Polycyclic compounds for the treatment of nervous system disorders and tumors

Abstract

The present invention discloses a polycyclic compound as a tubulin stabilizer having a structure represented by general formula (I) and a preparation method thereof, wherein the definitions of Ar, W, Z, X, Y, and heterocycle A are as described in the specification. The present invention also discloses a preparation method for this type of compound. The compound represented by general formula (I) of the present invention can be used to prepare a medicament for preventing and / or treating tumors and neurodegenerative diseases.

Description

[Technical Field]

[0001] Technical Field The present invention belongs to the field of medicinal chemistry, and specifically relates to compounds containing spirocyclic and fused ring structures for treating nervous system diseases and tumors (including gliomas) and methods for preparing the same.

[0002] Background technology Microtubules are essential components of the cytoskeleton and play important physiological roles, including cell proliferation, maintenance of cell morphology, and intracellular material transport. In the central nervous system, neurons, the primary functional cells, are a specific type of cell that does not undergo mitosis and has a polarized cell morphology. Axons, which transmit neural signals, rely on high-speed transport pathways formed by cytoskeletal proteins such as microtubules to rapidly propagate intracellular material between the cell body and nerve terminals. Under pathological conditions, the structure and function of microtubules change, contributing to the development of many important diseases. For example, Alzheimer's disease (AD) is characterized by two typical pathological features: aggregation of β-amyloid protein (Aβ) and tau protein. When hyperphosphorylated, tau loses its binding function to tubulin, resulting in the development of neurofibrillary tangles and the formation of neurodegenerative deposits. This affects the transport of axonal material mediated by microtubules and leads to distal axon degeneration. Tubulin stabilizers promote the binding of tau protein to tubulin, improve the transport and function of vesicular substances involved in the intracellular protein quality control system, and reduce the formation of tau-induced neurofibrillary tangle deposits. 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] However, some malignant tumors of the central nervous system, such as gliomas, are highly malignant and have poor therapeutic efficacy. These diseases generally originate in proliferating glial cells in the brain, and like most tumor cells, uncontrolled cell proliferation leads to the development of malignant cancer cells. Therefore, microtubule-stabilizing agents that can cross the blood-brain barrier and specifically affect the malignant proliferation of glial cells while being relatively harmless to neurons, hold great promise for their application in the treatment of these central nervous system diseases.

[0004] The present inventors have discovered compounds with spirocyclic and fused ring structures that have unexpectedly high tubulin stability. Summary of the Invention

[0005] Summary of the Invention The object of the present invention is to provide new compounds with spirocyclic and fused ring structures that have high tubulin-stabilizing activity.

[0006] Another object of the present invention is to provide a method for preparing said compound.

[0007] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof:

[0008] [ka] where: Ar is [ka] and X 1 is Cl, CN, vinyl group, -CH=CHC 1-6 Alkyl group, -CH=CHC 3-6 Cycloalkyl groups, -C≡CH, -C≡C 1-6 Alkyl group, -C≡CC 3-6 Cycloalkyl groups, C 1-6 Alkyl group, C 1-6Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 Halogenated cycloalkyl groups, OC 1-6 Alkyl group, OC 1-6 Halogenated alkyl groups, SC 1-6 is an alkyl group, R 1 is C1-C 10 Alkyl groups, C1-C 10 Halogenated alkyl groups, C3-C 10 Cycloalkyl groups, C3-C 10 Heterocyclyl groups, C3-C 10 a halogenated cycloalkyl group, or R 1 teeth, [ka] and R 1a and R 1b are independently hydrogen, C1-C 10 Alkyl groups, C1-C 10 Halogenated alkyl groups, C3-C 10 Cycloalkyl groups, C3-C 10 Halogenated cycloalkyl groups, C7-C 11 Spirocyclic alkanes, C5-C 10 a heterocyclic spiro ring, an aryl group, or a heteroaryl group, R 2 is hydrogen, R 3 and R 4 are independently hydrogen, F, Cl, or 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 group, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, C 6-10 an arylene group, a C5-C9 fused heteroarylene group, or a 5- or 6-membered heteroarylene group; R a and each R b are each independently hydrogen or a substituted or unsubstituted C-C 10 Alkyl groups, substituted or unsubstituted C3-C 10 Cycloalkyl groups, substituted or unsubstituted C2-C 10 Alkenyl groups, substituted or unsubstituted C6-C 20 Aryl group or substituted or unsubstituted C3-C 14 is a heteroaryl group, R a and R b can be taken together with the carbon atoms to which they are attached to form a 3- to 8-membered ring or a 4- to 8-membered heterocycle, where the heteroatom is sulfur, oxygen, NH, or NR e It can be, R c and each R d are each independently hydrogen, C1-C 10 Alkyl groups, C3-C 10 Cycloalkyl groups, C2-C 10 Alkenyl groups, C6-C 20 Aryl groups, C3-C 14 is a heteroaryl group, Rc and R d may be substituted by one or more groups selected from the group consisting of halogen, hydroxy group, amino group, nitro group, cyano group, aldehyde group, carboxyl group, alkoxy group, -CF3, and -SF5; R c and R d can be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered ring or a 4- to 8-membered heterocycle, where the heteroatom is sulfur, oxygen, NH, or NR e It can be, R e represents hydrogen, C1-C6 alkyl group, -(CR a R b ) n -C3-C6 cycloalkyl group, -(CR a R b ) n -aryl group, -(CR a R b ) n -heteroaryl group, R e may be substituted by one or more groups selected from the group consisting of halogen, hydroxy group, amino group, nitro group, cyano group, aldehyde group, carboxyl group, alkoxy group, -CF3, and -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 group, -(CR a R b ) n -C3-C6 cycloalkyl group, -(CR a R b ) n -aryl group, -(CR a R b ) n -heteroaryl group, -(CR a R b ) n -NRc 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 is. m and n are independently 0 or an integer from 1 to 6; [ka] is a monocyclic hydrocarbon group, a spirocyclic hydrocarbon group, a fused hydrocarbon group, a bridged ring hydrocarbon group, a monocyclic heterocyclyl group, a spirocyclic heterocyclyl group, a fused heterocyclyl group or a bridged ring heterocyclyl group structure, X and Z are independently C(R 5 ), N, R 5 is hydrogen, OH, CN, halogen, NR c R d , C1-C 10 Alkyl groups, C1-C10 Halogenated alkyl groups, -(CR a R b ) n -C3-C 10 Cycloalkyl groups, -(CR a R b ) n -C3-C 10 Halogenated cycloalkyl groups, -(CR a R b ) n -CO2H, -(CR a R b ) n -CONR c R d and In another preferred embodiment, Ar is as follows:

[0009] [ka]

[0010] In another preferred embodiment, in the general formula (I) [ka] is as follows: [ka]

[0011] In another preferred embodiment, W in general formula (I) is a chemical bond or O.

[0012] In another preferred embodiment, W in general formula (I) is —C≡C—.

[0013] In another preferred embodiment, X in general formula (I) is N or CH.

[0014] In another preferred embodiment, Y in the general formula (I) is H, a C1-C6 alkyl group, a C1-C6 fluoroalkyl group, a —C3-C6 cycloalkyl group, —(CR a Rb ) n -NR c R d , -SO2R a , -SO2NR c R d , -CONR c R d , an aryl group, or a heteroaryl group.

[0015] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (II). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group or a cyclopropyl group, and the definitions of W, Z, X, Y and heterocycle A are as shown in general formula (I).

[0016] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (III). [ka] where X 1 is Cl, a methyl group, an ethyl group or a cyclopropyl group, and the definitions of the heterocycles A, W, Z, X and Y are as shown in general formula (I), R 1a CF3, [ka] is.

[0017] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (IV). [ka] Here, X1 is Cl, a methyl group, CF3, an ethyl group, or a cyclopropyl group; the definitions of R1a, Ra, Rb, Rc, Rd, and Re are as defined in 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 of 1 to 3.

[0018] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (V). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group, or a cyclopropyl group, and R 1a , R a , R b , R c , R d and R e is defined as in the general formula (I), and 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 -, and n is 0 or an integer of 1 to 3.

[0019] In another preferred embodiment, the compound of general formula (I) is as shown in general formula (VI). [ka] where X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, and R 1a , R a , R b , R c , R d and R e is defined as in the general formula (I), and 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 -, and n is 0 or an integer of 1 to 3.

[0020] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (VII). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group, or a cyclopropyl group, and R 1a , R a , R b , R c , R d and R e is defined as in the general formula (I), and 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 -, and n is 0 or an integer of 1 to 3.

[0021] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (VIII). [ka] where X 1 is Cl, methyl, CF3, ethyl or cyclopropyl, and R 1a , R a , R b , R c , R d and R e is defined as in the general formula (I), and 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 -, and n is 0 or an integer of 1 to 3.

[0022] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (IX). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group, or a cyclopropyl group, and R 1a , R a , R b , R c , R d and R e is defined as in the general formula (I), and 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 -, and n is 0 or an integer of 1 to 3.

[0023] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (X). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group, or a cyclopropyl group, and R a , R b , R c , R d and R eis defined as in the general formula (I), and 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 -, and n is 0 or an integer of 1 to 3.

[0024] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (XI). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group, or a cyclopropyl group, and R a , R b , R c , R d and R e is defined as in the general formula (I), and 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-NRe (CR a R b ) n -, and n is 0 or an integer of 1 to 3.

[0025] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (XII). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group, or a cyclopropyl group, and R a , R b , R c , R d and R e is defined as in the general formula (I), and 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 -, and n is 0 or an integer of 1 to 3.

[0026] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (XIII). [ka] where R a , R b , R c , R d and R eis defined as in the general formula (I), and 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 -, and n is 0 or an integer of 1 to 3.

[0027] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (VIV). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group, or a cyclopropyl group, and R a , R b , R c , R d and R e is defined as in the general formula (I), and 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-NRe (CR a R b ) n -, and n is 0 or an integer of 1 to 3.

[0028] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (XV). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group, or a cyclopropyl group, and R a , R b , R c , R d and R e is defined as in the general formula (I), and 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 -, and n is 0 or an integer of 1 to 3.

[0029] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (XVI). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group, or a cyclopropyl group, and W is a chemical bond, -O(CR a Rb ) 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-, and R a , R b , Y and R e The definition is as shown in general formula (I), and n is 0 or an integer of 1 to 6.

[0030] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (XVII). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group, or a cyclopropyl group, and 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-, and R a , Rb , Y and R e is defined as shown in general formula (I), and n is 0 or an integer of 1 to 6.

[0031] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (XVIII). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group or a cyclopropyl group, Y is defined as shown in 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-, and R a , R b , Y and R e is defined as in general formula (I), n is 0 or an integer of 1 to 6, and R a , R b , Y and R e is defined as shown in general formula (I), and n is 0 or an integer of 1 to 6.

[0032] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (XIX). [ka] where X1 is Cl, a methyl group, CF3, an ethyl group or a cyclopropyl group, Y is defined as shown in 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-, and R a , R b , Y and R e is defined as shown in general formula (I), and n is 0 or an integer of 1 to 6.

[0033] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (XX). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group or a cyclopropyl group, Y is defined as shown in 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 Rb ) n -, -(CR a R b ) n NR e -, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, and R a , R b , Y and R e is defined as in general formula (I), and n is 0 or an integer of 1 to 6; R 1a CF3, [ka] is.

[0034] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (XXI). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group or a cyclopropyl group, Y is defined as shown in 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-, or -C≡C-, and n is 0 or an integer of 1 to 6; R 1a CF3, [ka] is.

[0035] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (XXII). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group or a cyclopropyl group, Y is defined as shown in 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-, or -C≡C-, and n is 0 or an integer of 1 to 6; R 1a CF, [ka] is.

[0036] In another preferred embodiment, the compound represented by general formula (I) is as represented by general formula (XXIII). [ka] where X 1 is Cl, a methyl group, CF3, an ethyl group or a cyclopropyl group, Y is defined as shown in general formula (I), W is a chemical bond, -O(CR a Rb ) 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-, or -C≡C-, and n is 0 or an integer of 1 to 3; R 1a CF3, [ka] is.

[0037] In another preferred embodiment, the compounds represented by the general formulae (I) to (XXIII) are as follows: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0038] In another preferred embodiment, the stereoisomers are cis-trans isomers.

[0039] In another preferred embodiment, the compound is racemic.

[0040] In another preferred embodiment, the stereoisomers are enantiomers.

[0041] In another preferred embodiment, one or more hydrogens in the compound may be replaced by deuterium.

[0042] In another preferred embodiment, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, triflate, benzenesulfonate, p-toluenesulfonate (toluenesulfonate), 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, and mandelate.

[0043] The compounds of the present invention represented by general formula (I) can be obtained by the following preparation methods, including the following procedures:

[0044] Route 1 [ka] Here, R is a C1-C6 alkyl group or a C1-C6 halogenated alkyl group, and Ar, X, W, Z, and Y are defined as above.

[0045] Route 2 [ka] where R is OH, (RO) or (OCMeCMeO), and Ar, R 1 , R 2 , X, W, Z, and Y are defined as above.

[0046] Route 3 [ka] where Ar, R 1 , R 2 , X, W, Z, and Y are defined as above.

[0047] Route 4 [ka] where Ar, R 1 , R 2 , X, W, Z, and Y are defined as above.

[0048] Route Five [ka] where Ar, R 1 , R 2 , X, W, Z, and Y are defined as above.

[0049] In the method, The alkali may be selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal hydrides, alkaline earth metal hydrides, alkali metal carbonate (hydrogen) salts, alkaline earth metal carbonates, bis(trimethylsilyl)amino alkali metal salts, pyridine, triethylamine, diisopropylethylamine, etc.

[0050] The acid may be selected from the group of hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, and the like.

[0051] The reducing agent may be selected from the group of lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, lithium borohydride, borane, sodium acetylborohydride, and the like.

[0052] The palladium catalyst may be selected from the group of tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, and the like.

[0053] The copper salt may be selected from the group of cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide, and the like.

[0054] The chlorinating reagent may be selected from the group of N-chlorosuccinimide, phosphine oxychloride, thionyl chloride, etc.

[0055] The brominating reagent may be selected from the group of liquid bromine, N-bromosuccinimide, phosphorus tribromide, etc.

[0056] In another aspect of the present invention, there is provided use of a compound represented by general formula (I) according to the first aspect, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, for the following purposes: (iii) Preparation of tubulin stabilizers; (iv) tubulin-mediated diseases; (iii) Preparation of medicaments for preventing and / or treating cancer and neurodegenerative diseases.

[0057] In another preferred embodiment, the cancer includes, but is not limited to, glioma, colon cancer, breast cancer, gastric cancer, lung cancer, colorectal cancer, pancreatic adenocarcinoma, ovarian cancer, prostate cancer, renal cancer, liver cancer, brain tumor, melanoma, multiple myeloma, chronic myelogenous leukemia, hematopoietic tumors, lymphoid tumors, or metastatic lesions in tissues or organs distant from the primary site of the tumor.

[0058] In another preferred embodiment, said neurodegenerative disease includes, but is not limited to, Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and traumatic brain injury.

