CDK inhibitor

Abstract

A class of compounds as selective CDK inhibitors, pharmaceutical compositions containing the compounds, useful intermediates for preparing the compounds, and use of the compounds for preparing drugs for treating cell proliferative diseases, such as cancer, the compounds having the structure shown in formula (I-A). #imgabs0#

Description

[0001] This application claims the priority of Chinese Patent Application No. 202110161786.5 with the filing date of February 5, 2021, Chinese Patent Application No. 202110483256.2 with the filing date of April 30, 2021, Chinese Patent Application No. 202111062178.5 with the filing date of September 10, 2021, Chinese Patent Application No. 202111398260.5 with the filing date of November 19, 2021, and the priority of Chinese Patent Application No. 202210048365.6 with the filing date of January 17, 2022. This application incorporates the entire texts of the above-mentioned Chinese patent applications by reference. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and particularly relates to novel compounds having CDK2 / 4 / 6 inhibitory activity, pharmaceutical compositions containing the compounds, useful intermediates for preparing the compounds, and methods for treating cell proliferative diseases such as cancer using the compounds of the present invention. Background Art

[0003] The cell cycle is a basic process of cell life activities, controlling cell growth, proliferation, and differentiation. Cyclin-dependent kinases (CDKs) are a class of important cellular enzymes that cooperate with cyclins and play an important role in the regulation of the cell cycle. Cyclin B / CDK1, Cyclin A / CDK2, Cyclin E / CDK2, Cyclin D / CDK4, Cyclin D / CDK6, and other possible heterodimers are important regulators at different stages of the cell cycle (Harper, J.W., Adams, P.D., Cyclin-Dependent Kinases, Chem. Rev. 2001, 101, 2511-2526).

[0004] As an important regulatory factor in the cell cycle, CDK2 forms a kinase complex with cyclin E or A and plays a decisive role in driving the cell cycle from the G1 phase into the S phase and maintaining the S phase. The main mechanism is that Cyclin E and CDK2 act together to phosphorylate the retinoblastoma susceptibility gene (Rb) protein, and the phosphorylation of the Rb protein leads to the release of E2F (transcription factor). The released E2F binds to the upstream of some genes (usually located in the promoter or enhancer region), initiating the transcriptional expression of those genes related to the cell cycle and enabling the cell to enter the S phase from the end of G1. Numerous studies have shown that the abnormal expression of CDK2 is closely related to the occurrence of cancer, such as ovarian cancer with CCNE1 amplification, KRAS mutant lung cancer, hormone-dependent breast cancer and prostate cancer, etc. (Tadesse S, Anshabo AT, Portman N, Lim E, Tilley W, Caldon CE, Wang S, Targeting CDK2 in cancer: challenges and opportunities for therapy, Drug Discovery Today, 2020, 25, 406 - 413).

[0005] With the important role of cyclin-dependent kinases (CDKs) in cell cycle regulation being determined, CDK inhibitors have become a research hotspot for current anti-tumor drugs. Currently, several CDK inhibitors have been approved for marketing globally, but most of them act on the CDK4 / 6 target and mainly use breast cancer as an indication, such as Palbociclib from Pfizer, Ribociclib from Novartis, and abemaciclib from Eli Lilly. Molecules such as fadraciclib, Roscovitine, and PF-06873600, which are multi-target inhibitors containing CDK2, are in different clinical stages. Currently, no CDK2 inhibitor has been approved for marketing. Therefore, continuing to develop new CDK inhibitors, especially inhibitors effective against the CDK2 target, has great research significance. Summary of the Invention

[0006] The purpose of the present invention is to provide a class of novel compounds with CDK2 / 4 / 6 inhibitory activity, pharmaceutical compositions containing the compounds, useful intermediates for preparing the compounds, and the application of the compounds in the preparation of anti-cancer drugs.

[0007] The present invention provides a compound represented by formula (I-A),

[0008]

[0009] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotopically labeled derivative thereof,

[0010] wherein,

[0011] R1 is selected from halogen, -CN, -NO2, or C 1- 4-haloalkyl;

[0012] Z is selected from -CH- or N;

[0013] L is a bond or is selected from -NR a -, -O-, -S-, -SO2-, -SO-, -CO-, -CR a R b -, or -CH═, wherein the R a and R b are each independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -SO2R c -, -SOR c -, -COR c -, -(CH2) m NR aa R ab or -(CH2) m C(O)NR aa R ab wherein the R c is selected from H, C 1-4 alkyl, R aa and R ab are each independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, or R aa and R ab together with the attached N atom form a 4- to 6-membered heterocycloalkyl;

[0014] R2 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl, or 5- to 6-membered heteroaryl, wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl, and 5- to 6-membered heteroaryl are optionally substituted with one or more R d wherein the R d are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, -(CH2) mOH, -(CH2) m NR e R f , C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl; R d the C as described in 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally substituted by C 1-4 alkyl, C 1-4 haloalkyl, -OH or -NH2;

[0015] R3 is selected from C 1-4 alkyl, C 1-4 haloalkyl, -(CH2) m NR e R f , -(CH2) m OH, -L1-aryl, -L1-(5- to 6-membered heteroaryl), -L1-(C 3-6 cycloalkyl) or -L1-(3- to 6-membered heterocycloalkyl), and the aryl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally substituted by one or more R g substituents, and R g can be R ga or R gb ;

[0016] R ga is independently selected from H, halogen, -OH, C 1-4 alkyl, C 1-4 haloalkyl, -(CH2) m NR e R f , R e R f NC(O)-C 1-4 alkyl-, -C 1-4 alkyl-OH, -S(O)2-(5- to 6-membered heteroaryl) or C 1-4 alkoxy;

[0017] R gb is independently selected from -L2-(C 3-6 cycloalkyl), -L2-(3- to 6-membered heterocycloalkyl), -L2-(3- to 6-membered heterocycloalkenyl), -L2-aryl, -L2-(5- to 6-membered heteroaryl), -L2-(7- to 11-membered spiroheterocyclic group), -L2-(6- to 14-membered fused heterocyclic group), wherein the C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkenyl, aryl, 5- to 6-membered heteroaryl, 7- to 11-membered spiroheterocyclic group, -L2-(6- to 14-membered fused heterocyclic group) are optionally substituted by one or more R gc substituents, and Rgc is independently selected from C 1-4 alkyl, halogen, C 1-4 haloalkyl, -(CH2) m NR e R f 、-(CH2) m OH or cyano, or any two Rs gc are connected to form C 1-2 alkylene chain;

[0018] L1 is a bond or is independently selected from C 1-4 alkylene;

[0019] L2 is a bond or is independently selected from C 1-4 alkylene or NH;

[0020] R e and R f are independently selected from H or C 1-4 alkyl;

[0021] m is independently selected from 0, 1, 2, 3 or 4;

[0022] R4, R4' and R5 are independently selected from H, OH, halogen, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy;

[0023] and, when L is a bond, R2 is not when L is -NH-, R2 is not and when the compound of formula (I) is R1 is not halogen.

[0024] In some embodiments of the present invention, the compound represented by the above formula (I-A) or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives, wherein the compound can be represented by formula (I-B),

[0025]

[0026] wherein,

[0027] R1 is selected from halogen, -CN, -NO2 or C 1-4 haloalkyl;

[0028] Z is selected from -CH- or N;

[0029] L is a bond, or is selected from -NR a -, -O-, -S-, -SO2-, -SO-, -CO-, -CR a Rb - or -CH═, where said R a and R b are each independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3 - 6 membered heteroalkyl, -SO₂R c , -SOR c , -COR c , -(CH₂) m NR aa R ab or -(CH₂) m C(O)NR aa R ab , where said R c is selected from H, C 1-4 alkyl, R aa and R ab are each independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3 - 6 membered heteroalkyl or R aa and R ab together with the attached N atom form a 4 - 6 membered heteroalkyl;

[0030] R₂ is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3 - 6 membered heteroalkyl, aryl or 5 - 6 membered heteroaryl, where the C 1-4 alkyl, C 3-6 cycloalkyl, 3 - 6 membered heteroalkyl, aryl and 5 - 6 membered heteroaryl are optionally substituted by one or more R d ; said R d is each independently selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, -(CH₂) m OH, -(CH₂) m NR e R f , C 3-6 cycloalkyl or 3 - 6 membered heteroalkyl; the C d cycloalkyl and 3 - 6 membered heteroalkyl in R 3-6 are optionally substituted by C 1-4 alkyl, C 1-4 haloalkyl, -OH or -NH₂;

[0031] R₃ is selected from C 1-4 alkyl, C 1-4 haloalkyl, -(CH₂) m NRe R f 、 -(CH2) m OH, -L1-aryl, -L1-(5- or 6-membered heteroaryl), -L1-(cycloalkyl), or -L1-(3- to 6-membered heterocycloalkyl), wherein the aryl, 5- or 6-membered heteroaryl, cycloalkyl, and 3- to 6-membered heterocycloalkyl are optionally substituted with one or more R 3-6 ; R 3-6 is R g or R g ; ga or R gb ;

[0032] R ga is independently selected from H, halogen, -OH, C 1-4 alkyl, C 1-4 haloalkyl, -(CH2) m NR e R f ; R e R f NC(O)-C 1-4 alkyl-, -C 1-4 alkyl-OH, -S(O)2-(5- or 6-membered heteroaryl), or C 1-4 alkoxy;

[0033] R gb is independently selected from -L2-(cycloalkyl), -L2-(3- to 6-membered heterocycloalkyl), -L2-(3- to 6-membered heterocycloalkenyl), -L2-aryl, -L2-(5- or 6-membered heteroaryl), -L2-(7- to 11-membered spiroheterocyclic), -L2-(6- to 14-membered fused heteroheterocyclic), wherein the cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkenyl, aryl, 5- or 6-membered heteroaryl, 7- to 11-membered spiroheterocyclic, and 6- to 14-membered fused heteroheterocyclic in R 3-6 are optionally substituted with one or more R gb ; 3-6 R gc is independently selected from C

[0034] alkyl, halogen, C gc haloalkyl, -(CH2) 1-4 NR 1-4 R m ; -(CH2) e R f ; -(CH2) m OH, or cyano;

[0035] Or any two R gc are joined to form a C 1-2 alkylene chain;

[0036] L1 is a bond or is independently selected from C 1-4 alkylene;

[0037] L2 is a bond or is independently selected from C 1-4 alkylene or NH;

[0038] R c and R f are independently selected from H or C 1-4 alkyl;

[0039] m is independently selected from 0, 1, 2, 3 or 4;

[0040] R4 and R5 are independently selected from H, OH, halogen, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy.

[0041] In some embodiments of the present invention, R1 is selected from -CN, -CF3 or -CHF2.

[0042] In some embodiments of the present invention, R1 is selected from -CN or -CF3.

[0043] In some embodiments of the present invention, R1 is selected from -CF3.

[0044] In some embodiments of the present invention, R1 is selected from -CN.

[0045] In some embodiments of the present invention, Z is selected from N.

[0046] In some embodiments of the present invention, L is selected from NH-, N(CH3)-, -O-, -CH2-, CH=, -N(CH(CH)2)- (i.e., ), -N(SO2CH3)-, -SO2-, -SO, -N(CH2CF3)-,

[0047] In some embodiments of the present invention, L is selected from a bond or -S-.

[0048] In some embodiments of the present invention, L is selected from -NH- or -O-.

[0049] In some embodiments of the present invention, L is selected from -NH-.

[0050] In some embodiments of the present invention, L is selected from -O-.

[0051] In some embodiments of the present invention, R gb-L2-(7-11 membered spiroheterocyclic group) is selected from -L2-(7-11 membered azaspiro group), and -L2-(6-14 membered fused heterocyclic group) is selected from -L2-(6-14 membered azafused ring group).

[0052] In some embodiments of the present invention, R2 is selected from methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, (for example ), (for example ), (for example ), (for example ), wherein, M is independently selected from -O- or -NR a -, R a and R d as defined in any one of the embodiments of the present invention, and n is independently 0, 1, 2, 3 or 4.

[0053] In some embodiments of the present invention, the 3-6 membered heteroalkyl group in R d is a 3-6 membered azoalkyl group, for example and for another example

[0054] In some embodiments of the present invention, R d is selected from H, -OH, -F, -N(CH3)CH3, -CH3, -OCH3, -CH2N(CH3)CH3 or

[0055] In some embodiments of the present invention, R d is selected from -OH, -F, -CH3.

[0056] In some embodiments of the present invention, the 3-6 membered heteroalkyl group in R2 is selected from 3-6 membered oxoalkyl groups, such as oxolanyl

[0057] In some embodiments of the present invention, R2 is selected from isopropyl, tert-butyl,

[0058] In some embodiments of the present invention, R2 is selected from

[0059] In some embodiments of the present invention, R2 is selected from

[0060] In some embodiments of the present invention, R2 is selected from

[0061] In some embodiments of the present invention, R3 is selected from methyl, isopropyl, -(CH2)3N(CH3)CH3, wherein M, n, R ga , R gc , L1, and L2 are as defined in any embodiment of the present invention.

[0062] In some embodiments of the present invention, R3 is selected from wherein n, R ga , R gc are as defined in any embodiment of the present invention.

[0063] In some embodiments of the present invention, in R3, any two of the Rs gc are connected to form a C 1-2 alkylene chain, for example wherein n, R ga , R gc are as defined in any embodiment of the present invention, wherein n, R ga , R gc are as defined in any embodiment of the present invention.

[0064] In some embodiments of the present invention, in R3, any two of the Rs gc are connected to form a C 1-2 alkylene chain, for example wherein n, R ga , R gc are as defined in any embodiment of the present invention.

[0065] In some embodiments of the present invention, in R3, any two of the Rs gc are connected to form a C 1-2 alkylene chain, for example wherein n, R ga , R gc are as defined in any embodiment of the present invention.

[0066] In some embodiments of the present invention, in R ga , the R e R f NC(O)-C 1-4 alkyl - is NH2COC(CH3)2-.

[0067] In some embodiments of the present invention, the -S(O)2-(5-6 membered heteroaryl) in R ga is -S(O)2-(5-6 membered azaheteroaryl), for example

[0068] In some embodiments of the present invention, R ga is selected from H, Br, F, -CH3, -CH(CH3)2, -CH2CH2N(CH3)CH3, -NH2, -CH2CH2OH, -C(CH3)2OH, NH2COC(CH3)2-, -OCH3.

[0069] In some embodiments of the present invention, R gb wherein L2 is a bond, -(CH2)2-.

[0070] In some embodiments of the present invention, Rgb is selected from

[0071] In some embodiments of the present invention, R gb is selected from

[0072] In some embodiments of the present invention, R gb is selected from

[0073] In some embodiments of the present invention, R gc is selected from H, -CH3, F, -OH, -NH2, -N(CH3)CH3, CN, -CF3;

[0074] Or any two Rs gc are connected to form a -CH2- or -CH2CH2- chain.

[0075] In some embodiments of the present invention, any two non-adjacent Rs gc are connected to form a C 1-2 alkylene chain.

[0076] In some embodiments of the present invention, any two non-adjacent Rs gc are connected to form a -CH2- or -CH2CH2- chain.

[0077] In some embodiments of the present invention, -L1-aryl in R3 is selected from -L1-phenyl.

[0078] In some embodiments of the present invention, -L1-(5-6 membered heteroaryl) in R3 is selected from -L1-(5-6 membered azaheteroaryl), such as -L1-pyrazolyl, -L1-pyridyl.

[0079] In some embodiments of the present invention, L1 in R3 is a bond.

[0080] In some embodiments of the present invention, R3 is selected from methyl, isopropyl, -(CH2)3N(CH3)CH3,

[0081] In some embodiments of the present invention, R3 is selected from

[0082] In some embodiments of the present invention, R3 is selected from

[0083] In some embodiments of the present invention, R3 is selected from

[0084] In some embodiments of the present invention, R3 is selected from

[0085] In some embodiments of the present invention, R3 is selected from

[0086] In some embodiments of the present invention, R4 and R5 are each independently selected from H, F, OH, CH3.

[0087] In some embodiments of the present invention, R4 and R5 are each independently selected from H, F.

[0088] In some embodiments of the present invention, R4 and R5 are selected from H.

[0089] In some embodiments of the present invention, the compounds of formula (I-A) and formula (I-B) or their stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives, wherein the compound is represented by formula (II),

[0090]

[0091] wherein,

[0092] R1, R2, R3, R4, R5, L are as defined in any embodiment of the present invention.

[0093] In some embodiments of the present invention, the compounds of formula (I-A) and formula (I-B) or their stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives, wherein the compound is represented by any one of the structures of formula (II-A), formula (II-B) and formula (II-C),

[0094]

[0095] wherein,

[0096] R1, R2, R4, R5, L, R g , n are as defined in any embodiment of the present invention.

[0097] In some embodiments of the present invention, the compounds of formula (I-A) and formula (I-B) or their stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives, wherein the compounds can be represented by any of the following structures,

[0098]

[0099]

[0100] wherein,

[0101] Z1 is selected from C, CH or N;

[0102] Z2 is selected from CH2, NH or O;

[0103] R1, R2, R4, R5, L, n, R ga R gc are as defined in any embodiment of the present invention.

[0104] In some embodiments of the present invention, the compounds of formula (I-A) and formula (I-B) or their stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives, wherein the compounds can be represented by any of the following structures,

[0105]

[0106]

[0107]

[0108] wherein, R1, L, R d M, n, R4, R5, R ga R gc Z1, Z2 are as defined in any embodiment of the present invention.

[0109] In some embodiments of the present invention, the compounds of formula (I-A) and formula (I-B) or their stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives, wherein the compounds can be represented by any of the following structures,

[0110]

[0111]

[0112] R1, L, R d n, R4, R5, R ga Rgc As defined in any aspect of the present invention.

[0113] In some aspects of the present invention, the compound of formula (I-A) and formula (I-B) or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled derivatives, wherein the compound can be represented by any of the following structures:

[0114]

[0115] wherein, R3, R gb , R gc , n are as defined in any aspect of the present invention.

[0116] In some aspects of the present invention, the compound represented by formula (I-A) or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled derivatives, wherein the compound can be represented by formula (I):

[0117]

[0118] wherein,

[0119] R1 is selected from halogen, -CN, -NO2 or C 1-4 haloalkyl;

[0120] Z is selected from -CH- or N;

[0121] L is a bond, or is selected from NR a -, -O-, -S-, -SO2-, -SO-, -CO-, -CR a R b -, or -CH═, and the R a and R b are each independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, -SO2R c , -SOR c , -COR c , -(CH2) m NR aa R ab or -(CH2) m C(O)NR aa R ab , wherein the R c is selected from H, C 1-4 alkyl, and R aa and R ab are each independently selected from H, C 1-4 alkyl, C1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl or R aa and R ab form a 4- to 6-membered heterocycloalkyl with the jointly attached N atom;

[0122] R2 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl or 5- to 6-membered heteroaryl, and the C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl and 5- to 6-membered heteroaryl are optionally substituted by one or more R d ; the R d are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, -(CH2) m OH, -(CH2) m NR e R f 、C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl; the C d in R 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally substituted by C 1-4 alkyl, C 1- 4-haloalkyl, -OH or -NH2;

[0123] R3 is selected from C 1-4 alkyl, C 1-4 haloalkyl, -(CH2) m NR e R f 、-(CH2) m OH, -L1-aryl, -L1-(5- to 6-membered heteroaryl), -L1-(C 3-6 cycloalkyl) or -L1-(3- to 6-membered heterocycloalkyl), and the aryl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally substituted by one or more R g ; R g can be R ga or R gb ;

[0124] R ga are each independently selected from H, halogen, -OH, C 1-4 alkyl, C 1-4 haloalkyl, -(CH2) m NR e R f 、Re R f NC(O)-C 1-4 alkyl-, -C 1-4 alkyl-OH or -S(O)2-(5-6-membered heteroaryl);

[0125] R gb independently optionally selected from -L2-(C 3-6 cycloalkyl), -L2-(3-6-membered heterocycloalkyl), -L2-(3-6-membered heterocycloalkenyl), -L2-aryl, -L2-(5-6-membered heteroaryl), wherein the C 3-6 cycloalkyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, aryl, 5-6-membered heteroaryl is optionally substituted with one or more R gc R gc independently optionally selected from C 1-4 alkyl, halogen, C 1-4 haloalkyl, -(CH2) m NR e R f or -(CH2) m OH;

[0126] L1 is a bond or independently optionally selected from C 1-4 alkylene;

[0127] L2 is a bond or independently optionally selected from C 1-4 alkylene;

[0128] R e and R f independently optionally selected from H or C 1-4 alkyl;

[0129] m is independently optionally selected from 0, 1, 2, 3 or 4;

[0130] R4 and R5 are independently optionally selected from H, OH, halogen, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy;

[0131] and, when L is a bond, R2 is not when L is -NH-, R2 is not and when the compound of formula (I) is R1 is not halogen.

