PYRIDONE COMPOUNDS AND PHARMACEUTICALS CONTAINING THEM

Abstract

The invention is in the field of pharmaceutical chemistry, and proposes compounds with the general formulas (A), (B), (C), (D), (E), (F), (G), (H) and (J), or their racemates, or their isomers and pharmaceutical salts, to act as PCSK9 inhibitors.

Description

A pyridone compound and its preparation method and application Technical Field

[0001] The present invention belongs to the field of chemical pharmaceutical technology and relates to a pyridone compound, or an isomer, racemate, or pharmaceutically acceptable salt thereof, as well as a preparation method and application thereof, as a PCSK9 inhibitor, and methods of using the same to treat various specific diseases or conditions. Background Art

[0002] Proprotein convertase subtilisin / kexin type 9 (PCSK9), also known as neural apoptosis-regulating convertase 1 (NARC-1), is a prohormone-to-proprotein convertase in the subtilisin (S8) family of serine proteases. It is expressed in cells capable of proliferation and differentiation, including hepatocytes, renal interstitial cells, ileal and colonic epithelial cells, and embryonic telencephalic neurons. Studies have shown that PCSK9 plays a role in the differentiation of hepatocytes and neurons. It not only specifically acts on cholesterol biosynthesis or uptake, but also circulating PCSK9 can directly bind to the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes. Together with the LDLR, it is phagocytosed by hepatocytes, promoting LDLR degradation in hepatocytes and hindering its recycling, thereby increasing plasma LDL cholesterol (LDL-C). Elevated LDL-C expression is closely associated with human dyslipidemia and cardiovascular diseases.

[0003] Research is currently underway to inhibit PCSK9 function or production. For example, attempts have been reported to inhibit PCSK9 function using monoclonal antibodies targeting PCSK9 and to inhibit PCSK9 production through RNA interference. However, for patients with cardiovascular disease, effective small molecule inhibitors to inhibit PCSK9 function are needed.

[0004] Summary of the Invention

[0005] In view of the problems existing in the prior art, the present application provides a compound represented by the general formula (A), (B), (C), (D), (E), (F), (G), (H), (J), or its isomers, racemates, or pharmaceutically acceptable salts, as well as preparation methods and uses thereof, as a PCSK9 inhibitor, and methods of using the same to treat various specific diseases or conditions.

[0006] Specifically, the present invention is achieved through the following technical solutions:

[0007] A compound represented by general formula (A), or its isomer, racemate, or pharmaceutically acceptable salt, comprising:

[0008] X=C or N. When X=N, R4 does not exist;

[0009] R1, R4, R6, R7 are selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, cyano, -C(O)-O-alkyl, phenylalkoxy, carboxyl, hydroxymethyl or cycloalkyl, the substituents are selected from hydroxy, amide, alkyl-substituted amide, ZC(O)-, Z is selected from alkyl or heterocycle, heteroaryl;

[0010] R2, R3, R5 are independently selected from hydrogen, alkyl, alkoxy, cyano, halogen, haloalkyl, amide, hydroxy, hydroxy-substituted alkyl, carboxyl, amino, amino-substituted alkyl, alkylcarbonyl or -(CH2)nO-(CH2)n-benzene, where n=1, 2 or 3;

[0011] R8 and R9 are independently selected from hydrogen, alkyl, halogen, cycloalkyl, alkylthio, alkoxy, aryl, and heteroaryl;

[0012] and R1, R2, R3, R4, R5, R6, and R7 are not hydrogen at the same time; or when R1, R2, R3, R4, R5, R6, and R7 are hydrogen at the same time, R8 and R9 are not hydrogen at the same time.

[0013] The present invention further provides a compound represented by general formula (AI), or its isomer, racemate, or pharmaceutically acceptable salt, including:

[0014] wherein R1, R4, R6, and R7 are selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, cyano, -C(O)-O-alkyl, phenylalkoxy, carboxyl, hydroxymethyl, or cycloalkyl, and the substituent is selected from hydroxy, amide, alkyl-substituted amide, ZC(O)-, and Z is selected from alkyl, heterocycle, or heteroaryl;

[0015] R2, R3, R5 are independently selected from hydrogen, alkyl, alkoxy, cyano, halogen, haloalkyl, amide, hydroxy, hydroxy-substituted alkyl, carboxyl, amino, amino-substituted alkyl, alkylcarbonyl or -(CH2)nO-(CH2)n-benzene, where n=1, 2 or 3;

[0016] R8 and R9 are independently selected from hydrogen, alkyl, halogen, cycloalkyl, alkylthio, alkoxy, aryl, and heteroaryl;

[0017] and R1, R2, R3, R4, R5, R6, and R7 are not hydrogen at the same time; or when R1, R2, R3, R4, R5, R6, and R7 are hydrogen at the same time, R8 and R9 are not hydrogen at the same time.

[0018] As a preferred technical solution of the present invention, in the general formula (A) or (AI), R1, R2, R4, R5, R6, and R7 are all hydrogen, and R3 is selected from alkyl, alkoxy, cyano, halogen, haloalkyl, amide, hydroxyl, hydroxyl-substituted alkyl, carboxyl, amino, amino-substituted alkyl, alkylcarbonyl or -(CH2)nO-(CH2)n-benzene, where n = 1, 2 or 3.

[0019] As a preferred technical solution of the present invention, in the general formula (A) or (AI), R1, R2, R3, R5, R6, and R7 are all hydrogen, and R2 is selected from alkyl, alkoxy, cyano, halogen, haloalkyl, amide, hydroxyl, hydroxyl-substituted alkyl, carboxyl, amino, amino-substituted alkyl, alkylcarbonyl or -(CH2)nO-(CH2)n-benzene, where n=1, 2 or 3.

[0020] As a preferred technical solution of the present invention, in general formula (A) or (AI), the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl. A haloalkyl group means that one or more hydrogen atoms on the alkyl group are replaced by halogen. A hydroxy-substituted alkyl group means that one or more hydrogen atoms on the alkyl group are replaced by hydroxyl groups.

[0021] As a preferred technical solution of the present invention, in the general formula (A) or (AI), the halogen is selected from fluorine, chlorine, bromine and iodine.

[0022] As a preferred technical solution of the present invention, in the general formula (A) or (AI), the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the heterocycle is a cycloalkane in which one or more carbon atoms are replaced by a heteroatom, and the heteroatom is selected from N, O, and S.

[0023] As a preferred technical solution of the present invention, in general formula (A) or (AI), the alkoxy group is selected from methoxy, ethoxy, propoxy, and isopropoxy.

[0024] As a preferred technical solution of the present invention, in the general formula (A) or (AI), the aryl group is selected from phenyl, and the heteroaryl group is preferably selected from: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, etc.

[0025] As a preferred technical solution of the present invention, in the general formula (A) or (AI), R2 or R3 is selected from F, Cl, Br, methyl, hydroxyl, hydroxymethyl, trifluoromethyl, -CF2H, -C(O)NH2, -NH2, cyano, -COOH, methoxy, -CH2-O-CH2-benzene,

[0026] As a preferred technical solution of the present invention, in the general formula (A) or (AI), R1 is selected from methyl, hydroxyl, hydroxymethyl, cyano, F, Cl, Br, -O-CH2-benzene, -COOH, -COOCH2CH3, Amide, formamide, CH3-C(O)-,

[0027] As a preferred technical solution of the present invention, in the general formula (A) or (AI), R6 and R7 are independently H or -COOH.

[0028] As a preferred technical solution of the present invention, in the general formula (A) or (AI), R4, R6, and R7 are independently H.

[0029] As a preferred technical solution of the present invention, in the general formula (A) or (AI), R8 and R9 are independently selected from hydrogen, chlorine, methyl, methoxy, methylthio, ethyl, isopropyl, phenyl, cyclopropyl,

[0030] As a preferred technical solution of the present invention, in the general formula (A) or (AI), the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt is selected from: A1, A5-A73.

[0031] As a preferred technical solution of the present invention, in the general formula (A) or (AI), the isomeric compound is selected from:

[0032] As a preferred technical solution of the present invention, in the general formula (A) or (AI), the pharmaceutically acceptable salt refers to the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt prepared with a pharmaceutically acceptable acid or base.

[0033] As a preferred technical solution of the present invention, in the general formula (A) or (AI), one or more hydrogen atoms of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt are substituted by deuterium isotope.

[0034] As a preferred technical solution of the present invention, in the general formula (A) or (AI), the deuterium-substituted compound is selected from:

[0035] A compound represented by general formula (B), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, comprising:

[0036] Among them, A is selected from

[0037] B is selected from

[0038] Q is selected from N or CR4, R4 is selected from H or halogen;

[0039] T1 and T2 are selected from N or CH;

[0040] X and Y are independently selected from C(O), O, S, NH, CH2,

[0041] Z is absent or selected from C(O), O, S, NH, CH2,

[0042] W is selected from C(O), O, S, NH, CH2,

[0043] Wherein, R1 is hydrogen or represents a hydrogen on the ring further replaced by alkyl, halogenated alkyl, carboxylic acid, alkoxy, halogenated alkoxy, cyano, halogen or substituted, U1, U2, U4 are independently selected from CH or N, U3 is selected from CH2 or NH, R1 is one or more;

[0044] R2 is selected from H, alkyl or halogen, R2 is one or more;

[0045] R3 is hydrogen or represents that the hydrogen on the ring is further replaced by alkyl, halogen, oxo, substituted or unsubstituted phenyl, the substituent of the substituted phenyl is selected from alkyl and halogen, and R3 is one or more.

[0046] As a preferred technical solution of the present invention, in the general formula (B), the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0047] As a preferred technical solution of the present invention, in the general formula (B), the alkoxy group is selected from C 1-6 Alkoxy, the C 1-6Alkoxy is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexoxy, isohexoxy, sec-hexoxy, tert-hexoxy, neohexoxy, 2-methylpentoxy, 1,2-dimethylbutoxy, 1-ethylbutoxy;

[0048] As a preferred technical solution of the present invention, in general formula (B), the halogen is selected from fluorine, chlorine, bromine, and iodine. The haloalkyl group refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen; the haloalkoxy group refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen.

[0049] As a preferred technical solution of the present invention, in the general formula (B), Q is selected from N.

[0050] As a preferred technical solution of the present invention, in the general formula (B), Q is selected from CH, and R2 is selected from F.

[0051] As a preferred technical solution of the present invention, in the general formula (B), T1 is selected from N.

[0052] As a preferred technical solution of the present invention, in general formula (B) Part, selected from: Indicates the connection location.

[0053] As a preferred technical solution of the present invention, in general formula (B) Part, selected from: Indicates the connection location.

[0054] As a preferred technical solution of the present invention, R3 is hydrogen, methyl, F, phenyl, or Indicates the connection location.

[0055] As a preferred technical solution of the present invention, A is selected from

[0056] B is selected from

[0057] As a preferred technical solution of the present invention, in the general formula (B), Selected from

[0058] As a preferred technical solution of the present invention, in general formula (B), the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt is selected from: B1-B34. A compound represented by general formula (C), or its isomer, or its racemate, or its pharmaceutically acceptable salt includes:

[0059] Among them, ring A is selected from wherein X and Y form a 5-7 membered saturated or unsaturated ring, wherein the 5-7 membered saturated or unsaturated ring contains 0, 1 or 2 heteroatoms selected from O, N and S;

[0060] B is selected from

[0061] Q is selected from N or CR1, R1 is selected from H or halogen;

[0062] T1 is selected from N or CH;

[0063] wherein R2 is selected from H, alkyl or halogen, and R2 is one or more;

[0064] R3 is selected from hydrogen or represents that the hydrogen on the A ring is further replaced by oxo, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, alkynyl, R3 is one or more, or adjacent R3 forms an alkoxy

[0065] R4 is selected from hydrogen, halogen, hydroxy, alkoxy, haloalkoxy, substituted or unsubstituted alkyl, cyano, -C(O)-O-alkyl, phenylalkoxy, carboxyl, hydroxymethyl or cycloalkyl, and the substituent is selected from hydroxy, amide, halogen, or substituted, U1, U2, U4 are independently selected from CH or N, U3 is selected from CH2 or NH, R4 is one or more;

[0066] And when the A ring is selected from When the B ring is not

[0067] As a preferred technical solution of the present invention, in the general formula (C), the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0068] As a preferred technical solution of the present invention, in the general formula (C), the alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0069] As a preferred technical solution of the present invention, in the general formula (C), the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0070] As a preferred technical solution of the present invention, in the general formula (C), the halogen is selected from fluorine, chlorine, bromine and iodine.

[0071] As a preferred technical solution of the present invention, in the general formula (C), Q is selected from N.

[0072] As a preferred technical solution of the present invention, in the general formula (C), Q is selected from CH, and R2 is selected from F.

[0073] As a preferred technical solution of the present invention, in the general formula (C), T1 is selected from N.

[0074] As a preferred technical solution of the present invention, in the general formula (C), R3 is selected from hydrogen, methyl, methoxy, cyclopropyl, cyclopropylmethyl, fluorine, chlorine, oxo, and CHF2-O-.

[0075] As a preferred technical solution of the present invention, in the general formula (C), R4 is selected from hydrogen, methyl, hydroxyl, hydroxymethyl, cyano, F, Cl, Br, -O-CH2-benzene, -COOH, -COOCH2CH3, Amide, formamide, CH3-C(O)-, ethynyl, trifluoromethyl, difluoromethoxy, methoxy.

[0076] As a preferred technical solution of the present invention, in the general formula (C), ring A is selected from

[0077] Furthermore, as a preferred technical solution of the present invention, in the general formula (C), the A ring substituted by R3 is selected from:

[0078] Furthermore, as a preferred technical solution of the present invention, in the general formula (C), the B ring substituted by R4 is selected from:

[0079] As a preferred technical solution of the present invention, the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, in the general formula (C), is selected from: C1-C13, C15-C95.

[0080] A compound represented by general formula (D), or its isomer, racemate, or pharmaceutically acceptable salt, comprising:

[0081] R1, R2, R3, and R4 are independently selected from hydrogen, halogen, alkyl, cyano, haloalkyl, or cycloalkyl;

[0082] X is selected from CH or N, Z is selected from CH or N, when Z is selected from N, R6 is absent;

[0083] Y is selected from CH or N, when Y is selected from N, R4 is absent;

[0084] T is selected from CH or N or CT1, T1 is selected from CN, alkyl or haloalkyl;

[0085] R5 and R6 are independently selected from hydrogen, halogen, and alkyl. When X is selected from CH, R5 and R6 are not hydrogen at the same time, or when X is selected from CH, R1, R2, R3, R4, R5, and R6 are hydrogen at the same time;

[0086] R7 is selected from hydrogen, alkyl, alkoxy, cyano, alkynyl, substituted or unsubstituted cycloalkyl, alkylsulfonyl, alkylphosphonyl, substituted or unsubstituted -N(C(O))nX1X2, substituted or unsubstituted -O-cycloalkyl, substituted or unsubstituted -O-heterocycloalkyl, boronic acid or halogen, wherein X1 and X2 are independently selected from alkyl, or X1X2 forms a heterocycloalkyl with the N to which it is connected, and the substituent is selected from hydrogen, halogen, alkyl, n=0 or 1; and when R7 is selected from alkyl, alkoxy or halogen, R5 and R6 are not hydrogen at the same time or X is selected from N.

[0087] As a preferred technical solution, a compound represented by general formula (D1), or its isomer, racemate, or pharmaceutically acceptable salt, comprises:

[0088] R1, R2, R3, and R4 are independently selected from hydrogen, halogen, alkyl, cyano, haloalkyl, or cycloalkyl;

[0089] X is selected from CH or N;

[0090] Y is selected from CH or N, when Y is selected from N, R4 is absent;

[0091] R5 and R6 are independently selected from hydrogen, halogen, and alkyl. When X is selected from CH, R5 and R6 are not hydrogen at the same time, or when X is selected from CH, R1, R2, R3, R4, R5, and R6 are hydrogen at the same time;

[0092] R7 is selected from hydrogen, alkyl, alkoxy, cyano, alkynyl, substituted or unsubstituted cycloalkyl, alkylsulfonyl, alkylphosphonyl, substituted or unsubstituted -N(C(O))nX1X2, substituted or unsubstituted -O-cycloalkyl, substituted or unsubstituted -O-heterocycloalkyl, boronic acid or halogen, wherein X1 and X2 are independently selected from alkyl, or X1X2 forms a heterocycloalkyl with the N to which it is connected, and the substituent is selected from hydrogen, halogen, alkyl, n=0 or 1; and when R7 is selected from alkyl, alkoxy or halogen, R5 and R6 are not hydrogen at the same time or X is selected from N.

[0093] As a preferred technical solution of the present invention, in general formula (D) or (D1), the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0094] As a preferred technical solution of the present invention, in the general formula (D) or (D1), the halogen is selected from fluorine, chlorine, bromine and iodine.

[0095] As a preferred technical solution of the present invention, in the general formula (D) or (D1), the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0096] As a preferred technical solution of the present invention, in the general formula (D) or (D1), the heterocycloalkyl group is a cycloalkyl group in which one or more carbon atoms are replaced by a heteroatom, and the heteroatom is selected from O, N or S.

[0097] As a preferred technical solution of the present invention, in the general formula (D) or (D1), the alkynyl group is selected from C 2-4 Alkynyl, for example, ethynyl, propynyl, butynyl.

[0098] As a preferred technical solution of the present invention, in the general formula (D) or (D1), the halogenated alkyl group is selected from -CF3.

[0099] As a preferred technical solution of the present invention, in the general formula (D) or (D1), R5 and R6 are independently selected from hydrogen, fluorine, and methyl.

[0100] As a preferred technical solution of the present invention, in the general formula (D) or (D1), R7 is selected from hydrogen, methyl, methoxy, ethoxy, fluorine, ethynyl, chlorine, or

[0101] As a preferred technical solution of the present invention, in the general formula (D) or (D1), R1 is selected from hydrogen, fluorine, chlorine, cyclopropyl, cyano, methyl, and -CF3; R2, R3, and R4 are independently selected from hydrogen.

[0102] As a preferred technical solution of the present invention, in the general formula (D) or (D1), X is selected from N.

[0103] As a preferred technical solution of the present invention, in the general formula (D) or (D1), R6 is selected from hydrogen and F.

[0104] As a preferred technical solution of the present invention, in the general formula (D) or (D1), the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt is selected from: D1-D29.

[0105] A compound represented by general formula (E), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, comprising:

[0106] wherein Ring A is a benzoheterocycle, further selected from benzofuran, benzothiazole, 1H-indole, indole, quinoline, or benzofuran, benzothiazole, 1H-indole, indole, quinoline, wherein one or more -C= or -CH- on the ring is replaced by a nitrogen atom;

[0107] T is selected from N or CR7;

[0108] R1, R2, R3, R4, R5, R6, and R7 are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, and alkoxy, and the substitution is selected from halogen or alkyl.

[0109] As a preferred technical solution of the present invention, in the general formula (E), the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0110] As a preferred technical solution of the present invention, in the general formula (E), the halogen is selected from fluorine, chlorine, bromine and iodine.

[0111] As a preferred technical solution of the present invention, in the general formula (E), the alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentoxy, 1,2-dimethylbutoxy, 1-ethylbutoxy, n-heptyloxy, and isoheptyloxy.

[0112] As a preferred technical solution of the present invention, in the general formula (E), the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the heterocycloalkyl group refers to a cycloalkane in which at least one carbon atom is replaced by a heteroatom selected from nitrogen, oxygen, and sulfur.

[0113] As a preferred technical solution of the present invention, in the general formula (E), T is selected from N.

[0114] As a preferred technical solution of the present invention, in the general formula (E), ring A is selected from

[0115] As a preferred technical solution of the present invention, in the general formula (E), R1 and R3 are selected from hydrogen, and R2 is selected from -OCHF2.

[0116] As a preferred technical solution of the present invention, in the general formula (E), R4, R5, and R6 are selected from hydrogen.

[0117] As a preferred technical solution of the present invention, in the general formula (E), the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt is selected from: E1-E18.

[0118] A compound represented by general formula (F), or its isomer, racemate, or pharmaceutically acceptable salt, comprising:

[0119] Ring A is selected from: or R1 is substituted or unsubstituted

[0120] Ring B is selected from

[0121] R1, R1a, R 1b 、R 1c 、R 1d are independently selected from hydrogen, oxo, hydroxy, alkynyl, alkylalkynyl, alkylalkynylalkyl, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cyano, or two adjacent substituents form a 5-6 membered saturated or unsaturated heterocyclic ring;

[0122] Q, X, Y, Z are independently selected from CR3 or N, R3 is independently selected from hydrogen, oxo, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cyano, and when A is selected from When , at least two are N;

[0123] T is independently selected from CH or N;

[0124] W1 is selected from CH2 or NH, and W2 is independently selected from CH or N.

[0125] As a preferred technical solution of the present invention, in the general formula (F), the alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0126] As a preferred technical solution of the present invention, in the general formula (F), the alkoxy group is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy; the alkylthio group is an alkoxy group in which the oxygen atom is replaced by a sulfur atom.

[0127] As a preferred technical solution of the present invention, in the general formula (F), the halogen is selected from fluorine, chlorine, bromine and iodine.

[0128] As a preferred technical solution of the present invention, in the general formula (F), the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; and the heteroatom is selected from O, N, and S.

[0129] As a preferred technical solution of the present invention, in the general formula (F), Q is N.

[0130] As a preferred technical solution of the present invention, in the general formula (F), R2 is -O-CHF2.

[0131] As a preferred technical solution of the present invention, in the general formula (F), ring A is selected from The substituted A ring is selected from

[0132] Alternatively, Ring A is selected from The substituted A ring is selected from

[0133] As a preferred technical solution of the present invention, in the general formula (F), the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt is selected from: F1-F37.

[0134] A compound represented by general formula (G), or its isomer, racemate, or pharmaceutically acceptable salt, comprising:

[0135] wherein X is selected from substituted or unsubstituted alkyl, amino, O, S, and the substituent is selected from oxo, alkyl, halogen, alkoxy, hydroxy, and alkoxycarbonyl;

[0136] Ring A is selected from a 5-14 membered saturated or unsaturated heterocyclic ring substituted or unsubstituted by R1, which can be a monocyclic, bicyclic or tricyclic ring;

[0137] R1 is independently selected from hydrogen, oxo, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cyano, m = 0, 1, 2, or 3;

[0138] Ring B is selected from a 5-7 membered saturated or unsaturated heterocyclic ring substituted or unsubstituted by R2;

[0139] R2 is independently selected from hydrogen, oxo, thio, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cyano, n = 0, 1, 2, or 3;

[0140] R3 is independently selected from hydrogen, alkyl, alkoxy, cyano, halogen, haloalkyl, amide, hydroxy, hydroxy-substituted alkyl, carboxyl, amino, and p=0, 1, 2, or 3.

[0141] As a preferred technical solution of the present invention, the alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0142] As a preferred technical solution of the present invention, in the general formula (G), the alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0143] As a preferred technical solution of the present invention, in the general formula (G), the alkylthio group is selected from methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, and tert-butylthio.

[0144] As a preferred technical solution of the present invention, in the general formula (G), the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0145] As a preferred technical solution of the present invention, in the general formula (G), the halogen is selected from fluorine, chlorine, bromine and iodine.

[0146] As a preferred technical solution of the present invention, ring A is selected from

[0147] As a preferred technical solution of the present invention, in the general formula (G), ring B is selected from

[0148] As a preferred technical solution of the present invention, in the general formula (G), the compound selected from (G1), or its isomer, racemate, or pharmaceutically acceptable salt:

[0149] As a preferred technical solution of the present invention, in the general formula (G) or (G1), R1 is selected from hydrogen, methyl, cyano, methoxy, cyclopropyl, cyclopropylmethyl, fluorine, chlorine, and CHF2-O-.

[0150] As a preferred technical solution of the present invention, in the general formula (G) or (G1), R2 is selected from hydrogen, methyl, oxo, and thioxo.

[0151] As a preferred technical solution of the present invention, in the general formula (G) or (G1), R3 is selected from hydrogen, methyl, cyano, methoxy, cyclopropyl, cyclopropylmethyl, fluorine, and chlorine.

[0152] As a preferred technical solution of the present invention, in the general formula (G) or (G1), X is selected from -CH2-, -C(O)-, -CH(OH)-, -NH2-, -NH(CH3)-, O.S.

[0153] As a preferred technical solution of the present invention, in the general formula (G) or (G1), the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt is selected from: G1-G21.

[0154] A compound represented by general formula (H), or its isomer, racemate, or pharmaceutically acceptable salt, comprising:

[0155] R1, R2, R3, and R4 are independently selected from hydrogen, halogen, alkyl, cyano, haloalkyl, or cycloalkyl;

[0156] X is selected from C or N. When X is selected from N, R5 is absent.

[0157] Y is selected from C or N. When Y is selected from N, R6 is absent.

[0158] Z is selected from C or N. When Z is selected from N, R7 is absent.

[0159] R5, R6, and R7 are independently selected from hydrogen, halogen, and alkyl;

[0160] R8 is one or more independently selected from hydrogen, halogen, phenyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkyl, and the substituent is selected from alkyl and halogen;

[0161] Ring A is selected from When A is selected from When X, Y, and Z are all C, R1, R2, R3, R4, R5, R6, and R7 are not all hydrogen atoms.

[0162] As a preferred technical solution of the present invention, in the general formula (H), the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0163] As a preferred technical solution of the present invention, in the general formula (H), the halogen is selected from fluorine, chlorine, bromine and iodine.

[0164] As a preferred technical solution of the present invention, in the general formula (H), the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0165] As a preferred technical solution of the present invention, in the general formula (H), R1 is selected from halogen and alkyl.

[0166] As a preferred technical solution of the present invention, in the general formula (H), Y is selected from N, or Y is selected from C, and R5 is selected from halogen and alkyl.

[0167] As a preferred technical solution of the present invention, in the general formula (H), R8 is selected from methyl, cyclopropyl, cyclobutyl,

[0168] As a preferred technical solution of the present invention, in the general formula (H), Z is selected from N.

[0169] As a preferred technical solution of the present invention, in the general formula (H), Selected from

[0170] As a preferred technical solution of the present invention, in the general formula (H), the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt is selected from: H1-H14.

[0171] A compound represented by general formula (J), or its isomer, racemate, or pharmaceutically acceptable salt, comprising:

[0172] Wherein, Ring A is selected from a 5-14 membered saturated or unsaturated heterocyclic ring substituted or unsubstituted by R1, and the heterocyclic ring can be a monocyclic, bicyclic or tricyclic ring;

[0173] R1 is independently selected from hydrogen, oxo, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cyano, m = 0, 1, 2, or 3;

[0174] Ring B is selected from 5-8 membered saturated or unsaturated monocyclic or bicyclic rings, and is not Among them, the bicyclic and tricyclic rings can be spirocyclic and bridged rings;

[0175] R2 is independently selected from hydrogen, oxo, thio, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cyano, n = 0, 1, 2, or 3;

[0176] R3 is independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, cyano, -C(O)-O-alkyl, phenylalkoxy, carboxyl, hydroxymethyl or cycloalkyl, substituents are selected from hydroxy, alkyl, amide, alkyl substituted amide, ZC(O)-, Z is selected from alkyl or heterocycle, aryl, heteroaryl, p = 0, 1, 2, or 3;

[0177] T1, T2, and T3 are independently selected from CH or N.

[0178] As a preferred technical solution of the present invention, in the general formula (J), the alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0179] As a preferred technical solution of the present invention, in the general formula (J), the alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0180] As a preferred technical solution of the present invention, in the general formula (J), the alkylthio group is selected from methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, and tert-butylthio.

[0181] As a preferred technical solution of the present invention, in the general formula (J), the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0182] As a preferred technical solution of the present invention, in the general formula (J), the halogen is selected from fluorine, chlorine, bromine and iodine.

[0183] As a preferred technical solution of the present invention, in the general formula (J), ring A is selected from

[0184] As a preferred technical solution of the present invention, in the general formula (J), the B ring is selected from

[0185] As a preferred technical solution of the present invention, in the general formula (J), R1 is selected from hydrogen, methyl, cyano, methoxy, cyclopropyl, cyclopropylmethyl, fluorine, chlorine, and CHF2-O-.

[0186] As a preferred technical solution of the present invention, in the general formula (J), R2 is selected from hydrogen, methyl, cyano, methoxy, cyclopropyl, cyclopropylmethyl, fluorine, and chlorine.

[0187] As a preferred technical solution of the present invention, in the general formula (J), the B ring is connected by the following method:

[0188] As a preferred technical solution of the present invention, in the general formula (J), the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt is selected from: J1-J9.

[0189] The present invention further provides a pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0190] The present invention further provides the medical use of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, specifically, its use in the preparation of a medicament for treating a disease, wherein the disease is a PCSK9 inhibitor-related disease, specifically selected from hypercholesterolemia and the like.

[0191] For the sake of clarity, general terms used in the description of the compounds are defined herein.

[0192] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered as undefined or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0193] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared by reacting a compound having a specific substituent discovered in the present invention with a pharmaceutically acceptable acid or base.

[0194] In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0195] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrates. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0196] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, atropisomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0197] Optically active (R)- and (S)-isomers, as well as D and L isomers, atropisomers, etc., can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0198] The atoms of the molecules of the compounds of the present invention are isotopes, and isotope derivatization can generally extend half-life, reduce clearance, stabilize metabolism, and increase in vivo activity. In addition, an embodiment is included in which at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (protons and neutrons). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, which respectively include 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomy testing of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with their amount nor are they radioactive, so they can be used safely. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0199] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), iodine-125( 125 I) or C-14( 14C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0200] Furthermore, the compounds of the present invention may have one or more hydrogen atoms replaced by deuterium isotopes ( 2 After deuteration, the compounds of the present invention have the effects of extending half-life, reducing clearance rate, stabilizing metabolism and improving in vivo activity.

[0201] The preparation method of the isotopic derivative generally includes a phase transfer catalytic method. For example, a preferred deuteration method uses a phase transfer catalyst (e.g., a tetraalkylammonium salt, NBu4HSO4). The use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in a higher deuterium incorporation than reduction with a deuterated silane (e.g., triethyldeuterated monosilane) in the presence of an acid (e.g., methanesulfonic acid) or with a Lewis acid such as aluminum trichloride using sodium deuterated borate.

[0202] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical medicine. For additional information about carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0203] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0204] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0205] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0206] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0207] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention. DETAILED DESCRIPTION

[0208] The present application is further described in detail below with reference to examples, but the implementation methods of the present application are not limited thereto.

[0209] Example A1

[0210] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-methyl-2H-[1,3'-bipyridyl]-2-one

[0211] At room temperature, (1S, 3S)-N 1 -(5-difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (300 mg, 0.67 mmol) and 3-methylpyridin-2(1H)one (146 mg, 1.34 mmol), (1S,2S)-N 1 , N 2 1,2-Dimethylcyclohexane-1,2-diamine (19.0 mg, 0.13 mmol) and potassium phosphate (284.5 mg, 1.34 mmol) were added to DMSO (8 ml), followed by copper iodide (38.2 mg, 0.20 mmol). After the addition, the system was replaced with nitrogen and heated to 140°C for 12 hours.

[0212] After the reaction was complete, the mixture was cooled to room temperature, and water (40 mL) was added to the mixture. The mixture was then extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried, filtered, and concentrated to dryness under reduced pressure to obtain a residue. The residue was purified via a normal phase column (dichloromethane / methanol = 10:1) to afford 80 mg of a white product, 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-methyl-2H-[1,3'-bipyridyl]-2-one (yield 27.8%).

[0213] LC-MS: [M+H] + =429.1 H NMR(400MHz, Methanol-d4)δ8.20-8.18(s,2H),7.96-7.93(d,J=2.6Hz,1H),7.52-7.43(m,3H),6.91-6.52(m,2H),6.42 -6.37(t,J=6.8Hz,1H),4.A48-4.30(m,2H),2.36-2.24(m,2H),2.18-2.14(s,3H),2.08-1.97(m,2H),1.71-1.56(m,2H).

[0214] Example A2

[0215] Synthesis of 6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-5-methyl-2H-[1,3'-bipyridyl]-2-one

[0216] (1S, 3S)-N 1 -(5-difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (300 mg, 0.67 mmol) was dissolved in DMSO (5 ml), and 5-methylpyridin-2(1H)-one (73 mg, 0.67 mmol), cuprous iodide (25 mg, 0.134 mmol), potassium phosphate (284 mg, 1.34 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (19 mg, 0.134 mmol) were added. The mixture was protected by nitrogen and reacted at 140 degrees Celsius for 13 hours.

[0217] After the reaction was completed, the mixture was cooled to room temperature, quenched with 10 ml of water, extracted with ethyl acetate (50 ml x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue C. 18 Column chromatography (water / acetonitrile = 95 / 5 → acetonitrile) afforded 130 mg of 6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-5-methyl-2H-[1,3'-bipyridyl]-2-one (yield: 45%).

[0218] LC-MS: [M+H] + =429. 1H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.90(d,J=2.7Hz,1H),7.50(d,J=7.2Hz,1H),7.43-7.31(m,3H),7.27-6.83(m,2H),6.51(d,J=8 .9Hz,1H),6.38(d,J=9.2Hz,1H),4.38-4.22(m,2H),2.19-2.05(m,2H),2.03(d,J=1.1Hz,3H),1.94-1.79(m,2H),1.58-1.40(m,2H).

[0219] Example A3

[0220] Synthesis of 6-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)-4-methyl-2H-[1,3'-bipyridyl]-2-one

[0221] At room temperature, (1S, 3S)-N 1 -(5-difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (300 mg, 0.67 mmol) and 4-methylpyridin-2(1H)one (146 mg, 1.34 mmol), (1S,2S)-N 1 , N 2 1,2-Dimethylcyclohexane-1,2-diamine (19.0 mg, 0.13 mmol) and potassium phosphate (284.5 mg, 1.34 mmol) were added to DMSO (8 ml), followed by copper iodide (38.2 mg, 0.20 mmol). After the addition, the system was replaced with nitrogen and heated to 140°C for 12 hours.

[0222] After the reaction was complete, the mixture was cooled to room temperature, and water (40 mL) was added to the mixture. The mixture was then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried, filtered, and concentrated to dryness under reduced pressure to obtain a residue. The residue was purified via a normal phase column (dichloromethane / methanol = 10:1) to afford 100 mg of a white product, 6-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)-4-methyl-2H-[1,3'-bipyridyl]-2-one (yield 34.7%).

[0223] LC-MS: [M+H] + =429.

[0224] 1H NMR (400MHz, DMSO-d6) δ8.24-8.22(s,2H),7.90-7.87(d,J=2.7Hz,1H),7.52-7.46(t,J=6.6Hz,2H),7.38-7.34(m,1H),7.23-6.84(m,2H),6. A53-6.49(d,J=8.9Hz,1H),6.26-6.24(m,1H),6.16-6.11(m,1H),4.35 -4.25(m,2H),2.20-2.07(m,5H),1.95-1.81(m,2H),1.60-1.44(m,2H).

[0225] Example A4

[0226] Synthesis of 6'-((1S,3S)-3-((5-(difluoromethoxy)-4-methylpyrimidin-2-yl)amino)cyclopentyl)-2H-[1,3'-bipyridyl]-2-one

[0227] Step A: 2-chloro-5-(difluoromethoxy)4-methylpyrimidine

[0228] 2-Chloro-4-methylpyrimidin-5-ol (1 g, 7.06 mmol) was dissolved in DMF (20 ml), and cesium carbonate (3 g, 9.19 mmol) was added. The mixture was reacted under nitrogen at room temperature for 1.5 hours. Subsequently, sodium chlorodifluoroacetate (3.5 g, 22.98 mmol) was added, and the mixture was stirred at 100 degrees Celsius for 3.5 hours.

[0229] After completion of the reaction, the mixture was cooled to room temperature and quenched with 50 mL of water. The mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 100 / 1 TO 10 / 1) to give 530 mg of 2-chloro-5-(difluoromethoxy)4-methylpyrimidine (yield: 38%).

[0230] Step B: 6'-((1S,3S)-3-((5-(difluoromethoxy)-4-methylpyrimidin-2-yl)amino)cyclopentyl)-2H-[1,3'-bipyridyl]-2-one

[0231] 2-Chloro-5-(difluoromethoxy)-4-methylpyrimidine (317 mg, 1.63 mmol) and 6'-((1S,3S)-3-aminocyclopentyl)amino-2H-[1,3'-bipyridyl]-2-one hydrochloride (500 mg, 1.63 mmol) were dissolved in DMSO (5 ml) and reacted at 100°C for 6 hours.

[0232] After completion of the reaction, the mixture was cooled to room temperature and quenched with 20 mL of water. The mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 100 / 10 EA) to give 80 mg of 6'-((1S,3S)-3-((5-(difluoromethoxy)-4-methylpyrimidin-2-yl)amino)cyclopentyl)-2H-[1,3'-bipyridyl]-2-one (yield: 11%).

[0233] LC-MS: [M+H] + =429. 1 H NMR (400MHz, DMSO-d6) δ8.08(s,1H),7.92(d,J=2.7Hz,1H),7.60(d,J=6.8H z,1H),7.47(t,J=7.9Hz,1H),7.43-7.31(m,2H),7.22-6.78(m,2H),6.52(d ,J=8.9Hz,1H),6.44(d,J=9.2Hz,1H),6.27(t,J=6.7Hz,1H),4.39-4.23(m, 2H),2.24(s,3H),2.18-2.03(m,2H),1.96-1.79(m,2H),1.56-1.42(m,2H).

[0234] Example A5

[0235] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-methyl-2H-[1,3'-bipyridyl]-2-one

[0236] Step A: Synthesis of 6'-chloro-5'-methyl-2H-[1,3'-bipyridyl]-2-one

[0237] Under nitrogen protection at room temperature, pyridin-2(1H)one (1.045 g, 11.0 mmol, 1.1 equiv), 2-chloro-5-iodo-3-methylpyridine (2.5 g, 10.0 mmol, 1.0 equiv), cuprous iodide (0.286 g, 1.5 mmol, 0.15 equiv), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (0.427 g, 3.0 mmol, 0.3 equiv), potassium phosphate (4.245 g, 20.0 mmol, 2.0 equiv) were dissolved in dimethyl sulfoxide (40 ml) and reacted at 120 °C for 14 h.

[0238] After the reaction was completed, cold water (100 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 5 / 10) to obtain 1.0 g of 6'-chloro-5'-methyl-2H-[1,3'-bipyridyl]-2-one as a yellow solid (yield 45%). LC-MS: [M+H] + =221.

