from the following group: N-chlorosuccinimide, phosphine oxychloride, thionyl chloride, etc.

[0104] The brominating agent can be selected from the following group: liquid bromine, N-bromosuccinimide, phosphine tribromide and the like.

[0105] Another aspect of the present invention provides the use of the compound of formula (I) or its stereoisomers or tautomers, or its pharmaceutically acceptable salts or prodrugs according to the first aspect, for:

[0106] (iii) preparing a tubulin stabilizer;

[0107] (iv) tubulin-mediated diseases;

[0108] (iii) preparing drugs for preventing and / or treating cancer and neurodegenerative diseases.

[0109] In another preferred embodiment, the cancer includes but is not limited to: glioma, colon cancer, breast cancer, gastric cancer, lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, liver cancer, brain cancer, melanoma, multiple myeloma, chronic myeloid leukemia, blood tumors, lymphomas, including metastatic lesions in other tissues or organs away from the primary site of the tumor.

[0110] In another preferred embodiment, the neurodegenerative diseases include but are not limited to Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis and traumatic brain injury.

[0111] Another aspect of the present invention provides a pharmaceutical composition comprising: other anti-tumor drugs, such as PD-1 antibody, PD-L1 antibody, CTLA-4 antibody and other anti-tumor chemotherapy drugs and targeted drugs.

[0112] 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 examples) 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.

[0113] After extensive and in-depth research, the present inventors discovered that a novel polycyclic compound can be used as a highly effective tubulin stabilizer for preventing and / or treating tubulin-mediated diseases. On this basis, the present invention was completed.

[0114] definition

[0115] The term "C1-C 10 "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-). In the present invention, the term includes substituted or unsubstituted alkyl groups.

[0116] As used herein, the term "substituted or unsubstituted" means that the group may be unsubstituted, or H in the group may be substituted with one or more (preferably 1 to 6, more preferably 1 to 3) substituents.

[0117] As used herein, the term "substituted" or "substituted" means that the group has one or more (preferably 1-6, more preferably 1-3) substituents selected from the group consisting of halogen, hydroxy, -NH2, nitro, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, benzyl, C1-C6 alkylS(O)2-, (C0-C6 alkyl)2NS(O)2-, C1-C6 alkylC(O)-, C3-C6 cycloalkylC(O)-, C0-C6 alkylOC(O)-, (C0-C6 alkyl)2NC(O)-, C0-C6 alkylC(O)NH-, (C0-C6 alkyl)2NC(O)NH-.

[0118] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group may be saturated or unsaturated, branched, linear, or cyclic. Preferably, the alkoxy group has 1 to 10 carbon atoms, i.e., C1-C 10 Alkoxy groups preferably have 1 to 6 carbon atoms. Representative examples include (but are not limited to): methoxy, ethoxy, and propoxy.

[0119] As used herein, the term "C6-C 20 "Aryl" refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6 to 14) carbon atoms, which has a single ring (such as phenyl) or a fused ring (such as naphthyl or anthracenyl). If the point of attachment is on the aromatic carbon atom, the fused ring may be non-aromatic (such as 2-benzoxazolone, 2H-1,4-benzoxazin-3(4H)-on-7-yl, etc.). Preferred aryl groups include phenyl and naphthyl. The term includes substituted and unsubstituted forms, wherein the substituents are as defined above.

[0120] As used herein, the term "C2-C 10 "Alkenyl" refers to an alkenyl group having 2 to 10 (e.g., 2 to 6 or 2 to 4) carbon atoms and having at least 1 (e.g., 1 to 2) unsaturated olefinic bonds (>C=C<). Examples of such groups include vinyl, allyl, and but-3-enyl.

[0121] As used herein, the term "C3-C 10"Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms, having a single ring or multiple rings (including fused systems, bridged cycloalkane systems and spirocycloalkane 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. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl. "Spirocycloalkane" or "spirocycloalkyl" refers to a polycyclic group with 5 to 20 members, in which the single rings share one carbon atom (called a spiro atom), which may contain one or more double bonds, and is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10).

[0122] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0123] As used herein, the term "heteroaromatic" or "heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring. As for the terms indicating the number of carbon atoms, such as "C3-C 20 "Heteroaryl" means an aromatic group having 3-20 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. Other similar groups. Such heteroaryl groups may be monocyclic (such as pyridyl or furyl) or fused rings (such as indolizinyl or benzothienyl), wherein the fused ring may be non-aromatic and / or contain one heteroatom, as long as the point of attachment is through the atom of the aromatic heteroaryl group. In one embodiment, the ring atoms nitrogen and / or sulfur of the heteroaryl group are optionally oxidized to N-oxide (NO), sulfinyl or sulfonyl. Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl and furyl. The term includes substituted or unsubstituted heteroaryl groups.

[0124] 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.

[0125] 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 a fused ring (including spirocyclic hydrocarbon groups, fused hydrocarbon groups, bridged hydrocarbon groups, monocyclic heterocyclic groups, spirocyclic heterocyclic groups, fused heterocyclic groups or bridged heterocyclic groups) having 1 to 10 carbon atoms and 1 to 4 (such as 3) heteroatoms selected from nitrogen, sulfur or oxygen in the ring. In the 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. Heterocyclic spirocyclic compounds are formed by replacing the carbon atoms of carbocyclic spirocyclic compounds with heteroatoms (such as O, S, N or NR) eIn practice, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide N-oxide, sulfinyl and sulfonyl moieties.

[0126] 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.

[0127] As used herein, the term "stereoisomer" refers to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

[0128] 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.

[0129] Unless otherwise specified, the monocyclic hydrocarbon group, spirocyclic hydrocarbon group, fused hydrocarbon group, bridged hydrocarbon group, monocyclic heterocyclic group, spirocyclic heterocyclic group, fused heterocyclic group or bridged heterocyclic group has 5-20 ring skeleton atoms. When the ring skeleton atoms have heteroatoms, the heteroatoms can be 1 to 4 (e.g., 3) heteroatoms selected from nitrogen, sulfur or oxygen.

[0130] "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.

[0131] Compounds of the present invention

[0132] As used herein, the term "compound of the present invention" refers to a compound of formula (I), a racemate thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0133] The present invention relates to racemic mixtures of these compounds, mixtures enriched in either enantiomer, and any isolated enantiomer. For the purposes of the present invention, the racemic mixture is understood to be a 50%:50% mixture of the two R and S enantiomers. The isolated enantiomer is understood to be a pure enantiomer (i.e., 100%) or highly enriched in one enantiomer (purity ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85%, ≥80%).

[0134] When the compounds described in the present invention exist as stereoisomers, the present invention includes all stereoisomers of the compounds.

[0135] When the compounds described in the present invention exist as tautomers, the present invention includes all tautomers of the compounds.

[0136] 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.

[0137] Pharmaceutical composition

[0138] The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective amount and a pharmaceutically acceptable carrier.

[0139] The "active ingredient" described in the present invention refers to the compound of general formula (I) described in the present invention or its stereoisomers or tautomers, or its pharmaceutically acceptable salts or prodrugs.

[0140] 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.

[0141] "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.

[0142] The compounds of the preferred embodiments of the present invention can be administered as a single active agent or in combination with one or more other agents used to treat cancer. The compounds of the preferred embodiments of the present invention are also effective when used in combination with known therapeutic agents and anticancer agents, and combinations of currently known compounds with other anticancer or chemotherapeutic agents are within the scope of the preferred embodiments. Examples of such agents can be found in Cancer Principles and Practice of Oncology, V.T. Devita and S. Hellman (eds.), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. Based on the specific properties of the drugs and the cancer involved, one of ordinary skill in the art will be able to discern effective combinations of agents. Such anticancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cytostatic agents, antiproliferative agents, prenyl protein transferase inhibitors, hemoacetylase (HDAC) inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, cell proliferation and survival signal inhibitors, apoptosis inducers and agents that interfere with cell cycle checkpoints, CTLA4 antibodies, PD-1 antibodies, PD-L1 antibodies, etc. The compounds of the preferred embodiments are also effective when administered concurrently with radiation therapy.

[0143] 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.

[0144] 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).

[0145] 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.

[0146] As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic acid or alkaline earth metal salt of a compound of formula (I). These salts can be prepared in situ during the final isolation and purification of the compound of formula (I), 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 compound of Formula I, 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.

[0147] As used herein, the term "pharmaceutically acceptable prodrug" refers to prodrugs of the compounds of the preferred embodiments that are rapidly converted in vivo to the parent compound of the above general formula, for example, by hydrolysis in the blood. A complete discussion is provided in "T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Volume 14 of the ACS 15 Symposium Series" and "Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987," both of which are incorporated herein by reference.

[0148] The present invention is beneficial in that:

[0149] (1) providing a compound of general formula (I) with a novel structure;

[0150] (2) The compounds of the present invention can serve as highly effective tubulin stabilizers;

[0151] (3) It has multiple pharmacological activities such as the treatment of cancer and neurodegenerative diseases (Huntington's disease, Alzheimer's disease, frontotemporal dementia, Parkinson's disease, multiple sclerosis and traumatic brain injury), and anti-inflammatory effects.

[0152] The present invention will be further described below with reference to specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be applied to the present invention. The preferred embodiments and materials described herein are for exemplary purposes only.

[0153] Pre-HPLC conditions: HPLC-MS analysis was performed on a Waters HPLC 2767 using a Waters QDA (KBD5205) as a mass detector and a Waters 2489 UV as a detector. The chromatographic column used was MS C 18 OBD TMColumn (5 μm, 19 × 100 mm). The mobile phase consisted of eluent A (water, 1.0‰ FA) and eluent B (CH3CN), with an elution rate of 20 mL / min. Initial conditions were 95% A for 0.5 minutes, followed by a linear decrease from 95% A to 40% A over 8.5 minutes, a maintenance period of 40% A from 8.5 minutes to 10.5 minutes, and a return to 95% A over 1.5 minutes. The total run time was 12 minutes. The mobile phase gradient and run time could be adjusted appropriately based on the properties of the compound.

[0154] Intermediate 1

[0155] 5,7-Dichloro-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine 1

[0156] Step 1: Diethyl 2-(2,4,6-trifluorophenyl)malonate 2

[0157] Sodium hydride (11.4 g, 60% wt.) was suspended in 1,4-dioxane, and diethyl malonate (45.7 g) was added dropwise at zero degree. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 10 minutes. Cuprous bromide (24.6 g) and 1-bromo-2,4,6-trifluorobenzene (30.0 g) were added and reacted at 100 degrees for 10 hours. The reaction solution was quenched with saturated ammonium chloride, the insoluble matter was removed by filtration, and the filtrate was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 0-20%) to obtain a colorless oil (38.0 g).

[0158] MS ESI: m / z = 291.08, [M+H] + .

[0159] Step 2: 6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diol 3

[0160] Compound 2 (20.0 g) and 1H-1,2,4-triazole-5-amine (6.08 g) were placed in a 100 mL sealed tube. Tri-n-butylamine (17.8 mL) was added at room temperature and allowed to react at 180°C for 6 hours. The reaction solution was then cooled to 110°C, diluted with an appropriate amount of toluene, and 14 mL of 50% sodium hydroxide solution was added. The precipitated white solid was washed three times with toluene, filtered, and dried to obtain a white solid. Step 3: 5,7-Dichloro-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine 1

[0161] The product 3 from the previous step was placed in a 500 mL sealed tube, and phosphorus oxychloride (130.0 mL) was slowly added under an ice-water bath. The reaction solution was heated to 140°C and reacted for 8 hours. The mixture was quenched with saturated sodium bicarbonate and then extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to give the target product (15 g) as a white solid.

[0162] MS ESI: m / z = 319.0, [M+H] + .

[0163] Intermediate 1A

[0164] 7-Chloro-5-methyl-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine 1A

[0165] Step 1: Methyl 3-oxo-2-(2,4,6-trifluorophenyl)butyrate 2A

[0166] 2-(2,4,6-trifluorophenyl)acetic acid (10.0 g) was dissolved in methanol (50.0 mL), and dichlorothionyl (12.0 mL) was added under ice-water bath conditions. The reaction was continued for 3 hours. 50 mL of ice water was added to the reaction solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product as a colorless oil (10.47 g). The product was used directly in the next step without further purification. The above product (10.47 g) was dissolved in tetrahydrofuran (51.0 mL) and lithium bis(trimethylsilyl)amide (107.75 mL, 1.0 M in HCl) was added at -65 degrees. The reaction was continued under the same conditions for 30 min. Acetyl chloride (4.1 mL) was added to the reaction system and the reaction was continued at room temperature for 5 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-10%) to obtain the target product 2A as a white solid (12.9 g).

[0167] 1 H NMR (400MHz, CDCl3): δ13.21 (s, 1H), 6.68 (t, J = 7.9Hz, 2H), 3.70 (d, J = 1.2Hz, 3H), 1.87 (s, 3H).

[0168] Step 2: 7-Chloro-5-methyl-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine 1A

[0169] The product 2A (11.9 g) from the previous step was dissolved in a 100 mL sealed tube with acetic acid (54.1 mL). 1H-1,2,4-triazole-5-amine (4.14 g) was added and the mixture was reacted at 120°C for 24 hours. Excess acetic acid was evaporated, and methyl tert-butyl ether was added and stirred at 60°C for 2 hours. The mixture was then slowly cooled to room temperature and filtered to obtain the target product as a yellow solid. The yellow solid was dissolved in phosphine oxychloride (30 mL) in a 100 mL sealed tube and reacted at 130°C for 20 hours. Saturated sodium bicarbonate was slowly added to the reaction solution for quenching, followed by extraction with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 0-5%) to obtain 1.5 g of intermediate 1A as a white solid.

[0170] MS ESI: m / z = 299.0, [M+H] + .

[0171] Intermediate 1B

[0172] 5,7-Dichloro-6-(2,6-difluoro-4-iodophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine 1B

[0173] Step 1: Diethyl 2-(2,6-difluoro-4-nitrophenyl)malonate 2B

[0174] 1,2,3-Trifluoro-5-nitrobenzene (5.0 g) was dissolved in N,N-dimethylformamide (32.0 mL), and diethyl malonate (4.28 g) and potassium carbonate (7.81 g) were added sequentially. The reaction was carried out at 65°C for 2 hours, and 1N hydrochloric acid was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, filtered, and the crude product was concentrated and purified by silica gel column chromatography (ethyl acetate; petroleum ether = 0-10%) to obtain the target product 2B (7.4 g) as a yellow oil.