[0059] Another aspect of the present invention provides pharmaceutical compositions comprising PD-1 antibodies, PD-L1 antibodies, CTLA-4 antibodies, and other anti-tumor chemotherapeutic and targeted agents.

[0060] It should be understood that the above-mentioned technical features of the present invention and the technical features specifically described below (for example, in the Examples) can be combined with each other within the scope of the present invention to form novel or preferred technical solutions, which will not be described here one by one due to space limitations.

[0061] Specific Embodiments As a result of extensive and thorough research, the inventors have discovered new polycyclic compounds that can be used as highly effective tubulin stabilizers for the prevention and / or treatment of tubulin-mediated diseases, and have completed the present invention based on this discovery.

[0062] definition "C1-C 10 The term "alkyl group" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, including straight-chain and branched-chain hydrocarbon groups, such as methyl (CH-), ethyl (CHCH-), n-propyl (CHCHCH-), isopropyl ((CH)CH-), n-butyl (CHCHCHCH-), isobutyl ((CH)CHCH-), s-butyl ((CH)(CHCH)CH-), tert-butyl ((CH)C-), n-pentyl (CHCHCHCHCHCH-), and neopentyl ((CH)CCH-). In the present invention, the term includes substituted and unsubstituted alkyl groups.

[0063] As used herein, the term "substituted or unsubstituted" means that the group is unsubstituted, or that H in the group can be substituted with one or more (preferably 1 to 6, more preferably 1 to 3) substituents.

[0064] As used herein, the term "substituted" or "substituted" refers to the group having one or more (preferably 1 to 6, more preferably 1 to 3) substituents selected from the group consisting of halogen, hydroxy, -NH, nitro, -CN, C-C alkyl, C-C alkyl halide, C-C alkoxy, C-C cycloalkyl, C-C alkenyl, C-C alkynyl, phenyl, benzyl, C-C alkyl S(O)-, (C-C alkyl)NS(O)-, C-C alkyl C(O)-, C-C cycloalkyl C(O)-, C-C alkyl OC(O)-, (C-C alkyl)NC(O)-, C-C alkyl C(O)NH-, and (C-C alkyl)NC(O)NH-.

[0065] As used herein, the term "alkoxy group" refers to an -O-alkyl group, where the alkyl group may be saturated or unsaturated, branched, straight chain, or cyclic. Preferably, the alkoxy group has 1 to 10 carbon atoms, i.e., C1-C 10 It is an alkoxy group, preferably having 1 to 6 carbon atoms. Representative examples include, but are not limited to, a methoxy group, an ethoxy group, and a proxi group.

[0066] As used herein, "C6-C 20 The term "aryl" refers to a monovalent aromatic carbocyclic group containing 6 to 20 (preferably 6 to 14) carbon atoms and having a single ring (e.g., phenyl) or fused rings (e.g., naphthyl or anthracenyl), although the fused ring may be non-aromatic when the point of attachment is on an aromatic carbon atom (e.g., 2-benzoxazolone, 2H-1,4-benzoxazin-3(4H)-on-7-yl). Preferred aryl groups include phenyl and naphthalene groups. The term includes substituted or unsubstituted forms, with the substituents being as defined above.

[0067] In this specification, "C2-C 10The term "alkenyl group" refers to an alkenyl group having 2 to 10 (e.g., 2 to 6 or 2 to 4) carbon atoms and at least one (e.g., 1 to 2) unsaturated olefinic bond (>C=C<). These groups include vinyl, allyl, butyl-3-alkenyl, and the like.

[0068] In this specification, "C3-C 10 The term "cycloalkyl group" refers to a cyclic alkyl group containing 3 to 10 carbon atoms and having a monocyclic or polycyclic ring (including fused, bridged, and spirocyclic alkane systems). In fused ring systems, one or more rings can be a cycloalkyl group, a heterocyclic aryl group, or a heteroaryl group, provided that the attachment point penetrates the ring of the cycloalkyl group. Suitable cycloalkyl groups include, for example, adamantane, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. The term "spirocyclic alkane" or "spirocycloalkyl group" refers to a 5- to 20-membered polycyclic group that shares one carbon atom (referred to as a spiro atom) between its monocyclic rings, may contain one or more double bonds, and is preferably 6 to 14-membered, and particularly preferably 7 to 10-membered (e.g., 7, 8, 9, or 10) members.

[0069] As used herein, the terms "halogenated" or "halogen" refer to fluorine, chlorine, bromine and iodine.

[0070] As used herein, the term "heteroaryl" or "heteroaryl group" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur within the ring. Terms indicating the number of carbon atoms include, for example, "C3-C 20A "heteroaryl group" refers to an aromatic heteroaryl group having 3 to 20 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. Other similar terms apply. Such heteroaryl groups can be monocyclic (e.g., pyridyl or furanyl) or fused-ring (e.g., indolizinyl or benzothienyl), where the fused ring can be non-aromatic and / or contain one heteroatom, so long as the point of attachment is through an atom in the aromatic heteroaryl group. In certain embodiments, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to N-oxide (NO), sulfinyl, or sulfonyl. Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, and furanyl. The term includes substituted and unsubstituted heteroaryl groups.

[0071] As used herein, the term "substituted heteroaryl group" refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, and more preferably 1 to 2, substituents, which are the same as those defined for the substituted aryl group.

[0072] As used herein, the terms "heterocycle" or "heterocyclic" or "heterocyclic alkyl group" or "heterocyclyl group" refer to saturated, partially saturated, or unsaturated (but not aromatic) groups having monocyclic or fused rings (including spirocyclic hydrocarbon groups, fused hydrocarbon groups, bridged hydrocarbon groups, monocyclic heterocyclyl groups, spirocyclic heterocyclyl groups, fused heterocyclyl groups, or bridged heterocyclyl groups) and having 1 to 10 carbon atoms and 1 to 4 (e.g., 3) heteroatoms selected from oxygen, nitrogen, and sulfur within the ring; in fused ring systems, one or more rings can be cycloalkyl, aryl, or heteroaryl groups, as long as the point of attachment penetrates a non-aromatic ring. Heterocyclic spirocyclic compounds are compounds in which a carbon atom in a carbocyclic spiro compound is replaced by a heteroatom (O, S, N, or NR eIn certain embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide the N-oxide, sulfinyl, or sulfonyl moieties.

[0073] As used herein, the terms "substituted heterocyclic" or "substituted heterocycloalkyl group" or "substituted heterocyclyl group" refer to a heterocyclyl group substituted with 1 to 5 (e.g., 1 to 3) substituents, which are the same as those defined for substituted cycloalkyl groups.

[0074] As used herein, the term "stereoisomer" refers to compounds that differ chirally at one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

[0075] As used herein, the term "tautomer" refers to alternative forms of a compound with different proton positions, such as enol-ketone and imine-enamine tautomers, or heteroaryl tautomers, where the heteroaryl group contains a ring atom attached to the -NH- portion of the ring and the -N- portion of the ring, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0076] Unless otherwise specified, the monocyclic hydrocarbon group, spirocyclic hydrocarbon group, fused hydrocarbon group, bridged hydrocarbon group, monocyclic heterocyclyl group, spirocyclic heterocyclyl group, fused heterocyclyl group, or bridged heterocyclyl group has 5 to 20 ring skeletal atoms, and when the ring skeletal atoms have heteroatoms, the heteroatoms may be 1 to 4 (e.g., 3) heteroatoms selected from nitrogen, sulfur, and oxygen.

[0077] "Prodrug" refers to a derivative of a compound of the embodiments that, when administered to a subject, is capable of directly or indirectly delivering the compound of the embodiments or its active metabolite or residue. Particularly preferred derivatives and prodrugs are those that, when administered to a subject, improve the bioavailability of the compound of the embodiments (e.g., an orally administered compound is more readily absorbed into the bloodstream) or improve delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) compared to the parent species. Prodrugs include ester forms of the compounds of the invention.

[0078] Compounds of the Invention As used herein, the term "compound of the invention" refers to a compound of general formula (I), a racemate, stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.

[0079] The present invention relates to racemic mixtures of these compounds, any enantiomerically enriched mixtures, and any separated enantiomers. The scope of the present invention is not to be understood as referring to a 50%:50% mixture of the two R and S enantiomers, as the racemic mixture. The separated enantiomers may be pure enantiomers (i.e., 100%) or mixtures enriched in a particular enantiomer (purity of ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85%, ≥80%). 100%, ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85%, ≥80%) mixtures.

[0080] When the compounds described in the present invention have stereoisomers, the present invention includes all stereoisomers of the compounds.

[0081] When the compounds described in the present invention have tautomers, the present invention includes all tautomers of the compounds.

[0082] The present invention also includes deuterated compounds resulting from the replacement of one or more hydrogen atoms of any of the above compounds with its stable isotope, deuterium.

[0083] Pharmaceutical Composition The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective amount range and a pharmaceutically acceptable carrier.

[0084] The "active ingredient" according to the present invention refers to a compound represented by general formula (I) according to the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0085] The term "safe and effective amount" refers to an amount of an active ingredient sufficient to clearly improve the condition without causing serious side effects. Generally, a pharmaceutical composition contains 1 to 2000 mg of an active ingredient / agent, preferably 10 to 200 mg of an active ingredient / agent. Preferably, the "single agent" is one tablet.

[0086] The term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human administration and must have sufficient purity and sufficiently low toxicity. The term "compatible" refers to the ability of the components of the composition to be mixed with the active ingredient of the present invention and with each other without significantly reducing the effectiveness of the active ingredient.

[0087] The compounds of preferred embodiments of the present invention can be administered as the sole active agent or in combination with one or more other agents used to treat cancer. The compounds of preferred embodiments of the present invention are also effective in combination with known therapeutic and anti-cancer agents, and combinations of currently known compounds with other anti-cancer or chemotherapeutic agents are also within the scope of preferred embodiments. Examples of such agents can be found in Cancer Principles and Practice of Oncology, VT Devita and S. Hellman (editors), 6th Edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. It will be apparent to one of skill in the art to identify effective combinations of agents based on the specific characteristics of the agents and the cancer involved. These anti-cancer agents include, but are not limited to, estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cytostatic agents, anti-proliferative agents, prenyl protein transferase inhibitors, acetylase (HDAC) inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, cell proliferation and survival signal inhibitors, apoptosis inducers and reagents that inhibit cell cycle checkpoints, CTLA4 antibodies, PD-1 antibodies, PD-L1 antibodies, etc. The compounds of preferred embodiments are also effective when used in combination with radiation therapy.

[0088] Generally, the compounds of the preferred embodiments are administered in a therapeutically effective amount in any acceptable manner, via drugs with similar effects. The actual dose of the compounds of the preferred embodiments (i.e., active ingredients) is determined by various factors, such as the severity of the disease being treated, the age and relative health of the patient, the potency of the administered compound, the route and form of administration, and other factors. The drug can be administered multiple times a day, preferably once or twice a day. All of these factors are within the consideration of the attending physician.

[0089] For purposes of the preferred embodiments, a therapeutically effective dose can be a total daily dose administered to a patient, typically in a single dose or divided doses, for example, about 0.001 to about 1,000 mg / kg body weight per day, preferably about 1.0 to about 30 mg / kg body weight per day. The dosage unit composition can include a dosing index to form the 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 oral, systemic (e.g., transdermal, intranasal, or suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) routes. The preferred mode of administration is oral, which allows convenient adjustment of the daily dosage depending on the level of bitterness. The composition can be in the form of a tablet, pill, capsule, semisolid, powder, sustained-release formulation, solution, suspension, elixir, aerosol, or any other suitable combination. Another preferred mode of administration of the compounds of the preferred embodiments is inhalation, which is an efficient method for delivering therapeutic agents directly to the respiratory tract (see, e.g., U.S. Pat. No. 5,607,915).

[0090] Suitable pharmaceutically acceptable carriers or excipients include handling agents and drug delivery modifiers and enhancers, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, sodium methylcellulose, carmellose sodium, glucose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low-melting 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 those of petroleum, animal, vegetable, or synthetic origin, such as peanut, soybean, mineral, and sesame oil. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and ethylene glycol. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), incorporated herein by reference.

[0091] As used herein, the term "pharmaceutically acceptable salts" refers to non-toxic acid or alkaline earth metal salts of the compounds of general formula (I). These salts can be prepared in situ during the final isolation and purification of the compounds of general 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, dodecyl sulfate, ethanesulfonate, glucose enanthate, glycerophosphate, hemisulfate, heptanoate, caproate, 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 salts. Furthermore, nitrogen-containing basic groups can be converted to quaternary ammonium salts with reagents such as alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl, and dipentyl sulfates; long-chain halides such as decyl, lauryl, myristyl, and stearalkyl chlorides, bromides, and iodides; and aryl halides such as benzyl and phenylethyl bromides. This results in water-soluble, oil-soluble, or dispersible products. 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 compounds of general formula I, or by reacting the carboxylic acid moiety with a suitable base (e.g., a pharmaceutically acceptable hydroxide, carbonate, or bicarbonate salt of a metal cation), or ammonia, or an organic primary, secondary, or tertiary amine, respectively. Pharmaceutically acceptable salts include, but are not limited to, basic metal and basic earth metal-based cations such as salts of sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines used to form base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0092] As used herein, the term "pharmaceutically acceptable prodrug" refers to a compound that is rapidly converted in vivo to the parent compound of the general formula above, for example, by hydrolysis in blood, and is a prodrug of a compound of a preferred embodiment. T. Higuchi and V. Stella, "Prodrugs 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 Publishers, 1987, provide a thorough discussion and are incorporated herein by reference.

[0093] The advantages of the present invention are as follows: (1) To provide a compound represented by general formula (I) having a new structure, (2) The compounds of the present invention can be used as highly efficient tubulin stabilizers; (3) They have a wide range of pharmacological activities, including anti-cancer and neurodegenerative diseases (Huntington's disease, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, multiple sclerosis, and traumatic nerve injury), and anti-inflammatory properties.

[0094] The following will describe the present invention in more detail in accordance with specific embodiments. It should be understood that it is used only to describe the present invention and is not used to limit the scope of the present invention. Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as those known to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred embodiments and materials described in this application are for illustrative purposes only.

[0095] Pre-HPLC conditions: A Waters QDA (KBD5205 model) was used as a mass detector, a Waters 2489 UV was used as a detector, and HPLC-MS analysis was performed on a Waters HPLC 2767. The column used was an XTerra (registered trademark) Prep MS C 18 The column was an OBD™ column (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. The starting conditions were 95% A for 0.5 min, followed by a linear decrease from 90% A to 40% A over 8.5 min, a hold at 40% A for 8.5–10.5 min, and a return to 95% A within 1.5 min. The total run time was 12 min. The mobile phase gradient and run time could be adjusted appropriately depending on the compound characteristics.

[0096] Intermediate 1 5,7-Dichloro-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine 1 [ka]

[0097] Step 1: Diethyl 2-(2,4,6-trifluorophenyl)malonate 2 [ka] Sodium hydroxide (11.4 g, 60% wt.) was suspended in 1,4-dioxane and diethyl malonate (45.7 g) was added dropwise at 0°C. The reaction mixture was heated 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. The reaction mixture was reacted at 100°C for 10 hours, quenched with saturated ammonium chloride, and insoluble materials were removed by suction filtration. The filtrate was extracted with ethyl acetate. 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 = 0-20%) to give a colorless oil (38.0 g). MS ESI: m / z =291.08, [M+H] + .