[0132] In some embodiments of the present invention, R1 is selected from -CN, -CF3 or -CHF2.

[0133] In some embodiments of the present invention, R1 is selected from -CN or -CF3.

[0134] In some embodiments of the present invention, R1 is selected from -CN.

[0135] In some embodiments of the present invention, Z is selected from N.

[0136] In some embodiments of the present invention, L is selected from -NH-, -N(CH3)-, -O-, -CH2-, CH=, -N(CH(CH)2)-, -N(SO2CH3)-, -SO2-, -SO-, -N(CH2CF3)-,

[0137] In some embodiments of the present invention, L is selected from -NH- or -O-.

[0138] In some embodiments of the present invention, L is selected from -NH-.

[0139] In some embodiments of the present invention, R2 is selected from methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, wherein M is independently selected from -O- or -NR a -, R a and R d As defined in any embodiment of the present invention, n is independently 0, 1, 2, 3 or 4.

[0140] In some embodiments of the present invention, R d is selected from H, -OH, -F, -N(CH3)CH3, -CH3, -OCH3, -CH2N(CH3)CH3 or

[0141] In some embodiments of the present invention, R d is selected from -OH, -F, -CH3.

[0142] In some embodiments of the present invention, R2 is selected from isopropyl, tert-butyl,

[0143] In some embodiments of the present invention, R3 is selected from methyl, isopropyl, -(CH2)3N(CH3)CH3, wherein M, n, R ga 、R gc 、L1 are as defined in any embodiment of the present invention.

[0144] In some embodiments of the present invention, R gaSelected from H, Br, F, -CH3, -CH(CH3)2, -CH2CH2N(CH3)CH3, -NH2, -CH2CH2OH, -C(CH3)2OH, NH2COC(CH3)2-,

[0145] In some embodiments of the present invention, Rgb is selected from

[0146] In some embodiments of the present invention, R gc is selected from H, -CH3, F, -OH, -NH2, -N(CH3)CH3.

[0147] In some embodiments of the present invention, R3 is selected from methyl, isopropyl, -(CH2)3N(CH3)CH3,

[0148] In some embodiments of the present invention, R4 and R5 are each independently selected from H, F, OH, CH3.

[0149] In some embodiments of the present invention, R4 and R5 are each independently selected from H, F.

[0150] In some embodiments of the present invention, the above compound or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives, wherein the compound is represented by formula (II),

[0151]

[0152] wherein,

[0153] R1, R2, R3, R4, R5, L are defined as in any embodiment of the present invention.

[0154] In some embodiments of the present invention, the above compound or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives, wherein the compound is represented by any of the following structures,

[0155]

[0156] wherein,

[0157] R1, R2, R4, R5, L, R g , n are defined as in any embodiment of the present invention;

[0158] In some embodiments of the present invention, the above-mentioned compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative, wherein the compound can be represented by any of the following structures,

[0159]

[0160] Wherein,

[0161] Z1 is selected from C, CH or N,

[0162] Z2 is selected from CH2, NH or O;

[0163] R1, R2, R4, R5, L, R g , n, R ga , R gc as defined in any of the embodiments of the present invention;

[0164] In some embodiments of the present invention, the above-mentioned compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative, wherein the compound can be represented by any of the following structures,

[0165]

[0166] Wherein, R1, L, R d , R g , M, n, R4, R5, R ga , R gc as defined in any of the embodiments of the present invention.

[0167] In some embodiments of the present invention, the above-mentioned compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative, wherein the compound can be represented by any of the following structures,

[0168]

[0169]

[0170] R1, L, R d , R g , n, R4, R5, R ga , R gc as defined in any of the embodiments of the present invention.

[0171] The present invention also provides the following compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative, wherein the compound can be selected from any of the following structures,

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181] The present invention also provides a pharmaceutical composition, which contains (preferably in a therapeutically effective amount) the above-mentioned compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative; and a pharmaceutically acceptable carrier, diluent and excipient. The pharmaceutical composition can be formulated for specific routes of administration, such as oral administration, parenteral administration and rectal administration, etc. For oral administration, for example, tablets, capsules (including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nano-suspensions, micro-suspensions, spray-dried dispersions), syrups and emulsions; sublingual administration; buccal administration; parenteral, for example, by subcutaneous, intravenous, intramuscular or intrasternal injection, or infusion techniques (such as as a sterile injectable aqueous solution or non-aqueous solution or suspension); nasal, including administration to the nasal mucosa, for example, by inhalation spray; topical, for example, in the form of a cream or ointment; or rectal, for example, in the form of a suppository. They can be administered alone, but are usually administered together with a pharmaceutical carrier selected according to the chosen route of administration and standard pharmaceutical practice.

[0182] "Pharmaceutically acceptable carrier" refers to a medium that is commonly acceptable in the art for delivering a bioactive agent to an animal, particularly a mammal, and includes, depending on the mode of administration and the nature of the dosage form, for example, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants. Pharmaceutically acceptable carriers are formulated within the purview of those of ordinary skill in the art based on a number of factors. These include, but are not limited to: the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media as well as a variety of solid and semi-solid dosage forms. In addition to the active agent, such carriers include many different ingredients and additives, and such additional ingredients included in a formulation for a variety of reasons (such as stabilizing the active agent, binders, etc.) are well known to those of ordinary skill in the art.

[0183] The dosing regimen for the compounds of the present invention may of course be varied according to known factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the species, age, sex, health, medical condition and body weight of the recipient, the nature and extent of the symptoms, the type of coexisting therapy, the frequency of treatment, the route of administration, the kidney and liver function of the patient, and the desired effect. The therapeutically effective dose of the compound, pharmaceutical composition or combination thereof depends on the species of the subject, body weight, age and individual circumstances, the disorder or disease being treated or its severity. A medical doctor, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a disorder or disease.

[0184] As an important regulatory factor in the cell cycle, CDK2 forms a kinase complex with cyclin E or A and plays a decisive role in driving the cell cycle from the G1 phase into the S phase and maintaining the S phase. The mechanism is mainly that Cyclin E and CDK2 act together to phosphorylate the retinoblastoma susceptibility gene (Rb) protein, and the phosphorylation of the Rb protein leads to the release of E2F (transcription factor). The released E2F binds to the upstream of some genes (usually located in the promoter or enhancer region), initiating the transcriptional expression of those genes related to the cell cycle and enabling the cell to enter the S phase from the end of G1. Numerous studies have shown that the abnormal expression of CDK2 is closely related to the occurrence of cancer, such as ovarian cancer with CCNE1 amplification, KRAS mutant lung cancer, hormone-dependent breast cancer and prostate cancer, etc. (Tadesse S, Anshabo AT, Portman N, Lim E, Tilley W, Caldon CE, Wang S, Targeting CDK2 in cancer: challenges and opportunities for therapy, Drug Discovery Today, 2020, 25, 406 - 413).

[0185] The present invention also provides the use of the above-mentioned compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative, or the above-mentioned pharmaceutical composition in the preparation of a drug (preferably a drug for treating CDK-mediated cancer).

[0186] The present invention also provides a method for treating CDK-mediated cancer, which comprises administering to a patient a therapeutically effective amount of the above-mentioned compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative, or the above-mentioned pharmaceutical composition.

[0187] In some embodiments of the present invention, the above-mentioned use, wherein the cancer includes ovarian cancer, breast cancer, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

[0188] The present invention also provides a compound represented by formula (III) or its stereoisomer, pharmaceutically acceptable salt,

[0189]

[0190] wherein,

[0191] X is selected from halogen, OH, -SO2Me, -OMs, OTf, OTs and H; preferably halogen (such as Cl);

[0192] Z, R1, R3, R4, and R5 are as defined in any aspect of the present invention.

[0193] In some aspects of the present invention, the compound of formula (III) is selected from

[0194]

[0195] wherein, R1, X, Rga, Rgc, and n are as defined in any aspect of the present invention.

[0196] The present invention also provides a compound represented by formula (IV-1) and (IV-2), or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0197]

[0198] wherein, X is selected from halogen, OH, -SO2Me, -OMs, OTf, OTs, preferably halogen (e.g., Br).

[0199] X1 is selected from halogen, OH, -SO2Me, -OMs, OTf, OTs, preferably halogen (e.g., Cl).

[0200] The above compounds are used for preparing the CDK inhibitor compounds represented by formula (I-A), formula (I-B), and formula (I) in the present invention.

[0201] Technical effects

[0202] The compounds of the present invention have good CDK 2 / 4 / 6 kinase inhibitory activity, especially excellent in the inhibitory activity of CDK 2 kinase; the compounds of the present invention can selectively inhibit CDK 2 / 4 / 6 kinases, especially have good selectivity for CDK 2 kinase, and the inhibitory selectivity of some compounds for CDK 1 / 7 / 9 kinases relative to CDK 2 kinase can reach nearly 10 times, even dozens of times, hundreds of times or more.

[0203] The compounds of the present invention have good cell proliferation inhibitory activity, and show good tumor inhibitory activity and good tolerance in in vivo pharmacodynamic experiments.

[0204] Description and definitions

[0205] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indefinite or unclear without a special definition, but should be understood according to its ordinary meaning.

[0206] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable for contact with human and animal tissues within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic reaction or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0207] The term "pharmaceutically acceptable salt" refers to a derivative prepared from a compound of the present invention and a relatively non-toxic acid or base. These salts can be prepared during the synthesis, separation, and purification of the compound, or the free form of the purified compound can be reacted with a suitable acid or base alone. When the compound contains relatively acidic functional groups, it reacts with alkali metal, alkaline earth metal hydroxides or organic amines to obtain base addition salts, including cations based on alkali metals and alkaline earth metals, as well as non-toxic ammonium, quaternary ammonium, and amine cations, and also includes salts of amino acids, etc. When the compound contains relatively basic functional groups, it reacts with organic acids or inorganic acids to obtain acid addition salts.

[0208] The compounds provided by the present invention also include prodrug forms, which refer to compounds that are rapidly converted in vivo to the parent compound of the above formula and are converted to the compounds of the present invention by chemical or biochemical methods in vivo or in vitro environments, for example, by hydrolysis in the blood.

[0209] The compounds of the present invention can exist in non-solvated and solvated forms, and solvation includes hydrate forms. Generally, the solvated form is equivalent to the non-solvated form and is also covered within the scope of the present invention.

[0210] The compounds of the present invention exist in geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, and their racemic mixtures and other mixtures, and all of these mixtures are within the scope of the present invention.

[0211] The term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0212] The term "diastereomer" refers to stereoisomers in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror image.

[0213] The term "cis-trans isomer" refers to the configuration that exists when the double bond or the single bond of the ring carbon atom in the molecule cannot rotate freely.

[0214] Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to different functional group isomers that are in dynamic equilibrium at room temperature and can rapidly interconvert. If tautomers are possible (such as in solution), the chemical equilibrium of the tautomers can be achieved. For example, keto-enol isomerization and imine-enamine isomerization.

[0215] Unless otherwise specified, a solid wedge bond and a wedge-shaped dashed bond represents the absolute configuration of a stereocenter, using a straight solid bond and a straight dashed bond represents the relative configuration of a stereocenter. For example represents that the hydroxyl group and the amino group are on the same side of the cyclopentane, and can be or

[0216] The stereoisomers of the compounds of the present invention can be prepared by chiral synthesis, chiral reagents or other conventional techniques. For example, an enantiomer of a certain compound of the present invention can be prepared by asymmetric catalysis or chiral auxiliary derivatization techniques. Or by chiral resolution techniques to obtain a compound with a single stereoconfiguration from a mixture. Or directly prepared using a chiral starting material. The separation of optically pure compounds in the present invention is usually accomplished using preparative chromatography, employing a chiral column to achieve the separation of chiral compounds.

[0217] The absolute stereoconfiguration of a compound can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction, or the absolute configuration of a compound can also be confirmed by the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis. Compounds marked as "absolute configuration not determined" in this article are usually obtained by chiral preparative SFC to resolve a racemic compound into a single isomer, and then characterized and tested.

[0218] For example, the following represents the cis compound 11. By chiral preparative resolution by SFC, a compound 12 with a single configuration and a compound 13 are obtained. Compounds 12 and 13 are enantiomers of each other, but the absolute stereoconfigurations corresponding to compounds 12 and 13 cannot be determined.

[0219] The term "optically pure" or "enantiomerically enriched" means that the content of this isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0220] Indicates that this carbon atom is a chiral carbon atom. This structure represents an optically pure compound with a (R) configuration or (S) configuration of the stereoconfiguration of the carbon atom and its mixture. The ratio of the mixture can be 1:1 or others. For example represents that this structure can be Or a mixture of both. When the ratio of the mixture is 1:1, the structure is a racemic compound

[0221] The present invention also includes isotopically labeled compounds, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, respectively 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds of the present invention containing the above isotopes and / or other isotopes of other atoms are all within the scope of the present invention.

[0222] The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering a bioactive agent to an animal, particularly a mammal, and includes, depending on the mode of administration and the nature of the dosage form, for example, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants. Pharmaceutically acceptable carriers are formulated within the purview of those of ordinary skill in the art based on a number of factors. These include, but are not limited to: the type and nature of the active agent being formulated, the subject to which the composition containing the agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media as well as a variety of solid and semi-solid dosage forms. In addition to the active agent, such carriers include many different components and additives, and such additional components included in a formulation for various reasons (such as stabilizing the active agent, binders, etc.) are well known to those of ordinary skill in the art.

[0223] The term "excipient" generally refers to a carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0224] The term "effective prophylactic or therapeutic amount" means an amount of a compound of the present invention or a pharmaceutically acceptable salt thereof that is sufficient to treat a disorder with a reasonable benefit / risk ratio applicable to any medical treatment and / or prophylaxis. However, it should be recognized that the total daily dosage of the compound or a pharmaceutically acceptable salt thereof and the composition of the present invention shown in Formula I must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level will depend on a variety of factors, including the disorder being treated and the severity thereof; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, the route of administration, and the excretion rate of the specific compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed; and similar factors well known in the medical arts.

[0225] The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of being chemically achievable. For example, the term "optionally substituted by one or more R d substituents" means that it may be substituted by one or more R d substituents or may not be substituted by R d substituents.

[0226] When any variable (e.g., R d ) appears more than once in the composition or structure of a compound, its definition in each case is independent. For example, represents that the cyclopentyl group is substituted by three R d substituents, and each R d has an independent option.

[0227] When the number of a linking group is 0 or defined as a bond, such as -O(CH2) n CH3, n = 0 indicates that the linking group is a single bond, i.e., -OCH3; for example, when R3 is -L1-(C 3-6 cycloalkyl), L1 is a bond or is independently selected from C 1-4 alkylene, and when L1 is a bond, it indicates that L1 does not exist, i.e., R3 is -(C 3-6 cycloalkyl).

[0228] When the bond of a substituent can cross-link to two atoms on a ring, such a substituent can be bonded to any atom on this ring. For example, the structural unit represents that the substituent R1 can be substituted at any position on the benzene ring.

[0229] When no atom through which a listed substituent is attached to a compound included in but not specifically mentioned in a chemical structure general formula is specified, such a substituent may be bonded through any of its atoms. For example, pyrazole as a substituent means that any one carbon atom on the pyrazole ring is attached to the group to be substituted; when or appears in the structure, it indicates that the atom is a bonding atom. For example, and both indicate that the N atom on the morpholine ring is a bonding atom.

[0230] Unless otherwise specified, "ring" means a saturated, partially saturated or unsaturated monocyclic and polycyclic ring, and "polycyclic ring" includes fused rings, spiro rings, fused rings or bridged rings. Representative "rings" include substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The term "hetero" means substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms, and the heteroatoms are generally selected from N, O, S, and the oxidized forms generally include NO, SO, S(O)2. The nitrogen atom may be substituted, i.e., NR (R is H or other substituents defined in the text); the number of atoms on the ring is usually defined as the ring member number. For example, "3-6 membered heterocycloalkyl" means a ring formed by 3-6 atoms arranged in a ring, and each ring optionally contains 1-3 heteroatoms, i.e., N, O, S, NO, SO, S(O)2 or NR, and each ring is optionally substituted by an R group, and R is a group defined in the text.

[0231] Unless otherwise specified, the term "aryl" means an unsaturated, usually aromatic hydrocarbon group, which may be a monocyclic or multiple rings fused together. Preferred is C 5-10 aryl, more preferably C 5-8 aryl, most preferably monocyclic C 5-6 aryl; examples of aryl include but are not limited to phenyl and naphthyl.

[0232] Unless otherwise specified, the term "heteroaryl" means a stable monocyclic or polycyclic aromatic hydrocarbon, which contains at least one heteroatom (N, O, S, NO, SO, S(O)2 or NR). Preferred is a 5-membered or 6-membered monocyclic heteroaryl. Examples of heteroaryl include but are not limited to pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl.

[0233] Unless otherwise specified, "cycloalkyl" means a saturated monocyclic or polycyclic hydrocarbon group. Cycloalkyl is preferably a 3-8 membered monocyclic alkyl group, more preferably a 3-6 membered monocyclic alkyl group. Examples of these monocyclic alkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0234] Unless otherwise specified, "heterocycloalkyl" refers to monocyclic heterocycloalkyl and polycyclic heterocycloalkyl containing a certain number of heteroatoms in the ring, and the heteroatoms are generally selected from N, O, S, NO, SO, S(O)2, and NR. Heterocycloalkyl is preferably a 3- to 8-membered monocyclic heterocycloalkyl, more preferably a 3- to 6-membered monocyclic heterocycloalkyl. Examples of these monocyclic heterocycloalkyls include, but are not limited to, oxiranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, 1,3-dioxolane, 1,4-dioxane, etc.

[0235] Unless otherwise specified, "heterocycloalkenyl" refers to a cyclic monoolefin containing a heteroatom, including 3- to 10-membered heterocyclic alkenyl, preferably 3- to 6-membered heterocycloalkenyl, and most preferably 5- to 6-membered heterocycloalkenyl. Examples of heterocycloalkenyl include, but are not limited to etc.

[0236] Unless otherwise specified, the term "alkyl" is used to denote a straight-chain or branched-chain saturated hydrocarbon group. Preferably C 1-6 alkyl, more preferably C 1-4 alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, n-hexyl, etc.

[0237] Unless otherwise specified, "spiroheterocyclic group" refers to a spiro group in which one or more carbon atoms in the spiro ring skeleton structure are replaced by heteroatoms selected from N, O, and S. The spiroheterocyclic group is preferably a 5- to 13-membered spiroheterocyclic group, a 6- to 12-membered spiroheterocyclic group, or a 7- to 11-membered spiroheterocyclic group. Examples of the spiroheterocyclic group include, but are not limited to, 2-oxa-7-azaspiro[5.3]nonan-7-yl, 2-oxa-7-azaspiro[4.4]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2-oxa-8-azaspiro[4.5]decane-8-yl, 1,4,9-triazaspiro[5.5]undecan-9-yl, 3-oxa-9-azaspiro[5.5]undecan-9-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,7-diazaspiro[5.3]nonan-7-yl, 2,7-dioxaspiro[5.3]nonyl, 3,9-diazaspiro[5.5]undecan-3-yl, 1-oxa-4,9-diazaspiro[5.5]undecan-9-yl, 1-oxa-4,8-diazaspiro[5.4]decane-8-yl, 3-azaspiro[5.5]undecan-3-yl, 7-azaspiro[3.5]decane-7-yl, 1-oxa-4,9-diazaspiro[5.5]undecan-4-yl, 6-oxa-2,9-diazaspiro[4.5]decane-9-yl, 9-oxa-2,6-diazaspiro[4.5]decane-6-yl, 3-azaspiro[5.5]undecan-3-yl, 4-oxa-1,9-diazaspiro[5.5]undecan-9-yl.