[0175] Step 2: Diethyl 2-(4-amino-2,6-difluorophenyl)malonate 3B

[0176] The first step product (5.0 g) was dissolved in methanol (50 mL), and palladium on carbon was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 8 hours. The mixture was filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-30%) to obtain the target compound 3B (3.57 g) as a white solid.

[0177] 1 H NMR (400MHz, CDCl3): δ6.20–6.13(m,2H),4.80(s,1H),4.22(q,J=7.1Hz,4H),1.25(t,J=7.1Hz,6H).

[0178] Step 3: Diethyl 2-(2,6-difluoro-4-iodophenyl)malonate 4B

[0179] The product from the second step (2.0 g) was dissolved in 6N aqueous hydrochloric acid (12.0 mL). A solution of sodium nitrite (492.0 mg) dissolved in water (2.7 mL) and a solution of potassium iodide (4.92 g) dissolved in water (5.0 mL) were added sequentially at zero degrees Celsius. The mixture was reacted at room temperature for 3 hours. The reaction solution was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-10%) to obtain the target product 4B (1.4 g) as a colorless oil.

[0180] 1 H NMR (400MHz, Chloroform-d): δ7.33–7.29 (m, 2H), 4.89 (s, 1H), 4.25 (q, J = 7.1Hz, 4H), 1.27 (t, J = 7.1Hz, 6H).

[0181] Step 4: Diethyl 2-(2,6-difluoro-4-iodophenyl)malonate 1B

[0182] The third step product 4B (2.0 g) and 1H-1,2,4-triazole-5-amine (443.67 mg) were dissolved in tri-n-butylamine (1.3 mL) and reacted at 170°C for 3 hours. An appropriate amount of toluene was then added to the reaction solution at 110°C to dilute it. 50% sodium hydroxide solution was then added at 50°C to cool it to room temperature and filtered to obtain a white solid. The white solid was dissolved in trichlorophosphine (10 mL) and then reacted at 130°C for 6 hours. Saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-22%) to obtain the target intermediate 1B.

[0183] MS ESI: m / z = 426.8, [M+H] + .

[0184] Intermediate 4

[0185] (R)-5-chloro-N-(3-methylbutan-2-yl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

[0186] Intermediate 1 (500.0 mg) was dissolved in N-methylpyrrolidone (3.1 mL), and (2R)-3-methylbutan-2-amine hydrochloride (407.96 mg) and sodium bicarbonate powder (329.7 mg) were added sequentially at room temperature. The mixture was reacted at 60°C for 3 hours. Saturated sodium chloride was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-20%) to give the target intermediate 4 (560.0 mg) as a white solid.

[0187] MS ESI: m / z = 370.0, [M+H] + .

[0188] Intermediate 4A

[0189] (R)-5-Methyl-N-(3-methylbutan-2-yl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 4A

[0190] Universal intermediate 1 (159.6 mg) was dissolved in N-methylpyrrolidone (1.1 mL), and (2R)-3-methylbutan-2-amine hydrochloride (139.5 mg) and sodium bicarbonate powder (112.7 mg) were added sequentially at room temperature. The mixture was reacted at 60°C for 3 hours. Saturated sodium chloride was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-29%) to obtain the target intermediate 4A (182.0 mg) as a white solid.

[0191] MS ESI: m / z = 350.1, [M+H] + .

[0192] Intermediate 4B

[0193] (R)-5-Chloro-6-(2,6-difluoro-4-iodophenyl)-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 4B

[0194] The target intermediate 4B (629.0 mg) was obtained as a white solid by the same synthesis method as intermediate 4 using (2R)-3-methylbutan-2-amine hydrochloride (258.1 mg) and intermediate 1B (0.5 g) as starting materials and sodium bicarbonate (207.92 mg) as a base.

[0195] MS ESI: m / z = 475.9, [MH] - .

[0196] Intermediate 5

[0197] (S)-5-chloro-6-(2,4,6-trifluorophenyl)-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 5

[0198] Using (S)-1,1,1-trifluoropropan-2-amine hydrochloride (491.76 mg) and intermediate 1 (0.5 g) as starting materials and sodium bicarbonate (330.2 mg), the target intermediate 5 (266.7 mg) was obtained as a white solid using the same synthesis method as intermediate 4.

[0199] MS ESI: m / z = 396.0, [M+H] + .

[0200] Intermediate 5B

[0201] (S)-5-Chloro-6-(2,6-difluoro-4-iodophenyl)-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 5B

[0202] Using (S)-1,1,1-trifluoropropan-2-amine hydrochloride (800.96 mg) and intermediate 4B (1.09 g) as starting materials and sodium bicarbonate (451.1 mg) as the same synthetic method as intermediate 4, the target intermediate 5B (964.7 mg) was obtained as a white solid.

[0203] MS ESI: m / z = 501.9, [MH] - .

[0204] Intermediate 6

[0205] (R)-5-chloro-N-(1-cyclobutylethyl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 6

[0206] Using (R)-1-cyclobutylethan-1-amine hydrochloride (447.9 mg) and intermediate 1 (0.5 g) as starting materials and sodium bicarbonate (330.2 mg), the target intermediate 6 (590 mg) was obtained as a white solid using the same synthesis method as intermediate 4.

[0207] MS ESI: m / z = 382.0, [M+H] + .

[0208] Intermediate 6A

[0209] (R)-5-Methyl-N-(1-cyclobutylethyl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 6A

[0210] Using (R)-1-cyclobutylethan-1-amine hydrochloride (191.25 mg) and intermediate 1A (0.2 g) as starting materials and sodium bicarbonate (140.91 mg), the target intermediate 6A (229 mg) was obtained as a white solid using the same synthesis method as intermediate 4.

[0211] MS ESI: m / z = 362.1, [M+H] + .

[0212] Intermediate 6B

[0213] (R)-5-Chloro-N-(1-cyclobutylethyl)-6-(2,6-difluoro-4-iodophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 6B

[0214] Using (R)-1-cyclobutylethan-1-amine hydrochloride (199.4 mg) and intermediate 4B (0.3 g) as starting materials and sodium bicarbonate (123.5 mg), the target intermediate 6B (253.6 mg) was obtained as a white solid using the same synthesis method as intermediate 4.

[0215] MS ESI: m / z = 488.0, [MH] - .

[0216] Intermediate 7

[0217] 5-Chloro-N-(2,2,2-trifluoroethyl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

[0218] Using 2,2,2-trifluoroethane-1-amine hydrochloride (446.8 mg) and intermediate 1 (0.5 g) as starting materials and sodium bicarbonate (329.7 mg), the target intermediate 7 (517 mg) was obtained as a white solid using the same synthesis method as intermediate 4.

[0219] MS ESI: m / z = 382.0, [M+H] +.

[0220] Intermediate 7A

[0221] 5-Methyl-N-(2,2,2-trifluoroethyl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 7A

[0222] Using 2,2,2-trifluoroethane-1-amine hydrochloride (286.5 mg) and intermediate 1A (0.3 g) as starting materials and sodium bicarbonate (211.3 mg) as the same synthetic method as intermediate 4, the target intermediate 7A (517 mg) was obtained as a white solid.

[0223] MS ESI: m / z = 382.0, [M+H] + .

[0224] Intermediate 7B

[0225] 5-Chloro-6-(2,6-difluoro-4-iodophenyl)-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 7B

[0226] Using 2,2,2-trifluoroethane-1-amine hydrochloride (199.2 mg) and intermediate 1B (0.3 g) as starting materials and sodium bicarbonate (123.5 mg) as the same synthetic method as intermediate 4, the target intermediate 7B (297.4 mg) was obtained as a white solid.

[0227] MS ESI: m / z = 487.9, [MH] - .

[0228] Intermediate 14

[0229] (±) tert-Butyl 2-(Hydroxy)-spiro[3.5]nonane-7-methylcarbamate 14

[0230] Step 1: Benzyl methyl (4-methylenecyclohexyl) carbamate 9

[0231] Methyltriphenylphosphonium bromide (58.9 g) was dissolved in 200 mL of tetrahydrofuran and cooled to -10°C. n-Butyl lithium (103.1 mL, 1.6 M in hexane) was added and stirred for 30 minutes. tert-Butyl (4-oxocyclohexyl)carbamate (25.0 g) previously dissolved in tetrahydrofuran (100 mL) was added at -78°C. After reacting for 10 minutes, the mixture was warmed to room temperature and stirred for 3 hours. The mixture was quenched with saturated ammonium chloride and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target intermediate 9 (22.0 g) was obtained by silica gel column chromatography (ethyl acetate:petroleum ether = 0-10%).

[0232] 1 H NMR (400MHz, CDCl3): δ4.64(t,J=1.8Hz,2H),2.70(s,3H),2.35(dp,J=13.4,2.1

[0233] Hz, 2H), 2.14 (td, J=12.4, 6.8Hz, 2H), 1.76 (ddt, J=12.7, 4.9, 2.3Hz, 2H), 1.47 (s, 12H).

[0234] Step 2: Benzyl methyl (4-methylenecyclohexyl) carbamate 11

[0235] To the intermediate 9 (5.0 g), trifluoroacetic acid (5.2 mL) was added at room temperature and the reaction was allowed to proceed for 2 hours. The reaction solution was concentrated to give a crude trifluoroacetate salt 10 as a dark oil (4.0 g). The crude product 10 (4.0 g) was dissolved in acetonitrile (41.0 mL) and water (41.0 mL) at room temperature, followed by the addition of benzyl chloroformate (4.6 g) and sodium bicarbonate powder (4.45 g). The mixture was stirred at room temperature for 10 hours, and the acetonitrile was distilled off. The residual liquid was extracted three times with ethyl acetate, and the combined organic phases were washed three times with saturated brine, and finally dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The target intermediate 11 (2.6 g) was obtained by silica gel column chromatography (ethyl acetate: petroleum ether = 0-5%) as a colorless oil.

[0236] MS ESI: m / z = 260.1, [M+H] + .

[0237] Step 3: Benzyl methyl (2-oxospiro[3.5]non-7-yl)carbamate 12

[0238] Intermediate 11 (2.6 g) was dissolved in ether, zinc copper couple (5.2 g) was added, and trichloroacetyl chloride (3.36 mL) previously dissolved in ether (104 mL) was slowly added dropwise. After reacting for 16 hours, the mixture was quenched with saturated sodium bicarbonate solution, the filtrate was filtered, washed three times with ethyl acetate, the filtrate was collected, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product (2.0 g); the crude product was dissolved in acetic acid (6.0 mL), zinc powder (1.4 g) was added, and the mixture was reacted at 80 degrees. After reacting for 5 hours, water was added and the mixture was filtered, the filtrate was extracted with dichloromethane, the organic phases were combined and washed three times with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The target intermediate 12 was obtained as a white solid (3.0 g) by silica gel column chromatography (ethyl acetate: petroleum ether = 0-22%).

[0239] MS ESI: m / z = 302.1, [M+H] + .

[0240] Step 4: tert-Butyl (2-hydroxyspiro[3.5]nonan-7-yl)(methyl)carbamate 14

[0241] Intermediate 12 (3.0 g) was dissolved in methanol (20.0 mL), and sodium borohydride powder (565.2 mg) was added. After 5 hours, saturated brine was added and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a viscous oil that was used directly in the next step without purification. The above oil was dissolved in 76 mL of methanol, and wet palladium carbon (760.0 mg, 10% wt.) was added. The reaction was carried out under a hydrogen atmosphere for 5 hours, filtered, and concentrated to obtain The crude product was a white solid, which was used directly in the next reaction without purification. The crude product was dissolved in dichloromethane (45 mL), and di-tert-butyl dicarbonate (2.73 mL) and triethylamine (2.1 mL) were added sequentially under an ice-water bath. The mixture was reacted at room temperature for 18 hours. Water was added to the reaction solution to quench the mixture, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 0-10%) to obtain the target intermediate 14 (2.5 g).

[0242] 1 H NMR (400MHz, CDCl3): δ4.21(t,J=7.2Hz,1H),2.65(s,3H),2.47(d,J=37.5Hz,1H),2.30–2.21(m,1H),2.08(dd,J=12.0,6.0Hz,1H),1.63–1.36(m,19H).

[0243] Intermediate 15

[0244] tert-Butyl (±)(6-hydroxyspiro[3.3]hept-2-yl)(methyl)carbamate 15

[0245] Step 1: 6-(Methylamino)spiro[3.3]heptan-2-ol

[0246] Tert-butyl (6-hydroxyspiro[3.3]hept-2-yl)carbamate (1.0 g) was dissolved in 20.0 mL of tetrahydrofuran, and lithium aluminum hydride (22.0 mL, 1.0 M in THF) was added dropwise at zero degrees Celsius. The reaction was carried out at 50 degrees Celsius for 3 hours, and methanol was added dropwise to quench the reaction. The mixture was spin-dried to give a viscous semisolid crude product, which was used directly in the next step without further treatment.

[0247] MS ESI: m / z = 142.2, [M+H] + .

[0248] Step 2: tert-Butyl (6-hydroxyspiro[3.3]hept-2-yl)(methyl)carbamate 15

[0249] The product from the previous step was dissolved in 20.0 mL of dichloromethane, and di-tert-butyl dicarbonate (1.5 g) and triethylamine (1.2 mL) were added at zero degrees Celsius. The reaction was allowed to react at room temperature for 18 hours, quenched with water, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (methanol:dichloromethane = 0-10%) to obtain the target fragment 15 (0.75 g).

[0250] MS ESI: m / z = 186.2, [M+H] + .

[0251] Intermediate 17

[0252] (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 17

[0253] Tert-butyl cis-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 16 (1.0 g) was dissolved in 10 mL of methanol, and sodium borohydride (251.83 mg) was added at zero degrees Celsius. The mixture was reacted for 2 hours, and saturated brine was added. The mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a viscous product. The target compound 17 (820.0 mg) was obtained by silica gel column chromatography (ethyl acetate:petroleum ether = 0-20%).