[0098] Step 2: 6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diol 3 [ka] Compound 2 (20.0 g) and 1H-1,2,4-triazolo-5-amine (6.08 g) were placed in a 100 mL sealed tube, and tri-n-butylamine (17.8 mL) was added at room temperature. The mixture was allowed to react at 180°C for 6 hours. The reaction mixture was then cooled to 110°C, diluted with an appropriate amount of toluene, and 14 mL of a 50% sodium hydroxide solution was added. The precipitated white solid was washed three times with toluene, suction filtered, and dried to obtain a white solid.

[0099] Step 3: 5,7-Dichloro-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine 1 [ka] 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 mixture was heated to 140°C and reacted for 8 hours, then quenched with saturated sodium bicarbonate and 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 and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-10%) to obtain the desired product (15 g of a white solid). MS ESI: m / z =319.0, [M+H] + .

[0100] Intermediate 1A 7-Chloro-5-methyl-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine 1A [ka]

[0101] Step 1: 3-Oxo-2-(2,4,6-trifluorophenyl)butyric acid methyl ester 2A 2-(2,4,6-Trifluorophenyl)acetic acid (10.0 g) was dissolved in methanol (50.0 mL), thionyl chloride (12.0 mL) was added in an ice-water bath, and the reaction was continued for another 3 hours. Ice water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and concentrated to obtain the crude product (10.47 g) as a colorless oil, which was used directly in the next step without further purification. The product (10.47 g) was dissolved in tetrahydrofuran (51.0 mL), and lithium bis(trimethylsilyl)amine (107.75 mL, 1.0 M in THF) was added at -65°C, and the reaction was continued for another 30 minutes under the same conditions. Acetyl chloride (4.1 mL) was added to the reaction mixture, and the mixture was allowed to react at room temperature for an additional 5 hours. Water was then added, and the mixture was extracted with ethyl acetate. 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 = 0-10%) to obtain the target product 2A (12.9 g of a white solid). 1 H NMR (400 MHz, CDCl3): δ 13.21 (s, 1H), 6.68 (t, J = 7.9 Hz, 2H), 3.70 (d, J = 1.2 Hz, 3H), 1.87 (s, 3H).

[0102] Step 2: 7-Chloro-5-methyl-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine 1A The product 2A (11.9 g) from the previous procedure was placed in a 100 mL sealed tube and dissolved in acetic acid (54.1 mL). 1H-1,2,4-triazolo-5-amine (4.14 g) was added and reacted at 120 °C for 24 hours. Excess acetic acid was removed by evaporation. Methyl tert-butyl ether was added and the mixture was stirred at 60 °C for 2 hours. The mixture was then slowly cooled to room temperature and suction filtered to obtain the desired product (yellow solid). The yellow solid was dissolved in phosphorus oxychloride (30 mL) in a 100 mL sealed tube and reacted at 130 °C for 20 hours. The reaction mixture was quenched by slowly adding saturated sodium bicarbonate to the mixture, extracted with dichloromethane, and 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 intermediate 1A (1.5 g) as a white solid. MS ESI: m / z =299.0, [M+H] + .

[0103] Intermediate 1B 5,7-Dichloro-6-(2,6-difluoro-4-iodophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine 1B [ka]

[0104] Step 1: Diethyl 2-(2,6-difluoro-4-nitrophenyl)malonate 2B 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 mixture was allowed to react at 65°C for 2 hours, quenched by the addition of 1N hydrochloric acid, and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, suction filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate; petroleum ether = 0-10%) to obtain the target product 2B (7.4 g, yellow oil).

[0105] Step 2: Diethyl 2-(4-amino-2,6-difluorophenyl)malonate 3B The product of step 1 (5.0 g) was dissolved in methanol (50 mL), palladium on carbon was added, and the mixture was reacted under a hydrogen gas atmosphere at room temperature for 8 hours. The mixture was then suction 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 of a white solid). 1 H NMR (400 MHz, CDCl3): δ 6.20 - 6.13 (m, 2H), 4.80 (s, 1H), 4.22 (q, J = 7.1 Hz, 4H), 1.25 (t, J = 7.1 Hz, 6H).

[0106] Step 3: Diethyl 2-(2,6-difluoro-4-iodophenyl)malonate 4B The product of step 2 (2.0 g) was dissolved in 6N aqueous hydrochloric acid (12.0 mL), and a solution of sodium nitrite (492.0 mg) in water (2.7 mL) and a solution of potassium iodide (4.92 g) in water (5.0 mL) were successively added at 0°C. The mixture was allowed to react at room temperature for 3 hours, and the reaction mixture was extracted with ethyl acetate. The organic phases were combined, 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 give the target product 4B (colorless oil, 1.4 g). 1H NMR (400 MHz, Chloroform-d): δ 7.33 - 7.29 (m, 2H), 4.89 (s, 1H), 4.25 (q, J = 7.1 Hz, 4H), 1.27 (t, J = 7.1 Hz, 6H).

[0107] Step 4: Diethyl 2-(2,6-difluoro-4-iodophenyl)malonate 1B The product 4B (2.0 g) from Step 3 and 1H-1,2,4-triazolo-5-amine (443.67 mg) were dissolved in tri-n-butylamine (1.3 mL) and reacted at 170°C for 3 hours. The reaction mixture was then diluted with an appropriate amount of toluene at 110°C, and 50% sodium hydroxide solution was added at 50°C. The mixture was cooled to room temperature and suction filtered to obtain a white solid. The white solid was dissolved in phosphorus oxychloride (10 mL) and reacted at 130°C for 6 hours. The mixture was quenched by adding saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, suction 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. MS ESI: m / z =426.8, [M+H] + .

[0108] Intermediate 4 (R)-5-chloro-N-(3-methylbutan-2-yl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 4 [ka] 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 successively at room temperature. The mixture was allowed to react at 60°C for 3 hours, saturated sodium chloride was added, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and washed three times with saturated brine. 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 = 0-20%) to obtain the desired intermediate 4 (white solid, 560.0 mg). MS ESI: m / z =370.0, [M+H] + .

[0109] Intermediate 4A (R)-5-Methyl-N-(3-methylbutan-2-yl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 4A [ka] Common intermediate 1 (159.6 mg) was dissolved in N-methylpyrrolidone (1.1 mL), and (2R)-3-methylbutan-2-amine hydrochloride (139.5 mg) and powdered sodium bicarbonate (112.7 mg) were added sequentially at room temperature. The mixture was allowed to react at 60°C for 3 hours. Saturated sodium chloride was added, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and washed three times with saturated brine. 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 = 0-29%) to give the target intermediate 4A (white solid, 182.0 mg). MS ESI: m / z =350.1, [M+H] + .

[0110] Intermediate 4B (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 [ka] Using (2R)-3-methylbutan-2-amine hydrochloride (258.1 mg) and intermediate 1B (0.5 g) as raw materials, and sodium bicarbonate (207.92 mg) as a base, the target intermediate 4B (white solid, 629.0 mg) was obtained in the same synthetic method as intermediate 4. MS ESI: m / z =475.9, [M−H] - .

[0111] Intermediate 5 (S)-5-chloro-6-(2,4,6-trifluorophenyl)-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 5 [ka] Using (S)-1,1,1-trifluoropropyl-2-amine hydrochloride (491.76 mg) and intermediate 1 (0.5 g) as raw materials and sodium bicarbonate (330.2 mg), the target intermediate 5 (white solid 266.7 mg) was obtained in the same synthetic manner as intermediate 4. MS ESI: m / z =396.0, [M+H] + .

[0112] Intermediate 5B (S)-5-chloro-6-(2,6-difluoro-4-iodophenyl)-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 5B [ka] Using (S)-1,1,1-trifluoropropyl-2-amine hydrochloride (800.96 mg) and intermediate 4B (1.09 g) as raw materials and sodium bicarbonate (451.1 mg), the target intermediate 5B (white solid 964.7 mg) was obtained in the same synthetic manner as for intermediate 4. MS ESI: m / z =501.9, [M−H] - .

[0113] Intermediate 6 (R)-5-chloro-N-(1-cyclobutylethyl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 6 [ka] Using (R)-1-cyclobutylethyl-1-amine hydrochloride (447.9 mg) and intermediate 1 (0.5 g) as raw materials and sodium bicarbonate (330.2 mg), the target intermediate 6 (white solid 590 mg) was obtained in the same synthetic manner as intermediate 4. MS ESI: m / z =382.0, [M+H] + .

[0114] Intermediate 6A (R)-5-Methyl-N-(1-cyclobutylethyl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 6A [ka] Using (R)-1-cyclobutylethyl-1-amine hydrochloride (191.25 mg) and intermediate 1A (0.2 g) as raw materials and sodium bicarbonate (140.91 mg), the target intermediate 6A (white solid 229 mg) was obtained in the same synthetic manner as intermediate 4. MS ESI: m / z =362.1, [M+H] + .

[0115] Intermediate 6B (R)-5-chloro-N-(1-cyclobutylethyl)-6-(2,6-difluoro-4-iodophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 6B [ka] Using (R)-1-cyclobutylethyl-1-amine hydrochloride (199.4 mg) and intermediate 4B (0.3 g) as raw materials and sodium bicarbonate (123.5 mg), the target intermediate 6B (white solid 253.6 mg) was obtained in the same synthetic manner as intermediate 4. MS ESI: m / z =488.0, [M−H] - .

[0116] Intermediate 7 5-chloro-N-(2,2,2-trifluoroethyl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 7 [ka] Using 2,2,2-trifluoroethan-1-amine hydrochloride (446.8 mg) and intermediate 1 (0.5 g) as raw materials and sodium bicarbonate (329.7 mg), the target intermediate 7 (white solid 517 mg) was obtained in the same synthetic method as intermediate 4. MS ESI: m / z =382.0, [M+H] + .

[0117] Intermediate 7A 5-Methyl-N-(2,2,2-trifluoroethyl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 7A [ka] Using 2,2,2-trifluoroethan-1-amine hydrochloride (286.5 mg) and intermediate 1A (0.3 g) as raw materials and sodium bicarbonate (211.3 mg), the target intermediate 7A (white solid 517 mg) was obtained in the same synthetic manner as intermediate 4. MS ESI: m / z =382.0, [M+H] + .

[0118] Intermediate 7B 5-chloro-6-(2,6-difluoro-4-iodophenyl)-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 7B [ka] Using 2,2,2-trifluoroethan-1-amine hydrochloride (199.2 mg) and intermediate 1B (0.3 g) as raw materials and sodium bicarbonate (123.5 mg), the target intermediate 7B (white solid 297.4 mg) was obtained in the same synthetic manner as intermediate 4. MS ESI: m / z =487.9, [M−H] - .

[0119] Intermediate 14 (±)tert-Butyl 2-(hydroxy)-spiro[3.5]nonane-7-methylcarbamate 14 [ka]

[0120] Step 1: Benzylmethyl(4-methylenecyclohexylidene)carbamate 9 Methyltriphenylphosphonium bromide (58.9 g) was dissolved in tetrahydrofuran (200 mL) and cooled to -10 °C. n-Butyllithium (103.1 mL, 1.6 M in hexane) was added and stirred for 30 minutes. tert-Butyl(4-oxocyclohexyl)carbamate (25.0 g) dissolved in tetrahydrofuran (100 mL) was added at -78 °C. The mixture was allowed to react for 10 minutes, then heated 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, suction filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-10%) to give the desired intermediate 9 (22.0 g) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.64 (t, J = 1.8 Hz, 2H), 2.70 (s, 3H), 2.35 (dp, J = 13.4, 2.1 Hz, 2H), 2.14 (td, J = 12.4, 6.8 Hz, 2H), 1.76 (ddt, J = 12.7, 4.9, 2.3 Hz, 2H), 1.47 (s, 12H).

[0121] Step 2: Benzyl methyl (4-methylenecyclohexyl) carbamate 11 Trifluoroacetic acid (5.2 mL) was added to intermediate 9 (5.0 g) at room temperature and reacted for 2 hours. The reaction mixture was concentrated to give the crude trifluoroacetate salt 10 (4.0 g) as a dark oil. The crude 10 (4.0 g) was dissolved in acetonitrile (41.0 mL) and water (41.0 mL) at room temperature. Benzyl chloroformate (4.6 g) and sodium bicarbonate powder (4.45 g) were added sequentially. The mixture was stirred at room temperature for 10 hours, and the acetonitrile was removed by distillation. The residual solution was extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-5%) to give the desired intermediate 11 (2.6 g as a colorless oil). MS ESI: m / z =260.1, [M+H] + .

[0122] Step 3: Benzylmethyl (2-oxospiro[3.5]nonan-7-yl)carbamate 12 Intermediate 11 (2.6 g) was dissolved in ether, zinc-copper couple (5.2 g) was added, and trichloroacetyl chloride (3.36 mL) dissolved in ether (104 mL) was slowly added dropwise. The reaction mixture was allowed to react for 16 hours, then quenched with saturated sodium bicarbonate solution, filtered under suction, and the filtrate was washed three times with ethyl acetate. The collected filtrate was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered under suction, and concentrated to give the 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 reaction mixture was allowed to react at 80 °C for 5 hours. Water was added, filtered under suction, and the filtrate was extracted with dichloromethane. The organic phases were combined, washed three times with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered under suction, and concentrated to give the crude product. The product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-22%) to give the target intermediate 12 (3.0 g, a white solid). MS ESI: m / z =302.1, [M+H] + .

[0123] Step 4: tert-Butyl (2-hydroxyspiro[3.5]nonan-7-yl)(methyl)carbamate 14 Intermediate 12 (3.0 g) was dissolved in methanol (20.0 mL), sodium borohydride powder (565.2 mg) was added, and after 5 hours, saturated brine was added and extracted with dichloromethane. The organic phase was successively dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to obtain a viscous oil, which was used directly in the next step without purification. The oil was dissolved in methanol (76 mL), wet palladium carbon (760.0 mg, 10% wt.) was added, and the mixture was reacted under a hydrogen gas atmosphere for 5 hours, suction filtered, and concentrated to obtain the crude product (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 successively in an ice-water bath. The reaction was allowed to proceed at room temperature for 18 hours. Water was added to the reaction mixture to quench the reaction, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, suction 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). 1 H NMR (400 MHz, CDCl3): δ 4.21 (t, J = 7.2 Hz, 1H), 2.65 (s, 3H), 2.47 (d, J = 37.5 Hz, 1H), 2.30 - 2.21 (m, 1H), 2.08 (dd, J = 12.0, 6.0 Hz, 1H), 1.63 - 1.36 (m, 19H).

[0124] Intermediate 15 (±)tert-Butyl (6-hydroxyspiro[3.3]hept-2-yl)(methyl)carbamate 15 [ka]

[0125] Step 1: 6-(methylamino)spiro[3.3]hept-2-ol tert-Butyl (6-hydroxyspiro[3.3]hept-2-yl)carbamate (1.0 g) was dissolved in tetrahydrofuran (20.0 mL), and lithium aluminum hydride (22.0 mL, 1.0 M in THF) was added dropwise at 0°C. The reaction was allowed to proceed at 50°C for 3 hours, quenched by adding methanol dropwise, and dried by centrifugation to obtain a viscous semi-solid crude product, which was used directly in the next step without further treatment. MS ESI: m / z =142.2, [M+H] + .

