A compound having antitumor activity and uses thereof

Abstract

The application provides a compound with a brand-new structure as a PRMT5 inhibitor, a preparation method of the compound and the use of the compound in treating diseases mediated by the PRMT5 inhibitor. Experiments prove that the compounds have strong inhibitory effect on PRMT5 enzyme, and can be used as promising compounds for treating diseases mediated by the PRMT5 inhibitor. In addition, the application studies a specific synthesis method, which is simple in process, convenient to operate, beneficial to large-scale industrial production and application.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to compounds serving as PRMT5 inhibitors, and preparation methods and uses of the compounds. Background Art

[0002] PRMT5, short for Protein arginine N-methyltransferase 5, is a novel anti-tumor target associated with epigenetic modifications. It has several aliases, including Hsl7, Jbp1, Skb1, Capsuleen, and Dart5. PRMT5 is the primary enzyme for arginine monomethylation and symmetrical dimethylation. A growing body of research demonstrates that protein arginine methyltransferases (PRMTs) play a key role in diverse biological processes, such as cell growth and proliferation, apoptosis, and metastasis.

[0003] Protein arginine methyltransferases (PRMTs) transfer a methyl group from S-adenosylmethionine (AdoMet or SAM) to arginine residues on histones or other proteins, forming methylarginine and S-adenosylhomocysteine ​​(SAH). Currently, nine members of this family (PRMT1–9) have been identified. PRMTs can be divided into three types based on the different ways they catalyze arginine methylation: type I PRMTs include PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8, which catalyze monomethylarginine (MMA) and asymmetric dimethylarginine (aDMA); type II PRMTs include PRMT5 and PRMT9, which catalyze MMA and symmetric dimethylarginine (sDMA); and type III PRMTs are PRMT7, which can only methylate monomethylation. PRMT5, an epigenetic enzyme, symmetrically methylates arginine residues on histone and non-histone substrates, affecting multiple target genes and signaling pathways. It plays a crucial role in protein methylation, including involvement in alternative splicing, post-transcriptional regulation, RNA processing, cell proliferation, cell differentiation, apoptosis, and tumor formation. Selective inhibition of PRMT5 could be a potentially powerful new anticancer drug. Research into the development of new drugs targeting PRMT5 has the potential to address unmet clinical needs.

[0004] Over the past few years, there have been numerous reports on PRMT5 inhibitors, such as those in WO2014100719A, WO2019102494A, WO2015200677A, WO2015200680A, WO2014100764A, WO2014100730A, WO2014100716A, WO2014100695A, WO2019173804A, CN108570059 A, and WO2018167269A. Two compounds, JNJ-64619178 and GSK-3326595, have already entered clinical trials for the treatment of solid tumors and mantle cell lymphoma.

[0005]

[0006] JNJ-64619178 is a selective PRMT5 inhibitor developed by Johnson & Johnson that inhibits the growth of various tumor cells in vitro. Johnson & Johnson has demonstrated its potent anti-tumor activity in a wide range of xenograft animal models, including small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), acute myeloid leukemia (AML), and non-Hodgkin lymphoma. Significant tumor growth inhibition of up to 99% was observed in these models, with sustained growth inhibition for weeks after drug discontinuation. JNJ-64619178 inhibits Sym-Arg dimethylation of SMD1 / 3 proteins, core components of the tumor spliceosome, as well as Sym-Arg dimethylation of serum proteins. These can serve as pharmacodynamic markers of PRMT5's ability to inhibit tumor growth in xenograft models. In SCLC models, potent and long-term inhibition of SMD1 / 3 dimethylation by PRMT5 was observed both during and after dosing. Based on these high selectivity and efficacy, favorable pharmacokinetics and safety profiles, and significant preclinical efficacy and pharmacodynamic results, JNJ-64619178 entered Phase I clinical trials in 2018.

[0007] GSK-3326595, derived from EPZ015666 (structure shown below), is a highly selective, orally available small molecule and a first-generation PRMT5 inhibitor. EPZ015666 has demonstrated significant in vitro and in vivo activity in mantle cell lymphoma. After two years of optimization and preclinical studies, GlaxoSmithKline (GSK) announced in September 2016 that GSK-3326595 had entered clinical trials. At the 2019 ESMO Congress, GSK presented Phase I clinical data for GSK-3326595. The Phase I trial of GSK-3326595 enrolled adult patients with solid tumors. The primary objectives were safety, tolerability, and PK / PD testing, as well as efficacy data (ORR and DCR). The data demonstrated a dose-dependent PK response in plasma.