[0254] 1H NMR (400MHz, CDCl3): δ4.30 (t, J=6.4Hz, 1H), 3.50 (dd, J=11.2, 7.7Hz, 2H), 3.34 (dd, J=11 .3,3.4Hz,2H),2.60(q,J=4.8,3.4Hz,2H),2.21–2.12(m,2H),2.03(s,1H),1.45(s,11H).

[0255] Intermediate 19

[0256] (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 19

[0257] Step 1: tert-Butyl (3aR,5s,6aS)-5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 18

[0258] Compound 17 (4.3 g) was dissolved in 126 mL of diethyl ether, and triphenylphosphine (4.96 g) and p-nitrobenzoic acid (2.37 g) were added. Diisopropyl azodicarboxylate (1.91 g) was added at -78 degrees Celsius. The mixture was reacted for 16 hours at room temperature. The mixture was quenched with methanol, and the crude product was dried and subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to obtain compound 18 (1.5 g).

[0259] 1 H NMR (400MHz, CDCl3): δ8.30–8.26(m,2H),8.19–8.15(m,2H),5.57(dt,J=5.6,2.9Hz,1H),3.59–3.50(m,2H) ),3.24(s,2H),2.89(dd,J=9.2,5.5Hz,2H),2.21–2.14(m,2H),1.93(dt,J=14.4,5.7Hz,2H),1.47(s,9H).

[0260] Step 2 (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 19

[0261] Compound 18 (1.5 g) was dissolved in methanol (49.0 mL) and water (16.0 mL) at room temperature, and solid potassium carbonate (1.1 g) was added. The mixture was reacted at room temperature for 8 hours. The methanol was dried and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The crude product was concentrated and subjected to silica gel column chromatography (ethyl acetate:petroleum ether = 0-50%) to obtain the target intermediate 19 (791.0 mg).

[0262] MS ESI: m / z = 172.1, [M-57+H] + .

[0263] Intermediate 19A

[0264] tert-Butyl (1R,5S,6s)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate 19A

[0265] Tert-butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (5.66 g) was dissolved in 50 mL of methanol, and potassium carbonate (5.54 g) and dimethyl (1-diazo-2-oxopropyl)phosphonate (6.16 g) were added sequentially. The reaction was carried out at room temperature for 8 hours, and the mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The target intermediate 19A (4.6 g) was obtained by column chromatography as a white solid.

[0266] 1 H NMR (400MHz, CDCl3): δ3.65 (d, J = 11.3Hz, 1H), 3.56 (d, J = 11.1Hz, 1H), 3.33 (tt, J = 7.9, 3. 4Hz,2H),1.87(d,J=2.2Hz,1H),1.82(t,J=2.9Hz,2H),1.42(s,9H),1.10(d,J=2.7Hz,1H).

[0267] Intermediate 19B

[0268] tert-Butyl (1R,5S,6s)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate 19B

[0269] Cuprous cyanide (211.36 mg) was suspended in tetrahydrofuran (6.32 mL) and n-butyl lithium (2.0 mL, 2.5 M in hexane) was added at -78 °C. The mixture was stirred at the same temperature for 15 min. Tri-n-butyltin hydride (1.35 mL) was added and stirred at the same temperature for 10 min. A solution of 19A (0.5 g) dissolved in tetrahydrofuran (2.1 mL) was added and the reaction was continued at the same temperature for 10 min. Ammonia-ammonium chloride (pH = 12) buffer solution was added to quench the reaction. The mixture was filtered and the filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product 19B (350.0 mg) which was used directly.

[0270] Example 1

[0271] (R)-6-(4-((2-azaspiro[3.3]hept-6-yl)oxy)-2,6-difluorophenyl)-5-chloro-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 23

[0272] Step 1: (R)-tert-butyl 6-(4-(5-chloro-7-((3-methylbutan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)-2-azaspiro[3.3]heptane-2-carboxylate 22

[0273] Sodium hydride (43.34 mg, 60% wt. in mineral oil) was suspended in dimethyl sulfoxide (0.86 mL) and tetrahydrofuran (0.43 mL). 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (231.12 mg) was added at room temperature and stirred at 60°C for 1 hour. Intermediate 4 (100.0 mg) dissolved in dimethyl sulfoxide (1.0 mL) and tetrahydrofuran (1.0 mL) was slowly added dropwise. The reaction was continued at 60°C for 3 hours. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 22 (149.0 mg).

[0274] Step 2: (R)-6-(4-((2-azaspiro[3.3]hept-6-yl)oxy)-2,6-difluorophenyl)-5-chloro-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 23

[0275] Intermediate 22 was dissolved in dichloromethane (2.77 mL), trifluoroacetic acid (0.89 mL) was added at zero degrees, and the reaction was carried out at room temperature for 2 hours. The mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by Pre-HPLC (eluent: acetonitrile and water containing 1‰ formic acid) to obtain the target compound 23 (80.0 mg) as a white powder.

[0276] MS ESI: m / z = 463.1, [M+H] + .

[0277] 1H NMR (400MHz, DMSO-d6): δ8.59(s,1H),8.40(s,1H),6.89(dd,J=9.7,3.4Hz,2H),4.71 (d,J=6.8Hz,1H),3.96(s,2H),3.89(s,2H),2.83(dd,J=12.8,6.7Hz,2H),2.26(p,J= 5.5Hz,2H),1.81–1.71(m,1H),1.04(d,J=6.5Hz,3H),0.69(d,J=6.7Hz,6H).

[0278] Example 2

[0279] (R)-6-(4-((2-methyl-2-azaspiro[3.3]hept-6-yl)oxy)-2,6-difluorophenyl)-5-chloro-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 24

[0280] Compound 23 (16.2 mg) was dissolved in 1,2-dichloroethane (2.0 mL), and sodium acetate borohydride (22.25 mg) and formaldehyde aqueous solution (6.0 μL, wt. 37%) were added in sequence at zero degrees. After reacting for 5 minutes, a 1.0 M sodium hydroxide aqueous solution (0.5 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product which was purified by Pre-HPLC (eluent: acetonitrile and water containing 1‰ formic acid) to obtain the target compound 24 (13.0 mg) as a white powder.

[0281] MS ESI: m / z = 477.2, [M+H] + .

[0282] 1 H NMR (400MHz, DMSO-d6): δ8.59(s,1H),7.93(s,1H),6.87(dd,J=10.4,4.3Hz,2H),4.72(q,J=7.0Hz,1H),3.22(s,1H),3.15( s,1H),2.70(d,J=10.6Hz,2H),2.18(d,J=12.9Hz,7H),1.76(q,J=7.1Hz,1H),1.04(d,J=6.4Hz,4H),0.69(d,J=6.5Hz,6H).

[0283] Example 3

[0284] (S)-6-(4-((2-azaspiro[3.3]hept-6-yl)oxy)-2,6-difluorophenyl-5-chloro-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 26

[0285] Step 1: (S)-tert-butyl 6-(4-(5-chloro-7-((1,1,1-trifluoropropan-2-yl)amino-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)-2-azaspiro[3.3]heptane-2-carboxylate 25

[0286] Intermediate 5 (100.0 mg) and tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (216.0 mg) were used as starting materials and sodium hydride (40.5 mg, 60% wt. in mineral oil) was used as a base. Intermediate 25 (142.7 mg) was obtained under the same conditions as in the first step of Example 1.

[0287] Step 2: (S)-6-(4-((2-azaspiro[3.3]hept-6-yl)oxy)-2,6-difluorophenyl-5-chloro-N-(1,1,1-trifluoroprop-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 26

[0288] Using intermediate 25 (142.7 mg) as starting material, compound 26 (61.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0289] MS ESI: m / z = 489.0, [M+H] + .

[0290] 1 H NMR (400MHz, DMSO-d6): δ8.34(s,1H),8.24(d,J=4.4Hz,1H),6.73(d,J=10.5Hz,2H),5.81(d,J=12.5Hz,1H),4.68( s,1H),4.02(s,2H),3.96(s,2H),2.84(dd,J=12.5,6.5Hz,2H),2.30(dd,J=12.0,7.0Hz,2H),1.30(d,J=6.5Hz,3H).

[0291] Example 4

[0292] (S)-6-(4-((2-methyl-2-azaspiro[3.3]hept-6-yl)oxy)-2,6-difluorophenyl-5-chloro-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 27

[0293] The target compound 27 (30.0 mg) was obtained as a white powder by the same method as Example 2 using compound 26 (34.2 mg) as raw material, sodium acetate borohydride (44.5 mg) and formaldehyde aqueous solution (8.08 μL, wt. 37%) as reagents.

[0294] MS ESI: m / z = 503.1, [M+H] + .

[0295] 1 H NMR (400MHz, DMSO-d6): δ8.33(s,1H),8.24(s,1H),6.74–6.68(m,2H),5.85–5.76(m,1H),4.73–4.65(m,1H ),3.60(s,2H),3.54(s,2H),2.78–2.71(m,2H),2.44(s,3H),2.22(d,J=9.9Hz,2H),1.29(d,J=6.6Hz,3H).

[0296] Example 5

[0297] (R)-6-(4-((7-azaspiro[3.5]nonan-2-yl)oxy)-2,6-difluorophenyl)-5-chloro-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 30

[0298] Step 1: (R)-tert-Butyl 2-(4-(5-chloro-7-((3-methylbutan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)-7-azaspiro[3.5]nonane-7-carboxylate 29

[0299] Intermediate 4 (100.0 mg) and tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (261.6 mg) were used as starting materials and sodium hydride (43.36 mg, 60% wt. in mineral oil) was used as a base. Intermediate 29 (159.0 mg) was obtained as a white powder under the same conditions as in the first step of Example 1.

[0300] Step 2: (R)-6-(4-((7-azaspiro[3.5]nonan-2-yl)oxy)-2,6-difluorophenyl)-5-chloro-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 30

[0301] Intermediate 29 (159.0 mg) was used as starting material and the same conditions as in the second step of Example 1 were used to obtain compound 30 (90.0 mg) as a white powder.

[0302] MS ESI: m / z = 491.1, [M+H] + .

[0303] 1 H NMR (400MHz, DMSO-d6): δ8.59(s,1H),8.40(s,1H),6.91–6.85(m,2H),4.87(t,J=6.8Hz,1H),2.97(t,J=5.7Hz,2H),2.88(d,J=6 .0Hz,2H),2.54(d,J=7.6Hz,3H),1.86(dq,J=10.2,3.4Hz,2H),1.80–1.66(m,5H),1.05(d,J=6.4Hz,3H),0.69(d,J=6.5Hz,6H).

[0304] Example 6

[0305] (R)-6-(4-((7-methyl-7-azaspiro[3.5]nonan-2-yl)oxy)-2,6-difluorophenyl)-5-chloro-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 31

[0306] The target compound 31 (51.0 mg) was obtained as a white powder by the same method as in Example 2 using compound 30 (66.0 mg) as raw material, sodium acetate borohydride (35.6 mg) and formaldehyde aqueous solution (22.92 μL, wt. 37%) as reagents.

[0307] MS ESI: m / z = 505.2, [M+H] + .

[0308] 1H NMR (400MHz, DMSO-d6): δ8.59(s,1H),7.93(s,1H),6.90–6.85(m,2H),4.86(t,J=6.8Hz,1H),2.42(d,J=9.5Hz,2H),2.27(d,J =31.2Hz,4H),2.15(s,3H),1.78(dq,J=13.3,6.8,6.0Hz,4H),1.62–1.56(m,4H),1.04(d,J=6.5Hz,3H),0.69(d,J=6.6Hz,6H).

[0309] Example 7

[0310] (S)-6-(4-((7-azaspiro[3.5]nonan-2-yl)oxy)-2,6-difluorophenyl)-5-chloro-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 33

[0311] Step 1: (S)-tert-Butyl 2-(4-(5-chloro)-7-((1,1,1-trifluoropropyl-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)-7-azaspiro[3.5]nonane-7-carboxylate 32

[0312] Intermediate 5 (100.0 mg) and tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (244.3 mg) were used as starting materials and sodium hydride (40.5 mg, 60% wt. in mineral oil) was used as a base. Intermediate 32 (142.7 mg) was obtained under the same conditions as in the first step of Example 1.

[0313] Step 2: (S)-6-(4-((7-azaspiro[3.5]nonan-2-yl)oxy)-2,6-difluorophenyl)-5-chloro-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 33

[0314] Using intermediate 32 (139.0 mg) as starting material, compound 33 (35.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0315] MS ESI: m / z = 517.0, [M+H] + .

[0316] 1H NMR (400MHz, DMSO-d6): δ8.26(d,J=27.8Hz,2H),6.72–6.64(m,2H),5.83–5.72(m,1H),4.82(t,J=6.8Hz,1H),3.02(t,J=5.3Hz,2H ), 2.94(t,J=5.6Hz,2H), 2.54(t,J=4.4Hz,2H), 1.89(dd,J=12.1,6.4Hz,2H), 1.74(dt,J=17.5,5.5Hz,4H), 1.25(d,J=6.7Hz,3H).

[0317] Example 8

[0318] (S)-6-(4-((7-methyl-7-azaspiro[3.5]nonan-2-yl)oxy)-2,6-difluorophenyl)-5-chloro-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 34

[0319] Compound 33 (19.6 mg) was used as raw material, sodium acetate borohydride (24.2 mg), and formaldehyde aqueous solution (5.5 μL, wt. 37%) were used as reagents to obtain the target compound 34 (13.0 mg) as a white powder by the same method as Example 2.

[0320] MS ESI: m / z = 531.2, [M+H] + .

[0321] 1 H NMR (400MHz, DMSO-d6): δ8.32(d,J=97.9Hz,2H),6.76(s,2H),5.88–5.77(m,1H),4.83(t,J=7 .1Hz,1H),2.45(s,4H),2.32(s,3H),1.87–1.78(m,3H),1.65(d,J=17.1Hz,6H),1.33(s,3H).