[0126] Step 2: tert-Butyl (6-hydroxyspiro[3.3]hept-2-yl)(methyl)carbamate 15 The product of the previous step was dissolved in dichloromethane (20.0 mL), and di-tert-butyl dicarbonate (1.5 g) and triethylamine (1.2 mL) were added at 0°C. The reaction was allowed to proceed at room temperature for 18 hours, followed by quenching with the addition of water. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 0-10%) to obtain the target fragment 15 (0.75 g). MS ESI: m / z =186.2, [M+H] + .

[0127] Intermediate 17 tert-Butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 17 [ka] tert-Butyl cis-5-oxohexahydrocyclopentadienyl[c]pyrrole-2(1H)-carboxylate 16 (1.0 g) was dissolved in methanol (10 mL), and sodium borohydride (251.83 mg) was added at 0°C. The mixture was allowed to react for 2 hours, saturated brine was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated to give a viscous substance. This was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-20%) to give the target compound 17 (820.0 mg). 1 H NMR (400 MHz, CDCl3): δ 4.30 (t, J = 6.4 Hz, 1H), 3.50 (dd, J = 11.2, 7.7 Hz, 2H), 3.34 (dd, J = 11.3, 3.4 Hz, 2H), 2.60 (q, J = 4.8, 3.4 Hz, 2H), 2.21 - 2.12 (m, 2H), 2.03 (s, 1H), 1.45 (s, 11H).

[0128] Intermediate 19 tert-Butyl (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 19 [ka]

[0129] Step 1: tert-Butyl (3aR,5s,6aS)-5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 18 Compound 17 (4.3 g) was dissolved in ether (126 mL), triphenylphosphine (4.96 g) and p-nitrobenzoic acid (2.37 g) were added, and diisopropyl azodicarboxylate (1.91 g) was added at −78°C. The mixture was reacted at room temperature for 16 hours, quenched with methanol, and dried by centrifugation. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-10%) to give compound 18 (1.5 g). 1 H NMR (400 MHz, CDCl3): δ 8.30 - 8.26 (m, 2H), 8.19 - 8.15 (m, 2H), 5.57 (dt, J = 5.6, 2.9 Hz, 1H), 3.59 - 3.50 (m, 2H), 3.24 (s, 2H), 2.89 (dd, J = 9.2, 5.5 Hz, 2H), 2.21 - 2.14 (m, 2H), 1.93 (dt, J = 14.4, 5.7 Hz, 2H), 1.47 (s, 9H).

[0130] Step 2 tert-Butyl (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 19 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 allowed to react at room temperature for 8 hours. The methanol was dried by centrifugation, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-50%) to obtain the desired intermediate 19 (791.0 mg). MS ESI: m / z =172.1, [M-57+H] + .

[0131] Intermediate 19A tert-Butyl (1R,5S,6s)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate 19A [ka] tert-Butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (5.66 g) was dissolved in methanol (50 mL), potassium carbonate (5.54 g), and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (6.16 g) were added sequentially. The mixture was allowed to react at room temperature for 8 hours, quenched by adding water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated, and purified by column chromatography to obtain the target intermediate 19A (4.6 g). 1 H NMR (400 MHz, CDCl3): δ 3.65 (d, J = 11.3 Hz, 1H), 3.56 (d, J = 11.1 Hz, 1H), 3.33 (tt, J = 7.9, 3.4 Hz, 2H), 1.87 (d, J = 2.2 Hz, 1H), 1.82 (t, J = 2.9 Hz, 2H), 1.42 (s, 9H), 1.10 (d, J = 2.7 Hz, 1H).

[0132] Intermediate 19B tert-Butyl (1R,5S,6s)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate 19B [ka] Cuprous cyanide (211.36 mg) was suspended in tetrahydrofuran (6.32 mL) and n-butyllithium (2.0 mL, 2.5 M in hexane) was added at -78 °C. The mixture was stirred at that temperature for 15 min, and then tri-n-butyltin hydride (1.35 mL) was added. After stirring at that temperature for 10 min, a solution of 19A (0.5 g) in tetrahydrofuran (2.1 mL) was added and the mixture was further reacted at that temperature for 10 min. The mixture was quenched with an ammonia-ammonium chloride (pH = 12) buffer solution, filtered under suction, and the filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered under suction, and concentrated to give crude product 19B (350.0 mg), which was used directly.

[0133] Example 1 (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 [ka]

[0134] 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)-2-azaspiro[3.3]heptane-2-carboxylate 22 Sodium hydroxide (43.34 mg, 60% wt. in mineral oil) was suspended in dimethyl sulfoxide (0.86 mL) and tetrahydrofuran (0.43 mL), tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (231.12 mg) was added at room temperature, and the mixture was 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, and the reaction was continued at 60°C for a further 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, suction filtered, and concentrated to obtain Intermediate 22 (149.0 mg).

[0135] 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 Intermediate 22 was dissolved in dichloromethane (2.77 mL), trifluoroacetic acid (0.89 mL) was added at 0°C, and the mixture was reacted at room temperature for 2 hours. The mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting crude product was purified by pre-HPLC (eluent: acetonitrile and water containing 1‰ formic acid) to give target compound 23 (80.0 mg of white powder). MS ESI: m / z =463.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 8.40 (s, 1H), 6.89 (dd, J = 9.7, 3.4 Hz, 2H), 4.71 (d, J = 6.8 Hz, 1H), 3.96 (s, 2H), 3.89 (s, 2H), 2.83 (dd, J = 12.8, 6.7 Hz, 2H), 2.26 (p, J = 5.5 Hz, 2H), 1.81 - 1.71 (m, 1H), 1.04 (d, J = 6.5 Hz, 3H), 0.69 (d, J = 6.7 Hz, 6H).

[0136] Example 2 (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 [ka] Compound 23 (16.2 mg) was dissolved in 1,2-dichloroethane (2.0 mL), and sodium triacetoxyborohydride (22.25 mg) and aqueous formaldehyde solution (6.0 μL, 37% by weight) were added successively at 0°C. After the reaction was allowed to proceed for 5 minutes, 1.0 M aqueous sodium hydroxide solution (0.5 mL) was added to the reaction mixture, which was then extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting crude product was purified by pre-HPLC (eluent: acetonitrile and water containing 1‰ formic acid) to give the target compound 24 (13.0 mg as a white powder). MS ESI: m / z =477.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 7.93 (s, 1H), 6.87 (dd, J = 10.4, 4.3 Hz, 2H), 4.72 (q, J = 7.0 Hz, 1H), 3.22 (s, 1H), 3.15 (s, 1H), 2.70 (d, J = 10.6 Hz, 2H), 2.18 (d, J = 12.9 Hz, 7H), 1.76 (q, J = 7.1 Hz, 1H), 1.04 (d, J = 6.4 Hz, 4H), 0.69 (d, J = 6.5 Hz, 6H).

[0137] Example 3 (S)-6-(4-((2-azaspiro[3.3]hept-6-yl)oxy)-2,6-difluorophenyl-5-chloro-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 26 [ka]

[0138] 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)-2-azaspiro[3.3]heptane-2-carboxylate 25 Intermediate 5 (100.0 mg) and tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (216.0 mg) were used as raw materials, and sodium hydroxide (40.5 mg, 60% wt. in mineral oil) was used as a base under the same conditions as in Procedure 1 of Example 1 to give Intermediate 25 (142.7 mg).

[0139] Step 2: (S)-6-(4-((2-azaspiro[3.3]hept-6-yl)oxy)-2,6-difluorophenyl-5-chloro-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 26

[0140] Compound 26 (white powder, 61.0 mg) was obtained from Intermediate 25 (142.7 mg) under the same conditions as in Step 2 of Example 1. MS ESI: m / z =489.0, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 8.24 (d, J = 4.4 Hz, 1H), 6.73 (d, J = 10.5 Hz, 2H), 5.81 (d, J = 12.5 Hz, 1H), 4.68 (s, 1H), 4.02 (s, 2H), 3.96 (s, 2H), 2.84 (dd, J = 12.5, 6.5 Hz, 2H), 2.30 (dd, J = 12.0, 7.0 Hz, 2H), 1.30 (d, J = 6.5 Hz, 3H).

[0141] Example 4 (S)-6-(4-((2-methyl-2-azaspiro[3.3]hept-6-yl)oxy)-2,6-difluorophenyl-5-chloro-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 27 [ka] Compound 26 (34.2 mg) was used as a raw material, and sodium triacetoxyborohydride (44.5 mg) and an aqueous formaldehyde solution (8.08 μL, 37% by weight) were used as reagents to obtain the target compound 27 (30.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =503.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.33 (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 = 9.9 Hz, 2H), 1.29 (d, J = 6.6 Hz, 3H).

[0142] Example 5 (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 [ka]

[0143] Step 1: tert-Butyl (R)-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 Intermediate 4 (100.0 mg) and tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (261.6 mg) were used as raw materials, and sodium hydroxide (43.36 mg, 60% wt. in mineral oil) was used as a base, under the same conditions as in Procedure 1 of Example 1, to obtain Intermediate 29 (white powder, 159.0 mg).

[0144] 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 Compound 30 (white powder, 90.0 mg) was obtained under the same conditions as in Step 2 of Example 1 using Intermediate 29 (159.0 mg) as a starting material. MS ESI: m / z =491.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 8.40 (s, 1H), 6.91 - 6.85 (m, 2H), 4.87 (t, J = 6.8 Hz, 1H), 2.97 (t, J = 5.7 Hz, 2H), 2.88 (d, J = 6.0 Hz, 2H), 2.54 (d, J = 7.6 Hz, 3H), 1.86 (dq, J = 10.2, 3.4 Hz, 2H), 1.80 - 1.66 (m, 5H), 1.05 (d, J = 6.4 Hz, 3H), 0.69 (d, J = 6.5Hz, 6H).

[0145] Example 6 (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 [ka] Compound 30 (66.0 mg) was used as a raw material, and sodium triacetoxyborohydride (35.6 mg) and an aqueous formaldehyde solution (22.92 μL, 37% by weight) were used as reagents to obtain the target compound 31 (51.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =505.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 7.93 (s, 1H), 6.90 - 6.85 (m, 2H), 4.86 (t, J = 6.8 Hz, 1H), 2.42 (d, J = 9.5 Hz, 2H), 2.27 (d, J = 31.2 Hz, 4H), 2.15 (s, 3H), 1.78 (dq, J = 13.3, 6.8, 6.0 Hz, 4H), 1.62 - 1.56 (m, 4H), 1.04 (d, J = 6.5 Hz, 3H), 0.69 (d, J = 6.6 Hz, 6H).

[0146] Example 7 (S)-6-(4-((7-Azaspiro[3.5]nonan-2-yl)oxy)-2,6-difluorophenyl)-5-chloro-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 33 [ka]

[0147] Step 1: tert-Butyl (S)-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 Intermediate 32 (142.7 mg) was obtained under the same conditions as in Procedure 1 of Example 1 using Intermediate 5 (100.0 mg) and tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (244.3 mg) as raw materials and sodium hydroxide (40.5 mg, 60% wt. in mineral oil) as a base.

[0148] Step 2: (S)-6-(4-((7-azaspiro[3.5]nonan-2-yl)oxy)-2,6-difluorophenyl)-5-chloro-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 33 Compound 33 (white powder, 35.0 mg) was obtained from Intermediate 32 (139.0 mg) under the same conditions as in Step 2 of Example 1. MS ESI: m / z =517.0, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.26 (d, J = 27.8 Hz, 2H), 6.72 - 6.64 (m, 2H), 5.83 - 5.72 (m, 1H), 4.82 (t, J = 6.8 Hz, 1H), 3.02 (t, J = 5.3 Hz, 2H), 2.94 (t, J = 5.6 Hz, 2H), 2.54 (t, J = 4.4 Hz, 2H), 1.89 (dd, J = 12.1, 6.4 Hz, 2H), 1.74 (dt, J = 17.5, 5.5 Hz, 4H), 1.25 (d, J = 6.7 Hz, 3H).

[0149] Example 8 (S)-6-(4-((7-methyl-7-azaspiro[3.5]nonan-2-yl)oxy)-2,6-difluorophenyl)-5-chloro-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 34 [ka] Compound 33 (19.6 mg) was used as a raw material, and sodium triacetoxyborohydride (24.2 mg) and an aqueous formaldehyde solution (5.5 μL, 37% by weight) were used as reagents to obtain the target compound 34 (13.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =531.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.32 (d, J = 97.9 Hz, 2H), 6.76 (s, 2H), 5.88 - 5.77 (m, 1H), 4.83 (t, J = 7.1 Hz, 1H), 2.45 (s, 4H), 2.32 (s, 3H), 1.87 - 1.78 (m, 3H), 1.65 (d, J = 17.1 Hz, 6H), 1.33 (s, 3H).

[0150] Example 9 (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 [ka]

[0151] 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)spiro[3.3]hept-2-yl)(methyl)carbamate Intermediate 4 (110.0 mg) and tert-butyl (6-hydroxyspiro[3.3]hept-2-yl)(methyl)carbamate 15 (287.5 mg) were used as raw materials, and sodium hydroxide (47.7 mg, 60% wt. in mineral oil, 4.0 eq.) was used as a base under the same conditions as in Step 1 of Example 1 to give Intermediate 35 (170.0 mg).

[0152] 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 Compound 36 (white powder, 93.0 mg) was obtained under the same conditions as in Step 2 of Example 1 using Intermediate 35 (170.0 mg) as a starting material. MS ESI: m / z =491.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 8.38 (s, 1H), 6.89 - 6.85 (m, 2H), 4.76 (t, J = 6.9 Hz, 1H), 3.21 (t, J = 7.7 Hz, 1H), 2.70 - 2.64 (m, 1H), 2.33 (q, J = 6.3 Hz, 1H), 2.24 (s, 5H), 2.11 - 2.03 (m, 3H), 1.95 (td, J = 8.3, 7.9, 4.3 Hz, 2H), 1.76 (q, J = 6.9 Hz, 1H), 1.04 (d, J = 6.5 Hz, 3H), 0.69 (d, J = 6.6 Hz, 6H).

[0153] Example 10 (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 [ka] Compound 36 (69.9 mg) was used as a starting material, and sodium triacetoxyborohydride (90.9 mg) and an aqueous formaldehyde solution (26.5 μL, 37% by weight) were used as reagents to obtain the target compound 37 (59.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =505.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (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 = 11.9 Hz, 1H), 2.19 (dd, J = 11.0, 5.7 Hz, 1H), 2.01 (s, 10H), 1.79 (dt, J = 30.5, 8.1 Hz, 4H), 1.04 (d, J = 6.4 Hz, 3H), 0.69 (d, J = 6.4 Hz, 6H).