[0239] Step B: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-methyl-2H-[1,3'-bipyridyl]-2-one

[0240] Under nitrogen protection at room temperature, 6'-chloro-5'-methyl-2H-[1,3'-bipyridyl]-2-one (0.33 g, 1.5 mmol, 1.2 equiv), (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (0.305 g, 1.25 mmol, 1.0 equiv), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.2 g, 0.25 mmol, 0.2 equiv), potassium tert-butoxide (0.281 g, 2.5 mmol, 2.0 equiv) were dissolved in 1,4-dioxane (5 ml) and the temperature was raised to 110 °C for reaction overnight.

[0241] After the reaction was completed, water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 / 10) to obtain 0.130 g of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-methyl-2H-[1,3'-bipyridyl]-2-one (yield 20%). LC-MS: [M+H]+ = 429.

[0242] NMR data: 1H NMR (400MHz, DMSO-d6) δ8.23 (s, 2H), 7.83 (d, J = 2.6Hz, 1H), 7.58 (dd, J = 6.9, 2.1Hz, 1H),7.54-7.42(m,2H),7.28(dd,J=2.6,1.0Hz,1H),7.03(t,J=74.0Hz,1H),6.A50-6 .40(m,1H),6.26(td,J=6.7,1.4Hz,1H),5.95(d,J=7.0Hz,1H),4.53(h,J=7.0Hz,1H) ,4.34(p,J=7.0Hz,1H),2.27-2.03(m,5H),1.94(t,J=7.1Hz,2H),1.63-1.48(m,2H).

[0243] Example A6

[0244] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-4,6-dimethyl-2H-[1,3'-bipyridyl]-2-one

[0245] Step A: Synthesis of 6'-chloro-4',6-dimethyl-2H-[1,3'-bipyridyl]-2-one

[0246] Under nitrogen protection at room temperature, 6-methylpyridin-2(1H)one (2.0 g, 18.35 mmol, 1.0 equivalent), 2-chloro-5-iodo-4-methylpyridine (5.0 g, 20.2 mmol, 1.1 equivalent), cuprous iodide (1.05 g, 5.5 mmol, 0.3 equivalent), 8-hydroxyquinoline (0.88 g, 6.05 mmol, 0.33 equivalent), potassium carbonate (8.88 g, 64.22 mmol, 3.5 equivalent) were dissolved in dimethyl sulfoxide (74 ml) and reacted at 140 °C overnight.

[0247] After the reaction was completed, cold water (150 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 5 / 10) to obtain 0.407 g of 6'-chloro-4',6-dimethyl-2H-[1,3'-bipyridyl]-2-one as a yellow solid (yield 10%). LC-MS: [M+H] + =235.

[0248] Step B: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-4,6-dimethyl-2H-[1,3'-bipyridyl]-2-one

[0249] Under nitrogen protection at room temperature, 6'-chloro-4',6-dimethyl-2H-[1,3'-bipyridyl]-2-one (0.407 g, 1.74 mmol, 1.2 equivalents), (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (0.472 g, 1.45 mmol, 1.0 equivalents), methanesulfonic acid (2 -Di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.231 g, 0.29 mmol, 0.2 eq) and potassium tert-butoxide (0.325 g, 2.9 mmol, 2.0 eq) were dissolved in 1,4-dioxane (6 ml) and heated to 110 °C for overnight reaction.

[0250] After the reaction, the organic solvent was directly evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 / 10) to obtain 0.36 g of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-4,6-dimethyl-2H-[1,3'-bipyridyl]-2-one (yield 56%). LC-MS: [M+H]+ = 443.

[0251] NMR data: 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.65(s,1H),7.47(dd,J=7.2,3.6Hz,1H),7.39(dd,J =9.2,6.8Hz,1H),7.21-6.84(m,1H),6.76(d,J=6.9Hz,1H),6.42(s,1H),6.32(d,J=9.2Hz ,1H),6.23(d,J=6.8Hz,1H),4.30(dtd,J=12.1,7.1,3.9Hz,2H),2.12(dtd,J=12.4,8.6,7 .7,3.7Hz,2H),1.92-1.85(m,5H),1.81(s,3H),1.51(dtd,J=18.5,10.6,9.8,4.1Hz,2H).

[0252] Pre-HPLC separation was performed using an IG-3 column (4.6 x 250 mm x 5 μm) with a mobile phase of n-hexane / ethanol (20:80) at a flow rate of 0.6 ml / min and a column temperature of 35°C. 22 mg of the product, designated 6A, was obtained with an HPLC retention time of 12 minutes and a purity of 96.16%. NMR data: 1 H NMR (400MHz, DMSO-d6) δ8.23 (s, 2H), 7.65 (s, 1H), 7.47 (d, J = 7.3Hz, 1H), 7.40 (dd, J=9.2,6.8Hz,1H),7.12(d,J=74.1Hz,1H),6.76(d,J=6.9Hz,1H),6.42(s,1H),6.3 2(d,J=9.1Hz,1H),6.23(dt,J=6.8,1.2Hz,1H),4.29(p,J=6.6Hz,2H),2.12(dq,J= 9.7,5.3,4.6Hz,2H),1.96-1.79(m,8H),1.51(tdd,J=15.8,12.9,11.1,5.3Hz,2H).

[0253] 32 mg of product with an HPLC retention time of 15.1 minutes and a purity of 80.37% was obtained and named 6B. 1 H NMR (400MHz, DMSO-d6) δ8.23 (s, 2H), 7.65 (s, 1H), 7.47 (d, J = 7.2Hz, 1H), 7.39 ( dd,J=9.2,6.7Hz,1H),7.03(s,1H),6.76(d,J=6.9Hz,1H),6.42(s,1H),6.32(d ,J=9.1Hz,1H),6.23(d,J=6.8Hz,1H),4.31(h,J=7.1,6.6Hz,2H),2.18-2.07(m ,2H),1.89(d,J=11.4Hz,5H),1.81(s,3H),1.51(td,J=17.8,16.3,6.9Hz,2H).

[0254] Among them, * represents racemate, and abs represents absolute configuration.

[0255] Example A7

[0256] Synthesis of 3-benzyloxy-6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0257] Step A: 3-Benzyloxy-6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0258] (1S, 3S)-N 1 -(5-difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (500 mg, 1.12 mmol) was dissolved in DMSO (5 ml), and 3-(benzyloxy)pyridin-2(1H)one (449 mg, 2.24 mmol), cuprous iodide (85 mg, 0.447 mmol), potassium phosphate (309 mg, 2.24 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (32 mg, 0.224 mmol) were added, and the mixture was reacted at 140 degrees Celsius for 16 hours under nitrogen protection.

[0259] After the reaction was completed, the mixture was cooled to room temperature, quenched with 10 ml of water, extracted with ethyl acetate (50 ml x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue C. 18 Column chromatography (water / acetonitrile = 95 / 5 → acetonitrile) afforded 0.35 g of 3-benzyloxy-6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (yield: 60%).

[0260] LC-MS: [M+H] + =521. NMR data 1 H NMR(400MHz,DMSO-d6)δ1H NMR (400MHz, DMSO-d6) δ8.23 (s, 2H), 7.92 (d, J = 2.7Hz, 1H), 7.A53-7.28 (m, 7H), 7.24-6.81 (m, 4H), 6.52 (d, J = 8.9Hz, 1H), 6.18 (t, J = 7.2Hz, 1H), 5.04 (s, 2H), 4.38-4.25 (m, 2H), 2.22-2.05 (m, 2H), 1.96-1.80 (m, 2H), 1.61-1.41 (m, 2H).

[0261] Example A8

[0262] Synthesis of 6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-3-hydroxy-2H-[1,3'-bipyridyl]-2-one

[0263] Under nitrogen protection, 3-benzyloxy-6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (200 mg, 0.384 mmol) was dissolved in methanol (5 ml), 10% Pd / C (40 mg) was added, and the reaction was carried out at room temperature under a hydrogen atmosphere for 12 hours.

[0264] After the reaction is complete, the solid is filtered out and concentrated to obtain the residue C 18 Column chromatography (water / acetonitrile = 100 / 0 → 10 / 90) afforded 0.12 g of 6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-hydroxy-2H-[1,3'-bipyridyl]-2-one (yield: 72.7%).

[0265] LC-MS: [M+H] + =431. 1 H NMR(400MHz,DMSO-d6)δ1H NMR(400MHz,DMSO-d6)δ1H NMR (400MHz, DMSO-d6) δ9.14 (s, 1H), 8.22 (s, 2H), 7.93 (d, J = 2.7Hz, 1H), 7.52-7.32 (m, 2H), 7.22-6.79 (m, 3H), 6.79-6.68 (m, 1H), 6.53(d,J=8.9Hz,1H),6.16(t,J=7.1Hz,1H),4.38-4.21(m,2H),2.21-2.03(m,2H),1.96-1.78(m,J=6.7Hz,2H),1.62-1.40(m,2H).

[0266] Example A9

[0267] Synthesis of 3-chloro-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl-)amino)cyclopentyl)amino-2H-[1,3'-bipyridyl]-2-one

[0268] Step A: Synthesis of (1S,3S)-N1-(5-difluoromethoxy)pyrimidin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[0269] Under nitrogen protection at room temperature, (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (7.32 g, 30.0 mmol, 1.0 equiv), 2-fluoro-5-iodopyridine (8.03 g, 36 mmol, 1.2 equiv), and potassium carbonate (20.73 g, 150 mmol, 5.0 equiv) were dissolved in dimethyl sulfoxide (140 ml) and reacted at 140 degrees Celsius overnight.

[0270] After the reaction was completed, cold water (200 mL) was added to quench the reaction and then extracted with ethyl acetate (250 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 5 / 10) to obtain 10 g of (1S,3S)-N1-(5-difluoromethoxy)pyrimidin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine as a white solid (yield 75%). LC-MS: [M+H] + =448.

[0271] Step B: Synthesis of 3-chloro-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl-)amino)cyclopentyl)amino-2H-[1,3'-bipyridyl]-2-one

[0272] Under nitrogen protection at room temperature, (1S,3S)-N1-(5-difluoromethoxy)pyrimidin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (0.448 g, 1.0 mmol, 1.0 equiv), 3-chloropyridin-2(1H)-one (0.260 g, 2.0 mmol, 2.0 equiv), cuprous iodide (0.076 g, 0.4 mmol, 0.4 equiv), N1,N2-dimethylcyclohexane-1,2-diamine (0.029 g, 0.2 mmol, 0.2 equiv), potassium phosphate (0.673 g, 3.0 mmol, 3.0 equiv) were dissolved in dimethyl sulfoxide (4 ml), and the temperature was raised to 140 °C for reaction overnight.

[0273] After the reaction was completed, cold water (50 ml) was added to quench the reaction and then extracted with ethyl acetate (50 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 0.1 g of 3-chloro-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl-)amino)cyclopentyl)amino-2H-[1,3'-bipyridine]-2-one (yield 22%).

[0274] LC-MS: [M+H] + =449. NMR data: 1H NMR(400MHz,DMSO-d6)δ8.23(s,2H),7.95(d,J=2.7Hz,1H),7.81(dd,J=7.3,1 .9Hz,1H),7.65(dd,J=6.8,1.9Hz,1H),7.A53-7.39(m,2H),7.22-6.84(m,2H) ,6.53(d,J=8.9Hz,1H),6.30(t,J=7.1Hz,1H),4.31(h,J=6.7Hz,2H),2.12(dq ,J=12.1,7.2Hz,2H),1.88(tdd,J=13.2,10.5,6.3Hz,2H),1.59-1.43(m,2H).

[0275] Example A10

[0276] Synthesis of 3-cyclopropyl-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0277] Under nitrogen protection at room temperature, (1S,3S)-N1-(5-difluoromethoxy)pyrimidin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (0.224 g, 0.5 mmol, 1.0 equiv), 3-cyclopropylpyridin-2(1H)-one (0.10 g, 0.735 mmol, 1.5 equiv), cuprous iodide (0.038 g, 0.2 mmol, 0.4 equiv), N1,N2-dimethylcyclohexane-1,2-diamine (0.015 g, 0.1 mmol, 0.2 equiv), potassium phosphate (0.320 g, 1.5 mmol, 3.0 equiv) were dissolved in dimethyl sulfoxide (2 ml), and the temperature was raised to 140 °C for reaction overnight.

[0278] After the reaction was completed, cold water (25 ml) was added to quench the reaction and then extracted with ethyl acetate (50 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 0.077 g of 3-cyclopropyl-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (yield 31%).

[0279] LC-MS: [M+H] + =455. NMR data: 1H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.91(d,J=2.7Hz,1H),7.48(d,J=7.2Hz,1H),7 .43-7.36(m,2H),7.22-6.85(m,3H),6.52(d,J=8.9Hz,1H),6.17(t,J=6.8Hz,1H),4. 30(p,J=6.6Hz,2H),2.18-2.08(m,2H),2.01(ddd,J=8.5,5.3,3.1Hz,1H),1.95-1.8 3(m,2H),1.51(ddd,J=18.9,13.8,7.3Hz,2H),0.88-0.81(m,2H),0.67-0.60(m,2H).

[0280] Example A11

[0281] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2',6-dimethyl-2H-[1,3'-bipyridyl]-2-one

[0282] Step A: 6-chloro-2,6-dimethyl-2H-[1,3'-bipyridyl]-2-one

[0283] Under nitrogen protection at room temperature, 6-methylpyridin-2(1H)one (2.0 g, 18.35 mmol, 1.0 equivalent), 6-chloro-3-iodo-2-methylpyridine (5.0 g, 20.2 mmol, 1.1 equivalent), cuprous iodide (1.05 g, 5.5 mmol, 0.3 equivalent), 8-hydroxyquinoline (0.88 g, 6.05 mmol, 0.33 equivalent), potassium carbonate (8.88 g, 64.22 mmol, 3.5 equivalent) were dissolved in dimethyl sulfoxide (40 ml) and reacted at 140 °C overnight.

[0284] After the reaction was completed, cold water (150 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 5 / 10) to obtain 0.203 g of 6-chloro-2,6-dimethyl-2H-[1,3'-bipyridyl]-2-one as a yellow solid (yield 5%). LC-MS: [M+H] + =235.

[0285] Step B: 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2',6-dimethyl-2H-[1,3'-bipyridyl]-2-one

[0286] Under nitrogen protection at room temperature, 6-chloro-2,6-dimethyl-2H-[1,3'-bipyridyl]-2-one (0.203 g, 0.86 mmol, 1.2 equiv), (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (0.24 g, 0.72 mmol, 1.0 equiv), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.12 g, 0.15 mmol, 0.2 equiv), potassium tert-butoxide (0.16 g, 1.45 mmol, 2.0 equiv) were dissolved in 1,4-dioxane (8 ml) and the temperature was raised to 110 °C for reaction overnight.

[0287] After the reaction was completed, the organic solvent was directly dried by spin drying, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 / 10) to obtain 0.18 g of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2',6-dimethyl-2H-[1,3'-bipyridyl]-2-one.

[0288] LC-MS: [M+H]+ = 443. 1H NMR (400 MHz, DMSO-d6) δ 8.26–8.21 (s, 2H), 7.52–7.44 (dd, J = 7.2, 2.3 Hz, 1H), 7.42–7.35 (dd, J = 9.2, 6.8 Hz, 1H), 7.23–7.02 (m, 2H), 6.86–6.75 (m, 1H), 6.41–6.29 (dd, J = 24.5, 8.9 Hz, 2H), 6.25–6.20 (m, 1H), 4.36–4.22 (m, 2H), 2.22–2.05 (m, 2H), 1.95–1.84 (m, 8H), 1.59–1.44 (m, 2H).

[0289] After Pre-SFC separation (method: chromatographic column model IG-3: 4.6*250mm*5um, mobile phase: n-hexane / ethanol = 20:80, flow rate: 0.6 ml / min, column temperature: 35°C), 25 mg of the front peak (RT = 10.53 min, purity: 99%, named A11A) and 35 mg of the back peak (RT = 12.985 min, purity: 76%, named A11B) were obtained.

[0290] Example A12

[0291] Synthesis of ethyl 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylate

[0292] Step A: 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylic acid ethyl ester

[0293] Under nitrogen protection at room temperature, (1S,3S)-N1-(5-difluoromethoxy)pyrimidin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (0.642 g, 1.5 mmol, 1.0 equiv), ethyl 2-oxo-1,2-dihydropyridine-3-carboxylate (0.502 g, 3 mmol, 2 equiv), cuprous iodide (0.114 g, 0.6 mmol, 0.4 equiv), N1,N2-dimethylcyclohexane-1,2-diamine (0.043 g, 0.3 mmol, 0.2 equiv), potassium phosphate (0.320 g, 1.5 mmol, 3.0 equiv) were dissolved in dimethyl sulfoxide (6 ml) and heated to 140 °C for overnight reaction.

[0294] After the reaction was completed, cold water (25 ml) was added to quench the reaction and then extracted with ethyl acetate (50 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 0.19 g of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylic acid ethyl ester.

[0295] LC-MS: [M+H] + =487. NMR data: 1H NMR(400MHz, DMSO-d6)δ8.23(s,2H),8.06(dd,J=7.1,2.2Hz,1H),8.00–7.87(m,2H),7.48(d,J =7.2Hz,1H),7.41(dd,J=8.9,2.7Hz,1H),7.21–6.85(m,2H),6.53(d,J=8.9Hz,1H),6.36(t,J=6 .9Hz,1H),4.31(h,J=6.7Hz,2H),4.21(q,J=7.1Hz,2H),2.13(ddt,J=14.6,12.4,7.1Hz,2H),1 .88(tdd,J=13.3,10.6,6.4Hz,2H), 1.51(ddd,J=18.6,13.9,7.2Hz,2H), 1.25(t,J=7.1Hz,3H).

[0296] Example A13

[0297] Synthesis of 6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile

[0298] Step A: 6-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile

[0299] At room temperature, (1S,3S)-N1-(5-difluoromethoxy)pyrimidin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (300 mg, 0.67 mmol), 2-oxo-1,2-dihydropyridine-3-carbonitrile (161 mg, 1.34 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (19.0 mg, 0.13 mmol), and potassium phosphate (284.5 mg, 1.34 mmol) were added to DMSO (8 ml), followed by cuprous iodide (38.2 mg, 0.20 mmol). After the addition was complete, the atmosphere was replaced with nitrogen and the temperature was raised to 140°C for 12 hours.

[0300] After the reaction was complete, the mixture was cooled to room temperature, and water (40 mL) was added to the mixture, followed by extraction with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried, filtered, and concentrated to dryness under reduced pressure to obtain a residue. The residue was purified by normal phase column chromatography (dichloromethane / methanol = 10:1) to yield 18 mg of 6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile.

[0301] LC-MS: [M+H] + =440. 1H NMR data (400 MHz, DMSO-d6) δ 8.24–8.20 (m, 3H), 8.06–8.03 (dd, J = 6.8, 2.1 Hz, 1H), 7.99–7.96 (d, J = 2.7 Hz, 1H), 7.51–7.42 (m, 2H), 7.23–6.84 (m, 2H), 6.57–6.51 (d, J = 9.0 Hz, 1H), 6.49–6.43 (t, J = 7.0 Hz, 1H), 4.37–4.26 (m, 2H), 2.20–2.07 (m, 2H), 1.96–1.81 (m, 2H), 1.60–1.43 (m, 2H).

[0302] Example A14

[0303] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-3-fluoro-2H-[1,3'-bipyridyl]-2-one

[0304] Under nitrogen protection at room temperature, (1S,3S)-N1-(5-difluoromethoxy)pyrimidin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (0.448 g, 1.0 mmol, 1.0 equiv), 3-fluoropyridin-2(1H)one (0.226 g, 2.0 mmol, 2.0 equiv), cuprous iodide (0.076 g, 0.4 mmol, 0.4 equiv), N1,N2-dimethylcyclohexane-1,2-diamine (0.029 g, 0.2 mmol, 0.2 equiv), potassium phosphate (0.673 g, 3.0 mmol, 3.0 equiv) were dissolved in dimethyl sulfoxide (4 ml), and the temperature was raised to 140 °C for reaction overnight.

[0305] After the reaction was completed, cold water (50 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-3-fluoro-2H-[1,3'-bipyridyl]-2-one. LC-MS: [M+H] + =433.

[0306] NMR data: 1 H NMR(400MHz, DMSO-d6)δ8.23(s,2H),7.96(d,J=2.7Hz,1H),7.54–7.39(m,4H),7.22–6.84(m,2H),6.54(d,J=8.9Hz,1H),6.24 (td,J=7.3,4.8Hz,1H),4.31(h,J=6.8,6.3Hz,2H),2.19–2.06(m,2H),1.88(tdd,J=13.2,10.4,6.3Hz,2H),1.58–1.45(m,2H).

[0307] Example A15

[0308] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2'-methyl-2H-[1,3'-bipyridyl]-2-one

[0309] Step A: 6-Chloro-2-methyl-2H-[1,3'-bipyridyl]-2-one

[0310] Under nitrogen protection at room temperature, 6-methylpyridin-2(1H)one (2.0 g, 21.0 mmol, 1.0 eq), 6-chloro-3-iodo-2-methylpyridine (5.85 g, 23.1 mmol, 1.1 eq), cuprous iodide (1.21 g, 6.3 mmol, 0.3 eq), 8-hydroxyquinoline (1.0 g, 6.9 mmol, 0.33 eq), potassium carbonate (10.1 g, 74.7 mmol, 3.5 eq) were dissolved in dimethyl sulfoxide (40 ml) and reacted at 140 °C for 2 hours.

[0311] After the reaction was completed, cold water (150 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 5 / 10) to obtain 0.17 g of 6-chloro-2-methyl-2H-[1,3'-bipyridyl]-2-one as a yellow solid (yield 3.6%). LC-MS: [M+H] + =221.

[0312] Step B: 6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2'-methyl-2H-[1,3'-bipyridyl]-2-one

[0313] Under nitrogen protection at room temperature, 6-chloro-2-methyl-2H-[1,3'-bipyridyl]-2-one (0.17 g, 0.77 mmol, 1.0 equiv), (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (0.207 g, 0.84 mmol, 1.1 equiv), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.12 g, 0.15 mmol, 0.2 equiv), potassium tert-butoxide (0.17 g, 1.54 mmol, 2.0 equiv) were dissolved in 1,4-dioxane (8 ml) and the temperature was raised to 110 °C for reaction overnight.

[0314] After the reaction, the organic solvent was directly evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 / 10) to obtain 6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2'-methyl-2H-[1,3'-bipyridyl]-2-one. LC-MS: [M+H]+ = 429.

[0315] NMR data: 1 H NMR (400MHz, DMSO-d6) δ7.42–7.38(s,2H),6.69–6.62(m,3H),6.40–6.33(m,1H),6.22–5.85(m,2H),5.66–5.59(d,J=9.6Hz,1H),5.56–5.50(d,J= 8.6Hz,1H),5.46–5.41(t,J=6.7Hz,1H),3.52–3.39(m,2H),1.37–1.23(m ,2H),1.20–1.13(s,3H),1.10–0.99(t,J=6.8Hz,2H),0.77–0.60(m,2H)..

[0316] Example A16

[0317] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-5'-(trifluoromethyl)-2H-[1,3'-bipyridyl]-2-one

[0318] At room temperature, 5-bromo-2-fluoro-3-trifluoromethylpyridine (500.0 mg, 2.05 mmol) and (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine hydrochloride (626 mg, 2.25 mmol) were dissolved in DMSO (10 ml), followed by the addition of K2CO3 (1.7 g, 12.3 mmol). After the addition, the system was heated to 100 degrees Celsius and reacted for 3 hours.

[0319] After the reaction was complete, the mixture was cooled to room temperature, and water (40 mL) was added to the system. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried, filtered, and concentrated to dryness under reduced pressure to obtain a residue. The residue was purified by normal phase column chromatography (n-hexane / ethyl acetate = 1:2) to obtain 600 mg of the white product (1S,3S)-N1-(5-bromo-3-trifluoromethylpyridin-2-yl)-N3-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (yield 62%). LC-MS: [M+H] + =468.

[0320] Step B: 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-5'-(trifluoromethyl)-2H-[1,3'-bipyridyl]-2-one

[0321] At room temperature, (1S,3S)-N1-(5-bromo-3-trifluoromethylpyridin-2-yl)-N3-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (300 mg, 0.64 mmol), pyridin-2(1H)one (122 mg, 1.28 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (18.2 mg, 0.13 mmol), and potassium phosphate (408.5 mg, 1.92 mmol) were added to DMSO (8 ml), followed by cuprous iodide (24.6 mg, 0.128 mmol). After the addition, the atmosphere was replaced with nitrogen, and the temperature of the system was raised to 140°C for 12 hours.

[0322] After the reaction was complete, the mixture was cooled to room temperature, and water (40 mL) was added to the system. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried, filtered, and concentrated to dryness under reduced pressure to obtain a residue. The residue was purified by normal phase column chromatography (dichloromethane / methanol = 10:1) to obtain 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-5'-(trifluoromethyl)-2H-[1,3'-bipyridyl]-2-one. LC-MS: [M+H]+ = 483.

[0323] NMR data: 1 H NMR(400MHz, DMSO-d6)δ8.31–8.28(d,J=2.5Hz,1H),8.25–8.22(s,2H),7.90–7.8 7(d,J=2.5Hz,1H),7.71–7.66(dd,J=7.0,2.1Hz,1H),7.53–7.46(m,2H),7.23–6.8 4(t,J=74.0Hz,1H),6.49–6.45(d,J=9.2Hz,1H),6.35–6.28(m,2H),4.76–4.65(m, 1H),4.39–4.29(m,1H),2.18–2.06(m,,2H),2.04–1.90(m,2H),1.70–1.49(m,2H).

[0324] Example A17

[0325] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridyl]-2-one

[0326] Under nitrogen protection at room temperature, 5-bromo-2,3-difluoropyridine (0.464 g, 2.4 mmol, 1.2 equiv), (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (0.488 g, 2 mmol, 1.0 equiv), and potassium carbonate (1.4 g, 10.0 mmol, 5.0 equiv) were dissolved in dimethyl sulfoxide (8 ml) and reacted at 140 degrees Celsius for 14 hours.

[0327] After the reaction was completed, cold water (50 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 5 / 10) to obtain 0.641 g of (1S,3S)-N1-(5-bromo-3-fluoropyridin-2-yl)-N3-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine as a yellow solid (yield 77%). LC-MS: [M+H] + =418.

[0328] Step B: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridyl]-2-one

[0329] Under nitrogen protection at room temperature, (1S,3S)-N1-(5-bromo-3-fluoropyridin-2-yl)-N3-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (0.641 g, 1.537 mmol, 1.0 equiv), pyridin-2(1H)one (0.292 g, 3.08 mmol, 2.0 equiv), cuprous iodide (0.117 g, 0.615 mmol, 0.4 equiv), N1,N2-dimethylcyclohexane-1,2-diamine (0.044 g, 0.307 mmol, 0.2 equiv), potassium phosphate (0.98 g, 4.6 mmol, 3.0 equiv) were dissolved in dimethyl sulfoxide (6 ml) and the temperature was raised to 140 °C for reaction overnight.

[0330] After the reaction was completed, cold water (50 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridyl]-2-one. LC-MS: [M+H] + =433.

[0331] NMR data: 1H NMR(400MHz, DMSO-d6)δ8.23(s,2H),7.84(d,J=2.1Hz,1H),7.64(dd,J=6.9,2.1Hz,1H),7.60–7.42(m,3H),7.22–6.84(m,2H),6.50–6.42( m,1H),6.28(td,J=6.7,1.4Hz,1H),4.50(h,J=6.9Hz,1H),4.33(p,J=6.8Hz,1H),2.18–2.07(m,2H),1.99–1.89(m,2H),1.65–1.49(m,2H).

[0332] Referring to the preparation methods of compound 17 and compound 34, compound A17-D was prepared:

[0333] Example A18

[0334] Synthesis of 5'-chloro-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0335] Step A: Synthesis of (1S,3S)-N1-(5-bromo-3-chloropyridin-2-yl)-N3-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0336] Under nitrogen protection at room temperature, 5-bromo-3-chloro-2-fluoropyridine (0.502 g, 2.4 mmol, 1.2 equiv), (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (0.488 g, 2 mmol, 1.0 equiv), and potassium carbonate (1.4 g, 10.0 mmol, 5.0 equiv) were dissolved in dimethyl sulfoxide (8 ml) and reacted at 140 degrees Celsius for 14 hours.

[0337] After the reaction was completed, cold water (50 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 5 / 10) to obtain 0.706 g of (1S,3S)-N1-(5-bromo-3-chloropyridin-2-yl)-N3-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine as a yellow solid (yield 82%). LC-MS: [M+H] + =434.

[0338] Step B: Synthesis of 5'-chloro-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0339] Under nitrogen protection at room temperature, (1S,3S)-N1-(5-bromo-3-chloropyridin-2-yl)-N3-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (0.706 g, 1.627 mmol, 1.0 equiv), pyridin-2(1H)one (0.31 g, 3.25 mmol, 2.0 equiv), cuprous iodide (0.124 g, 0.65 mmol, 0.4 equiv), N1,N2-dimethylcyclohexane-1,2-diamine (0.046 g, 0.325 mmol, 0.2 equiv), potassium phosphate (1.04 g, 4.9 mmol, 3.0 equiv) were dissolved in dimethyl sulfoxide (6.5 ml) and the temperature was raised to 140 °C for reaction overnight.

[0340] After the reaction was completed, cold water (50 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 5'-chloro-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one. LC-MS: [M+H] + =449.

[0341] NMR data: 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),8.00(d,J=2.3Hz,1H),7.76(d,J=2.3Hz,1H),7.64 (dd,J=6.9,2.1Hz,1H),7.49(ddd,J=8.7,6.7,2.0Hz,2H),7.03(t,J=74.0Hz,1H),6.54( d,J=7.3Hz,1H),6.49–6.43(m,1H),6.29(td,J=6.7,1.4Hz,1H),4.56(p,J=7.1Hz,1H),4 .33(q,J=6.8Hz,1H),2.12(qt,J=7.5,3.6Hz,2H),2.01–1.90(m,2H),1.67–1.50(m,2H).

[0342] Example A19

[0343] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2H-[1,3'-bipyridine]-5'-carboxamide

[0344] Step A: 5-Bromo-2-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)nicotinonitrile

[0345] 5-Bromo-2-fluoronicotinonitrile (500 mg, 2.5 mmol) and (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine hydrochloride (770 mg, 2.75 mmol) were dissolved in DMSO (10 ml) at room temperature, followed by the addition of K2CO3 (1.38 g, 10.0 mmol). After the addition, the system was heated to 100°C and reacted for 30 minutes.

[0346] After the reaction was complete, the mixture was cooled to room temperature, and water (40 mL) was added to the system, followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried, filtered, and concentrated to dryness under reduced pressure to obtain a residue. The residue was purified by normal phase column chromatography (n-hexane / ethyl acetate = 1:2) to obtain 700 mg of 5-bromo-2-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)nicotinonitrile (yield 66%). LC-MS: [M+H] + =425.

[0347] Step B: 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2H-[1,3'-bipyridine]-5'-carboxamide

[0348] 5-Bromo-2-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)nicotinonitrile (300 mg, 0.70 mmol), pyridin-2(1H)one (134 mg, 1.40 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (20.0 mg, 0.14 mmol), and potassium carbonate (195.2 mg, 1.40 mmol) were added to DMSO (8 ml) at room temperature, followed by cuprous iodide (27.1 mg, 0.14 mmol). After the addition was complete, the atmosphere was replaced with nitrogen, and the system was heated to 140°C for 12 hours.

[0349] After the reaction was complete, the mixture was cooled to room temperature, and water (40 mL) was added to the system. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried, filtered, and concentrated to dryness under reduced pressure to obtain a residue. The residue was purified by normal phase column chromatography (dichloromethane / methanol = 10:1) to obtain 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2H-[1,3'-bipyridine]-5'-carboxamide. LC-MS: [M+H]+ = 458.

[0350] NMR data: 1H NMR (400 MHz, DMSO-d6) δ8.96–8.90 (d, J=6.8 Hz, 1H), 8.28–8.22 (s, 2H), 8.20–8.18 (d, J=2.5 Hz, 1H), 8.09–8.00 (m, 2H), 7.70–7.65 (dd, J=6.9, 2.1 Hz, 1H), 7.55–7.43 (m, 3H), 7.24–6.84 (t, J=74.0 Hz, 1 H),6.51–6.45(d,J=9.2Hz,1H),6.36–6.29(td,J=6.7,1.4Hz,1H),4.57–4.47(q,J=6.7Hz,1H),4.3 6–4.27(q,J=7.0Hz,1H),2.28–2.07(m,2H),2.04–1.93(m,1H),1.91–1.81(m,1H),1.65–1.40(m,2H)

[0351] Example A20

[0352] Synthesis of 5'-((Benzyloxy)methyl-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0353] Step A: 2-chloro-5-iodopyridine-3-methanol

[0354] Under nitrogen protection at room temperature, methyl 2-chloro-5-iodonicotinate (1.0 g, 3.3 mmol) and anhydrous calcium chloride (1.3 g, 11.5 mmol) were dissolved in anhydrous ethanol (20 ml) and stirred for 15 minutes. Then, solid sodium borohydride (0.51 g, 13.2 mmol) was added in portions and the reaction was allowed to react at room temperature overnight.

[0355] After the reaction was complete, saturated aqueous ammonium chloride (150 mL) was added to quench the reaction and then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was used directly in the next step without purification to obtain 0.85 g of 2-chloro-5-iodopyridine-3-methanol as a yellow solid (yield 94.4%). LC-MS: [M+H] + =270.

[0356] Step B: 3-(Benzyloxy)methyl-2-chloro-5-iodopyridine

[0357] Under nitrogen protection at room temperature, 2-chloro-5-iodopyridine-3-methanol (0.85 g, 3.1 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml), and then the system was cooled to 0 degrees Celsius. Sodium hydride (0.16 g, 4.0 mmol, 60% content) was added in batches. After stirring for 15 minutes, benzyl bromide (0.68 g, 3.7 mmol) was added and the reaction was carried out at 0 degrees for one hour.

[0358] After the reaction was completed, saturated aqueous ammonium chloride (150 mL) was added to quench the reaction and then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 20) to obtain 0.95 g of 3-(benzyloxy)methyl-2-chloro-5-iodopyridine as a yellow solid (yield 84%). LC-MS: [M+H] + =360.

[0359] Step C: 5-Benzyloxymethyl-6-chloro-2H-[1,3'-bipyridyl]-2-one

[0360] At room temperature, 3-(benzyloxy)methyl-2-chloro-5-iodopyridine (0.95 g, 2.6 mmol), pyridin-2(1H)one (0.5 g, 5.2 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (0.075 g, 0.52 mmol), and potassium phosphate (0.73 g, 5.2 mmol) were added to DMSO (20 ml), followed by cuprous iodide (0.1 g, 0.52 mmol). After the addition, the atmosphere was replaced with nitrogen, and the temperature was raised to 140°C for 12 hours.

[0361] After the reaction was complete, the mixture was cooled to room temperature, and water (40 mL) was added to the system. The mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried, filtered, and concentrated to dryness under reduced pressure to obtain a residue. The residue was purified by normal phase column chromatography (ethyl acetate / n-hexane = 4:1) to obtain 200 mg of the white product, 5-benzyloxymethyl-6-chloro-2H-[1,3'-bipyridyl]-2-one (yield 23.2%). LC-MS: [M+H]+ = 327.

[0362] Step D: 5-(Benzyloxy)methyl-6-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0363] Under nitrogen protection at room temperature, 5-benzyloxymethyl-6-chloro-2H-[1,3'-bipyridyl]-2-one (0.2 g, 0.6 mmol), (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (0.179 g, 0.72 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (0.097 g, 0.12 mmol), potassium tert-butoxide (0.27 g, 2.4 mmol) were dissolved in 1,4-dioxane (8 ml) and the temperature was raised to 110 degrees Celsius for reaction overnight.

[0364] After the reaction, the organic solvent was directly dried by spin-drying, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 / 10) to obtain 5'-((benzyloxy)methyl-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one. LC-MS: [M+H]+ = 535.

[0365] NMR data: 1H NMR (400 MHz, DMSO-d6) δ8.24–8.21 (s, 2H), 7.97–7.94 (d, J = 2.6 Hz, 1H), 7.64–7.60 (m, 1H), 7.52–7.44 (m, 3H), 7.41–7.27 (m, 5H), 7.23–6.84 (t, J = 74.0 Hz, 1H), 6.48–6.43 (m, 1H),6.31–6.25(td,J=6.7,1.4Hz,1H),5.96–5.90(d,J=6.9Hz,1H),4.60–4.46(d,J=22 .1Hz,5H),4.34–4.26(m,1H),2.21–2.04(m,2H),1.99–1.83(m,2H),1.60–1.43(m,2H).

[0366] Example A21

[0367] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5'-carbonitrile

[0368] 5-Bromo-2-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)nicotinonitrile (300 mg, 0.70 mmol), pyridin-2(1H)one (134 mg, 1.40 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (20.0 mg, 0.14 mmol), and potassium phosphate (300 mg, 1.40 mmol) were added to DMSO (8 ml) at room temperature, followed by cuprous iodide (27.1 mg, 0.14 mmol). After the addition, the atmosphere was replaced with nitrogen, and the temperature was raised to 140°C for 12 hours.

[0369] After the reaction was complete, the mixture was cooled to room temperature, and water (40 mL) was added to the system. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried, filtered, and concentrated to dryness under reduced pressure to obtain a residue. The residue was purified by normal phase column chromatography (dichloromethane / methanol = 10:1) to obtain 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5'-carbonitrile. LC-MS: [M+H]+ = 440.

[0370] NMR data: 1H NMR (400MHz, DMSO-d6) δ8.32–8.29 (d, J=2.6Hz, 1H), 8.25–8.22 (s, 2H), 8.08–8.06 (d, J=2.7Hz, 1H), 7.68–7.64 (dd, J=7.0, 2.0Hz, 1H), 7.53–7.46 (m, 2H), 7.37–7.33 (d, J=7.2Hz, 1H), 7.23–6.84(t,J=74.0Hz,1H),6.50–6.45(m,1H),6.34–6.27(m,1H),4.67–4.54(q,J=7.3Hz ,1H),4.41–4.30(q,J=6.9Hz,1H),2.19–2.06(m,2H),2.05–1.89(m,2H),1.70–1.49(m,2H).

[0371] Example A22

[0372] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylic acid

[0373] Step A: Synthesis of ethyl 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylate

[0374] Under nitrogen protection at room temperature, (1S,3S)-N1-(5-difluoromethoxy)pyrimidin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (0.642 g, 1.5 mmol, 1.0 equiv), ethyl 2-oxo-1,2-dihydropyridine-3-carboxylate (0.502 g, 3 mmol, 2 equiv), cuprous iodide (0.114 g, 0.6 mmol, 0.4 equiv), N1,N2-dimethylcyclohexane-1,2-diamine (0.043 g, 0.3 mmol, 0.2 equiv), potassium phosphate (0.320 g, 1.5 mmol, 3.0 equiv) were dissolved in dimethyl sulfoxide (6 ml) and heated to 140 °C for overnight reaction.