[0238] Unless otherwise specified, the term "fused ring group" refers to a polycyclic hydrocarbon group sharing two adjacent carbon atoms, and the fused ring group is preferably a C 8-10 bicyclo fused ring group, more preferably a three-membered ring fused to a five-membered ring, a five-membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, etc. Examples of the fused ring group include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.1.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[4.3.0]nonyl, bicyclo[4.4.0]decyl, etc.

[0239] Unless otherwise specified, the term "fused heterocyclic group" refers to a fused ring in which the skeletal carbon atoms are substituted by 1 to 3 heteroatoms selected from N, O, and S. Examples of the fused heterocyclic group include, but are not limited to, 1,4-diazabicyclo[4.4.0]dec-4-yl, 1,4-diazabicyclo[4.3.0]non-4-yl, 8-oxa-1,4-diazabicyclo[4.4.0]dec-4-yl, 1,4-diazabicyclo[4.4.0]dec-4-yl, 4,7-diazabicyclo[4.3.0]non-4-yl, 3,7-diazabicyclo[4.3.0]non-3-yl, 3,7-diazabicyclo[3.3.0]oct-3-yl, 3,7-diazabicyclo[4.4.0]dec-3-yl, 3,6-diazabicyclo[4.3.0]non-3-yl, 3,6-diazabicyclo[4.4.0]dec-3-yl, 3,6,9-triazabicyclo[4.4.0]dec-3-yl, 3,7-diazabicyclo[4.2.0]oct-3-yl, 3,7-diazabicyclo[3.3.0]oct-3-yl.

[0240] Unless otherwise specified, the term "alkylene" represents a divalent hydrocarbon group having a specified number of carbon atoms, including straight-chain alkylene and branched-chain alkylene, preferably C 1-6 alkylene, more preferably C 1-4 alkylene. Examples of the alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -CH2CH2CH(CH3)CH2-, and -CH2CH2CH2CH(CH3)-, etc.

[0241] Unless otherwise specified, the term "alkoxy" refers to an alkyl group connected by an oxygen bridge, that is, a group obtained by substituting a hydrogen atom in a hydroxyl group with an alkyl group. Preferably C 1-6 alkoxy, more preferably C 1-4 alkoxy. Examples of the alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy.

[0242] Unless otherwise specified, the term "halogen" represents a fluorine, chlorine, bromine, or iodine atom.

[0243] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted by halogen atoms. Preferably C 1-6 haloalkyl, more preferably C 1-4Halogenated alkyl. Examples of halogenated alkyl include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc.

[0244] Unless otherwise specified, the term "C 1-4 alkyl-OH" refers to a structure in which a hydrogen atom in C 1-4 alkyl is optionally replaced by a hydroxyl group. Examples of "C 1-4 alkyl-OH" include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH2CH(OH)CH3, -CH2CH2CH2CH2OH, -CH2CH(OH)CH2CH3, -CH2CH2CH(OH)CH3, etc.

[0245] Unless otherwise specified, in the structure represents that the bond can be a single bond or a double bond. For example, the structural unit can be or can also be

[0246] Specifically noted that all combinations of substituents and / or their variants in this article are only allowed if such combinations result in stable compounds.

[0247] In the embodiments of the present invention, the naming of the title compound is converted from the compound structure by means of Chemdraw. If there is an inconsistency between the compound name and the compound structure, it can be determined by comprehensively considering relevant information and reaction routes; if it cannot be confirmed by other means, the given compound structural formula shall prevail.

[0248] In the present invention, the preparation methods of some compounds refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should be aware that when using or referring to the cited preparation methods, the feeding ratios of reactants, reaction solvents, reaction temperatures, etc. can be appropriately adjusted according to the differences in reactants.

[0249] The compounds of the present invention can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and the equivalent replacement methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0250] The abbreviations used in the embodiments of the present invention and their corresponding chemical names are as follows:

[0251]

[0252] Detailed implementation manners

[0253] The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS), or ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is carried out using a Bruker Neo 400M or Bruker Ascend 400 nuclear magnetic instrument, and the solvents for measurement are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and heavy water (D2O), with tetramethylsilane (TMS) as the internal standard.

[0254] The LC-MS measurement is carried out using an Agilent 1260-6125B single quadrupole mass spectrometer, with a Welch Biomate column (C18, 2.7um, 4.6*50mm) or a waters H-Class SQD2, and a Welch Ultimate column (XB-C18, 1.8um, 2.1*50mm) mass spectrometer (the ion source is electrospray ionization).

[0255] The UPLC-MS measurement is carried out using a Waters UPLC H-class SQD mass spectrometer (the ion source is electrospray ionization).

[0256] The HPLC measurement uses a Waters e2695-2998 or Waters ARC and an Agilent 1260 or Agilent Poroshell HPH high-performance liquid chromatography.

[0257] The preparative HPLC uses a Waters 2555-2489 (10μm, ODS 250cm×5cm) or GILSON Trilution LC, with a Welch XB-C18 column (5um, 21.2*150mm).

[0258] Chiral HPLC determination was performed using Waters Acquity UPC2; the columns used were Daicel Chiralpak AD-H (5 μm, 4.6 * 250 mm), Daicel Chiralpak OD-H (5 μm, 4.6 * 250 mm), Daicel Chiralpak IG-3 (3 μm, 4.6 * 150 mm), Chiral Technologies Europe AD-3 (3 μm, 3.0 * 150 mm), and Trefoil TM Technology Trefoil TM AMY1 (2.5 μm, 3.0 * 150 mm).

[0259] Supercritical fluid chromatography (SFC) was performed using Waters SFC 80Q; the columns used were Daicel Chiralcel OD / OJ / OZ (20 x 250 mm, 10 μm) or Daicel Chiralpak IC / IG / IH / AD / AS (20 x 250 mm, 10 μm).

[0260] TLC silica gel plates used were GF254 silica gel plates from Yantai Jiangyou Silica Gel Development Co., Ltd. or GF254 silica gel plates from Rushan Shangbang New Materials Co., Ltd. The TLC specifications used were 0.15 mm - 0.20 mm, the preparative type was 20 x 20 cm, and for column chromatography, silica gel with 200 - 300 mesh from Chenghua Chemical was generally used as the carrier.

[0261] The starting materials in the examples of the present invention are known and commercially available, or can be synthesized by methods known in the art or according to such methods.

[0262] Unless otherwise specified, all reactions of the present invention were carried out under continuous magnetic stirring, in an atmosphere of dry nitrogen or argon, with the solvent being a dry solvent, and the reaction temperature unit being degrees Celsius.

[0263] Intermediate 1A

[0264] 4-chloro-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0265]

[0266] Step 1: At room temperature, dissolve 2,4-dichloro-5-cyanopyrimidine (5.0 g, 28.4 mmol) in a 1 / 1 mixed solvent of tert-butanol and 1,2-dichloroethane (70 mL). Subsequently, under cooling in an ice-water bath and under nitrogen protection, slowly dropwise add a tetrahydrofuran solution of zinc chloride (1 mol / L, 33.6 mL, 33.6 mmol) to the above solution, and stir the reaction solution in the ice bath for 1 hour. Under cooling in an ice bath, successively and slowly dropwise add a 1 / 1 mixed solution of tert-butyl 1-carboxylate-4-aminopiperidine (5.9 g, 28.4 mmol) in tert-butanol and 1,2-dichloroethane and a 1 / 1 mixed solution of triethylamine (3.6 mL, 33.6 mmol) in tert-butanol and 1,2-dichloroethane to the above reaction solution. Raise the reaction solution to room temperature and stir for 2 hours. Quench the reaction solution by adding water (50 mL), concentrate under reduced pressure, extract the mixture with dichloromethane (40 mL × 3 times), combine the organic phases, wash the organic phase first with saturated brine (30 mL), then dry with anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 3.8 g of tert-butyl 4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate (1A-2).

[0267] MS(ESI) M / Z: 338.1 [M+H] + 。

[0268] 1 1H NMR (400 MHz, DMSO-d6) δ 8.84 - 8.77 (m, 1H), 8.76 (s, 0.5H), 8.69 (s, 0.4H), 4.09 - 3.83 (m, 3H), 2.87 (br.s., 2H), 1.80 (d, J = 10.9 Hz, 2H), 1.40 (s, 9H), 1.38 - 1.29 (m, 2H).

[0269] Step 2: At room temperature, dissolve compound 1A-2 (1 g, 2.9 mmol) in 1,4-dioxane (3 mL). Subsequently, add a hydrogen chloride-dioxane solution (2 mol / L, 3 mL, 6 mmol) thereto. Stir the reaction solution at room temperature for 2 hours. Concentrate under reduced pressure to obtain 700 mg of 4-chloro-2-(piperidin-4-ylamino)pyrimidine-5-carbonitrile (1A-3).

[0270] MS(ESI) M / Z: 238.1 [M+H] + 。

[0271] Step 3: At room temperature, dissolve compound 1A-3 (700 mg, 2.9 mmol) in dichloromethane (10 mL). Subsequently, add N,N-diisopropylethylamine (1.08 g, 8.4 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (637.0 mg, 3.5 mmol) to the above reaction solution in sequence. Stir the reaction solution at room temperature for 1.5 h. Concentrate the reaction solution under reduced pressure, and quench the resulting residue with water (30 mL). Extract the mixture with dichloromethane (30 mL × 3 times), combine the organic phases, wash the organic phases successively with saturated brine (10 mL × 3 times), then dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. Purify the resulting residue by silica gel column chromatography to obtain 740.0 mg of 4-chloro-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (Intermediate 1A).

[0272] MS(ESI) M / Z: 382.0 [M+H] + 。

[0273] 1 1H NMR (400 MHz, DMSO-d6) δ 8.94 - 8.80 (m, 1H), 8.73 (s, 0.5H), 8.69 (s, 0.4H), 8.32 (s, 1H), 7.77 (s, 1H), 3.91 (s, 3H), 3.87 - 3.69 (m, 1H), 3.53 - 3.40 (m, 2H), 2.48 - 2.38 (m, 2H), 2.04 - 1.82 (m, 2H), 1.69 - 1.52 (m, 2H).

[0274] Intermediate 1B

[0275] 4-chloro-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0276]

[0277] Step 1: At room temperature, dissolve 2,4-dichloro-5-(trifluoromethyl)pyrimidine (500 mg, 2.3 mmol) in acetonitrile (10 mL). Subsequently, under cooling in an ice-water bath, slowly add triethylamine (349.0 mg, 3.5 mmol) and 4-amino-1-(tert-butoxycarbonyl)piperidine (552.0 mg, 2.8 mmol) to the above solution. The reaction mixture is stirred for 1 hour under cooling in an ice-water bath. Quench the reaction mixture by adding water (30 mL), concentrate the mixture under reduced pressure, extract with ethyl acetate (8 mL × 3 times), combine the organic phases, wash the organic phase first with saturated brine (30 mL), then dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 340 mg of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (1B-2).

[0278] MS(ESI) M / Z: 325.0 [M + H - t-Bu] + 。

[0279] 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 0.6H), 8.61 - 8.49 (m, 1.4H), 4.05 - 3.82 (m, 3H), 2.87 (br.s., 2H), 1.81 (d, J = 11.4 Hz, 2H), 1.50 - 1.21 (m, 11H).

[0280] Step 2: At room temperature, dissolve compound 1B-2 (130 mg, 0.3 mmol) in 1,4-dioxane (1 mL). Subsequently, add hydrogen chloride - dioxane solution (4 mol / L, 2 mL, 8 mmol) to the above solution. The reaction mixture is stirred for 2 hours at room temperature. Concentrate the reaction mixture under reduced pressure to obtain 95.0 mg of 4-chloro-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (1B-3).

[0281] MS(ESI) M / Z: 281.0 [M + H] + 。

[0282] Step 3: At room temperature, dissolve compound 1B-3 (95.0 mg, 0.3 mmol) in dichloromethane (5 mL). Subsequently, under cooling in an ice-water bath, add N,N-diisopropylethylamine (132.0 mg, 1.0 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (72.0 mg, 0.4 mmol) to the above reaction solution in sequence. The reaction solution is stirred at room temperature for 15 hours. Add water (30 mL) to quench the reaction. The mixture is extracted with dichloromethane (10 mL × 3 times), and the organic phases are combined. The organic phase is first washed with saturated brine (10 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 120.0 mg of 4-chloro-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 1B).

[0283] MS(ESI) M / Z: 425.0 [M+H] + 。

[0284] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.52 (m, 2H), 8.32 (s, 1H), 7.77 (s, 1H), 3.91 (s, 3H), 3.86 - 3.66 (m, 1H), 3.51 - 3.39 (m, 2H), 2.48 - 2.32 (m, 2H), 1.97 - 1.86 (m, 2H), 1.66 - 1.50 (m, 2H).

[0285] Example 1:

[0286] 4-(Cyclopentylamino)-2-(((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0287]

[0288] Step 1: Dissolve compound 1-1 (9.0 g, 40.7 mmol) and diisopropylethylamine (5.3 g, 40.7 mmol) in 90 mL of dichloromethane. At 0 °C, slowly add cyclopentylamine (3.64 g, 42.8 mmol) dropwise to the above solution. After the addition is complete, the reaction solution is stirred at room temperature for 1 hour. Add saturated aqueous sodium bicarbonate solution (40 mL) to quench the reaction. The mixture is extracted with dichloromethane (100 mL × 2 times), and the organic phases are combined. The organic phase is first washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 12.3 g of 4-(cyclopentylamino)-2-(((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (1-2). This product is used directly in the next step without purification.

[0289] MS(ESI) M / Z: 270.0 [M+H] + 。

[0290] Step 2: At room temperature, dissolve compound 1-2 (12.3 g, 45.6 mmol) in tetrahydrofuran / water (2 / 1, 150 mL). Subsequently, add lithium hydroxide monohydrate (3.83 g, 91.3 mmol) to the above solution in batches. After the reaction mixture is stirred at room temperature for 3 hours, remove tetrahydrofuran by concentration under reduced pressure, and then neutralize the solution to pH 4 with 3 mol / L hydrochloric acid aqueous solution. The mixture is extracted with dichloromethane (100 mL × 2 times), the organic phases are combined, the organic phase is first washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 7.5 g of 2-chloro-4-(cyclopentylamino)pyrimidine-5-carboxylic acid (1-3).

[0291] MS(ESI) M / Z: 240.1 [M-H] - 。

[0292] Step 3: At room temperature, dissolve N,N-dimethylformamide (10 drops) and 1-3 (7.5 g, 31.1 mmol) in dichloromethane (100 mL). Cool the reaction mixture to 0 °C, and then slowly add oxalyl chloride (5.75 mL, 68.5 mmol) to the above reaction mixture within 20 minutes. Raise the reaction mixture to room temperature and stir for 2 hours. At 0 °C, add the above reaction mixture dropwise to ammonia water (100 mL) within 30 minutes. Filter and dry to obtain 6.0 g of 2-chloro-4-(cyclopentylamino)pyrimidine-5-carboxamide (1-4).

[0293] MS(ESI) M / Z: 241.0 [M+H] + 。

[0294] Step 4: Dissolve 1-4 (400 mg, 1.8 mmol), 1-(methylsulfonyl)piperidin-4-amine (581 mg, 2.7 mmol), and cesium carbonate (1.77 g, 5.4 mmol) in 1,4-dioxane (10 mL). Heat this reaction mixture to 120 °C and react for 3 hours, then cool to room temperature. Concentrate under reduced pressure, and the residue is extracted with dichloromethane. The organic phases are combined, the organic phase is first washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 405 mg of 4-(cyclopentylamino)-2-(((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carboxamide (1-5).

[0295] MS(ESI) M / Z: 383.4 [M+H] + 。

[0296] Step 5: Dissolve 1-5 (200 mg, 0.5 mmol) and triethylamine (636 mg, 6.3 mmol) in tetrahydrofuran (10 mL). At -65 °C, add trifluoroacetic anhydride (1.1 g, 5.2 mmol) to the reaction solution. The reaction solution was stirred at -65 °C for an additional 30 minutes. Add saturated aqueous sodium bicarbonate solution to the reaction solution, and the mixture was extracted with dichloromethane (100 mL × 2 times). The combined organic phases were washed first with saturated brine and then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 100 mg of N-(5-cyano-2-(((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-N-cyclopentyl-2,2,2-trifluoroacetamide (1-6).

[0297] MS(ESI) M / Z: 461.2 [M+H] + 。

[0298] Step 6: At room temperature, dissolve 1-6 (100 mg, 0.22 mmol) in tetrahydrofuran (5 mL), and then add ammonia water (5 mL) to this solution. After the reaction solution reacted at room temperature for 1 hour, add water to quench the reaction. The mixture was extracted with dichloromethane (100 mL × 2 times). The combined organic phases were washed first with saturated brine and then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 40 mg of 4-(cyclopentylamino)-2-(((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (Compound 1).

[0299] MS(ESI) M / Z: 365.4 [M+H] + 。

[0300] 1 HNMR(400 MHz, DMSO-d6 + TFA) δ 9.06 - 8.82 (m, 2H), 8.57 (br.s., 1H), 4.52 - 4.31 (m, 1H), 4.02 - 3.67 (m, 1H), 3.64 - 3.45 (m, 2H), 3.01 - 2.65 (m, 5H), 2.09 - 1.81 (m, 4H), 1.78 - 1.41 (m, 8H).

[0301] Example 2:

[0302] 4-(Cyclopentylamino)-6-((1-(methylsulfonyl)piperidin-4-yl)amino)nicotinamide

[0303]

[0304] Step 1: At room temperature, cyclopentylamine (830 mg, 9.8 mmol) was dissolved in tetrahydrofuran (10 mL). At 0 °C, sodium hydride (60% dispersed in mineral oil, 530 mg, 13.3 mmol) was slowly added portionwise to the above solution, and the reaction mixture was stirred at 0 °C for an additional 20 minutes. Subsequently, a solution of 2-1 (1.54 g, 8.9 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise to the above reaction mixture at this temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution. The mixture was extracted with dichloromethane (40 mL × 2 times), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 810 mg of a mixture of 2-2A and 2-2B.

[0305] Step 2: A mixture of 2-2A and 2-2B (200 mg, 0.9 mmol), 1-(methylsulfonyl)piperidin-4-amine (400 mg, 2.25 mmol), and cesium carbonate (734 mg, 2.25 mmol) was dissolved in 1,4-dioxane (10 mL). The reaction system was heated to 120 °C and stirred for 5 hours. The reaction mixture was cooled to room temperature, and most of the solvent was removed by concentration under reduced pressure. The residue was extracted with dichloromethane (40 mL × 2 times), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give 25 mg of 4-(cyclopentylamino)-6-((1-(methylsulfonyl)piperidin-4-yl)amino)nicotinamide (Compound 2).

[0306] MS(ESI) M / Z: 364.3 [M+H] + 。

[0307] 1 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.45 (s, 1H), 4.69 (d, J = 5.2 Hz, 1H), 3.92 - 3.82 (m, 1H), 3.82 - 3.69 (m, 3H), 3.01 - 2.90 (m, 2H), 2.81 (s, 3H), 2.19 - 2.10 (m, 2H), 2.10 - 1.98 (m, 2H), 1.84 - 1.72 (m, 2H), 1.71 - 1.51 (m, 7H).

[0308] Example 3:

[0309] 4-(Cyclopentyloxy)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0310]

[0311] Step 1: At room temperature, cyclopentanolamine (270 mg, 3.16 mmol) was dissolved in tetrahydrofuran (10 mL). The reaction solution was cooled to 0 °C, and sodium hydride (60% dispersed in mineral oil, 130 mg, 3.16 mmol) was slowly added portionwise to the above solution. The reaction solution was stirred at room temperature for 15 minutes. Subsequently, at 0 °C, 1A-1 (0.5 g, 2.87 mmol) was slowly added dropwise to the above reaction solution. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour. The reaction was quenched by adding saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was first washed with saturated brine and then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 420 mg of 2-chloro-4-(cyclopentyloxy)pyrimidine-5-carbonitrile (3-2). This product was used directly in the next step without purification.