[0154] Example 11 (S)-5-Chloro-6-(2,6-difluoro-4-((6-(methylamino)spiro[3.3]hept-2-yl)oxy)phenyl)-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 39 [ka]

[0155] 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 Intermediate 5 (100.0 mg) and tert-butyl (6-hydroxyspiro[3.3]hept-2-yl)(methyl)carbamate 15 (244.06 mg) were used as raw materials, and sodium hydroxide (40.48 mg, 60% wt. in mineral oil, 4.0 eq.) was used as a base under the same conditions as in Step 1 of Example 1 to give Intermediate 38 (134.1 mg).

[0156] Step 2: (S)-5-chloro-6-(2,6-difluoro-4-((6-(methylamino)spiro[3.3]hept-2-yl)oxy)phenyl)-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 39 Compound 39 (51.0 mg) was obtained under the same conditions as in Step 2 of Example 1 using Intermediate 38 (134.1 mg) as a starting material. MS ESI: m / z =517.0, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J = 7.0 Hz, 2H), 6.63 (dd, J = 10.0, 3.4 Hz, 2H), 5.77 - 5.68 (m, 1H), 4.64 (t, J = 6.9 Hz, 1H), 3.41 (t, J = 7.9 Hz, 1H), 2.63 (dt, J = 11.1, 5.5 Hz, 1H), 2.52 - 2.46 (m, 1H), 2.32 (s, 4H), 2.19 (ddd, J = 12.1, 7.3, 4.6 Hz, 1H), 2.07 (dq, J = 11.8, 6.1, 5.5 Hz, 4H), 1.21 (d, J = 6.7 Hz, 3H).

[0157] Example 12 (S)-5-chloro-6-(4-((6-(dimethylamino)spiro[3.3]hept-2-yl)oxy)-2,6-difluorophenyl)-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 40 [ka] Compound 39 (23.5 mg) was used as a raw material, and sodium triacetoxyborohydride (28.93 mg) and an aqueous formaldehyde solution (5.5 μL, 37% by weight) were used as reagents to obtain the target compound 40 (22.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =531.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1H), 6.78 (d, J = 10.6 Hz, 2H), 5.84 (q, J = 7.5, 7.0 Hz, 1H), 4.73 (t, J = 6.9 Hz, 1H), 2.70 (dt, J = 29.5, 6.9 Hz, 2H), 2.24 (p, J = 5.7 Hz, 1H), 2.16 - 2.03 (m, 11H), 1.91 (t, J = 9.7 Hz, 2H), 1.36 (d, J = 6.8 Hz, 3H).

[0158] Example 13 (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 [ka]

[0159] 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 Intermediate 41 (white powder, 85.6 mg) was obtained under the same conditions as in Procedure 1 of Example 1 using Intermediate 6 (60.0 mg) and tert-butyl (6-hydroxyspiro[3.3]hept-2-yl)(methyl)carbamate 15 (151.8 mg) as raw materials and sodium hydroxide (25.12 mg, 60% wt. in mineral oil) as a base.

[0160] 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 Compound 42 (white powder, 21.0 mg) was obtained from Intermediate 41 (85.6 mg) under the same conditions as in Step 2 of Example 1. MS ESI: m / z =503.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 1H), 8.37 (s, 1H), 6.90 (dd, J = 14.9, 11.7 Hz, 2H), 4.77 (t, J = 6.8 Hz, 1H), 3.20 (t, J = 7.7 Hz, 1H), 2.68 (p, J = 6.2, 5.5 Hz, 1H), 2.55 (d, J = 6.9 Hz, 1H), 2.46 (s, 1H), 2.34 (p, J = 6.2, 5.7 Hz, 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, 4.9 Hz, 1H), 1.43 (t, J = 9.2 Hz, 1H), 1.34 - 1.20 (m, 2H), 0.95 (d, J = 6.3Hz, 3H).

[0161] Example 14 ((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 [ka] Compound 42 (9.6 mg) was used as a starting material, and sodium triacetoxyborohydride (12.65 mg) and an aqueous formaldehyde solution (3.0 μL, 37% by weight) were used as reagents to obtain the target compound 40 (8.1 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =517.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 1H), 7.89 (s, 1H), 6.89 (t, J = 13.2 Hz, 2H), 4.77 (t, J = 6.9 Hz, 1H), 2.71 - 2.61 (m, 1H), 2.24 - 1.38 (m, 19H), 1.25 (d, J = 14.2 Hz, 2H), 0.95 (d, J = 6.3 Hz, 3H).

[0162] Example 15 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 [ka]

[0163] 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 Intermediate 7 (100.0 mg) and tert-butyl (6-hydroxyspiro[3.3]hept-2-yl)(methyl)carbamate 15 (253.2 mg) were used as raw materials, and sodium hydroxide (42.0 mg, 60% wt. in mineral oil) was used as a base, and the same conditions as in Step 1 of Example 1 were used to obtain Intermediate 44 (108.0 mg).

[0164] 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 Compound 42 (white powder, 30.0 mg) was obtained from Intermediate 44 (86.9 mg) under the same conditions as in Step 2 of Example 1. MS ESI: m / z =503.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.37 (s, 1H), 8.29 (s, 1H), 6.75 (d, J = 9.4 Hz, 2H), 4.74 - 4.67 (m, 3H), 3.43 (t, J = 7.8 Hz, 1H), 2.69 (dt, J = 11.4, 5.3 Hz, 1H), 2.59 - 2.54 (m, 1H), 2.36 (s, 4H), 2.29 - 2.20 (m, 1H), 2.11 (dt, J = 12.1, 6.3 Hz, 4H).

[0165] Example 16 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 [ka] Compound 45 (18.6 mg) was used as a starting material, and sodium triacetoxyborohydride (23.55 mg) and an aqueous formaldehyde solution (4.3 μL, 37% by weight) were used as reagents to obtain the target compound 46 (17.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =517.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.55 (s, 1H), 6.82 (d, J = 10.3 Hz, 2H), 4.73 (d, J = 8.7 Hz, 3H), 2.66 (t, J = 7.6 Hz, 2H), 2.27 - 2.19 (m, 1H), 2.08 (s, 10H), 1.89 (t, J = 9.7 Hz, 2H).

[0166] Example 17 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 [ka]

[0167] Step 1: tert-Butyl (R)-(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 Intermediate 47 (96.7 mg) was obtained under the same conditions as in Step 1 of Example 1 using Intermediate 4 (100.0 mg) and tert-butyl (2-hydroxyspiro[3.5]nonan-7-yl)(methyl)carbamate 14 (291.8 mg) as raw materials and sodium hydroxide (43.36 mg, 60% wt. in mineral oil) as a base.

[0168] Step 2: (R)-5-chloro-6-(2,6-difluoro-4-((7-(methylamino)spiro[3.5]nonan-2-yl)oxy)phenyl-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 48 Compound 48 (white powder, 35.0 mg) was obtained from Intermediate 47 (96.7 mg) under the same conditions as in Step 2 of Example 1. MS ESI: m / z =519.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 8.40 (s, 1H), 6.88 (dd, J = 10.0, 4.5 Hz, 2H), 4.89 - 4.80 (m, 1H), 2.64 (d, J = 22.3 Hz, 2H), 2.36 (d, J = 31.2 Hz, 3H), 1.90 - 1.62 (m, 8H), 1.44 - 1.20 (m, 5H), 1.05 (d, J = 6.4 Hz, 3H), 0.69 (d, J = 6.6 Hz, 6H).

[0169] Example 18 (R)-5-chloro-6-(2,6-difluoro-4-((7-(dimethylamino)spiro[3.5]nonan-2-yl)oxy)phenyl-N-(3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 49 [ka] Compound 48 (11.9 mg) was used as a starting material, and sodium triacetoxyborohydride (14.62 mg) and an aqueous formaldehyde solution (3.3 μL, 37% by weight) were used as reagents to obtain the target compound 49 (9.1 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =533.3, [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 7.93 (s, 1H), 6.87 (d, J = 10.3 Hz, 2H), 4.84 (t, J = 6.9 Hz, 1H), 2.31 (d, J = 10.6 Hz, 1H), 2.18 (s, 7H), 1.83 - 1.59 (m, 8H), 1.28 (dt, J = 42.8, 15.7 Hz, 5H), 1.05 (d, J = 6.5 Hz, 3H), 0.69 (d, J = 6.6 Hz, 6H).

[0170] Example 19 (S)-5-chloro-6-(2,6-difluoro-4-((7-(methylamino)spiro[3.5]nonan-2-yl)oxy)phenyl)-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 51 [ka]

[0171] Step 1: tert-Butyl (S)-(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 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 hydroxide (40.48 mg, 60% wt. in mineral oil) was used as a base under the same conditions as in Procedure 1 of Example 1 to obtain Intermediate 50 (white powder, 60.2 mg).

[0172] Step 2: (S)-5-chloro-6-(2,6-difluoro-4-((7-(methylamino)spiro[3.5]nonan-2-yl)oxy)phenyl)-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 51 Compound 51 (white powder, 40.0 mg) was obtained under the same conditions as in Step 2 of Example 1 using Intermediate 50 (60.2 mg) as a starting material. MS ESI: m / z =545.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 8.15 (s, 1H), 6.65 (d, J = 10.5 Hz, 2H), 5.76 (p, J = 7.8 Hz, 1H), 4.78 (p, J = 6.5 Hz, 1H), 2.83 (s, 1H), 2.31 (d, J = 9.8 Hz, 1H), 1.93 - 1.67 (m, 8H), 1.30 (dd, J = 54.8, 7.9 Hz, 9H).

[0173] Example 20 (S)-5-chloro-6-(2,6-difluoro-4-((7-(dimethylamino)spiro[3.5]nonan-2-yl)oxy)phenyl)-N-(1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 52 [ka] Compound 51 (31.4 mg) was used as a raw material, and sodium triacetoxyborohydride (36.68 mg) and an aqueous formaldehyde solution (6.67 μL, 37% by weight) were used as reagents to obtain the target compound 52 (22.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =559.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.29 (d, J = 41.2 Hz, 2H), 6.72 (d, J = 10.6 Hz, 2H), 5.80 (q, J = 7.8 Hz, 1H), 4.80 (p, J = 6.8 Hz, 1H), 2.41 (s, 6H), 2.32 (d, J = 7.2 Hz, 1H), 1.87 - 1.82 (m, 2H), 1.75 - 1.69 (m, 4H), 1.39 - 1.29 (m, 6H).

[0174] Example 21 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 [ka]

[0175] Step 1: tert-Butyl (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-carboxylate 54 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 raw materials, and sodium hydroxide (43.35 mg, 60% wt. in mineral oil) was used as a base under the same conditions as in Procedure 1 of Example 1 to give Intermediate 54 (138.7 mg).

[0176] 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 Compound 55 (white powder, 56.0 mg) was obtained under the same conditions as in Step 2 of Example 1 using Intermediate 54 (138.7 mg) as a starting material. MS ESI: m / z =463.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 8.28 (s, 1H), 6.97 (dd, J = 10.0, 3.4 Hz, 2H), 4.00 (d, J = 7.2 Hz, 2H), 3.13 (d, J = 11.4 Hz, 2H), 3.02 (d, J = 11.2 Hz, 2H), 2.54 (s, 1H), 1.82 - 1.71 (m, 1H), 1.66 (s, 2H), 1.34 (dt, J = 7.5, 3.6 Hz, 1H), 1.06 (d, J = 6.5 Hz, 3H), 0.71 (d, J = 6.6 Hz, 6H).

[0177] Example 22 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)methoxy)phenyl)-N-((R)-3-methylbutyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 56 [ka] Compound 55 (33.3 mg) was used as a starting material, and sodium triacetoxyborohydride (45.78 mg) and an aqueous formaldehyde solution (10.2 μL, 37% by weight) were used as reagents to obtain the target compound 56 (20.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =477.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 7.88 (s, 1H), 6.96 (td, J = 7.6, 2.9 Hz, 2H), 3.93 (d, J = 7.3 Hz, 2H), 2.95 (d, J = 8.9 Hz, 2H), 2.27 (d, J = 23.5 Hz, 5H), 1.77 (q, J = 6.9 Hz, 1H), 1.56 (dq, J = 7.3, 3.4 Hz, 1H), 1.48 (d, J = 3.2 Hz, 2H), 1.05 (d, J = 6.5 Hz, 3H), 0.70 (d, J = 6.6 Hz, 6H).

[0178] Example 23 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-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 [ka]

[0179] Step 1: tert-Butyl (1R,5S,6r)-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 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 raw materials, and sodium hydroxide (41.2 mg, 60% wt. in mineral oil) was used as a base under the same conditions as in Procedure 1 of Example 1 to give Intermediate 54A (118.7 mg).

[0180] Step 2: 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-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 Compound 55A (white powder, 40.0 mg) was obtained under the same conditions as in Step 2 of Example 1 using Intermediate 54A (118.7 mg) as a starting material. MS ESI: m / z =443.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 7.21 (d, J = 10.2 Hz, 1H), 7.00 - 6.95 (m, 2H), 3.99 (d, J = 7.1 Hz, 2H), 3.12 (d, J = 11.3 Hz, 2H), 3.01 (d, J = 11.2 Hz, 2H), 2.13 (s, 3H), 1.65 (t, J = 2.7 Hz, 4H), 1.32 (tt, J = 6.9, 3.2 Hz, 1H), 1.02 (d, J = 6.5 Hz, 3H), 0.70 (d, J = 6.5 Hz, 6H).

[0181] Example 24 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 58 [ka]

[0182] Step 1: tert-Butyl (1R,5S,6r)-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-carboxylate 57 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 hydroxide (40.5 mg, 60% wt. in mineral oil) was used as a base under the same conditions as in Procedure 1 of Example 1 to give Intermediate 57 (140.0 mg).

[0183] 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-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 58 Compound 58 (white powder, 39.0 mg) was obtained under the same conditions as in Step 2 of Example 1 using Intermediate 57 (140.0 mg) as a starting material. MS ESI: m / z =489.0, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.43 (s, 1H), 8.21 (s, 1H), 6.85 (dd, J = 9.9, 4.1 Hz, 2H), 5.91 - 5.80 (m, 1H), 3.97 (d, J = 7.0 Hz, 2H), 3.26 (d, J = 11.5 Hz, 2H), 3.18 (d, J = 11.3 Hz, 2H), 1.76 (t, J = 2.9 Hz, 2H), 1.36 (dd, J = 19.4, 5.2 Hz, 4H).

[0184] Example 25 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)methoxy)phenyl)-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 59 [ka] Compound 58 (28.7 mg) was used as a starting material, and sodium triacetoxyborohydride (37.38 mg) and an aqueous formaldehyde solution (8.3 μL, 37% by weight) were used as reagents to obtain the target compound 59 (15.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =503.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 6.90 (d, J = 10.2 Hz, 2H), 5.96 - 5.84 (m, 1H), 3.91 (d, J = 7.2 Hz, 2H), 3.00 (d, J = 9.0 Hz, 2H), 2.36 (d, J = 9.1 Hz, 2H), 2.28 (s, 3H), 1.60 - 1.48 (m, 3H), 1.39 (d, J = 6.8 Hz, 3H).

[0185] Example 26 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-((R)-1-cyclobutylethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 61 [ka]

[0186] 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 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 hydroxide (42.0 mg, 60% wt. in mineral oil) was used as a base under the same conditions as in Procedure 1 of Example 1 to give Intermediate 60 (137.3 mg).