[0322] Example 9

[0323] (R)-5-chloro-6-(2,6-difluoro-4-((6-(methylamino)spiro[3.3]hept-2-yl)oxy)phenyl)-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 36

[0324] Step 1: tert-Butyl (R)-(6-(4-(5-chloro-7-((3-methylbutan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)spiro[3.3]hept-2-yl)(methyl)carbamate

[0325] Intermediate 4 (110.0 mg) and tert-butyl (6-hydroxyspiro[3.3]hept-2-yl)(methyl)carbamate 15 (287.5 mg) were used as starting materials and sodium hydride (47.7 mg, 60% wt. in mineral oil, 4.0 eq.) was used as a base. Intermediate 35 (170.0 mg) was obtained under the same conditions as in the first step of Example 1.

[0326] Step 2: (R)-5-chloro-6-(2,6-difluoro-4-((6-(methylamino)spiro[3.3]hept-2-yl)oxy)phenyl)-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 36

[0327] Using intermediate 35 (170.0 mg) as starting material, compound 36 (93.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0328] MS ESI: m / z = 491.1, [M+H] + .

[0329] 1 H NMR (400MHz, DMSO-d6): δ8.59(s,1H),8.38(s,1H),6.89–6.85(m,2H),4.76(t,J=6.9Hz,1H),3.21(t,J=7.7Hz,1H),2.70–2.64(m,1H),2.33(q,J= 6.3Hz,1H),2.24(s,5H),2.11–2.03(m,3H),1.95(td,J=8.3,7.9,4.3Hz, 2H), 1.76 (q, J=6.9Hz, 1H), 1.04 (d, J=6.5Hz, 3H), 0.69 (d, J=6.6Hz, 6H).

[0330] Example 10

[0331] (R)-5-chloro-6-(4-((6-(dimethylamino)spiro[3.3]hept-2-yl)oxy)-2,6-difluorophenyl)-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 37

[0332] Using compound 36 (69.9 mg) as raw material, sodium acetate borohydride (90.9 mg) and formaldehyde aqueous solution (26.5 μL, wt. 37%) as reagents, the target compound 37 (59.0 mg) was obtained as a white powder by the same method as Example 2.

[0333] MS ESI: m / z = 505.2, [M+H] + .

[0334] 1 H NMR (400MHz, DMSO-d6): δ8.59(s,1H),7.92(s,1H),6.90–6.83(m,2H),4.76(s,1H),2.70–2.61(m,1H),2.54(d,J=11.9Hz,1 H), 2.19 (dd, J = 11.0, 5.7Hz, 1H), 2.01 (s, 10H), 1.79 (dt, J = 30.5, 8.1Hz, 4H), 1.04 (d, J = 6.4Hz, 3H), 0.69 (d, J = 6.4Hz, 6H).

[0335] Example 11

[0336] (S)-5-Chloro-6-(2,6-difluoro-4-((6-(methylamino)spiro[3.3]hept-2-yl)oxy)phenyl)-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 39

[0337] Step 1: tert-Butyl (S)-(6-(4-(5-chloro-7-((1,1,1-trifluoropropyl-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)spiro[3.3]hept-2-yl)(methyl)carbamate 38

[0338] Intermediate 5 (100.0 mg) and tert-butyl (6-hydroxyspiro[3.3]hept-2-yl)(methyl)carbamate 15 (244.06 mg) were used as starting materials and sodium hydride (40.48 mg, 60% wt. in mineral oil, 4.0 eq.) was used as a base. Intermediate 38 (134.1 mg) was obtained under the same conditions as in the first step of Example 1.

[0339] Step 2: (S)-5-chloro-6-(2,6-difluoro-4-((6-(methylamino)spiro[3.3]hept-2-yl)oxy)phenyl)-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 39

[0340] Using intermediate 38 (134.1 mg) as starting material, compound 39 (51.0 mg) was obtained under the same conditions as in the second step of Example 1.

[0341] MS ESI: m / z = 517.0, [M+H] + .

[0342] 1 H NMR (400MHz, DMSO-d6): δ8.21(d,J=7.0Hz,2H),6.63(dd,J=10.0,3.4Hz,2H),5.77–5.68(m,1H),4.64(t,J=6.9Hz,1H),3.41(t,J=7.9Hz,1H),2.63( dt,J=11.1,5.5Hz,1H),2.52–2.46(m,1H),2.32(s,4H),2.19(ddd,J=12.1 ,7.3,4.6Hz,1H),2.07(dq,J=11.8,6.1,5.5Hz,4H),1.21(d,J=6.7Hz,3H).

[0343] Example 12

[0344] (S)-5-Chloro-6-(4-((6-(dimethylamino)spiro[3.3]hept-2-yl)oxy)-2,6-difluorophenyl)-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 40

[0345] Compound 39 (23.5 mg) was used as starting material, sodium acetate borohydride (28.93 mg), and formaldehyde aqueous solution (5.5 μL, wt. 37%) were used as reagents to obtain the target compound 40 (22.0 mg) as a white powder by the same method as in Example 2.

[0346] MS ESI: m / z = 531.2, [M+H] + .

[0347] 1 H NMR (400MHz, DMSO-d6): δ8.51(s,1H),6.78(d,J=10.6Hz,2H),5.84(q,J=7.5,7.0Hz,1H),4.73(t,J=6.9Hz,1H),2. 70(dt,J=29.5,6.9Hz,2H),2.24(p,J=5.7Hz,1H),2.16–2.03(m,11H),1.91(t,J=9.7Hz,2H),1.36(d,J=6.8Hz,3H).

[0348] Example 13

[0349] (R)-5-chloro-N-(1-cyclobutylethyl)-6-(2,6-difluoro-4-((6-(methylamino)spiro[3.3]hept-2-yl)oxy)phenyl))-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 42

[0350] Step 1: tert-Butyl (R)-(6-(4-(5-chloro-7-((1-cyclobutylethyl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)spiro[3.3]hept-2-yl)(methyl)carbamate 41

[0351] Intermediate 6 (60.0 mg) and tert-butyl (6-hydroxyspiro[3.3]hept-2-yl)(methyl)carbamate 15 (151.8 mg) were used as starting materials and sodium hydride (25.12 mg, 60% wt. in mineral oil) was used as a base. Intermediate 41 (85.6 mg) was obtained as a white powder under the same conditions as in the first step of Example 1.

[0352] Step 2: (R)-5-chloro-N-(1-cyclobutylethyl)-6-(2,6-difluoro-4-((6-(methylamino)spiro[3.3]hept-2-yl)oxy)phenyl))-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 42

[0353] Using intermediate 41 (85.6 mg) as starting material, compound 42 (21.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0354] MS ESI: m / z = 503.2, [M+H] + .

[0355] 1H NMR (400MHz, DMSO-d6): δ8.58(s,1H),8.37(s,1H),6.90(dd,J=14.9,11.7Hz,2H),4.77(t,J=6.8Hz ,1H),3.20(t,J=7.7Hz,1H),2.68(p,J=6.2,5.5Hz,1H),2.55(d,J=6.9Hz,1H),2.46(s,1H),2.34(p ,J=6.2,5.7Hz,1H),2.24(s,4H),2.08(qd,J=8.7,5.7,3.9Hz,2H),1.98–1.78(m,4H),1.76–1.67(m ,1H),1.60(dd,J=9.6,4.9Hz,1H),1.43(t,J=9.2Hz,1H),1.34–1.20(m,2H),0.95(d,J=6.3Hz,3H).

[0356] Example 14

[0357] ((R)-5-chloro-N-(1-cyclobutylethyl)-6-(4-((6-(dimethylamino)spiro[3.3]hept-2-yl)oxy)-2,6-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 43

[0358] Using compound 42 (9.6 mg) as raw material, sodium acetate borohydride (12.65 mg) and formaldehyde aqueous solution (3.0 μL, wt. 37%) as reagents, the target compound 40 (8.1 mg) was obtained as a white powder by the same method as Example 2.

[0359] MS ESI: m / z = 517.2, [M+H] + .

[0360] 1 H NMR (400MHz, DMSO-d6): δ8.58(s,1H),7.89(s,1H),6.89(t,J=13.2Hz,2H),4.77(t,J=6.9Hz ,1H),2.71–2.61(m,1H),2.24–1.38(m,19H),1.25(d,J=14.2Hz,2H),0.95(d,J=6.3Hz,3H).

[0361] Example 15

[0362] 5-Chloro-6-(2,6-difluoro-4-((6-(methylamino)spiro[3.3]hept-2-yl)oxy)phenyl)-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 45

[0363] Step 1: tert-Butyl (6-(4-(5-chloro-7-((2,2,2-trifluoroethyl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)spiro[3.3]hept-2-yl)(methyl)carbamate 44

[0364] Intermediate 7 (100.0 mg) and tert-butyl (6-hydroxyspiro[3.3]hept-2-yl)(methyl)carbamate 15 (253.2 mg) were used as starting materials and sodium hydride (42.0 mg, 60% wt. in mineral oil) was used as a base. Intermediate 44 (108.0 mg) was obtained under the same conditions as in the first step of Example 1.

[0365] Step 2: 5-chloro-6-(2,6-difluoro-4-((6-(methylamino)spiro[3.3]hept-2-yl)oxy)phenyl)-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 45

[0366] Using intermediate 44 (86.9 mg) as starting material, compound 42 (30.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0367] MS ESI: m / z = 503.1, [M+H] + .

[0368] 1 H NMR (400MHz, DMSO-d6): δ8.37(s,1H),8.29(s,1H),6.75(d,J=9.4Hz,2H),4.74–4.67(m,3H),3.43(t,J=7.8Hz,1H ),2.69(dt,J=11.4,5.3Hz,1H),2.59–2.54(m,1H),2.36(s,4H),2.29–2.20(m,1H),2.11(dt,J=12.1,6.3Hz,4H).

[0369] Example 16

[0370] 5-Chloro-6-(4-(((6-(dimethylamino)spiro[3.3]hept-2-yl)oxy)-2,6-difluorophenyl)-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 46

[0371] Using compound 45 (18.6 mg) as raw material, sodium acetate borohydride (23.55 mg) and formaldehyde aqueous solution (4.3 μL, wt. 37%) as reagents, the target compound 46 (17.0 mg) was obtained as a white powder by the same method as Example 2.

[0372] MS ESI: m / z = 517.1, [M+H] + .

[0373] 1 H NMR (400MHz, DMSO-d6): δ8.55(s,1H),6.82(d,J=10.3Hz,2H),4.73(d,J=8.7Hz,3 H),2.66(t,J=7.6Hz,2H),2.27–2.19(m,1H),2.08(s,10H),1.89(t,J=9.7Hz,2H).

[0374] Example 17

[0375] 5-Chloro-6-(2,6-difluoro-4-((6-(methylamino)spiro[3.3]hept-2-yl)oxy)phenyl)-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 48

[0376] Step 1: (R)-tert-butyl (2-(4-(7-chloro-5-((3-methylbutan-2-yl)amino)imidazo[1,2-a]pyrimidin-6-yl)-3,5-difluorophenoxy)spiro[3.5]nonan-7-yl)(methyl)carbamate 47

[0377] Intermediate 4 (100.0 mg) and tert-butyl (2-hydroxyspiro[3.5]nonan-7-yl)(methyl)carbamate 14 (291.8 mg) were used as starting materials and sodium hydride (43.36 mg, 60% wt. in mineral oil) was used as a base. Intermediate 47 (96.7 mg) was obtained under the same conditions as in the first step of Example 1.

[0378] Step 2: (R)-5-chloro-6-(2,6-difluoro-4-((7-(methylamino)spiro[3.5]non-2-yl)oxy)phenyl-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 48

[0379] Using intermediate 47 (96.7 mg) as starting material, compound 48 (35.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0380] MS ESI: m / z = 519.2, [M+H] + .

[0381] 1 H NMR (400MHz, DMSO-d6): δ8.59(s,1H),8.40(s,1H),6.88(dd,J=10.0,4.5Hz,2H),4.89–4.80(m,1H),2.64(d,J=22.3 Hz,2H),2.36(d,J=31.2Hz,3H),1.90–1.62(m,8H),1.44–1.20(m,5H),1.05(d,J=6.4Hz,3H),0.69(d,J=6.6Hz,6H).

[0382] Example 18

[0383] (R)-5-chloro-6-(2,6-difluoro-4-((7-(dimethylamino)spiro[3.5]non-2-yl)oxy)phenyl-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 49

[0384] Using compound 48 (11.9 mg) as raw material, sodium acetate borohydride (14.62 mg) and formaldehyde aqueous solution (3.3 μL, wt. 37%) as reagents, the target compound 49 (9.1 mg) was obtained as a white powder by the same method as Example 2.

[0385] MS ESI: m / z = 533.3, [M+H] + .

[0386] 1H NMR (400MHz, DMSO-d6): δ8.59(s,1H),7.93(s,1H),6.87(d,J=10.3Hz,2H),4.84(t,J=6.9Hz,1H),2.31(d,J=10.6H z,1H),2.18(s,7H),1.83–1.59(m,8H),1.28(dt,J=42.8,15.7Hz,5H),1.05(d,J=6.5Hz,3H),0.69(d,J=6.6Hz,6H).

[0387] Example 19

[0388] (S)-5-Chloro-6-(2,6-difluoro-4-((7-(methylamino)spiro[3.5]non-2-yl)oxy)phenyl)-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 51

[0389] Step 1: (S)-tert-Butyl (2-(4-(5-chloro-7-((1,1,1-trifluoropropyl-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)spiro[3.5]nonan-7-yl)(methyl)carbamate 50

[0390] Intermediate 5 (100.0 mg) and tert-butyl (2-hydroxyspiro[3.5]nonan-7-yl)(methyl)carbamate 14 (272.4 mg) were used as raw materials and sodium hydride (40.48 mg, 60% wt. in mineral oil) was used as a base. The same conditions as in the first step of Example 1 were used to obtain intermediate 50 (60.2 mg) as a white powder.

[0391] Step 2: (S)-5-chloro-6-(2,6-difluoro-4-((7-(methylamino)spiro[3.5]non-2-yl)oxy)phenyl)-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 51

[0392] Intermediate 50 (60.2 mg) was used as starting material and the same conditions as in the second step of Example 1 were used to obtain compound 51 (40.0 mg) as a white powder.