[0312] Step 2: 3-2 (400 mg, 1.79 mmol), 1-(methylsulfonyl)piperidin-4-amine (479 mg, 2.69 mmol), and cesium carbonate (1.24 g, 4.48 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction system was heated to 120 °C and stirred for 3 hours. The reaction solution was cooled to room temperature, and water (30 mL) and ethyl acetate (30 mL) were added. The mixture was filtered, the filter cake was washed with water, dried in vacuo, and purified by preparative high performance liquid chromatography to obtain 30 mg of 4-(cyclopentyloxy)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (Compound 3).

[0313] MS(ESI) M / Z: 366.2 [M+H] + 。

[0314] 1 1H NMR (400 MHz, CDCl3 + TFA) δ 8.55 (s, 1H), 5.66 - 5.56 (m, 1H), 4.21 - 4.08 (m, 1H), 3.76 - 3.59 (m, 2H), 3.22 - 3.07 (m, 2H), 2.96 (s, 3H), 2.13 - 1.87 (m, 10H), 1.77 - 1.73 (m, 2H).

[0315] Example 4:

[0316] 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-4-phenylpyrimidine-5-carbonitrile

[0317]

[0318] Step 1: Dissolve compound 1-1 (1.0 g, 4.52 mmol), phenylboronic acid (0.55 g, 4.52 mmol), sodium carbonate (1.45 g, 13.57 mmol) and palladium dichloride bis(triphenylphosphine) (158 mg, 0.22 mmol) in 1,4-dioxane / water (10 / 1, 10 mL). The reaction system was purged with nitrogen three times. Heat the reaction solution to 95 °C and stir for 12 h. After the reaction, cool the reaction solution to room temperature, add water (25 mL) to the reaction solution. The mixture was extracted with ethyl acetate (20 mL × 2 times), the organic phases were combined, the organic phase was first washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.65 g of ethyl 2-chloro-4-phenylpyrimidine-5-carboxylate (4-2).

[0319] MS(ESI) M / Z: 263.2 [M+H] + 。

[0320] Step 2: Dissolve 4-2 (650 mg, 2.48 mmol), 1-(methylsulfonyl)piperidin-4-amine (880 mg, 4.95 mmol), and cesium carbonate (2.44 g, 7.45 mmol) in 1,4-dioxane (10 mL). Heat the reaction system to 120 °C and stir for 3 h. Cool the reaction solution to room temperature, concentrate under reduced pressure to remove most of the solvent, the residue was extracted with dichloromethane, the organic phases were combined, the organic phase was first washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 600 mg of ethyl 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-4-phenylpyrimidine-5-carboxylate (4-3).

[0321] MS(ESI) M / Z: 405.3 [M+H] + 。

[0322] Step 3: At room temperature, dissolve compound 4-3 (600 mg, 2.29 mmol) in tetrahydrofuran / water (2.5 / 1, 7.5 mL). Subsequently, add lithium hydroxide monohydrate (290 mg, 2.85 mmol) to the above solution. After stirring the reaction solution at room temperature for 3 h, concentrate under reduced pressure to remove tetrahydrofuran, and then neutralize the solution to pH 4 with 3 mol / L hydrochloric acid aqueous solution. The mixture was extracted with dichloromethane (100 mL × 2 times), the organic phases were combined, the organic phase was first washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give 450 mg of 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-4-phenylpyrimidine-5-carboxylic acid (4-4).

[0323] MS(ESI) M / Z: 377.2 [M+H]+ .

[0324] Step 4: At room temperature, dissolve N,N-dimethylformamide (1 drop) and 4-4 (200 mg, 0.53 mmol) in dichloromethane (5 mL). Cool the reaction solution to 0 °C, and then, within 5 minutes, add oxalyl chloride (203 mg, 1.6 mmol) dropwise to the above reaction solution. Raise the reaction solution to room temperature and stir for 0.5 h. At 0 °C, add the above reaction solution dropwise to ammonia water (10 mL) within 30 minutes. Filter and dry to obtain 155 mg of 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-4-phenylpyrimidine-5-carboxamide (4-5).

[0325] MS(ESI) M / Z: 376.2 [M+H] + .

[0326] Step 5: At room temperature, dissolve 4-5 (100 mg, 0.27 mmol) and triethylamine (300 mg, 3.24 mmol) in tetrahydrofuran (5 mL). Cool the reaction system to -65 °C, and slowly add trifluoroacetic anhydride (270 mg, 1.3 mmol) dropwise to this solution. Stir the reaction solution at -65 °C for 30 minutes. Quench the reaction by adding saturated aqueous sodium bicarbonate solution to the reaction solution. Extract the mixture with dichloromethane (100 mL × 2 times), combine the organic phases, wash the organic phase with saturated brine first, then dry it with anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 50 mg of 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-4-phenylpyrimidine-5-carbonitrile (Compound 4).

[0327] MS(ESI) M / Z: 358.3 [M+H] + .

[0328] 1 HNMR(400 MHz, CDCl3) δ 8.63 (s, 0.6H), 8.56 (s, 0.5H), 8.01 (d, J = 6.7 Hz, 1H), 7.96 (d, J = 7.0 Hz, 1H), 7.64 - 7.48 (m, 3H), 5.87 - 5.67 (m, 1H), 4.22 - 4.05 (m, 1H), 3.80 (br.s., 2H), 2.93 (t, J = 11.3 Hz, 2H), 2.83 (s, 3H), 2.26 - 2.14 (m, 2H), 1.86 - 1.54 (m, 2H).

[0329] Example 5:

[0330] N 4 -Cyclopentyl-N 2-(1-(Methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0331]

[0332] Step 1: At 0 °C, 1B-1 (100 mg, 0.92 mmol) and N,N-diisopropylethylamine (550 mg, 1.38 mmol) were dissolved in dichloromethane (5 mL). At this temperature, cyclopentylamine (78.2 mg, 0.92 mmol) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (100 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine and then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 155 mg of a mixture of 5-2A and 5-2B. This mixture was used directly in the next step without purification.

[0333] Step 2: 5-2A and 5-2B (150 mg, 0.57 mmol), 1-(methylsulfonyl)piperidin-4-amine (151 mg, 0.85 mmol), and cesium carbonate (372 mg, 1.14 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction solution was reacted at 120 °C for 5 hours and then cooled to room temperature. Most of the solvent was removed by concentration under reduced pressure, and the residue was extracted with dichloromethane. The organic phases were combined. The organic phase was first washed with saturated brine and then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography to obtain 22 mg of N 4 -Cyclopentyl-N 2 -(1-(Methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 5).

[0334] MS(ESI) M / Z: 408.2 [M+H] + 。

[0335] 1 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 0.4H), 7.99 (s, 0.6H), 7.39 (d, J = 6.0 Hz, 0.6H), 7.21 (d, J = 6.8 Hz, 0.6H), 6.26 - 6.10 (m, 1H), 4.55 - 4.46 (m, 0.4H), 4.43 - 4.29 (m, 0.6H), 3.92 - 3.73 (m, 1H), 3.62 - 3.46 (m, 2H), 2.67 - 2.72 (m, 5H), 2.03 - 1.78 (m, 4H), 1.76 - 1.39 (m, 8H).

[0336] Example 6:

[0337] 4-(Cyclopentyloxy)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0338]

[0339] At room temperature, cyclopentanol (33.7 mg, 0.4 mmol) was dissolved in N,N-dimethylformamide (2 mL). Subsequently, sodium hydride (9.7 mg, 0.4 mmol) was added to the above reaction solution under an ice bath and nitrogen protection. After the above reaction solution was stirred for 15 minutes under an ice bath, compound 1A (100.0 mg, 0.3 mmol) was added. The reaction solution was heated to 100 °C and stirred for 1 hour. The reaction was quenched by adding water (10 mL). The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (10 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 9.2 mg of 4-(cyclopentyloxy)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (Compound 6).

[0340] MS(ESI) M / Z: 432.2 [M+H] + 。

[0341] 1 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 0.4H), 8.43 (s, 0.6H), 8.33 (s, 0.5H), 8.31 (s, 0.5H), 8.27 (d, J = 7.3 Hz, 0.6H), 8.11 (d, J = 7.8 Hz, 0.4H), 7.79 (s, 0.5H), 7.77 (s, 0.4H), 5.48 - 5.38 (m, 1H), 3.91 (s, 3H), 3.78 (br.s, 1H), 3.53 - 3.40 (m, 2H), 2.44 - 2.30 (m, 2H), 2.02 - 1.84 (m, 4H), 1.78 - 1.51 (m, 8H).

[0342] Example 7:

[0343] (S)-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine

[0344]

[0345] Under room temperature and nitrogen protection, (S)-3-hydroxytetrahydrofuran (16.0 g, 0.2 mmol) was dissolved in N,N-dimethylformamide (1 mL). Subsequently, sodium hydride (7.2 mg, 0.2 mmol, 60% dispersed in mineral oil) was added to the above solution under cooling with an ice-water bath. After the reaction solution was stirred at room temperature for 10 minutes, compound 1B (50.0 mg, 0.1 mmol) was slowly added to the reaction solution. The reaction system was heated to 100 °C and stirred for 1 hour. Water (20 mL) was added to quench the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3 times). The organic phases were combined, and the organic phase was first washed with saturated brine (20 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 28.0 mg of (S)-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 7).

[0346] MS(ESI) M / Z: 477.2 [M+H] + 。

[0347] 1 H NMR (400 MHz, DMSO-d6) δ 8.41 - 8.27 (m, 2H), 8.03 (d, J = 7.3 Hz, 0.6H), 7.88 (d, J = 7.2 Hz, 0.4H), 7.78 (d, J = 6.4 Hz, 1H), 5.65 - 5.50 (m, 1H), 4.03 - 3.85 (m, 4H), 3.85 - 3.66 (m, 4H), 3.55 - 3.42 (m, 2H), 2.48 - 2.30 (m, 2H), 2.29 - 2.14 (m, 1H), 2.07 - 1.85 (m, 3H), 1.70 - 1.50 (m, 2H).

[0348] Example 8:

[0349] (S)-2-((1-((4-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)piperidin-4-yl)amino)-4-((tetrahydrofuran-3-yl)amino)pyrimidine-5-carbonitrile

[0350]

[0351] Step 1: At room temperature, dissolve compound 1A-3 (556.0 mg, 2.4 mmol) in dichloromethane (3 mL). Subsequently, add N,N-diisopropylethylamine (940.0 mg, 7.3 mmol) to the reaction solution. At 0 °C, add p-bromobenzenesulfonyl chloride (743.0 mg, 3.3 mmol) dropwise to the above solution, and stir the reaction solution at room temperature overnight. Quench the reaction solution by adding water (20 mL). Extract the mixture with ethyl acetate (30 mL × 3 times), combine the organic phases, wash the organic phase first with saturated brine (30 mL), then dry it over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 830.0 mg of 2-((1-((4-bromophenyl)sulfonyl)piperidin-4-yl)amino)-4-chloropyrimidine-5-carbonitrile (8-2).

[0352] MS(ESI) M / Z: 456.0 [M+H] + 。

[0353] Step 2: At room temperature, dissolve compound 8-2 (100.0 mg, 0.2 mmol) in N,N-dimethylacetamide (1 mL). Subsequently, add N,N-diisopropylethylamine (85.0 mg, 0.7 mmol) and (S)-3-aminotetrahydrofuran (29.0 mg, 0.3 mmol) to the above reaction solution in sequence. Heat the reaction solution to 80 °C and stir for 4 hours. Quench the reaction solution by adding water (20 mL). Extract the mixture with ethyl acetate (30 mL × 3 times), combine the organic phases, wash the organic phase first with water (30 mL × 3 times) and then with saturated brine (30 mL), then dry it over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by preparative high performance liquid chromatography to obtain 95.0 mg of (S)-2-((1-((4-bromophenyl)sulfonyl)piperidin-4-yl)amino)-4-((tetrahydrofuran-3-yl)amino)pyrimidine-5-carbonitrile (8-3).

[0354] MS(ESI) M / Z: 507.0 [M+H] + 。

[0355] Step 3: Under room temperature and nitrogen protection, dissolve compound 8-3 (95.0 mg, 0.2 mmol) in 1,4-dioxane / water (5 / 1 mL). Subsequently, successively add pinacol 1-methylpyrazole-4-boronate (50.0 mg, 0.2 mmol), PdCl2(dppf) (15.0 mg, 0.02 mmol) and anhydrous sodium carbonate (42 mg, 0.4 mmol) to the above reaction solution. Heat the reaction solution to 100 °C and stir for 1 hour. Cool the reaction solution to room temperature and concentrate it under reduced pressure. The obtained residue is purified by preparative high performance liquid chromatography to obtain (35.6 mg S)-2-((1-((4-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)piperidin-4-yl)amino)-4-((tetrahydrofuran-3-yl)amino)pyrimidine-5-carbonitrile (compound 8). ee value: 98.4%.

[0356] MS(ESI) M / Z: 509.2 [M+H] + 。

[0357] 1 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.17 (s, 0.3H), 8.13 (s, 0.7H), 8.00 (s, 1H), 7.82 (s, 0.7H), 7.80 (s, 1.3H), 7.73 - 7.64 (m, 2.7H), 7.50 (d, J = 5.9 Hz, 1H), 7.38 (d, J = 6.8 Hz, 0.4H), 4.59 - 4.37 (m, 1H), 3.89 (s, 3H), 3.84 - 3.61 (m, 5H), 3.59 - 3.45 (m, 3H), 2.15 - 1.80 (m, 5H), 1.63 - 1.46 (m, 2H).

[0358] Example 9:

[0359] 4-(Cyclopentylmethylene)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0360]

[0361] Step 1: At room temperature, dissolve 2,2,6,6 - tetramethylpiperidine (850.0 mg, 6.0 mmol) in tetrahydrofuran (10 mL). Cool to - 30 °C, and then slowly add n - butyllithium (3.76 mL, 6.0 mmol) dropwise to the above - mentioned solution at - 30 °C under nitrogen protection. Stir the reaction solution at - 30 °C for 30 minutes. After 30 minutes, cool the above - mentioned solution to - 78 °C, and slowly add dropwise a mixed solution of bis[(pinacolato)boryl]methane (1350.0 mg, 5.0 mmol) and tetrahydrofuran (5 mL) and a mixed solution of cyclopentanone (422 mg, 5.0 mmol) and tetrahydrofuran (5 mL) in sequence. Stir the solution at room temperature for 18 hours. Quench the reaction solution by adding aqueous ammonium chloride solution (10 mL), concentrate under reduced pressure, extract the mixture with ethyl acetate (40 mL × 3 times), combine the organic phases, wash the organic phase with saturated brine (30 mL) first, then dry with anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 510 mg of 2 - (cyclopentylidenemethyl)-4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolane (1A).

[0362] 1 H NMR(400MHz, CDCl3)δ5.27(t, J = 2.0Hz, 1H), 2.52(t, J = 7.2Hz, 2H), 2.36(t, J = 7.1Hz, 2H), 1.77 - 1.59(m, 4H), 1.25(s, 12H).

[0363] Step 2: At room temperature and under nitrogen protection, dissolve compound 1A (100.0 mg, 0.3 mmol) in 1,4 - dioxane / water (5 / 1 mL). Subsequently, add 2 - (cyclopentylidenemethyl)-4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolane (62.0 mg, 0.3 mmol), PdCl2(dppf) (20.0 mg, 0.03 mmol) and anhydrous sodium carbonate (56 mg, 0.5 mmol) to the above - mentioned reaction solution in sequence. Heat the reaction solution to 100 °C and stir for 1 hour. Cool the reaction solution to room temperature and concentrate under reduced pressure. The obtained residue is purified by preparative high - performance liquid chromatography to obtain 44 mg of 4 - (cyclopentylmethylene)-2 - ((1 - ((1 - methyl - 1H - pyrazol - 4 - yl)sulfonyl)piperidin - 4 - yl)amino)pyrimidine - 5 - carbonitrile (Compound 9).

[0364] MS(ESI)M / Z: 428.2[M + H] + 。

[0365] 11H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 0.3H), 8.55 (s, 0.7H), 8.35 (s, 0.7H), 8.32 (s, 0.3H), 8.16 (d, J = 7.5 Hz, 0.7H), 7.95 (d, J = 7.5 Hz, 0.4H), 7.79 (s, 0.6H), 7.77 (s, 0.4H), 6.47 (s, 0.7H), 6.42 (s, 0.4H), 3.91 (s, 3H), 3.83 - 3.70 (m, 1H), 3.56 - 3.45 (m, 2H), 2.96 - 2.76 (m, 2H), 2.59 - 2.53 (m, 2H), 2.44 - 2.35 (m, 2H), 2.01 - 1.86 (m, 2H), 1.77 - 1.52 (m, 6H).

[0366] Example 10:

[0367] 4-(Cyclopentylmethyl)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0368]

[0369] At room temperature, 4-(cyclopentylmethylene)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (33 mg, 0.07 mmol) was dissolved in methanol (2 mL). Subsequently, 10% palladium-carbon (10 mg) was added to the above solution. After the reaction system was purged with hydrogen three times, the reaction solution was stirred under a hydrogen atmosphere for 1 hour. The mixture was filtered and the reaction solution was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 3.6 mg of 4-(cyclopentylmethyl)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (Compound 10).

[0370] MS (ESI) M / Z: 430.2 [M + H] + 。

[0371] 11H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 0.5H), 8.56 (s, 0.5H), 8.33 (s, 0.5H), 8.32 (s, 0.5H), 8.26 (d, J = 8.0 Hz, 0.5H), 8.22 (d, J = 7.2 Hz, 0.5H), 7.77 (d, J = 6.8 Hz, 1H), 3.91 (s, 3H), 3.79 (br.s., 1H), 3.51 - 3.43 (m, 2H), 2.69 - 2.64 (m, 2H), 2.46 - 2.38 (m, 2H), 2.26 - 2.19 (m, 1H), 1.98 - 1.85 (m, 2H), 1.72 - 1.42 (m, 8H), 1.26 - 1.14 (m, 2H).

[0372] Example 11:

[0373] 4 - ((1,3 - cis) - 3 - hydroxycyclopentyl)amino) - 2 - ((1 - ((1 - methyl - 1H - pyrazol - 4 - yl)sulfonyl)piperidin - 4 - yl)amino)pyrimidine - 5 - carbonitrile

[0374]

[0375] Step 1: At room temperature, dissolve compound 1A - 2 (80.0 mg, 0.2 mmol) in N,N - dimethylformamide (1 mL). Subsequently, add N,N - diisopropylethylamine (50.0 mg, 0.39 mmol) and (1,3 - cis) - 3 - aminocyclopentanol hydrochloride (49.0 mg, 0.3 mmol) to the above reaction solution in sequence. Heat the reaction solution to 120 °C and stir for 6 hours. Cool the reaction solution to room temperature and concentrate it under reduced pressure. Quench the resulting residue with water (10 mL). Extract the mixture with ethyl acetate (30 mL × 3 times), combine the organic phases, wash the organic phases first with saturated brine (10 mL × 3 times), then dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. Purify the resulting residue by silica gel column chromatography to obtain 53.0 mg of tert - butyl 4 - ((5 - cyano - 4 - (((1,3 - cis) - 3 - hydroxycyclopentyl)amino)pyrimidin - 2 - yl)amino)piperidine - 1 - carboxylate (11 - 2).

[0376] MS (ESI) M / Z: 403.2 [M + H] + 。

[0377] Step 2: At room temperature, dissolve compound 11-2 (53.0 mg, 0.1 mmol) in 1,4-dioxane (1 mL). Subsequently, add hydrogen chloride-dioxane solution (4 mol / L, 2 mL) thereto. The reaction solution was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain 40.0 mg of 4-((1,3-cis)-3-hydroxycyclopentyl)amino)-2-(piperidin-4-ylamino)pyrimidine-5-carbonitrile (11-3).