[0187] Step 2: 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-((R)-1-cyclobutylethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 61 Compound 61 (white powder, 65.0 mg) was obtained from Intermediate 60 (131.9 mg) under the same conditions as in Step 2 of Example 1. MS ESI: m / z =475.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 8.28 (s, 1H), 6.98 (s, 2H), 4.00 (d, J = 7.0 Hz, 2H), 3.08 (d, J = 11.3 Hz, 2H), 2.95 (d, J = 11.1 Hz, 2H), 1.85 (ddt, J = 22.9, 11.0, 3.7 Hz, 3H), 1.72 (dt, J = 10.8, 8.2 Hz, 2H), 1.61 (s, 3H), 1.46 (t, J = 9.2 Hz, 1H), 1.32 (dd, J = 7.2, 4.0 Hz, 2H), 0.96 (d, J = 6.4 Hz, 3H).

[0188] Example 27 5-Chloro-N-((R)-1-cyclobutylethyl)-6-(2,6-difluoro-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)methoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 62 [ka] Compound 61 (47.2 mg) was used as a raw material, and sodium triacetoxyborohydride (63.26 mg) and an aqueous formaldehyde solution (14.4 μL, 37% by weight) were used as reagents to obtain the target compound 62 (30.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =489.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 7.84 (s, 1H), 7.03 - 6.94 (m, 2H), 3.94 (d, J = 7.4 Hz, 2H), 2.95 (d, J = 8.8 Hz, 2H), 2.47 (d, J = 8.3 Hz, 1H), 2.26 (d, J = 21.8 Hz, 5H), 1.94 - 1.53 (m, 6H), 1.47 (q, J = 7.6, 5.2 Hz, 3H), 1.31 (t, J = 9.4 Hz, 1H), 0.96 (d, J = 6.4Hz, 3H).

[0189] Example 28 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl)-5-methyl-N-((R)-1-cyclobutylethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 61A [ka]

[0190] Step 1: tert-Butyl (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-carboxylate 60A 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 raw materials, and sodium hydroxide (44.4 mg, 60% wt. in mineral oil) was used as a base under the same conditions as in Procedure 1 of Example 1 to give Intermediate 60A (72.4 mg).

[0191] Step 2: 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl)-5-methyl-N-((R)-1-cyclobutylethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 61 Using Intermediate 60A (72.4 mg) as a starting material, compound 61A (white powder, 30.0 mg) was obtained under the same conditions as in Step 2 of Example 1. MS ESI: m / z =455.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.47 (s, 1H), 8.31 (s, 1H), 7.20 (d, J = 10.0 Hz, 1H), 6.99 (t, J = 11.6 Hz, 2H), 4.00 (d, J = 7.1 Hz, 2H), 3.08 (d, J = 11.2 Hz, 2H), 2.95 (d, J = 11.2 Hz, 2H), 2.46 - 2.39 (m, 1H), 2.12 (s, 3H), 1.85 (dqd, J = 23.0, 7.9, 4.0 Hz, 2H), 1.71 (dt, J = 10.7, 8.4 Hz, 1H), 1.60 (d, J = 13.0 Hz, 4H), 1.45 (p, J = 8.7 Hz, 1H), 1.35 - 1.25 (m, 2H), 0.93 (d, J = 6.3 Hz, 3H).

[0192] Example 29 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 [ka]

[0193] Step 1: tert-Butyl (1R,5S,6s)-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 Intermediate 4 (100.0 mg) and tert-butyl (1R,5S,6s)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 63 (231.18 mg) were used as raw materials, and sodium hydroxide (43.35 mg, 60% wt. in mineral oil) was used as a base under the same conditions as in Procedure 1 of Example 1 to give Intermediate 64 (111.3 mg).

[0194] 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 Compound 65 (white powder, 56.0 mg) was obtained from Intermediate 64 (113.3 mg) under the same conditions as in Step 2 of Example 1. MS ESI: m / z =463.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 7.89 (s, 1H), 7.00 (dd, J = 9.8, 2.8 Hz, 2H), 4.24 (d, J = 7.4 Hz, 2H), 3.27 (d, J = 11.2 Hz, 2H), 3.05 (d, J = 11.4 Hz, 2H), 1.90 - 1.72 (m, 4H), 1.43 (p, J = 7.8 Hz, 1H), 1.06 (d, J = 6.5 Hz, 3H), 0.71 (d, J = 6.6 Hz, 6H).

[0195] Example 30 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)methoxy)phenyl)-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 66 [ka] Compound 65 (30.3 mg) was used as a raw material, and sodium triacetoxyborohydride (41.685 mg) and aqueous formaldehyde solution (8.5 μL, 37% by weight) were used as reagents to obtain the target compound 66 (15.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =477.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 7.87 (s, 1H), 6.98 - 6.90 (m, 2H), 4.46 (d, J = 7.1 Hz, 2H), 2.98 (d, J = 9.4 Hz, 2H), 2.21 (s, 3H), 1.77 (q, J = 6.9 Hz, 2H), 1.67 - 1.60 (m, 2H), 1.28 - 1.18 (m, 2H), 1.06 (d, J = 6.5 Hz, 4H), 0.70 (d, J = 6.6 Hz, 6H).

[0196] Example 31 6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 68 [ka]

[0197] Step 1: tert-Butyl (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-carboxylate 67 Intermediate 5 (100.0 mg) and tert-butyl (1R,5S,6s)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 63 (215.93 mg) were used as raw materials, and sodium hydroxide (40.5 mg, 60% wt. in mineral oil) was used as a base, under the same conditions as in Procedure 1 of Example 1, to give Intermediate 67 (106.7 mg).

[0198] Step 2: 6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl))-5-chloro-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 68 Compound 68 (white powder, 20.0 mg) was obtained from Intermediate 67 (106.7 mg) under the same conditions as in Step 2 of Example 1. MS ESI: m / z =489.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.37 (s, 1H), 8.15 (s, 1H), 6.83 (d, J = 10.6 Hz, 2H), 5.81 (t, J = 7.5 Hz, 1H), 4.12 (d, J = 7.6 Hz, 2H), 3.36 (d, J = 10.6 Hz, 2H), 3.05 (d, J = 11.8 Hz, 2H), 1.93 (dd, J = 8.1, 3.3 Hz, 2H), 1.46 (p, J = 7.9 Hz, 1H), 1.27 (d, J = 6.8 Hz, 3H).

[0199] Example 32 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)methoxy)phenyl)-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 69 [ka] Compound 68 (10.7 mg) was used as a starting material, and sodium triacetoxyborohydride (14.0 mg) and an aqueous formaldehyde solution (2.53 μL, 37% by weight) were used as reagents to obtain the target compound 69 (7.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =503.1, [M+H] + .

[0200] Example 33 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 71 [ka]

[0201] 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 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 hydroxide (42.0 mg, 60% wt. in mineral oil) was used as a base under the same conditions as in Procedure 1 of Example 1 to give Intermediate 70 (134.8 mg).

[0202] Step 2: 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 71 Compound 71 (white powder, 41.0 mg) was obtained under the same conditions as in Step 2 of Example 1 using Intermediate 70 (126.1 mg) as a starting material. MS ESI: m / z =475.0, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1H), 8.25 (s, 1H), 6.89 (d, J = 9.6 Hz, 2H), 4.72 (q, J = 9.2 Hz, 2H), 3.98 (d, J = 6.8 Hz, 2H), 3.20 (d, J = 11.2 Hz, 2H), 3.11 (d, J = 11.2 Hz, 2H), 1.71 (s, 2H), 1.39 - 1.33 (m, 1H).

[0203] Example 34 5-Chloro-6-(2,6-difluoro-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)methoxy)phenyl)-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 72 [ka] Compound 71 (23.1 mg) was used as a raw material, and sodium triacetoxyborohydride (30.98 mg) and an aqueous formaldehyde solution (5.61 μL, 37% by weight) were used as reagents to obtain the target compound 72 (17.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =489.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.52 (s, 1H), 6.86 (d, J = 9.8 Hz, 2H), 4.67 (q, J = 9.0 Hz, 2H), 3.84 (d, J = 7.2 Hz, 2H), 2.91 (d, J = 8.9 Hz, 2H), 2.23 (d, J = 8.8 Hz, 2H), 2.18 (s, 3H), 1.50 (d, J = 3.2 Hz, 1H), 1.41 (d, J = 2.9 Hz, 2H).

[0204] Example 35 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl)-5-chloro-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 71A [ka]

[0205] Procedure 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 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 raw materials, and sodium hydroxide (44.3 mg, 60% wt. in mineral oil) was used as a base under the same conditions as in Procedure 1 of Example 1 to give Intermediate 70A (132.8 mg).

[0206] Step 2: 6-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-2,6-difluorophenyl)-5-methyl-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 71A Using Intermediate 70A (125.1 mg) as a starting material, compound 71A (white powder 70.0 mg) was obtained under the same conditions as in Step 2 of Example 1. MS ESI: m / z =469.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1H), 8.23 ​​(s, 1H), 6.90 (d, J = 9.6 Hz, 2H), 4.63 (q, J = 9.0 Hz, 2H), 3.92 (d, J = 6.9 Hz, 2H), 3.11 (d, J = 11.3 Hz, 2H), 3.00 (d, J = 11.3 Hz, 2H), 2.10 (s, 3H), 1.62 (s, 2H), 1.30 (dq, J = 7.3, 3.5 Hz, 1H).

[0207] Example 36 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 [ka]

[0208] 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 Intermediate 4 (200.0 mg) and tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 17 (492.46 mg) were used as raw materials, and sodium hydroxide (87.0 mg, 60% wt. in mineral oil) was used as a base under the same conditions as in Procedure 1 of Example 1 to give Intermediate 73 (270 mg).

[0209] 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 Compound 74 (white powder, 90.0 mg) was obtained under the same conditions as in Step 2 of Example 1 using Intermediate 73 (270 mg) as a starting material. MS ESI: m / z =477.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.36 (s, 1H), 7.04 - 7.00 (m, 2H), 4.97 (t, J = 5.2 Hz, 1H), 3.26 - 3.21 (m, 2H), 2.92 (dd, J = 11.7, 4.4 Hz, 2H), 2.81 - 2.75 (m, 2H), 2.26 - 2.19 (m, 2H), 1.74 (tt, J = 13.8, 5.7 Hz, 4H), 1.05 (d, J = 6.5 Hz, 3H), 0.69 (d, J = 6.6 Hz, 7H).

[0210] Example 37 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 [ka] Compound 74 (40.0 mg) was used as a raw material, and sodium triacetoxyborohydride (53.4 mg) and aqueous formaldehyde solution (14.34 μL, 37% by weight) were used as reagents to obtain the target compound 75 (33.1 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =491.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 7.94 (s, 1H), 6.97 (dd, J = 11.4, 5.4 Hz, 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 = 6.9 Hz, 1H), 1.53 (dt, J = 13.1, 6.1 Hz, 2H), 1.05 (d, J = 6.5 Hz, 3H), 0.69 (d, J = 6.7 Hz, 6H).

[0211] Example 38 5-Chloro-6-(2,6-difluoro-4-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 77 [ka]

[0212] 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 Intermediate 5 (200.0 mg) and tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 17 (459.75 mg) were used as raw materials, and sodium hydroxide (81.0 mg, 60% wt. in mineral oil) was used as a base under the same conditions as in Procedure 1 of Example 1 to give Intermediate 76 (280.7 mg).

[0213] Step 2: 5-chloro-6-(2,6-difluoro-4-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 77 Compound 77 (white powder, 120.0 mg) was obtained under the same conditions as in Step 2 of Example 1 using Intermediate 76 (280.7 mg) as a starting material. MS ESI: m / z =503.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.32 (s, 1H), 8.24 (d, J = 4.7 Hz, 1H), 6.85 (d, J = 10.7 Hz, 2H), 5.78 (q, J = 7.2 Hz, 1H), 4.95 (p, J = 4.5, 4.1 Hz, 1H), 3.36 (dt, J = 12.5, 4.3 Hz, 2H), 3.01 (dd, J = 11.3, 5.0 Hz, 2H), 2.84 (s, 2H), 2.22 (dd, J = 13.8, 6.8 Hz, 2H), 1.78 (dd, J = 11.8, 7.0 Hz, 2H), 1.29 (d, J = 5.8 Hz, 3H).

[0214] Example 39 5-Chloro-6-(2,6-difluoro-4-(((3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 78 [ka] Compound 77 (38.8 mg) was used as a starting material, and sodium triacetoxyborohydride (49.1 mg) and an aqueous formaldehyde solution (13.2 μL, 37% by weight) were used as reagents to obtain the target compound 78 (35.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =517.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.50 (s, 1H), 8.19 (s, 1H), 6.90 (d, J = 10.6 Hz, 2H), 5.88 - 5.80 (m, 1H), 4.82 (t, J = 6.4 Hz, 1H), 2.64 (s, 6H), 2.41 (s, 3H), 2.29 - 2.24 (m, 2H), 1.61 (d, J = 10.5 Hz, 2H), 1.36 (d, J = 6.7 Hz, 3H).

[0215] Example 40 (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 [ka]

[0216] 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 Intermediate 4 (100.0 mg) and tert-butyl (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 19 (246.23 mg) were used as raw materials, and sodium hydroxide (43.36 mg, 60% wt. in mineral oil) was used as a base under the same conditions as in Procedure 1 of Example 1 to give Intermediate 79 (150.0 mg).

[0217] 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 Compound 80 (white powder, 75.0 mg) was obtained from Intermediate 79 (150 mg) under the same conditions as in Step 2 of Example 1. MS ESI: m / z =477.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.37 (s, 1H), 6.99 (dd, J = 10.5, 4.7 Hz, 2H), 5.11 - 5.07 (m, 1H), 3.10 (dd, J = 11.5, 6.4 Hz, 2H), 2.94 (d, J = 10.9 Hz, 2H), 2.85 (s, 2H), 2.03 (dq, J = 13.0, 3.7 Hz, 2H), 1.90 - 1.71 (m, 4H), 1.05 (d, J = 6.5 Hz, 3H), 0.70 (d, J = 6.6 Hz, 6H).

[0218] Example 41 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 [ka] Compound 80 (25.6 mg) was used as a raw material, and sodium triacetoxyborohydride (34.2 mg) and an aqueous formaldehyde solution (6.19 μL, 37% by weight) were used as reagents to obtain the target compound 81 (25.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =491.1, [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 6.60 - 6.55 (m, 2H), 6.28 (d, J = 10.6 Hz, 1H), 4.91 (d, J = 4.6 Hz, 1H), 3.31 (s, 1H), 2.93 - 2.86 (m, 2H), 2.75 (d, J = 9.7 Hz, 2H), 2.43 (d, J = 9.4 Hz, 4H), 2.25 - 2.19 (m, 2H), 1.87 (dt, J = 14.5, 5.4 Hz, 2H), 1.65 (dt, J = 12.9, 6.6 Hz, 1H), 1.25 (s, 1H), 1.06 (d, J = 6.6 Hz, 3H), 0.80 (t, J = 6.6 Hz, 6H).