[0008]

[0009] Although several small molecule PRMT5 inhibitors have been developed, none have yet been developed and marketed. Therefore, there is an urgent need to develop new compounds with potential for market development and improved efficacy and pharmacokinetic properties. The present invention designs a series of compounds with novel structures represented by the general formula and finds that these compounds exhibit excellent efficacy and effects, which has positive implications for the development of PRMT5 inhibitors. Summary of the Invention

[0010] The object of the present invention is to provide a compound with a novel structure as a PRMT5 inhibitor, a method for preparing the compound, and its use in treating diseases mediated by PRMT5 inhibitors.

[0011] In the first aspect of the present invention, there is provided a compound represented by the following formula (I), and its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs:

[0012]

[0013] Among them, L 1 and L 2 Each independently selected from -C(R 1 )(R 2 )-、-C(R 1 )(R 2 )C(R 1 )(R 2 )-、-C(R 1 )(R 2 )C(R 1 )(R 2 )C(R 1 )(R2 )-one of them; among them, R 1 、R 2 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, -OR 3 、-NHR 3 、-NR 3 R 4 One of them; R 3 、R 4 Each occurrence is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl.

[0014] X is selected from C(R 5 ) or N; wherein R 5 Each occurrence is independently selected from one of hydrogen, halogen, hydroxy, thiol, amino, and cyano;

[0015] Y is selected from -(chemical bond), -H, -OH, -NH2, halogen, -O-, -S-, -CO-, -C(R 6 )F-, -CF2-, -SO-, -SO2-, -(CH2) p N(R 6 )-、-N(R 6 )(CH2) p -、-S(O)N(R 6 )-、-S(O)2N(R 6 )-、-N(R 6 )SO-、-N(R 6 )S(O)2-、-C(O)N(R 6 )-、-N(R 6 )C(O)-、-CH(R 6 )-one of them; wherein, p=0, 1, 2 or 3; R 6 may be selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclic group; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently selected from halogen, hydroxyl, thiol, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6substituted with a substituent selected from the group consisting of hydrogen, halogen, hydroxy, thiol, amino, cyano, optionally substituted R 4 absent;

[0016] Z is selected from the group consisting of -(a chemical bond), -O-, -S-, -CO-, -N(R 7 )-, -S(O)N(R 7 )-, -S(O)2N(R 7 )-, -N(R 7 )SO-, -N(R 7 )S(O)2-, -C(O)N(R 7 )-, -N(R 7 )C(O)-, -N(R 7 )C(O)N(R 7 )-, -CH(R 7 )-, wherein each occurrence of R 7 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 4-6 membered heterocyclyl, wherein the optional substitution means that the hydrogen on the substituent group is unsubstituted or one or more substitutable sites on the substituent group are independently substituted with a substituent selected from the group consisting of halogen, hydroxy, thiol, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;

[0017] G 1 is independently selected from the group consisting of hydrogen, halogen, hydroxy, thiol, amino, cyano, C 1-5 straight chain alkyl or branched chain alkyl;

[0018] G 2 is selected from the group consisting of hydrogen, halogen, hydroxy, thiol, amino, cyano, optionally substituted R 8 , optionally substituted -O(R 8 ), optionally substituted -S(R 8 ), optionally substituted -NH(R 8 ), optionally substituted -N(R 8 )(R 8 ), wherein each occurrence of R 8 is independently selected from the group consisting of C 1-6 alkyl, C 3-6Cycloalkyl, 4-6 membered heterocyclic group; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently selected from halogen, hydroxyl, thiol, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 substituted by a cycloalkyl group, a 4-6 membered heterocyclic group, an aryl group, or a 5-6 membered heteroaryl group;

[0019] G 3 Selected from optionally substituted C 6-10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C 3-7 One of cycloalkyl, optionally substituted 4-10 membered heterocyclic group; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R 16 Replaced by, where R 16 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, -R 9 、-OR 9 、-SR 9 、SO(R 9 )、-SO2(R 9 ), -COOR 9 、-NH(R 9 )、-N(R 9 )(R 10 ),-CONHR 9 、-CON(R 9 )(R 10 )、-SONH(R 9 )、-SON(R 9 )(R 10 )、SO2NH(R 9 )、-SO2N(R 9 )(R 10 ); where R 9 、R 10 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 3-6 One or more substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;