[0375] After the reaction was completed, cold water (25 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 0.19 g of ethyl 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylate as a yellow solid (yield 26%). LC-MS: [M+H] + =487.

[0376] Step B: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylic acid

[0377] Ethyl 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylate (0.140 g, 0.288 mmol, 1.0 eq) and lithium hydroxide monohydrate (0.085 g, 2.01 mmol, 7.0 eq) were dissolved in a mixture of ethanol (2 ml) and water (3 ml) at room temperature and stirred at room temperature for 4 hours.

[0378] After the reaction, the pH of the reaction solution was adjusted to approximately 6 with 1M dilute hydrochloric acid solution. A large amount of light yellow solid precipitated and was filtered to obtain 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylic acid. LC-MS: [M+H] + =459.

[0379] NMR data: 1 H NMR(400MHz, DMSO-d6)δ14.36(s,1H),8.44(dd,J=7.3,2.1Hz,1H),8.40–8.12(m,3H),8.04(d,J=2.7Hz,1H),7.66–7.42(m,2H),7.22–6.84( m,2H),6.76(t,J=7.0Hz,1H),6.56(d,J=8.9Hz,1H),4.46–4.24(m,2H),2.27–2.04(m,2H),2.03–1.78(m,2H),1.52(tt,J=13.9,7.4Hz,2H).

[0380] Example A23

[0381] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxylic acid

[0382] Step A: Synthesis of ethyl 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxylate

[0383] Under nitrogen protection at room temperature, (1S,3S)-N1-(5-difluoromethoxy)pyrimidin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (0.642 g, 1.5 mmol, 1.0 equiv), ethyl 2-oxo-1,2-dihydropyridine-4-carboxylate (0.502 g, 3 mmol, 2 equiv), cuprous iodide (0.114 g, 0.6 mmol, 0.4 equiv), N1,N2-dimethylcyclohexane-1,2-diamine (0.043 g, 0.3 mmol, 0.2 equiv), potassium phosphate (0.320 g, 1.5 mmol, 3.0 equiv) were dissolved in dimethyl sulfoxide (6 ml) and the temperature was raised to 140 °C for reaction overnight.

[0384] After the reaction was completed, cold water (25 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 0.146 g of ethyl 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxylate as a yellow solid (yield 22%). LC-MS: [M+H] + =487.

[0385] Step B: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxylic acid

[0386] Ethyl 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxylate (0.103 g, 0.211 mmol, 1.0 eq) and lithium hydroxide monohydrate (0.085 g, 2.01 mmol, 7.0 eq) were dissolved in a mixture of ethanol (2 ml) and water (3 ml) at room temperature and stirred at room temperature for 4 hours.

[0387] After the reaction, the pH of the reaction solution was adjusted to approximately 6 with 1M dilute hydrochloric acid solution. A large amount of light yellow solid precipitated and was filtered to obtain 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxylic acid. LC-MS: [M+H] + =459.

[0388] NMR data: 1 H NMR (400MHz, DMSO-d6) δ13.68(s,1H),8.23(s,2H),7.98(d,J=2.7Hz,1H),7.73(d,J=7.0Hz,1H),7.49(d,J=7.1Hz,2H),7.37–6.78(m,3H),6.60( dt,J=7.0,3.1Hz,2H),4.31(h,J=6.7Hz,2H),2.13(dq,J=20.4,7.3,6.4H z,2H),1.90(dq,J=17.5,6.6Hz,2H),1.53(qd,J=14.7,13.2,8.0Hz,2H).

[0389] Example A24

[0390] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-3-(hydroxymethyl)-2H-[1,3'-bipyridyl]-2-one

[0391] Step A: 3-(((Triisopropylsilyl)oxy)methyl)pyridin-2(1H)one

[0392] At room temperature, 3-hydroxymethylpyridin-2(1H)one (0.5 g, 4.0 mmol) was added to anhydrous DMF (10 ml), and then imidazole (0.54 g, 4.0 mmol) and triisopropylsilyl chloride (2.0 g, 5.2 mmol) were added to the system. The nitrogen atmosphere was replaced twice, and then the reaction was carried out at room temperature for 12 hours.

[0393] After the reaction was complete, water (40 mL) was added to the system and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed twice with saturated brine (30 mL), washed twice with a 1 M aqueous solution of hydrogen chloride, dried, and spin-dried. The product was used directly in the next step without purification to obtain 1.05 g of a light yellow liquid 3-(((triisopropylsilyl)oxy)methyl)pyridin-2(1H)one (yield 93%). LC-MS: [M+H] + =282.

[0394] Step B: 6-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)-3-((triisopropylsilyloxy)oxy)methyl)-2H-[1,3'-bipyridyl]-2-one

[0395] At room temperature, (1S,3S)-N1-(5-difluoromethoxy)pyrimidin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (300 mg, 0.67 mmol), 3-(((triisopropylsilyl)oxy)methyl)pyridin-2(1H)one (378 mg, 1.34 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (19.0 mg, 0.13 mmol), and potassium phosphate (284.5 mg, 1.34 mmol) were added to DMSO (8 ml), followed by cuprous iodide (38.2 mg, 0.20 mmol). After the addition was complete, the atmosphere was replaced with nitrogen and the temperature was raised to 140 degrees Celsius for 12 hours.

[0396] After the reaction was complete, the mixture was cooled to room temperature, and water (40 mL) was added to the system. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried, filtered, and concentrated to dryness under reduced pressure to obtain a residue. The residue was purified by normal phase column chromatography (dichloromethane / methanol = 10:1) to obtain 130 mg of a white product, 6-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)-3-((triisopropylsilyloxy)oxy)methyl)-2H-[1,3'-bipyridyl]-2-one (yield 32%). LC-MS: [M+Na] + =623.

[0397] Step C: 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-3-(hydroxymethyl)-2H-[1,3'-bipyridyl]-2-one

[0398] At room temperature, 6-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)-3-((triisopropylsilyloxy)oxy)methyl)-2H-[1,3'-bipyridyl]-2-one (130 mg) was dissolved in tetrahydrofuran (5 ml), and then a pyridine hydrofluoride solution (2.5 ml) was added and the mixture was reacted at room temperature for 12 hours.

[0399] After the reaction, 20 ml of water was added for dilution, followed by the slow addition of a 2 M aqueous solution of potassium carbonate to adjust the pH to approximately 6. Ethyl acetate (20 ml) was then added for extraction three times, dried, and spun down. The residue was purified by normal phase column chromatography (dichloromethane / methanol = 10:1) to yield 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-3-(hydroxymethyl)-2H-[1,3'-bipyridyl]-2-one. LC-MS: [M+H] + =445.

[0400] NMR data: 1 H NMR(400MHz, DMSO-d6)δ7.43–7.37(s,2H),7.10–7.07(d,J=2.7Hz,1H),6.70–6.6 2(t,J=7.4Hz,3H),6.58–6.53(dd,J=8.9,2.7Hz,1H),6.40–6.00(m,2H),5.72–5. 65(d,J=8.9Hz,1H),5.52–5.45(t,J=6.8Hz,1H),4.30–4.25(t,J=5.5Hz,1H),3.5 3–3.42(d,J=5.8Hz,4H),1.37–1.24(m,2H),1.12–0.98(m,2H),0.76–0.62(m,2H).

[0401] Example A25

[0402] Synthesis of 5-amino-6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0403] Step A: 5-amino-6-chloro-2H-[1,3'-bipyridyl]-2-one

[0404] At room temperature, pyridin-2(1H)one (0.82 g, 8.65 mmol, 1.1 eq), 2-chloro-5-iodopyridin-3-amine (2.0 g, 7.87 mmol, 1.0 eq), cuprous iodide (0.30 g, 1.57 mmol, 0.2 eq), N1,N2-dimethylethane-1,2-diamine (0.27 g, 3.14 mmol, 0.4 eq), and potassium phosphate (5.0 g, 23.61 mmol, 3.0 eq) were added to 1,4-dioxane (20 ml). The solution was purged with nitrogen three times and then reacted at 120°C for 12 hours.

[0405] After the reaction was completed, cold water (100 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 0.6 g of 5-amino-6-chloro-2H-[1,3'-bipyridyl]-2-one as a gray solid (yield 34%). LC-MS: [M+H] + =222.

[0406] Step B: 5-amino-6-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0407] At room temperature, 5-amino-6-chloro-2H-[1,3'-bipyridyl]-2-one (0.6 g, 2.7 mmol, 1.0 equiv), (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (0.66 g, 2.7 mmol, 1.0 equiv), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.43 g, 0.54 mmol, 0.2 equiv), and potassium tert-butoxide (0.60 g, 5.4 mmol, 2.0 equiv) were added to 1,4-dioxane (12 ml). The solution was purged with nitrogen three times and then reacted at 110°C for 12 hours.

[0408] After the reaction was completed, cold water (50 ml) was added to quench the reaction and then extracted with ethyl acetate (50 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1 to obtain 0.25 g of a gray solid 5-amino-6-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (yield 21.5%).

[0409] LC-MS: [M+H]+=430. NMR data: 1H NMR(400MHz,DMSO-d6)δ8.25–8.22(s,2H),7.56–7.52(m,1H),7.50–7.42(m,2H),7.30–7.27 (d,J=2.3Hz,1H),7.23–6.84(t,J=74.0Hz,1H),6.68–6.64(d,J=2.4Hz,1H),6.44–6.39(m,1 H),6.26–6.21(m,1H),5.79–5.74(d,J=6.5Hz,1H),5.07–5.01(s,2H),4.50–4.41(q,J=6.5H z,1H),4.37–4.29(p,J=6.9Hz,1H),2.25–2.06(m,2H),1.97–1.86(m,2H),1.60–1.48(m,2H).

[0410] Example A26

[0411] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-hydroxy-2H-[1,3'-bipyridyl]-2-one

[0412] Step A: Synthesis of (1S,3S)-N 1 -(3-(Benzyl)-5-bromopyridin-2-yl)-N 3 -(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0413] (1S,3S)-N 1 -(5-(Difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine hydrochloride (200 mg, 0.712 mmol) was dissolved in DMSO (5 ml), and 3-(benzyloxy)-5-bromo-2-fluoropyridine (201 mg, 0.712 mmol) and potassium carbonate (412 mg, 3.56 mmol) were added. Under nitrogen protection, the reaction system was slowly heated to 130°C and reacted overnight.

[0414] After the reaction was complete, water (50 ml) was added and the mixture was extracted with ethyl acetate (25 ml x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane → dichloromethane / methanol (10 / 1)) to obtain 0.2 g of a yellow oily substance (1S,3S)-N1-(3-(benzyl)-5-bromopyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine. LC-MS: [M+H] + =506.

[0415] Step B: Synthesis of 5'-(phenoxy)-6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0416] At room temperature, (1S,3S)-N1-(3-(benzyl)-5-bromopyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (0.2 g, 0.395 mmol) was dissolved in DMSO (5 ml), and 2-pyridone (56 mg, 0.592 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (11 mg, 0.079 mmol), cuprous iodide (30 mg, 0.158 mmol), and potassium carbonate (109 mg, 0.79 mmol) were added. Under nitrogen protection, the reaction system was heated to 140°C and reacted overnight.

[0417] After the reaction was complete, water (50 ml) was added and the mixture was extracted with ethyl acetate (25 ml x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified via a reverse-phase C18 column (water → acetonitrile) to yield 120 mg of 5'-(phenoxy)-6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one as a yellow solid. LC-MS: [M+H] + =521.

[0418] Step C: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-hydroxy-2H-[1,3'-bipyridyl]-2-one

[0419] 5'-(Phenoxy)-6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (100 mg, 0.192 mmol) was dissolved in methanol (5 ml), 10% palladium on carbon (20 mg) was added, and the mixture was reacted at room temperature under hydrogen protection.

[0420] After the reaction was completed, the solid was filtered off and the mixture was concentrated under reduced pressure. The residue was purified by reverse phase C18 column (water → acetonitrile) to obtain 27 mg of yellow solid 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-hydroxy-2H-[1,3'-bipyridyl]-2-one. LC-MS: [M+H]+ = 431.1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.22(s,2H),7.58(dd,J=6.8,2.1Hz,1H),7 .47(ddd,J=10.4,5.4,2.2Hz,3H),7.22–6.79(m,2H),6.47–6.39(m,1H),6.26(td, J=6.7,1.4Hz,1H),5.88(d,J=7.3Hz,1H),4.46(q,J=6.9Hz,1H),4.30(q,J=6.8Hz, 1H),2.19–2.04(m,2H),1.91(t,J=6.9Hz,2H),1.54(tdd,J=13.1,9.0,5.9Hz,2H).

[0421] Example A27

[0422] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-methoxy-2H-[1,3'-bipyridyl]-2-one

[0423] Step A: 6'-chloro-5'-methoxy-2H-[1,3'-bipyridyl]-2-one

[0424] At room temperature, pyridin-2(1H)one (0.94 g, 9.89 mmol, 1.1 eq), 5-bromo-2-chloro-3-methoxypyridine (2.0 g, 8.99 mmol, 1.0 eq), cuprous iodide (0.34 g, 1.8 mmol, 0.2 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (0.38 g, 2.7 mmol, 0.3 eq), and potassium carbonate (2.48 g, 17.98 mmol, 2.0 eq) were added to dimethyl sulfoxide (20 ml). The solution was purged with nitrogen three times and then reacted at 140°C for 12 hours.

[0425] After the reaction was completed, cold water (100 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 0.6 g of 6'-chloro-5'-methoxy-2H-[1,3'-bipyridyl]-2-one as a yellow solid (yield 28%). LC-MS: [M+H] + =237.

[0426] Step B: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-methoxy-2H-[1,3'-bipyridyl]-2-one

[0427] At room temperature, 6'-chloro-5'-methoxy-2H-[1,3'-bipyridyl]-2-one (0.6 g, 2.54 mmol, 1 eq), (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (0.62 g, 2.54 mmol, 1.0 eq), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.4 g, 0.51 mmol, 0.2 eq), and potassium tert-butoxide (0.57 g, 5.08 mmol, 2.0 eq) were added to 1,4-dioxane (10 ml). The solution was purged with nitrogen three times and then reacted at 110°C for 12 hours.

[0428] After the reaction was completed, the mixture was diluted with ethyl acetate (50 mL) and filtered through celite. The solid was washed three times with ethyl acetate. The filtrate was concentrated, and the resulting residue was purified by C18 reverse-phase column chromatography (eluent: acetonitrile / water, 45% acetonitrile) to obtain 0.5919 g of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-methoxy-2H-[1,3'-bipyridyl]-2-one as a yellow solid (yield 52%). LC-MS: [M+H]+ = 445.

[0429] NMR data: 1H NMR (400MHz, DMSO) δ8.24(s,2H),7.62(dd,J=6.8,2.1Hz,1H),7.56(d,J=2.1Hz,1H),7 .53–7.44(m,2H),7.25–6.83(m,2H),6.45(dt,J=9.2,1.0Hz,1H),6.28(td,J=6.7,1.4 Hz,1H),6.15(d,J=7.3Hz,1H),4.51(p,J=6.8Hz,1H),4.31(h,J=6.7Hz,1H),3.80(s,3 H),2.11(dq,J=17.6,7.1,5.9Hz,2H),1.92(td,J=6.8,1.7Hz,2H),1.68–1.44(m,2H).

[0430] Example A28

[0431] Synthesis of 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-fluoropyridin-3-yl)pyridazin-3(2H)-one

[0432] At 20°C, (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)-N3-(5-iodopyrimidin-2-yl)cyclopentane-1,3-diamine (0.4 g, 0.9558 mmol), pyridazin-3(2H)-one (275 mg, 2.867 mmol) and potassium phosphate (608.5 mg, 2.867 mmol) were dissolved in DMSO (20 mL), and CuI (72.8 mg, 0.3823 mmol) and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (27.19 mg, 0.191 mmol) were added. Then, N2 was replaced three times, and the atmosphere was heated to 130°C and stirred overnight.

[0433] The mixture was filtered, washed with 50 mL of EA, 50 mL of water was added, and then extracted with EA (30 mL*4). The organic phases were combined, washed with saturated brine (50 mL), and concentrated to give a crude product. The crude product was purified by column chromatography (DCM:MeOH=20:1) to give a brown solid, and then purified by reverse phase column to give a yellow solid 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-fluoropyridin-3-yl)pyridazin-3(2H)-one (213 mg, 51.4% yield).

[0434] LC-MS: [M+H] + =434. 1H NMR(400MHz, DMSO-d6)δ8.24(s,2H),8.07–8.00(m,2H),7.63(dd,J=12.0,2.1Hz,1H),7.56–7.45(m,2H),7.24–6.83(m,3H),4.5 1(p,J=7.0Hz,1H),4.33(p,J=6.9Hz,1H),2.12(ddt,J=15.7,12.0,6.0Hz,2H),1.94(dq,J=10.7,6.5Hz,2H),1.69–1.42(m,2H).

[0435] Example A29

[0436] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-(difluoromethyl)-2H-[1,3'-bipyridyl]-2-one

[0437] Step A: Synthesis of ((1S,3S)-N1-(5-bromo-3-(difluoromethyl)pyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0438] Under nitrogen protection at room temperature, (1S,3S)-N1-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (1.16 g, 4.77 mmol, 1.0 equiv), 5-bromo-3-difluoromethyl-2-fluoropyridine (1.287 g, 5.72 mmol, 1.2 equiv), cesium fluoride (2.90 g, 19.08 mmol, 4 equiv), triethylamine (2.41 g, 23.85 mmol, 5 equiv) were dissolved in dimethyl sulfoxide (19 ml) and heated in an oil bath to 110 degrees Celsius for overnight reaction.

[0439] After the reaction was completed and cooled to room temperature, the reaction solution was diluted with ethyl acetate (100 mL). Solid impurities were then removed by filtration, and extraction was performed with saturated brine (75 mL). The separated aqueous phase was repeatedly extracted with ethyl acetate (75 mL). The combined organic phases were concentrated in vacuo and dried by spin drying. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 3 / 1) to obtain 1.89 g of ((1S,3S)-N1-(5-bromo-3-(difluoromethyl)pyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine as a yellow solid (yield 88%). LC-MS: [M+H] + =450.

[0440] Step B: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-(difluoromethyl)-2H-[1,3'-bipyridyl]-2-one

[0441] Under nitrogen protection at room temperature, ((1S,3S)-N1-(5-bromo-3-(difluoromethyl)pyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (1.0 g, 2.23 mmol, 1.0 eq), 2-hydroxypyridine (0.424 g, 4.46 mmol, 2 eq), cuprous iodide (0.064 g, 0.335 mmol, 0.15 eq), N1,N2-bis(2-thienylmethyl)-ethanedamide (0.188 g, 0.669 mmol, 0.3 eq), potassium carbonate (0.923 g, 6.69 mmol, 3.0 eq) were dissolved in dimethyl sulfoxide (9 ml) and heated to 140 °C in an oil bath for overnight reaction.

[0442] After the reaction was completed and cooled to room temperature, ethyl acetate (75 mL) was added to dilute the reaction solution. Solid impurities were then removed by filtration, and saturated brine (50 mL) was added for extraction. The separated aqueous phase was repeatedly extracted with ethyl acetate (50 mL). The combined organic phases were concentrated in vacuo and dried. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 0.148 g of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-(difluoromethyl)-2H-[1,3'-bipyridyl]-2-one as a pale yellow solid (yield 14.3%). LC-MS: [M+H] + =465.

[0443] H NMR spectrum: 1 H NMR(400MHz, DMSO-d6)δ8.24(s,2H),8.16(dd,J=2.6,1.4Hz,1H),7.71–7.62(m,2H),7.50(ddd,J=8.9,6.5,2.0Hz,2H),7.31–6.85(m,2H),6.54–6 .43(m,2H),6.29(td,J=6.7,1.3Hz,1H),4.58(h,J=7.0Hz,1H),4.33(h,J =7.0Hz,1H),2.21–2.07(m,2H),1.94(t,J=7.1Hz,2H),1.62–1.49(m,2H).

[0444] Example A30

[0445] Referring to the method of the above-mentioned Preparation Example A, compound 30 was prepared:

[0446] Example 31

[0447] Synthesis of 2-(6-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)-5-methylpyridin-3-yl)pyridazin-3(2H)one

[0448] At 25°C, (1S,3S)-N1-(5-bromo-3-methylpyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (300 mg, 0.729 mmol), pyridazin-3(2H)-one (76.6 mg, 0.797 mmol), potassium phosphate (446 mg, 1.46 mmol), cuprous iodide (30 mg, 0.146 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (42 mg, 0.292 mmol) were dissolved in DMSO (10 mL). After addition, the temperature was raised to 140°C and the reaction was carried out for 16 h.

[0449] 50 mL of water was added, followed by extraction with EA (50 mL*4). The organic phases were combined, washed with saturated brine (50 mL), and concentrated to give a crude product. The resulting residue was purified by reverse column chromatography (acetonitrile:water 5:95 to 60:40) to give 130 mg of 2-(6-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)-5-methylpyridin-3-yl)pyridazin-3(2H)one (0.123 g, 41.8% yield) as a white solid. LC-MS: [M+H] + =430.

[0450] 1H NMR (400MHz, DMSO-d6) δ8.24(s,2H),8.04–7.98(m,2H),7.51–7.42(m,2H),7.42–7.37(m,1H),7.07–6.99(m,1H),5.98(d,J=7.0H z,1H),4.54(h,J=6.9Hz,1H),4.33(h,J=6.9Hz,1H),2.23–2.07(m,4H),1.95(t,J=7.1Hz,2H),1.56(tdd,J=16.0,9.3,4.6Hz,2H).

[0451] 31D was prepared by referring to the above method: 1H NMR (400MHz, DMSO) δ8.24(s,2H),8.01(dd,J=3.9,1.6Hz,1H),7.52–7.43(m,2H),7.39(s,1H),7.26–6.81(m,2H),5.97(d ,J=7.0Hz,1H),4.55(q,J=7.0Hz,1H),4.34(q,J=6.9Hz,1H),2.22–2.06(m,5H),1.95(t,J=7.1Hz,2H),1.66–1.48(m,2H).

[0452] Example A32

[0453] Referring to the method of the above-mentioned preparation example, compound 32 was prepared:

[0454] Example A33

[0455] Synthesis of 5'-bromo-6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)-2H-[1,3'-bipyridyl]-2-one

[0456] Step A: (1S,3S)-N1-(3-bromo-5-iodopyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0457] At 20°C, (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine hydrochloride (590 mg, 2.10 mmol), 3-bromo-2-chloro-5-iodopyridine (1.00 g, 3.15 mmol), potassium carbonate (0.87 g, 6.30 mmol) and DMSO (20 ml) were added to a 50 ml single-necked bottle and the temperature was raised to 100°C for overnight reaction.

[0458] 50 mL of water was added, followed by extraction with EA (30 mL*4). The organic phases were combined, washed with saturated brine (50 mL), and concentrated to give a crude product. The crude product was purified by column chromatography (DCM:MeOH = 100:3) to give (1S,3S)-N1-(3-bromo-5-iodopyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (460 mg, 41.6% yield) as a yellow solid. LC-MS: [M+H] + =526.

[0459] Step B: 5'-Bromo-6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)-2H-[1,3'-bipyridyl]-2-one

[0460] (1S,3S)-N1-(3-bromo-5-iodopyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (360 mg, 0.68 mmol), 1,2-dihydropyridin-2-one (0.19 g, 2.04 mmol), potassium phosphate (0.14 g, 0.68 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (0.039 g, 0.27 mmol), CuI (0.052 g, 0.27 mmol), and DMSO (10 mL) were added to a reaction flask and the temperature was raised to 130°C for overnight reaction.

[0461] 50 mL of water was added, and the mixture was extracted with EA (30 mL x 5). The combined organic phases were concentrated, the solvent removed, and the mixture was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain 130 mg of crude product. This was then used for preparative purification to obtain 5'-bromo-6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)-2H-[1,3'-bipyridyl]-2-one (25 mg, yield 7.41%) as a white solid. LC-MS: [M+H] + =493.

[0462] 1 H NMR (400MHz, DMSO-d6) δ8.24(s,2H),8.04(d,J=2.3Hz,1H),7.90(d,J=2.3Hz,1H),7.65(dd,J=6.9,2.0Hz,1H),7.53–7.47(m,2H),7.03(s,1H),6.49 –6.44(m,1H),6.29(ddd,J=8.9,5.1,1.8Hz,2H),4.54(q,J=7.2Hz,1H),4. 39–4.30(m,1H),2.21–2.06(m,2H),2.03–1.92(m,2H),1.69–1.50(m,2H).

[0463] Example A34 Compound 5D

[0464] NMR data: 1H NMR (400MHz, DMSO) δ8.24(s,2H),8.01(dd,J=3.9,1.6Hz,1H),7.52–7.43(m,2H),7.39(s,1H),7.26–6.81(m,2H),5.97(d ,J=7.0Hz,1H),4.55(q,J=7.0Hz,1H),4.34(q,J=6.9Hz,1H),2.22–2.06(m,5H),1.95(t,J=7.1Hz,2H),1.66–1.48(m,2H).

[0465] Example A35

[0466] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]-3-(1-hydroxyethyl)-2H-[1,3'-bipyridyl]-2-one (Compound 1)

[0467] Step A: 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]-3-(1-hydroxyethyl)-2H-[1,3'-bipyridyl]-2-one

[0468] At room temperature, 3-acetyl-1-(6-{[(1S,3S)-3-[(5-(difluoromethoxy)pyrimidin-2-yl)amino]cyclopentyl]amino}pyridin-3-yl)-1,2-dihydropyridin-2-one (800 mg, 1.75 mmol) was dissolved in methanol (10 mL), and sodium borohydride (86.06 mg, 2.27 mmol) was added. The mixture was kept at room temperature and reacted for 1 hour.

[0469] After the reaction was completed, saturated aqueous ammonium chloride solution (2 ml) was added to quench the reaction, and then the mixture was concentrated by rotary evaporation to a residue. The resulting residue was purified by C18 reverse phase column chromatography (ACN / H2O, 40% ACN) to give a light yellow mixture of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]-3-(1-hydroxyethyl)-2H-[1,3'-bipyridyl]-2-one (570 mg, yield 70%).

[0470] Step B: 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]-3-((S)-1-hydroxyethyl)-2H-[1,3'-bipyridyl]-2-one and 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]-3-((R)-1-hydroxyethyl)-2H-[1,3'-bipyridyl]-2-one

[0471] The mixture obtained in step A was subjected to chiral separation (chromatographic column model: CHIRALCEL OD-H 5μm 10mm*250mm; mobile phase: n-hexane / ethanol = 70:30; flow rate: 5ml / min; column temperature, 30°C) to afford a white solid front peak (RT = 12.69min) and a back peak (213mg) (RT = 16.03min). LC-MS: [M+H] + =459.

[0472] NMR data:

[0473] RT=12.69min compound: 1 H NMR (400MHz, DMSO) δ8.24 (s, 2H), 7.91 (d, J = 2.6Hz, 1H), 7.58–7.45 (m, 3H), 7.39 (dd ,J=8.9,2.6Hz,1H),7.26–6.82(m,2H),6.52(d,J=8.9Hz,1H),6.32(t,J=6.9Hz,1H), 5.11(d,J=4.5Hz,1H),4.71(p,J=6.0Hz,1H),4.31(q,J=7.0Hz,2H),2.13(p,J=8.1, 7.5Hz,2H),1.90(hept,J=6.9Hz,2H),1.53(d,J=21.6Hz,2H),1.26(d,J=6.4Hz,3H).

[0474] RT=16.03 min Compound: 1 H NMR (400MHz, DMSO) δ8.24(s,2H),7.91(d,J=2.7Hz,1H),7.52(td,J=7.8,7.2,2.2Hz,3 H),7.39(dd,J=8.9,2.7Hz,1H),7.25–6.82(m,2H),6.52(d,J=8.9Hz,1H),6.32(t,J=6. 8Hz,1H),5.08(d,J=4.6Hz,1H),4.71(p,J=6.0Hz,1H),4.30(p,J=6.9Hz,2H),2.21–2.0 4(m,2H),1.98–1.80(m,2H),1.52(td,J=13.1,11.9,6.9Hz,2H),1.26(d,J=6.3Hz,3H).

[0475] Example A36

[0476] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxamide

[0477] Step A: Synthesis of ethyl 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylate

[0478] Under nitrogen protection at room temperature, (1S,3S)-N1-(5-difluoromethoxy)pyrimidin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (6.71 g, 15 mmol, 1.0 equiv), ethyl 2-oxo-1,2-dihydropyridine-3-carboxylate (5.01 g, 30 mmol, 2 equiv), cuprous iodide (1.14 g, 6.0 mmol, 0.4 equiv), N1,N2-dimethylcyclohexane-1,2-diamine (0.43 g, 3.0 mmol, 0.2 equiv), potassium phosphate (9.55 g, 45 mmol, 3.0 equiv) were dissolved in dimethyl sulfoxide (60 ml) and heated to 140 °C for overnight reaction.

[0479] After the reaction was completed, cold water (150 mL) was added to quench the reaction, followed by extraction with ethyl acetate (250 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 2.92 g of ethyl 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylate as a yellow solid. LC-MS: [M+H] + =487.

[0480] Step B: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylic acid

[0481] Ethyl 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylate (2.92 g, 6.37 mmol, 1.0 eq) and lithium hydroxide monohydrate (1.90 g, 44.6 mmol, 7.0 eq) were dissolved in a mixed solution of ethanol (6 ml) and water (9 ml) at room temperature and stirred at room temperature for 4 hours.

[0482] After the reaction, the pH of the reaction solution was adjusted to approximately 6 with 1 M dilute hydrochloric acid solution. A large amount of light yellow solid precipitated and was filtered to obtain 2.63 g of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylic acid. LC-MS: [M+H] + =459.

[0483] Step C: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxamide

[0484] 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylic acid (0.25 g, 0.44 mmol, 1.0 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 0.251 g, 0.66 mmol, 1.5 eq), and N-methylmorpholine (0.135 g, 1.32 mmol, 3.0 eq) were dissolved in a mixture of dichloromethane (3 ml) and N,N-dimethylformamide (1 ml) at room temperature and stirred vigorously for 15 minutes. Subsequently, ammonium chloride (0.036 g, 0.66 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature for 4 hours.

[0485] After the reaction, the reaction solvent was evaporated under reduced pressure. The resulting crude product was dissolved in an appropriate amount of dimethyl sulfoxide and purified on a C18 reverse-phase column (120 g, mobile phase: acetonitrile / water) to yield 140 mg of a red solid, 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxamide (70% yield). LC-MS: [M+H] + =458.

[0486] NMR data: 1H NMR(400MHz, DMSO-d6)δ8.91(d,J=4.4Hz,1H),8.39(dd,J=7.3,2.2Hz,1H),8.23(s,2H),8.05–7.92(m,2H),7.61(d,J=4.4Hz,1H),7.54–7.42(m,2H) ,7.22–6.85(m,2H),6.62–6.49(m,2H),4.32(p,J=6.7Hz,2H),2.13(tt,J= 11.9,7.0Hz,2H),1.97–1.83(m,2H),1.52(ddt,J=18.9,14.1,6.3Hz,2H).

[0487] Example A37

[0488] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-N-methyl-2-oxo-2H-[1,3'-bipyridine]-3-carboxamide

[0489] 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2H-[1,3'-bipyridine]-3-carboxylic acid (200 mg, 0.42 mmol) was dissolved in DCM / DMF (6 / 2 ml) at room temperature. HATU (150 mg, 0.42 mmol) and N-methylmorpholine (200 μl, 2.9 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Methylamine hydrochloride (30 mg, 0.48 mmol) was added, and the mixture was stirred at room temperature for 2 hours.

[0490] The reaction was terminated, water (20 mL) was added, and the mixture was extracted with DCM (20 mL x 4). The organic phases were combined and subjected to reverse-phase column chromatography (CAN / H2O = 40%) to obtain 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-N-methyl-2-oxo-2H-[1,3'-bipyridine]-3-carboxamide as a yellow solid. Yield: 81.27%. LC-MS: [M+H] + =472. 1H NMR (400MHz, DMSO-d6) δ9.47 (q, J=4.8Hz, 1H), 8.40 (dd, J=7.3, 2.2Hz, 1H), 8.2 4(s,2H),7.97(dd,J=7.8,2.5Hz,2H),7.51(d,J=7.2Hz,1H),7.47–7.38(m,1H) ,7.25–6.70(m,2H),6.61–6.51(m,2H),4.33(p,J=7.0Hz,2H),2.81(d,J=4.8Hz ,3H),2.19–2.08(m,2H),1.98–1.81(m,2H),1.53(td,J=13.7,11.9,7.0Hz,2H).

[0491] Example A38

[0492] Synthesis of 2'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-(morpholine-4-carbonyl)-2H-[1,4'-bipyridyl]-2-one

[0493] 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)-amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxylic acid (0.25 g, 0.44 mmol, 1.0 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 0.251 g, 0.66 mmol, 1.5 eq), and N-methylmorpholine (0.135 g, 1.32 mmol, 3.0 eq) were dissolved in a mixture of dichloromethane (3 ml) and N,N-dimethylformamide (1 ml) at room temperature and stirred vigorously for 15 minutes. Subsequently, morpholine (0.058 g, 0.66 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature for 4 hours.

[0494] After the reaction, the reaction solvent was evaporated under reduced pressure. The resulting crude product was dissolved in an appropriate amount of dimethyl sulfoxide and purified on a C18 reverse-phase column (120 g, mobile phase: acetonitrile / water) to yield 164 mg of a pale yellow solid, 2'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-(morpholine-4-carbonyl)-2H-[1,4'-bipyridyl]-2-one (71% yield). LC-MS: [M+H] + =528.

[0495] NMR data: 1H NMR (400MHz, DMSO-d6) δ8.23 (s, 2H), 7.95 (d, J = 2.7Hz, 1H), 7.74 (dd, J = 6.8, 2.1H z,1H),7.63–7.37(m,3H),7.23–6.85(m,2H),6.53(d,J=8.9Hz,1H),6.36(t,J=6.8 Hz,1H),4.30(p,J=6.8Hz,2H),3.56(ddt,J=12.6,9.0,5.0Hz,6H),3.25(t,J=4.7H z,2H),2.20–2.04(m,2H),1.88(tdd,J=13.2,10.4,6.3Hz,2H),1.60–1.43(m,2H).

[0496] Example A39

[0497] Synthesis of 3-acetyl-6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)-2H-[1,3'-bipyridyl]-2-one

[0498] At room temperature, (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (2.75 g, 6.15 mmol), 3-acetyl-1,2-dihydropyridin-2-one (1.69 g, 12.3 mmol), cuprous iodide (0.23 g, 1.23 mmol), 8-hydroxyquinoline (0.36 g, 2.46 mmol) and potassium phosphate (3.92 g, 18.45 mmol) were added to dimethyl sulfoxide (20 mL), the atmosphere was replaced with nitrogen three times, and the mixture was placed in an oil bath and heated to 140 ° C for 8 hours.

[0499] After the reaction was completed, the reaction solution was filtered through celite, and the solid was washed with ethyl acetate (3*50 mL). Water (150 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (3*80 mL). The organic phases were combined, washed with saturated brine (3*50 mL), and then dried over anhydrous sodium sulfate. The residue was filtered and rotary evaporated to a residue. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 0 / 100%, v / v) to give 3-acetyl-6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)-2H-[1,3'-bipyridyl]-2-one (1.51 g, Yield 51.11%, Purity 95%) as a yellow-green solid. LC-MS: [M+H] + =457.

[0500] NMR data: 1H NMR (400MHz, DMSO) δ8.24(s,2H),8.07(dd,J=7.3,2.2Hz,1H),8.00(dd,J=6.6,2.3Hz,1H) ,7.97(d,J=2.7Hz,1H),7.51(d,J=7.2Hz,1H),7.45(dd,J=8.9,2.7Hz,1H),7.26–6.82(m, 2H),6.55(d,J=8.9Hz,1H),6.44(t,J=6.9Hz,1H),4.32(h,J=6.7Hz,2H),2.53(s,3H),2.2 3–2.06(m,2H),1.89(tdd,J=13.2,10.5,6.3Hz,2H),1.52(ddt,J=16.4,14.0,9.2Hz,2H).

[0501] Example A40

[0502] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2'-(difluoromethyl)-2H-[1,3'-bipyridyl]-2-one

[0503] Step A: Synthesis of (1S,3S)-N1-(5-bromo-6-difluoromethylpyridin-2-yl)-N3-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0504] At room temperature, (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine hydrochloride (500 mg, 1.5 mmol) was dissolved in DMSO (10 ml), and 3-bromo-2-difluoromethyl-6-fluoropyridine (382 mg, 1.7 mmol) and potassium carbonate (1.2 g, 8.6 mmol) were added. Under nitrogen protection, the reaction system was heated to 140°C and stirred overnight.

[0505] The reaction was terminated, water (100 mL) was added, and the mixture was extracted with DCM (50 mL x 4). The organic phases were combined and chromatographed on a silica gel column (EA / Hex = 1:1, 50%) to obtain 635 mg of (1S,3S)-N1-(5-bromo-6-difluoromethylpyridin-2-yl)-N3-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine as a yellow solid (yield 94.3%). LC-MS: [M+H] + =450.

[0506] Step B: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2'-(difluoromethyl)-2H-[1,3'-bipyridyl]-2-one

[0507] At room temperature, (1S,3S)-N1-(5-bromo-6-difluoromethylpyridin-2-yl)-N3-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (615 mg, 1.23 mmol) was dissolved in DMSO (10 ml), and pyridin-2(1H)-one (351 mg, 3.7 mmol), 8-hydroxyquinoline (53 mg, 0.369 mmol), cuprous iodide (70 mg, 0.37 mmol), potassium carbonate (389 mg, 2.46 mmol) were added. Under nitrogen protection, the reaction system was slowly heated to 140°C and reacted overnight.

[0508] After the reaction was complete, water (100 ml) was added and the mixture was extracted with ethyl acetate (80 ml x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (ACN / H2O = 50%) and lyophilized to obtain 24 mg of a yellow solid product, 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2'-(difluoromethyl)-2H-[1,3'-bipyridyl]-2-one (yield 44%). LC-MS: [M+H] + =465. 1 H NMR (400MHz, DMSO-d6) δ8.24(s,2H),7.52(d,J=8.1Hz,3H),7.39(d,J=8.8Hz,1H),7.31(d,J=6.7Hz,1H),7.04(t,J=74.0Hz,1H),6.70 (d,J=8.8Hz,1H),6.62–6.33(m,2H),6.29(t,J=6.9Hz,1H),4.34–4.29(m,2H),2.26–2.05(m,2H),1.93(t,J=7.0Hz,2H),1.53(s,2H).