[0219] Example 42 5-Chloro-6-(2,6-difluoro-4-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 83 [ka]

[0220] Step 1: tert-Butyl (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)-carboxylate 82 Intermediate 5 (88.9 mg) and tert-butyl (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 19 (204.5 mg) were used as raw materials, and sodium hydroxide (36.0 mg, 60% wt. in mineral oil) was used as a base, under the same conditions as in Procedure 1 of Example 1, to give Intermediate 82 (115.0 mg).

[0221] Step 2: 5-Chloro-6-(2,6-difluoro-4-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 83 Compound 83 (white powder, 50.0 mg) was obtained under the same conditions as in Step 2 of Example 1 using Intermediate 82 (95.1 mg) as a starting material. MS ESI: m / z =503.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.29 (d, J = 21.9 Hz, 2H), 6.83 (d, J = 10.7 Hz, 2H), 5.86 - 5.75 (m, 1H), 5.04 (t, J = 4.5 Hz, 1H), 3.24 (dd, J = 11.8, 6.4 Hz, 2H), 3.05 (d, J = 11.6 Hz, 2H), 2.93 (s, 2H), 2.08 - 1.99 (m, 2H), 1.90 (d, J = 13.3 Hz, 2H), 1.29 (d, J = 6.6 Hz, 3H).

[0222] Example 43 5-Chloro-6-(2,6-difluoro-4-(((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 84 [ka] Compound 83 (40.9 mg) was used as a raw material, and sodium triacetoxyborohydride (51.5 mg) and an aqueous formaldehyde solution (8.9 μL, 37% by weight) were used as reagents to obtain the target compound 84 (33.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =517.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1H), 6.85 (d, J = 10.8 Hz, 2H), 5.84 (q, J = 7.6 Hz, 1H), 5.05 - 5.00 (m, 1H), 2.75 (d, J = 9.5 Hz, 2H), 2.61 (d, J = 9.4 Hz, 2H), 2.45 (d, J = 7.2 Hz, 2H), 2.34 (s, 3H), 2.04 (dq, J = 13.2, 3.5 Hz, 2H), 1.77 (dt, J = 13.7, 5.0 Hz, 2H), 1.36 (d, J = 6.8 Hz, 3H).

[0223] Example 44 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 [ka]

[0224] 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 Intermediate 4B (100.0 mg) was dissolved in N,N-dimethylformamide (1.24 mL), and the solution was reacted with Intermediate 19A (130.3 mg), tetrakis(triphenylphosphine)palladium (24.22 mg), cuprous iodide (5.98 mg), and triethylamine (88.0 μL) in this order in an inert atmosphere at 80°C for 20 minutes, and then at room temperature for 8 hours. Saturated sodium chloride solution and ethyl acetate were added for extraction, and the organic phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated to obtain Intermediate 85 (yellow oily substance 116.9 mg).

[0225] 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 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 evaporated and purified by pre-HPLC (eluent: acetonitrile and water containing 1% formic acid) to give compound 86 (40.0 mg) as a white powder. MS ESI: m / z =457.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.60 (d, J = 2.2 Hz, 1H), 8.31 - 8.18 (m, 1H), 7.41 - 7.36 (m, 2H), 3.06 - 3.00 (m, 2H), 2.82 (d, J = 11.4 Hz, 2H), 1.94 - 1.90 (m, 2H), 1.76 (q, J = 6.9 Hz, 1H), 1.59 (q, J = 3.1 Hz, 1H), 1.05 (d, J = 6.5 Hz, 4H), 0.69 (d, J = 6.6 Hz, 6H).

[0226] Example 45 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 [ka]

[0227] 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 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 that order. The mixture was allowed to react at room temperature for 8 hours, and then extracted with saturated sodium chloride solution and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated to obtain intermediate 87 (yellow oil, 109.5 mg).

[0228] 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 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 evaporated and purified by pre-HPLC (eluent: acetonitrile and water containing 1% formic acid) to give compound 88 (white powder, 51.0 mg). MS ESI: m / z =469.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.54 (s, 1H), 8.17 (s, 1H), 7.34 (t, J = 10.9 Hz, 2H), 2.97 (d, J = 11.6 Hz, 2H), 2.76 (d, J = 11.5 Hz, 2H), 2.39 (d, J = 8.4 Hz, 1H), 1.88 - 1.61 (m, 6H), 1.53 (h, J = 6.6, 5.5 Hz, 2H), 1.39 (t, J = 9.1 Hz, 1H), 1.25 (d, J = 13.7 Hz, 1H), 0.90 (d, J = 6.3 Hz, 3H).

[0229] Example 46 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 [ka] Compound 88 (22.7 mg) was used as a raw material, and sodium triacetoxyborohydride (28.5 mg) and an aqueous formaldehyde solution (5.2 μL, 37% by weight) were used as reagents to obtain the target compound 89 (20.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =483.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 7.90 (s, 1H), 7.39 (t, J = 10.8 Hz, 2H), 2.99 (d, J = 9.2 Hz, 2H), 2.45 (d, J = 10.1 Hz, 1H), 2.25 (d, J = 24.4 Hz, 5H), 1.94 - 1.53 (m, 8H), 1.46 (q, J = 9.1 Hz, 1H), 1.37 - 1.25 (m, 1H), 0.96 (d, J = 6.3 Hz, 3H).

[0230] Example 47 (6-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)ethynyl)-2,6-difluorophenyl)-5-chloro-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 91 [ka]

[0231] Step 1: tert-Butyl (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-difluorophenyl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 90 Intermediate 5B (100.0 mg) and Intermediate 19A (123.5 mg) were used as raw materials, and tetrakis(triphenylphosphine)palladium (22.97 mg) and cuprous iodide (5.675 mg) were used as catalysts, and triethylamine (83.0 μL) was used as a base, in the same synthetic method as in Procedure 1 of Example 45 to obtain Intermediate 90 (yellow oil, 122.9 mg).

[0232] 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-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 91 Starting from Intermediate 90 (122.9 mg), Compound 91 (white powder, 60.0 mg) was obtained by the same synthetic method as in Step 2 of Example 45. MS ESI: m / z =483.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.37 (s, 1H), 8.18 (s, 1H), 7.24 (t, J = 7.8 Hz, 2H), 5.98 - 5.87 (m, 1H), 3.21 (d, J = 11.6 Hz, 2H), 3.05 (d, J = 11.4 Hz, 2H), 2.04 (t, J = 2.8 Hz, 2H), 1.67 (t, J = 3.6 Hz, 1H), 1.30 (d, J = 6.8 Hz, 3H).

[0233] Example 48 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-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 92 [ka] Using Example 47 (29.6 mg) as a starting material, sodium triacetoxyborohydride (36.2 mg), and an aqueous formaldehyde solution (6.6 μL, 37% by weight) as reagents, the target compound 92 (25.0 mg of white powder) was obtained in the same manner as in Example 2. MS ESI: m / z =497.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.14 (s, 1H), 7.33 (s, 2H), 6.04 (s, 1H), 3.05 (d, J = 9.4 Hz, 2H), 2.37 (d, J = 9.4 Hz, 4H), 2.27 (s, 4H), 1.91 (s, 2H), 1.86 (d, J = 3.4 Hz, 2H), 1.42 - 1.38 (m, 3H).

[0234] Example 49 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 [ka]

[0235] 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 Intermediate 7B (100.0 mg) and Intermediate 19A (127.1 mg) were used as raw materials, and tetrakis(triphenylphosphine)palladium (23.63 mg) and cuprous iodide (5.84 mg) were used as catalysts, and triethylamine (85.3 μL) was used as a base, in the same synthetic method as in Procedure 1 of Example 45 to obtain Intermediate 93 (yellow oily substance 88.6 mg).

[0236] 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 Starting from Intermediate 93 (88.6 mg), Compound 94 (white powder, 40.0 mg) was obtained by the same synthetic method as in Step 2 of Example 45. MS ESI: m / z =469.0, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.20 (s, 1H), 7.29 (d, J = 7.5 Hz, 2H), 4.76 (q, J = 9.4 Hz, 2H), 3.13 (d, J = 11.6 Hz, 2H), 2.94 (d, J = 11.4 Hz, 2H), 2.00 - 1.96 (m, 2H), 1.63 (t, J = 3.6 Hz, 1H).

[0237] Example 50 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 [ka] Compound 94 (22.7 mg) was used as a raw material, and sodium triacetoxyborohydride (28.5 mg) and an aqueous formaldehyde solution (5.2 μL, 37% by weight) were used as reagents to obtain the target compound 95 (16.0 mg of white powder) in the same manner as in Example 2. MS ESI: m / z =483.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.61 (s, 1H), 8.15 (s,1H), 7.34 (d, J = 7.9 Hz, 2H), 4.77 (q, J = 9.1 Hz, 2H), 3.02 (d, J = 9.2 Hz, 2H), 2.30 (d, J = 9.1 Hz, 2H), 2.24 (s, 3H), 1.87 (dt, J = 17.6, 2.9 Hz, 3H).

[0238] Example 51 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 [ka]

[0239] 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 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 this order, and the mixture was allowed to react at 80°C for 1 hour. Saturated sodium chloride and ethyl acetate were added for extraction, and the organic phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated to obtain intermediate 96 (yellow oily substance 110.9 mg).

[0240] 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 Starting from Intermediate 96 (110.9 mg), Compound 97 (white powder, 70.0 mg) was obtained by the same synthetic method as in Step 2 of Example 45. MS ESI: m / z =459.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.54 (d, J = 3.6 Hz, 1H), 8.24 (s, 1H), 7.29 (d, J = 10.0 Hz, 2H), 6.38 (d, J = 15.9 Hz, 1H), 6.22 (dd, J = 15.9, 9.0 Hz, 1H), 3.00 (d, J = 11.4 Hz, 2H), 2.86 (d, J = 11.2 Hz, 2H), 1.73 - 1.66 (m, 3H), 1.56 (dt, J = 6.8, 3.3 Hz, 1H), 0.98 (d, J = 6.6 Hz, 4H), 0.62 (dt, J = 6.8, 4.4 Hz, 6H).

[0241] Example 52 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 [ka]

[0242] 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 Intermediate 98 (yellow oil, 127.9 mg) was obtained in the same manner as in Procedure 1 of Example 51 using Intermediate 6B (100.0 mg) and Intermediate 19B (204.2 mg) as raw materials and tetrakis(triphenylphosphine)palladium (23.6 mg) and cuprous iodide (4.0 mg) as catalysts.

[0243] 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 Starting from Intermediate 98 (127.9 mg), Compound 99 (white powder, 90.0 mg) was obtained by the same synthetic method as in Step 2 of Example 45. MS ESI: m / z =471.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.31 (s, 1H), 7.38 (t, J = 10.8 Hz, 2H), 6.46 (d, J = 15.9 Hz, 1H), 6.30 (dd, J = 15.9, 9.1 Hz, 1H), 3.08 (d, J = 11.4 Hz, 2H), 2.94 (d, J = 11.2 Hz, 2H), 2.44 (d, J = 8.1 Hz, 1H), 1.91 - 1.79 (m, 2H), 1.76 - 1.54 (m, 6H), 1.45 (p, J = 8.7 Hz, 1H), 1.25 (s, 1H), 0.95 (d, J = 6.4 Hz, 3H).

[0244] Example 53 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-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 101 [ka]

[0245] 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 Intermediate 5B (70.0 mg) and Intermediate 19B (138.99 mg) were used as raw materials, and tetrakis(triphenylphosphine)palladium (16.1 mg) and cuprous iodide (2.65 mg) were used as catalysts in the same manner as in Procedure 1 of Example 51 to obtain Intermediate 100 (yellow oil, 78.1 mg).

[0246] 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-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride 101 Compound 101 (white powder, 40.0 mg) was obtained by the same synthetic method as in Step 2 of Example 45 using Intermediate 100 (78.1 mg) as a starting material. MS ESI: m / z =485.1, [M+H] + .

[0247] Example 54 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 [ka]

[0248] 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 Intermediate 7B (120.0 mg) and Intermediate 19B (245.1 mg) were used as raw materials, and tetrakis(triphenylphosphine)palladium (28.36 mg) and cuprous iodide (4.67 mg) were used as catalysts in the same manner as in Procedure 1 of Example 51 to obtain Intermediate 102 (yellow oil, 235.7 mg).

[0249] 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 Starting from Intermediate 102 (235.7 mg), Compound 103 (white powder, 160.0 mg) was obtained by the same synthetic method as in Step 2 of Example 45. MS ESI: m / z =471.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.42 (s, 1H), 8.25 (s, 1H), 7.26 (d, J = 8.8 Hz, 2H), 6.45 (d, J = 15.8 Hz, 1H), 6.22 (dd, J = 15.9, 8.9 Hz, 1H), 4.71 (q, J = 9.3 Hz, 2H), 3.21 (d, J = 11.5 Hz, 2H), 3.11 (d, J = 11.3 Hz, 2H), 1.83 (t, J = 2.6 Hz, 2H), 1.67 (dt, J = 9.4, 3.3 Hz, 1H).

[0250] Example 55 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 [ka]

[0251] Using Example 44 (24.7 mg) as a starting material, sodium triacetoxyborohydride (31.9 mg), and an aqueous formaldehyde solution (5.83 μL, 37% by weight) as reagents, the target compound (12.0 mg of white powder) was obtained in the same manner as in Example 2. MS ESI: m / z =471.1, [M+H] + .

[0252] Example 56 5-chloro-N-((R)-1-cyclobutylethyl)-6-(2,6-difluoro-4-((E)-2-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)vinyl)phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine [ka] Using Example 52 (27.1 mg) as a starting material, sodium triacetoxyborohydride (34.04 mg), and an aqueous formaldehyde solution (6.2 μL, 37% by weight) as reagents, the target compound (20.0 mg of white powder) was obtained in the same manner as in Example 2. MS ESI: m / z =485.2, [M+H] + .

[0253] Example 57 6-(2,6-difluoro-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)methoxy)phenyl)-5-methyl-N-((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine [ka] Using Example 23 (20.1 mg) as a starting material, sodium triacetoxyborohydride (29.0 mg), and an aqueous formaldehyde solution (5.3 μL, 37% by weight) as reagents, the target compound (13.0 mg of white powder) was obtained in the same manner as in Example 2. MS ESI: m / z =457.2, [M+H] + .

[0254] Example 58 5-chloro-6-(difluoro-4-((E)-2-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)vinyl)phenyl)-N -(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine [ka] Using Example 54 (34.4 mg) as a starting material, sodium triacetoxyborohydride (43.2 mg), and an aqueous formaldehyde solution (7.8 μL, 37% by weight) as reagents, the target compound (22.0 mg of white powder) was obtained in the same manner as in Example 2. MS ESI: m / z =485.1, [M+H] + .

[0255] Example 59 5-chloro-6-(2,6-difluoro-4-((E)-2-((1R,5S,6s)-methyl-3-azabicyclo[3.1.0]hex-6-yl)vinyl)-phenyl)-N -((R)-3-methylbutan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine [ka] Using Example 51 (28.5 mg) as a starting material, sodium triacetoxyborohydride (36.7 mg), and an aqueous formaldehyde solution (6.7 μL, 37% by weight) as reagents, the target compound (15.0 mg of white powder) was obtained in the same manner as in Example 2. MS ESI: m / z =473.1, [M+H] + .