[0020] G 4 Selected from the following groups: optionally substituted C1-12 Alkyl, optionally substituted C 2-12 Alkenyl, optionally substituted C 2-12 Alkynyl, optionally substituted C 3-12 Cycloalkyl, optionally substituted 4-10 membered heterocyclic group, optionally substituted C 6-10 Aryl, one of an optionally substituted 5-10 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R 17 Replacement, R 17 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, carbonyl, -R 11 、-OR 11 、-SR 11 、-NH(R 11 )、-N(R 11 )(R 11 ), Among them, R 11 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 3-6 One or more substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; D is independently selected from a bond, -CH2-, -C(=O)-, -NH-, -N(CH3)-, -O-, -S-, and f is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8 at each occurrence;

[0021] m=0 or 1. When m=1, A can be selected from -N(R 12 )-、-CH(R 12 )- or -CH(NHR 12 )-, where R 12 Can be selected from hydrogen, hydroxyl, halogen, C 1-6 Alkyl, C 3-6 One of cycloalkyl and 4-6 membered heterocyclic group; when m=0, A does not exist;

[0022] B can be selected from -N- or -CH-;

[0023] n=0 or 1. When n=1, E can be selected from -NR 13 -or-C(R 13 )(R 13 )-,R 13 Each occurrence is independently selected from hydrogen, hydroxy, halogen, C1-6 Alkyl, C 3-6 One of cycloalkyl and 4-6 membered heterocyclic group; when n=0, E does not exist;

[0024] At least one of A, B, and E is a nitrogen atom that meets the respective definitions;

[0025] o = 0, 1, 2 or 3;

[0026] H ring is selected from C 6-10 One of an aryl ring and a 5-10 membered heteroaryl ring; the aryl ring or heteroaryl ring may be substituted by one or more R 15 Independently substituted, where R 15 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, optionally substituted -R 14 , optionally substituted -OR 14 , optionally substituted -NHR 14 , optionally substituted -N(R 14 )(R 14 ); where R 14 Each occurrence is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, aryl, 5-6 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently selected from halogen, hydroxyl, thiol, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The alkyl group is substituted by a substituent of a cycloalkyl group, a 4-6 membered heterocyclic group, an aryl group, or a 5-6 membered heteroaryl group.

[0027] In a preferred embodiment of the present invention, the compound represented by formula (I) is further represented by formula (II)A, (II)B or (II)C:

[0028]

[0029]

[0030] Wherein, the substituents in formula (II)A, (II)B and (II)C are defined as described in formula (I).

[0031] In a further preferred embodiment, R 1 、R 2 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 3-6Cycloalkyl, 4-6 membered heterocyclic group, -OR 3 、-NH(R 3 )、-N(R 3 )(R 4 ) one of them; R 3 、R 4 Each occurrence is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, aryl, 5-6 membered heteroaryl. More preferably, R 1 、R 2 Each occurrence is independently one of hydrogen, halogen, hydroxy, amino, methyl, methylamino, and dimethylamino; most preferably, hydrogen.

[0032] In some preferred embodiments of the present invention, X is preferably selected from one of CH, C(OH), and N.

[0033] Preferably, Y is selected from -(chemical bond), -H, -OH, -NH2, halogen, -O-, -S-, -CO-, -C(R 6 )F-, -CF2-, -SO-, -SO2-, -(CH2) p N(R 6 )-、-N(R 6 )(CH2) p -、-S(O)N(R 6 )-、-S(O)2N(R 6 )-、-N(R 6 )SO-、-N(R 6 )S(O)2-、-C(O)N(R 6 )-、-N(R 6 )C(O)-、-CH(R 6 )-one of them, wherein p=0, 1, 2 or 3; R 6 Can be selected from hydrogen, C 1-6 Alkyl, C 3-6 One of cycloalkyl and 4-6 membered heterocyclic groups, when Y is selected from one of -H, -OH, -NH2, and halogen, G 4 Does not exist.

[0034] More preferably, Y is selected from -(chemical bond), -H, -OH, -NH2, -NH-, -O-, -S-, -CO-, -CHF-, -CF2-, -SO-, -SO2-, -(CH2) pOne of NH-, -N(CH3)-, -S(O)NH-, -S(O)2NH-, -NHSO-, -NHS(O)2-, -C(O)NH-, -NHC(O)-, and -CH2-, wherein p=1, 2 or 3.

[0035] Most preferably, Y is selected from one of -(chemical bond), -H, -OH, -NH2, -NH-, -CH2NH-, -(CH2)2NH-, -N(CH3)-, -O-, and -S-.