[0509] Example A41

[0510] Synthesis of 6-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)-2-fluoromethyl-2H-[1,3'-bipyridyl]-2-one

[0511] Step A: Synthesis of 3-bromo-6-chloro-2-fluoromethylpyridine

[0512] 3-Bromo-6-chloropyridine-2-methanol (500 mg, 2.45 mmol) was dissolved in DCM (20 mL) at room temperature, and DAST (789 μL, 4.90 mmol) was added under ice-cooling, and the mixture was stirred at 0°C for 3 hours.

[0513] The reaction was terminated, water (100 mL) was added, and the mixture was extracted with DCM (50 mL x 4). The organic phases were combined and chromatographed on a silica gel column (EA / Hex = 1:9, 10%) to obtain 420 mg of 3-bromo-6-chloro-2-fluoromethylpyridine as a yellow oily liquid (yield 82.8%). LC-MS: [M+H] + =207.

[0514] Step B: Synthesis of (1S,3S)-N1-(5-bromo-6-fluoromethylpyridin-2-yl)-N3-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0515] At room temperature, (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine hydrochloride (380 mg, 1.55 mmol) was dissolved in DMSO (10 ml), and 3-bromo-6-chloro-2-fluoromethylpyridine (420 mg, 1.87 mmol) and potassium carbonate (1.29 g, 9.4 mmol) were added. Under nitrogen protection, the reaction system was heated to 140°C and stirred overnight.

[0516] The reaction was terminated, water (100 mL) was added, and the mixture was extracted with DCM (50 mL x 4). The organic phases were combined and chromatographed on a silica gel column (EA / Hex = 1:1, 50%) to obtain 206 mg of (1S,3S)-N1-(5-bromo-6-fluoromethylpyridin-2-yl)-N3-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine as a yellow oil (yield 30.6%). LC-MS: [M+H] + =433.

[0517] Step C: Synthesis of 6-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)-2-fluoromethyl-2H-[1,3'-bipyridyl]-2-one

[0518] At room temperature, (1S,3S)-N1-(5-bromo-6-fluoromethylpyridin-2-yl)-N3-(5-difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (189 mg, 0.44 mmol) was dissolved in DMSO (10 ml), and pyridin-2(1H)one (130 mg, 1.3 mmol), 8-hydroxyquinoline (53 mg, 0.369 mmol), cuprous iodide (25 mg, 0.13 mmol), and potassium carbonate (120 mg, 0.88 mmol) were added. Under nitrogen protection, the reaction system was slowly heated to 140°C and reacted overnight.

[0519] After the reaction was complete, water (100 ml) was added and the mixture was extracted with ethyl acetate (80 ml x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (ACN / H2O = 50%) and lyophilized to afford 20 mg of a yellow solid product, 6-(5-(difluoromethoxy)pyrimidin-2-amino)cyclopentyl)amino)-2-fluoromethyl-2H-[1,3'-bipyridyl]-2-one (yield 10%).

[0520] LC-MS: [M+H] + =447. 1 H NMR (400MHz, DMSO-d6) δ8.24(s,2H),8.09(dd,J=5.0,2.0Hz,1H),7.83(ddd,J=8.7,7.1,2.0Hz,1H),7 .49(d,J=7.2Hz,1H),7.27(d,J=8.9Hz,1H),7.09(dd,J=7.2,5.0Hz,1H),7.04(s,1H),7.02(t,1H),6.7 4(d,J=6.8Hz,1H),6.57(dd,J=8.9,2.3Hz,1H),5.14(d,J=47.9Hz,2H),4.29(dq,J=18.4,6.8Hz,2H), 2.14(ddd,J=21.9,10.6,4.8Hz,2H), 1.90(td,J=6.8,3.0Hz,2H), 1.52(ddt,J=18.8,12.8,8.1Hz,2H).

[0521] Example A42

[0522] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-(1H-tetrazol-5-yl)-2H-[1,3'-bipyridyl]-2-one

[0523] Synthesis route

[0524] Step A: Synthesis of 6'-fluoro-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile

[0525] 2-Oxo-1,2-dihydropyridine-3-carbonitrile (6.50 g, 54.1 mmol, 1 eq), (6-fluoro-3-pyridine)boronic acid (15.3 g, 108 mmol, 2 eq), copper acetate (19.7 g, 108 mmol, 2 eq), and triethylamine (27.4 g, 271 mmol, 5 eq) were dissolved in tetrahydrofuran (150 ml). 4A molecular sieves (1.00 g) were then added and stirred at 70°C for 3 hours. LCMS (EW45820-25-P1A1) detected the product (RT = 0.323 min). The reaction mixture was filtered through celite, the filter cake was rinsed several times with dichloromethane, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column to give 6'-fluoro-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile (450 mg, 2.09 mmol, yield 3.86%). MS (ESI) m / z [M+1] + =216.1.

[0526] Step B: Synthesis of 6'-fluoro-3-(1H-tetrazol-5-yl)-2H-[1,3'-bipyridyl]-2-one

[0527] 6'-Fluoro-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile (350 mg, 1.63 mmol, 1 eq), trimethylsilylazide (562 mg, 4.88 mmol, 3 eq), and dibutyltin oxide (203 mg, 813 μmol, 2.5 eq) were dissolved in toluene (10 ml) and stirred at 100°C for 6 hours. LCMS (EW45820-55-P1B1) detected the product (RT = 0.342 min). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase preparative chromatography (Phenomenex luna C18 150*25mm*10um column; mobile phase: [water (TFA)-ACN]; gradient: 5%-38% B over min) to afford 6'-fluoro-3-(1H-tetrazol-5-yl)-2H-[1,3'-bipyridinyl]-2-one (180 mg, 697 μmol, 42.9% yield). MS (ESI) m / z [M+1] + =259.1.

[0528] Step C: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-(1H-tetrazol-5-yl)-2H-[1,3'-bipyridyl]-2-one

[0529] 6'-Fluoro-3-(1H-tetrazol-5-yl)-2H-[1,3'-bipyridinyl]-2-one (180 mg, 697 μmol, 1 eq), (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine hydrochloride (235 mg, 837 μmol, 1.2 eq, hydrochloride), and potassium carbonate (289 mg, 2.09 mmol, 3 eq) were dissolved in dimethyl sulfoxide (10 ml) and stirred at 120°C for 12 hours. LCMS (EW45820-59-P1A1) detected the product (RT = 0.396 min). The reaction mixture was cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase preparation (column: water s Xbridge 150*25mm*5um; mobile phase: [water (ammonium hydroxide v / v)-ACN]; gradient: 0%-25% B over 10 min) to give 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-(1H-tetrazol-5-yl)-2H-[1,3'-bipyridyl]-2-one (68.0 mg, 134 μmol, 19.3% yield, 95.4% purity).

[0530] RT = 0.396 min, MS (ESI) m / z [M+1] + =483.2, 1 H NMR: (400MHz, DMSO-d6): δ8.46-8.39(m,1H),8.23(s,2H),8.04(d,J=2.6Hz,1H),7.95(dd,J=2.0,6.6Hz,1H),7.55-7.45( m,2H),7.24-6.82(m,2H),6.61-6.52(m,2H),4.38-4.26(m,2H),2.21-2.08(m,2H),1.98-1.82(m,2H),1.61-1.44(m,2H).

[0531] Example A43

[0532] Compound A43 and its isomers A43A, A43B, A43A-D and A43B-D were prepared by referring to the above preparation method:

[0533] Example A44

[0534] Synthesis of 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)-4-methylpyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)one

[0535] Step A: Synthesis of 2-chloro-5-difluoromethoxy-4-methylpyrimidine

[0536] Under nitrogen protection at room temperature, 2-chloro-4-methyl-5-hydroxypyrimidine (2.0 g, 13.84 mmol, 1.0 equivalent) was dissolved in N,N-dimethylformamide (20 ml), followed by the addition of cesium fluoride (4.20 g, 27.68 mmol, 2.0 equivalent), triethylamine (4.20 g, 41.52 mmol, 3.0 equivalent) and sodium difluorochloroacetate (6.43 g, 41.52 mmol, 3.0 equivalent). After stirring evenly, the reaction was transferred to an oil bath and heated to 110 degrees Celsius for overnight reaction.

[0537] After the reaction was complete, ethyl acetate (50 mL) was added to dilute the reaction solution. Insoluble impurities were removed by filtration. Water (150 mL) was added, followed by extraction with ethyl acetate (80 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 3 / 10) to obtain 1.52 g of 2-chloro-5-difluoromethoxy-4-methylpyrimidine as a yellow oil (yield 53%). LC-MS: [M+H] + =195.

[0538] Step B: Synthesis of 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)-4-methylpyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)one

[0539] Under nitrogen protection at room temperature, 2-chloro-5-difluoromethoxy-4-methylpyrimidine (0.195 g, 1 mmol, 1.0 equiv) was dissolved in dimethyl sulfoxide (4 ml), followed by the addition of cesium fluoride (0.304 g, 2.0 mmol, 2.0 equiv), triethylamine (0.303 g, 3 mmol, 3.0 equiv) and 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)one (0.271 g, 1.0 mmol, 1.0 equiv) and stirring. The reaction mixture was transferred to an oil bath and heated to 140°C for overnight reaction.

[0540] After the reaction was completed, water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by C18 column chromatography (120 g, eluent: acetonitrile / water) to obtain 0.050 g of a light yellow solid 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)-4-methylpyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)one (yield 12%). LC-MS: [M+H] + =430.

[0541] NMR data: 1 H NMR(400MHz,DMSO-d6)δ8.21–8.03(m,2H),8.01(dd,J=3.8,1.6Hz,1H),7.4 8(ddd,J=19.9,9.2,3.3Hz,2H),7.36(d,J=7.3Hz,1H),7.19–6.81(m,3H),6. 52(d,J=9.0Hz,1H),4.31(p,J=6.6Hz,2H),2.24(s,3H),2.12(tt,J=12.8,6. 2Hz, 2H), 1.87 (ddp, J=18.7, 13.3, 6.8Hz, 2H), 1.51 (td, J=16.3, 8.0Hz, 2H).

[0542] Example A45

[0543] Step A: Synthesis of Compound A45-2

[0544] Compound A45-1 (5.0 g, 28 mmol) was dissolved in 50 ml of tetrahydrofuran and replaced with nitrogen three times. Iron acetylacetonate (988 mg, 2.8 mmol) and ethylmagnesium bromide (14.5 ml, 29 mmol) were added at 0°C and the mixture was returned to room temperature for 16 hours. The reaction solution was poured into a saturated ammonium chloride solution and extracted with ethyl acetate (50 ml x 3). The organic phases were combined and dried. The resulting product was purified using a flash silica gel column (0–20% ethyl acetate / petroleum ether) to obtain 3.2 g of a colorless oily mixture A45-2. LCMS: [M+H] + =173.

[0545] Step B: Synthesis of Compound A45-3

[0546] Compound A45-2 (3.2 g, 18.6 mmol) was dissolved in 30 ml of dichloromethane, and boron tribromide (8.9 ml, 93 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was poured into ice water (50 ml) to quench, and the pH was adjusted to 3 with saturated sodium carbonate. The mixture was extracted with ethyl acetate (50 ml x 3), and the organic phases were combined and dried. The resulting product was purified using a flash silica gel column (0-40% ethyl acetate / petroleum ether) to obtain 500 mg of A45-3 as a white solid (34% yield). LCMS: [M+H] + =159.

[0547] Step C: Synthesis of Compound A45-5

[0548] Compound A45-3 (420 mg, 2.66 mmol) was added to 5 ml of N,N-dimethylformamide, and cesium carbonate (1 g, 3.2 mmol) was added. The reaction was allowed to react at room temperature for 0.5 hours. Compound A45-4 (1.2 g, 7.98 mmol) was added and the reaction was allowed to react at 100 degrees for 16 hours. The reaction solution was poured into saturated ammonium chloride (20 ml) and extracted with ethyl acetate (10 ml x 3). The organic phases were combined and dried by spin drying. The resulting product was purified using a flash silica gel column (0-20% ethyl acetate / petroleum ether) to obtain 380 mg of a yellow solid A45-5 (68.7% yield). LCMS: [M+H] + =209.

[0549] Step D: Synthesis of target compound

[0550] Compound A45-5 (320 mg, 1.54 mmol) and compound A45-6 (346 mg, 1.28 mmol) were added to 5 mL of anhydrous dioxane. Potassium tert-butoxide (287 mg, 2.56 mmol) and (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (203 mg, 0.26 mmol) were added. The mixture was heated to 80°C under nitrogen for 16 hours. The reaction mixture was poured into saturated ammonium chloride (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and dried by spin drying. The resulting product was purified using a flash silica gel column (0-10% methanol / dichloromethane) and then purified using a preparative silica gel plate to obtain 36 mg of the title compound (5.3% yield). LCMS: [M+H] + =443.

[0551] 1H NMR (400MHz, DMSO-d6) δ8.11(s,1H),7.94(d,J=2.7Hz,1H),7.62(dd,J=6.7,2.1Hz,1H),7.50(ddd,J=9.0,6 .6,2.1Hz,1H),7.42(dd,J=8.9,2.7Hz,1H),7.36(d,J=7.1Hz,1H),6.93(d,J=6.9Hz,1H),6.55(d,J=8.9Hz, 1H),6.46(dt,J=9.1,1.1Hz,1H),6.29(td,J=6.7,1.4Hz,1H),4.34(dd,J=11.8,6.0Hz,2H),2.61(q,J=7.5H z,2H),2.15(dq,J=14.3,7.1Hz,2H),2.01–1.82(m,2H),1.54(tt,J=13.7,8.5Hz,2H),1.18(t,J=7.5Hz,3H).

[0552] Example A46

[0553] Step A: Synthesis of Compound A46-2

[0554] Compound A46-1 (5 g, 27.9 mmol) was dissolved in tetrahydrofuran (30 ml), and ferric acetylacetonate (985.4 mg, 2.79 mmol) was added at 0 degrees. A tetrahydrofuran solution of 1-isopropylmagnesium bromide (34 ml, 34 mmol) was added dropwise, and the mixture was reacted for 12 hours under a nitrogen atmosphere. The reaction solution was quenched with a saturated aqueous ammonium chloride solution and extracted with dichloromethane (50 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resultant was purified by flash silica gel column (5–20% ethyl acetate / petroleum ether) to obtain 2.5 g of yellow oily liquid mixture A46-2 (yield: 48.0%). LCMS: [M+H] + =187.

[0555] Step B: Synthesis of Compound A46-3

[0556] The mixture A46-2 (2.5 g, 13.4 mmol) was dissolved in a 1 mol / L boron tribromide dichloromethane solution (24.1 ml, 24.1 mmol), and boron tribromide (3.4 ml, 42.9 mmol) was added and reacted at room temperature for 8 hours. The reaction solution was quenched by adding 20 ml of ice water, and the pH was adjusted to 5-6 with saturated sodium carbonate aqueous solution. It was extracted with dichloromethane (30 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried. The resultant was purified by flash silica gel column (0-100% ethyl acetate / petroleum ether) and then purified by reverse phase column to obtain 1.2 g of yellow solid compound A46-3 (yield: 52.1%). LCMS: [M+H] + =173.

[0557] Step C: Synthesis of Compound A46-5

[0558] Compound A46-3 (1 g, 5.8 mmol) was dissolved in N, N-dimethylformamide (15 ml), cesium carbonate (2.28 g, 6.96 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Compound A46-4 (2.65 g, 17.4 mmol) was added and the mixture was heated to 100 degrees under a nitrogen atmosphere for 3 hours. The reaction solution was quenched with aqueous ammonium chloride solution and extracted with dichloromethane (20 ml × 3). The organic phases were combined, dried, and concentrated. The resultant was purified by Flash silica gel column (10–50% ethyl acetate / petroleum ether) to obtain 700 mg of yellow oily liquid compound A46-5 (yield: 54.2%). LCMS: [M+H] + =223.

[0559] Step D: Synthesis of target compound

[0560] Compound A46-5 (222 mg, 1 mmol) and compound A46-6 (270 mg, 1 mmol) were dissolved in anhydrous dimethyl sulfoxide (8 mL). Potassium phosphate (424 mg, 2 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (159 mg, 0.2 mmol) were added. The mixture was heated to 110°C under nitrogen for 2 hours. The reaction mixture was quenched with aqueous ammonium chloride and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried, and concentrated. The resulting product was purified using a reverse-phase column to obtain 30 mg of the target compound as a yellow solid (yield: 6.5%).

[0561] LCMS: [M+H] + =457. 1H NMR (400MHz, DMSO-d6) δ8.10(s,1H),7.92(d,J=2.7Hz,1H),7.60(dd,J=6.8,2.1Hz,1H),7.48(ddd,J=9.0,6 .6,2.1Hz,1H),7.40(dd,J=8.9,2.7Hz,1H),7.31(d,J=7.0Hz,1H),7.02(s,1H),6.91(d,J=6.7Hz,1H),6.53( d,J=8.9Hz,1H),6.44(d,J=8.9Hz,1H),6.27(td,J=6.7,1.4Hz,1H),4.30(q,J=7.1Hz,2H),3.21–3.14(m,1H) ,2.14(dt,J=13.4,5.6Hz,2H),1.90(dq,J=28.1,6.5Hz,2H),1.59–1.45(m,2H),1.15(dd,J=6.8,2.7Hz,6H).

[0562] Example A47

[0563] Synthesis of 6'-(((1S,3S)-3-((4-chloro-5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amine)-2H-[1,3'-bipyridyl]-2-one

[0564] Step A: Synthesis of 5-(difluoromethoxy)pyrimidine-2,4-diol

[0565] At room temperature, 2,4-dichloropyrimidin-5-ol (0.5 g, 3.03 mmol) and difluoromethanesulfonylbenzene (1.34 g, 6.97 mmol) were dissolved in acetonitrile (20 ml), potassium hydroxide (1.87 g, 33.33 mmol) and water (6 ml) were added, and the reaction system was heated to 50°C and stirred overnight.

[0566] The mixture was concentrated under reduced pressure, water (20 mL) was added, and EA was extracted (30 mL x 3). The aqueous phase was taken and the pH was adjusted to acidic with 1 M HCl. EA was extracted (20 mL x 3). The organic phases were combined and purified by column chromatography (EA / Hex = 6:4, 60%) to obtain 184 mg of 5-(difluoromethoxy)pyrimidine-2,4-diol as a white solid (yield 34%). LC-MS: [M+H] + =197.1.

[0567] Step B: Synthesis of 2,4-dichloro-5-(difluoromethoxy)pyrimidine

[0568] 5-(Difluoromethoxy)pyrimidine-2,4-diol (184 mg, 1.03 mmol) was dissolved in phosphorus oxychloride (4 mL) at room temperature under nitrogen protection. The temperature was raised to 105°C and stirred overnight to terminate the reaction. The reaction was concentrated under reduced pressure and purified by silica gel column chromatography (EA / Hex = 1:4, 20%) to give 115 mg of brown liquid 2,4-dichloro-5-(difluoromethoxy)pyrimidine (yield 51.8%).

[0569] Step C: Synthesis of 6'-(((1S,3S)-3-((4-chloro-5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amine)-2H-[1,3'-bipyridyl]-2-one

[0570] At room temperature, 1-(6-[(1S,3S)-3-aminocyclopentyl]amino}pyridin-3-yl)-1,2-dihydropyridin-2-one (100.02 mg, 0.367 mmol), 2,4-dichloro-5-(difluoromethoxy)pyrimidine (95.45 mg, 0.44 mmol), and DIPEA (0.24 g, 1.85 mmol) were added to a 100 mL round-bottom flask. DMSO (10 mL) was added under nitrogen protection and the reaction system was heated to 140°C for overnight reaction.

[0571] The reaction was terminated, water (40 mL) was added, and the mixture was extracted with EA (40 mL x 3). The organic phases were combined and subjected to reverse phase column chromatography (ACN / H2O = 40%). The mixture was concentrated under reduced pressure and lyophilized to give 115 mg of 6'-(((1S,3S)-3-((4-chloro-5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amine)-2H-[1,3'-bipyridyl]-2-one as a white solid (yield 65.8%).

[0572] LC-MS: [M+H] + =449.3. 1H NMR (400MHz, DMSO-d6) δ7.96(d,J=7.8Hz,1H),7.93(d,J=2.7Hz,1H),7.92(s,1H),7.61(dd,J=6. 8,2.1Hz,1H),7.48(ddd,J=9.0,6.6,2.1Hz,1H),7.41(dd,J=8.9,2.7Hz,1H),7.23(t,J=72.8Hz,1 H),6.97(d,1H),6.53(d,J=8.9Hz,1H),6.45(d,J=8.9Hz,1H),6.28(td,J=6.7,1.4Hz,1H),4.45( dq,J=69.1,7.0Hz,2H),2.14(tdd,J=11.6,7.1,3.4Hz,2H),2.08–1.85(m,2H),1.69–1.45(m,2H).

[0573] Example A48

[0574] Step A: Synthesis of Compound A48-2

[0575] Compound A48-1 (1.2 g, 7.3 mmol) was added to 10 ml of N,N-dimethylacetamide, sodium thiomethoxide (0.76 g, 10.9 mmol), the atmosphere was replaced with nitrogen, and the reaction was allowed to proceed at room temperature for 6 hours. The reaction solution was added to 40 ml of saturated aqueous ammonium chloride solution, the pH was adjusted to 4 with 1 mol / L aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate (25 ml x 3). The organic phases were combined, dried, and concentrated. The resultant was purified by flash silica gel column (28–32% ethyl acetate / petroleum ether) to obtain 540 mg of light yellow solid compound A48-2 (42.5% yield). LCMS: [M+H] + =177.

[0576] Step B: Synthesis of Compound A48-4

[0577] Compound A48-2 (540 mg, 3.1 mmol) was added to 10 ml of anhydrous N,N-dimethylformamide, cesium carbonate (1.2 g, 3.7 mmol) and compound A48-3 (1.4 g, 3.1 mmol) were added, the atmosphere was replaced with nitrogen, the temperature was raised to 80 degrees Celsius, and the reaction was continued for 6 hours. The reaction solution was added to 40 ml of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (25 ml × 3), and the organic phases were combined, dried, and concentrated. The resultant was purified by flash silica gel column (1–3% ethyl acetate / petroleum ether) to obtain 400 mg of light yellow solid compound A48-4 (56.9% yield). LCMS: [M+H] + =227.

[0578] Step C: Synthesis of target compound

[0579] Compound A48-4 (360 mg, 1.6 mmol) and compound 5 (519 mg, 1.9 mmol) were dissolved in 5 mL of anhydrous dimethyl sulfoxide. Potassium phosphate (679 mg, 3.2 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (254 mg, 0.3 mmol) were added. The atmosphere was purged with nitrogen and the temperature was raised to 110°C for 16 hours. The reaction mixture was added to 20 mL of saturated aqueous ammonium chloride and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated. The resulting product was purified using a flash silica gel column (2–3% methanol / dichloromethane) and then reverse-phase column chromatography (18–23% acetonitrile / water) to obtain 30.7 mg of the target compound as a white solid (4.2% yield).

[0580] LCMS: [M+H] + =461. 1 H NMR(400MHz,DMSO-d6)δ7.92(d,J=3.7Hz,2H),7.60(d,J=6.9Hz,1H),7.48(td ,J=6.9,3.5Hz,2H),7.39(dd,J=8.9,2.6Hz,1H),6.93(d,J=6.9Hz,1H),6.52(d ,J=8.9Hz,1H),6.44(d,J=9.2Hz,1H),6.27(t,J=6.7Hz,1H),4.39–4.23(m,2H) ,2.45(s,3H),2.14(d,J=8.8Hz,2H),1.91(t,J=7.0Hz,2H),1.62–1.44(m,2H).

[0581] Example A49

[0582] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)-4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0583] Step A: Synthesis of tert-butyl (1S,3S)-3-((4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)carbamate

[0584] At room temperature, 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (5 g, 26.8 mmol), tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (5.55 g, 28.2 mmol) and cesium carbonate (17.5 g, 53.7 mmol) were added to acetonitrile (100 mL) and heated to 90 °C for overnight reaction.

[0585] After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with ethyl acetate (3*50 mL). The filtrate was rotary evaporated to a residue, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 2 / 3, V / V) to give a light yellow solid (1S,3S)-tert-butyl 3-((4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)carbamate (5.05 g, yield 61%), LC-MS: [M+H] + =307.

[0586] Step B: Synthesis of tert-butyl (1S,3S)-3-((5-bromo-4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)carbamate

[0587] At room temperature, tert-butyl (1S,3S)-3-((4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)carbamate (5.05 g, 16.5 mmol) was dissolved in acetonitrile (50 mL), and NBS (4.36 g, 24.5 mmol) was added. The mixture was stirred at room temperature for 2 hours.

[0588] After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (150 mL) and extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to a residue. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 4, V / V) to give tert-butyl (1S,3S)-3-((5-bromo-4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)carbamate (5.5 g, yield 86%) as a light yellow solid. LC-MS: [M+H] + =385.

[0589] Step C: Synthesis of tert-butyl (1S,3S)-3-((5-hydroxy-4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)carbamate

[0590] At room temperature, tert-butyl (1S,3S)-3-((5-bromo-4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)carbamate (5.5 g, 14.3 mmol), Pd2(dba)3 (1.3 g, 1.4 mmol) and potassium hydroxide (2.4 g, 42.9 mmol) were added to a mixed solution of 1,4-Dioxane (50 mL) and Water (50 mL). The mixture was replaced with nitrogen three times and placed in an oil bath and heated to 100 ° C for 3 hours.

[0591] After the reaction was complete, H2O (50 mL) was added, and the mixture was extracted with methyl tert-butyl ether (2*50 mL). The aqueous phase was taken and adjusted to a pH of approximately 5-6 with 1M HCl (aq), then extracted with ethyl acetate (3*50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and rotary evaporated to a residue. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1, V / V) to obtain tert-butyl (1S,3S)-3-((5-hydroxy-4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)carbamate (1.5 g, yield 32%) as a white solid. LC-MS: [M+H] + =323.

[0592] Step D: Synthesis of tert-butyl (1S,3S)-3-((5-(difluoromethoxy)-4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)carbamate

[0593] At room temperature, tert-butyl (1S,3S)-3-((5-hydroxy-4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)carbamate (0.3 g, 0.93 mmol) was added to acetonitrile (10 mL). Under an ice-water bath, sodium hydroxide (0.52 g, 9.3 mmol) was dissolved in water (mL) and added to the above solution. Diethyl bromofluoromethylphosphonate (0.74 g, 2.79 mmol) was added dropwise. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out for 2 hours.

[0594] After the reaction was completed, H2O (30 mL) was added, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and rotary evaporated to a residue. The resulting residue was purified by C18 reverse phase column chromatography (ACN / H2O, 55% ACN) to give a white solid product (1S,3S)-3-((5-(difluoromethoxy)-4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester (0.1 g, yield 28.86%), LC-MS: [M+H] + =373.

[0595] Step E: Synthesis of (1S,3S)-N1-(5-(difluoromethoxy)-4,6-dimethylpyrimidin-2-yl)cyclopentane-1,3-diamine hydrochloride

[0596] Dissolve tert-butyl (1S,3S)-3-((5-(difluoromethoxy)-4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)carbamate (0.1 g, 0.27 mmol) in dichloromethane (5 mL) and add 4M HCl / 1,4-dioxane (2 mL). Incubate at room temperature for 1 hour. After the reaction is complete, spin dry the product and use it in the next step. LC-MS: [M+H] + =273.

[0597] Step F: Synthesis of (6'-(((1S,3S)-3-((5-(difluoromethoxy)-4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0598] (1S,3S)-N1-(5-(difluoromethoxy)-4,6-dimethylpyrimidin-2-yl)cyclopentane-1,3-diamine hydrochloride (70 mg, 0.26 mmol), 1-(6-fluoropyridin-3-yl)-1,2-dihydropyridin-2-one (74.17 mg, 0.39 mmol) and potassium carbonate (179.67 mg, 1.3 mmol) were added to DMSO (3 mL) and reacted at 120 ° C for 16 hours.

[0599] After the reaction was completed, the mixture was filtered and the filtrate was directly purified by C18 column chromatography (eluent: acetonitrile / water = 45 / 55, V / V) to give a white solid (6'-(((1S,3S)-3-((5-(difluoromethoxy)-4,6-dimethylpyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (54.7 mg, yield 47.61%, purity 99%), LC-MS: [M+H] + =443.

[0600] NMR data: 1H NMR (400MHz, DMSO) δ7.92(d,J=2.6Hz,1H),7.67–7.55(m,1H),7.48(ddd,J=8.9,6.6,2.1Hz,1 H),7.40(dd,J=8.9,2.7Hz,1H),7.24(d,J=7.4Hz,1H),7.16–6.69(m,2H),6.52(d,J=8.9Hz,1 H),6.45(d,J=9.2Hz,1H),6.27(t,J=6.7Hz,1H),4.32(dp,J=13.2,6.7Hz,2H),2.23(s,6H),2 .11(ddd,J=18.0,8.6,4.9Hz,2H), 1.87(dh,J=26.8,6.8Hz,2H), 1.49(dq,J=11.2,7.1Hz,2H).

[0601] Example A50

[0602] Step A: Synthesis of Compound A50-2

[0603] Compound A50-1 (2.0 g, 12.1 mmol) was dissolved in 20 mL of methanol, and sodium methoxide methanol solution (3.6 mL, 18.1 mmol) was added. The mixture was reacted at 40°C for 2 days. The reaction solution was concentrated under reduced pressure. The resulting product was purified using a flash silica gel column (0–10% methanol / dichloromethane) to obtain 820 mg of compound A50-2 as a yellow oil (42.4% yield). LCMS: [M+H] + =161.

[0604] Step B: Synthesis of Compound A50-4

[0605] Compound A50-2 (820 mg, 5.13 mmol) was dissolved in 10 ml of N,N-dimethylformamide, cesium carbonate (2 g, 6.16 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. Compound A50-3 (2.34 g, 15.4 mmol) was added, and the temperature was raised to 100 degrees Celsius for 2 hours. Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml x 3). The organic phases were combined and dried by spin drying. The resulting product was purified using a flash silica gel column (0%-20% ethyl acetate / petroleum ether) to obtain 230 mg of yellow oil A50-4 (21.4% yield). LCMS: [M+H] + =211.

[0606] Step C: Synthesis of target compound

[0607] Compound A50-4 (230 mg, 1.1 mmol) and compound A50-5 (355 mg, 1.3 mmol) were added to 5 mL of anhydrous dimethyl sulfoxide. Potassium phosphate (466 mg, 2.2 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (177 mg, 0.22 mmol) were added. The atmosphere was purged with nitrogen and the temperature was raised to 100°C for 2 hours. The reaction mixture was added to saturated aqueous ammonium chloride and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and dried by spin drying. The resulting product was purified using a flash silica gel column (0%-10% methanol / dichloromethane) and then purified using a preparative silica gel plate to obtain 11 mg of the target compound as a white solid (5.3% yield). LCMS: [M+H] + =445.

[0608] 1 H NMR (400MHz, DMSO-d6) δ7.96 (s, 1H), 7.92 (d, J = 2.4Hz, 1H), 7.60 (dd, J = 6.8, 2.1Hz, 1H), 7 .48(ddd,J=9.2,6.7,2.1Hz,1H),7.39(dd,J=8.8,2.6Hz,2H),6.93(d,J=6.8Hz,1H),6.88 (s,1H),6.52(d,J=8.8Hz,1H),6.44(d,J=9.2Hz,1H),6.27(t,J=6.8Hz,1H),4.30(d,J=8. 0Hz,2H),3.88(s,3H),2.19–2.09(m,2H),1.97–1.84(m,2H),1.51(dq,J=19.2,7.2Hz,2H).

[0609] Example A51

[0610] Step A: Synthesis of Compound A51-2

[0611] Compound A51-1 (3 g, 16.7 mmol) and phenylboronic acid (3.05 g, 25 mmol) were dissolved in toluene (60 ml) and methanol (12 ml), and 2 mol / L aqueous sodium carbonate solution (16.7 ml, 33.4 mmol) and tetrakistriphenylphosphine palladium (1.93 g, 1.67 mmol) were added. The temperature was raised to 110 degrees under a nitrogen atmosphere and the reaction was carried out for 3 hours. The reaction solution was filtered, the filtrate was extracted with ethyl acetate (20 ml × 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant was purified by Flash column (0–20% ethyl acetate / petroleum ether) to obtain 3.3 g of yellow oily liquid compound A51-2 (yield: 88.2%). LCMS: [M+H] + =221

[0612] Step B: Synthesis of Compound A51-4

[0613] Compound A51-2 (3.3 g, 15.4 mmol) was dissolved in dichloromethane (30 ml), and boron tribromide (7.4 ml, 77 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was added to 30 ml of ice water to quench, and the pH was adjusted to 5-6 with saturated aqueous sodium carbonate solution. It was extracted with ethyl acetate (30 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The resultant was purified by Flash column (0–100% ethyl acetate / petroleum ether) to obtain 2.6 g of yellow solid compound A51-3 (yield: 82.0%). LCMS: [M+H] + =207.

[0614] Step C: Synthesis of Compound A51-5

[0615] Compound A51-3 (2.6 g, 12.6 mmol) was dissolved in N, N-dimethylformamide (25 ml), cesium carbonate (4.9 g, 15.1 mmol) was added, stirred at room temperature for 1 hour, compound A51-4 (5.7 g, 37.8 mmol) was added, and the temperature was raised to 100 degrees under a nitrogen atmosphere for 3 hours. The reaction solution was cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and extracted with dichloromethane (30 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The resultant was purified by Flash column (0–30% ethyl acetate / petroleum ether) to obtain 1.2 g of yellow oily liquid compound A51-5 (yield: 37.2%). LCMS: [M+H] + =257.

[0616] Step D: Synthesis of target compound

[0617] Compound A51-5 (80 mg, 0.3 mmol) and compound A51-6 (81 mg, 0.3 mmol) were dissolved in dimethyl sulfoxide (3 ml), N,N-diisopropylethylamine (0.16 ml, 0.93 mmol) was added, and the mixture was reacted at 110 degrees under microwave for 1 hour. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane (10 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting product was purified by reverse phase preparative to obtain 65 mg of the target compound as an off-white solid (yield: 44.2%). LCMS: [M+H] + =491.

[0618] 1 H NMR (400MHz, DMSO-d6) δ8.30 (s, 1H), 7.90 (dd, J = 16.7, 4.1Hz, 3H), 7.64–7.55 (m ,2H),7.53–7.45(m,4H),7.40(dd,J=8.9,2.7Hz,1H),7.17–6.74(m,2H),6.53(d, J=8.9Hz,1H),6.44(d,J=9.1Hz,1H),6.27(td,J=6.7,1.3Hz,1H),4.35(dq,J=20. 8,6.7Hz,2H),2.17(dd,J=9.1,4.4Hz,2H),2.02–1.88(m,2H),1.63–1.45(m,2H).

[0619] Example A52

[0620] Synthesis of 1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)-4-(1H-pyrrol-2-yl)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]pyridin-2-one

[0621] Step 1: 2,4-Dichloro-5-methoxy-pyrimidine

[0622] Dissolve 2,4-dichloropyrimidin-5-ol (5.00 g, 30.3 mmol, 1.00 eq) and potassium carbonate (10.5 g, 75.8 mmol, 2.50 eq) in N,N-dimethylformamide (50 mL), add iodomethane (6.45 g, 45.5 mmol, 2.83 mL, 1.50 eq), heat to 80 degrees, and react for 2 hours.

[0623] TLC (petroleum ether: ethyl acetate = 3:1) showed a new spot (R f =0.60).

[0624] Water (200 mL) was slowly added to the reaction mixture to quench the reaction, followed by extraction with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried, and concentrated to afford the product, 2,4-dichloro-5-methoxy-pyrimidine (2.50 g, 46.1% yield).

[0625] Step 2: tert-Butyl 2-(2-chloro-5-methoxy-pyrimidin-4-yl)pyrrole-1-carboxylate

[0626] Dissolve 2,4-dichloro-5-methoxy-pyrimidine (2.50 g, 14.0 mmol, 1.00 eq), (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid (2.95 g, 14.0 mmol, 1.00 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1.14 g, 1.40 mmol, 0.10 eq), and potassium phosphate (17.8 g, 83.8 mmol, 6.00 eq) in N,N-dimethylformamide (30 mL). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 60°C for 12 hours. LCMS showed that the product had an MS value.

[0627] The reaction mixture was diluted with water (200 mL) and then extracted with ethyl acetate (40 mL * 4). The concentrated organic phase was washed with saturated brine (30 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was prepared by reverse phase (hydrochloric acid system) to obtain the product tert-butyl 2-(2-chloro-5-methoxy-pyrimidin-4-yl)pyrrole-1-carboxylate (1.50 g, 34.7% yield). LCMS: MS (ESI) m / z = 480.1 [M-100+1] +

[0628] Step 3: 2-Chloro-4-(1H-pyrrol-2-yl)pyrimidin-5-ol

[0629] 2-(2-chloro-5-methoxy-pyrimidin-4-yl)pyrrole-1-carboxylate (1.50 g, 4.84 mmol, 1.00 eq) was dissolved in dichloromethane (10 mL). The temperature was cooled to 0°C, and boron tribromide (7.28 g, 29.1 mmol, 6.00 eq) was added dropwise. The temperature was then raised to 40°C and the reaction was allowed to react for 4 hours. TLC (petroleum ether:ethyl acetate = 1:1) indicated the formation of a new major spot. Methanol was slowly added dropwise at low temperature to quench the reaction, and the mixture was concentrated to afford the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to afford 2-chloro-4-(1H-pyrrol-2-yl)pyrimidin-5-ol (0.50 g, 52.8% yield).

[0630] Step 4: 2-Chloro-5-(difluoromethoxy)-4-(1H-pyrrol-2-yl)pyrimidine

[0631] At 20°C, 2-chloro-4-(1H-pyrrol-2-yl)pyrimidin-5-ol (331 mg, 1.69 mmol, 1.00 eq) and cesium carbonate (551 mg, 1.69 mmol, 1.00 eq) were dissolved in N,N-dimethylformamide (5 mL) and stirred for one hour. Then, sodium 2-chloro-2,2-difluoroacetate (284 mg, 1.86 mmol, 1.10 eq) was added portionwise. After the addition was complete, the temperature was raised to 100°C and stirred for 2 hours.

[0632] TLC (petroleum ether: ethyl acetate = 2:1) showed that the starting material (R f =0.1) is consumed and there is a new main point (R f =0.6) is generated.

[0633] The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 50:1 to 1:1) to afford 2-chloro-5-(difluoromethoxy)-4-(1H-pyrrol-2-yl)pyrimidine (250 mg, 60.2% yield).