[0393] MS ESI: m / z = 545.2, [M+H] + .

[0394] 1H NMR (400MHz, DMSO-d6): δ8.29(s,1H),8.15(s,1H),6.65(d,J=10.5Hz,2H),5.76(p,J=7.8Hz,1H),4.78 (p,J=6.5Hz,1H),2.83(s,1H),2.31(d,J=9.8Hz,1H),1.93–1.67(m,8H),1.30(dd,J=54.8,7.9Hz,9H).

[0395] Example 20

[0396] (S)-5-Chloro-6-(2,6-difluoro-4-((7-(dimethylamino)spiro[3.5]non-2-yl)oxy)phenyl)-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 52

[0397] Compound 51 (31.4 mg) was used as starting material, sodium acetate borohydride (36.68 mg), and formaldehyde aqueous solution (6.67 μL, wt. 37%) were used as reagents to obtain the target compound 52 (22.0 mg) as a white powder by the same method as in Example 2.

[0398] MS ESI: m / z = 559.2, [M+H] + .

[0399] 1 H NMR (400MHz, DMSO-d6): δ8.29(d,J=41.2Hz,2H),6.72(d,J=10.6Hz,2H),5.80(q,J=7.8Hz,1H),4.80(p,J =6.8Hz,1H),2.41(s,6H),2.32(d,J=7.2Hz,1H),1.87–1.82(m,2H),1.75–1.69(m,4H),1.39–1.29(m,6H).

[0400] Example 21

[0401] 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 55

[0402] Step 1: (1R,5S,6r)-6-((4-(5-chloro-7-(((R)-3-methylbutan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 54

[0403] Intermediate 4 (100.0 mg) and tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 53 (231.18 mg) were used as starting materials and sodium hydride (43.35 mg, 60% wt. in mineral oil) was used as a base. Intermediate 54 (138.7 mg) was obtained under the same conditions as in the first step of Example 1.

[0404] Step 2: 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 55

[0405] Using intermediate 54 (138.7 mg) as starting material, compound 55 (56.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0406] MS ESI: m / z = 463.1, [M+H] + .

[0407] 1 H NMR (400MHz, DMSO-d6): δ8.59(s,1H),8.28(s,1H),6.97(dd,J=10.0,3.4Hz,2H),4.00(d,J=7.2Hz,2H),3.13(d,J=11.4Hz,2H),3.0 2(d,J=11.2Hz,2H),2.54(s,1H),1.82–1.71(m,1H),1.66(s,2H),1.34(dt,J=7.5,3.6Hz,1H),1.06(d,J=6.5Hz,3H),0.71(d,J=6.6 Hz,6H).

[0408] Example 22

[0409] 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)phenyl)-N-((R)-3-methylbutyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 56

[0410] Using compound 55 (33.3 mg) as raw material, sodium acetate borohydride (45.78 mg) and formaldehyde aqueous solution (10.2 μL, wt. 37%) as reagents, the target compound 56 (20.0 mg) was obtained as a white powder by the same method as Example 2.

[0411] MS ESI: m / z = 477.2, [M+H] + .

[0412] 1 H NMR (400MHz, DMSO-d6): δ8.59(s,1H),7.88(s,1H),6.96(td,J=7.6,2.9Hz,2H),3.93(d,J=7.3Hz,2H),2.95(d,J=8.9Hz,2H),2.27(d, J=23.5Hz,5H),1.77(q,J=6.9Hz,1H),1.56(dq,J=7.3,3.4Hz,1H),1.48(d,J=3.2Hz,2H),1.05(d,J=6.5Hz,3H),0.70(d,J=6.6Hz,6H).

[0413] Example 23

[0414] 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl)-5-methyl-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 55A

[0415] Step 1: (1R,5S,6r)-tert-butyl 6-((4-(5-methyl-7-(((R)-3-methylbutan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 54A

[0416] Intermediate 4A (90.0 mg) and tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 53 (219.67 mg) were used as starting materials and sodium hydride (41.2 mg, 60% wt. in mineral oil) was used as a base. Intermediate 54A (118.7 mg) was obtained under the same conditions as in the first step of Example 1.

[0417] Step 2: 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl)-5-methyl-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 55A

[0418] Intermediate 54A (118.7 mg) was used as starting material and the same conditions as in the second step of Example 1 were used to obtain compound 55A (40.0 mg) as a white powder.

[0419] MS ESI: m / z = 443.2, [M+H] + .

[0420] 1 H NMR (400MHz, DMSO-d6): δ8.48(s,1H),7.21(d,J=10.2Hz,1H),7.00–6.95(m,2H),3.99(d,J=7.1Hz,2H),3.12(d,J=11.3Hz,2H),3. 01(d,J=11.2Hz,2H),2.13(s,3H),1.65(t,J=2.7Hz,4H),1.32(tt,J=6.9,3.2Hz,1H),1.02(d,J=6.5Hz,3H),0.70(d,J=6.5Hz,6H).

[0421] Example 24

[0422] 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-((S)-1,1,1-trifluoroprop-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 58

[0423] Step 1: (1R,5S,6r)-6-((4-(5-chloro-7-(((S)-1,1,1-trifluoropropan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 57

[0424] Intermediate 5 (100.0 mg) and tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 53 (215.93 mg) were used as raw materials and sodium hydride (40.5 mg, 60% wt. in mineral oil) was used as a base. Intermediate 57 (140.0 mg) was obtained under the same conditions as in the first step of Example 1.

[0425] Step 2: 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-((S)-1,1,1-trifluoroprop-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 58

[0426] Using intermediate 57 (140.0 mg) as starting material, compound 58 (39.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0427] MS ESI: m / z = 489.0, [M+H] + .

[0428] 1 H NMR (400MHz, DMSO-d6): δ8.43(s,1H),8.21(s,1H),6.85(dd,J=9.9,4.1Hz,2H),5.91–5.80(m,1H),3.97(d,J=7 .0Hz,2H),3.26(d,J=11.5Hz,2H),3.18(d,J=11.3Hz,2H),1.76(t,J=2.9Hz,2H),1.36(dd,J=19.4,5.2Hz,4H).

[0429] Example 25

[0430] 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 59

[0431] Compound 58 (28.7 mg) was used as starting material, sodium acetate borohydride (37.38 mg), and formaldehyde aqueous solution (8.3 μL, wt. 37%) were used as reagents to obtain the target compound 59 (15.0 mg) as a white powder by the same method as in Example 2.

[0432] MS ESI: m / z = 503.1, [M+H]+ .

[0433] 1 H NMR (400MHz, DMSO-d6): δ8.60(s,1H),6.90(d,J=10.2Hz,2H),5.96–5.84(m,1H),3.91(d,J=7.2Hz,2H ),3.00(d,J=9.0Hz,2H),2.36(d,J=9.1Hz,2H),2.28(s,3H),1.60–1.48(m,3H),1.39(d,J=6.8Hz,3H).

[0434] Example 26

[0435] 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-((R)-1-cyclobutylethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 61

[0436] Step 1: tert-Butyl (1R,5S,6r)-6-((4-(5-chloro-7-(((R)-1-cyclobutylethyl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 60

[0437] Intermediate 6 (100.0 mg) and tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 53 (223.85 mg) were used as raw materials and sodium hydride (42.0 mg, 60% wt. in mineral oil) was used as a base. The same conditions as in the first step of Example 1 were used to obtain intermediate 60 (137.3 mg).

[0438] Step 2: 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-((R)-1-cyclobutylethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 61

[0439] Using intermediate 60 (131.9 mg) as starting material, compound 61 (65.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0440] MS ESI: m / z = 475.1, [M+H] + .

[0441] 1 H NMR (400MHz, DMSO-d6): δ8.59(s,1H),8.28(s,1H),6.98(s,2H),4.00(d,J=7.0Hz,2H),3.08(d,J=11.3Hz,2H),2.95(d,J=11.1Hz,2H),1.85(ddt ,J=22.9,11.0,3.7Hz,3H),1.72(dt,J=10.8,8.2Hz,2H),1.61(s,3H),1.46(t,J=9.2Hz,1H),1.32(dd,J=7.2,4.0Hz,2H),0.96(d,J=6.4Hz,3H).

[0442] Example 27

[0443] 5-Chloro-N-((R)-1-cyclobutylethyl)-6-(2,6-difluoro-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 62

[0444] Using compound 61 (47.2 mg) as raw material, sodium acetate borohydride (63.26 mg) and formaldehyde aqueous solution (14.4 μL, wt. 37%) as reagents, the target compound 62 (30.0 mg) was obtained as a white powder by the same method as Example 2.

[0445] MS ESI: m / z = 489.2, [M+H] + .

[0446] 1 H NMR (400MHz, DMSO-d6): δ8.59(s,1H),7.84(s,1H),7.03–6.94(m,2H),3.94(d,J=7.4Hz,2H),2.95(d,J=8.8Hz,2H),2.47(d,J= 8.3Hz,1H),2.26(d,J=21.8Hz,5H),1.94–1.53(m,6H),1.47(q,J=7.6,5.2Hz,3H),1.31(t,J=9.4Hz,1H),0.96(d,J=6.4Hz,3H).

[0447] Example 28

[0448] 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl)-5-methyl-N-((R)-1-cyclobutylethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 61A

[0449] Step 1: (1R,5S,6r)-6-((4-(5-methyl-7-(((R)-1-cyclobutylethyl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 60A

[0450] Intermediate 6A (100.0 mg) and tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 53 (236.3 mg) were used as starting materials and sodium hydride (44.4 mg, 60% wt. in mineral oil) was used as a base. Intermediate 60A (72.4 mg) was obtained under the same conditions as in the first step of Example 1.

[0451] Step 2: 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl)-5-methyl-N-((R)-1-cyclobutylethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 61

[0452] Intermediate 60A (72.4 mg) was used as starting material and the same conditions as in the second step of Example 1 were used to obtain compound 61A (30.0 mg) as a white powder.

[0453] MS ESI: m / z = 455.2, [M+H] + .

[0454] 1H NMR (400MHz, DMSO-d6): δ8.47(s,1H),8.31(s,1H),7.20(d,J=10.0Hz,1H),6.99(t,J=11 .6Hz,2H),4.00(d,J=7.1Hz,2H),3.08(d,J=11.2Hz,2H),2.95(d,J=11.2Hz,2H),2.46–2. 39(m,1H),2.12(s,3H),1.85(dqd,J=23.0,7.9,4.0Hz,2H),1.71(dt,J=10.7,8.4Hz,1H) ,1.60(d,J=13.0Hz,4H),1.45(p,J=8.7Hz,1H),1.35–1.25(m,2H),0.93(d,J=6.3Hz,3H).

[0455] Example 29

[0456] 6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl-5-chloro-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine)65

[0457] Step 1: (1R,5S,6s)-tert-butyl 6-((4-(5-chloro-7-(((R)-3-methylbutan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 64

[0458] Intermediate 4 (100.0 mg) and (1R,5S,6s)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 63 (231.18 mg) were used as raw materials and sodium hydride (43.35 mg, 60% wt. in mineral oil) was used as a base. Intermediate 64 (111.3 mg) was obtained under the same conditions as in the first step of Example 1.

[0459] Step 2: 6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl-5-chloro-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 65

[0460] Using intermediate 64 (113.3 mg) as starting material, compound 65 (56.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0461] MS ESI: m / z = 463.1, [M+H] + .

[0462] 1 H NMR (400MHz, DMSO-d6): δ8.60(s,1H),7.89(s,1H),7.00(dd,J=9.8,2.8Hz,2H),4.24 (d,J=7.4Hz,2H),3.27(d,J=11.2Hz,2H),3.05(d,J=11.4Hz,2H),1.90–1.72(m,4H), 1.43(p,J=7.8Hz,1H), 1.06(d,J=6.5Hz,3H), 0.71(d,J=6.6Hz,6H).

[0463] Example 30

[0464] 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)phenyl)-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 66

[0465] Compound 65 (30.3 mg) was used as raw material, sodium acetate borohydride (41.685 mg), and formaldehyde aqueous solution (8.5 μL, wt. 37%) were used as reagents to obtain the target compound 66 (15.0 mg) as a white powder by the same method as Example 2.

[0466] MS ESI: m / z = 477.2, [M+H] + .

[0467] 1 H NMR (400MHz, DMSO-d6): δ8.59(s,1H),7.87(s,1H),6.98–6.90(m,2H),4.46(d,J=7.1Hz,2H),2.98(d,J=9.4Hz,2H),2 .21(s,3H),1.77(q,J=6.9Hz,2H),1.67–1.60(m,2H),1.28–1.18(m,2H),1.06(d,J=6.5Hz,4H),0.70(d,J=6.6Hz,6H).

[0468] Example 31

[0469] 6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 68

[0470] Step 1: (1R,5S,6s)-6-((4-(5-chloro-7-(((S)-1,1,1-trifluoropropyl-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 67

[0471] Intermediate 5 (100.0 mg) and (1R,5S,6s)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 63 (215.93 mg) were used as raw materials and sodium hydride (40.5 mg, 60% wt. in mineral oil) was used as a base. The same conditions as in the first step of Example 1 were used to obtain intermediate 67 (106.7 mg).

[0472] Step 2: 6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl))-5-chloro-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 68

[0473] Using intermediate 67 (106.7 mg) as starting material, compound 68 (20.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0474] MS ESI: m / z = 489.1, [M+H] + .

[0475] 1 H NMR (400MHz, DMSO-d6): δ8.37(s,1H),8.15(s,1H),6.83(d,J=10.6Hz,2H),5.81(t,J=7.5Hz,1H),4.12(d,J=7.6Hz,2H), 3.36(d,J=10.6Hz,2H), 3.05(d,J=11.8Hz,2H), 1.93(dd,J=8.1,3.3Hz,2H), 1.46(p,J=7.9Hz,1H), 1.27(d,J=6.8Hz,3H).

[0476] Example 32

[0477] 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 69

[0478] Compound 68 (10.7 mg) was used as starting material, sodium acetate borohydride (14.0 mg), and formaldehyde aqueous solution (2.53 μL, wt. 37%) were used as reagents to obtain the target compound 69 (7.0 mg) as a white powder by the same method as in Example 2.