[0378] MS(ESI) M / Z: 303.2 [M+H] + 。

[0379] Step 3: At room temperature, dissolve compound 11-3 (40.0 mg, 0.1 mmol) in dichloromethane (3 mL). Subsequently, add N,N-diisopropylethylamine (50.0 mg, 0.6 mmol) thereto. At 0 °C, 1-methyl-1H-pyrazole-4-sulfonyl chloride (28.0 mg, 0.1 mmol) was added dropwise to the above solution, and the reaction solution was stirred at room temperature overnight. Water (20 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 28.4 mg of 4-((1,3-cis)-3-hydroxycyclopentyl)amino)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (Compound 11).

[0380] MS(ESI) M / Z: 447.2 [M+H] + 。

[0381] 11H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.6H), 8.31 (s, 0.4H), 8.17 (s, 0.4H), 8.13 (s, 0.5H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.65 (d, J = 7.2 Hz, 0.6H), 7.48 (d, J = 7.6 Hz, 0.4H), 7.07 (d, J = 7.6 Hz, 0.6H), 7.01 (d, J = 8.0 Hz, 0.4H), 4.81 (d, J = 3.6 Hz, 0.5H), 4.77 (d, J = 4.0 Hz, 0.7H), 4.51 - 4.29 (m, 1H), 4.17 - 4.08 (m, 1H), 3.90 (s, 3H), 3.72 (br.s., 1H), 3.51 - 3.39 (m, 3H), 2.41 - 2.31 (m, 1H), 2.05 - 1.79 (m, 4H), 1.76 - 1.46 (m, 6H).

[0382] Examples 12 and 13:

[0383] 4 - ((1S,3R) - 3 - hydroxycyclopentyl)amino) - 2 - ((1 - ((1 - methyl - 1H - pyrazol - 4 - yl)sulfonyl)piperidin - 4 - yl)amino)pyrimidine - 5 - carbonitrile

[0384] 4 - ((1R,3S) - 3 - hydroxycyclopentyl)amino) - 2 - ((1 - ((1 - methyl - 1H - pyrazol - 4 - yl)sulfonyl)piperidin - 4 - yl)amino)pyrimidine - 5 - carbonitrile

[0385]

[0386] Compound 12:

[0387] The chiral resolution of Compound 11 was carried out under the following conditions: preparative column 0.46 cm I.D. * 15 cm L; mobile phase: CO2:MeOH(0.1% DEA) = 60:40; flow rate: 2.5 mL / min; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure. The compound with a retention time of 3.77 minutes was obtained, and the ee value was 99.66%. The absolute configuration was not determined and it was the enantiomer of Compound 13.

[0388] MS(ESI) M / Z: 447.2 [M + H] + .

[0389] 11H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.6H), 8.31 (s, 0.4H), 8.17 (s, 0.4H), 8.13 (s, 0.5H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.65 (d, J = 7.2 Hz, 0.6H), 7.48 (d, J = 7.6 Hz, 0.4H), 7.07 (d, J = 7.6 Hz, 0.6H), 7.01 (d, J = 8.0 Hz, 0.4H), 4.81 (d, J = 3.6 Hz, 0.5H), 4.77 (d, J = 4.0 Hz, 0.7H), 4.51 - 4.29 (m, 1H), 4.17 - 4.08 (m, 1H), 3.90 (s, 3H), 3.72 (br.s., 1H), 3.51 - 3.39 (m, 3H), 2.41 - 2.31 (m, 1H), 2.05 - 1.79 (m, 4H), 1.76 - 1.46 (m, 6H).

[0390] Compound 13:

[0391] Compound 11 was subjected to chiral resolution under the following conditions: preparative column 0.46 cm I.D. * 15 cm L; mobile phase: CO2:MeOH (0.1% DEA) = 60:40; flow rate: 2.5 mL / min; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure. The compound with a retention time of 4.60 minutes was obtained, and the ee value was 99.88%. The absolute configuration was not determined, and it was the enantiomer of Compound 12.

[0392] MS (ESI) M / Z: 447.2 [M + H] + 。

[0393] 11H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.6H), 8.31 (s, 0.4H), 8.17 (s, 0.4H), 8.13 (s, 0.5H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.65 (d, J = 7.2 Hz, 0.6H), 7.48 (d, J = 7.6 Hz, 0.4H), 7.07 (d, J = 7.6 Hz, 0.6H), 7.01 (d, J = 8.0 Hz, 0.4H), 4.81 (d, J = 3.6 Hz, 0.5H), 4.77 (d, J = 4.0 Hz, 0.7H), 4.51 - 4.29 (m, 1H), 4.17 - 4.08 (m, 1H), 3.90 (s, 3H), 3.72 (br.s., 1H), 3.51 - 3.39 (m, 3H), 2.41 - 2.31 (m, 1H), 2.05 - 1.79 (m, 4H), 1.76 - 1.46 (m, 6H).

[0394] Example 14:

[0395] 4 - ((((1R,2R)-2 - Methoxycyclopentyl)amino)-2 - ((((1 - ((1 - methyl - 1H - pyrazol - 4 - yl)sulfonyl)piperidin - 4 - yl)amino)pyrimidine - 5 - carbonitrile

[0396]

[0397] Step 1: At room temperature, dissolve (1R,2R)-2 - aminocyclopentanol hydrochloride (240.0 mg, 1.7 mmol) in acetone / water (20 mL / 1.4 mL). Subsequently, add potassium carbonate (720.0 mg, 5.2 mmol) and benzyl bromide (0.4 mL, 3.5 mmol) to the above reaction solution in sequence. Heat the reaction solution to 56 °C and stir for 16 hours. Quench the reaction solution by adding water (20 mL), concentrate the mixture under reduced pressure, extract with ethyl acetate (30 mL × 3 times), combine the organic phases, wash the organic phase first with saturated brine (30 mL), then dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 340 mg of (1R,2R)-2 - (dibenzylamino)cyclopentan - 1 - ol (Compound 14).

[0398] MS(ESI) M / Z: 282.2 [M + H] + 。

[0399] Step 2: At room temperature, dissolve compound 14-2 (100.0 mg, 0.4 mmol) in tetrahydrofuran (5 mL). Subsequently, add sodium hydride (27 mg, 0.7 mmol, 60% dispersed in mineral oil) portionwise to the above solution under cooling in an ice-water bath. After the reaction mixture was stirred at room temperature for 30 minutes, iodomethane (99 mg, 0.7 mmol) was slowly added dropwise to the above reaction mixture. The reaction mixture was stirred at room temperature overnight. Water (10 mL) was added to the reaction system to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 80 mg of (1R,2R)-N,N-dibenzyl-2-methoxycyclopentan-1-amine (14-3).

[0400] MS(ESI) M / Z: 296.2 [M+H] + 。

[0401] Step 3: Dissolve compound 14-3 (80 mg, 0.3 mmol) in methanol (5 mL). Subsequently, add 10% palladium / carbon (8 mg) to the above solution. After the reaction system was purged with hydrogen three times, it was stirred at room temperature for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with methanol (10 mL × 3 times). The obtained filtrate was concentrated under reduced pressure to give 46 mg of (1R,2R)-2-methoxycyclopentan-1-amine (14-4).

[0402] 1 1H NMR (400 MHz, DMSO-d6) δ 8.26 (br.s., 2H), 3.80 - 3.68 (m, 1H), 3.37 - 3.27 (m, 1H), 3.25 (s, 3H), 2.06 - 1.86 (m, 2H), 1.79 - 1.47 (m, 4H).

[0403] Step 4: At room temperature, dissolve compound 14-4 (70.0 mg, 0.2 mmol) in N,N-dimethylacetamide (1 mL). Subsequently, add N,N-diisopropylethylamine (70.0 mg, 0.6 mmol) and compound 1A (31.0 mg, 0.3 mmol) to the above reaction solution in sequence. Heat the reaction solution to 80 °C and stir for 4 hours. Quench the reaction solution by adding water (20 mL). Extract the mixture with ethyl acetate (30 mL × 3 times), combine the organic phases, wash the organic phases successively with water (30 mL × 3 times) and saturated brine (30 mL), then dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by preparative high performance liquid chromatography to obtain 31.5 mg of 4-(((1R,2R)-2-methoxycyclopentyl)amino)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 14).

[0404] MS(ESI) M / Z: 461.2 [M+H] + 。

[0405] 1 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 0.6H), 8.31 (s, 0.4H), 8.17 (s, 0.4H), 8.13 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.67 (d, J = 7.4 Hz, 0.6H), 7.46 (d, J = 7.8 Hz, 0.4H), 7.35 (d, J = 7.6 Hz, 1H), 4.47 - 4.37 (m, 0.5H), 4.28 - 4.19 (m, 0.7H), 3.91 (s, 3H), 3.79 - 3.65 (m, 2H), 3.53 - 3.41 (m, 2H), 3.20 (s, 1.3H), 3.13 (s, 1.7H), 2.44 - 2.29 (m, 2H), 2.00 - 1.72 (m, 4H), 1.72 - 1.39 (m, 6H).

[0406] Example 15:

[0407] 4-(Cyclopentylamino)-2-((1-((4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0408]

[0409] Step 1: At room temperature, dissolve compound 1A-2 (605 mg, 1.79 mmol) in N,N-dimethylacetamide (4 mL). Subsequently, add cyclopentylamine (183.2 mg, 2.15 mmol) and N,N-diisopropylethylamine (463.9 mg, 3.59 mmol) to the reaction solution in sequence. Heat the reaction solution to 80 °C and stir overnight. Cool the reaction solution to room temperature and quench it by adding water (40 mL). Extract the mixture with dichloromethane (40 mL × 3 times). Combine the organic phases. Wash the organic phase first with saturated brine (100 mL), then dry it over anhydrous sodium sulfate, filter, and finally concentrate it under reduced pressure. Purify the obtained residue by silica gel column chromatography to obtain 580 mg of tert-butyl 4-((5-cyano-4-(cyclopentylamino)pyrimidin-2-yl)amino)piperidine-1-carboxylate (15-2).

[0410] MS(ESI) M / Z: 387.2 [M+H] + 。

[0411] Step 2: At room temperature, dissolve compound 15-2 (580 mg, 1.50 mmol) in 1,4-dioxane (3 mL). Subsequently, add hydrogen chloride-dioxane solution (3 mL, 6 mmol) to it. Stir the reaction solution at room temperature for 2 hours. Concentrate it under reduced pressure to obtain 610 mg of 4-(cyclopentylamino)-2-(piperidin-4-ylamino)pyrimidine-5-carbonitrile (15-3).

[0412] MS(ESI) M / Z: 287.2 [M+H] + 。

[0413] Step 3: At room temperature, dissolve compound 15-3 (610.0 mg, 2.13 mmol) in dichloromethane (9 mL). Subsequently, add N,N-diisopropylethylamine (826.0 mg, 6.39 mmol) to it. Dropwise add p-bromobenzenesulfonyl chloride (649.0 mg, 2.56 mmol) to the above solution at 0 °C. Stir the reaction solution at room temperature for 3 hours. Quench the reaction solution by adding water (40 mL). Extract the mixture with dichloromethane (40 mL × 3 times). Combine the organic phases. Wash the organic phase first with saturated brine (100 mL), then dry it over anhydrous sodium sulfate, filter, and finally concentrate it under reduced pressure. Purify the obtained residue by silica gel column chromatography to obtain 605.0 mg of 2-((1-((4-bromophenyl)sulfonyl)piperidin-4-yl)amino)-4-(cyclopentylamino)pyrimidine-5-carbonitrile (15-4).

[0414] MS(ESI) M / Z: 505.0 [M+H] + 。

[0415] Step 4: At room temperature, dissolve compound 15-4 (300.0 mg, 0.59 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL). Subsequently, sequentially add compound 15-1A (130.0 mg, 0.21 mmol), sodium carbonate (126 mg, 1.19 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (92 mg, 0.12 mmol) to it, and stir the reaction solution at 100 °C overnight. After cooling the reaction solution to room temperature, add water (40 mL) to quench the reaction. Extract the mixture with dichloromethane (40 mL × 3 times), combine the organic phases, wash the organic phases with saturated brine (100 mL) first, then dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. Purify the obtained residue by silica gel column chromatography to obtain 330.0 mg of tert-butyl 4-(4-((4-((5-cyano-4-(cyclopentylamino)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (15-5).

[0416] MS(ESI) M / Z: 608.2 [M+H] + 。

[0417] Step 5: At room temperature, dissolve compound 15-5 (80 mg, 1.50 mmol) in 1,4-dioxane (3 mL). Subsequently, add hydrogen chloride-dioxane solution (3 mL, 6 mmol) to it. Stir the reaction solution at room temperature for 2 hours. Add dichloromethane (20 mL × 3 times) to the reaction solution and concentrate under reduced pressure. Purify the obtained residue by preparative high performance liquid chromatography to obtain 20.2 mg of 4-(cyclopentylamino)-2-((1-((4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (Compound 15).

[0418] MS(ESI) M / Z: 508.2 [M+H] + 。

[0419] 11H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 0.4H), 8.10 (s, 0.6H), 7.72 - 7.64 (m, 4H), 7.60 (d, J = 7.2 Hz, 0.6H), 7.43 (d, J = 7.8 Hz, 0.4H), 7.23 (d, J = 6.6 Hz, 0.6H), 7.13 (d, J = 7.6 Hz, 0.4H), 6.43 (s, 1H), 4.44 - 4.31 (m, 0.4H), 4.27 - 4.14 (m, 0.6H), 3.68 (br.s., 1H), 3.60 - 3.46 (m, 2H), 3.40 (br.s., 2H), 2.92 (s, 2H), 2.44 - 2.31 (m, 4H), 1.95 - 1.74 (m, 4H), 1.72 - 1.36 (m, 9H).

[0420] Example 16:

[0421] 4-(Cyclopentylamino)-2-((1-((4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0422]

[0423] At room temperature, compound 15 (70.0 mg, 0.14 mmol) was dissolved in methanol (4 mL). Subsequently, acetic acid (16.8 mg, 0.28 mmol) and aqueous formaldehyde solution (21 mg, 0.70 mmol) were added successively, and the mixture was stirred at room temperature for 0.5 h; then sodium cyanoborohydride (152.6 mg, 0.70 mmol) was added to the system, and the reaction was continued for 0.5 h. Dichloromethane (20 mL × 3 times) was added to the reaction solution and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 9.8 mg of 4-(cyclopentylamino)-2-((1-((4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 16).

[0424] MS (ESI) M / Z: 522.2 [M + H] + 。

[0425] 11H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 0.4H), 8.10 (s, 0.6H), 7.73 - 7.64 (m, 4H), 7.60 (d, J = 7.2 Hz, 0.6H), 7.43 (d, J = 7.8 Hz, 0.4H), 7.23 (d, J = 6.6 Hz, 0.6H), 7.13 (d, J = 7.6 Hz, 0.4H), 6.41 - 6.35 (m, 1H), 4.42 - 4.30 (m, 0.4H), 4.27 - 4.14 (m, 0.6H), 3.68 (br.s., 1H), 3.60 - 3.43 (m, 2H), 3.05 (d, J = 3.0 Hz, 2H), 2.62 - 2.54 (m, 2H), 2.51 (s, 2H), 2.47 - 2.31 (m, 2H), 2.28 (s, 3H), 1.95 - 1.75 (m, 4H), 1.70 - 1.35 (m, 8H).

[0426] Example 17:

[0427] 4-(Cyclopentylamino)-2-((1-((4-(1-methylpiperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0428]

[0429] At room temperature, compound 16 (50.0 mg, 0.10 mmol) was dissolved in ethanol (4 mL). Subsequently, wet palladium on carbon (30 mg, 60%) was added thereto, and the mixture was stirred at room temperature for 6 hours. The reaction solution was filtered, and the filter cake was washed with ethanol (20 mL × 3 times). The residue obtained by concentrating the filtrate under reduced pressure was purified by preparative high performance liquid chromatography to give 9.3 mg of 4-(cyclopentylamino)-2-((1-((4-(1-methylpiperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (Compound 17).

[0430] MS (ESI) M / Z: 524.3 [M + H] + 。

[0431] 11H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 0.4H), 8.10 (s, 0.6H), 7.72 - 7.58 (m, 2.5H), 7.52 (s, 1H), 7.50 (s, 1H), 7.43 (d, J = 7.7 Hz, 0.4H), 7.24 (d, J = 6.6 Hz, 0.6H), 7.13 (d, J = 7.6 Hz, 0.4H), 4.44 - 4.30 (m, 0.4H), 4.26 - 4.13 (m, 0.6H), 3.67 (s, 1H), 3.60 - 3.44 (m, 2H), 2.87 (d, J = 11.3 Hz, 2H), 2.69 - 2.55 (m, 2H), 2.44 - 2.30 (m, 2H), 2.19 (s, 3H), 2.04 - 1.33 (m, 17H).

[0432] Example 18:

[0433] 4-(Cyclopentylamino)-2-((1-((4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0434]

[0435] At room temperature and under nitrogen protection, compound 15-4 (60.0 mg, 0.1 mmol) was dissolved in toluene (5 mL). Subsequently, N-methylpiperazine (17.8 mg, 0.2 mmol), Pd2(dba)3 (11.0 mg, 0.01 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (11.4 mg, 0.02 mmol) and anhydrous cesium carbonate (78 mg, 0.2 mmol) were successively added to the above reaction solution. The reaction solution was heated to 100 °C and stirred for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to give 6.3 mg of 4-(cyclopentylamino)-2-((1-((4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (Compound 18).

[0436] MS (ESI) M / Z: 525.2 [M + H] + 。

[0437] 11H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 0.4H), 8.10 (s, 0.6H), 7.61 (d, J = 7.0 Hz, 0.6H), 7.51 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 7.4 Hz, 0.4H), 7.24 (d, J = 6.8 Hz, 0.6H), 7.13 (d, J = 7.8 Hz, 0.4H), 7.07 (d, J = 9.0 Hz, 2H), 4.45 - 4.30 (m, 0.4H), 4.28 - 4.13 (m, 0.6H), 3.74 - 3.58 (m, 1H), 3.55 - 3.39 (m, 2H), 3.31 - 3.25 (m, 2H), 2.45 - 2.26 (m, 7H), 2.22 (s, 3H), 1.94 - 1.76 (m, 4H), 1.72 - 1.61 (m, 2H), 1.60 - 1.34 (m, 7H)

[0438] Example 19:

[0439] 4-(trans-2-Hydroxy-2-methylcyclopentyl)amino)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0440]

[0441] Step 1: At room temperature, methyl 1,2-cyclopentene epoxide (70.0 mg, 0.7 mmol) was dissolved in ammonia water (1 mL). The reaction system was heated to 90 °C and reacted for 15 hours. Hydrochloric acid methanol solution (4 mol) was added to the reaction solution under an ice-water bath until the pH reached 3. Finally, it was concentrated under reduced pressure to obtain 200 mg of compound 19-2, which was directly used in the next step of the reaction.

[0442] MS (ESI) M / Z: 116.2 [M+H] + 。

[0443] Step 2: At room temperature, dissolve compound 19-2 (90.0 mg, 0.2 mmol) in N,N-dimethylformamide (0.5 mL). Subsequently, add N,N-diisopropylethylamine (91.0 mg, 0.7 mmol) and compound 1A (91.0 mg, 0.6 mmol) to the above solution. The reaction system is heated to 80 °C and stirred for 15 h. Quench the reaction solution by adding water (20 mL), extract the mixture with ethyl acetate (8 mL × 3 times), combine the organic phases, wash the organic phase first with saturated brine (30 mL), then dry it over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by preparative high performance liquid chromatography to obtain 35.0 mg of the final product 4-((trans-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 19).

[0444] MS(ESI) M / Z: 461.2 [M+H] + 。

[0445] 1 H NMR(400 MHz, DMSO-d6) δ 8.35 - 8.29 (m, 1H), 8.22 - 8.11 (m, 1H), 7.81 - 7.73 (m, 1H), 7.64 (d, J = 7.2 Hz, 0.6H), 7.53 (d, J = 7.6 Hz, 0.4H), 6.87 (d, J = 8.0 Hz, 0.5H), 6.77 (d, J = 8.4 Hz, 0.4H), 4.50 (s, 0.4H), 4.41 (s, 0.5H), 4.38 - 4.24 (m, 1H), 3.91 (s, 3H), 3.80 - 3.68 (m, 1H), 3.59 - 3.32 (m, 2H), 2.48 - 2.28 (m, 2H), 2.09 - 1.81 (m, 3H), 1.71 - 1.41 (m, 7H), 1.13 - 0.99 (m, 3H).