[0634] Step 5: 1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)-4-(1H-pyrrol-2-yl)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]pyridin-2-one

[0635] At 20°C, the obtained product, 2-chloro-5-(difluoromethoxy)-4-(1H-pyrrol-2-yl)pyrimidine (180 mg, 733 μmol, 1.00 eq), 1-[6-[[[(1S,3S)-3-aminocyclopentyl]amino]-3-pyridinyl]pyridin-2-one (237.74 mg, 879.43 μmol, 1.2 eq), and potassium carbonate (203 mg, 1.47 mmol, 2.00 eq), were dissolved in N,N-dimethylformamide (1 mL). The mixture was then heated to 80°C and stirred for 12 hours. LCMS showed that MS values ​​were detected.

[0636] The reaction mixture was diluted with water (50 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product, which was then purified by preparative chromatography (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 μm; mobile phase: [water (NH₄HCO₃)-ACN]; gradient: 25% to 55% B over 20 min) to afford 1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)-4-(1H-pyrrol-2-yl)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]pyridin-2-one (187 mg, 53.1% yield).

[0637] LCMS: MS (ESI) m / z = 480.1 [M+1] + , 1 H NMR: (400MHz, CDCl3): δ9.95-9.46(m,1H),8.13(s,1H),8.04(d,J=2.4Hz,1H),7.55(dd,J =2.4,8.8Hz,1H),7.40(ddd,J=2.0,6.8,9.2Hz,1H),7.30(dd,J=2.0,6.8Hz,1H),7.10(br s,1H),7.04(br s,1H),6.66(d,J=9.2Hz,1H),6.59-6.18(m,3H),6.18-6.18(m,1H),5.22-5.01(m,2H),4.59 -4.43(m,1H),4.34-4.18(m,1H),2.44-2.26(m,2H),2.09(t,J=6.8Hz,2H),1.66-1.57(m,2H)

[0638] Example A53

[0639] Step A: Synthesis of Compound A53-2

[0640] Compound A53-1 (5 g, 27.9 mmol) was dissolved in tetrahydrofuran (30 ml), and iron acetylacetonate (985 mg, 2.79 mmol) was added at 0 degrees. A tetrahydrofuran solution of cyclopropylmagnesium bromide (34 ml, 1 mol / L, 34 mmol) was added dropwise under a nitrogen atmosphere, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane (50 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resultant was purified by Flash column (5–30% ethyl acetate / petroleum ether) to obtain 720 mg of light yellow solid compound A53-2 (yield: 14%). LCMS: [M+H] + =185.

[0641] Step B: Synthesis of Compound A53-3

[0642] Compound A53-2 (750 mg, 3.9 mmol) was dissolved in a 1 mol / L dichloromethane solution of boron tribromide (7 ml, 7 mmol), and boron tribromide (1.2 ml, 12.5 mmol) was added and stirred at room temperature for 4 hours. The reaction solution was added to 10 ml of ice water to quench, and the pH was adjusted to 5-6 with saturated sodium carbonate aqueous solution, then extracted with ethyl acetate (20 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The resultant was purified by Flash column (0–50% ethyl acetate / petroleum ether) to obtain 300 mg of light yellow solid compound A53-3 (yield: 45%). LCMS: [M+H] + =171.

[0643] Step C: Synthesis of Compound A53-5

[0644] Compound A53-3 (300 mg, 1.76 mmol) was dissolved in N, N-dimethylformamide (10 ml), cesium carbonate (687 mg, 2.11 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Compound A53-4 (805 mg, 5.28 mmol) was added and the temperature was raised to 100 degrees under a nitrogen atmosphere for 3 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane (10 ml × 3). The organic phases were combined, dried, and concentrated. The resultant was purified by Flash column (0–20% ethyl acetate / petroleum ether) to obtain 80 mg of yellow oily compound A53-5 (yield: 20%). LCMS: [M+H] + =221.

[0645] Step D: Synthesis of target compound

[0646] Compound A53-5 (80 mg, 0.36 mmol) and compound 6 (97 mg, 0.36 mmol) were dissolved in anhydrous dimethyl sulfoxide (5 mL). Potassium phosphate (153 mg, 0.72 mmol) and [methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)] palladium(II) (57 mg, 0.072 mmol) were added. The temperature was raised to 110°C under a nitrogen atmosphere for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated. The resulting product was purified on preparative silica gel (developing solvent: dichloromethane / methanol = 12:1) to obtain 4 mg of the title compound as an off-white solid (yield: 2.5%). LCMS: [M+H] + =455.

[0647] 1 H NMR (400MHz, DMSO-d6) δ8.04(s,1H),7.91(d,J=2.7Hz,1H),7.60(dd,J=6.8,2.0Hz,1H),7.48(dd d,J=8.9,6.5,2.1Hz,1H),7.39(dd,J=8.9,2.7Hz,1H),7.22(d,J=7.4Hz,1H),6.91(d,J=6.9Hz,1H ),6.52(d,J=8.9Hz,1H),6.44(d,J=9.1Hz,1H),6.27(t,J=6.7Hz,1H),4.25(dq,J=20.1,6.8Hz,2 H),2.19–2.04(m,3H),1.86(dt,J=20.3,6.7Hz,2H),1.55–1.44(m,2H),1.23(s,2H),1.01(s,2H).

[0648] Example A54

[0649] Synthesis of 3-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridyl]-3-yl)-1,2,4-oxadiazol-5(4H)one

[0650] Step A: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile

[0651] At room temperature, 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carboxamide, 2.2 g, 4.82 mmol, 1.0 eq), triethylamine (2.43 g, 24.1 mmol, 5.0 eq), and phosphorus oxychloride (1.2 g, 14.5 mmol, 3.0 eq) were dissolved in dichloromethane (20 ml) and stirred at room temperature for 3 hours.

[0652] After the reaction, the pH of the reaction mixture was adjusted to 7–8 with 2M hydrochloric acid solution. Cold water (30 mL) was added to dilute the reaction solution, followed by extraction with ethyl acetate (75 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.83 g of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile as a brown foamy solid powder (yield 87%). LC-MS: [M+H] + =439.

[0653] Step B: Synthesis of (Z)-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-N'-hydroxy-2-oxo-2H-[1,3'-bipyridine]-3-carboxamidine

[0654] At room temperature, 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile, 0.63 g, 1.44 mmol, 1.0 eq), hydroxylamine hydrochloride (0.8 g, 11.52 mmol, 8.0 eq), and triethylamine (1.16 g, 11.52 mmol, 8.0 eq) were dissolved in ethanol (6 ml), heated to 80 degrees Celsius, and stirred for 4 hours.

[0655] After the reaction was complete, the organic solvent was removed by concentration under reduced pressure. The resulting crude product was purified via a C18 column (eluent: acetonitrile / water) to afford 0.493 g of a brown solid powder of (Z)-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-N'-hydroxy-2-oxo-2H-[1,3'-bipyridine]-3-carboximidamide (yield 73%). LC-MS: [M+H] + =473.

[0656] Step C: Synthesis of 3-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridyl]-3-yl)-1,2,4-oxadiazol-5(4H)one

[0657] (Z)-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-N'-hydroxy-2-oxo-2H-[1,3'-bipyridine]-3-carboximidazole, 0.4 g, 0.85 mmol, 1.0 eq), N,N'-carbonyldiimidazole (0.152 g, 0.94 mmol, 1.1 eq), and DBU (0.194 g, 1.28 mmol, 1.5 eq) were dissolved in 1,4-dioxane (6 ml) and stirred vigorously at room temperature for 6 h.

[0658] After the reaction was completed, the organic solvent was removed by concentration under reduced pressure. The resulting crude product was purified by C18 column (eluent: acetonitrile / water) to obtain 0.175 g of a yellow solid powder of 3-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridyl]-3-yl)-1,2,4-oxadiazol-5(4H)-one (yield 41%). LC-MS: [M+H] + =499.

[0659] H NMR spectrum: 1 H NMR(400MHz, DMSO-d6)δ8.23(s,2H),8.14–7.82(m,3H),7.56–7.38(m,2H),7.22–6.84(m,2H),6.64–6.43(m,2H),4. 31(q,J=7.0Hz,2H), 2.13(tt,J=13.0,6.8Hz,2H), 1.89(qt,J=12.9,6.7Hz,2H), 1.51(ddd,J=19.0,14.1,7.1Hz,2H).

[0660] Examples A55-73

[0661] Example B1 (Compound B1)

[0662] Synthesis of 6'-(((1S,3S)-3-((6,7-dihydro-5H-cyclopentyl[d]pyrimidin-2-yl)amino)cyclopentyl)amino]-2H-[1,3'-bipyridyl]-2-one

[0663] At 25°C, 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one hydrochloride (342 mg, 1.0 mmol), 2-chloro-6,7-dihydro-5H-cyclopentadien[d]pyrimidine (0.2 g, 1.29 mmol) and TEA (1.01 g, 10 mmol) were dissolved in DMSO (15 mL). After addition, the temperature was raised to 110°C and the reaction was carried out for 2 days.

[0664] 100 mL of water was added, followed by extraction with EA (50 mL*4), the organic phases were combined, washed with saturated brine (50 mL), and concentrated to give a crude product. The crude product was purified by column chromatography (DCM:MeOH=10:1) to give a crude product, which was then purified by reverse phase column to give a crude product, and 100 mg of 6'-(((1S,3S)-3-((6,7-dihydro-5H-cyclopentyl[d]pyrimidin-2-yl)amino)cyclopentyl)amino]-2H-[1,3'-bipyridine]-2-one was obtained.

[0665] LC-MS: [M+H] + =389. 1 H NMR (400MHz, DMSO-d6) δ8.07 (s, 1H), 7.92 (d, J = 2.6Hz, 1H), 7.61 (s, 1H), 7.48 (ddd, J = 9. 0,6.6,2.1Hz,1H),7.38(d,J=2.7Hz,1H),6.94(dd,J=10.7,7.1Hz,2H),6.52(d,J=8.9Hz ,1H),6.44(d,J=9.1Hz,1H),6.27(d,J=1.4Hz,1H),4.33(dp,J=20.4,6.7Hz,2H),2.70(t d,J=7.5,4.2Hz,4H),2.19–2.05(m,2H),2.03–1.79(m,4H),1.49(td,J=12.4,7.0Hz,2H).

[0666] Example B2 (Compound B2)

[0667] Synthesis of 6'-(((1S,3S)-3-((5,6,7,8-tetrahydroquinolin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0668] At 25°C, 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one hydrochloride (172 mg, 0.5 mmol) and 2-chloro-5,6,7,8-tetrahydroquinazoline (126 mg, 0.75 mmol) were dissolved in DMSO (5 mL). Potassium phosphate (634 mg, 3 mmol) was added, and the temperature was raised to 140°C and the reaction was allowed to proceed overnight.

[0669] 10 mL of water was added, followed by extraction with EA (10 mL*3). The organic phases were combined and concentrated to give a crude product, which was purified by column chromatography (EA:MeOH=13:1) to give 6'-(((1S,3S)-3-((5,6,7,8-tetrahydroquinolin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one.

[0670] LC-MS: [M+H] + =403.2. 1 H NMR(400MHz,Chloroform-d)δ8.02(d,J=2.6Hz,1H),7.98(s,1H),7.50(dd,J=8.9,2.7Hz,1H),7.42–7.34( m,1H),7.29(dd,J=6.9,2.1Hz,1H),6.64(dd,J=9.2,1.2Hz,1H),6.43(d,J=8.9Hz,1H),6.23(t,J=6.7Hz,1H ),5.03(d,J=7.3Hz,1H),4.90(d,J=6.8Hz,1H),4.43(q,J=6.8Hz,1H),4.21(q,J=6.4Hz,1H),2.65(t,J=6.4 Hz,2H),2.56(t,J=6.2Hz,2H),2.35–2.24(m,2H),2.03–1.99(m,2H),1.85–1.71(m,4H),1.61–1.50(m,2H).

[0671] Example B3 (Compound B3)

[0672] Synthesis of 6'-(((1S,3S)-3-((6,7-dihydro-dioxa[2,3-d]pyrimidin-2-yl)amino)pentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0673] Step A: Synthesis of compound 2-chloro-6,7-dihydro-[1,4]dioxa[2,3-d]pyrimidine

[0674] Compound 2,4-dichloropyrimidin-5-ol (3 g, 18.2 mmol) was added to 30 ml of anhydrous N,N-dimethylformamide, potassium carbonate (12.5 g, 90.9 mmol) was added, nitrogen was replaced, and the mixture was stirred at room temperature for 30 minutes. Bromoethanol (6.8 g, 54.6 mmol) was added and the mixture was reacted at 100 degrees for 16 hours.

[0675] The reaction solution was added to 100 mL of saturated aqueous ammonium chloride solution, extracted with dichloromethane (40 mL×3), and the organic phases were combined, dried, and concentrated.

[0676] The resulting product was purified using a flash silica gel column (9–13% ethyl acetate / petroleum ether) to obtain 1 g of a light yellow solid compound, 2-chloro-6,7-dihydro-[1,4]dioxa[2,3-d]pyrimidine (yield: 31.9%). LCMS: Rt = 0.946 min, [M+H] + =173.

[0677] Step B: Synthesis of tert-butyl (1S,3S)-3-((6,7-dihydro-[1,4]dioxolane[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)carbamate

[0678] 2-Chloro-6,7-dihydro-[1,4]dioxa[2,3-d]pyrimidine (1 g, 5.8 mmol) was added to 10 ml of anhydrous dimethyl sulfoxide, followed by N,N-diisopropylethylamine (3.2 ml, 18.2 mol) and tert-butyl (1S,3S)-3-aminocyclopentyl)carbamate (1.16 g, 5.8 mmol). The mixture was heated to 120°C under nitrogen and reacted for 16 hours. The reaction mixture was added to 50 ml of saturated aqueous ammonium chloride and extracted with ethyl acetate (20 ml x 3). The organic phases were combined, dried, and concentrated. The resulting product was purified using a flash silica gel column (20–35% ethyl acetate / petroleum ether) to obtain 400 mg of a pale yellow solid compound (tert-butyl (1S,3S)-3-((6,7-dihydro-[1,4]dioxolane[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)carbamate (yield: 20.7%). LCMS: Rt = 1.128 min, [M+H] + =337.

[0679] Step C: Synthesis of compound (1S,3S)-N1-(6,7-dihydro[1,4]dioxa[2,3-d]pyrimidin-2-yl)cyclopentane-1,3-diamine

[0680] The compound (1S,3S)-tert-butyl 3-((6,7-dihydro-[1,4]dioxolane[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)carbamate (400 mg, 1.2 mmol) was dissolved in 5 mL of dichloromethane, and a 4 M solution of hydrogen chloride in dioxane (4 mL, 16 mmol) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 3 mL of methanol. The pH was adjusted to 8 using a hydroxide-type ion exchange resin, filtered, and the filtrate was concentrated. 340 mg of the compound (1S,3S)-N1-(6,7-dihydro[1,4]dioxolane[2,3-d]pyrimidin-2-yl)cyclopentane-1,3-diamine was obtained as a light yellow solid. LCMS: Rt = 0.334 min, [M+H] + =237.

[0681] Step D: Synthesis of compound 6'-(((1S,3S)-3-((6,7-dihydro-dioxa[2,3-d]pyrimidin-2-yl)amino)pentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0682] Compound (1S,3S)-N1-(6,7-dihydro[1,4]dioxo[2,3-d]pyrimidin-2-yl)cyclopentane-1,3-diamine (340 mg crude product, 1.2 mmol) and compound 6 (297.5 mg, 1.44 mmol) were added to 5 ml of anhydrous dimethyl sulfoxide, potassium tert-butoxide (269.3 mg, 2.4 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (190.6 mg, 0.24 mmol), the atmosphere was replaced with nitrogen, and the temperature was raised to 110 degrees for reaction for 16 hours.

[0683] The reaction mixture was added to 20 ml of saturated aqueous ammonium chloride solution and extracted with dichloromethane (10 ml x 3). The organic phases were combined, dried, and concentrated. The resulting product was purified using a flash silica gel column (3–4% methanol / dichloromethane) and then a reverse phase column (17–20% acetonitrile / water) to obtain 93.9 mg of 6'-(((1S,3S)-3-((6,7-dihydro-dioxa[2,3-d]pyrimidin-2-yl)amino)pentyl)amino)-2H-[1,3'-bipyridyl]-2-one. LCMS: Rt = 0.827 min, [M+H] + =407.

[0684] 1H NMR (400MHz, DMSO-d6) δ7.91 (d, J=2.6Hz, 1H), 7.83 (s, 1H), 7.61 (dd, J=6.9, 2.0Hz, 1H), 7.48 (ddd, J= 8.9,6.5,2.1Hz,1H),7.39(dd,J=8.9,2.7Hz,1H),6.91(d,J=6.9Hz,1H),6.80(d,J=7.2Hz,1H),6.51(d ,J=8.9Hz,1H),6.44(d,J=9.2Hz,1H),6.27(td,J=6.7,1.2Hz,1H),4.39(dd,J=5.5,2.7Hz,2H),4.24(d q,J=27.3,6.7Hz,2H),4.16–4.09(m,2H),2.16–2.02(m,2H),1.83(q,J=7.1Hz,2H),1.52–1.40(m,2H).

[0685] Example B4 (Compound B4)

[0686] Step A: Synthesis of Compound B4-2

[0687] Compound B4-1 (1.89 g, 10 mmol) was dissolved in methanol (20 ml), acetic acid (1.8 g, 30 mmol) was added, and zinc powder (1.3 g, 20 mmol) was added in batches under a water bath. The reaction was continued for 2 hours. The reaction solution was filtered and the filtrate was concentrated. The resulting product was purified using a flash silica gel column (0-30% ethyl acetate / petroleum ether) to obtain 1.16 g of white solid compound B4-2 (yield: 75%). LCMS: [M+H] + =155.

[0688] Step B: Synthesis of Compound B4-4

[0689] Compound B4-2 (464 mg, 3 mmol) was dissolved in N-methylpyrrolidone (12 ml), and compound B4-3 (600 mg, 3 mmol) and N,N-diisopropylethylamine (1.5 ml, 9 mmol) were added. Nitrogen was replaced and microwaved at 180 degrees for 45 minutes. A total of 6 batches were added. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (50 ml × 3). The organic phases were combined, dried and concentrated. The resultant was purified by flash silica gel column (0–60% ethyl acetate / petroleum ether) to obtain 0.5 g of white solid compound B4-4 (yield: 8.7%). LCMS: [M+H] + =319.

[0690] Step C: Synthesis of Compound B4-5

[0691] Compound B4-4 (580 mg, 1.8 mmol) was dissolved in methanol (10 ml), replaced with nitrogen, and rhodium on carbon (100 mg) was added. The reaction was allowed to react at room temperature overnight under a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated. The resulting product was purified using a flash silica gel column (0-60% ethyl acetate / petroleum ether). 110 mg of white solid compound B4-5 was obtained (yield: 18.8%). LCMS: [M+H] + =321.

[0692] Step D: Synthesis of Compound B4-8

[0693] Compound B4-5 (110 mg, 0.34 mmol) was dissolved in methanol (2 ml), and a 4 mol / L hydrogen chloride dioxane solution (2 ml, 8 mmol) was added. The reaction was allowed to react at room temperature for 2 hours, and the reaction solution was directly spin-dried for the next step. The above residue was dissolved in 2 ml of dimethyl sulfoxide, and compound 4-7 (115 mg, 0.51 mmol) and potassium carbonate (138 mg, 1 mmol) were added. Nitrogen was replaced and the reaction was continued overnight at 120 degrees. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried and concentrated. The resultant was purified by flash silica gel column (0–70% ethyl acetate / petroleum ether). 47 mg of light yellow solid compound B4-8 was obtained (yield: 32.6%). LCMS: [M+H] + =424.

[0694] Step E: Synthesis of Compound B4

[0695] Compound 4-8 (47 mg, 0.11 mmol) and 2-pyridone (16 mg, 0.17 mmol) were dissolved in anhydrous 1,4-dioxane (2 ml), and potassium carbonate (31 mg, 0.22 mmol), cuprous iodide (5 mg, 0.02 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (3 mg, 0.02 mmol) were added. The atmosphere was replaced with nitrogen and the reaction was carried out at 110 degrees for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting product was purified by silica gel chromatography (developing solvent: dichloromethane / methanol = 10 / 1) to obtain 19.2 g of off-white solid compound B4 (yield: 44%). LCMS: Rt = 0.832 min, [M+H] + =391.

[0696] 1H NMR (400MHz, DMSO-d6) δ7.97(d,J=2.6Hz,1H),7.84(s,1H),7.66(dd,J=6.9,2.0Hz,1H),7.54(ddd,J=8 .9,6.6,2.1Hz,1H),7.45(dd,J=8.9,2.7Hz,1H),6.98(d,J=6.9Hz,1H),6.81(d,J=7.3Hz,1H),6.58(d,J =8.9Hz,1H),6.50(d,J=9.2Hz,1H),6.37–6.29(m,1H),4.54(t,J=8.7Hz,2H),4.34(p,J=7.2Hz,2H),3.1 7(t,J=8.7Hz,2H),2.18(ddd,J=16.9,8.3,5.1Hz,2H),1.98–1.85(m,2H),1.54(td,J=12.4,7.0Hz,2H).

[0697] Example 5 (Compound B5)

[0698] Step A: Synthesis of Compound B5-2

[0699] Compound B5-1 (330 mg, 2 mmol) and potassium vinyl trifluoroborate (281 mg, 2.1 mmol) were added to 15 ml of isopropanol, and N,N-diisopropylethylamine (0.7 ml, 4 mol) was added. The atmosphere was replaced with nitrogen, and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (73 mg, 0.1 mmol) was added. The mixture was microwaved at 100°C for 0.5 hours. A total of 10 batches were added. The reaction solution was filtered through a pad of silica gel, and the filtrate was concentrated. 7 g of light yellow liquid compound B5-2 (crude product) was obtained. LCMS: [M+H] + =157.

[0700] Step B: Synthesis of Compound B5-3

[0701] Compound B5-2 (7 g, crude product) was added to 100 ml of acetonitrile, potassium carbonate (5.5 g, 40 mol) and allyl bromide (2.9 g, 24 mol) were added, and the reaction was allowed to proceed at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, filtered, and the filtrate was concentrated. The resulting product was purified by flash silica gel column (0-10% ethyl acetate / petroleum ether) to obtain 1.92 g of light yellow solid compound B5-3 (two-step yield: 4.9%). LCMS: [M+H] + =197.

[0702] Step C: Synthesis of Compound B5-4

[0703] Compound B5-3 (1.92 g, 9.7 mmol) was dissolved in 800 ml of 1,2-dichloroethane and purged with nitrogen for 10 minutes. 1 g of Grubbs' second-generation catalyst was added and the mixture was allowed to react at 90°C for 16 hours under nitrogen. The reaction solution was concentrated under reduced pressure. The resulting product was purified using a flash silica gel column (0-15% ethyl acetate / petroleum ether) to obtain 1.37 g of a khaki solid, Compound B5-4 (yield: 81%). LCMS: [M+H] + =169.

[0704] Step D: Synthesis of Compound B5-6

[0705] Compound B5-4 (700 mg, 4.1 mmol) was dissolved in N-methylpyrrolidone (10 ml), and compound B5-5 (820 mg, 4.1 mmol) and N,N-diisopropylethylamine (2.1 ml, 12.4 mmol) were added. Nitrogen was replaced and microwaved at 150 degrees for 1 hour. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (50 ml × 3). The organic phases were combined, dried and concentrated. The resultant was purified by Flash silica gel column (0–60% ethyl acetate / petroleum ether) to obtain 125 mg of white solid compound B5-6 (yield: 9.1%). LCMS: [M+H] + =333.

[0706] Step E: Synthesis of Compound B5-7

[0707] Compound B5-6 (125 mg, 0.38 mmol) was dissolved in methanol (5 ml), the atmosphere was replaced with nitrogen, and palladium carbon (20 mg) was added. The reaction was allowed to react at room temperature overnight under a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated to obtain 90 mg of an off-white solid compound B5-7 (yield: 72%). LCMS: [M+H] + =335.

[0708] Step F: Synthesis of Compound B5-10

[0709] Compound B5-7 (90 mg, 0.27 mmol) was dissolved in methanol (2 ml), and a 4 mol / L hydrogen chloride dioxane solution (2 ml, 8 mmol) was added. The reaction was allowed to react at room temperature for 2 hours, and the reaction solution was directly spin-dried for the next step. The above residue was dissolved in 2 ml of dimethyl sulfoxide, and compound B5-9 (90 mg, 0.4 mmol) and potassium carbonate (112 mg, 0.8 mmol) were added. Nitrogen was replaced and the reaction was continued at 120 degrees overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried and concentrated. The resultant was purified by Flash silica gel column (0–70% ethyl acetate / petroleum ether). 43 mg of light yellow solid compound B5-10 was obtained (yield: 37%). LCMS: [M+H] + =438.

[0710] Step G: Synthesis of Compound B5

[0711] Compound B5-10 (43 mg, 0.1 mmol) and 2-pyridone (14 mg, 0.15 mmol) were dissolved in anhydrous 1,4-dioxane (2 ml), and potassium carbonate (28 mg, 0.22 mmol), cuprous iodide (5 mg, 0.02 mmol) and trans-(1R, 2R)-N, N'-dimethyl-1,2-cyclohexanediamine (3 mg, 0.02 mmol) were added. The atmosphere was replaced with nitrogen and the reaction was carried out at 110 degrees for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting product was purified by silica gel chromatography (developing solvent: dichloromethane / methanol = 10 / 1) to obtain 8.9 g of yellow solid compound 10 (yield: 22%). LCMS: [M+H] + =405.

[0712] 1 H NMR(400MHz, Methanol-d4)δ7.93(d,J=2.6Hz,1H),7.80(s,1H),7.65–7.56(m ,2H),7.43(dd,J=9.0,2.7Hz,1H),6.65–6.55(m,2H),6.46(td,J=6.8,1.3Hz, 1H),4.32(td,J=6.6,4.3Hz,2H),4.13–4.06(m,2H),2.73(t,J=6.6Hz,2H),2. 29–2.19(m,2H),2.07–2.02(m,2H),1.97(t,J=6.7Hz,2H),1.61–1.54(m,2H).

[0713] Example 6 (Compound B6)

[0714] Synthesis of 6'-(((1S,3S)-3-((6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0715] Step 1: Synthesis of 2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine

[0716] 2,4-Dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (1.00 g, 4.83 mmol, 1 eq) and acetic acid (1.74 g, 29.0 mmol, 6 eq) were dissolved in methanol (20 mL). Iron powder (1.08 g, 19.3 mmol, 4 eq) was then added portionwise to the reaction mixture. After the addition was complete, the temperature was raised to 70°C and the reaction was allowed to proceed for 3 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column to afford 2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine (570 mg, 3.30 mmol, 68.4% yield).

[0717] Step 2: Synthesis of 6'-(((1S,3S)-3-((6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0718] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (313 mg, 1.16 mmol, 1 eq) and 2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine (200 mg, 1.16 mmol, 1 eq) were dissolved in dioxane (5 mL). Sodium tert-butoxide (278 mg, 2.90 mmol, 2.5 eq) and XPhos Pd G3 (490 mg, 579 μmol, 0.5 eq) were then added. After the addition, the temperature was raised to 100°C and the reaction was allowed to react for 1 hour. LCMS analysis revealed the product (RT = 0.372 min). The reaction mixture was filtered, the filtrate diluted with water (20 mL), and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product, which was then purified via reverse phase preparative chromatography (column: YMC-Actus Triart C18 150*30 mm*7 μm; mobile phase: [water(FA)-ACN]; gradient: 8%-38% B over 10 min) to afford 6'-(((1S,3S)-3-((6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (10.0 mg, 23.5 μmol, 2.03% yield, 95.6% purity). LCMS (ESI) m / z = 407.2 [M+1]. +

[0719] 1 H NMR: (400MHz, DMSO-d6): δ8.07(s,1H),7.91(d,J=2.6Hz,1H),7.59(dd,J=1.6,6.8Hz,1H),7.47(d dd,J=2.1,6.8,9.1Hz,1H),7.38(dd,J=2.8,8.9Hz,1H),7.04(d,J=7.4Hz,1H),6.89(d,J=6.9Hz,1 H),6.52(d,J=8.9Hz,1H),6.44(d,J=8.9Hz,1H),6.27(dt,J=1.3,6.7Hz,1H),4.30(td,J=6.4,12. 7Hz,2H),3.28(s,2H),3.13-3.04(m,2H),2.19-2.03(m,2H),1.95-1.78(m,2H),1.56-1.41(m,2H).

[0720] Example B7 (Compound B7)

[0721] Synthesis of 6'-(((1S,3S)-3-((7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0722] Step 1: Synthesis of ethyl 4-((2-ethoxy-2-oxoethyl)thio)butanoate

[0723] Sodium ethoxide (6.98 g, 103 mmol, 1 eq) was dissolved in ethanol (200 mL). The mixture was then cooled to 0°C. Ethyl 2-sulfonylacetate (12.3 g, 103 mmol, 1 eq) and ethyl 4-bromobutyrate (20.0 g, 103 mmol, 1 eq) were added portionwise. After complete addition, the mixture was allowed to react at room temperature for 12 hours. TLC (petroleum ether / ethyl acetate = 5 / 1) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield ethyl 4-((2-ethoxy-2-oxoethyl)thio)butanoate (24.0 g, 102 mmol, 99.9% yield). This product was used directly in the next step without purification.

[0724] Step 2: Synthesis of ethyl 3-oxotetrahydro-2H-thiopyran-2-carboxylate

[0725] Ethyl 4-((2-ethoxy-2-oxoethyl)thio)butanoate (24.0 g, 102 mmol, 1 eq) and potassium tert-butoxide (23.0 g, 205 mmol, 2 eq) were dissolved in tetrahydrofuran (240 mL). After complete addition, the temperature was raised to 70°C and the reaction mixture was allowed to react for 2 hours. TLC (petroleum ether / ethyl acetate = 10 / 1) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was diluted with water (200 mL). The aqueous phase was adjusted to pH 5 with 2M hydrochloric acid, and then extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford ethyl 3-oxotetrahydro-2H-thiopyran-2-carboxylate (16.0 g, 85.0 mmol, 83.0% yield). This product was used directly in the next step without purification.

[0726] Step 3: Synthesis of 2-(ethylthio)-7,8-dihydro-3H-thiopyrano[3,2-d]pyrimidin-4(6H)-one

[0727] Sodium carbonate (9.01 g, 85.0 mmol, 1 eq) and ethyl 3-oxotetrahydro-2H-thiopyran-2-carboxylate (16.0 g, 85.0 mmol, 1 eq) were added to a solution of S-ethylisothiourea hydrobromide (15.73 g, 85.00 mmol, 1 eq) in water (150 mL). After the addition, the mixture was stirred at 20°C in the dark for 12 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated the reaction was complete. The resulting solid precipitate was collected by filtration, washed with water (50 mL) and petroleum ether (50 mL), and concentrated under reduced pressure to dryness to afford 2-(ethylthio)-7,8-dihydro-3H-thiopyrano[3,2-d]pyrimidin-4(6H)-one (14.0 g, 61.3 mmol, 72.1% yield). This product was used directly in the next step without purification.

[0728] Step 4: Synthesis of 7,8-dihydro-1H-thiopyrano[3,2-d]pyrimidine-2,4(3H,6H)-dione

[0729] 2-(Ethylthio)-7,8-dihydro-3H-thiopyrano[3,2-d]pyrimidin-4(6H)-one (14.0 g, 61.3 mmol, 1 eq) was dissolved in water (150 mL). Concentrated hydrochloric acid (21.8 mL, 4.26 eq) and acetic acid (19.6 g, 326 mmol, 5.32 eq) were added, and the mixture was stirred at 100°C for 12 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated the reaction was complete. The reaction mixture was cooled to room temperature and then filtered. The filter cake was concentrated to dryness under reduced pressure to yield 7,8-dihydro-1H-thiopyrano[3,2-d]pyrimidine-2,4(3H,6H)-dione (9.40 g, 51.0 mmol, 83.2% yield).

[0730] Step 5: Synthesis of 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine

[0731] 7,8-Dihydro-1H-thiopyrano[3,2-d]pyrimidine-2,4(3H,6H)-dione (5.00 g, 27.1 mmol, 1 eq) was dissolved in phosphorus oxychloride (20 mL) and stirred at 110°C for 12 hours. LCMS detected the product (RT = 0.594 min). The reaction mixture was cooled to 20°C, slowly poured into ice water (20 mL), stirred for 10 minutes, and extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with aqueous sodium bicarbonate (50 mL x 2) and saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified on a silica gel column to yield 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (4.70 g, 21.3 mmol, 78.3% yield).

[0732] Step 6: Synthesis of 2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine

[0733] 2,4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (4.70 g, 21.3 mmol, 1 eq) and acetic acid (7.66 g, 128 mmol, 6 eq) were dissolved in methanol (50 ml). Iron powder (4.75 g, 85.0 mmol, 4 eq) was then added portionwise to the reaction mixture. After complete addition, the temperature was raised to 70°C and the reaction mixture was allowed to react for 3 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated completion of the reaction. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column to obtain 2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (2.50 g, 13.4 mmol, 63.0% yield).

[0734] Step 7: Synthesis of 6'-(((1S,3S)-3-((7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0735] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (434 mg, 1.61 mmol, 1 eq) and 2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (300 mg, 1.61 mmol, 1 eq) were dissolved in dioxane (8 mL). Sodium tert-butoxide (386 mg, 4.02 mmol, 2.5 eq) and XPhos Pd G3 (680 mg, 804 μmol, 0.5 eq) were then added. After the addition, the temperature was raised to 100°C and the reaction was allowed to react for 1 hour. LCMS analysis revealed the product (RT = 0.372 min). The reaction mixture was filtered, the filtrate diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product, which was then purified via reverse phase preparative chromatography (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [water(FA)-ACN]; gradient: 5%-35% over 15 min) to afford 6'-(((1S,3S)-3-((7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (36.0 mg, 84.2 μmol, 5.24% yield, 98.4% purity). LCMS (ESI) m / z = 421.2 [M+1]. +

[0736] 1 H NMR: (400MHz, DMSO-d6): δ7.95(s,1H),7.91(d,J=2.6Hz,1H),7.59(dd,J=1.8,6.8Hz,1H),7.47(dd d,J=2.1,6.7,9.0Hz,1H),7.39(dd,J=2.7,8.9Hz,1H),6.98(d,J=7.4Hz,1H),6.89(d,J=6.8Hz,1H) ,6.52(d,J=8.9Hz,1H),6.44(d,J=9.0Hz,1H),6.26(dt,J=1.3,6.7Hz,1H),4.29(sxt,J=6.7Hz,2H) ,2.99-2.92(m,2H),2.67(t,J=6.4Hz,2H),2.17-2.02(m,4H),1.94-1.77(m,2H),1.56-1.41(m,2H).

[0737] Example 8 (Compound B8)

[0738] Step A: Synthesis of Compound B8-2

[0739] Compound B8-1 (1.3 g, 7.9 mmol) was added to 15 ml of anhydrous dimethyl sulfoxide, N, N-diisopropylethylamine (6.9 ml, 39.5 mmol) and 2-mercaptoethanol (1.9 g, 23.7 mmol) were added, and the reaction temperature was raised to 100 degrees under nitrogen protection for 12 hours. The reaction solution was cooled and added to 60 ml of saturated aqueous ammonium chloride solution. It was extracted with ethyl acetate (20 ml × 3), the organic phases were combined, dried and concentrated. The resultant was purified by Flash silica gel column (1-2% methanol / dichloromethane) to obtain 1.2 g of light yellow oily compound B8-2 (yield: 73.5%). LCMS: [M+H] + =207.

[0740] Step B: Synthesis of Compound B8-3

[0741] Compound B8-2 (1.2 g, 5.8 mmol) was added to 15 ml of anhydrous tetrahydrofuran, triphenylphosphine (2.3 g, 8.7 mol) was added, and the atmosphere was replaced with nitrogen. Diethyl azodicarboxylate (1.5 g, 8.7 mmol) was added under an ice-water bath, and the mixture was heated to room temperature and reacted for 3 hours. The reaction solution was added to 40 ml of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (25 ml × 3), and the organic phases were combined, dried, and concentrated. The resultant was purified by flash silica gel column (35-37% ethyl acetate / petroleum ether) to obtain 420 mg of light yellow oily compound B8-3 (yield: 35.2%). LCMS: [M+H] + =189.

[0742] Step C: Synthesis of Compound B8-5

[0743] Compound B8-3 (420 mg, 2.2 mmol) and compound B8-4 (444 mg, 2.2 mmol) were added to 5 ml of dimethyl sulfoxide, potassium tert-butoxide (497 mg, 4.4 mmol) was added, and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (351 mg, 0.44 mmol) was added under nitrogen protection. The reaction was allowed to react at 110 degrees overnight. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane (20 ml × 3). The organic phases were combined, dried, and spin-dried. The resulting product was purified on a flash silica gel column (0–10% methanol / dichloromethane) to obtain 300 mg of off-white solid compound B8-5 (yield: 38.1%). LCMS: [M+H] + =353.

[0744] Step D: Synthesis of Compound B8-6

[0745] Compound B8-5 (300 mg, 0.85 mmol) was dissolved in 10 mL of dichloromethane, and 5 mL of a 4 M solution of hydrogen chloride in dioxane was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in 10 mL of methanol. The pH was adjusted to alkaline using an OH-type ion exchange resin, filtered, and concentrated. 214 mg of compound B8-6 (crude) was obtained as a brown oil. LCMS: [M+H] + =253.

[0746] Step E: Synthesis of Compound B8

[0747] Compound B8-6 (214 mg, 0.85 mmol) and compound 7 (171 mg, 0.85 mmol) were added to 5 mL of dimethyl sulfoxide, followed by potassium tert-butoxide (192.0 mg, 1.7 mmol). Methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (135 mg, 0.17 mmol) was then added under nitrogen. The mixture was allowed to react overnight at 110°C. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried, and spin-dried. The resulting product was purified by flash silica gel column purification (0-10% methanol / dichloromethane) and then by preparative plate purification (developing solvent: dichloromethane / methanol = 10:1) to obtain 16.1 mg of white solid compound 16 (two-step yield: 4.5%). LCMS: [M+H] + =423.

[0748] 1 H NMR (400MHz, DMSO-d6) δ7.91(d,J=2.7Hz,1H),7.75(s,1H),7.60(ddd,J=6.8,2.1,0.7Hz,1H ),7.48(ddd,J=9.0,6.6,2.1Hz,1H),7.39(dd,J=8.9,2.7Hz,1H),6.90(t,J=7.0Hz,2H),6.51 (d,J=8.9Hz,1H),6.44(dt,J=9.1,1.0Hz,1H),6.27(td,J=6.6,1.4Hz,1H),4.31–4.16(m,4H ),3.31–3.25(m,2H),2.15–2.03(m,2H),1.91–1.78(m,2H),1.47(dp,J=8.6,5.8,3.9Hz,2H).