[0036] In some preferred embodiments of the present invention, Z is selected from -(chemical bond), -O-, -S-, -CO-, -N(R 7 )-、-S(O)N(R 7 )-、-S(O)2N(R 7 )-、-N(R 7 )SO-、-N(R 7 )S(O)2-、-C(O)N(R 7 )-、-N(R 7 )C(O)-、-N(R 7 )C(O)N(R 7 )-、-CH(R 7 ) - one of which R 7 Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 3-6 One of cycloalkyl and 4-6 membered heterocyclic group.

[0037] More preferably, Z is selected from one of -(chemical bond), -O-, -S-, -CO-, -NH-, -S(O)NH-, -S(O)2NH-, -NHSO-, -NHS(O)2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, and -CH2-.

[0038] Most preferably, Z is selected from one of -(chemical bond), -O-, -S-, -CO-, -NH-, -C(O)NH-, and -CH2-.

[0039] In some preferred embodiments of the present invention, G 1 Each occurrence is independently selected from one of hydrogen, halogen, hydroxyl, thiol, amino, cyano, and methyl; more preferably, G 1 Selected from hydrogen.

[0040] In some preferred embodiments of the present invention, G 2 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, -R 8 、-O(R 8 )、-S(R8 )、-NH(R 8 )、-N(R 8 )(R 8 ) one of which R 8 Each occurrence is independently selected from C 1-6 Alkyl, C 3-6 One of cycloalkyl and 4-6 membered heterocyclic group; more preferably, G 2 is selected from one of hydrogen, halogen, hydroxyl, thiol, amino, cyano, -CH3, cyclopropyl, -OCH3, -SCH3, -NHCH3, -N(CH3)(CH3), -NH(CH3); most preferably, G 2 Selected from hydrogen, fluorine, hydroxyl, amino.

[0041] In some preferred embodiments of the present invention, G 3 Selected from optionally substituted C 6-10 One of aryl and optionally substituted 5-10 membered heteroaryl, wherein the heteroatom in the 5-10 membered heteroaryl is N, O, S, and the number of heteroatoms is 1, 2, 3 or 4, and the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R 16 replaced.

[0042] In a further preferred embodiment of the present invention, G 3 is one of an optionally substituted 6-10 membered aryl group and an optionally substituted 5-10 membered heteroaryl group, wherein the 6-10 membered aryl group or the 5-10 membered heteroaryl group is selected from:

[0043] One of them, the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R 16 replaced.

[0044] More preferably, R 16 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, methyl, methoxy.

[0045] In some preferred embodiments of the present invention, G 4 Selected from the following groups: optionally substituted C 3-12 Cycloalkyl, optionally substituted 4-10 membered heterocyclic group, optionally substituted C 6-10 One of aryl and optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R 17 Replacement, R 17each occurrence is independently selected from hydrogen, halogen, hydroxyl, thiol, amino, cyano, carbonyl, -R 11 11 11 11 11 11 wherein, R 11 each occurrence is independently selected from C 1-6 alkyl, C 3-6 alkenyl, C 1-6 alkynyl, C 2-6 cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl, which can be optionally substituted with one or more of hydrogen, halogen, hydroxyl, thiol, amino, cyano, C 2-6 alkyl, C 3-6 alkenyl, C 4 alkynyl, C 17 cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; D each occurrence is independently selected from a bond, -CH2-, -C(=O)-, -NH-, -N(CH3)-, -O-, -S-,

[0046] In still further preferred embodiments of the application, G 4 is selected from:

[0047]

[0048] one of the above groups, wherein the above groups are optionally substituted with one or more R 17 at any substitutable position of the group.

[0049] Preferably, R 17 each occurrence is independently selected from hydrogen, halogen, hydroxyl, thiol, amino, cyano, carbonyl, sulfoxide, sulfone, -R 11 , - OR 11 , - SR 11 , -NH(R 11 ), -N(R 11 )(R 11 ),

[0050] Preferably, R 11 ​​one of hydrogen, hydroxyl, cyano, amino, trifluoromethyl, difluoromethyl, trifluoroethyl, difluoroethyl, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, t-butyl, s-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, cyclopropyloxy, n-butyloxy, i-butyloxy, t-butyloxy, s-butyloxy, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl.

[0051] In some preferred embodiments of the present application, A is absent.

[0052] In some preferred embodiments of the present application, B is selected from N.