[0479] MS ESI: m / z = 503.1, [M+H] + .

[0480] Example 33

[0481] 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 71

[0482] Step 1: tert-Butyl (1R,5S,6r)-6-((4-(5-chloro-7-((2,2,2-trifluoroethyl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl))-3,5-difluorophenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 70

[0483] Intermediate 7 (100.0 mg) and tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 53 (224.0 mg) were used as raw materials and sodium hydride (42.0 mg, 60% wt. in mineral oil) was used as a base. Intermediate 70 (134.8 mg) was obtained under the same conditions as in the first step of Example 1.

[0484] Step 2: 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 71

[0485] Using intermediate 70 (126.1 mg) as starting material, compound 71 (41.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0486] MS ESI: m / z = 475.0, [M+H] + .

[0487] 1 H NMR (400MHz, DMSO-d6): δ8.49(s,1H),8.25(s,1H),6.89(d,J=9.6Hz,2H),4.72(q,J=9.2Hz,2H),3. 98(d,J=6.8Hz,2H),3.20(d,J=11.2Hz,2H),3.11(d,J=11.2Hz,2H),1.71(s,2H),1.39–1.33(m,1H).

[0488] Example 34

[0489] 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)phenyl)-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 72

[0490] Compound 71 (23.1 mg) was used as starting material, sodium acetate borohydride (30.98 mg), and formaldehyde aqueous solution (5.61 μL, wt. 37%) were used as reagents to obtain target compound 72 (17.0 mg) as a white powder in the same manner as in Example 2.

[0491] MS ESI: m / z = 489.1, [M+H] + .

[0492] 1 H NMR (400MHz, DMSO-d6): δ8.52(s,1H),6.86(d,J=9.8Hz,2H),4.67(q,J=9.0Hz,2H),3.84(d,J=7.2Hz,2H) ,2.91(d,J=8.9Hz,2H),2.23(d,J=8.8Hz,2H),2.18(s,3H),1.50(d,J=3.2Hz,1H),1.41(d,J=2.9Hz,2H).

[0493] Example 35

[0494] 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 71A

[0495] Step 1: tert-Butyl (1R,5S,6r)-6-((4-(5-methyl-7-((2,2,2-trifluoroethyl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl))-3,5-difluorophenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 70A

[0496] Intermediate 7A (100.0 mg) and tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 53 (236.08 mg) were used as starting materials and sodium hydride (44.3 mg, 60% wt. in mineral oil) was used as a base. Intermediate 70A (132.8 mg) was obtained under the same conditions as in the first step of Example 1.

[0497] Step 2: 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2,6-difluorophenyl)-5-methyl-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 71A

[0498] Intermediate 70A (125.1 mg) was used as starting material and the same conditions as in the second step of Example 1 were used to obtain compound 71A (70.0 mg) as a white powder.

[0499] MS ESI: m / z = 469.2, [M+H] + .

[0500] 1 H NMR (400MHz, DMSO-d6): δ8.49(s,1H),8.23(s,1H),6.90(d,J=9.6Hz,2H),4.63(q,J=9.0Hz,2H),3.92(d,J=6.9 Hz,2H),3.11(d,J=11.3Hz,2H),3.00(d,J=11.3Hz,2H),2.10(s,3H),1.62(s,2H),1.30(dq,J=7.3,3.5Hz,1H).

[0501] Example 36

[0502] 5-Chloro-6-(2,6-difluoro-4-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl-N-((R)-3-methylbutyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 74

[0503] Step 1: tert-Butyl (3aR,5r,6aS)-5-(4-(5-chloro-7-(((R)-3-methylbutan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 73

[0504] Intermediate 4 (200.0 mg) and (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 17 (492.46 mg) were used as starting materials and sodium hydride (87.0 mg, 60% wt. in mineral oil) was used as a base. Intermediate 73 (270 mg) was obtained under the same conditions as in the first step of Example 1.

[0505] Step 2: 5-chloro-6-(2,6-difluoro-4-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl-N-((R)-3-methylbutyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 74

[0506] Using intermediate 73 (270 mg) as starting material, compound 74 (90.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0507] MS ESI: m / z = 477.1, [M+H] + .

[0508] 1 H NMR (400MHz, DMSO-d6): δ8.60(s,1H),8.36(s,1H),7.04–7.00(m,2H),4.97(t,J=5.2Hz,1H),3.26–3.21(m,2H),2.92(dd,J=11. 7,4.4Hz,2H),2.81–2.75(m,2H),2.26–2.19(m,2H),1.74(tt,J=13.8,5.7Hz,4H),1.05(d,J=6.5Hz,3H),0.69(d,J=6.6Hz,7H).

[0509] Example 37

[0510] 5-Chloro-6-(2,6-difluoro-4-(((3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((R)-3-methylbutyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 75

[0511] Using compound 74 (40.0 mg) as raw material, sodium acetate borohydride (53.4 mg) and formaldehyde aqueous solution (14.34 μL, wt. 37%) as reagents, the target compound 75 (33.1 mg) was obtained as a white powder by the same method as Example 2.

[0512] MS ESI: m / z = 491.2, [M+H] + .

[0513] 1 H NMR (400MHz, DMSO-d6): δ8.59(s,1H),7.94(s,1H),6.97(dd,J=11.4,5.4Hz,2H),4.85–4.77(m,1H),2.55(s,2H),2.43–2. 35(m,4H),2.24(s,6H),1.77(q,J=6.9Hz,1H),1.53(dt,J=13.1,6.1Hz,2H),1.05(d,J=6.5Hz,3H),0.69(d,J=6.7Hz,6H).

[0514] Example 38

[0515] 5-Chloro-6-(2,6-difluoro-4-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 77

[0516] Step 1: tert-Butyl (3aR,5r,6aS)-5-(((S)-1,1,1-trifluoropropyl-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 76

[0517] Intermediate 5 (200.0 mg) and (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 17 (459.75 mg) were used as starting materials and sodium hydride (81.0 mg, 60% wt. in mineral oil) was used as a base. Intermediate 76 (280.7 mg) was obtained under the same conditions as in the first step of Example 1.

[0518] Step 2: 5-chloro-6-(2,6-difluoro-4-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((S)-1,1,1-trifluoropropane-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 77

[0519] Using intermediate 76 (280.7 mg) as starting material, compound 77 (120.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0520] MS ESI: m / z = 503.0 [M+H] + .

[0521] 1 H NMR (400MHz, DMSO-d6): δ8.32(s,1H),8.24(d,J=4.7Hz,1H),6.85(d,J=10.7Hz,2H ),5.78(q,J=7.2Hz,1H),4.95(p,J=4.5,4.1Hz,1H),3.36(dt,J=12.5,4.3Hz,2H), 3.01(dd,J=11.3,5.0Hz,2H),2.84(s,2H),2.22(dd,J=13.8,6.8Hz,2H),1.78(dd,J=11.8,7.0Hz,2H),1.29(d,J=5.8Hz,3H).

[0522] Example 39

[0523] 5-Chloro-6-(2,6-difluoro-4-(((3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 78

[0524] Using compound 77 (38.8 mg) as raw material, sodium acetate borohydride (49.1 mg) and formaldehyde aqueous solution (13.2 μL, wt. 37%) as reagents, the target compound 78 (35.0 mg) was obtained as a white powder by the same method as Example 2.

[0525] MS ESI: m / z = 517.1, [M+H] + .

[0526] 1 H NMR (400MHz, DMSO-d6): δ8.50(s,1H),8.19(s,1H),6.90(d,J=10.6Hz,2H),5.88–5.80(m,1H),4.82(t,J =6.4Hz,1H),2.64(s,6H),2.41(s,3H),2.29–2.24(m,2H),1.61(d,J=10.5Hz,2H),1.36(d,J=6.7Hz,3H).

[0527] Example 40

[0528] (2,6-difluoro-4-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((R)-3-methylbutyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 80

[0529] Step 1: tert-Butyl (3aR,5s,6aS)-5-(4-(5-chloro-7-(((R)-3-methylbutan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 79

[0530] Intermediate 4 (100.0 mg) and (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 19 (246.23 mg) were used as starting materials and sodium hydride (43.36 mg, 60% wt. in mineral oil) was used as a base. Intermediate 79 (150.0 mg) was obtained under the same conditions as in the first step of Example 1.

[0531] Step 2: (2,6-difluoro-4-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((R)-3-methylbutyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 80

[0532] Using intermediate 79 (150 mg) as starting material, compound 80 (75.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0533] MS ESI: m / z = 477.1, [M+H] +.

[0534] 1 H NMR (400MHz, DMSO-d6): δ8.60(s,1H),8.37(s,1H),6.99(dd,J=10.5,4.7Hz,2H),5.11–5.07(m,1H),3.10(dd,J=11.5,6.4Hz,2H), 2.94(d,J=10.9Hz,2H),2.85(s,2H),2.03(dq,J=13.0,3.7Hz,2H),1.90–1.71(m,4H),1.05(d,J=6.5Hz,3H),0.70(d,J=6.6Hz,6H).

[0535] Example 41

[0536] 5-Chloro-6-(2,6-difluoro-4-(((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl))-N-((R)-3-methylbutyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 81

[0537] Using compound 80 (25.6 mg) as raw material, sodium acetate borohydride (34.2 mg), and formaldehyde aqueous solution (6.19 μL, wt. 37%) as reagents, the target compound 81 (25.0 mg) was obtained as a white powder by the same method as Example 2.

[0538] MS ESI: m / z = 491.1, [M+H] + .

[0539] 1 H NMR (400MHz, CDCl3): δ8.32 (s, 1H), 6.60–6.55 (m, 2H), 6.28 (d, J = 10.6Hz, 1H), 4.91(d,J=4.6Hz,1H),3.31(s,1H),2.93–2.86(m,2H),2.75(d,J=9.7Hz,2H),2 .43(d,J=9.4Hz,4H),2.25–2.19(m,2H),1.87(dt,J=14.5,5.4Hz,2H),1.65(dt ,J=12.9,6.6Hz,1H),1.25(s,1H),1.06(d,J=6.6Hz,3H),0.80(t,J=6.6Hz,6H).

[0540] Example 42

[0541] 5-Chloro-6-(2,6-difluoro-4-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 83

[0542] Step 1: (3aR,5s,6aS)-5-(4-(5-chloro-7-(((S)-1,1,1-trifluoropropyl-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 82

[0543] Intermediate 5 (88.9 mg) and (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 19 (204.5 mg) were used as starting materials and sodium hydride (36.0 mg, 60% wt. in mineral oil) was used as a base. Intermediate 82 (115.0 mg) was obtained under the same conditions as in the first step of Example 1.

[0544] Step 2: 5-Chloro-6-(2,6-difluoro-4-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((S)-1,1,1-trifluoropropane-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 83

[0545] Using intermediate 82 (95.1 mg) as starting material, compound 83 (50.0 mg) was obtained as a white powder under the same conditions as in the second step of Example 1.

[0546] MS ESI: m / z = 503.1, [M+H] + .

[0547] 1 H NMR (400MHz, DMSO-d6): δ8.29(d,J=21.9Hz,2H),6.83(d,J=10.7Hz,2H),5.86–5.75(m,1H),5.04(t,J=4.5Hz,1H),3.24(dd ,J=11.8,6.4Hz,2H),3.05(d,J=11.6Hz,2H),2.93(s,2H),2.08–1.99(m,2H),1.90(d,J=13.3Hz,2H),1.29(d,J=6.6Hz,3H).

[0548] Example 43

[0549] 5-Chloro-6-(2,6-difluoro-4-(((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 84

[0550] Compound 83 (40.9 mg) was used as starting material, sodium acetate borohydride (51.5 mg), and formaldehyde aqueous solution (8.9 μL, wt. 37%) were used as reagents to obtain the target compound 84 (33.0 mg) as a white powder by the same method as in Example 2.

[0551] MS ESI: m / z = 517.1, [M+H] + .

[0552] 1 H NMR (400MHz, DMSO-d6): δ8.51(s,1H),6.85(d,J=10.8Hz,2H),5.84(q,J=7.6Hz,1H),5.05–5.00(m,1H),2.75(d,J=9.5Hz,2H),2.61(d ,J=9.4Hz,2H),2.45(d,J=7.2Hz,2H),2.34(s,3H),2.04(dq,J=13.2,3.5Hz,2H),1.77(dt,J=13.7,5.0Hz,2H),1.36(d,J=6.8Hz,3H).

[0553] Example 44

[0554] 6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)-2,6-difluorophenyl)-5-chloro-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 86

[0555] Step 1: tert-Butyl (1R,5S,6s)-6-(((R)-3-methylbutan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenyl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 85

[0556] Intermediate 4B (100.0 mg) was dissolved in N,N-dimethylformamide (1.24 mL) and intermediate 19A (130.3 mg), tetrakis(triphenylphosphine)palladium (24.22 mg), cuprous iodide (5.98 mg), and triethylamine (88.0 μL) were added in sequence. The mixture was reacted at 80°C under an inert atmosphere for 20 minutes, then at room temperature for 8 hours. Saturated sodium chloride solution and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 85 (116.9 mg) as a yellow oil.

[0557] Step 2: 6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)-2,6-difluorophenyl)-5-chloro-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 86

[0558] Intermediate 85 (116.9 mg) was dissolved in methanol (2.1 mL) at room temperature, and 4.0 M hydrochloric acid in dioxane (0.95 mL) was added and stirred at room temperature for 5 hours. The solvent was dried and purified by Pre-HPLC (eluent: acetonitrile and water containing 1‰ formic acid) to give compound 86 (40.0 mg) as a white powder.

[0559] MS ESI: m / z = 457.1, [M+H] + .

[0560] 1H NMR (400MHz, DMSO-d6): δ8.60(d,J=2.2Hz,1H),8.31–8.18(m,1H),7.41–7.36(m,2H),3.06–3.00(m,2H),2.82(d,J=11. 4Hz,2H),1.94–1.90(m,2H),1.76(q,J=6.9Hz,1H),1.59(q,J=3.1Hz,1H),1.05(d,J=6.5Hz,4H),0.69(d,J=6.6Hz,6H).