[0749] Example 9 Compound B9

[0750] Synthesis of 6'-((1S,3S)-3-((6,6-difluoro-6,7-dihydro-[1,4]dioxy[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0751] Step 1: 2,4-dichloro-5-((4-methoxybenzyl)oxy)pyrimidine

[0752] At room temperature, compound B9-1 (2.0 g, 12.2 mmol), potassium carbonate (3.4 g, 24.4 mmol, 2 eq), sodium iodide (1.8 g, 12.2 mmol, 1 eq), and acetonitrile (100 mL) were added in sequence to a 250 mL round-bottom flask, and PMBCl (2.8 g, 18.3 mmol, 1.5 eq) was slowly added, and the reaction liquid was stirred at room temperature overnight.

[0753] LC-MS detected the disappearance of the starting material and the formation of the desired product. 100 mL of EA was added for dilution, and the reaction mixture was filtered and washed with EA. The organic phase was concentrated and purified using silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound B9-2 (3 g, 86.6% yield) as a light yellow oil.

[0754] Step 2: Synthesis of 4-(2-bromo-2,2-difluoroethoxy)-2-chloro-5-((4-methoxybenzyl)oxy)pyrimidine

[0755] At room temperature, a 250 mL round-bottom flask was replaced with a nitrogen atmosphere, and THF (100 mL) and sodium hydride (632 mg, 15.8 mmol, 60 wt%, 1.5 eq) were added sequentially. The mixture was cooled to 0°C, and 2-bromo-2,2-difluoroethanol (2.5 g, 15.8 mmol, 1.5 eq) was slowly added dropwise. After stirring at 0°C for 30 min, compound 2 (3 g, 10.5 mmol, 1 eq) was slowly added. After the addition was complete, the reaction solution was warmed to room temperature and stirred for three hours.

[0756] LCMS detected the formation of the target product. The reaction was quenched by slowly adding 30 mL of saturated aqueous ammonium chloride solution, extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound B9-3 (4.0 g, 94% yield) as a light yellow oily liquid.

[0757] Step 3: Synthesis of 4-(2-bromo-2,2-difluoroethoxy)-2-chloropyrimidin-5-ol

[0758] To a 250 mL round-bottom flask at room temperature, compound B9-3 (4.0 g, 9.8 mmol, 1.00 eq), DCM (50 mL), and TFA (2.2 g, 19.6 mmol, 2 eq) were added and stirred overnight at room temperature. LCMS confirmed the formation of the desired product. The reaction mixture was directly spin-dried. Purification was performed using silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound B9-4 (0.6 g, 21% yield) as a white solid.

[0759] Step 4: 2-Chloro-6,6-difluoro-6,7-dihydro-[1,4]dioxa[2,3-d]pyrimidine

[0760] At room temperature, compound B9-4 (0.6 g, 2.1 mmol, 1.0 eq), DMSO (10 mL), and potassium carbonate (0.4 g, 3.2 mmol, 1.5 eq) were added sequentially to a 100 mL round-bottom flask, and the mixture was stirred at room temperature overnight.

[0761] LCMS detected the formation of the target product. 100 mL of EA and 50 mL of water were added to the reaction system, and the organic and aqueous phases were separated. The aqueous phase was extracted twice more with EA. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound B9-5 (140 mg, 32% yield) as a light yellow oily liquid.

[0762] Step 5: Synthesis of 6'-((1S,3S)-3-((6,6-difluoro-6,7-dihydro-[1,4]dioxy[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0763] At room temperature, compound B9-5 (60 mg, 0.29 mmol, 1.0 eq), compound B9-6 (94 mg, 0.35 mmol, 1.2 eq), cesium fluoride (220 mg, 1.45 mmol, 5.0 eq), DMSO (2 mL), and triethylamine (118 mg, 1.16 mmol, 4.0 eq) were added sequentially to a 25 mL round-bottom flask, and the reaction mixture was stirred at 120 degrees Celsius overnight.

[0764] LCMS detected the formation of the desired product. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Purification by C18 reverse phase column (mobile phase: water (FA)-ACN; gradient: 0%-80% B over 50 min) afforded 6'-((1S,3S)-3-((6,6-difluoro-6,7-dihydro-[1,4]dioxy[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (92 mg).

[0765] 1 H NMR (400MHz, DMSO-d6) δ8.17(s,1H),7.91(d,J=2.7Hz,1H),7.60(dd,J=6.8,2.1Hz,1H),7.47(ddd ,J=9.0,6.6,2.1Hz,1H),7.39(dd,J=8.8,2.7Hz,1H),7.35(d,J=7.2Hz,1H),6.90(d,J=6.9Hz,1H) ,6.52(d,J=8.9Hz,1H),6.44(d,J=9.2Hz,1H),6.27(td,J=6.7,1.4Hz,1H),4.77(t,J=6.4Hz,2H), 4.28(dt,J=17.7,7.7Hz,2H),2.20–2.07(m,2H),1.95–1.78(m,2H),1.49(td,J=13.6,7.5Hz,2H).

[0766] Examples B10-B11 (Compounds B10 and B11)

[0767] Referring to the general preparation methods 1 and 2 and the preparation methods of the embodiments of the present invention, the following compound was prepared:

[0768] Example B12 Compound B12

[0769] Synthesis of 6-(1S,3S)-3-quinazolin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0770] Intermediate Compound B12-2 (50 mg, 0.3 mmol) was added to 5 mL of dimethyl sulfoxide, followed by Intermediate Compound B12-1 (100 mg, 0.37 mmol) and NN-diisopropylethylamine (0.2 mL, 1.16 mmol). The mixture was reacted at 110°C under nitrogen for 5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting product was purified using a reverse phase column to yield 51.3 mg of 6-(1S,3S)-3-quinazolin-2-ylamino)cyclopentylamino)-2H-[1,3'-bipyridyl]-2-one.

[0771] LCMS: Rt=0.879min, [M+H] + =399. 1 H NMR (400MHz, DMSO-d6) δ9.10(s,1H),7.92(d,J=2.6Hz,1H),7.78(d,J=7.9Hz,1H),7.67(dd,J =8.6,6.8Hz,1H),7.61(dd,J=6.8,1.9Hz,1H),7.55–7.38(m,4H),7.21(t,J=7.5Hz,1H),6.98( d,J=6.9Hz,1H),6.54(d,J=8.9Hz,1H),6.44(d,J=9.2Hz,1H),6.29–6.24(m,1H),4.51(d,J=7. 3Hz,1H),4.34(d,J=5.6Hz,1H),2.17(d,J=10.1Hz,2H),2.02–1.91(m,2H),1.62–1.50(m,2H).

[0772] Example B13 Compound B13

[0773] Synthesis of 6-(1S,3S)-3-(pyridyl[2,3-d]pyrimidin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0774] The intermediate compound B13-2 (50 mg, 0.3 mmol) was added to 5 ml of dimethyl sulfoxide, and the intermediate compound B13-1 (100 mg, 0.37 mmol), potassium tert-butoxide (67 mg, 0.6 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (48 mg, 0.06 mmol) were added, and the reaction was carried out at 110 degrees Celsius under nitrogen protection for 5 hours.

[0775] The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate (10 ml x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.

[0776] The resulting product was purified using a reverse phase column to obtain 60.2 mg of 6-(1S,3S)-3-(pyridyl[2,3-d]pyrimidin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one. LCMS: Rt = 0.725 min, [M+H] + =400.

[0777] 1 H NMR(400MHz, DMSO-d6)δ9.16(s,1H),8.84(s,1H),8.21(dd,J=7.8,2.1Hz,1H),8.01–7.89(m,2H),7.66– 7.58(m,1H),7.48(ddd,J=9.0,6.6,2.1Hz,1H),7.40(dd,J=8.9,2.7Hz,1H),7.22(dd,J=7.9,4.5Hz,1H), 7.01(d,J=6.9Hz,1H),6.55(d,J=8.9Hz,1H),6.44(d,J=9.1Hz,1H),6.27(td,J=6.7,1.3Hz,1H),4.52(d, J=6.6Hz,1H),4.35(q,J=6.6Hz,1H),2.26–2.13(m,2H),1.98(dt,J=13.0,6.7Hz,2H),1.67–1.51(m,2H).

[0778] Example B14 Compound 14

[0779] Step A: Synthesis of Compound B14-2

[0780] Compound B14-1 (400 mg, 2.1 mmol) was dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (870 mg, 6.3 mmol) and iodomethane (300 mg, 2.1 mmol) were added. The mixture was reacted at room temperature for 16 hours. The reaction solution was slowly added to water and extracted with ethyl acetate (15 mL × 3). The organic phase was dried by rotary evaporation. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=99:1) to obtain 250 mg of white solid product B14-2 (yield: 59%). LCMS: [M+H] + =200.

[0781] Step B: Synthesis of Compound B14

[0782] Compound B14-2 (200 mg, 1.0 mmol) and compound 79-3 (270 mg, 1.0 mmol) were dissolved in 5 ml of dimethyl sulfoxide, and N,N-diisopropylethylamine (387 mg, 3.0 mmol) was added. The atmosphere was replaced with nitrogen and microwaved at 120°C for 1 hour. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (50 ml x 3). The organic phases were combined, dried, and concentrated. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to obtain 23 mg of light yellow solid compound B14 (yield: 5.3%). LCMS: [M+H] + =434.

[0783] 1 H NMR (400MHz, DMSO-d6) δ7.96(d,J=3.0Hz,2H),7.64(dd,J=7.0,2.1Hz,1H),7.52(ddd,J=9.0,6.6,2 .1Hz,1H),7.43(dd,J=8.9,2.7Hz,1H),7.10(d,J=7.0Hz,1H),6.96(d,J=6.8Hz,1H),6.56(d,J=8.9H z,1H),6.48(dt,J=9.1,1.1Hz,1H),6.31(td,J=6.7,1.4Hz,1H),4.68(s,2H),4.33(p,J=6.5Hz,2H), 3.29(s,3H),2.16(h,J=6.4,5.6Hz,2H),1.93(dq,J=22.2,6.4Hz,2H),1.54(tt,J=12.7,6.5Hz,2H).

[0784] Example B15 Compound B15

[0785] Step A: Synthesis of compound B15-2

[0786] Compound B15-1 (1 g, 5.2 mmol) was added to 10 mL of methanol, followed by glacial acetic acid (0.9 mL, 15.6 mmol). Zinc powder (680 mg, 10.4 mmol) was added in portions under a water bath and allowed to react at room temperature for 4 hours. The reaction solution was filtered and the filtrate was concentrated. The resulting product was purified using a flash silica gel column (5–30% ethyl acetate / petroleum ether) to obtain 200 mg of a light yellow solid, compound B15-2. (Yield: 24.5%). LCMS: [M+H] + =157.

[0787] Step B: Synthesis of Compound B15

[0788] Compound B15-2 (150 mg, 0.95 mmol) and compound B15-3 (256.8 mg, 0.95 mmol) were added to 4 ml of N-methylpyrrolidone, and NN-diisopropylethylamine (0.5 ml, 2.97 mmol) was added. After nitrogen substitution, the mixture was microwaved at 150 degrees for 30 minutes. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (20 ml x 3). The organic phases were combined, dried, and concentrated. The resulting product was purified using a C18 reverse phase column to obtain 90 mg of a light yellow solid compound B15. (Yield: 24.2%). LCMS: [M+H] + =391.

[0789] 1 H NMR (400MHz, DMSO-d6) δ8.23 (s, 1H), 7.92 (d, J = 2.7Hz, 1H), 7.60 (dd, J = 6.8, 2.1Hz, 1H), 7.48 (ddd, J = 9. 0,6.6,2.1Hz,1H),7.39(dd,J=8.9,2.7Hz,1H),7.33(d,J=7.3Hz,1H),6.93(d,J=6.9Hz,1H),6.52(d,J=8 .9Hz,1H),6.49–6.39(m,1H),6.27(td,J=6.7,1.3Hz,1H),4.91(d,J=2.0Hz,2H),4.71(t,J=1.8Hz,2H), 4.34(dq,J=24.4,6.9Hz,2H),2.18–2.06(m,2H),1.94–1.81(m,2H),1.50(ddd,J=16.4,12.8,7.0Hz,2H).

[0790] Example B16 Compound B16

[0791] Step A: Synthesis of compound B16-2

[0792] Compound B16-1 (1 g, 4.9 mmol) was dissolved in 10 ml of methanol, acetic acid (0.84 ml, 14.7 mmol) was added, and zinc powder (637 mg, 9.8 mmol) was added in batches. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was filtered and the filtrate was concentrated. The resulting product was purified using a flash silica gel column (5–30% ethyl acetate / petroleum ether) to obtain 350 mg of yellow oily compound B16-2 (yield: 39.4%). LCMS: [M+H] + =171.

[0793] Step B: Synthesis of Compound B16

[0794] Compound B16-2 (170 mg, 1 mmol) and compound B16-3 (270 mg, 1 mmol) were dissolved in 5 mL of N-methylpyrrolidone. N,N-diisopropylethylamine (0.35 mL, 2 mmol) was added, the atmosphere was replaced with nitrogen, and the mixture was microwaved at 150°C for 0.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried, and concentrated.

[0795] The resulting product was purified by flash silica gel column (0%-10% methanol / dichloromethane) to obtain 56.8 mg of target compound B16 as a yellow solid (yield: 14.1%).

[0796] LCMS: [M+H] + =405. 1 H NMR (400MHz, DMSO-d6) δ8.34(s,2H),8.26(s,2H),7.73(d,J=7.6Hz,1H),7.68(dd,J=6.8,2.0Hz,1H),7.56(d,J=7.6Hz,1H),7.51(ddd,J=8.8,6.6,2.0 Hz,1H),7.06(s,1H),6.51–6.44(m,1H),6.32(td,J=6.6,1.2Hz,1H),5.96( s,2H),5.14(q,J=6.4,5.8Hz,1H),5.10–5.03(m,1H),2.14(t,J=6.0Hz,2H).

[0797] Example B17 Compound B17

[0798] Step A: Synthesis of compound B17-3

[0799] Compound B17-1 (1 g, 6.1 mmol) was dissolved in 10 mL of dioxane, and compound B17-2 (457 mg, 12.2 mmol) was added. The mixture was allowed to react at 60°C for 16 hours. The reaction solution was spin-dried to dryness. The resulting product was purified using a flash silica gel column (0–50% ethyl acetate / petroleum ether) to obtain 900 mg of compound B17-2 as a white solid (yield: 75%). LCMS: [M+H] + =204.

[0800] Step B: Synthesis of Compound B17-4

[0801] Compound B17-3 (900 mg, 5.4 mmol) was dissolved in 10 ml of N,N-dimethylformamide, and triphenylphosphine (2.1 g, 8.1 mmol) and diisopropyl azodicarboxylate (1.6 ml, 8.1 mmol) were added. The mixture was reacted at room temperature for 2 hours under nitrogen protection. The reaction solution was added to 20 ml of water and extracted with ethyl acetate (20 ml x 3). The organic phases were combined and dried. The resulting product was purified by flash silica gel column (0-30% ethyl acetate / petroleum ether) to obtain 170 mg of white solid compound B17-4 (yield: 17%). LCMS: [M+H] + =186.

[0802] Step C: Synthesis of Compound B17

[0803] Compound B17-4 (160 mg, 0.86 mmol) and compound B17-5 (232 mg, 0.86 mmol) were dissolved in 1 ml of N-methylpyrrolidone, N,N-diisopropylethylamine (0.3 ml, 1.73 mmol) was added, nitrogen was replaced, and microwave reaction was performed at 180 degrees for 1 hour. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried, and concentrated. The resultant was purified by C18 reverse phase column (0-30% acetonitrile / water) to obtain 5.8 mg of white solid compound B17 (yield: 1.6%). LCMS: [M+H] + =420.

[0804] 1 H NMR(400MHz,DMSO-d6)δ7.92(d,J=2.7Hz,1H),7.60(dd,J=7.0,2.1Hz,1H),7.52 –7.33(m,3H),7.00(d,J=6.5Hz,1H),6.54(d,J=8.9Hz,1H),6.44(d,J=9.1Hz,1H ),6.27(td,J=6.8,1.4Hz,1H),4.29(d,J=7.2Hz,2H),4.10(d,J=5.0Hz,2H),3.5 4(s,2H),3.11(s,3H),2.13(t,J=5.8Hz,2H),1.90(t,J=6.8Hz,2H),1.51(s,2H).

[0805] Example B18 Compound B18

[0806] Synthesis of 6'-(((1S,3S)-3-((5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0807] Step 1: Synthesis of 2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine

[0808] 2,4-Dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (1.00 g, 4.83 mmol, 1 eq) and acetic acid (1.74 g, 29.0 mmol, 6 eq) were dissolved in methanol (20 ml). Iron powder (1.08 g, 19.3 mmol, 4 eq) was then added portionwise to the reaction mixture. After the addition was complete, the temperature was raised to 70°C and the reaction was allowed to proceed for 3 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column to afford 2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine (570 mg, 3.30 mmol, 68.4% yield).

[0809] Step 2: Synthesis of 2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide

[0810] To a solution of 2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine (600 mg, 3.48 mmol, 1 eq) in dichloromethane (10 mL) was added a solution of m-chloroperbenzoic acid (811 mg, 4.00 mmol, 85% purity, 1.15 eq) in dichloromethane (5 mL) at 0°C. After complete addition, the mixture was stirred at 20°C for 2 hours. LCMS revealed the product (RT = 0.328 min). The reaction mixture was quenched with 10% Na₂SO₃ solution and extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product, which was then purified on a silica gel column to afford 2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (450 mg, 2.39 mmol, 68.6% yield).

[0811] Step 3: Synthesis of 6'-(((1S,3S)-3-((5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0812] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (516 mg, 1.91 mmol, 1 eq) and 2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (360 mg, 1.91 mmol, 1 eq) were dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (791 mg, 5.73 mmol, 3 eq) was then added. After the addition, the reaction mixture was stirred at 100°C for 3 hours. LCMS analysis revealed the product (RT = 0.412 min). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase preparative chromatography (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 0%-22% B over 10 min) to afford 6'-(((1S,3S)-3-((5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (100 mg, 232 μmol, 12.2% yield, 98.0% purity). LCMS: MS (ESI) m / z = 423.1 [M+1] + .

[0813] Step 4: SFC separation

[0814] 6'-(((1S,3S)-3-((5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (100 mg, 232 μmol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [CO2-ACN / i-PrOH (0.1% NH3H2O)]; B%: 60%, isocratic elution mode). The two peaks obtained after separation were purified by reverse phase column (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 0%-25% B over 10 min) to give B18A (peak 1, 10.24 mg, 25.7 μmol, 22.2% yield, 98.7% purity) and B18B (peak 2, 11.06 mg, 28.2 μmol, 24.3% yield, 99.1% purity).

[0815] B18A:LCMS MS(ESI)m / z=423.1[M+1] + , 1 H NMR:(400MHz,DMSO-d6):

[0816] δ8.72(s,1H),7.94(d,J=2.6Hz,1H),7.88-7.80(m,1H),7.54(dd,J=1.9,6.9Hz,1H),7.45(ddd,J=2.1,6.7,9.1Hz,1H),7.39(dd,J=2.8,8.9Hz,1H),6.67(br d,J=6.5Hz,1H),6.55(d,J=8.9Hz,1H),6.43(d,J=9.4Hz,1H),6.25(dt,J=1.3,6.7Hz,1H),4.55-4.45(m,1H),4.42-4.31(m,1H),3.61-3.47(m,1H),3.38(td,J=8.1,13.6Hz,1H),3.12(br s,1H),2.98(ddd,J=2.7,7.6,13.6Hz,1H),2.25-2.12(m,2H),2.07-1.88(m,2H),1.68-1.47(m,2H).

[0817] B18B:LCMS m / z=423.1[M+1] + , 1 H NMR:(400MHz,DMSO-d6):

[0818] δ8.72(s,1H),7.94(d,J=2.6Hz,1H),7.84(br d,J=6.5Hz,1H),7.54(dd,J=1.9,6.8Hz,1H),7.45(ddd,J=2.1,6.7,9.1Hz,1H),7.39(dd,J=2.8,8.9Hz,1H),6.67(br d,J=6.9Hz,1H),6.55(d,J=8.9Hz,1H),6.43(d,J=9.3Hz,1H),6.25(dt,J=1.3,6.7Hz,1H),4.55-4.44(m,1H),4.36(sxt,J=6.5Hz,1H),3.60-3.49(m,1H),3.38(td,J=8.2,13.6Hz,1H),3.12(br d,J=2.4Hz,1H),2.98(ddd,J=2.6,7.6,13.6Hz,1H),2.27-2.11(m,2H),2.07-1.87(m,2H),1.66-1.49(m,2H).

[0819] Example B19 Compound B19

[0820] Synthesis of 6'-(((1S,3S)-3-((5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0821] Step 1: Synthesis of 2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide

[0822] To a solution of 2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (600 mg, 3.21 mmol, 1 eq) in dichloromethane (10 mL) was added a solution of m-chloroperbenzoic acid (750 mg, 3.70 mmol, 85% purity, 1.15 eq) in dichloromethane (8 mL) at 0°C. The mixture was stirred at 20°C for 2 hours. LCMS analysis revealed the product (RT = 0.255 min). The reaction mixture was quenched with 10% Na2SO3 solution and extracted with dichloromethane (20 mL x 2). The pooled organic phase was washed with saturated brine (50 ml * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column to obtain 2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (350 mg, 1.73 mmol, 53.7% yield, 100% purity).

[0823] Step 2: Synthesis of 6'-(((1S,3S)-3-((5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0824] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (400 mg, 1.48 mmol, 1 eq) and 2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5-oxide (300 mg, 1.48 mmol, 1 eq) were dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (614 mg, 4.44 mmol, 3 eq) was then added. After the addition, the reaction mixture was stirred at 120°C for 12 hours. LCMS analysis revealed the product (RT = 0.400 min). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase preparation (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 0%-22% B over 10 min) to give 6'-(((1S,3S)-3-((5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (330 mg, 756 μmol, 51.1% yield, 100% purity).

[0825] Step 3: SFC separation

[0826] 6'-(((1S,3S)-3-((5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (330 mg, 756 μmol, 1 eq) was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm*50 mm, 10 um); mobile phase: [CO2-ACN / EtOH (0.1% NH3H2O)]; B%: 48%, isocratic elution mode) to give B19A (peak 1, 92.95 mg, 213 μmol, 56.4% yield, 100% purity) and B19B (peak 2). 2,126.02mg, 287μmol, 76.0% yield, 98.8% purity).

[0827] B19A: LCMS(ESI)m / z=437.1[M+1] +

[0828] 1H NMR (400MHz, DMSO-d6): δ8.54-8.41(m,1H),8.02-7.86(m,2H),7.59(dd,J=1.6,6.8Hz,1H) ,7.47(ddd,J=2.1,6.8,9.1Hz,1H),7.39(dd,J=2.8,8.9Hz,1H),6.92(d,J=6.9Hz,1H),6.52 (d,J=8.9Hz,1H),6.44(d,J=9.3Hz,1H),6.27(dt,J=1.3,6.7Hz,1H),4.48-4.23(m,2H),3.1 3-3.02(m,1H),2.96-2.83(m,1H),2.82-2.70(m,2H),2.20-1.77(m,6H),1.64-1.42(m,2H).

[0829] B19B: LCMS(ESI)m / z=437.1[M+1] +

[0830] 1 H NMR (400MHz, DMSO-d6): δ8.55-8.40(m,1H),8.03-7.86(m,2H),7.59(dd,J=1.7,6.8Hz,1H),7.47(ddd,J=2.0,6.7,9.0Hz,1H),7.39(dd,J=2 .6,8.9Hz,1H),6.93(d,J=6.9Hz,1H),6.52(d,J=8.9Hz,1H),6.44(d,J=9.1Hz,1H),6.27(dt,J=1.2,6.7Hz,1H),4.47-4.26(m,2H),3.08(br dd,J=3.6,13.2Hz,1H),2.89(dt,J=1.9,13.3Hz,1H),2.82-2.64(m,2H),2.21-1.78(m,6H),1.60-1.44(m,2H).

[0831] Example B20 Compound B20

[0832] Step A: Synthesis of target compound

[0833] Compound B20-1 (272 mg, 2 mmol) and benzotriazole (600 mg, 5 mmol) were dissolved in 3 mL of acetonitrile. Triethylamine (0.84 mL, 6 mmol) was added, followed by dropwise addition of phosphorus oxychloride (0.28 mL, 3 mmol). The temperature was raised to 80°C under nitrogen for 6 hours. The reaction mixture was spin-dried, and the residue was dissolved in 5 mL of dimethyl sulfoxide. N,N-diisopropylethylamine (780 mg, 6 mmol) and compound B20-3 (270 mg, 1 mmol) were added and allowed to react at room temperature overnight. The reaction mixture was added to 20 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting product was purified on a silica gel column (eluent: 0-10% methanol / dichloromethane) to obtain 55 mg of the title compound as an off-white solid (yield: 14%).

[0834] LCMS: [M+H] + =389. 1 H NMR(400MHz, DMSO-d6)δ8.96(d,J=8.0Hz,1H),8.20–8.09(m,2H),7.93(d,J=2.7Hz,1H),7.61(dd,J=6.9,2.0H z,1H),7.48(ddd,J=9.0,6.6,2.1Hz,1H),7.41(dd,J=8.9,2.7Hz,1H),7.00(d,J=6.8Hz,1H),6.55(d,J=8.9Hz ,1H),6.49–6.40(m,2H),6.27(td,J=6.7,1.4Hz,1H),4.76(h,J=7.6Hz,1H),4.39(q,J=6.4Hz,1H),2.17(ddd, J=13.2,10.9,6.5Hz,3H),1.95(ddd,J=13.1,8.1,5.0Hz,1H),1.85–1.76(m,1H),1.55(dt,J=15.6,7.6Hz,1H).

[0835] Example B21 Compound B21

[0836] Step A: Synthesis of target compound

[0837] Compound B21-1 (100 mg, 0.37 mmol) was dissolved in 3 ml of dimethyl sulfoxide, and compound B21-2 (72.9 mg, 0.37 mmol) and N,N-diisopropylethylamine (142 mg, 1.1 mmol) were added. The mixture was reacted at 120°C for 2 hours. The reaction solution was added to 20 ml of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (10 ml x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting product was purified using preparative silica gel plates (developing solvent: dichloromethane / methanol = 10 / 1) to obtain 12.6 mg of the target compound as a white solid (yield: 8.8%). LCMS: [M+H] + =388.

[0838] 1 H NMR (400MHz, DMSO-d6) δ8.48(d,J=7.6Hz,1H),7.99(d,J=2.8Hz,1H),7.81(d,J=2.0Hz,1H),7. 67(dd,J=6.8,2.0Hz,1H),7.62–7.50(m,2H),7.47(dd,J=8.8,2.8Hz,1H),7.06(d,J=6.8Hz,1H ),6.60(d,J=8.8Hz,1H),6.50(d,J=9.2Hz,1H),6.40–6.23(m,2H),6.01(d,J=2.0Hz,1H),4.45 (dq,J=28.4,6.8Hz,2H),2.34–2.17(m,1H),1.97(t,J=6.8Hz,2H),1.57(dd,J=7.2,4.2Hz,1H).

[0839] Example B22 Compound B22

[0840] Step A: Synthesis of Compound B22-2

[0841] Compound B22-1 (9 g, 56.6 mmol) was dissolved in dichloromethane (1 L), and boron tribromide (87 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was slowly added to ice water to quench the reaction and extracted with dichloromethane (1 L x 3). The aqueous phase was adjusted to a weak base with aqueous ammonia and dried by rotary evaporation. The resulting solid was extracted with 1 L of dichloromethane / methanol = 10:1, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to obtain 5.5 g of compound B22-2 as a white solid (yield: 67%). LCMS: [M+H] + =146.

[0842] Step B: Synthesis of Compound B22-3

[0843] Compound B22-2 (3 g, 20.6 mmol) was dissolved in NN-dimethylformamide (30 ml), N,N-diisopropylethylamine (7.9 g, 61.8 mmol) was added, and chloroacetyl chloride (2.3 g, 20.6 mmol) was added at 0 degrees, and stirred at room temperature for 16 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (50 ml × 3). The organic phases were combined, dried, and concentrated. The resultant was purified by flash silica gel column (dichloromethane: methanol = 97: 3) to obtain 1.5 g of gray solid compound B22-3 (yield: 39%). LCMS: [M+H] + =186.

[0844] Step C: Synthesis of target compound

[0845] Compound B22-3 (150 mg, 0.81 mmol) and compound B22-4 (218 mg, 0.81 mmol) were dissolved in dimethyl sulfoxide (5 mL), and NN-diisopropylethylamine (0.42 mL, 2.43 mmol) was added. The reaction mixture was heated to 120°C under a nitrogen atmosphere for 12 hours. The reaction solution was added to a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and concentrated. The resulting product was purified on a silica gel plate (dichloromethane:methanol = 10:1) to obtain 4.8 mg of the title compound as a white solid (yield: 1.4%).

[0846] LCMS: [M+H] + =420. 1 H NMR (400MHz, DMSO-d6) δ11.28(s,1H),8.25–7.87(m,2H),7.66(dd,J=6.8,2.0Hz,1H),7.54( ddd,J=8.8,6.4,2.0Hz,1H),7.45(dd,J=8.8,2.8Hz,1H),6.94(dd,J=13.2,7.2Hz,2H),6.58 (d,J=8.8Hz,1H),6.50(d,J=9.2Hz,1H),6.33(td,J=6.8,1.2Hz,1H),4.59(s,2H),4.33(q,J =7.2,6.4Hz,2H),2.31–2.11(m,2H),2.02–1.81(m,1H),1.55(td,J=13.2,11.6,7.2Hz,2H).

[0847] Example B23 Compound B23

[0848] Step A: Synthesis of compound B23-3

[0849] Compound B23-1 (10 g, 67.6 mmol) was dissolved in 100 mL of dioxane, and compound B23-2 (10 g, 133.4 mmol) was added. The mixture was heated to 110°C and reacted for 16 hours. The reaction solution was spin-dried to dryness. The resulting product was purified using a flash column (0–40% ethyl acetate / petroleum ether) to obtain 11.2 g of compound B23-3 as a yellow oil (yield: 88.2%). LCMS: [M+H] + =188.

[0850] Step B: Synthesis of Compound B23-4

[0851] Compound B23-3 (940 mg, 5.0 mmol) was dissolved in 30 ml of chloroform, and dichlorothionyl (1.1 ml, 15 mmol) was added. The mixture was reacted at 60°C for 16 hours. The reaction solution was spin-dried, and the residue was dissolved in methanol. The pH was adjusted to 8 using an OH-type ion exchange resin, filtered, and spin-dried. The resulting product was purified using a flash column (0-10% methanol / dichloromethane) to obtain 320 mg of a white solid B23-4 (yield: 37.9%). LCMS: [M+H] + =170.

[0852] Step C: Synthesis of target compound

[0853] Compound B23-4 (320 mg, 1.9 mmol) and compound 5 (612 mg, 2.27 mmol) were added to 5 ml of anhydrous dimethyl sulfoxide. Potassium phosphate (806 mg, 3.8 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (302 mg, 0.38 mmol) were added. The mixture was reacted at 100°C under nitrogen for 16 hours. The reaction solution was poured into saturated ammonium chloride (20 ml) and extracted with ethyl acetate (10 ml x 3). The organic phases were combined and dried by spin drying. The resulting product was purified using a C18 column (0-20% acetonitrile / water) to obtain 7.1 mg of the light yellow title compound (yield 1%). LCMS: [M+H] + =404.

[0854] 1H NMR (400MHz, DMSO-d6) δ10.48(s,1H),8.38(d,J=6.4Hz,1H),7.93(d,J=2.8Hz,1H),7.61(dd,J=6.8,2.0Hz,1H),7.48(ddd,J=9. 2,6.6,2.0Hz,1H),7.44–7.36(m,3H),6.99(d,J=6.8Hz,1H),6.55(d,J=8.8Hz,1H),6.48–6.41(m,1H),6.27(td,J=6.8,1.2Hz,1H ),5.00–4.85(m,1H),4.45(h,J=6.4Hz,1H),4.34(p,J=6.4Hz,1H),4.16(t,J=11.2Hz,1H),3.62(dd,J=11.2,8.4Hz,1H),2.18(dd d,J=12.0,9.2,5.6Hz,2H),2.06(dq,J=13.2,6.4Hz,1H),1.97–1.88(m,1H),1.69(dt,J=14.4,6.0Hz,1H),1.53(d,J=6.4Hz,4H).

[0855] Examples B24, B25, B27-B33

[0856] Referring to the above-mentioned compound preparation method, the following compound was prepared:

[0857] Example B26 Compound B26

[0858] Synthesis of 3-(6-(((1S,3S)-3-((6,7-dihydro-[1,4]dioxy[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-5-fluoropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0859] At room temperature, compound B26-1 (200 mg, 0.49 mmol), compound B26-2 (110 mg, 0.73 mmol, 1.5 eq), potassium carbonate (200 mg, 1.47 mmol, 3 eq), cuprous iodide (47 mg, 0.24 mmol, 0.5 eq), 8-hydroxyquinoline (36 mg, 0.24 mmol, 0.5 eq), and DMSO (3 mL) were added sequentially to a 10 mL microwave reaction tube. The reaction system was replaced with a nitrogen atmosphere, and then the temperature was raised to 160 ° C for reaction and microwave reaction for 2 h.

[0860] LC-MS detected the formation of the target product. The reaction mixture was filtered, concentrated, and purified by C18 reverse phase column (mobile phase: water (FA)-ACN; gradient: 0%-80% B over 50 min) to obtain the target compound (99 mg).

[0861] 1 H NMR(400MHz, DMSO-d6)δ8.04(d,J=2.1Hz,1H),7.95(dd,J=5.2,1.4Hz,1H),7.83(s,1H),7.64–7.56 (m,2H),7.16(dd,J=7.7,5.2Hz,1H),6.87(d,J=7.0Hz,1H),6.76(d,J=7.2Hz,1H),4.49(h,J=7.0Hz, 1H),4.43–4.34(m,2H),4.22(dt,J=14.1,6.9Hz,1H),4.17–4.10(m,2H),3.41(s,4H),2.12(dq,J=13 .5,4.5Hz,2H),1.91(td,J=6.7,3.6Hz,2H),1.58(ddd,J=16.7,14.2,8.6Hz,1H),1.53–1.42(m,1H).

[0862] Example C1

[0863] Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0864] Step 1: Synthesis of 5-bromo-2-(difluoromethoxy)pyridine

[0865] At room temperature, 5-bromopyridin-2-ol (10.0 g, 57.5 mmol, 1.00 eq) was dissolved in DMF (200 mL), and cesium carbonate (22.5 g, 69.0 mmol, 1.20 eq) was added. Under nitrogen protection, the mixture was stirred at 25°C for 1.5 hours. Then, sodium 2-chloro-2,2-difluoroacetate (26.3 g, 172 mmol, 3.00 eq) was added, and the temperature was raised to 100°C and the mixture was stirred for 1.5 hours.

[0866] LCMS showed the target product MS (RT = 0.537min, m / z = 223.9 [M + H] +The mixture was cooled to room temperature, and 600 ml of water was added. The mixture was extracted with 600 ml of ethyl acetate. The organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The sample was mixed with silica gel and purified by column chromatography using pure petroleum ether to obtain the product. 5-Bromo-2-(difluoromethoxy)pyridine (3.01 g, 13.4 mmol, 23.38% yield) was obtained as a colorless oily liquid. LCMS (ESI) m / z = 223.9 [M+H] + .

[0867] Step 2: Synthesis of 6-(difluoromethoxy)pyridin-3-amine

[0868] At room temperature, 5-bromo-2-(difluoromethoxy)pyridine (3.00 g, 13.4 mmol, 1.00 eq), aqueous ammonia (2.35 g, 20.1 mmol, 2.58 mL, 30% purity, 1.50 eq), cuprous iodide (510 mg, 2.68 mmol, 0.2 eq), potassium carbonate (2.78 g, 20.09 mmol, 1.50 eq), and L-proline (616.76 mg, 5.36 mmol, 0.40 eq) were added to N-methylpyrrolidone (30 mL), the temperature was raised to 140°C in a sealed container, and the reaction was stirred for 12 hours.

[0869] TLC (petroleum ether / ethyl acetate = 5 / 1) showed complete reaction of the starting material. 20 ml of aqueous solution was added, and the mixture was extracted with ethyl acetate (30 ml x 4). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The sample was mixed with silica gel and separated by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 6-(difluoromethoxy)pyridin-3-amine (1.3 g, 8.12 mmol, 60.62% yield) as a yellow oil.

[0870] Step 3: Synthesis of 5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine

[0871] In an ice bath at 0°C, 6-(difluoromethoxy)pyridin-3-amine (1.00 g, 6.25 mmol, 1.00 eq) and potassium thiocyanate (4.86 g, 50.0 mmol, 4.84 mL, 8.00 eq) were dissolved in glacial acetic acid (3.00 mL). A solution of bromide (2.99 g, 18.8 mmol, 965 μL, 3.00 eq) in glacial acetic acid (1.00 mL) was slowly added dropwise, keeping the reaction temperature below 0°C. After the addition was complete, the temperature was naturally raised to 20°C, and the reaction was stirred at 20°C for 8 hours.

[0872] TLC (petroleum ether / ethyl acetate = 2 / 1) showed that the starting material was completely reacted. 5 ml of water was added, the temperature was raised to 85°C, and the mixture was filtered while hot. 1.5 ml of acetic acid was added to the filter cake, the temperature was raised to 85°C, and the mixture was filtered while hot. The two filtrates were combined and the pH was adjusted to 8 with aqueous ammonia in an ice-water bath. A large amount of yellow solid precipitated. The mixture was filtered under reduced pressure and the filter cake was dried to give the yellow target product 5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine (0.9 g, 4.14 mmol, 66.35% yield).

[0873] Step 4: Synthesis of 2-chloro-5-(difluoromethoxy)thiazolo[5,4-b]pyridine

[0874] At room temperature, 5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine (0.90 g, 4.14 mmol, 1.00 eq) was dissolved in acetonitrile (15 mL) under nitrogen protection. Isoamyl nitrite (728 mg, 6.22 mmol, 837 μL, 1.50 eq) and copper chloride (669 mg, 4.97 mmol, 161 μL, 1.20 eq) were added. The mixture was stirred at 25°C for 3 hours.