[0446] Examples 20 and 21:

[0447] 4-((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0448] 4-((1S,2S)-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0449]

[0450] Compound 20:

[0451] Compound 19 was subjected to chiral resolution under the following conditions: preparative column IG 25*250 mm, 10 um (Daicel); mobile phase: CO2:MeOH (0.2% ammonia in methanol) = 60:40; flow rate: 100 g / min; detection wavelength: 214 nm. The product was collected and freeze-dried under reduced pressure. The resulting product was purified by preparative high performance liquid chromatography. A compound with a retention time of 4.05 minutes was obtained with an ee value of 100%.

[0452] The absolute configuration was not determined and it is an enantiomer of Compound 21.

[0453] MS(ESI) M / Z: 461.2 [M+H] + .

[0454] 1 H NMR(400 MHz, DMSO-d6) δ 8.32(s, 0.5H), 8.31(s, 0.5H), 8.21(s, 0.4H), 8.18(s, 0.5H), 7.77(s, 0.5H), 7.79 - 7.75(m, 1H), 7.72(d, J = 6.4 Hz, 0.6H), 7.61(d, J = 6.4 Hz, 0.5H), 7.05(d, J = 7.6 Hz, 0.6H), 6.84(d, J = 8.0 Hz, 0.5H), 4.39 - 4.28(m, 1H), 3.91(s, 3H), 3.78 - 3.75(m, 1H), 3.53 - 3.38(m, 2H), 2.46 - 2.28(m, 2H), 2.07 - 1.83(m, 3H), 1.69 - 1.45(m, 7H), 1.12 - 1.00(m, 3H).

[0455] Compound 21:

[0456] Compound 19 was subjected to chiral resolution under the following conditions: preparative column IG 25*250 mm, 10 um (Daicel); mobile phase: CO2:MeOH (0.2% ammonia in methanol) = 60:40; flow rate: 100 g / min; detection wavelength: 214 nm. The product was collected and freeze-dried under reduced pressure. The resulting product was purified by preparative high performance liquid chromatography. A compound with a retention time of 5.44 minutes was obtained with an ee value of 100%.

[0457] The absolute configuration was not determined and it is an enantiomer of Compound 20.

[0458] MS(ESI) M / Z: 461.2 [M+H] + .

[0459] 1 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.5H), 8.31 (s, 0.5H), 8.19 (s, 0.5H), 8.13 (s, 0.6H), 7.77 (s, 0.5H), 7.76 (s, 0.5H), 7.63 (d, J = 7.6 Hz, 0.7H), 7.53 (d, J = 7.6 Hz, 0.5H), 6.87 (d, J = 7.6 Hz, 0.6H), 6.76 (d, J = 8.0 Hz, 0.5H), 4.50 (s, 0.5H), 4.41 (s, 0.6H), 4.39 - 4.26 (m, 1H), 3.91 (s, 3H), 3.81 - 3.66 (m, 1H), 3.54 - 3.39 (m, 2H), 2.46 - 2.33 (m, 2H), 2.07 - 1.81 (m, 3H), 1.72 - 1.45 (m, 7H), 1.12 - 1.00 (m, 3H)

[0460] Example 22:

[0461] 4-(Cyclopentylamino)-2-((1-((4-((4-methylpiperazin-1-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0462]

[0463] Step 1: At room temperature, dissolve compound 15-4 (100.0 mg, 0.2 mmol) in tetrahydrofuran (6 mL). Subsequently, add n-butyllithium / n-hexane solution (2.5 mol / L, 0.8 mL, 2.0 mmol) thereto under nitrogen protection at -78 °C, and stir the reaction solution at -78 °C for 10 minutes. Then add N,N-dimethylacetamide (146.2 mg, 2.4 mmol) thereto. Stir the reaction solution at room temperature for 2 hours. Quench the reaction solution with saturated aqueous ammonium chloride solution (20 mL). Extract the mixture with ethyl acetate (10 mL × 3 times), combine the organic phases, wash the organic phases first with saturated brine (30 mL), then dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 80.0 mg of 4-(cyclopentylamino)-2-(((1-((4-formylphenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (22-2).

[0464] MS (ESI) M / Z: 455.2 [M + H] + .

[0465] Step 2: At room temperature, dissolve compound 22-2 (80.0 mg, 0.18 mmol) and N-methylpiperazine (18.0 mg, 0.18 mmol) in 1,2-dichloroethane (1 mL). After purging the system with nitrogen three times, add acetic acid (108.2 mg, 1.8 mmol) thereto under an ice-water bath. The reaction solution was stirred at room temperature for 2 hours. Finally, sodium cyanoborohydride (114.4 mg, 0.54 mmol) was added thereto under an ice-water bath. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution (30 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to give 12.2 mg of 4-(cyclopentylamino)-2-((1-((4-((4-methylpiperazin-1-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (Compound 22).

[0466] MS(ESI) M / Z: 539.2 [M+H] + 。

[0467] 1 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 0.4H), 8.11 (s, 0.6H), 7.87 - 7.77 (m, 2H), 7.71 - 7.62 (m, 1.6H), 7.52 - 7.43 (m, 1.4H), 7.25 (d, J = 6.6 Hz, 0.6H), 7.14 (d, J = 7.6 Hz, 0.4H), 4.50 - 4.20 (m, 1H), 3.93 - 3.70 (m, 3H), 3.61 (d, J = 12.4 Hz, 2H), 2.83 - 2.68 (m, 2H), 2.47 - 2.25 (m, 8H), 2.16 (s, 3H), 1.97 - 1.78 (m, 4H), 1.72 - 1.59 (m, 2H), 1.59 - 1.40 (m, 6H).

[0468] Example 23:

[0469] 4-((1S,2R-cis)-2-(dimethylamino)cyclopentyl)amino)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0470]

[0471] Step 1: 6-Oxabicyclo[3.1.0]hexane (1000 mg, 12 mmol, 1.00 eq) was stirred with an aqueous ammonia solution (8 mL) in a sealed tube at 90 °C for 3 h. The reaction mixture was cooled to room temperature, and the pH was adjusted to 2 with concentrated hydrochloric acid. A large amount of white solid precipitated from the solution, which was then filtered. 1600 mg of (1R,2R-trans)-2-aminocyclopentan-1-ol (23-2) was obtained.

[0472] MS(ESI) M / Z: 102.2 [M+H] + 。

[0473] Step 2: Compound 23-2 (1600 mg, 12 mmol) was dissolved in water / tetrahydrofuran (20 mL / 2 mL). Sodium hydroxide (960 mg, 24 mmol) and benzyloxycarbonyl chloride (2251 mg, 13.2 mmol) were added at 0 °C. The reaction mixture was warmed to room temperature and reacted for 4 h. After quenching with water (60 mL), the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic phases were washed first with saturated brine (30 mL), then dried over anhydrous sodium sulfate, and filtered. The residue was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 800 mg of benzyl ((1R,2R-trans)-2-hydroxycyclopentyl)carbamate (23-3).

[0474] MS(ESI) M / Z: 236.2 [M+H + 。

[0475] 1 H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.26 (m, 5H), 7.18 (d, J = 7.2 Hz, 1H), 5.00 (s, 2H), 4.67 (d, J = 4.3 Hz, 1H), 3.83 - 3.78 (m, 1H), 3.61 - 3.51 (m, 1H), 1.92 - 1.78 (m, 1H), 1.76 - 1.72 (m, 1H), 1.64 - 1.51 (m, 2H), 1.45 - 1.30 (m, 2H).

[0476] Step 3: Dissolve compound 23-3 (500 mg, 2.15 mmol) in dichloromethane (15 mL). Add methanesulfonyl chloride (365 mg, 3.23 mmol) and triethylamine (0.90 mL, 6.45 mmol) sequentially at 0 °C. Warm the reaction mixture to room temperature and stir for 1 h. Quench the reaction by adding water (60 mL), and extract with dichloromethane (3 x 20 mL). Combine the organic layers, wash the organic layer first with saturated brine (30 mL), then dry over anhydrous sodium sulfate, filter, and concentrate. Stir the concentrated crude product with aqueous dimethylamine solution (10 mL) at room temperature for 4 h. Concentrate the solvent under pressure to obtain 360 mg of benzyl ((1R,2S-cis)-2-(dimethylamino)cyclopentyl)carbamate (23-4).

[0477] MS(ESI) M / Z: 263.2 [M+H] + 。

[0478] Step 4: Dissolve compound 23-4 (360 mg, 1.37 mmol) in methanol (15 mL) under a hydrogen atmosphere. Add palladium on carbon (10%, 730 mg), and stir at room temperature for 3 h. Filter and concentrate under reduced pressure to obtain 150 mg of (1S,2R-cis)-N1,N1-dimethylcyclopentane-1,2-diamine (23-5).

[0479] MS(ESI) M / Z: 129.2 [M+H] + 。

[0480] Step 5: Dissolve compound 23-5 (100 mg, 0.26 mmol) in N,N-dimethylacetamide (1 mL) in a sealed tube. Add diisopropylethylamine (67 mg, 0.52 mmol), and then add compound 1A (37 mg, 0.29 mmol). Heat the mixture to 80 °C and stir for 2 h. Quench the reaction by adding water (60 mL), and extract with dichloromethane (3 x 20 mL). Combine the organic layers, wash the organic layer first with saturated brine (30 mL), then dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. Purify the resulting residue by preparative high performance liquid chromatography to obtain 8.0 mg of 4-((1S,2R-cis)-2-(dimethylamino)cyclopentyl)amino)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 23).

[0481] MS(ESI) M / Z: 474.2 [M+H] + 。

[0482] 11H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 0.6H), 8.31 (s, 0.4H), 8.16 (s, 0.4H), 8.11 (s, 0.6H), 7.80 - 7.75 (m, 1H), 7.64 (d, J = 7.3 Hz, 0.5H), 7.46 (d, J = 7.5 Hz, 0.4H), 7.34 (d, J = 7.9 Hz, 0.5H), 7.24 (d, J = 8.5 Hz, 0.4H), 4.49 - 4.29 (m, 1H), 3.91 (s, 3H), 3.78 - 3.65 (m, 1H), 3.61 - 3.39 (m, 2H), 2.91 - 2.76 (m, 1H), 2.45 - 2.30 (m, 2H), 2.15 - 2.05 (m, 6H), 1.97 - 1.82 (m, 3H), 1.75 - 1.41 (m, 7H).

[0483] Example 24:

[0484] 4-(Cyclopentylamino)-2-((1-((4-(2-Hydroxypropan-2-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

[0485]

[0486] Under -78 °C and nitrogen protection, n-butyllithium (0.83 mL, 0.6 mmol, 2.5 mol / L in tetrahydrofuran) was dissolved in tetrahydrofuran (5 mL). Subsequently, compound 15-4 (400.0 mg, 0.8 mmol) was slowly added to the above reaction solution and stirred for 1 hour, then acetone (69.0 mg, 1.2 mmol) was slowly added dropwise. The reaction solution was warmed to room temperature and stirred for 3 hours. The reaction solution was cooled in an ice bath, quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate (40 mL × 3 times). The organic phases were combined, washed first with saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 30.2 mg of 4-(cyclopentylamino)-2-((1-((4-(2-hydroxypropan-2-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (Compound 24).

[0487] MS (ESI) M / Z: 485.0 [M + H] + 。

[0488] 11H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 0.4H), 8.10 (s, 0.6H), 7.76 - 7.64 (m, 4H), 7.62 (d, J = 7.1 Hz, 0.6H), 7.44 (d, J = 7.9 Hz, 0.4H), 7.24 (d, J = 6.5 Hz, 0.6H), 7.14 (d, J = 7.4 Hz, 0.4H), 5.26 (s, 1H), 4.44 - 4.31 (m, 0.4H), 4.25 - 4.14 (m, 0.6H), 3.77 - 3.60 (m, 1H), 3.60 - 3.47 (m, 2H), 2.48 - 2.40 (m, 1H), 2.40 - 2.31 (m, 1H), 1.96 - 1.75 (m, 4H), 1.67 - 1.39 (m, 14H).

[0489] Examples 25 and 26:

[0490] (S)-N-(1-(((1H-Pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine

[0491] (S)-N-(1-((1-((1H-Pyrazol-4-yl)sulfonyl)-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine

[0492]

[0493] Step 1: Under room temperature and nitrogen protection, dissolve (S)-(-)-3-hydroxytetrahydrofuran (696.0 mg, 7.9 mmol) in tetrahydrofuran (30 mL). Subsequently, add sodium hydride (316.0 mg, 7.9 mmol, 60% dispersed in mineral oil) to the above solution under an ice-water bath. After stirring the reaction solution for 10 minutes under the ice-water bath, slowly add compound 1B-2 (2.0 g, 5.2 mmol) to the reaction solution. Heat the reaction system to 100 °C and stir for 2 hours. Cool to room temperature, quench the reaction solution by adding water (50 mL), extract the mixture with ethyl acetate (15 mL × 3 times), combine the organic phases, wash the organic phase with saturated brine (50 mL) first, then dry with anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 1.8 g of tert-butyl (S)-4-((4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (25-2).

[0494] MS (ESI) M / Z: 433.0 [M + H] + .

[0495] 1 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 0.4H), 8.31 (s, 0.6H), 8.01 (d, J = 7.2 Hz, 0.6H), 7.82 (d, J = 8.0 Hz, 0.4H), 5.62 - 5.55 (m, 1H), 3.99 - 3.84 (m, 4H), 3.83 - 3.73 (m, 3H), 3.00 - 2.75 (m, 2H), 2.32 - 2.18 (m, 1H), 2.06 - 1.95 (m, 1H), 1.90 - 1.77 (m, 2H), 1.40 (s, 9H), 1.39 - 1.30 (m, 2H).

[0496] Step 2: At room temperature, dissolve compound 25-2 (1.8 g, 4.2 mmol) in 1,4-dioxane (10 mL). Subsequently, add hydrogen chloride-dioxane solution (10 mL, 40 mmol) to the above solution. The reaction mixture is stirred at room temperature for 16 h. The reaction mixture is concentrated under reduced pressure to obtain 1.38 g of (S)-N-(piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (25-3).

[0497] MS (ESI) M / Z: 333.0 [M+H] + 。

[0498] Step 3: At room temperature, dissolve compound 25-3 (700.0 mg, 2.1 mmol) in dichloromethane (40 mL). Subsequently, under an ice-water bath, add N,N-diisopropylethylamine (812.0 mg, 6.3 mmol) and pyrazole-4-sulfonyl chloride (349.0 mg, 2.1 mmol) to the above reaction mixture in sequence. The reaction mixture is stirred at room temperature for 3 h. Add water (30 mL) to quench the reaction. The mixture is extracted with dichloromethane (20 mL × 3 times), and the organic phases are combined. The organic phase is first washed with saturated brine (10 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 700.0 mg of (S)-N-(1-(((1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 25).

[0499] MS (ESI) M / Z: 462.8 [M+H] + 。

[0500] 11H NMR (400 MHz, DMSO-d6) δ 13.74 (s, 1H), 8.41 - 8.33 (m, 1H), 8.32 - 8.27 (m, 1H), 8.03 (d, J = 7.3 Hz, 0.6H), 7.87 (d, J = 7.6 Hz, 0.4H), 7.83 (s, 1H), 5.63 - 5.52 (m, 1H), 3.96 - 3.84 (m, 1H), 3.83 - 3.65 (m, 4H), 3.56 - 3.42 (m, 2H), 2.47 - 2.34 (m, 2H), 2.27 - 2.14 (m, 1H), 2.02 - 1.87 (m, 3H), 1.67 - 1.52 (m, 2H).

[0501] (S)-N-(1-((1-((1H-Pyrazol-4-yl)sulfonyl)-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 26).

[0502] MS(ESI) M / Z: 592.8 [M + H] + 。

[0503] 1 1H NMR (400 MHz, DMSO-d6) δ 14.19 (s, 1H), 8.92 (d, J = 8.4 Hz, 1H), 8.78 - 8.35 (m, 2H), 8.31 (d, J = 5.6 Hz, 1H), 8.23 (s, 0.6H), 8.21 (s, 0.4H), 8.05 (d, J = 7.6 Hz, 0.6H), 7.88 (d, J = 8.0 Hz, 0.4H), 5.63 - 5.51 (m, 1H), 3.95 - 3.89 (m, 1H), 3.84 - 3.71 (m, 4H), 3.59 - 3.48 (m, 2H), 2.65 - 2.53 (m, 2H), 2.27 - 2.15 (m, 1H), 2.03 - 1.87 (m, 3H), 1.67 - 1.51 (m, 2H).

[0504] Example 27:

[0505] (S)-2-(4-((4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)ethanol

[0506]

[0507] Step 1: Under room temperature and nitrogen protection, dissolve compound 25 (100.0 mg, 0.2 mmol), triphenylphosphine (275.0 mg, 1.0 mmol) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (63.0 mg, 0.4 mmol) in tetrahydrofuran (5 mL). Subsequently, diisopropyl azodicarboxylate (212.1 mg, 1.0 mmol) was slowly added to the reaction solution under an ice-water bath. The reaction solution was stirred at room temperature for 18 h. Water (20 mL) was added to the reaction solution to quench it, and the mixture was extracted with ethyl acetate (5 mL × 3 times). The combined organic phases were first washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 60.0 mg of compound 27-2.

[0508] MS(ESI) M / Z: 591.8 [M+H] + 。

[0509] Step 2: At room temperature, dissolve compound 27-2 (60.0 mg, 0.1 mmol) in methanol (5 mL). Subsequently, p-toluenesulfonic acid (18.0 mg, 0.1 mmol) was added to the above reaction solution. The reaction solution was stirred at room temperature for 16 h. Saturated sodium bicarbonate (5 mL) was added to the reaction solution to quench it. Water (10 mL) was added to the mixture, and then it was extracted with ethyl acetate (20 mL × 3 times). The combined organic phases were first washed with saturated brine (10 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 21.1 mg of (S)-2-(4-((4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)ethanol (compound 27).

[0510] MS(ESI) M / Z: 506.8 [M+H] + 。

[0511] 11H NMR (400 MHz, DMSO-d6) δ 8.34 - 8.26 (m, 2H), 8.03 (d, J = 7.4 Hz, 0.6H), 7.87 (d, J = 7.6 Hz, 0.4H), 7.81 (s, 0.5H), 7.80 (s, 0.4H), 5.61 - 5.51 (m, 1H), 4.95 (t, J = 5.3 Hz, 1H), 4.21 (t, J = 5.4 Hz, 2H), 3.95 - 3.85 (m, 1H), 3.83 - 3.66 (m, 6H), 3.56 - 3.44 (m, 2H), 2.46 - 2.35 (m, 2H), 2.26 - 2.13 (m, 1H), 2.04 - 1.87 (m, 3H), 1.68 - 1.52 (m, 2H).

[0512] Example 99

[0513] (S)-N-(1-(((4-Bromophenyl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine

[0514]

[0515] Step 1: At room temperature, dissolve compound 1B-3 (508 mg, 1.81 mmol) in dichloromethane (30 mL). Subsequently, add N,N-diisopropylethylamine (702 mg, 5.43 mmol) and 4-bromobenzenesulfonyl chloride (508 mg, 2.00 mmol) thereto under an ice-water bath. After stirring the reaction mixture at room temperature for 2 h, quench it with water (60 mL). Extract the mixture with dichloromethane (20 mL × 3 times), combine the organic phases, wash the organic phase first with saturated brine (30 mL), then dry it over anhydrous sodium sulfate, filter, and finally concentrate it under reduced pressure. Purify the obtained residue by silica gel column chromatography to obtain 830 mg of N-(1-(1-(4-bromophenyl)sulfonyl)piperidin-4-yl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (99-1).