[0053] In some preferred embodiments of the present application, n = 1, E is selected from -CH(R 13 )- or -N(R 13 )-, R 13 is selected from one of hydrogen, hydroxyl, halogen, methyl; more preferably, n = 1, E is selected from -CH2- or -NH-.

[0054] In some preferred embodiments of the present application, o = 0, 1 or 2, more preferably, o = 1.

[0055] In some preferred embodiments of the present application, H ring is selected from one of phenyl ring, 5-6 membered heteroaryl ring, 5-membered and 6-membered heteroaromatic ring, 6-membered and 5-membered heteroaromatic ring, which can be independently substituted by one or more R 15 , wherein R 15 is selected from one of hydrogen, halogen, hydroxyl, thiol, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl.

[0056] As one of the preferred options, H ring is phenyl ring, which can be independently substituted by one or more R 15 .

[0057] As one of the preferred options, H ring is 5-6 membered heteroaryl ring, selected from:

[0058] which can be independently substituted by one or more R 15 .

[0059] As one of the preferred options, H ring is 5-membered and 6-membered heteroaromatic ring, selected from:

[0060] The 5- and 6-membered heteroaromatic rings can be independently substituted by one or more R 15 substituents.

[0061] As a preferred option, the H ring is a 6- and 5-membered heteroaromatic ring selected from the group consisting of:

[0062] The 6- and 5-membered heteroaromatic rings can be independently substituted by one or more R 15 substituents.

[0063] Further preferably, R 15 is selected from the group consisting of hydrogen, halogen, hydroxyl, thiol, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl.

[0064] In a preferred embodiment of the present application, there is provided a compound according to Formula (II) A, Formula (II) B or Formula (II) C, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled analogs thereof,

[0065]

[0066] wherein X is N, B is N, m = 0, o = 1, n = 1, E is -C(R 13 )(R 13 ), wherein R 13 is, at each occurrence, independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 3-6 cycloalkyl, preferably from the group consisting of hydrogen and halogen, more preferably hydrogen; the H ring is a benzene ring and can be independently substituted by one or more R 15 , wherein R 15 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 3-6 cycloalkyl, preferably from the group consisting of hydrogen and halogen, more preferably hydrogen; G 1 is, at each occurrence, independently selected from the group consisting of hydrogen, halogen, C 1-5 straight chain alkyl or branched chain alkyl, preferably from the group consisting of hydrogen and halogen, more preferably hydrogen; G 2 is selected from the group consisting of hydroxyl, thiol, amino and cyano, preferably from the group consisting of hydroxyl, thiol and amino; more preferably hydroxyl; the groups R 1 , R 2 , Z, G 3 , Y, G 4 are defined as described above in the definition of Formula (I), preferably as described in the following embodiments.

[0067] In a preferred embodiment of the present invention, there is provided a compound represented by formula (II) A, formula (II) B or formula (II) C, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs thereof, wherein R 1 、R 2 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, -OR 3 、-NH(R 3 ) and -N(R 3 )(R 4 ), R 3 、R 4 Each occurrence is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; preferably, R 1 、R 2 Each occurrence is independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and -OC 1-6 Alkyl is more preferably selected from hydrogen, halogen and methyl, and most preferably hydrogen.

[0068] In a preferred embodiment of the present invention, a compound represented by formula (II)A, formula (II)B or formula (II)C, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs thereof are provided, wherein Z is selected from -(chemical bond) and -CO-, preferably -CO-.

[0069] In a preferred embodiment of the present invention, there is provided a compound represented by formula (II) A, formula (II) B or formula (II) C, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs thereof, wherein G 3 Selected from optionally substituted C 6-10 Aryl and optionally substituted 5-10 membered heteroaryl, wherein the heteroatom in the 5-10 membered heteroaryl is N, O, S, and the number of heteroatoms is 1, 2, 3 or 4, preferably 1 or 2; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R 16 Replaced by R 16 The definitions of are as described above in the definition of formula (I), preferably as described in the following embodiments.

[0070] In a preferred embodiment of the present invention, there is provided a compound represented by formula (II) A, formula (II) B or formula (II) C, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs thereof, wherein G 3 Selected from optionally substituted More preferably, optionally substituted The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R 16 Replaced by, where R 16 The definition of is as described above in formula (I); further preferably, R 16 Each occurrence is independently selected from hydrogen, halogen, -R 9 、-OR 9 、-SR 9 、SO(R 9 )、-NH(R 9 )、-N(R 9 )(R 10 ), where R 9 、R 10 Each occurrence is independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-6 One or more optionally substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, aryl and 5-6 membered heteroaryl.