[0875] TLC (petroleum ether / ethyl acetate = 2 / 1) showed complete reaction. 8 ml of saturated ammonium chloride solution was added and stirred for 10 minutes. The mixture was diluted with 25 ml of water and extracted with 80 ml of ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The sample was mixed with silica gel and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The desired product, 2-chloro-5-(difluoromethoxy)thiazolo[5,4-b]pyridine, was obtained as a white solid (0.7 g, 2.96 mmol, 71.39% yield). LCMS (ESI) m / z = 236.9 [M+H] + .

[0876] Step 5: Synthesis of 6'-(((1S,3S)-3-((5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0877] At room temperature, 2-chloro-5-(difluoromethoxy)thiazolo[5,4-b]pyridine (200 mg, 845 μmol, 1 eq), 1-[6-[[[(1S,3S)-3-aminocyclopentyl]amino]-3-pyridinyl]pyridin-2-one hydrochloride (259 mg, 845 μmol, 1.00 eq, HCl) and triethylamine (257 mg, 2.54 mmol, 352 μL, 3.00 eq) were added to DMSO (10.0 mL). Under nitrogen protection, the temperature was raised to 60 ° C for 12 hours.

[0878] LCMS showed the target product MS (RT = 0.423min, m / z = 471.1 [M + H] + The reaction mixture was quenched by adding 30 ml of aqueous solution and extracted with 60 ml of ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The sample was mixed with silica gel and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0–1 / 1). The product, 6'-(((1S,3S)-3-((5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one, was obtained as a yellow solid (124 mg, 264 μmol, 31.18% yield).

[0879] LCMS (ESI) m / z = 471.1 [M+H] +

[0880] 1 H NMR (400MHz, CDCl3): δ8.41(d,J=6.6Hz,1H),7.93(d,J=2.6Hz,1H),7.84-7.77(m,1H ),7.64-7.56(m,1H),7.47(ddd,J=2.1,6.8,9.1Hz,1H),7.44-7.37(m,1H),7.02-6.8 8(m,2H),6.53(d,J=9.0Hz,1H),6.44(d,J=9.1Hz,1H),6.27(dt,J=1.2,6.7Hz,1H),4 .47-4.26(m,2H),2.26-2.11(m,2H),1.96(tq,J=6.6,13.7Hz,2H),1.65-1.49(m,2H).

[0881] Example C2

[0882] Synthesis of 6'-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0883] Step 1: Synthesis of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine

[0884] 7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (2.00 g, 9.39 mmol, 1 eq), copper bromide (3.15 g, 14.1 mmol, 1.5 eq) and tert-butyl nitrite (1.45 g, 14.1 mmol, 1.5 eq) were dissolved in acetonitrile (120 ml) and stirred at 80°C for 3 hours. The MS value of the product was monitored by LCMS (RT = 0.452 min), and the reaction solution was cooled to room temperature. The reaction mixture was then diluted with water (200 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic phases were washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (2.00 g, 7.22 mmol, 76.9% yield). This product was used directly in the next step without purification. LCMS (ESI) m / z = 277.9 [M+1] +

[0885] Step 2: Synthesis of 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ol

[0886] 2,7-Dibromo-[1,2,4]triazolo[1,5-a]pyridine (2.00 g, 7.22 mmol, 1 eq), potassium hydroxide (1.2 g, 21.7 mmol, 3 eq), t-Bu Xphos (675 mg, 1.59 mmol, 0.22 eq), and Pd2(dba)3 (728 mg, 794 μmol, 0.11 eq) were dissolved in 1-4, dioxane (20 mL), and water (5 mL) and stirred at 100°C for 4 hours. LCMS revealed the product (RT = 0.358 min). The reaction mixture was cooled to room temperature and then diluted with water (60 mL) and ethyl acetate (40 mL). The organic phase was separated and discarded. The pH of the aqueous phase was adjusted to pH 5 with dilute hydrochloric acid and then extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ol (860 mg, 3.97 mmol, 54.9% yield, 98.7% purity). This product was used directly in the next step without purification. LCMS (ESI) m / z = 215.9 [M+1] +

[0887] Step 3: Synthesis of 2-bromo-7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine

[0888] 2-Bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ol (400 mg, 1.84 mmol, 1 eq) and cesium carbonate (721 mg, 2.21 mmol, 1.2 eq) were dissolved in N,N-dimethylformamide (10 ml) and stirred at 20°C for 1 hour. Sodium difluorochloroacetate (844 mg, 5.53 mmol, 3 eq) was then added to the reaction mixture, which was then stirred at 100°C for 3 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (100 ml), and extracted with ethyl acetate (20 ml x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product, which was then purified via reverse phase preparative chromatography (column: C18 150 × 30 mm; mobile phase: [water(FA)-ACN]; gradient: 30%-60% B over 7 min) to afford 2-bromo-7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine (230 mg, 871 μmol, 47.2% yield, 100% purity). LCMS (ESI) m / z = 263.9 [M+1] +

[0889] Step 4: Synthesis of 6'-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0890] 2-Bromo-7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine (100 mg, 379 μmol, 1 eq), 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one (123 mg, 455 μmol, 1.2 eq), Xantphos (17.5 mg, 30.3 μmol, 0.08 eq), sodium phenolate (66.0 mg, 568 μmol, 1.5 eq), and Pd2(dba)3 (13.9 mg, 15.2 μmol, 0.04 eq) were dissolved in dioxane (4 mL) and stirred at 135°C in a microwave for 40 minutes. The product was detected by LCMS (RT = 0.391 min). The reaction solution was filtered and the filtrate was concentrated to obtain a crude product, which was purified by reverse phase preparative chromatography (column: C18 150×30 mm; mobile phase: [water(FA)-ACN]; gradient: 12%-42% B over 7 min) to afford 6'-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (49.0 mg, 103 μmol, 27.1% yield, 95.1% purity).

[0891] LCMS (ESI) m / z = 454.2 [M+1] +

[0892] 1 H NMR: (400MHz, DMSO-d6): δ8.63(d,J=7.3Hz,1H),7.92(d,J=2.5Hz,1H),7.63-7.22( m,4H),7.14(d,J=2.6Hz,1H),6.91(d,J=6.9Hz,1H),6.78-6.70(m,2H),6.52(d,J=9 .0Hz,1H),6.44(d,J=8.9Hz,1H),6.26(dt,J=1.3,6.7Hz,1H),4.38-4.26(m,1H),4. 15(qd,J=6.8,13.4Hz,1H),2.22-2.09(m,2H),2.02-1.82(m,2H),1.64-1.43(m,2H).

[0893] Example C3

[0894] Synthesis of 6'-(((1S,3S)-3-((6-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0895] Step 1: Synthesis of 3-bromo-5-(difluoromethoxy)pyridine

[0896] At room temperature, 3-bromo-5-hydroxypyridine (40.0 g, 230 mmol, 1.00 eq) was dissolved in DMF (800 mL).

[0897] Cs2CO3 (89.9 g, 276 mmol, 1.20 eq) was added to the reaction mixture, and the mixture was stirred at 25°C for 1.5 hours under nitrogen protection. Then, sodium 2-chloro-2,2-difluoroacetate (105 g, 690 mmol, 3.00 eq) was added, and the mixture was heated to 100°C and stirred for 1.5 hours.

[0898] TLC (petroleum ether / ethyl acetate = 5 / 1) showed that the starting materials had reacted completely and the desired product had formed. 60 ml of water was added, and the mixture was extracted with ethyl acetate (50 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The sample was mixed with silica gel and purified by column chromatography (pure petroleum ether gave the product). 3-Bromo-5-(difluoromethoxy)pyridine (6.3 g, 28.1 mmol, 12.23% yield) was obtained as a yellow oil.

[0899] Step 2: Synthesis of 5-(difluoromethoxy)pyridin-3-amine

[0900] At room temperature, 3-bromo-5-(difluoromethoxy)pyridine (5.00 g, 22.3 mmol, 1.00 eq), aqueous ammonia (3.91 g, 33.5 mmol, 4.30 mL, 30% purity, 1.50 eq), CuI (850 mg, 4.46 mmol, 0.20 eq), K2CO3 (4.63 g, 33.48 mmol, 1.5 eq), and N,N'-bis(2-furylmethyl)oxamide (2.22 g, 8.93 mmol, 0.4 eq) were added to NMP (10 mL), the reaction was carried out in a sealed tank, the temperature was raised to 145 ° C, and the reaction was stirred for 36 hours.

[0901] TLC (petroleum ether / ethyl acetate = 1 / 1) showed complete reaction of the starting material, with the formation of a new major site. The reaction mixture was quenched with 100 mL of water and extracted with ethyl acetate (100 mL x 4). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1). The desired product, 5-(difluoromethoxy)pyridin-3-amine, was obtained (3 g, 18.7 mmol, 83.94% yield).

[0902] Step 3: Synthesis of 6-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine

[0903] Under ice bath at 0℃, 5-(difluoromethoxy)pyridin-3-amine (2.00 g, 12.5 mmol, 1.00 eq) and KSCN (9.71 g, 100 mmol, 9.68 mL, 8.00 eq) were dissolved in AcOH (6 mL). A solution of Br2 (5.99 g, 37.5 mmol, 1.93 mL, 3.00 eq) in AcOH (2 mL) was slowly added dropwise while keeping the reaction temperature below 0℃. After the addition was complete, the mixture was naturally warmed to 20℃ and stirred for 8 hrs.

[0904] TLC (petroleum ether / ethyl acetate = 2 / 1) showed incomplete reaction of the starting material, with new spots of the target product forming. Add 5 ml of water, heat to 85°C, and filter while hot. Add 1.5 ml of acetic acid to the filter cake, heat to 85°C, and filter while hot. Combine the two filtrates and adjust the pH to 8 with aqueous ammonia in an ice-water bath. A large amount of yellow solid precipitates. Filter under reduced pressure and dry the filter cake. Mix the sample with silica gel and separate and purify by column chromatography (petroleum ether / ethyl acetate = 2 / 1). The target product, 6-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine, is obtained as a yellow solid (460 mg, 2.12 mmol, 16.96% yield). LCMS (ESI) m / z = 218.0 [M+H] +

[0905] Step 4: Synthesis of 2-chloro-6-(difluoromethoxy)thiazolo[5,4-b]pyridine

[0906] At room temperature, 6-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine (450 mg, 2.07 mmol, 1.00 eq) was dissolved in acetonitrile (10 mL) under nitrogen protection. Isoamyl nitrite (364 mg, 3.11 mmol, 418 μL, 1.50 eq) and CuCl2 (334 mg, 2.49 mmol, 1.20 eq) were added. The mixture was stirred at 25°C for 12 hours.

[0907] LCMS showed the target product MS (RT = 0.524min, m / z = 236.9 [M + H] + 20 ml of saturated ammonium chloride solution was added and stirred for 10 minutes. 100 ml of water was added for dilution, and the mixture was extracted with 150 ml of ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification was performed by column chromatography (petroleum ether / ethyl acetate = 5 / 1). The target product, 2-chloro-6-(difluoromethoxy)thiazolo[5,4-b]pyridine, was obtained as a white solid (275 mg, 1.16 mmol, 56.09% yield). LCMS (ESI) m / z = 236.9 [M+H] +

[0908] Step 5: Synthesis of 6'-(((1S,3S)-3-((6-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0909] At room temperature, 2-chloro-6-(difluoromethoxy)thiazolo[5,4-b]pyridine (100 mg, 423 μmol, 1.00 eq), 1-[6-[[[(1S,3S)-3-aminocyclopentyl]amino]-3-pyridinyl]pyridin-2-one (114 mg, 423 μmol, 1 eq), and TEA (128 mg, 1.27 mmol, 176 μL, 3.00 eq) were added to DMSO (2.00 mL) and stirred at 70 °C for 6 h.

[0910] LCMS showed the target product MS (RT = 0.417min, m / z = 471.2 [M + H] + ). Cool to room temperature, add 10ml of water to dilute, extract with 60ml*4 of ethyl acetate, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography (petroleum ether / ethyl acetate = 0 / 1). The target product 6'-(((1S,3S)-3-((6-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one was obtained as a light yellow solid (198 mg, 421 μmol, 99.58% yield)

[0911] LCMS (ESI) m / z = 471.2 [M+H] +

[0912] 1 H NMR (400MHz, DMSO-d6): δ8.67(d,J=6.8Hz,1H), 8.01(d,J=2.4Hz,1H), 7.93(d,J=2. 6Hz,1H),7.60(dd,J=1.6,6.8Hz,1H),7.56(d,J=2.5Hz,1H),7.51-7.07(m,3H),6.97 (d,J=6.9Hz,1H),6.53(d,J=8.9Hz,1H),6.44(d,J=8.9Hz,1H),6.27(dt,J=1.2,6.7 Hz,1H),4.46-4.28(m,2H),2.28-2.11(m,2H),2.06-1.87(m,2H),1.69-1.45(m,2H).

[0913] Example C4

[0914] Synthesis of 1-[6-[[[(1S,3S)-3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridin-2-one

[0915] Step 1: 5,6,7,8-Tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

[0916] At 25 degrees, [1,2,4]triazolo[1,5-a]pyridin-2-amine (2.50 g, 18.6 mmol, 1.00 eq), wet palladium carbon (0.40 g, 10% purity) and HCl (3.65 mL, 36.5% purity, 2.00 eq) were dissolved in ethanol (30 mL), and then replaced with hydrogen three times, and then reacted under a hydrogen atmosphere (50 psi) for 72 hours.

[0917] LCMS showed that the MS value of the product was detected. After the reaction was completed, the mixture was filtered and concentrated to obtain 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (2.50 g, 97.1% yield). MS (ESI) m / z = 139.1 [M+1] +

[0918] Step 2: 2-iodo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

[0919] 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.20 g, 1.45 mmol, 1.00 eq), potassium iodide (601 mg, 3.62 mmol, 2.50 eq), p-toluenesulfonic acid (997 mg, 5.79 mmol, 4.00 eq) and sodium nitrite (200 mg, 2.89 mmol, 2.00 eq) were dissolved in acetonitrile (2 mL) and water (0.40 mL), then heated to 50 degrees and reacted for 2 hours.

[0920] TLC (dichloromethane:methanol=20:1) showed that the starting material (R f =0.24) is consumed.

[0921] The reaction mixture was concentrated, then diluted with ethyl acetate (50 mL) and water (70 mL), separated, and the aqueous phase extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 50:1 to 1:1) to afford 2-iodo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (250 mg, 69.4% yield).

[0922] Step 3: 1-[6-[[[(1S,3S)-3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridin-2-one

[0923] 2-iodo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (200 mg, 1.00 eq), 1-[6-[[[(1S,3S)-3-aminocyclopentyl]amino]-3-pyridinyl]pyridin-2-one (217 mg, 1.00 eq), sodium tert-butoxide (232 mg, 2.41 mmol, 3.00 eq) and t-BuXPhos Pd G3 (63.8 mg, 0.10 eq) were dissolved in dioxane (15 mL), replaced with nitrogen three times, and then heated to 90 degrees and reacted for 12 hours.

[0924] LCMS showed that the product was detected.

[0925] The reaction solution was concentrated to give a crude product, which was then purified by reverse phase chromatography (column: C18 150×30 mm; mobile phase: [water(FA)-ACN]; gradient: 2%-32% B over 7 min) to give the product 1-[6-[[[(1S,3S)-3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridin-2-one (45 mg, 13.80% yield, 96.4% purity).

[0926] LCMS (ESI) m / z = 392.2 [M+1] +

[0927] 1H NMR (400MHz, CD3OD): δ7.98-7.89(m,1H),7.66-7.54(m,2H),7.49-7.36(m ,1H),6.61(dd,J=5.2,8.8Hz,2H),6.47(dt,J=1.2,6.8Hz,1H),4.40-4.27( m,1H),4.06(quin,J=6.4Hz,1H),3.94(t,J=6.0Hz,2H),2.74(t,J=6.4Hz, 2H),2.66(s,1H),2.35-2.16(m,2H),2.09-1.87(m,5H),1.66-1.51(m,2H).

[0928] Example C5

[0929] Synthesis of 1-[6-[[[(1S,3S)-3-[(7-cyclopropyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)amino]cyclopentyl]amino]-3-pyridyl]pyridin-2-one

[0930] Step 1: 2-Bromo-[1,2,4]triazolo[1,5-a]pyrazine

[0931] [1,2,4]triazolo[1,5-a]pyrazin-2-amine (7.00 g, 51.8 mmol, 1.00 eq) and hydrobromic acid (29.3 mL, 48% purity, 5.00 eq) were dissolved in acetic acid (40 mL) at 0°C. A solution of sodium nitrite (7.15 g, 2.00 eq) dissolved in water (40 mL) was then added dropwise to the reaction solution. The mixture was heated for 2 hours.

[0932] LCMS showed that the product was detected.

[0933] The reaction mixture was concentrated, then diluted with water (100 mL) and ethyl acetate (60 mL), and the aqueous phase was extracted with ethyl acetate (20 mL * 3). The concentrated organic phase was washed with saturated brine (30 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20:1 to 1:1) to obtain the product 2-bromo-[1,2,4]triazolo[1,5-a]pyrazine (3.50 g, 33.9% yield). LCMS (ESI) m / z = 200.9 [M+1] +

[0934] Step 2: 2-Bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine

[0935] 2-Bromo-[1,2,4]triazolo[1,5-a]pyrazine (3.00 g, 1.00 eq) was dissolved in ethanol (20 mL) at 20°C. Lithium borohydride (2.00 M, 30.2 mL, 4.00 eq) was then added to the solution. After addition, the reaction mixture was heated to 50°C and reacted for 5 hours.

[0936] LCMS showed that the product was detected.

[0937] After the reaction, the reaction mixture was quenched with 1M hydrochloric acid (800 mL) and then washed with ethyl acetate (30 mL x 2). The organic phase was discarded. The aqueous phase was adjusted to pH 9 with saturated sodium carbonate solution and then extracted with dichloromethane (40 mL x 5). The organic phase from the second extraction was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reverse phase chromatography (column: Waters Xbridge 150 x 25 mm 5 μm; mobile phase: [water (NH₄HCO₃)-ACN]; gradient: 1%-30% Bover 9 min) to obtain the product, 2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (1.60 g, 52.3% yield). MS (ESI) m / z = 203.0 [M+1]. +

[0938] Step 3: 2-Bromo-7-cyclopropyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine

[0939] 2-Bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (0.70 g, 3.45 mmol, 1.00 eq), cyclopropylboronic acid (4441 mg, 5.17 mmol, 1.50 eq), copper acetate (1.25 g, 6.90 mmol, 2.00 eq) and N,N-diisopropylethylamine (891 mg, 1.20 mL, 2.00 eq) were dissolved in dichloromethane (2 mL) and then reacted at 20 degrees for 12 hours.

[0940] LCMS showed that the product was detected.

[0941] The reaction mixture was diluted with dichloromethane (50 mL) and water (30 mL), and the aqueous phase was subsequently extracted with dichloromethane (10 mL x 4). The pooled organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 1:1) to afford 2-bromo-7-cyclopropyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine (160 mg, 19.09% yield). MS (ESI) m / z = 243.0 [M+1] +

[0942] Step 4: 1-[6-[[[(1S,3S)-3-[(7-cyclopropyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]pyridin-2-one

[0943] 2-Bromo-7-cyclopropyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine (140 mg, 1.00 eq), 1-[6-[[[(1S,3S)-3-aminocyclopentyl]amino]-3-pyridinyl]pyridin-2-one (156 mg, 1.00 eq), sodium tert-butoxide (166 mg, 3.00 eq) and t-BuXPhos Pd G3 (45.7 mg, 0.10 eq) were dissolved in dioxane (12 mL), replaced with nitrogen three times, and then heated to 90 degrees and reacted for 12 hours.

[0944] LCMS showed that the product was detected.

[0945] The reaction solution was concentrated to give a crude product, which was then purified by reverse phase chromatography (column: C18 150×30 mm; mobile phase: [water(FA)-ACN]; gradient: 5%-35% B over 7 min and column: C18 150×30 mm; mobile phase: [water(FA)-ACN]; gradient: 5%-35% B over 7 min) to give the product 1-[6-[[[(1S,3S)-3-[(7-cyclopropyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)amino]cyclopentyl]amino]-3-pyridyl]pyridin-2-one (20 mg, 8.03% yield).

[0946] LCMS (ESI) m / z = 433.2 [M+1] +

[0947] 1H NMR (400MHz, CDCl3): δ8.03(d,J=2.4Hz,1H),7.52(dd,J=2.4,8.8Hz,1H),7.39(ddd,J=2.4,6.8,9.2Hz,1H),7 .30(dd,J=2.0,7.2Hz,1H),6.65(d,J=9.2Hz,1H),6.44(d,J=8.8Hz,1H),6.23(dt,J=1.2,6.8Hz,1H),4.77(br dd,J=1.2,5.6Hz,1H),4.28-4.12(m,2H),4.07-3.95(m,3H),3.79(s,2H),3.12(t,J=5.6Hz,2H) ,2.39-2.23(m,2H),2.11-1.97(m,2H),1.95-1.86(m,1H),0.62-0.55(m,2H),0.54-0.48(m,2H).

[0948] Example C6

[0949] Synthesis of 1-[5-[[[(1S,3S)-3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl]amino]pyrazin-2-yl]pyridin-2-one

[0950] Step 1: 1-[6-[[[(1S,3S)-3-[(7-cyclopropyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]pyridin-2-one

[0951] 2-iodo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (300 mg, 1.00 eq), 1-[5-[[[(1S,3S)-3-aminocyclopentyl]amino]pyrazin-2-yl]pyridin-2-one (327 mg, 1.00 eq), sodium tert-butoxide (347 mg, 3.61 mmol, 3.00 eq) and t-BuXPhos Pd G3 (95.7 mg, 0.10 eq) were dissolved in dioxane (10 mL), replaced with nitrogen three times, and then heated to 90 degrees and reacted for 12 hours.

[0952] LCMS showed that the product was detected.

[0953] The reaction solution was concentrated to give a crude product, which was purified by reverse phase chromatography (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 0%-25% B over 10 min) to give the product 1-[6-[[[(1S,3S)-3-[(7-cyclopropyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)amino]cyclopentyl]amino]-3-pyridyl]pyridin-2-one (30 mg, 6.35% yield).

[0954] LCMS (ESI) m / z = 391.1 [M-1] +

[0955] 1 H NMR: (400MHz, CDCl3): δ7.76 (d, J=1.2Hz, 1H), 7.63 (dd, J=2.0, 6.8Hz, 1H), 7.38 (ddd,J=2.0,6.8,9.2Hz,1H),6.64(d,J=9.2Hz,1H),6.32-6.22(m,1H),4.93(br d,J=6.8Hz,1H),4.41-4.29(m,1H),4.24-4.12(m,1H),4.04(br d,J=6.8Hz,1H),3.97(t,J=6.0Hz,2H),2.78(t,J=6.4Hz,2H),2.42-2.25(m,2H),2.12-1.99(m,4H),1.96-1.87(m,2H),1.60-1.51(m,2H).

[0956] Example C7

[0957] Synthesis of 6'-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0958] Step 1: Synthesis of 2-bromo-[1,2,4]triazolo[1,5-a]pyridine

[0959] [1,2,4]triazolo[1,5-a]pyridin-2-amine (1.90 g, 14.2 mmol, 1.0 eq), copper bromide (4.75 g, 21.3 mmol, 1.5 eq), and tert-butyl nitrite (2.19 g, 21.3 mmol, 1.50 eq) were dissolved in acetonitrile (30 mL) and stirred at 70°C for 4 hours. TLC (petroleum ether / ethyl acetate = 1 / 1) indicated the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 2-bromo-[1,2,4]triazolo[1,5-a]pyridine (2.17 g, 11.0 mmol, 77.4% yield). This product was used directly in the next step without purification. LCMS MS (ESI) m / z = 200.0 [M+1] + .

[0960] Step 2: Synthesis of 6'-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0961] 2-Bromo-[1,2,4]triazolo[1,5-a]pyridine (100 mg, 505 μmol, 1.0 eq), 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one (150 mg, 556 μmol, 1.1 eq), Xantphos (23.4 mg, 40.4 μmol, 0.08 eq), sodium phenolate (87.9 mg, 758 μmol, 1.5 eq), and Pd2(dba)3 (18.5 mg, 20.2 μmol, 0.04 eq) were dissolved in dioxane (4 ml) and stirred at 140°C under microwave conditions for 1 hour. The product was detected by LCMS (RT = 0.347 min). The reaction solution was filtered and the filtrate was concentrated to obtain a crude product, which was first purified by reverse phase preparation (column: Waters Xbridge 150*25mm*5um; mobile phase: [water(NH4HCO3)-ACN]; gradient: 12%-42% Bover 9min) to obtain 6'-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (microwave-assisted four batches, 83.1 mg, 211 μmol, 10.5% yield, 98.4% purity).

[0962] LCMS MS (ESI) m / z = 388.2 [M+1] + .

[0963] 1 H NMR, (400MHz, DMSO-d6): δ8.61-8.55(m,1H),7.92(d,J=2.8Hz,1H),7.60(dd,J=1.6,6.8Hz,1H),7. 47(ddd,J=2.1,6.7,9.1Hz,1H),7.44-7.34(m,2H),6.92(d,J=6.9Hz,1H),6.85(dt,J=1.6,6.8Hz,1H ),6.64(d,J=7.3Hz,1H),6.53(d,J=8.8Hz,1H),6.44(d,J=8.8Hz,1H),6.26(dt,J=1.3,6.7Hz,1H),4 .40-4.26(m,1H),4.18(sxt,J=6.7Hz,1H),2.21-2.09(m,2H),2.00-1.84(m,2H),1.63-1.43(m,2H).

[0964] Among them, the deuterated compound C7A of compound 7 was prepared by combining this preparation method with the deuterated preparation method, and the structure is as follows:

[0965] The identification data is as follows: 1 H NMR(400MHz, DMSO-d6)δ8.59(s,1H),7.92(d,J=2.7Hz,1H),7.61(dd,J=6.8,2.1Hz,1H),7.53–7.4 6(m,1H),7.46–7.33(m,3H),6.94(d,J=6.9Hz,1H),6.66(d,J=7.3Hz,1H),6.53(d,J=8.9Hz,1H),6 .49–6.40(m,1H),6.27(td,J=6.7,1.4Hz,1H),4.33(q,J=6.6Hz,1H),4.19(q,J=6.7Hz,1H),2.15( ddt,J=12.1,7.0,4.5Hz,2H),1.97(dt,J=13.4,6.8Hz,1H),1.93–1.83(m,1H),1.65–1.40(m,2H).

[0966] Example C8

[0967] Synthesis of 6'-(((1S,3S)-3-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0968] Step 1: Synthesis of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine

[0969] 7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (2.00 g, 9.39 mmol, 1.0 eq), copper bromide (3.15 g, 14.1 mmol, 1.5 eq), and tert-butyl nitrite (1.45 g, 14.1 mmol, 1.5 eq) were dissolved in acetonitrile (120 mL) and stirred at 80°C for 3 hours. LCMS (EW45820-76-P1A) detected the product (RT = 0.452 min). The reaction mixture was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (80 mL x 2). The combined organic phases were washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (2.00 g, 7.22 mmol, 76.9% yield). This product was used directly in the next step without purification. LCMS MS (ESI) m / z = 277.9 [M+1] + .

[0970] Step 2: Synthesis of 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ol

[0971] 2,7-Dibromo-[1,2,4]triazolo[1,5-a]pyridine (2.00 g, 7.22 mmol, 1.0 eq), potassium hydroxide (1.20 g, 21.7 mmol, 3.0 eq), t-Bu Xphos (675 mg, 1.59 mmol, 0.22 eq), and Pd2(dba)3 (728 mg, 794 μmol, 0.11 eq) were dissolved in 1-4, dioxane (20 ml) and water (5 ml) and stirred at 100°C for 4 hours. LCMS monitoring revealed the product (RT = 0.358 min). The reaction mixture was cooled to room temperature and then diluted with water (60 ml) and ethyl acetate (40 ml). The organic phase was separated and discarded. The pH of the aqueous phase was adjusted to pH 5 with dilute hydrochloric acid and then extracted with ethyl acetate (60 ml x 2). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ol (860 mg, 3.97 mmol, 54.9% yield, 98.7% purity). This product was used directly in the next step without purification. LCMS MS (ESI) m / z = 215.9 [M+1] + .

[0972] Step 3: Synthesis of 2-bromo-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine

[0973] 2-Bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ol (1.30 g, 6.07 mmol, 1.0 eq) and cesium carbonate (4.95 g, 15.2 mmol, 2.5 eq) were dissolved in N,N-dimethylformamide (20 ml). Methyl iodide (1.72 g, 12.2 mmol, 2.0 eq) was then added to the reaction mixture. After complete addition, the mixture was stirred at 40°C for 2 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (100 ml), and extracted with ethyl acetate (30 ml x 2). The combined organic phases were washed with saturated brine (50 ml * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography to give 2-bromo-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine (1.00 g, 4.39 mmol, 72.2% yield).

[0974] Step 4: Synthesis of 6'-(((1S,3S)-3-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0975] 2-Bromo-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine (100 mg, 439 μmol, 1 eq), 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one (130 mg, 482 μmol, 1.1 eq), Xantphos (20.3 mg, 35.1 μmol, 0.08 eq), sodium phenolate (76.4 mg, 658 μmol, 1.5 eq), and Pd2(dba)3 (16.1 mg, 17.5 μmol, 0.04 eq) were dissolved in dioxane (5 ml) and stirred at 140°C under microwave conditions for 1 hour. The product was detected by LCMS (RT = 0.366 min). The reaction solution was filtered and the filtrate was concentrated to obtain a crude product, which was first purified by reverse phase preparative purification (acidic conditions) (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water(FA)-ACN]; gradient: 20%-50% B over 15min), and then by reverse phase preparative purification (alkaline conditions) (column: Waters Xbridge 150*25mm*5um; mobile phase: [water(ammonia hydroxide v / v)-ACN]; gradient: 0%-30% B over 10 min) to give 6'-(((1S,3S)-3-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one (8 batches were microwaved in parallel, 69.9 mg, 166 μmol, 4.72% yield, 98.9% purity).

[0976] LCMS MS (ESI) m / z = 418.2 [M+1] + . 1H NMR, (400MHz, DMSO-d6): δ8.39(d,J=7.4Hz,1H),7.91(d,J=2.6Hz,1H),7.59(dd,J=1.7,6.8Hz ,1H),7.47(ddd,J=2.0,6.7,9.1Hz,1H),7.39(dd,J=2.6,8.9Hz,1H),6.89(d,J=6.9Hz,1H),6. 81(d,J=2.6Hz,1H),6.58-6.38(m,4H),6.26(dt,J=1.3,6.7Hz,1H),4.31(sxt,J=6.4Hz,1H),4 .13(sxt,J=6.7Hz,1H),3.82(s,3H),2.19-2.08(m,2H),1.99-1.82(m,2H),1.62-1.44(m,2H).

[0977] Example C9

[0978] Synthesis of 1-(5-((((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)pyrazin-2-yl)pyridin-2(1H)-one

[0979] Step 1: Synthesis of 2-bromo-[1,2,4]triazolo[1,5-a]pyridine

[0980] [1,2,4]triazolo[1,5-a]pyridin-2-amine (1.90 g, 14.2 mmol, 1.0 eq), copper bromide (4.75 g, 21.3 mmol, 1.5 eq), and tert-butyl nitrite (2.19 g, 21.3 mmol, 1.50 eq) were dissolved in acetonitrile (30 mL) and stirred at 70°C for 4 hours. TLC (petroleum ether / ethyl acetate = 1 / 1) indicated the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 2-bromo-[1,2,4]triazolo[1,5-a]pyridine (2.17 g, 11.0 mmol, 77.4% yield). This product was used directly in the next step without purification. LCMS MS (ESI) m / z = 200.0 [M+1] + .

[0981] Step 2: Synthesis of 1-(5-((((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)pyrazin-2-yl)pyridin-2(1H)-one

[0982] 2-Bromo-[1,2,4]triazolo[1,5-a]pyridine (300 mg, 1.51 mmol, 1.0 eq), 1-(5-((((1S,3S)-3-aminocyclopentyl)amino)pyrazin-2-yl)pyridin-2(1H)-one (411 mg, 1.51 mmol, 1.0 eq), sodium tert-butoxide (437 mg, 4.54 mmol, 3.0 eq), and tBuXPhos Pd G3 (120 mg, 152 μmol, 0.10 eq) were dissolved in dioxane (10 ml) and stirred at 100° C. for 12 hours. LCMS detected the product (RT=0.394 min). The reaction mixture was filtered, and the filtrate was concentrated to obtain a crude product, which was then purified by reverse phase preparative chromatography (column: Phenomenex luna C18). The HPLC-MS / MS was 400 x 100 nm, 150*40mm*15um; mobile phase: [water(FA)-ACN]; gradient: 10%-40% B over 15min) to afford 1-(5-((((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)pyrazin-2-yl)pyridin-2(1H)-one (79.6 mg, 201 μmol, 13.2% yield, 97.9% purity).

[0983] LCMS MS (ESI) m / z = 389.2 [M+1] + . 1 H NMR, (400MHz, DMSO-d6): δ8.62-8.54(m,1H),8.25(d,J=1.4Hz,1H),7.87(d,J= 1.3Hz,1H),7.72(dd,J=1.5,6.9Hz,1H),7.56-7.32(m,4H),6.87(dt,J=1.5,6.8 Hz,1H),6.66(d,J=7.3Hz,1H),6.47(d,J=9.0Hz,1H),6.32(dt,J=1.3,6.7Hz,1 H),4.41-4.15(m,2H),2.25-2.11(m,2H),2.06-1.86(m,2H),1.67-1.47(m,2H).

[0984] Example C10

[0985] Synthesis of 1-[5-[[[(1S,3S)-3-[(4-oxo-6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]thiazin-2-yl)amino]cyclopentyl]amino]pyrazin-2-yl]pyridin-2-one

[0986] Step 1: 2-Bromo-6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine

[0987] Compound 10-1 (3.00 g, 13.2 mmol, 1.00 eq), 3-chloropropane-1-thiol (1.76 g, 15.8 mmol, 1.55 mL, 1.20 eq), and K2CO3 (3.60 g, 26.5 mmol, 2.00 eq) were dissolved in DMF (20 mL), and the reaction liquid was stirred at 50°C for 5 hours.

[0988] LCMS detected the formation of the desired product. The reaction mixture was quenched with 200 ml of water, then extracted with ethyl acetate (100 x 3 mL). The organic phases were combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The solid organic phase reaction solution was purified using a normal silica gel column (petroleum ether:ethyl acetate = 1:1) to obtain compound 10-2 (800 mg, 3.63 mmol, yield: 27.5%) as a white solid.

[0989] Step 2: Synthesis of 1-[5-[[[(1S,3S)-3-(6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]thiazin-2-ylamino)cyclopentyl]amino]pyrazin-2-yl]pyridin-2-one

[0990] Under nitrogen protection, compound 10-3 (300 mg, 1.11 mmol, 1.00 eq), compound 10-2 (4988 mg, 2.27 mmol, 2.05 eq), t-BuONa (318 mg, 3.32 mmol, 3.00 eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (175 mg, 221 μmol, 0.20 eq) were dissolved in 1,4-dioxane (20 mL), and the reaction liquid was stirred at 90 ° C for 16 hours.

[0991] LCMS and HPLC detected the formation of the target product. The reaction mixture was quenched with 200 ml of water, then extracted with ethyl acetate (100*3 mL). The organic phases were combined, washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated. The organic phase was purified using reverse preparative chromatography (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 12%-42% B over 11 min) to obtain the target compound (60.0 mg, 146 μmol, yield: 13.2%) as a light yellow gel. LC-MS: [M+H]+ = 411.

[0992] 1H NMR(400MHz,Chloroform-d)δ8.52(s,1H),7.73(d,J=1.6Hz,1H),7.62(dd,J=7.2,2.1Hz,1H),7.41–7.33(m,1H),6.62(d,J=9.3Hz,1H),6.33–6.21( m,1H),5.01(d,J=6.8Hz,1H),4.31(q,J=6.6Hz,1H),4.22–4.04(m,4H),3. 23–3.06(m,2H),2.43–2.22(m,4H),2.07–1.99(m,2H),1.63–1.49(m,3H).

[0993] Example C11

[0994] Synthesis of 1-[5-[[[(1S,3S)-3-[(4-oxo-6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]thiazin-2-yl)amino]cyclopentyl]amino]pyrazin-2-yl]pyridin-2-one

[0995] Compound 10 (20.0 mg, 48.7 μmol, 1.00 eq) was dissolved in THF (8.00 mL), and NaIO4 (10.4 mg, 48.7 μmol, 2.70 μL, 1.00 eq) dissolved in H2O (3 mL) was added. The reaction mixture was stirred at 70°C for 12 hours.

[0996] LCMS and HPLC confirmed the formation of the target product. The reaction mixture was concentrated under reduced pressure. The compound was purified by reverse preparative chromatography (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 10%-40% B over 11 minutes) to yield the target compound (18.0 mg, 42.2 μmol, yield: 86.6%) as a white solid. LC-MS: [MH] - =427.1.

[0997] 1 H NMR, (CHLOROFORM-d, 400MHz): 8.54 (dd, 1H, J = 1.0, 4.3Hz), 8.04 (d, 1H, J = 5.6H z),7.7-7.8(m,1H),7.52(ddd,1H,J=1.9,6.9,9.0Hz),6.81(d,1H,J=9.1Hz),6 .46(dt,1H,J=0.9,6.8Hz),4.3-4.4(m,2H),4.1-4.2(m,2H),3.42(dd,1H,J=5. 9,12.6Hz),2.9-3.2(m,2H),2.3-2.5(m,3H),2.0-2.2(m,2H),1.6-1.8(m,2H).