[0516] MS (ESI) M / Z: 499.0 [M+H] + 。

[0517] Step 2: In a sealed flask, dissolve (S)-3-hydroxytetrahydrofuran (42 mg, 0.48 mmol) in tetrahydrofuran (2 mL). Subsequently, add sodium hydride (21 mg, 0.88 mmol) thereto under an ice-water bath. After reacting for 15 minutes, add Compound 99-1 (200 mg, 0.40 mmol). After heating the reaction solution to 100 °C and reacting for 4 hours, add water (60 mL) to quench the reaction. The mixture is extracted with dichloromethane (20 mL × 3 times), and the organic phases are combined. The organic phase is first washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 150 mg of (S)-N-(1-(((4-bromophenyl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 99).

[0518] MS(ESI) M / Z: 551.0 [M+H] + 。

[0519] 1 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.4 Hz, 0.6H), 7.92 - 7.83 (m, 2.4H), 7.73 - 7.65 (m, 2H), 5.62 - 5.51 (m, 1H), 3.96 - 3.86 (m, 1H), 3.85 - 3.68 (m, 4H), 3.63 - 3.46 (m, 2H), 2.65 - 2.55 (m, 2H), 2.28 - 2.13 (m, 1H), 2.03 - 1.84 (m, 3H), 1.64 - 1.48 (m, 2H).

[0520] Example 100

[0521] (S)-4-((Tetrahydrofuran-3-yl)oxy)-N-(1-((4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0522]

[0523] Step 1: Under nitrogen protection, dissolve compound 99 (200 mg, 0.36 mmol), compound 15A-1 (79 mg, 0.44 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (26 mg, 0.036 mmol) and sodium carbonate (76 mg, 0.72 mmol) in 1,4-dioxane / water (20 mL / 2 mL). Heat the reaction mixture to 110 °C and stir overnight. After cooling the reaction mixture to room temperature, quench it with water (60 mL) and extract with ethyl acetate (3 × 20 mL). Combine the organic phases, wash the organic phase first with saturated brine (60 mL), dry over anhydrous sodium sulfate, filter, and concentrate. Purify the obtained residue by silica gel column chromatography to obtain 220 mg of tert-butyl (S)-4-(4-((4-((4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (compound 100-1).

[0524] MS(ESI) M / Z: 653.8 [M+H] + 。

[0525] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.2 Hz, 0.6H), 7.86 (d, J = 7.4 Hz, 0.4H), 7.75 - 7.65 (m, 4H), 6.37 (s, 1H), 5.59 - 5.48 (m, 1H), 4.04 (s, 2H), 3.95 - 3.83 (m, 1H), 3.81 - 3.67 (m, 4H), 3.63 - 3.49 (m, 4H), 2.59 - 2.51 (m, 2H), 2.49 - 2.39 (m, 2H), 2.25 - 2.11 (m, 1H), 2.02 - 1.85 (m, 3H), 1.64 - 1.49 (m, 2H), 1.43 (s, 9H).

[0526] Step 2: Dissolve compound 100-1 (120 mg, 0.18 mmol) in 1,4-dioxane (5 mL), add hydrochloric acid dioxane solution (4 mL), and stir at room temperature overnight. Concentrate under reduced pressure, and purify the obtained residue by preparative high performance liquid chromatography to obtain 59.6 mg of (S)-4-((tetrahydrofuran-3-yl)oxy)-N-(1-((4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride (compound 100).

[0527] MS(ESI) M / Z: 554.2 [M+H] + 。

[0528] 1 1H NMR (400 MHz, DMSO-d6) δ 9.65 - 9.30 (m, 2H), 8.30 (d, J = 7.0 Hz, 1H), 8.16 - 8.06 (m, 0.5H), 8.10 - 7.86 (s, 0.5H), 7.80 - 7.76 (m, 3H), 6.41 (br.s., 1H), 5.55 (br.s., 1H), 3.97 - 3.84 (m, 1H), 3.84 - 3.66 (m, 5H), 3.66 - 3.46 (m, 2H), 3.31 (br.s., 2H), 2.70 (s, 2H), 2.64 - 2.55 (m, 1H), 2.47 - 2.38 (m, 1H), 2.27 - 2.11 (m, 1H), 2.02 - 1.83 (m, 3H), 1.67 - 1.49 (m, 2H).

[0529] Example 112

[0530] (S)-4-((Tetrahydrofuran-3-yl)oxy)-N-(1-((4-(1,2,5,6-tetrahydropyridin-3-yl)phenyl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0531]

[0532] The preparation method refers to Example 100 to obtain (S)-4-((tetrahydrofuran-3-yl)oxy)-N-(1-((4-(1,2,5,6-tetrahydropyridin-3-yl)phenyl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 112).

[0533] MS (ESI) M / Z: 554.1 [M + H] + .

[0534] 1 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.01 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.6 Hz, 0.4H), 7.73 - 7.57 (m, 4H), 6.45 (s, 1H), 5.62 - 5.50 (m, 1H), 3.95 - 3.84 (m, 1H), 3.82 - 3.65 (m, 4H), 3.62 - 3.47 (m, 4H), 2.81 (t, J = 5.6 Hz, 2H), 2.57 - 2.51 (m, 2H), 2.46 - 2.39 (m, 1H), 2.26 - 2.12 (m, 3H), 2.02 - 1.83 (m, 3H), 1.63 - 1.47 (m, 2H).

[0535] Example 113

[0536] N-(1-((4-(Piperidin-3-yl)phenyl)sulfonyl)piperidin-4-yl)-4-(((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine

[0537]

[0538] The preparation method refers to Example 17 to obtain N-(1-((4-(Piperidin-3-yl)phenyl)sulfonyl)piperidin-4-yl)-4-(((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 113).

[0539] MS(ESI) M / Z: 556.2 [M+H] + 。

[0540] 1 H NMR(400 MHz, DMSO-d6) δ 8.29(s, 1H), 8.02(d, J = 7.3 Hz, 0.6H), 7.86(d, J = 7.1 Hz, 0.4H), 7.69 - 7.61(m, 2H), 7.50(d, J = 8.3 Hz, 2H), 5.60 - 5.51(m, 1H), 3.94 - 3.83(m, 1H), 3.82 - 3.66(m, 4H), 3.62 - 3.49(m, 2H), 3.02 - 2.89(m, 2H), 2.76 - 2.68(m, 1H), 2.54 - 2.51(m, 2H), 2.45 - 2.36(m, 2H), 2.26 - 2.11(m, 1H), 2.01 - 1.83(m, 4H), 1.71 - 1.39(m, 5H).

[0541] Examples 114 and 115

[0542] N-(1-((4-((S)-Piperidin-3-yl)phenyl)sulfonyl)piperidin-4-yl)-4-(((S-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 114)

[0543] N-(1-((4-((R)-Piperidin-3-yl)phenyl)sulfonyl)piperidin-4-yl)-4-(((S-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 115)

[0544]

[0545] The chiral resolution of compound 113 was carried out under the following conditions. The preparative column was Daicel OZ (25*250 mm, 10 μm), the mobile phase: CO2 / MeOH (0.2% methanol ammonia water) = 50 / 50; the flow rate: 100 g / min, and the detection wavelength: 214 nm. The product was collected and freeze-dried under reduced pressure. Compound 114 with a retention time of 2.374 minutes was obtained, and the ee value was 100%. The absolute configuration was not determined, and it was the enantiomer of compound 115.

[0546] MS(ESI) M / Z: 556.2 [M+H] + 。

[0547] 1 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 8.02 (d, J = 7.2 Hz, 0.6H), 7.86 (d, J = 7.7 Hz, 0.4H), 7.74 - 7.61 (m, 2H), 7.50 (d, J = 8.3 Hz, 2H), 5.64 - 5.48 (m, 1H), 3.97 - 3.83 (m, 1H), 3.83 - 3.67 (m, 4H), 3.67 - 3.47 (m, 2H), 3.08 - 2.88 (m, 2H), 2.81 - 2.66 (m, 1H), 2.66 - 2.54 (m, 2H), 2.47 - 2.24 (m, 2H), 2.25 - 2.11 (m, 1H), 2.10 - 1.82 (m, 4H), 1.70 - 1.42 (m, 5H).

[0548] Compound 115:

[0549] The chiral resolution of compound 113 was carried out under the following conditions. The preparative column was Daicel OZ (25*250 mm, 10 μm), the mobile phase: CO2 / MeOH (0.2% methanol ammonia water) = 50 / 50; the flow rate: 100 g / min; the detection wavelength: 214 nm. The product was collected and freeze-dried under reduced pressure. Compound 115 with a retention time of 3.247 minutes was obtained, and the ee value was 99.34%. The absolute configuration was not determined, and it was the enantiomer of compound 114.

[0550] MS(ESI) M / Z: 556.2 [M+H] + .

[0551] 11H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.5 Hz, 0.4H), 7.66 (t, J = 6.7 Hz, 2H), 7.52 (d, J = 12.0 Hz, 2H), 5.55 (d, J = 4.3 Hz, 1H), 3.96 - 3.83 (m, 1H), 3.83 - 3.65 (m, 4H), 3.65 - 3.48 (m, 2H), 3.07 - 2.89 (m, 2H), 2.82 - 2.66 (m, 1H), 2.64 - 2.53 (m, 2H), 2.49 - 2.35 (m, 2H), 2.34 - 2.11 (m, 1H), 2.04 - 1.82 (m, 4H), 1.73 - 1.40 (m, 5H).

[0552] Example 116

[0553] (S)-N-(1-(((4-(Piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine

[0554]

[0555] Step 1: Under nitrogen protection, dissolve compound 99 (2.0 g, 3.7 mmol), tert-butyl piperazine-1-carboxylate (1.02 g, 5.5 mmol), tris(dibenzylideneacetone)dipalladium (338.8 mg, 0.37 mmol) and cesium carbonate (2.4 g, 7.4 mmol) in 1,4-dioxane (100 mL). Heat the reaction mixture to 100 °C and stir overnight. Cool the reaction mixture to room temperature, concentrate it under reduced pressure, and extract with ethyl acetate (3 x 20 mL). Combine the organic phases, wash the organic phase with saturated brine (60 mL), dry over anhydrous sodium sulfate, filter, and concentrate. Purify the resulting residue by silica gel column chromatography to obtain 1.35 g of (S)-4-(4-((4-((4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (Compound 116-1).

[0556] MS(ESI) M / Z: 657.2 [M+H] + .

[0557] Step 2: Dissolve compound 116-1 (1.35 g, 2.05 mmol) in 1,4-dioxane (10 mL). Subsequently, add a dioxane hydrochloride solution (15 mL) thereto. After the reaction solution was stirred overnight at room temperature, the reaction solution was concentrated under reduced pressure. It was extracted with dichloromethane (3 x 100 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. It was slurried with ethanol to obtain 818 mg of ((S)-N-(1-(((4-(piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 116).

[0558] MS(ESI) M / Z: 557.2 [M+H] + .

[0559] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.2 Hz, 0.4H), 7.51 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 5.62 - 5.49 (m, 1H), 3.95 - 3.83 (m, 1H), 3.83 - 3.65 (m, 4H), 3.57 - 3.43 (m, 2H), 3.27 - 3.17 (m, 4H), 2.89 - 2.76 (m, 4H), 2.46 - 2.33 (m, 3H), 2.26 - 2.12 (m, 1H), 2.02 - 1.83 (m, 3H), 1.64 - 1.46 (m, 2H).

[0560] Example 117

[0561] N-(1-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-3-yl)sulfonyl)piperidin-4-yl)-4-((((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine

[0562]

[0563] Step 1: Under room temperature and nitrogen protection, dissolve (S)-(-)-3-hydroxy tetrahydrofuran (365.0 mg, 0.83 mmol) in tetrahydrofuran (20 mL). Subsequently, add sodium hydride (335.0 mg, 1.1 mmol, 60% dispersed in mineral oil) to the above solution under an ice-water bath. After stirring the reaction solution under the ice-water bath for 10 minutes, slowly add Compound 1B-2 (1.0 g, 0.55 mmol) to the reaction solution. Heat the reaction system to 100 °C and stir for 2 hours. After cooling the reaction solution to room temperature, quench it with water (20 mL). Extract the mixture with ethyl acetate (15 mL × 3 times), combine the organic phases, wash the organic phase first with saturated brine (30 mL), then dry it over anhydrous sodium sulfate, filter, and finally concentrate it under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 0.85 g of tert-butyl (S)-4-(((4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (Compound 117-1).

[0564] MS(ESI) M / Z: 433.0 [M+H] + .

[0565] 1 H NMR(400 MHz, DMSO-d6) δ 8.36(s, 0.4H), 8.31(s, 0.5H), 8.01(d, J = 7.5 Hz, 0.5H), 7.82(d, J = 7.9 Hz, 0.4H), 5.61 - 5.55(m, 1H), 3.99 - 3.85(m, 3H), 3.82 - 3.68(m, 3H), 2.89(br.s., 2H), 2.31 - 2.16(m, 1H), 2.06 - 1.95(m, 2H), 1.91 - 1.76(m, 2H), 1.43 - 1.30(m, 11H).

[0566] Step 2: Under room temperature, dissolve Compound 117-1 (0.85 g, 1.9 mmol) in 1,4-dioxane (10 mL). Subsequently, add hydrogen chloride - dioxane solution (10 mL) to the above solution. Stir the reaction solution at room temperature for 16 hours. Concentrate the reaction solution under reduced pressure to obtain 0.7 g of (S)-N-(piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 117-2).

[0567] MS(ESI) M / Z: 333.4 [M+H] + .

[0568] Step 3: At room temperature, dissolve compound 117-2 (150.0 mg, 2.0 mmol) in dichloromethane (8 mL). Subsequently, under an ice-water bath, sequentially add N,N-diisopropylethylamine (774.0 mg, 6.0 mmol) and 6-chloropyridine-3-sulfonyl chloride (508 mg, 2.4 mmol) to the above reaction solution. Stir the reaction solution at room temperature for 16 hours. Quench the reaction by adding water (20 mL). Extract the mixture with dichloromethane (10 mL × 3 times), combine the organic phases, wash the organic phases with saturated brine (20 mL) first, then dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 105 mg of (S)-N-(1-(((6-chloropyridin-3-yl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (compound 117-3).

[0569] MS(ESI) M / Z: 508.0 [M+H] + .

[0570] 1 1H NMR (400 MHz, DMSO-d6) δ 8.81 - 8.75 (m, 1H), 8.30 (s, 1H), 8.24 - 8.18 (m, 1H), 8.02 (d, J = 7.4 Hz, 0.5H), 7.87 - 7.79 (m, 1.5H), 5.62 - 5.50 (m, 1H), 3.95 - 3.68 (m, 5H), 3.66 - 3.49 (m, 2H), 2.78 - 2.59 (m, 2H), 2.26 - 2.12 (m, 1H), 1.98 - 1.84 (m, 2H), 1.64 - 1.45 (m, 2H).

[0571] Step 4: At room temperature, dissolve (S)-N-(1-((6-chloropyridin-3-yl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.20 mmol) in n-butanol (1 mL). Subsequently, sequentially add N,N-diisopropylethylamine (0.10 mL, 0.59 mmol) and tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate (63 mg, 0.30 mmol) to the above reaction solution. Stir the reaction solution at 120 °C for 16 hours. After cooling the reaction solution to room temperature, concentrate it under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 120 mg of tert-butyl (2S,6R)-2,6-dimethyl-4-(5-((4-((((((S)-tetrahydrofuran-3-yl)oxy])-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-ylsulfonyl)pyridin-2-yl)piperazine-1-carboxylate (compound 117-4).

[0572] MS(ESI) m / z: 686.2 [M+H] + .

[0573] Step 5: At room temperature, dissolve compound 117-4 (120.0 mg, 0.18 mmol) in 1,4-dioxane (0.5 mL). Subsequently, add hydrogen chloride-dioxane solution (1 mL) thereto. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was quenched with saturated aqueous sodium bicarbonate solution (3 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 69.3 mg of N-(1-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-3-yl)sulfonyl)piperidin-4-yl)-4-((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 117).

[0574] MS(ESI) m / z: 586.2 [M+H] + 。

[0575] 1 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 2.4 Hz, 1H), 8.29 (s, 1H), 8.02 (d, J = 7.4 Hz, 0.6H), 7.87 (d, J = 7.5 Hz, 0.4H), 7.71 (dd, J = 9.2, 2.5 Hz, 1H), 6.95 (d, J = 9.1 Hz, 1H), 5.60 - 5.52 (m, 1H), 4.31 (d, J = 12.1 Hz, 2H), 3.95 - 3.85 (m, 1H), 3.84 - 3.68 (m, 4H), 3.58 - 3.44 (m, 2H), 2.75 - 2.67 (m, 2H), 2.59 - 2.54 (m, 2H), 2.46 - 2.34 (m, 3H), 2.26 - 2.12 (m, 1H), 2.04 - 1.81 (m, 3H), 1.64 - 1.48 (m, 2H), 1.03 (d, J = 6.2 Hz, 6H).

[0576] Example 168

[0577] N-(1-((4-((3S,5S)-3,5-dimethylpiperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-4-((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine

[0578]

[0579] Step 1: Under nitrogen protection, dissolve compound 99 (25 g, 45.3 mmol), tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate (11.6 g, 45.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.1 g, 4.53 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.3 g, 9.02 mmol) and cesium carbonate (29.4 g, 90.6 mmol) in 1,4-dioxane (1.25 L). Heat the reaction mixture to 100 °C and stir overnight. Concentrate the reaction mixture under reduced pressure and extract with ethyl acetate (3 x 100 mL). Combine the organic phases, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate. Purify the resulting residue by silica gel column chromatography to obtain 18.1 g of tert-butyl (2S,6S)-2,6-dimethyl-4-(4-((S)-tetrahydrofuran-3-yloxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazine-1-carboxylate (Compound 168-1).

[0580] MS(ESI) M / Z: 685.2 [M+H] + .

[0581] Step 2: Dissolve Compound 168-1 (18.1 g, 26.4 mmol) in 1,4-dioxane (100 mL). Subsequently, add hydrochloric acid in dioxane solution (100 mL) thereto. Stir the reaction mixture at room temperature overnight. Concentrate the reaction mixture under reduced pressure. Add saturated aqueous sodium bicarbonate solution (300 mL) to the resulting residue for washing, and extract the mixture with ethyl acetate (200 mL x 3 times). Combine the organic phases. Wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. Purify the resulting residue by silica gel column chromatography to obtain 9.2 g of N-(1-((4-((3S,5S)-3,5-dimethylpiperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-4-((S)-tetrahydrofuran-3-yloxy)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 168).

[0582] MS(ESI) M / Z: 585.2 [M+H] + .

[0583] 11H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.00 (d, J = 7.1 Hz, 0.6H), 7.85 (d, J = 6.9 Hz, 0.4H), 7.49 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 5.60 - 5.51 (m, 1H), 3.95 - 3.83 (m, 1H), 3.81 - 3.65 (m, 4H), 3.57 - 3.44 (m, 2H), 3.37 - 3.33 (m, 2H), 3.21 - 3.09 (m, 2H), 3.02 - 2.91 (m, 2H), 2.46 - 2.37 (m, 2H), 2.28 - 2.03 (m, 2H), 2.02 - 1.84 (m, 3H), 1.66 - 1.47 (m, 2H), 1.06 (d, J = 6.4 Hz, 6H).

[0584] Example 169

[0585] N-(1-((4-cis-3,5-dimethylpiperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-4-((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine

[0586]

[0587] Step 1: Under nitrogen protection, dissolve compound 99 (50 mg, 0.09 mmol), tert-butyl cis-2,6-dimethylpiperazine-1-carboxylate (23.1 mg, 0.108 mmol), tris(dibenzylideneacetone)dipalladium (8.2 mg, 0.009 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (8.6 mg, 0.018 mmol) and cesium carbonate (69.3 mg, 0.21 mmol) in 1,4-dioxane (5 mL). Heat the reaction mixture to 100 °C and stir overnight. Concentrate the reaction mixture under reduced pressure and extract with ethyl acetate (3 x 10 mL). Combine the organic phases, wash the organic phase with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate. Purify the resulting residue by silica gel column chromatography to obtain 40 mg of tert-butyl cis-2,6-dimethyl-4-(4-((4-((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazine-1-carboxylate (Compound 169-1).