[0071] More preferably, R 16 Each occurrence is independently selected from hydrogen, halogen, methyl, methoxy.

[0072] More preferably, R 16 Each occurrence is independently selected from ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-pentyloxy, isopentyl, trifluoromethyl, methoxy, amino, methylamino, dimethylamino, phenyl, pyridyl, vinyl, ethynyl, -OCF3, -SCH(CH3)2, -OCH(CH2CH3)2, -S(O)CH(CH3)2,

[0073] In a preferred embodiment of the present invention, a compound represented by formula (II)A, formula (II)B or formula (II)C, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs thereof are provided, wherein Y is selected from -(chemical bond), -NH-, -O-, -S-, -SO-, -SO2-, -N(CH3)-, -S(O)NH-, -S(O)2NH-, -NHSO and -NHS(O)2-; more preferably, Y is selected from -(chemical bond), -S-, -O- and -NH-; further preferably, Y is -NH-.

[0074] In a preferred embodiment of the present invention, there is provided a compound represented by formula (II) A, formula (II) B or formula (II) C, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs thereof, wherein G 4 The definition of is as described in the above embodiments, more preferably, G 4 Selected from Most preferably Among them, there are one or more R 17 A substituent is located at any substitutable position of a group.

[0075] In a preferred embodiment of the present invention, there is provided a compound represented by formula (II) A, formula (II) B or formula (II) C, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs thereof, wherein G 4 To be substituted with one or more R 17 of Preferably at least one R 17 Located on the N atom.

[0076] In a preferred embodiment of the present invention, there is provided a compound represented by formula (II) A, formula (II) B or formula (II) C, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs thereof, wherein R 17 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, carbonyl, -R 11 、-OR 11 、-SR 11 、 Preferably, R 17 For-OR 11 or The most preferred 17 for Among them, R 11The definitions of are as described above for formula (I), preferably, R 11 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, C 1-6 One or more optionally substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, aryl, 5-6 membered heteroaryl; More preferably, R 11 Each occurrence is independently selected from one of hydrogen, hydroxy, cyano, amino, trifluoromethyl, difluoromethyl, trifluoroethyl, difluoroethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, 4-6 membered heterocyclyl, aryl, and 5-6 membered heteroaryl.

[0077] In a preferred embodiment of the present invention, there is provided a compound represented by formula (II) A, formula (II) B or formula (II) C, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs thereof, wherein G 4 To replace the N atom of where R 11 Selected from hydrogen, halogen, hydroxyl, C 1-6 One or more optionally substituted C 1-6 Alkyl or aryl, or R 11 is selected from trifluoromethyl, difluoromethyl, trifluoroethyl, difluoroethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, difluorocyclobutyl, 4-6 membered heterocyclyl and phenyl.

[0078] In a preferred embodiment of the present invention, there is provided a compound represented by formula (II) A, formula (II) B or formula (II) C, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs thereof, wherein G 4 R 17 Substituted C 1-6 Alkyl, preferably optionally replaced by R 17 Substituted C 1-4 Alkyl, more preferably optionally replaced by R 17 Substituted ethyl, n-propyl, n-butyl; said R 17 Selected from halogen, methoxy.

[0079] In a preferred embodiment of the present application, the compound represented by formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled analogs thereof, is selected from the following compounds:

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090] The present application also includes a method for preparing a compound represented by formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled analogs thereof.

[0091] The method can be, for example, the method shown in Scheme 1: the target compound can be synthesized by first connecting LG a (leaving group a) of the left chain of the G3-Z structure to G 4 -YH, and then connecting LG c (leaving group c) of the cyclic structure to LG b (leaving group b) of the right chain of the G3-Z structure. Scheme 1 is as follows:

[0092]

[0093] The method can be, for example, the method shown in Scheme 2: the target compound can be synthesized by first connecting LG c (leaving group c) of the cyclic structure to LG b (leaving group b) of the right chain of the G3-Z structure, and then connecting LG a (leaving group a) of the left chain of the G3-Z structure to G 4-YH connection, the target compound was synthesized. Scheme 2 is as follows:

[0094]

[0095] Wherein, in the above preparation method, the definitions of the substituents in the compounds shown are as described above.

[0096] The present invention also provides a pharmaceutical composition comprising the compound of formula (I), (II)A, (II)B, (II)C described in the present invention, or its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs, and pharmaceutically acceptable excipients.