[0561] Example 45

[0562] 6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)-2,6-difluorophenyl)-5-chloro-N-((R)-1-cyclobutylethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 88

[0563] Step 1: tert-Butyl(1R,5S,6s)-6-((4-(5-chloro-7-(((R)-1-cyclobutylethyl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenyl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 87

[0564] Intermediate 6B (100.0 mg) was dissolved in N,N-dimethylformamide (1.20 mL) and intermediate 19A (127.1 mg), tetrakis(triphenylphosphine)palladium (23.63 mg), cuprous iodide (5.84 mg), and triethylamine (85.3 μL) were added in sequence. The mixture was reacted at room temperature for 8 hours. Saturated sodium chloride solution and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 87 (109.5 mg) as a yellow oil.

[0565] Step 2: 6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)-2,6-difluorophenyl)-5-chloro-N-((R)-1-cyclobutylethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 88

[0566] Intermediate 87 (109.5 mg) was dissolved in methanol (1.92 mL) at room temperature, and 4.0 M hydrochloric acid in dioxane (0.86 mL) was added and stirred at room temperature for 5 hours. The solvent was dried and purified by Pre-HPLC (eluent: acetonitrile and water containing 1‰ formic acid) to give compound 88 (51.0 mg) as a white powder.

[0567] MS ESI: m / z = 469.1, [M+H] + .

[0568] 1 H NMR (400MHz, DMSO-d6): δ8.54(s,1H),8.17(s,1H),7.34(t,J=10.9Hz,2H),2.97(d,J=11.6Hz,2H),2.76(d,J=11.5Hz,2H),2.39(d ,J=8.4Hz,1H),1.88–1.61(m,6H),1.53(h,J=6.6,5.5Hz,2H),1.39(t,J=9.1Hz,1H),1.25(d,J=13.7Hz,1H),0.90(d,J=6.3Hz,3H).

[0569] Example 46

[0570] 5-Chloro-N-((R)-1-cyclobutylethyl)-6-(2,6-difluoro-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 89

[0571] Using compound 88 (22.7 mg) as starting material, sodium acetate borohydride (28.5 mg) and formaldehyde aqueous solution (5.2 μL, wt. 37%) as reagents, the target compound 89 (20.0 mg) was obtained as a white powder by the same method as in Example 2.

[0572] MS ESI: m / z = 483.2, [M+H] + .

[0573] 1 H NMR (400MHz, DMSO-d6): δ8.60(s,1H),7.90(s,1H),7.39(t,J=10.8Hz,2H),2.99(d,J=9.2Hz,2H),2.45(d,J=10.1H z,1H),2.25(d,J=24.4Hz,5H),1.94–1.53(m,8H),1.46(q,J=9.1Hz,1H),1.37–1.25(m,1H),0.96(d,J=6.3Hz,3H).

[0574] Example 47

[0575] (6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)-2,6-difluorophenyl)-5-chloro-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 91

[0576] Step 1: tert-Butyl (1R,5S,6s)-6-((4-(5-chloro-7-(((S)-1,1,1-trifluoropropan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenyl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 90

[0577] Intermediate 90 (122.9 mg) was obtained as a yellow oil by the same synthesis method as in the first step of Example 45 using Intermediate 5B (100.0 mg) and Intermediate 19A (123.5 mg) as raw materials, tetrakis(triphenylphosphine)palladium (22.97 mg) and cuprous iodide (5.675 mg) as catalysts and triethylamine (83.0 μL) as a base.

[0578] Step 2: (6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)-2,6-difluorophenyl)-5-chloro-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 91

[0579] Intermediate 90 (122.9 mg) was used as starting material and the same synthesis method as in the second step of Example 45 was used to obtain compound 91 (60.0 mg) as a white powder.

[0580] MS ESI: m / z = 483.1, [M+H] + .

[0581] 1 H NMR (400MHz, DMSO-d6): δ8.37(s,1H),8.18(s,1H),7.24(t,J=7.8Hz,2H),5.98–5.87(m,1H),3.21(d,J= 11.6Hz, 2H), 3.05 (d, J = 11.4Hz, 2H), 2.04 (t, J = 2.8Hz, 2H), 1.67 (t, J = 3.6Hz, 1H), 1.30 (d, J = 6.8Hz, 3H).

[0582] Example 48

[0583] 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 92

[0584] Using Example 47 (29.6 mg) as raw material, sodium acetate borohydride (36.2 mg), and formaldehyde aqueous solution (6.6 μL, wt. 37%) as reagents, the target compound 92 (25.0 mg) was obtained as a white powder by the same method as Example 2.

[0585] MS ESI: m / z = 497.1, [M+H] + .

[0586] 1 H NMR (400MHz, DMSO-d6): δ8.67(s,1H),8.14(s,1H),7.33(s,2H),6.04(s,1H),3.05(d,J=9.4Hz, 2H),2.37(d,J=9.4Hz,4H),2.27(s,4H),1.91(s,2H),1.86(d,J=3.4Hz,2H),1.42–1.38(m,3H).

[0587] Example 49

[0588] 6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)-2,6-difluorophenyl)-5-chloro-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 94

[0589] Step 1: tert-Butyl (1R,5S,6s)-6-((4-(5-chloro-7-((2,2,2-trifluoroethyl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenyl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 93

[0590] Intermediate 93 (88.6 mg) was obtained as a yellow oil by using the same synthesis method as in the first step of Example 45 from Intermediate 7B (100.0 mg) and Intermediate 19A (127.1 mg) as raw materials, tetrakis(triphenylphosphine)palladium (23.63 mg) and cuprous iodide (5.84 mg) as catalysts and triethylamine (85.3 μL) as a base.

[0591] Step 2: 6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)-2,6-difluorophenyl)-5-chloro-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 94

[0592] Intermediate 93 (88.6 mg) was used as starting material and the same synthesis method as in the second step of Example 45 was used to obtain compound 94 (40.0 mg) as a white powder.

[0593] MS ESI: m / z = 469.0, [M+H] + .

[0594] 1H NMR (400MHz, DMSO-d6): δ8.44(s,1H),8.20(s,1H),7.29(d,J=7.5Hz,2H),4.76(q,J=9.4Hz,2 H),3.13(d,J=11.6Hz,2H),2.94(d,J=11.4Hz,2H),2.00–1.96(m,2H),1.63(t,J=3.6Hz,1H).

[0595] Example 50

[0596] 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)phenyl)-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

[0597] Compound 94 (22.7 mg) was used as starting material, sodium acetate borohydride (28.5 mg), and formaldehyde aqueous solution (5.2 μL, wt. 37%) were used as reagents to obtain the target compound 95 (16.0 mg) as a white powder by the same method as in Example 2.

[0598] MS ESI: m / z = 483.1, [M+H] + .

[0599] 1 H NMR (400MHz, DMSO-d6): δ8.61(s,1H),8.15(s,1H),7.34(d,J=7.9Hz,2H), 4.77(q,J=9.1Hz, 2H), 3.02 (d, J = 9.2Hz, 2H), 2.30 (d, J = 9.1Hz, 2H), 2.24 (s, 3H), 1.87 (dt, J = 17.6, 2.9Hz, 3H).

[0600] Example 51

[0601] 6-(4-((E)-2-((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)vinyl)-2,6-difluorophenyl)-5-chloro-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 97

[0602] Step 1: tert-Butyl (1R,5S,6s)-6-((E)-4-(5-chloro-7-(((R)-3-methylbutan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenylvinyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 96

[0603] Intermediate 4B (100.0 mg) was dissolved in N-methylpyrrolidone (3.0 mL) and intermediate 19B (209.28 mg), tetrakis(triphenylphosphine)palladium (24.2 mg), and cuprous iodide (4.0 mg) were added in sequence. The mixture was reacted at 80°C for 1 hour. Saturated sodium chloride and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered. The concentrated intermediate 96 (110.9 mg) was a yellow oil.

[0604] Step 2: 6-(4-((E)-2-((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)vinyl)-2,6-difluorophenyl)-5-chloro-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 97

[0605] Intermediate 96 (110.9 mg) was used as starting material and the same synthesis method as in the second step of Example 45 was used to obtain compound 97 (70.0 mg) as a white powder.

[0606] MS ESI: m / z = 459.1, [M+H] + .

[0607] 1 H NMR (400MHz, DMSO-d6): δ8.54(d,J=3.6Hz,1H),8.24(s,1H),7.29(d,J=10.0Hz,2H),6.38(d,J=15.9Hz,1H),6.22(dd,J=15.9,9.0Hz,1H),3.0 0(d,J=11.4Hz,2H),2.86(d,J=11.2Hz,2H),1.73–1.66(m,3H),1.56(dt,J=6.8,3.3Hz,1H),0.98(d,J=6.6Hz,4H),0.62(dt,J=6.8,4.4Hz,6H).

[0608] Example 52

[0609] 6-(4-((E)-2-((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)vinyl)-2,6-difluorophenyl)-5-chloro-N-((R)-1-cyclobutylethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 99

[0610] Step 1: tert-Butyl (1R,5S,6s)-6-((E)-4-(5-chloro-7-(((R)-1-cyclobutylethyl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenylvinyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 98

[0611] Intermediate 6B (100.0 mg) and intermediate 19B (204.2 mg) were used as raw materials, and tetrakistriphenylphosphine palladium (23.6 mg) and cuprous iodide (4.0 mg) were used as catalysts. A method similar to the first step of Example 51 was used to obtain intermediate 98 (127.9 mg) as a yellow oil.

[0612] Step 2: 6-(4-((E)-2-((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)vinyl)-2,6-difluorophenyl)-5-chloro-N-((R)-1-cyclobutylethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 99

[0613] Intermediate 98 (127.9 mg) was used as starting material and the same synthesis method as in the second step of Example 45 was used to obtain compound 99 (90.0 mg) as a white powder.

[0614] MS ESI: m / z = 471.1, [M+H] + .

[0615] 1 H NMR (400MHz, DMSO-d6): δ8.60 (s, 1H), 8.31 (s, 1H), 7.38 (t, J = 10.8Hz, 2H), 6.46 (d, J = 15.9Hz, 1H), 6.30 (dd, J = 15.9, 9.1Hz, 1H), 3.08 (d, J = 11.4Hz, 2H),2.94(d,J=11.2Hz,2H),2.44(d,J=8.1Hz,1H),1.91–1.79(m,2H),1.7 6–1.54(m,6H),1.45(p,J=8.7Hz,1H),1.25(s,1H),0.95(d,J=6.4Hz,3H).

[0616] Example 53

[0617] 6-(4-((E)-2-((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)vinyl)-2,6-difluorophenyl)-5-chloro-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 101

[0618] Step 1: tert-Butyl (1R,5S,6s)-6-((E)-4-(5-chloro-7-(((S)-1,1,1-trifluoropropyl-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenylvinyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 100

[0619] Intermediate 5B (70.0 mg) and intermediate 19B (138.99 mg) were used as raw materials, and tetrakistriphenylphosphine palladium (16.1 mg) and cuprous iodide (2.65 mg) were used as catalysts. A method similar to the first step of Example 51 was used to obtain intermediate 100 (78.1 mg) as a yellow oil.

[0620] Step 2: 6-(4-((E)-2-((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)vinyl)-2,6-difluorophenyl)-5-chloro-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 101

[0621] Intermediate 100 (78.1 mg) was used as starting material and the same synthesis method as in the second step of Example 45 was used to obtain compound 101 (40.0 mg) as a white powder.

[0622] MS ESI: m / z = 485.1, [M+H] + .

[0623] Example 54

[0624] 6-(4-((E)-2-((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)vinyl)-2,6-difluorophenyl)-5-chloro-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 103

[0625] Step 1: tert-Butyl (1R,5S,6s)-6-((E)-4-(5-chloro-7-((2,2,2-trifluoroethyl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenylvinyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 102

[0626] Intermediate 7B (120.0 mg) and intermediate 19B (245.1 mg) were used as raw materials, tetrakistriphenylphosphine palladium (28.36 mg) and cuprous iodide (4.67 mg) were used as catalysts, and a method similar to the first step of Example 51 was used to obtain intermediate 102 (235.7 mg) as a yellow oil.

[0627] Step 2: 6-(4-((E)-2-((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)vinyl)-2,6-difluorophenyl)-5-chloro-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 103

[0628] Intermediate 102 (235.7 mg) was used as starting material and the same synthesis method as in the second step of Example 45 was used to obtain compound 103 (160.0 mg) as a white powder.

[0629] MS ESI: m / z = 471.1, [M+H] + .

[0630] 1 H NMR (400MHz, DMSO-d6): δ8.42(s,1H),8.25(s,1H),7.26(d,J=8.8Hz,2H),6.45(d,J=15.8Hz,1H),6.22(dd,J=15.9,8.9Hz,1 H), 4.71 (q, J = 9.3Hz, 2H), 3.21 (d, J = 11.5Hz, 2H), 3.11 (d, J = 11.3Hz, 2H), 1.83 (t, J = 2.6Hz, 2H), 1.67 (dt, J = 9.4, 3.3Hz, 1H).

[0631] Example 55

[0632] 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)phenyl)-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

[0633] Using Example 44 (24.7 mg) as raw material, sodium acetate borohydride (31.9 mg), and formaldehyde aqueous solution (5.83 μL, wt. 37%) as reagents, the target compound (12.0 mg) was obtained as a white powder by the same method as Example 2.

[0634] MS ESI: m / z = 471.1, [M+H] + .

[0635] Example 56

[0636] 5-Chloro-N-((R)-1-cyclobutylethyl)-6-(2,6-difluoro-4-((E)-2-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

[0637] Using Example 52 (27.1 mg) as raw material, sodium acetate borohydride (34.04 mg), and formaldehyde aqueous solution (6.2 μL, wt. 37%) as reagents, the target compound (20.0 mg) was obtained as a white powder by the same method as Example 2.

[0638] MS ESI: m / z = 485.2, [M+H] + .