[0588] MS(ESI) M / Z: 685.2 [M+H] + .

[0589] Step 2: Dissolve Compound 169-1 (40 mg, 0.06 mmol) in 1,4-dioxane (1 mL). Subsequently, add dioxane hydrochloride solution (1 mL) thereto. Stir the reaction mixture overnight at room temperature. Concentrate the reaction mixture under reduced pressure. Extract with ethyl acetate (8 x 3 mL), wash with saturated aqueous sodium bicarbonate (30 mL), and combine the organic phases. Wash the organic phase with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give 6 mg of N-(1-((4-cis-3,5-dimethylpiperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-4-((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 169).

[0590] MS(ESI) M / Z: 585.2 [M+H] + .

[0591] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.0 Hz, 0.4H), 7.50 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 9.1 Hz, 2H), 5.63 - 5.44 (m, 1H), 3.96 - 3.82 (m, 1H), 3.82 - 3.62 (m, 6H), 3.56 - 3.43 (m, 2H), 2.86 - 2.71 (m, 2H), 2.42 - 2.37 (m, 2H), 2.29 - 2.14 (m, 4H), 1.99 - 1.84 (m, 3H), 1.63 - 1.44 (m, 2H), 1.03 (d, J = 6.2 Hz, 6H).

[0592] The compounds given in Table 1 were prepared by substantially the same method as described in the examples.

[0593] Table 1. List of Compounds

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644] Biological test evaluation:

[0645] CDK in vitro enzymatic experiment

[0646] This experiment uses the method of capillary migration ability change experiment (MSA) to test the inhibitory effect of compounds on the kinase activities of CDK1 / CDK2 / CDK4 / CDK6 / CDK7 / CDK9, and obtains the half inhibitory concentration IC of the compounds on the kinase activities of CDK1 / CDK2 / CDK4 / CDK6 / CDK7 / CDK9 50 .

[0647] 1. Experimental materials

[0648] CDK1 / CDK2 / CDK4 / CDK6 / CDK7 / CDK9 were purchased from Carna, Carliper substrates CTD3 / Substrate 18 / Substrate 8 were purchased from Gil Biochemical, Dinaciclib / Palbociclib were purchased from Selleckchem, DMSO was purchased from Sigma, and 384-well plates were purchased from Corning.

[0649] 2. Experimental methods

[0650] (1) Prepare 1×Kinase buffer.

[0651] (2) Preparation of compound concentration gradients: The test concentrations of the test compounds started at 1 μM, 10 μM or 30 μM, were diluted 3-fold, with 10 concentrations, and duplicate wells were detected. Dilute to a 100-fold final concentration of 100% DMSO solution in a 384-source plate. Use a dispenser Echo 550 to transfer 250 nL of the compound at a 100-fold final concentration to the destination 384-well plate. Add 250 nL of DMSO to the positive and negative control wells.

[0652] (3) Prepare a kinase solution at 2.5-fold the final concentration with 1×Kinase buffer.

[0653] (4) Add 10 μL of the kinase solution at 2.5-fold the final concentration to the compound wells and the positive control wells; add 10 μL of 1×Kinase buffer to the negative control wells.

[0654] (5) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, mix the reaction plate by shaking, and incubate at room temperature for 10 minutes.

[0655] (6) Prepare a mixed solution of ATP and Kinase substrate at 25 / 15-fold the final concentration with 1×Kinase buffer.

[0656] (7) Add 15 μL of the mixed solution of ATP and substrate at 25 / 15-fold the final concentration to start the reaction.

[0657] (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, mix by shaking, and incubate at room temperature for the corresponding time.

[0658] (9) Add 30 μL of the termination detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and mix by shaking.

[0659] (10) Read the conversion rate with a Caliper EZ Reader.

[0660] Calculation formula:

[0661] % inhibition = (conversion%_max - conversion%_sample) / (conversion%_max - conversion%_min) × 100%

[0662] Where: Conversion%_sample is the conversion rate reading of the sample; Conversion%_min: the average value of the negative control wells, representing the conversion rate reading of the wells without enzyme activity; Conversion%_max: the average value of the positive control wells, representing the conversion rate reading of the wells without compound inhibition.

[0663] Fitting the concentration-effect curve

[0664] Using the log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis, the concentration-effect curve was fitted using the log(inhibitor) vs. response - Variable slope in the analysis software GraphPad Prism 5, so as to obtain the IC 50 value of each compound on enzyme activity.

[0665] Calculation formula: Y = Bottom + (Top - - Bottom) / (1 + 10^((LogIC 50 - X) * HillSlope)).

[0666] 3. Experimental results

[0667] The inhibitory IC 50 data of the compounds of the present invention on CDK kinase activity are shown in Table 2. Among them, compounds with IC 50 <10 nM are labeled with A, 10 nM ≤ IC 50 <50 nM compounds are labeled with B, 50 nM ≤ IC 50 <100 nM compounds are labeled with C, 100 nM ≤ IC 50 <1000 nM compounds are labeled with D, and compounds with IC 50 >1000 nM are labeled with E. Among them, compounds with less than IC 50 <10 nM, specifically, compounds with IC 50 <0.5 nM are represented by AA, 0.5 nM ≤ IC 50 <2.5 nM compounds are represented by AB, and 2.5 nM ≤ IC 50 <10 nM compounds are represented by AC.

[0668] Table 2: Enzymatic inhibition results of CDK1 / CDK2 / CDK4 / CDK6 / CDK7 / CDK9

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676] Conclusion: The compounds of the present invention have good CDK 2 / 4 / 6 kinase inhibitory activity, especially excellent in the inhibitory activity of CDK 2 kinase; the compounds of the present invention can selectively inhibit CDK 2 / 4 / 6 kinases, especially have good selectivity for CDK 2 kinase, and the inhibitory selectivity of some compounds for CDK 1 / 7 / 9 kinases relative to CDK 2 kinase can reach nearly 10 times, even dozens of times, more than a hundred times.

[0677] Cell proliferation inhibition experiment

[0678] HCC1806 / NIH: OVCAR-3 cell proliferation inhibition experiment

[0679] In this experiment, the CellTiter-Glo method was used to test the inhibitory effect of the compounds on the proliferation of HCC1806 / NIH: OVCAR-3 cells, and the concentration IC 50 (nM) at which the compounds inhibited half of the cell growth was obtained.

[0680] 1. Experimental materials

[0681] HCC1806 was purchased from Tongpai (Shanghai) Biotechnology Co., Ltd.; NIH: OVCAR-3 was purchased from the American Type Culture Collection (ATCC).

[0682] 1640 medium, fetal bovine serum (FBS), Penicillin-Streptomycin, and GlutaMAX-I Supplement were purchased from GIBCO.

[0683] PF-06873600 was purchased from Selleck.

[0684] CellTiter-Glo reagent was purchased from Promega.

[0685] 2. Experimental method

[0686] 1) Seed HCC1806 / NIH: OVCAR-3 cells into a 96-well culture plate at a density of 600 / 1500 cells per well, 100 μL per well.

[0687] 2) Day 0: Add 100 nL of the test compound diluted in a gradient to the cells in the culture plate using an Echo, with the final concentration of DMSO being 0.5%. Incubate the culture plate in a cell culture incubator for 168 hours (37 °C, 5% CO2). Add 30 nL of DMSO to each well as a blank control.

[0688] 3) Day 7: Add 30 μL of Cell Titer-Glo reagent to each well and incubate in the dark at room temperature for 30 minutes

[0689] 4) Detect the chemiluminescence signal using an Envision microplate reader (PerkinElmer).

[0690] Use GraphPad Prism 6 software for data analysis to obtain the IC 50 (nM) of the compound.

[0691] Experimental results and conclusions: After testing, the compound of the present invention has an IC 50 against cell proliferation of HCC1806 / NIH: OVCAR-3 cell line that can be less than 100 nM, showing better inhibitory effect than the reference compound PF-06873600.

[0692] In vivo pharmacodynamic experiment on HCC1806 human breast cancer model

[0693] Experimental materials:

[0694] HCC1806 was purchased from Tongpai (Shanghai) Biotechnology Co., Ltd.; NIH: OVCAR-3 was purchased from the American Type Culture Collection (ATCC).

[0695] RPMI 1640 medium, fetal bovine serum (FBS), and Penicillin-Streptomycin were purchased from GIBCO. PF-06873600 was purchased from MCE Company.

[0696] Experimental methods:

[0697] Collect cells in the logarithmic growth phase and inoculate them subcutaneously on the right side of BALB / c nude mice to establish a tumor model. The inoculation day was named D0. On the fourth day after inoculation (D4), when the average tumor volume reached about 150 mm 3 , select mice with moderate tumor volumes for grouping, 6 mice in each group. Start gavage administration on the day of grouping. Statistically analyze the body weight data and tumor volume data 2-3 times a week, and plot the body weight and tumor growth curves. Tumor volume V = 1 / 2 × a × b 2, where a and b represent the major and minor diameters of the tumor, respectively.

[0698] Experimental results and conclusions: After testing, the tumors in the treatment group administered with the compound of the present invention were effectively inhibited. Compared with the reference compound PF-06873600, the compound of the present invention had better tumor inhibitory effects, and the body weights of the mice did not significantly decrease, indicating that it could be well tolerated under each treatment regimen (10 mg / kg BID, 20 mg / kg BID, 30 mg / kg QD).

[0699] In vivo pharmacodynamic experiment of OVCAR-3 human ovarian cancer model

[0700] Experimental materials:

[0701] OVCAR-3 was purchased from the American Type Culture Collection (ATCC). RPMI 1640 medium, fetal bovine serum (FBS), and Penicillin-Streptomycin were purchased from GIBCO. PF-06873600 was purchased from MedChemExpress (MCE).

[0702] Experimental methods:

[0703] Cells in the logarithmic growth phase were collected and subcutaneously inoculated on the right side of BALB / c nude mice to establish a tumor model. The inoculation day was named D0. When the average tumor volume reached about 180 mm 3 at around 27 days after inoculation (D27), mice with moderate tumor volumes were selected for grouping, with 6 mice in each group. Gavage administration started on the day of grouping and continued for 21 days. Body weight data and tumor volume data were statistically analyzed 2 - 3 times a week, and body weight and tumor growth curves were plotted. Tumor volume V = 1 / 2 × a × b 2 , where a and b represent the major and minor diameters of the tumor, respectively.

[0704] Experimental results and conclusions: After testing, the tumors in the treatment group administered with the compound of the present invention were effectively inhibited. Compared with the reference compound PF-06873600, the compound of the present invention had better tumor inhibitory effects, and the body weights of the mice did not significantly decrease, indicating that it could be well tolerated under each treatment regimen (5 mg / kg BID, 7.5 mg / kg BID, 10 mg / kg QD, 20 mg / kg QD).

Claims

1. A compound represented by formula (I-A), or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from -CN or C 1-4 haloalkyl; Z is selected from -CH- or N; L is -NR a -, -O-, -S-, -SO2-, -SO-, -CR a R b -, or -CH=, where R a and R b are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl; R2 is selected from C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or C 5-10 aryl, wherein the C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or C 5-10 aryl is optionally substituted with one or more R d ; the R d are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, -(CH2) m OH or -(CH2) m NR e R f ; R3 is selected from C 1-4 alkyl, -L1-C 5-10 aryl, -L1-(5- or 6-membered heteroaryl) or -L1-(3- to 6-membered heterocycloalkyl), wherein the C 5-10 aryl, 5- or 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl are optionally substituted by one or more R g substituents, and R g is R ga or R gb ; R ga each independently selected from H, halogen, -OH, C 1-4 alkyl, -(CH2) m NR e R f 、R e R f NC(O)-C 1-4 alkyl-, -C 1-4 alkyl-OH, -S(O)2-(5-6 membered heteroaryl) or C 1-4 alkoxy; R gb each independently selected from -L2-(3-6 membered heterocycloalkyl), -L2-(3-6 membered heterocycloalkenyl), -L2-(5-6 membered heteroaryl), -L2-(7-11 membered spiroheterocyclic group), -L2-(6-14 membered fused heterocyclic group), wherein R gb the 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, 7-11 membered spiroheterocyclic group, 6-14 membered fused heterocyclic group described in gc is optionally substituted by one or more R R gc each independently selected from C 1-4 alkyl, C 1-4 haloalkyl, -(CH2) m NR e R f 、-(CH2) m OH or cyano; or any two Rs gc are connected to form a 1-2 C alkylene chain; L1 is a bond; L2 is a bond or is independently selected from C 1-4 alkylene or NH; R e With R f Each independently selected from H or C 1-4 Alkyl m is independently selected from 0, 1 or 2; R4, R4 ’ R5 is independently selected from H, OH, halogen, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy; And, when L is -NH-, R2 is not The compound represented by the formula (I-A) is not any of the following compounds:

2. The compound of formula (I-A) as claimed in claim 1, or its stereoisomer or pharmaceutically acceptable salt, wherein, the compound is represented by formula (I-B), wherein, R1 is selected from -CN, or C 1-4 haloalkyl; Z is selected from -CH- or N; L is -NR a -, -O-, -S-, -SO2-, -SO-, -CR a R b -, or -CH=, where the R a and R b are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl; R2 is selected from C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl or C 5-10 aryl, wherein the C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl or C 5-10 aryl is optionally substituted by one or more R d ; the R d are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, -(CH2) m OH or -(CH2) m NR e R f ; R3 is selected from C 1-4 alkyl, -L1-C 5-10 aryl, -L1-(5- to 6-membered heteroaryl) or -L1-(3- to 6-membered heterocycloalkyl), wherein the C 5-10 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl are optionally substituted by one or more R g substituents, and R g is R ga or R gb ; R ga each independently selected from H, halogen, -OH, C 1-4 alkyl, -(CH2) m NR e R f 、R e R f NC(O)-C 1-4 alkyl-, -C 1-4 alkyl-OH or -S(O)2-(5-6-membered heteroaryl); R gb is independently selected from -L2-(3-6 membered heterocycloalkyl), -L2-(3-6 membered heterocycloalkenyl), or -L2-(5-6 membered heteroaryl), where the 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl as described in R gb is optionally substituted by one or more R gc groups; R gc each independently selected from C 1-4 alkyl, C 1-4 haloalkyl, -(CH2) m NR e R f or -(CH2) m OH; L1 is a bond; L2 is a key or is independently selected from C 1-4 alkylene; R e and R f each independently selected from H or C 1-4 alkyl; m is independently selected from 0, 1 or 2; R4 and R5 are each independently selected from H, OH, halogen, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy.

3. The compound of formula (I-A) as claimed in claim 1, or its stereoisomer or pharmaceutically acceptable salt, wherein, R1 is selected from -CN, -CF3 or -CHF2.

4. The compound represented by formula (I-A) as claimed in claim 3, or its stereoisomer or pharmaceutically acceptable salt, wherein, R1 is selected from -CN or -CF3.

5. The compound represented by formula (I-A) as described in claim 4, or its stereoisomer or pharmaceutically acceptable salt, wherein, R1 is selected from -CF3.

6. The compound of formula (I-A) as claimed in claim 1, or its stereoisomer or pharmaceutically acceptable salt, wherein, Z is selected from N.

7. The compound of formula (I-A) as claimed in claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, L is selected from -NH-, -N(CH3)-, -O-, -S-, -CH2-, -CH═, -SO2-, -SO- or 8. The compound of formula (I-A) as claimed in claim 7, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, L is selected from -NH- or -O-.

9. The compound of formula (I-A) as claimed in claim 1, or its stereoisomers or pharmaceutically acceptable salts, wherein, R2 is selected from wherein, M is independently selected from -O- or -NR a -, R a and R d As defined in claim 1, n is independently 0, 1, 2, 3 or 4.

10. The compound of formula (I-A) as described in claim 9, or its stereoisomer or pharmaceutically acceptable salt, wherein, R2 is selected from 11. The compound of formula (I-A) as claimed in claim 9, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R2 is selected from 12. The compound of formula (I-A) as described in claim 9, or its stereoisomer or pharmaceutically acceptable salt, wherein, R2 is selected from 13. The compound of formula (I-A) as claimed in claim 1, or its stereoisomer or pharmaceutically acceptable salt, wherein, R3 is selected from methyl, isopropyl, where M and n are as defined in claim 9, R ga and R gc and L1, L2 are as defined in claim 1.

14. The compound represented by formula (I-A) according to claim 13, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from 15. The compound represented by formula (I-A) according to claim 13, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from methyl, isopropyl, 16. The compound represented by formula (I-A) as described in claim 15, or its stereoisomer or pharmaceutically acceptable salt, wherein, R3 is selected from 17. The compound represented by formula (I-A) as claimed in claim 1, or its stereoisomer or pharmaceutically acceptable salt, wherein, R4 and R5 are independently selected from H, F, OH, CH3.

18. The compound of formula (I-A) as described in claim 17, or its stereoisomer or pharmaceutically acceptable salt, wherein, R4 and R5 are selected from H.

19. A compound of formula (I-A) as described in any one of claims 1-18, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein, the compound is represented by formula (II), wherein, R1, R2, R3, R4, R5, L are defined as in any one of claims 1-18.

20. The compound of formula (I-A) as described in claim 19, or its stereoisomer or pharmaceutically acceptable salt, wherein, the compound is represented by any one of the structures of formula (II-A), formula (II-B) and formula (II-C), wherein, R1, R2, R4, R5, and L are as defined in claim 19, and R g is as defined in any one of claims 1 to 18; and n is as defined in claim 9.

21. The compound represented by formula (I-A) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 20, wherein the compound is represented by any one of the following structures, wherein, Z1 is selected from C, CH or N; Z2 is selected from CH2, NH or O; R1, R2, R4, R5, L, and n are as defined in claim 20; R ga , R gc is as defined in any one of claims 1-18.

22. The compound represented by formula (I-A) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 21, wherein the compound is represented by any one of the following structures, wherein, R1, L, n, R ga , R gc , R4, R5, Z1, Z2 are as defined in claim 21; R d as defined in claim 1; M is defined as in claim 9.

23. The compound represented by formula (I-A) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 22, wherein the compound is represented by any one of the following structures, wherein, R1, L, R d , n, R ga , R gc , R4, R5 are as defined in claim 22.

24. The compound represented by formula (I-A) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 19, wherein the compound is represented by any one of the following structures, Among them, R3, R gb , R gc , n are as defined in any one of claims 1 - 18.

25. The compound represented by formula (I-A) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by the following structure, Among them, R3, R gb , R gc , n are as defined in any one of claims 1 - 18.

26. The compound represented by formula (I-A) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by the following structure, wherein, R1 is selected from -CN or -CF3; L is selected from -NH- or -O-; R2 is selected from R4 and R5 are independently selected from H or F; Z1 is selected from C, CH or N; Z2 is selected from CH2, NH or O; R gb and R gc and n are as defined in any one of claims 1 to 18.

27. The compound represented by formula (I-A) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula (I-A) is selected from any one of the following structures, 28. A pharmaceutical composition comprising the compound represented by formula (I-A) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-27, and a pharmaceutically acceptable carrier, diluent or excipient.

29. Use of the compound represented by formula (I-A) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-27, or the pharmaceutical composition according to claim 28 in the preparation of a medicament for treating CDK-mediated cancer.

30. The application according to claim 29, wherein the cancer includes ovarian cancer, breast cancer, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL).

31. A compound represented by any of the following structures or its stereoisomers, pharmaceutically acceptable salts, Among them, R1, R ga , R gc , n are as defined in any one of claims 1 - 27; X is selected from halogen.

32. A compound represented by formula (IV-1) and (IV-2) or its stereoisomers, pharmaceutically acceptable salts, Among them, X is selected from halogen, OH, -SO2Me, -OMs, OTf, OTs; X1 is selected from halogen, OH, -SO2Me, -OMs, OTf, OTs.

33. The compound or its stereoisomer or pharmaceutically acceptable salt shown by formula (IV-1) and (IV-2) as claimed in claim 32, wherein, X is selected from halogen; X1 is selected from halogen.

34. Use of the compound according to any one of claims 31-33 in the preparation of the compound according to any one of claims 1-27 or its stereoisomers or pharmaceutically acceptable salts.

Images