[0097] The present invention also aims to provide the use of the compounds of formula (I), (II)A, (II)B, (II)C of the present invention, or their stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs in the preparation of drugs for treating diseases mediated by PRMT5 inhibitors.

[0098] In some embodiments, the disease mediated by the PRMT5 inhibitor is a cancer or tumor-related disease, and representative examples of the cancer or tumor may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, blastoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myeloma, liposarcoma, fibrosarcoma, Ewing sarcoma, or plasmacytoma.

[0099] The present invention also aims to provide a method for preventing and / or treating diseases mediated by PRMT5 inhibitors, which comprises administering to a patient a therapeutically effective dose of a compound represented by the general formula (I), (II)A, (II)B, or (II)C, or its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled analogs, or the pharmaceutical composition of the present invention.

[0100] In some embodiments, the disease mediated by the PRMT5 inhibitor is a cancer or tumor-related disease, and representative examples of the cancer or tumor may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myeloid leukemia, liposarcoma, fibrosarcoma, Ewing sarcoma, or plasmacytoma.

[0101] When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for treating cancer or tumors, the compound of the present invention or a pharmaceutically acceptable salt thereof may provide enhanced anticancer effects.

[0102] Representative examples of anticancer agents for treating cancer or tumors may include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen ... Oxifen, flutamide, gonadorelin analogs, megestrol acetate, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danucetinib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, inipa rib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tiratinib, tivantinib, tivozanib, tofacitinib, tremetinib tinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, berentuzumab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies and anti-CTLA-4 antibodies, anti-OX40 antibodies and anti-OX40L antibodies or any combination thereof.

[0103] In some embodiments, the pharmaceutical composition of the present invention may further comprise the above-mentioned additional anticancer agents or immune checkpoint inhibitors.

[0104] In some embodiments, the methods of the present invention for preventing and / or treating diseases mediated by PRMT5 inhibitors may further comprise administering to the patient an additional anticancer agent or immune checkpoint inhibitor as described above.

[0105] definition

[0106] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl), more preferably containing 1-6 carbon atoms (ie C 1-6 Alkyl), such as "G 1-6 "Alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0107] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably containing 3 to 10 carbon atoms (C 3-10 cycloalkyl), further preferably 3-6 carbon atoms (C 3-6 Cycloalkyl), 4-6 carbon atoms (C 4-6 Cycloalkyl), 5-6 carbon atoms (C 5-6 Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

[0108] Unless otherwise specified, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above, i.e., containing 1-20 carbon atoms, preferably, containing 1-10 carbon atoms, more preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

[0109] Unless otherwise specified, the term "halogen" or "halo" refers to F, Cl, Br, I. The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all of the hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, and the like.

[0110] Unless otherwise specified, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon substituent, which is a non-aromatic structure containing 3-20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably, it contains 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups.

[0111] Unless otherwise specified, the term "carbocyclyl" or "carbocycle" refers to a non-aromatic cyclic hydrocarbon radical ("C 3-14 In some embodiments, the carbocyclyl group has 3-12 ring carbon atoms ("C 3-12 carbocyclyl”), or 4-12 ring carbon atoms (“C 4-12 carbocyclyl”), or 3 to 10 ring carbon atoms (“C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl”), or 5 to 7 ring carbon atoms (“C 5-7 Carbocyclyl”). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-8 Carbocyclyl groups include, but are not limited to, the aforementioned C 3-6Carbocyclyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclyl groups include, but are not limited to, the aforementioned C 3-8 Carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like. As illustrated in the above examples, in certain embodiments, the carbocyclyl group is a monocyclic ("monocyclic carbocyclyl") or a fused (fused cyclyl), bridged (bridged cyclyl) or spiro-fused (spirocyclyl) ring system, such as a bicyclic system ("bicyclic carbocyclyl") and can be saturated or can be partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring as defined above is fused by one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such cases, the number of carbons continues to indicate the number of carbons in the carbocyclyl system. In certain embodiments, each example of a carbocyclyl group is independently optionally substituted, for example, unsubstituted (a "unsubstituted carbocyclyl") or substituted by one or more substituents (a "substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is unsubstituted C 3-10 In certain embodiments, the carbocyclyl group is a substituted C 3-10 Carbocyclic group.

[0112] Unless otherwise specified, the term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic ring system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms. The term "aryl" can be used interchangeably with the term "aromatic ring." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl.