[0639] Example 57

[0640] 6-(2,6-difluoro-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)phenyl)-5-methyl-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

[0641] Using Example 23 (20.1 mg) as raw material, sodium acetate borohydride (29.0 mg), and formaldehyde aqueous solution (5.3 μL, wt. 37%) as reagents, the target compound (13.0 mg) was obtained as a white powder by the same method as Example 2.

[0642] MS ESI: m / z = 457.2, [M+H] + .

[0643] Example 58

[0644] 5-Chloro-6-(difluoro-4-((E)-2-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)phenyl)-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

[0645] Using Example 54 (34.4 mg) as raw material, sodium acetate borohydride (43.2 mg), and formaldehyde aqueous solution (7.8 μL, wt. 37%) as reagents, the target compound (22.0 mg) was obtained as a white powder by the same method as Example 2.

[0646] MS ESI: m / z = 485.1, [M+H] + .

[0647] Example 59

[0648] 5-Chloro-6-(2,6-difluoro-4-((E)-2-((1R,5S,6s)-methyl-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)phenyl)-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

[0649] Using Example 51 (28.5 mg) as raw material, sodium acetate borohydride (36.7 mg), and formaldehyde aqueous solution (6.7 μL, wt. 37%) as reagents, the target compound (15.0 mg) was obtained as a white powder by the same method as Example 2.

[0650] MS ESI: m / z = 473.1, [M+H] + .

[0651] Example 60

[0652] 6-(2,6-difluoro-4-(((1R,5S,6r)-methyl-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-phenyl)-5-methyl-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

[0653] Using Example 35 (41.6 mg) as raw material, sodium acetate borohydride (58.2 mg), and formaldehyde aqueous solution (10.7 μL, wt. 37%) as reagents, the target compound (23.0 mg) was obtained as a white powder by the same method as Example 2.

[0654] MS ESI: m / z = 469.1, [M+H] + .

[0655] Example 61

[0656] 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6s)-3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 92

[0657] Example 47 (40 mg) was used as the starting material and dissolved in anhydrous N,N-dimethylformamide (2 mL). Ethyl bromide (7 uL) was added under ice-cooling and stirred for 30 minutes before adding cesium carbonate (36 mg). The reaction solution was stirred in a 60°C oil bath for 4 hours, then cooled to room temperature and quenched with saturated brine. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by HPLC to obtain the target product T-1 5-chloro-6-(2,6-difluoro-4-(((1R,5S,6s)-3-ethyl-3-azabicyclo[3.1.0]hexane-6-yl)ethynyl)phenyl)-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (8 mg).

[0658] MS-ESI: m / z = 511.0 [M+H] + .

[0659] Example 62

[0660] 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6s)-3-isopropyl-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 92

[0661] Using Example 47 (40 mg) as starting material, iodoisopropyl (10 μL) and Cs 2 CO 3 (35 mg) as reagents, the title compound (6.0 mg) was obtained by the same method as Example 61.

[0662] MS ESI: m / z = 525.0, [M+H] + .

[0663] Example 63

[0664] 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6s)-3-methyl-d3-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 92

[0665] Example 47 (80 mg) was used as the starting material, dissolved in anhydrous N,N-dimethylformamide (2 mL), CD3I (15 μL) and Cs2CO3 (60.1 mg) were used as reagents, and the target compound (16.0 mg) was obtained by the same method as Example 61.

[0666] MS-ESI: m / z = 500.0 [M+H] + .

[0667] Example 64

[0668] Tubulin stabilization activity test

[0669] Solvent for compounds: 100% dimethyl sulfoxide (DMSO).

[0670] Cell line: HEK293T (ATCC, CRL3216).

[0671] Culture conditions: Cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum, 1% penicillin / streptomycin, and 1% glutathione. Cells were cultured in a 37°C Thermo-Fisher cell culture incubator with a humidified atmosphere containing 5% carbon dioxide.

[0672] Test method:

[0673] One day before the experiment, 100,000 cells were seeded at a density of 200,000 cells / ml in a 24-well plate.

[0674] On the day of the experiment, 20 μl of PBS phosphate buffer containing the test compound at the experimental concentration or an equal volume of DMSO was added to the wells. After incubation at 37°C for 1 hour, colchicine was added to each well at a final concentration of 1 μM. Incubation was continued at 37°C for 3 hours, and the plate was placed on ice. The culture medium was removed from each well, and the cells were rinsed with pre-chilled PBS. The PBS was then aspirated and quickly added to 0.1 ml of pre-chilled RIPA cell lysis buffer (containing 0.5% sodium deoxycholate, 0.1% SDS, 1% NP-40, 5 mM EDTA, pH 8.0). Prior to use, the cell lysate was supplemented with a commercial protease inhibitor cocktail (1:500) and 1 μM of the deacetylase inhibitor Trichostatin A (Sangon Biotechnology Co., Ltd.). The cell lysate was added to a 1.5 ml centrifuge tube, sonicated, and centrifuged at 13,000 rpm for 10 minutes. The supernatant was then collected and protein concentration was determined using the BCA assay.

[0675] According to prior literature (Black, 1989; Kurt, 2011), acetylated tubulin was used as an indicator of microtubule polymerization to assess the effectiveness of compounds in stabilizing microtubules. HEK293T cell lysates were analyzed by SDS-PAGE (7.5% gel) and immunoblotted using antibodies against acetylated tubulin (1:20,000, Sigma-Aldrich, T7451) and α-tubulin (1:2000, Proteintech, 11224-1-AP). The blotting was then incubated with fluorescently conjugated IgG (1:40,000, Licor) and visualized using an Odyssey-Dlx imaging system. Grayscale analysis was performed using ImageJ.

[0676] The activity of the compound was quantified with the microtubule stabilization activity of 500 nM of CNDR-51657 (C5) (Jane, 2016) being 1.00. The test results of the microtubule stabilization activity of each example are shown in Table 1.

[0677] Table 1 Tubulin stabilization activity test results

[0678] Example 65

[0679] Oral pharmacokinetic studies in mice:

[0680] Healthy male CD1 mice were used as experimental animals and administered orally at a dose of 10 mg / kg in a volume of 10 mL / kg. The compound was prepared by dissolving 10 mg of the compound in 10 mL of 50% PEG-400 or 20% HPb-cyclodextrin, grinding and shaking to achieve uniform distribution of the compound into small particles, and then orally administering the compound. Blood samples were collected 30 minutes, 1 hour, 2 hours, and 4 hours after administration, and brain tissue samples were collected 4 hours after administration. The blood samples were supplemented with potassium EDTA and centrifuged to obtain plasma, which was diluted with 5 volumes of acetonitrile, centrifuged, and analyzed. The brain tissue trituration solution was diluted with 3.5 volumes of acetonitrile, centrifuged, and analyzed. The samples were then analyzed by liquid chromatography-tandem mass spectrometry (LC-MS / MS) using an ABSciex 3500 instrument with a gradient elution consisting of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B).

[0681] Table 2 PK test results of some compounds

[0682] The above results indicate that the compounds of the present invention have stabilizing activity against tubulin. In addition, compared with the control substances Cevipubulin and CNDR-51657, the compounds of the present invention are surprisingly found to have significantly improved exposure in plasma and brain tissue.

[0683] 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

A compound represented by general formula I or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a prodrug thereof: Where Ar is: X 1 Selected from the group consisting of Cl, CN, vinyl, -CH=CHC 1-6 Alkyl, -CH=CHC 3-6 Cycloalkyl, -C≡CH, -C≡C 1-6 Alkyl, -C≡CC 3-6 Cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, SC 1-6 Alkyl; R 1 Select from the following groups: C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic, C3-C 10 Halogenated cycloalkyl, or R 1 for: R 1a and R 1b are independently hydrogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, C3-C 10 Halogenated cycloalkyl, C7-C 11 Spiroalkanes, C5-C 10 Heterocyclic spirocyclic ring, aryl, heteroaryl; R 2 is hydrogen; R 3 and R 4 Independently hydrogen, F, Cl, Br; W is a chemical bond, -O(CR a R b ) n -、-(CR a R b ) n O-、-S(CR a R b ) n -、-(CR a R b ) n S-、-(CR a R b ) n -NR e -、-N(R e )-(CR a R b ) n -、-C(O)N(R e )-(CR a R b ) n -、-N(R e )C(O)-(CR a R b ) n -、-(CR a R b ) n -、-C(O)(CR a R b ) n -、-(CR a R b ) n C(O)-, arylene, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, C5-C9 fused heteroarylene, 5-membered or 6-membered heteroarylene; R a and each R b are independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Alkenyl, substituted or unsubstituted C6-C 20 Aryl, or substituted or unsubstituted C3-C 14 Heteroaryl; R a and R b Together with the carbon atoms to which they are attached, they can form a three- to eight-membered ring or a four- to eight-membered heterocyclic ring, wherein the heteroatom can be sulfur, oxygen, NH or NR e ; R c and each R d Each is independently hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C2-C 10 Alkenyl, C6-C 20 Aryl, C3-C 14 Heteroaryl; R c and R d It may be substituted by one or more groups selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, aldehyde, carboxyl, alkoxy, -CF3, -SF5. c and R d Together with the nitrogen atom to which they are attached, they can form a three- to eight-membered ring or a four- to eight-membered heterocyclic ring, wherein the heteroatom can be sulfur, oxygen, NH or NR e ; R e is hydrogen, C1-C6 alkyl, -(CR a R b ) n -C3-C6 cycloalkyl, -(CR a R b ) n -aryl, -(CR a R b ) n -heteroaryl; R e It may be substituted by one or more groups selected from the group consisting of halogen, hydroxyl, amino, nitro, cyano, aldehyde, carboxyl, alkoxy, -CF3, -SF5. Y is H, halogen, OR e 、-(CR a R b ) m -CO2H、-(CR a R b ) m -CO(CR a R b ) n -NR a R b , C1-C6 alkyl, C1-C6 haloalkyl, -(CR a R b ) n -C3-C6 cycloalkyl, -(CR a R b ) n -C3-C6 halocycloalkyl, -(CR a R b ) n -aryl, -(CR a R b ) n -heteroaryl, -(CR a R b ) n -NR c R d 、-O(CR a R b ) n -NR c R d 、-S(CR a R b ) n -NR c R d 、-NR e (CR a R b ) n -NR c R d 、-(CR a R b ) n -P(O)Me2、-(CR a R b ) n -SO2R a 、-(CR a R b ) n -SO2NR c R d 、-(CR a R b ) n -NR e CONR c R d -(CR a R b ) n -CONR c R d m and n are independently 0, 1, 2, 3, 4, 5 or 6; is a monocyclic hydrocarbon group, a spirocyclic hydrocarbon group, a condensed hydrocarbon group, a bridged hydrocarbon group, a monocyclic heterocyclic group, a spirocyclic heterocyclic group, a condensed heterocyclic group or a bridged heterocyclic group structure; X and Z are independently C(R 5 ), N; R 5 For hydrogen, OH, CN, halogen, NR c R d 、C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, -(CR a R b ) n -C3-C 10 Cycloalkyl, -(CR a R b ) n -C3-C 10 Halogenated cycloalkyl, -(CR a R b ) n -CO2H、-(CR a R b ) n -CONR c R d ; Unless otherwise specified, the monocyclic hydrocarbon group, spirocyclic hydrocarbon group, fused hydrocarbon group, bridged hydrocarbon group, monocyclic heterocyclic group, spirocyclic heterocyclic group, fused heterocyclic group or bridged heterocyclic group has 5-20 ring skeleton atoms. When the ring skeleton atoms have heteroatoms, the heteroatoms can be 1 to 4 (such as 3) heteroatoms selected from nitrogen, sulfur or oxygen. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a prodrug thereof, characterized in that: The R 1a For: CF3, R 1b is hydrogen, methyl or CF3. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a prodrug thereof, characterized in that: The Ar is: The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a prodrug thereof, characterized in that: for: 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. 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. 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 the structure shown in the following formula, where R 1 Selected from the following structures: X 1 is selected from Cl, methyl, CF3, ethyl or cyclopropyl; Y is selected from H, C 1-6 Alkyl, C 1-6 Fluorinated alkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, -SO2R a 、-SO2NR c R d 、-CONR c R d , aryl or heteroaryl. 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 the structure shown in the following formula, where R 1 Selected from the following structures: X 1 is selected from Cl, methyl, CF3, ethyl or cyclopropyl; Y is selected from H, C 1-6 Alkyl, C 1-6 Fluorinated alkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, -SO2R a 、-SO2NR c R d 、-CONR c R d , aryl or heteroaryl. 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 the structure shown in the following formula, where R 1 Selected from the following structures: X 1 is selected from Cl, methyl, CF3, ethyl or cyclopropyl; Y is selected from H, C 1-6 Alkyl, C 1-6 Fluorinated alkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, -SO2R a 、-SO2NR c R d 、-CONR c R d , aryl or heteroaryl. 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 the structure shown in the following formula, where R 1 Selected from the following structures: X 1 is selected from Cl, methyl, CF3, ethyl or cyclopropyl; Y is selected from H, C 1-6 Alkyl, C 1-6 Fluorinated alkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, -SO2R a 、-SO2NR c R d 、-CONR c R d , aryl or heteroaryl. The compound according to claim 1, characterized in that The compound is selected from the group consisting of: The use of the compound according to any one of claims 1 to 11, characterized in that Used for: (i) preparing microtubule stabilizers; (ii) preparing pharmaceutical compositions for treating microtubule-mediated diseases; (iii) preparing drugs for preventing and / or treating cancer and neurodegenerative diseases. The use according to claim 12, characterized in that The cancer is selected from the group consisting of glioma, colon cancer, breast cancer, gastric cancer, lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, liver cancer, brain cancer, melanoma, multiple myeloma, chronic myeloid leukemia, blood tumors, lymphomas, or metastatic lesions in tissues or organs away from the primary site of the tumor. The use according to claim 12, characterized in that The neurodegenerative disease is selected from the group consisting of Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis and traumatic brain injury. 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 6, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 15, characterized in that The pharmaceutical composition contains other anti-tumor drugs. Preferably, the pharmaceutical composition is selected from the following group: PD-1 antibody, PD-L1 antibody, CTLA-4 antibody, anti-tumor chemotherapy drugs (such as temozolomide), and targeted drugs.

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