[0256] Example 60 6-(2,6-difluoro-4-(((1R,5S,6r)-methyl-3-azabicyclo[3.1.0]hex-6-yl)methoxy)-phenyl)-5-methyl-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine [ka] Using Example 35 (41.6 mg) as a starting material, sodium triacetoxyborohydride (58.2 mg), and an aqueous formaldehyde solution (10.7 μL, 37% by weight) as reagents, the target compound (23.0 mg of white powder) was obtained in the same manner as in Example 2. MS ESI: m / z =469.1, [M+H] + .

[0257] Example 61 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-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 92 [ka] Example 47 (40 mg) was dissolved in anhydrous N,N-dimethylformamide (2 mL), and ethyl bromide (7 μL) was added under ice bath cooling. After stirring for 30 minutes, cesium carbonate (36 mg) was added. The reaction mixture was stirred for 4 hours while heating in a 60°C oil bath, then cooled to room temperature, quenched with saturated brine, and 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 give the desired product T-1 5-chloro-6-(2,6-difluoro-4-(((1R,5S,6s)-3-ethyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)phenyl)-N-((S)-1,1,1-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (8 mg). MS-ESI: m / z =511.0 [M+H] + .

[0258] Example 62 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-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 92 [ka] Using Example 47 (40 mg) as a starting material, 2-iodopropane (10 μL) and Cs 2 CO 3 (35 mg) as reagents, the target compound (6.0 mg) was obtained in the same manner as in Example 61. MS ESI: m / z =525.0, [M+H] + .

[0259] Example 63 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-trifluoropropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 92 [ka] The target compound (16.0 mg) was obtained in the same manner as in Example 61 using Example 47 (80 mg) as the starting material, dissolved in anhydrous N,N-dimethylformamide (2 mL), and CD3I (15 μL) and Cs2CO3 (60.1 mg) as reagents. MS-ESI: m / z =500.0 [M+H] + .

[0260] Example 64 Tubulin stabilization activity test Compound solvent: 100% dimethyl sulfoxide (DMSO). Cell line: HEK293T (ATCC, CRL3216). Culture conditions: Cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum and 1% penicillin / streptomycin at 37°C in a Thermo Fisher cell culture incubator in a humidified atmosphere containing 5% carbon dioxide.

[0261] Test Method: One day before the test, 100,000 cells were seeded into 24-well plates at a density of 200,000 cells / ml. On the day of the test, 20 μL of PBS phosphate buffer containing the test compound at the test concentration or an equal volume of DMSO was added to each well. After 1 hour of incubation at 37°C, colchicine was added to each well to a final concentration of 1 μM. After an additional 3 hours of incubation at 37°C, the plate was placed on ice. The medium was removed from each well, and the cells were washed with pre-chilled PBS. The PBS was then aspirated and 0.1 ml of pre-chilled RIPA cell lysis solution (0.5% sodium deoxycholate, 0.1% SDS, 1% NP-40, 5 mM EDTA, pH 8.0) was quickly added. The cell lysate was supplemented with a commercially available protease inhibitor mixture (1:500) and 1 μM of the deacetylase inhibitor trichostatin A (Seiko Biotechnology Co., Ltd.) prior to use. The cell lysate was added to a 1.5 ml centrifuge tube, and after ultrasonic treatment, it was centrifuged at 13,000 rpm for 10 minutes. The supernatant was collected and the protein concentration was measured by the BCA method.

[0262] The efficacy of compounds in stabilizing microtubules was tested using acetylated tubulin as an indicator of microtubule polymerization, following previous literature (Black, 1989; Kurt, 2011). HEK293T cell lysates were analyzed by SDS-PAGE (7.5% gel), immunoblotted with acetylated tubulin antibody (1:20,000, Sigma-Aldrich, T7451) and α-tubulin antibody (1:2000, Proteintech, 11224-1-AP), incubated with fluorescently conjugated IgG (1:40,000, Licor), and developed using an Odyssey-Dlx imaging system. Grayscale analysis was performed using ImageJ.

[0263] The compound activity was quantified by setting the microtubule-stabilizing activity of 500 nM of CNDR-51657 (C5) (Jane, 2016.) as 1.00. The results of the tubulin-stabilizing activity test for each embodiment are shown in Table 1. Table 1. Tubulin stabilization activity test results [Table 1-1] [Table 1-2]

[0264] Example 65 Oral pharmacokinetic study in mice: Healthy male CD1 mice were used as experimental animals and orally administered at a dose of 10 mg / kg and a volume of 10 mL / kg. Drug preparation: 10 mg of the compound was placed in 50% PEG400 or 20% HPb-cyclodextrin (10 mL), crushed and shaken to uniformly disperse the compound into small particles, and then orally administered. Blood samples were collected 30 minutes, 1 hour, 2 hours, and 4 hours after administration, and brain tissue was collected 4 hours later. EDTA dipotassium salt was added to the blood samples and centrifuged to obtain plasma, which was then diluted with 5 times the volume of acetonitrile. After centrifugation, the clear liquid was collected and submitted for analysis. The brain tissue pulverized solution was diluted with 3.5 times the volume of acetonitrile, centrifuged, and the clear liquid was collected and submitted for analysis. Sample analysis by liquid chromatography tandem mass spectrometry (LC-MS / MS): The instrument was an ABSciex3500, and the mobile phase was a 0.1% formic acid aqueous solution (A) / 0.1% formic acid acetonitrile solution (B), with gradient elution.

[0265] Table 2. PK test results for some compounds [Table 2]

[0266] The above results demonstrate that the compounds of the present invention have stable activity against tubulin, and unexpectedly, significantly improved plasma and brain tissue exposure compared to the controls Cevipubulin and CNDR-51657.

[0267] All documents related to the present invention are incorporated herein by reference as if each document were individually incorporated by reference. After reading the above content of the present invention, it will be understood that those skilled in the art can make various changes and modifications to the present invention, and that equivalents thereof are within the scope of the claims of the present invention.

Claims

【Request Item 1】 【Chemistry 1】 where: Ar is 【Chemistry 2】 and X 1 is Cl, CN, vinyl group, -CH=CHC 1-6 Alkyl group, -CH=CHC 3-6 Cycloalkyl groups, -C≡CH, -C≡C 1-6 Alkyl group, -C≡CC 3-6 Cycloalkyl groups, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 Halogenated cycloalkyl groups, OC 1-6 Alkyl group, OC 1-6 Halogenated alkyl groups, SC 1-6 selected from the group of alkyl groups, R 1 is C 1 -C 10 Alkyl group, C 1 -C 10 Halogenated alkyl groups, C 3 -C 10 Cycloalkyl groups, C 3 -C 10 Heterocyclyl group, C 3 -C 10 halogenated cycloalkyl groups, or R 1 teeth 【Transformation 3】 and R 1a and R 1b are each independently hydrogen, C 1 -C 10 Alkyl group, C 1 -C 10 Halogenated alkyl groups, C 3 -C 10 Cycloalkyl groups, C 3 -C 10 Halogenated cycloalkyl groups, C 7 -C 11 Spirocyclic alkanes, C 5 -C 10 a heterocyclic spiro ring, an aryl group, or a heteroaryl group, R 2 is hydrogen, R 3 and R 4 are independently hydrogen, F, Cl, or 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 group, (Z)-CH=CH-, (E)-CH=CH-, -C≡C-, C 5 -C 9 a fused heteroarylene group, a 5- or 6-membered heteroarylene group, R a and each R b are each independently hydrogen, substituted or unsubstituted C 1 -C 10 Alkyl groups, substituted or unsubstituted C 3 -C 10 Cycloalkyl groups, substituted or unsubstituted C 2 -C 10 Alkenyl group, substituted or unsubstituted C 6 -C 20 an aryl group, or a substituted or unsubstituted C 3 -C 14 is a heteroaryl group, R a and R b can be taken together with the carbon atoms to which they are attached to form a 3- to 8-membered ring or a 4- to 8-membered heterocycle, where the heteroatom is sulfur, oxygen, NH, or NR e It can be, R c and each R d are each independently hydrogen, C 1 -C 10 Alkyl group, C 3 -C 10 Cycloalkyl groups, C 2 -C 10 Alkenyl group, C 6 -C 20 Aryl group, C 3 -C 14 is a heteroaryl group, R c and R d is a halogen, hydroxy group, amino group, nitro group, cyano group, aldehyde group, carboxyl group, alkoxy group, -CF 3 ,-SCIENCE FICTION 5 and R c and R d can be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered ring or a 4- to 8-membered heterocycle, where the heteroatom is sulfur, oxygen, NH, or NR e It can be, R e is hydrogen, C 1 -C 6 Alkyl group, -(CR a R b ) n -C 3 -C 6 Cycloalkyl groups, -(CR a R b ) n -aryl group, -(CR a R b ) n -heteroaryl group; R e is a halogen, hydroxy group, amino group, nitro group, cyano group, aldehyde group, carboxyl group, alkoxy group, -CF 3 ,-SCIENCE FICTION 5 may be substituted with one or more groups selected from the group Y is H, halogen, OR e , -(CR a R b ) m -CO 2 H, -(CR a R b ) m -CO(CR a R b ) n -NR a R b , C 1 -C 6 Alkyl group, C 1 -C 6 Halogenated alkyl groups, -(CR a R b ) n -C 3 -C 6 Cycloalkyl groups, -(CR a R b ) n -C 3 -C 6 Halogenated cycloalkyl groups, -(CR a R b ) n -aryl group, -(CR a R b ) n -heteroaryl group, -(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)Me 2 , -(CR a R b ) n -SO 2 R a , -(CR a R b ) n -SO 2 NR c R d , -(CR a R b ) n -NR e CONR c R d -(CR a R b ) n -CONR c R d and m and n are independently 0, 1, 2, 3, 4, 5, or 6; 【Chemistry 4】 is a monocyclic hydrocarbon group, a spirocyclic hydrocarbon group, a fused hydrocarbon group, a bridged hydrocarbon group, a monocyclic heterocyclyl group, a spirocyclic heterocyclyl group, a fused heterocyclyl group or a bridged heterocyclyl group structure, X and Z are independently C(R 5 ), N, R 5 is hydrogen, OH, CN, halogen, NR c R d , C 1 -C 10 Alkyl group, C 1 -C 10 Halogenated alkyl groups, -(CR a R b ) n -C 3 -C 10 Cycloalkyl groups, -(CR a R b ) n -C 3 -C 10 Halogenated cycloalkyl groups, -(CR a R b ) n -CO 2 H, -(CR a R b ) n -CONR c R d and Unless otherwise specified, the monocyclic hydrocarbon group, spirocyclic hydrocarbon group, fused hydrocarbon group, bridged hydrocarbon group, monocyclic heterocyclyl group, spirocyclic heterocyclyl group, fused heterocyclyl group, or bridged ring heterocyclyl group has 5 to 20 ring skeletal atoms, and if the ring skeletal atoms contain heteroatoms, the heteroatoms may be 1 to 4 (e.g., 3) heteroatoms selected from nitrogen, sulfur, or oxygen. A compound of general formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.

2. R 1a CF 3 , 【Transformation 5】 and R 1b is a hydrogen, a methyl group, or CF 3 2. The compound of claim 1, wherein:

3. The Ar is 【Transformation 6】 2. The compound of claim 1, wherein: 【Request Item 4】 【Chemistry 7】 teeth 【Transformation 8】 2. The compound of claim 1, wherein:

5. The compound has a structure represented by a general formula selected from the group consisting of: 【Chemistry 9】 wherein the definition of each group is as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof of the compound according to claim 1.

6. The compound has a structure represented by a general formula selected from the group consisting of: 【Chemistry 10】 【Chemistry 11】 wherein the definition of each group is as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof of the compound according to claim 1.

7. The compound has the structure shown in the formula: 【Chemistry 12】 where: R 1 is selected from the following structures: 【Chemistry 13】 X 1 is Cl, methyl group, CF 3 , an ethyl group, or a cyclopropyl group; Y is selected from H, C 1-6 Alkyl group, C 1-6 Fluoroalkyl group, C 3-6 Cycloalkyl groups, C 3-6 Fluorocycloalkyl group, -SO 2 R a , -SO 2 NR c R d , -CONR c R d , an aryl group, or a heteroaryl group, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof of the compound according to claim 1 .

8. The compound has the structure shown in the formula: 【Chemistry 14】 where: R 1 is selected from the following structures: 【Chemistry 15】 X 1 is Cl, methyl group, CF 3 , ethyl, or cyclopropyl; Y is H, C 1-6 Alkyl group, C 1-6 Fluoroalkyl group, C 3-6 Cycloalkyl groups, C 3-6 Fluorocycloalkyl group, -SO 2 R a , -SO 2 NR c R d , -CONR c R d , an aryl group, or a heteroaryl group, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof of the compound according to claim 1 .

9. The compound has the structure shown in the formula: 【Chemistry 16】 where: R 1 is selected from the following structures: 【Chemistry 17】 X 1 is Cl, methyl group, CF 3 , an ethyl group, or a cyclopropyl group; Y is selected from H, C 1-6 Alkyl group, C 1-6 Fluoroalkyl group, C 3-6 Cycloalkyl groups, C 3-6 Fluorocycloalkyl group, -SO 2 R a , -SO 2 NR c R d , -CONR c R d , an aryl group, or a heteroaryl group, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof of the compound according to claim 1 .

10. The compound has the structure shown in the formula: [Chemistry 18] where: R 1 is selected from the following structures: 【Chemistry 19】 X 1 is Cl, methyl group, CF 3 , an ethyl group, or a cyclopropyl group; Y is selected from H, C 1-6 Alkyl group, C 1-6 Fluoroalkyl group, C 3-6 Cycloalkyl groups, C 3-6 Fluorocycloalkyl group, -SO 2 R a , -SO 2 NR c R d , -CONR c R d , an aryl group, or a heteroaryl group, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof of the compound according to claim 1 .

11. The compound according to claim 1, characterized in that the compound is selected from the following group: 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】

12. (i) Preparation of tubulin stabilizers; (ii) preparing a pharmaceutical composition for treating a tubulin-mediated disease; (iii) Use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for the prevention and / or treatment of cancer and neurodegenerative diseases.

13. 13. The use according to claim 12, characterized in that the cancer is selected from the group of glioma, colon cancer, breast cancer, gastric cancer, lung cancer, colorectal cancer, pancreatic adenocarcinoma, ovarian cancer, prostate cancer, renal cancer, liver cancer, brain tumor, melanoma, multiple myeloma, chronic myelogenous leukemia, hematopoietic tumors, lymphoid tumors, or metastatic lesions in tissues or organs distant from the primary site of the tumor.

14. 13. 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.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier therefor.

16. The pharmaceutical composition according to claim 15, characterized in that the pharmaceutical composition comprises another anti-tumor drug, preferably selected from the group consisting of PD-1 antibodies, PD-L1 antibodies, CTLA-4 antibodies, anti-tumor chemotherapeutic drugs (such as temozolomide), and targeted drugs.

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