[0998] Example C12

[0999] Referring to the preparation methods of Examples C1 and C3 above, compounds C12, C12A and C12B were prepared. The synthetic routes are as follows:

[1000] Compound 12 was subjected to chiral separation (chromatographic column model: CHIRALCEL OD-H 5um 10mm*250mm; mobile phase: n-hexane / ethanol = 70:30; flow rate: 5ml / min; column temperature: 30°C) to obtain white solids C12A and C12B:

[1001] Compound C12A, 1H NMR: (400MHz, DMSO-d6): δ8.59-8.33(m,1H),8.08(dd,J=1.6,4.8Hz,1H),7.92(d,J=2.4Hz,1H),7.66(dd,J=1.4,8.0Hz,1H),7.55-7.48(m ,2H),7.40(dd,J=2.8,8.9Hz,1H),7.24(dd,J=4.8,8.0Hz,1H),6.96(d,J=6.9Hz,1H),6.53(d,J=8.9Hz,1H),6.31(t,J=6.8Hz,1H),5.06(br s,1H),4.79-4.62(m,1H),4.37(dt,J=6.4,13.8Hz,2H),2.27-2.12(m,2H),2.04-1.90(m,2H),1.65-1.48(m,2H),1.26(d,J=6.4Hz,3H);

[1002] Compound C12B, 1 H NMR: (400MHz, DMSO-d6): δ8.54-8.37(m,1H),8.08(dd,J=1.4,4.8Hz,1H),7.92(d,J=2.6Hz,1H),7.66( dd,J=1.4,8.1Hz,1H),7.55-7.48(m,2H),7.40(dd,J=2.6,8.9Hz,1H),7.24(dd,J=4.8,8.0Hz,1H),6.9 6(d,J=6.9Hz,1H),6.53(d,J=8.9Hz,1H),6.31(t,J=6.8Hz,1H),5.06(d,J=4.6Hz,1H),4.75-4.67(m,1 H),4.44-4.29(m,2H),2.27-2.13(m,2H),2.03-1.91(m,2H),1.66-1.49(m,2H),1.25(d,J=6.4Hz,3H).

[1003] Example C45

[1004] Synthesis of 6'-(((1S,3S)-3-((7,8-dihydro-[1,4]dioxo[2,3-d][1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[1005] Step 1: Synthesis of 2-((6-bromo-4-iodopyridin-3-yl)oxy)ethan-1-ol

[1006] To a solution of C45-1 (8.00 g, 26.5 mmol, 1.00 eq) and ethylene glycol (55.6 g, 896 mmol, 50 mL, 33.8 eq) in NMP (50 mL) was added t-BuOK (5.95 g, 53.0 mmol, 2.00 eq) and the mixture was stirred at 60° C. for 3 hours.

[1007] LCMS detected the formation of the desired product. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and spun down to dryness. The crude product was purified by reverse-phase HPLC (0.1% FA condition) to obtain compound C45-2 (3.50 g, 10.1 mmol, 38.4% yield) as a white solid.

[1008] Step 2: Synthesis of 7-bromo-2,3-dihydro-[1,4]dioxo[2,3-c]pyridine

[1009] To a solution of C45-2 (3.50 g, 10.1 mmol, 1.00 eq) in isopropanol (35 mL) were added CuI (116 mg, 610 μmol, 0.06 eq), t-BuOK (1.60 g, 14.2 mmol, 1.40 eq), and 3,4,7,8-tetramethyl-1,10-phenanthroline (192 mg, 814 μmol, 0.08 eq). The mixture was stirred at 80° C. for 1 hour under nitrogen protection.

[1010] The target product was detected by LCMS. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to obtain compound C45-3 (2.20 g, 9.12 mmol, 89.6% yield) as a brown solid.

[1011] Step 3: Synthesis of 2,3-dihydro-[1,4]dioxo[2,3-c]pyridin-7-amine

[1012] To a solution of C45-3 (2.20 g, 10.1 mmol, 1.00 eq) in ethylene glycol (20 mL) were added CuO (14.5 mg, 101 μmol, 10.4 μL, 0.01 eq), NHHO (50.9 g, 407 mmol, 56.0 mL, 40.0 eq), KCO (281 mg, 2.04 mmol, 0.200 eq), and N',N'-dimethylethane-1,2-diamine (89.7 mg, 1.02 mmol, 111 μL, 0.100 eq). The mixture was stirred at 80° C. for 4 h.

[1013] The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to obtain compound C45-4 (1.50 g, crude) as a yellow oil.

[1014] Step 4: Synthesis of ethyl N-(2,3-dihydro-[1,4]dioxo[2,3-c]pyridin-7-ylaminothio)carbamate

[1015] To a solution of C45-4 (1.50 g, 9.86 mmol, 1.00 eq) in dichloromethane (15 mL) was added ethyl N-(thiomethylene)carbamate (1.29 g, 9.86 mmol, 1.00 eq) and the mixture was stirred at 25° C. for 1 hour.

[1016] The target product was detected by LCMS. The reaction solution was poured into water and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to obtain compound C45-5 (2.20 g, 7.77 mmol, 78.7% yield) as a yellow solid.

[1017] Step 5: Synthesis of 7,8-dihydro-[1,4]dioxo[2,3-d][1,2,4]triazolo[1,5-a]pyridin-2-amine

[1018] To a solution of C45-5 (2.20 g, 7.77 mmol, 1.00 eq) in methanol (15 mL) were added NH2OH.HCl (2.43 g, 34.9 mmol, 4.50 eq) and DIEA (3.01 g, 23.30 mmol, 4.06 mL, 3 eq) and the mixture was stirred at 70°C for 2 hours.

[1019] The target product was detected by LCMS. The reaction mixture was cooled to 25°C and filtered, and the filter residue was compound C45-6 (1.30 g, 6.76 mmol, 87.1% yield) as a white solid.

[1020] Step 6: Synthesis of 2-bromo-7,8-dihydro-[1,4]dioxo[2,3-d][1,2,4]triazolo[1,5-a]pyridine

[1021] To a solution of C45-6 (500 mg, 2.60 mmol, 1.00 eq) in acetonitrile (5 mL) were added NaNO2 (359 mg, 5.20 mmol, 2.00 eq) and HBr (1.21 g, 5.98 mmol, 812 μL, 2.30 eq) at 0° C. The mixture was stirred at 25° C. for 2 hours.

[1022] The target product was detected by LCMS. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to obtain compound C45-7 (300 mg, 1.17 mmol, 45.0% yield) as a yellow solid.

[1023] Step 7: Synthesis of 6'-(((1S,3S)-3-((7,8-dihydro-[1,4]dioxo[2,3-d][1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[1024] To a solution of C45-7 (300 mg, 1.17 mmol, 1.00 eq) and C45-8 (316 mg, 1.17 mmol, 1.00 eq) in dioxane (5 mL) were added t-BuONa (225 mg, 2.34 mmol, 2.00 eq), Pd2(dba)3 (107 mg, 117 μmol, 0.100 eq) and Xantphos (135 mg, 234 μmol, 0.200 eq), and the mixture was stirred at 100°C under nitrogen protection for 12 hours.

[1025] LCMS detected the formation of the target product. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and spun down to dryness. The crude product was purified by reverse preparative chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(NH4HCO3)-ACN]; gradient: 10%-40% B over 52 min) and (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN]; gradient: 1%-25% B over 10 min) to obtain the target compound (36.6 mg).

[1026] LC-MS: [M+H] - =446.1. 1H NMR: (DMSO-d6, 400MHz): δ (ppm) = 8.38 (s, 1H), 7.91 (d, J = 2.4Hz, 1H), 7.60 (dd, J = 2.0, 6.8Hz, 1H),7.49-7.45(m,1H),7.39(dd,J=2.8,8.8Hz,1H),6.90(d,J=6.8Hz,1H),6.78(s,1H),6.52 (d,J=9.2Hz,1H),6.44(d,J=9.2Hz,1H),6.36(d,J=7.2Hz,1H),6.26(dt,J=1.2,6.8Hz,1H),4 .37-4.24(m,5H),4.18-4.05(m,1H),2.20-2.06(m,2H),1.99-1.78(m,2H),1.64-1.41(m,2H).

[1027] Example C46

[1028] Synthesis of 6'-((((1S,3S)-3-((7,8-dihydro-[1,4]dioxo[2,3-d][1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridyl]-2-one

[1029] Step 1: Synthesis of 2-iodo-7,8-dihydro-[1,4]dioxo[2,3-d][1,2,4]triazolo[1,5-a]pyridine

[1030] To a solution of C46-1 (300 mg, 1.56 mmol, 1.00 eq) in acetonitrile (5 mL) were added NaNO2 (215 mg, 3.12 mmol, 2.00 eq) and HI (1.02 g, 3.59 mmol, 600 μL, 2.30 eq) at 0° C. The mixture was stirred at 25° C. for 2 hours.

[1031] The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, concentrated, and spin-dried to give compound C46-2 (480 mg, 1.11 mmol, 71.0% yield) as a brown solid.

[1032] Step 2: Synthesis of 6'-((((1S,3S)-3-((7,8-dihydro-[1,4]dioxo[2,3-d][1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridyl]-2-one

[1033] To a solution of C46-2 (300 mg, 989 μmol, 1.00 eq) and C46-3 (285 mg, 989 μmol, 1.00 eq) in dioxane (5 mL) were added t-BuONa (190.26 mg, 1.98 mmol, 2 eq) and tBuBrettphos Pd G3 (84.5 mg, 98.9 μmol, 0.100 eq). The mixture was stirred at 100° C. for 4 hours under nitrogen protection.

[1034] LCMS detected the formation of the desired product. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The crude product was purified by reverse preparative chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(NH4HCO3)-ACN]; gradient: 16%-46% B over 15 min) to afford the desired compound (20.0 mg).

[1035] LC-MS: [M+H] - =464.1. 1 H NMR: (DMSO-d6, 400MHz): δ (ppm) = 8.38 (s, 1H), 7.84 (d, J = 2.0Hz, 1H), 7.64 (dd, J = 1.6, 6.8Hz, 1H), 7.57-7.45 (m, 2H), 6.90 (br d,J=7.2Hz,1H),6.78(s,1H),6.46(d,J=8.8Hz,1H),6.35(d,J=7.2Hz,1H),6.28(t,J=6.4Hz,1H),4.57-4.47(m,1H),4.35(br dd,J=2.0,5.2Hz,2H),4.31-4.24(m,2H),4.17-4.07(m,1H),2.18-2.06(m,2H),1.99-1.90(m,2H),1.63-1.50(m,2H).

[1036] Example C47

[1037] Synthesis of 2-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)-5-fluoropyridin-3-yl)pyridazin-3(2H)-one

[1038] Step A: tert-Butyl ((1S,3S)-3-((5-bromo-3-fluoropyridin-2-yl)amino)cyclopentyl)carbamate

[1039] At room temperature, 5-bromo-2,3-difluoropyridine (100.0 g, 0.52 mol) and tert-butyl ((1S, 3S)-3-aminocyclopentyl) carbamate (114.58 g, 0.57 mol) were added to DMF (800 ml), and then triethylamine (156.99 g, 1.55 mol) was added to the system, and then the temperature was raised to 100 degrees Celsius for 8 hours.

[1040] After the reaction was completed, the mixture was cooled to room temperature, water (500 ml) was added to the system, and the mixture was extracted with ethyl acetate (400 ml x 3). The organic phases were combined, washed twice with saturated brine (300 ml), dried, filtered, and concentrated under reduced pressure. The resulting residue was slurried with isopropyl ether (300 mL) to give 130 g of a white solid product, tert-butyl ((1S, 3S)-3-((5-bromo-3-fluoropyridin-2-yl)amino)cyclopentyl)carbamate (yield 67%). LC-MS: [M+H] + =374.

[1041] Step B: tert-Butyl ((1S,3S)-3-((3-fluoro-5-(6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)amino)carbamate

[1042] At room temperature, tert-butyl ((1S,3S)-3-((5-bromo-3-fluoropyridin-2-yl)amino)cyclopentyl)carbamate (120 g, 0.32 mol), pyridazine-3(2H)-one (40 g, 0.41 mol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (9.1 g, 0.064 mol), potassium carbonate (133.19 g, 0.96 mol) were added to NMP (960 ml), followed by cuprous iodide (12.3 g, 0.064 mol). After the addition was complete, the system was replaced with nitrogen and the temperature was raised to 120°C for 12 hours.

[1043] After the reaction was complete, the mixture was cooled to room temperature, and water (1000 mL) was added to the system. The mixture was extracted with ethyl acetate (400 mL x 3). The organic phases were combined, washed three times with saturated brine (400 mL), dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by normal phase column chromatography (dichloromethane / methanol = 50:1) to obtain 70 g of black oily product, tert-butyl ((1S,3S)-3-((3-fluoro-5-(6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)amino)carbamate (yield 56%). LC-MS: [M+H] + =390.

[1044] Step C: 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)-5-fluoropyridin-3-yl)pyrazin-3(2H)-one

[1045] At room temperature, tert-butyl ((1S,3S)-3-((3-fluoro-5-(6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)amino)carbamate (70 g, 0.17 mol) was dissolved in hydrochloric acid / 1,4-dioxane (2 M, 300 ml) and reacted at room temperature for 4 hours.

[1046] After the reaction was completed, the product was concentrated to dryness to obtain 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)-5-fluoropyridin-3-yl)pyrazin-3(2H)-one hydrochloride, which was then dissolved in methanol (200 mL). The pH of the system was then adjusted to approximately 9 using a basic ion resin and filtered. The filter cake was rinsed three times with methanol (100 mL). The filtrate was collected and then dried in a rotary evaporation chamber to obtain 55 g of a brown solid product, 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)-5-fluoropyridin-3-yl)pyrazin-3(2H)-one. The product was used directly in the next reaction without further treatment. LC-MS: [M+H] + =290.

[1047] Step D: 2-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)-5-fluoropyridin-3-yl)pyridazin-3(2H)-one

[1048] At room temperature, 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)-5-fluoropyridin-3-yl)pyrazin-3(2H)-one (55 g, 0.19 mol) and 2-bromo-[1,2,4]triazolo[1,5-a]pyridine (37.4 g, 0.19 mol) were dissolved in 1,4-dioxane (550 ml). Sodium tert-butoxide (36.5 g, 0.38 mol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (30 g, 0.037 mol) were then added. After the addition, the atmosphere was replaced with nitrogen, and the system was slowly heated to 100°C for 1 hour.

[1049] After the reaction was complete, the mixture was cooled to room temperature, and water (400 mL) was added to the system. The mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified by normal phase column chromatography (dichloromethane / methanol = 10:1) to obtain 20.5 g of 2-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)-5-fluoropyridin-3-yl)pyridazin-3(2H)-one. LC-MS: [M+H]+ =407.

[1050] 1 H NMR(400MHz, DMSO-d6)δ8.61–8.58(dd,J=6.7,1.1Hz,1H),8.06–8.04(q,J=1.7Hz,2H),7.67–7.61(dd,J=12.1 ,2.2Hz,1H),7.52–7.47(dd,J=9.5,3.9Hz,1H),7.46–7.41(m,1H),7.40–7.37(dt,J=8.8,1.3Hz,1H),7.09–7.0 5(dd,J=9.5,1.6Hz,1H),6.99–6.94(m,1H),6.90–6.84(td,J=6.7,1.6Hz,1H),6.68–6.63(d,J=7.2Hz,1H),4.6 1–4.51(p,J=7.0Hz,1H),4.26–4.17(p,J=6.6Hz,1H),2.22–2.12(m,2H),2.02–1.97(m,2H),1.67–1.54(m,2H).

[1051] Example C54

[1052] Synthesis of 2-(6-((((1S,3S)-3-((7,8-dihydro-[1,4]dioxo[2,3-d][1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one

[1053] Step 1: Synthesis of 2-(6-((((1S,3S)-3-((7,8-dihydro-[1,4]dioxo[2,3-d][1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one

[1054] To a dioxane solution (4 mL) of C54-1 (120 mg, 395 μmol, 1.00 eq) and C54-2 (107 mg, 395 μmol, 1.00 eq) were added t-BuONa (190 mg, 1.98 mmol, 5.00 eq) and tBuBrettphos PD G3 (33.8 mg, 39.60 μmol, 0.100 eq). The mixture was stirred at 100° C. for 12 hours under nitrogen protection.

[1055] LCMS detected the formation of the desired product. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The crude product was purified by reverse phase preparative chromatography (Phenomenex luna C18 column, 150 x 25 mm x 10 μm; mobile phase, [water (FA)-ACN]; gradient, 1% to 30% B over 10 min) to yield the desired compound (18.6 mg).

[1056] LC-MS: [M+H] - =447.1. 1 H NMR: (DMSO-d6, 400MHz): δ (ppm) = 8.37 (s, 1H), 8.09 (d, J = 2.4Hz, 1H), 8.01 (dd, J = 1.6, 4.0 Hz,1H),7.51(dd,J=2.4,8.8Hz,1H),7.46(dd,J=4.0,9.6Hz,1H),7.02(dd,J=1.6,9.6Hz,1 H),6.91(d,J=7.2Hz,1H),6.77(s,1H),6.52(d,J=8.8Hz,1H),6.35(d,J=7.6Hz,1H),4.37 -4.25(m,5H),4.16-4.07(m,1H),2.18-2.08(m,2H),1.99-1.83(m,2H),1.56-1.44(m,2H).

[1057] Example C13

[1058] Referring to the preparation methods of Examples C1, C3 and C12 above, compounds C13, C13A and C13B were prepared:

[1059] Compound 13A, 1H NMR: (400MHz, DMSO-d6): δ8.49(br d,J=6.4Hz,1H),8.16-8.08(m,1H),7.89(d,J=2.0Hz,1H),7.70(dd,J=1.2,8.0Hz,1H),7.62-7.55(m,3H),7.28(dd,J=4.8,8.0Hz,1H),7.03(br d,J=7.2Hz,1H),6.37(t,J=6.8Hz,1H),5.12(d,J=4.4Hz,1H),4.76(quin,J=5.6Hz,1H),4.66-4.53(m, 1H),4.51-4.39(m,1H),2.31-2.16(m,2H),2.11-2.02(m,2H),1.74-1.60(m,2H),1.30(d,J=6.4Hz,3H);

[1060] Compound 13B, 1 H NMR: (400MHz, DMSO-d6): δ8.45(br d,J=4.4Hz,1H),8.08(dd,J=1.2,4.8Hz,1H),7.84(d,J=2.0Hz,1H),7.66(dd ,J=1.2,8.0Hz,1H),7.60-7.51(m,3H),7.24(dd,J=4.8,8.0Hz,1H),6.98(br d,J=6.8Hz,1H),6.33(t,J=6.8Hz,1H),5.08(d,J=4.4Hz,1H),4.80-4.65(m,1H),4.55(sxt,J=7.2Hz,1H ),4.46-4.35(m,1H),2.27-2.15(m,2H),2.02(t,J=7.2Hz,2H),1.69-1.56(m,2H),1.26(d,J=6.4Hz,3H).

[1061] Example C14

[1062] Referring to the preparation method of Example 2 above, compound C14 was prepared:

[1063] Example C17

[1064] Synthesis of 6'-((((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridyl]-2-one

[1065] Step 1: Synthesis of tert-butyl N-[(1S,3S)-3-[(5-bromo-3-fluoro-2-pyridyl)amino]cyclopentyl]carbamate

[1066] Tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (3.00 g, 15.0 mmol, 1 eq), 5-bromo-2,3-difluoropyridine (2.91 g, 15.0 mmol, 1.0 eq), and N,N-diisopropylethylamine (4.84 g, 37.5 mmol, 2.5 eq) were dissolved in dimethyl sulfoxide (40 ml) and stirred at 100°C for 12 hours. LCMS (EW45820-218-P1A1) detected the product (RT = 0.568 min). The reaction mixture was cooled to room temperature, diluted with water (200 ml), and extracted with ethyl acetate (100 ml x 2). The combined organic phases were washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a crude product, which was then purified on a silica gel column to yield tert-butyl N-[(1S,3S)-3-[(5-bromo-3-fluoro-2-pyridyl)amino]cyclopentyl]carbamate (4.00 g). LCMS: RT = 0.568 min, MS (ESI) m / z = 374.0 [M+1]. +

[1067] Step 2: Synthesis of tert-butyl N-[(1S,3S)-3-[[3-fluoro-5-(2-oxo-1-pyridinyl)-2-pyridinyl]amino]cyclopentyl]carbamate

[1068] Tert-butyl N-[(1S,3S)-3-[(5-bromo-3-fluoro-2-pyridinyl)amino]cyclopentyl]carbamate (1.5 g, 4.01 mmol, 1.0 eq), 1H-pyridin-2-one (457 mg, 4.81 mmol, 1.2 eq), potassium phosphate (2.55 g, 12.0 mmol, 3.0 eq), cuprous iodide (153 mg, 802 μmol, 0.20 eq), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (114 mg, 802 μmol, 0.2 eq) were dissolved in dioxane (20 mL) and stirred at 100°C for 12 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (100 ml * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography to give tert-butyl N-[(1S,3S)-3-[[3-fluoro-5-(2-oxo-1-pyridinyl)-2-pyridinyl]amino]cyclopentyl]carbamate (1.00 g).

[1069] Step 3: Synthesis of 6'-((((1S,3S)-3-aminocyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridyl]-2-one

[1070] Tert-butyl N-[(1S,3S)-3-[[3-fluoro-5-(2-oxo-1-pyridinyl)-2-pyridinyl]amino]cyclopentyl]carbamate (1.00 g, 2.57 mmol, 1.0 eq) was dissolved in dichloromethane (10 ml), and then ethyl acetate HCl / EtOAc (2 M, 20 mL, 15.5 eq) was added thereto, and the mixture was stirred at 20°C for 2 hours. LCMS (EW45820-225-P1A) detected the product (RT = 0.320 min). The reaction solution was concentrated to dryness to give 6'-((((1S,3S)-3-aminocyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridyl]-2-one (600 mg, 2.08 mmol, 80.8% yield). The product was used directly in the next step without purification. LCMS: RT = 0.320 min, MS (ESI) m / z = 577.3 [2M+1]. +

[1071] Step 4: Synthesis of 6'-((((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridy...

Claims

1. A compound represented by general formula (A), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, characterized in that: X=C or N. When X=N, R4 does not exist; R1, R4, R6, R7 are selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted alkyl, cyano, -C(O)-O-alkyl, phenyloxy, carboxyl, hydroxymethyl or cycloalkyl, the substituent is selected from hydroxyl, amide, alkyl substituted amide, ZC(O)-, Z is selected from alkyl or heterocycle, heteroaryl; R2, R 3、 R5 is independently selected from hydrogen, alkyl, alkoxy, cyano, halogen, haloalkyl, amide, hydroxy, hydroxy-substituted alkyl, carboxyl, amino, amino-substituted alkyl, alkylcarbonyl or -(CH2)nO-(CH2)n-benzene, n = 1, 2 or 3; R8 and R9 are independently selected from hydrogen, alkyl, halogen, cycloalkyl, alkylthio, alkoxy, aryl, and heteroaryl; And R1, R2, R3, R4, R5, R6, and R7 are not hydrogen at the same time; or when R1, R2, R3, R4, R5, R6, and R7 are hydrogen at the same time, R8 and R9 are not hydrogen at the same time.

2. The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: A compound selected from the group consisting of the compounds represented by the general formula (A1), or isomers, racemates, or pharmaceutically acceptable salts thereof: R1, R4, R6, R7 are selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted alkyl, cyano, -C(O)-O-alkyl, phenyloxy, carboxyl, hydroxymethyl or cycloalkyl, the substituent is selected from hydroxyl, amide, alkyl substituted amide, ZC(O)-, Z is selected from alkyl or heterocycle, heteroaryl; R2, R 3、 R5 is independently selected from hydrogen, alkyl, alkoxy, cyano, halogen, haloalkyl, amide, hydroxy, hydroxy-substituted alkyl, carboxyl, amino, amino-substituted alkyl, alkylcarbonyl or -(CH2)nO-(CH2)n-benzene, n = 1, 2 or 3; R8 and R9 are independently selected from hydrogen, alkyl, halogen, cycloalkyl, alkylthio, alkoxy, aryl, and heteroaryl; And R1, R2, R3, R4, R5, R6, and R7 are not hydrogen at the same time; or when R1, R2, R3, R4, R5, R6, and R7 are hydrogen at the same time, R8 and R9 are not hydrogen at the same time.

3. The compound according to claim 1 or 2, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: R1, R2, R4, R5, R6, R7 are simultaneously hydrogen, R3 is selected from alkyl, alkoxy, cyano, halogen, haloalkyl, amide, hydroxy, hydroxy-substituted alkyl, carboxyl, amino, amino-substituted alkyl, alkylcarbonyl or -(CH2)nO-(CH2)n-benzene, n=1, 2 or 3; Alternatively, R1, R2, R3, R5, R6, and R7 are all hydrogen, and R2 is selected from alkyl, alkoxy, cyano, halogen, haloalkyl, amide, hydroxyl, hydroxyl-substituted alkyl, carboxyl, amino, amino-substituted alkyl, alkylcarbonyl or -(CH2)nO-(CH2)n-benzene, where n=1, 2 or 3.

4. The compound according to claim 1 or 2, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, 1-ethylbutyl, a haloalkyl group means that one or more hydrogen atoms on the alkyl group are replaced by halogen, and a hydroxy-substituted alkyl group means that one or more hydrogen atoms on the alkyl group are replaced by hydroxyl groups; the halogen is selected from fluorine, chlorine, bromine, and iodine; The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the heterocycle is a cycloalkane group in which one or more carbon atoms are replaced by heteroatoms, and the heteroatoms are selected from N, O and S; the alkoxy group is selected from methoxy, ethoxy, propoxy and isopropoxy.

5. The compound according to claim 1 or 2, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: R2 or R3 is selected from F, Cl, Br, methyl, hydroxy, hydroxymethyl, trifluoromethyl, -CF2H, -C(O)NH2, -NH2, cyano, -COOH, methoxy, -CH2-O-CH2-benzene, and / or R1 is selected from methyl, hydroxyl, hydroxymethyl, cyano, F, Cl, Br, -O-CH2-benzene, -COOH, -COOCH2CH3, Amide, formamide, CH3-C(O)-, and / or R6 and R7 are independently H or -COOH; and / or R4, R6 and R7 are independently H; and / or R8 and R9 are independently selected from hydrogen, chlorine, methyl, methoxy, methylthio, ethyl, isopropyl, phenyl, cyclopropyl, 6. The compound according to claim 1 or 2, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Selected from:

7. A compound represented by general formula (B), or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Among them, A is selected from B is selected from Q is selected from N or CR4, R4 is selected from H or halogen; T1 and T2 are selected from N or CH; X and Y are independently selected from C(O), O, S, NH, CH2, Z is absent or selected from C(O), O, S, NH, CH2, W is selected from C(O), O, S, NH, CH2, Wherein, R1 is hydrogen or represents a hydrogen on the ring further replaced by alkyl, halogenated alkyl, carboxylic acid, alkoxy, halogenated alkoxy, cyano, halogen or substituted, U1, U2, U4 are independently selected from CH or N, U3 is selected from CH2 or NH, R1 is one or more; R2 is selected from H, alkyl or halogen, R2 is one or more; R3 is hydrogen or represents that the hydrogen on the ring is further replaced by alkyl, halogen, oxo, substituted or unsubstituted phenyl, the substituent of the substituted phenyl is selected from alkyl and halogen, and R3 is one or more.

8. The compound according to claim 7, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl; The alkoxy group is selected from C 1-6 Alkoxy, the C 1-6 The alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentyloxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy; and the halogen is selected from fluorine, chlorine, bromine, and iodine.

9. The compound according to claim 7, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Q is selected from N; and / or Q is selected from CH, R2 is selected from F; and / or T1 is selected from N.

10. The compound according to claim 7, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: In the general formula (B) Part, selected from: Indicates the connection location; In the general formula (B) Part, selected from: Indicates the connection location.

11. The compound according to claim 7, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: R3 is hydrogen, methyl, F, phenyl, or Indicates the connection location; and / or A is selected from and / or B is selected from and / or Selected from 12. The compound according to claim 7, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Selected from:

13. A compound represented by general formula (C), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from Wherein, X and Y form a 5-7 membered saturated or unsaturated ring, the 5-7 membered saturated or unsaturated ring contains 0, 1 or 2 heteroatoms, the heteroatoms are selected from O, N and S; B is selected from Q is selected from N or CR1, R1 is selected from H or halogen; T1 is selected from N or CH; Wherein, R2 is selected from H, alkyl or halogen, and R2 is one or more; R3 is selected from hydrogen or represents that the hydrogen on the A ring is further replaced by oxo, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, alkynyl, R3 is one or more, or adjacent R3 forms an alkoxy R4 is selected from hydrogen, halogen, hydroxy, alkoxy, haloalkoxy, substituted or unsubstituted alkyl, cyano, -C(O)-O-alkyl, phenylalkoxy, carboxyl, hydroxymethyl or cycloalkyl, and the substituent is selected from hydroxy, amide, halogen, or substituted, U1, U2, U4 are independently selected from CH or N, U3 is selected from CH2 or NH, R4 is one or more; And when the A ring is selected from When the B ring is not 14. The compound according to claim 13, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl; The alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy; The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; The halogen is selected from fluorine, chlorine, bromine and iodine.

15. The compound according to claim 13, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Q is selected from N; and / or Q is selected from CH, R2 is selected from F; and / or T1 is selected from N; and / or R3 is selected from hydrogen, methyl, methoxy, cyclopropyl, cyclopropylmethyl, fluorine, chlorine, oxo, CHF2-O-; R4 is selected from hydrogen, methyl, hydroxyl, hydroxymethyl, cyano, F, Cl, Br, -O-CH2-benzene, -COOH, -COOCH2CH3, Amide, formamide, CH3-C(O)-, ethynyl, trifluoromethyl, difluoromethoxy, methoxy.

16. The compound according to claim 13, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from Further, the A ring substituted by R3 is selected from: Further, the B ring substituted by R4 is selected from:

17. The compound according to claim 13, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Selected from:

18. A compound represented by general formula (D), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, characterized in that: R1, R2, R3, and R4 are independently selected from hydrogen, halogen, alkyl, cyano, haloalkyl, or cycloalkyl; X is selected from CH or N, Z is selected from CH or N, when Z is selected from N, R6 is absent; Y is selected from CH or N. When Y is selected from N, R4 is absent; T is selected from CH or N or CT1, T1 is selected from CN, alkyl or haloalkyl; R5 and R6 are independently selected from hydrogen, halogen, and alkyl. When X is selected from CH, R5 and R6 are not hydrogen at the same time, or when X is selected from CH, R1, R2, R3, R4, R5, and R6 are hydrogen at the same time; R7 is selected from hydrogen, alkyl, alkoxy, cyano, alkynyl, substituted or unsubstituted cycloalkyl, alkylsulfonyl, alkylphosphoryl, substituted or unsubstituted -N(C(O))nX1X2, substituted or unsubstituted -O-cycloalkyl, substituted or unsubstituted -O-heterocycloalkyl, boric acid or halogen, wherein X1 and X2 are independently selected from alkyl, or X1X2 forms a heterocycloalkyl with the N to which it is connected, and the substituent is selected from hydrogen, halogen, alkyl, and n=0 or 1; and when R7 is selected from alkyl, alkoxy or halogen, R5 and R6 are not hydrogen at the same time or X is selected from N.

19. The compound according to claim 18, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl; The halogen is selected from fluorine, chlorine, bromine and iodine; The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; The heterocycloalkyl group is a cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms, wherein the heteroatoms are selected from O, N or S; The alkynyl group is selected from C 2-4 Alkynyl, for example, ethynyl, propynyl, butynyl.

20. The compound according to claim 18, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The haloalkyl group is selected from -CF3.

21. The compound according to claim 18, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: R5 and R6 are independently selected from hydrogen, fluorine, and methyl; R7 is selected from hydrogen, methyl, methoxy, ethoxy, fluorine, ethynyl, chlorine, or and / or said R1 is selected from hydrogen, fluorine, chlorine, cyclopropyl, cyano, methyl, -CF3; R2, R3, R4 are independently selected from hydrogen; And / or X is selected from N.

22. The compound according to claim 18, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Selected from:

23. A compound represented by general formula (E), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, characterized in that: wherein the A ring is selected from benzofuran, benzothiazole, 1H-indole, indole, quinoline, or benzofuran, benzothiazole, 1H-indole, indole, quinoline, wherein one or more -C= or -CH- on the ring is replaced by a N atom; T is selected from N or CR7; R1, R2, R3, R4, R5, R6, and R7 are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, and alkoxy, and the substitution is selected from halogen or alkyl.

24. The compound according to claim 23, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl; The halogen is selected from fluorine, chlorine, bromine and iodine; The alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutoxy, 1-ethylbutoxy, n-heptyl, isoheptyl; The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the heterocycloalkyl group refers to that at least one carbon atom on the cycloalkane is replaced by a heteroatom, and the heteroatom is selected from nitrogen, oxygen and sulfur.

25. The compound according to claim 23, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: T is selected from N; and / or R1, R3 are selected from hydrogen, and R2 is selected from -OCHF2.

26. The compound according to claim 23, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from 27. The compound according to claim 23, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Selected from:

28. A compound represented by general formula (F), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from: or R1 is substituted or unsubstituted Ring B is selected from R1, R1a, R 1b , R 1c , R 1d are independently selected from hydrogen, oxo, hydroxy, alkynyl, alkylalkynyl, alkylalkynylalkyl, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cyano, Or two adjacent substituents form a 5-6 membered saturated or unsaturated heterocyclic ring; R2 is one or more, independently selected from hydrogen, halogen, hydroxyl, alkoxy, haloalkoxy, substituted or unsubstituted alkyl, cyano, -C(O)-O-alkyl, phenylalkoxy, carboxyl, hydroxymethyl or cycloalkyl, and the substituent is selected from hydroxyl, amide, halogen; Q, X, Y, Z are independently selected from CR3 or N, R3 is independently selected from hydrogen, oxo, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cyano, and when A is selected from When , at least two are N; T is independently selected from CH or N; W1 is selected from CH2 or NH, and W2 is independently selected from CH or N.

29. The compound according to claim 28, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, 1-ethylbutyl; the halogen group is selected from fluorine, chlorine, bromine, and iodine; The alkoxy group is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy; the alkylthio group is an alkoxy group in which the oxygen atom is replaced by a sulfur atom; and the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

30. The compound according to claim 28, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Q is N; and / or R2 is -O-CHF2.

31. The compound according to claim 28, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from The substituted A ring is selected from Alternatively, ring A is selected from The substituted A ring is selected from 32. The compound according to claim 28, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Selected from:

33. A compound represented by general formula (G), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, characterized in that: Wherein, X is selected from substituted or unsubstituted alkyl, amino, O, S, and the substituent is selected from oxo, alkyl, halogen, alkoxy, hydroxyl, alkoxycarbonyl; Ring A is selected from a 5-14 membered saturated or unsaturated heterocyclic ring substituted or unsubstituted by R1, and the heterocyclic ring may be a monocyclic, bicyclic or tricyclic ring; R1 is independently selected from hydrogen, oxo, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cyano, m = 0, 1, 2, or 3; B is a B ring selected from a 5-7 membered saturated or unsaturated heterocyclic ring substituted or unsubstituted by R2, or an oxo-substituted alkyl group, or -C(O)-pyridine; R2 is independently selected from hydrogen, oxo, thio, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cyano, carboxylic acid, n = 0, 1, 2, or 3; R3 is independently selected from hydrogen, alkyl, alkoxy, cyano, halogen, haloalkyl, amide, hydroxy, hydroxy-substituted alkyl, carboxyl, amino, and p=0, 1, 2, or 3.

34. The compound according to claim 33, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, 1-ethylbutyl; The alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy; The alkylthio group is selected from methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio and tert-butylthio; The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; The halogen is selected from fluorine, chlorine, bromine and iodine.

35. The compound according to claim 33, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from and / or Ring B is selected from 36. The compound according to claim 33, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from hydrogen, methyl, cyano, methoxy, cyclopropyl, cyclopropylmethyl, fluorine, chlorine, CHF2-O-; and / or R2 is selected from hydrogen, methyl, oxo, thio; and / or R3 is selected from hydrogen, methyl, cyano, methoxy, cyclopropyl, cyclopropylmethyl, fluorine, chlorine; and / or X is selected from -CH2-, -C(O)-, -CH(OH)-, -NH2-, -NH(CH3)-, O.S.

37. The compound according to claim 33, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Selected from:

38. A compound represented by general formula (H), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, characterized in that: R1, R2, R3, and R4 are independently selected from hydrogen, halogen, alkyl, cyano, haloalkyl, or cycloalkyl; X is selected from C or N. When X is selected from N, R5 is absent. Y is selected from C or N. When Y is selected from N, R6 is absent. Z is selected from C or N. When Z is selected from N, R7 is absent. R5, R6, and R7 are independently selected from hydrogen, halogen, and alkyl; R8 is one or more, independently selected from hydrogen, halogen, phenyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkyl, the substituent is selected from alkyl, halogen; Ring A is selected from When A is selected from When X, Y, and Z are C at the same time, R1, R2, R3, R4, R5, R6, and R7 are not hydrogen atoms at the same time.

39. The compound according to claim 38, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl; The halogen is selected from fluorine, chlorine, bromine and iodine; The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

40. The compound according to claim 38, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from halogen, alkyl; and / or Y is selected from N, or Y is selected from C, R5 is selected from halogen, alkyl; and / or R8 is selected from methyl, cyclopropyl, cyclobutyl, and / or Z is selected from N.

41. The compound according to claim 38, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Said Selected from 42. The compound according to claim 38, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: Selected from:

43. A compound represented by general formula (J), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, characterized in that: Wherein, the A ring is selected from a 5-14 membered saturated or unsaturated heterocyclic ring substituted or unsubstituted by R1, and the heterocyclic ring may be a monocyclic, bicyclic or tricyclic ring; R1 is independently selected from hydrogen, oxo, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cyano, m = 0, 1, 2, or 3; Ring B is selected from a 5-8 membered saturated or unsaturated monocyclic or bicyclic ring, and is not R2 is independently selected from hydrogen, oxo, thio, alkyl, halogen, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cyano, n = 0, 1, 2, or 3; R3 is independently selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted alkyl, cyano, -C(O)-O-alkyl, phenyloxy, carboxyl, hydroxymethyl or cycloalkyl, the substituents are selected from hydroxyl, alkyl, amide, alkyl substituted amide, ZC(O)-, Z is selected from alkyl or heterocycle, aryl, heteroaryl, p = 0, 1, 2, or 3; T1, T2, T3 are independently selected from CH or N.

44. The compound according to claim 43, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, 1-ethylbutyl; The alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy; The alkylthio group is selected from methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio and tert-butylthio; The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; The halogen is selected from fluorine, chlorine, bromine and iodine.

45. The compound according to claim 43, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: Ring A is selected from 46. ​​The compound according to claim 43, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that Ring B is selected from and / or R1 is selected from hydrogen, methyl, cyano, methoxy, cyclopropyl, cyclopropylmethyl, fluorine, chlorine, CHF2-O-; and / or R2 is selected from hydrogen, methyl, cyano, methoxy, cyclopropyl, cyclopropylmethyl, fluorine, chlorine; and / or Ring B is connected by:

47. The compound according to claim 43, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: Selected from:

48. A pharmaceutical composition, characterized in that The invention comprises a therapeutically effective amount of the compound according to any one of claims 1 to 47, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

49. The medical use of the compound according to any one of claims 1 to 47, or its isomer, or its racemate, or its pharmaceutically acceptable salt, specifically, its use in the preparation of a drug for treating a disease, wherein the disease is a PCSK9 inhibitor-related disease, preferably selected from hypercholesterolemia and the like.