[0113] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system containing 5-12 members, or preferably 5-10 members, 5-8 members, and more preferably 5-6 members, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms being preferably 1, 2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridinyl, benzopyrimidinyl, benzo pyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0114] The term "pharmaceutically acceptable salt," "pharmaceutical salt," or "pharmaceutically acceptable salt" means a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, particularly humans, without undue toxicity, irritation, allergic response, and the like, and commensurate with a reasonable benefit / risk ratio, such as the medically acceptable salts of amines, carboxylic acids and other types of compounds are well-known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the application, or separately by reacting the free base or free acid with a suitable reagent, as outlined below. For example, a free base function can be reacted with a suitable acid. Additionally, where the compounds of the present application carry an acidic moiety, suitable pharmaceutically acceptable salts thereof can include metal salts, such as alkali metal salts, e.g., sodium or potassium salts; and alkaline earth metal salts, e.g., calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acid, or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0115] Unless otherwise specified, the term "solvate" means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of isolation. The solvent molecules in the solvate may exist in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0116] Unless otherwise specified, the term "isotopically labeled analogues" refers to molecules of Formula I to Formula II that are isotopically labeled to provide isotopically labeled analogues that may have improved pharmacological activity. Isotopes commonly used as isotope labels are: hydrogen isotopes, 2 H and 3 H; Carbon isotope: 11 C, 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 2 H), 3 H and carbon 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H), substitution can enhance metabolic stability and prolong half-life, thereby achieving a reduction in dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques similar to those used for synthesizing non-isotope-labeled compounds.

[0117] Unless otherwise specified, the term "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are often useful because, in certain circumstances, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited to, is any compound of Formula I administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to mobility, but once inside the cell, water solubility is beneficial, which is then metabolically hydrolyzed to a carboxylic acid, the active entity. Another example of a prodrug would be a short peptide (polyamino acid) conjugated to an acid group, where the peptide is metabolized to reveal the active moiety.

[0118] In the compounds of the present invention, "trans-" means that -G 2 and-(A) m -B are connected to XL 2 -CCL 1 On both sides of the ring plane, "cis-" means that in formula (I) -G 2 and-(A) m -B connection in XL 2 -CCL 1 Same side of the ring plane.

[0119] In the compounds of the present invention, the bonds of equal width represents a mixture of two orientations, e.g. express

[0120] Unless otherwise specified, the term "optionally substituted" means that the hydrogen at the substitutable site of the group is not replaced or is replaced by one or more substituents, the substituents being preferably selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, amino, azido, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-10 membered heteroaromatic ring group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14The aryl or 5-10 membered heteroaromatic ring group may be optionally selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 The oxo group is substituted by one or more of the alkoxy groups, and the oxo group means that two H at the same substitution position are replaced by the same O to form a double bond.

[0121] The beneficial effects of the present invention are:

[0122] This invention designs a class of novel compounds, providing a new direction for the development of PRMT5 inhibitors. In vitro enzyme inhibition studies have shown that these compounds have strong inhibitory effects on the PRMT5 enzyme, making them promising compounds for treating diseases mediated by PRMT5 inhibitors. Furthermore, the invention develops a specific synthesis method that is simple and easy to operate, facilitating large-scale industrial production and application. DETAILED DESCRIPTION

[0123] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. Experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials shown herein are for demonstration purposes only.

[0124] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or liquid chromatography (HPLC). NMR measurements are performed using a Bruker AVANCE NEO 400 MHz instrument, LC-MS using a LCMS WATERS ACQUITY UPLC H-Class PLUS or / and SQD2, and HPLC using a WATERS ACQUITY UPLC or / and Agilent 1260.

[0125] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0126] Example 1

[0127] Preparation of 4-((6-(cyclobutylamino)pyrimidin-4-yl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol:

[0128]

[0129] Step 1: Preparation of tert-butyl (cyclopent-3-ene-1-oxy) diphenylsilane:

[0130]

[0131] The compound cyclopent-3-ene-1-ol (2.0 g, 23.78 mol) and imidazole (3.24 g, 45.76 mol) were dissolved in 12 mL of anhydrous DMF (N,N-dimethylformamide). TBDPSCl (tert-butyldiphenylchlorosilane) (7.19 g, 26.16 mmol) was added in portions under ice bath conditions. The mixture was then returned to room temperature (20-25° C.). The reaction solution was stirred for 18 hours. TLC detection showed that the reaction was complete. 20 mL of water and 50 mL of ethyl acetate were added to the reaction solution, and the aqueous phase was extracted three times with ethyl acetate (3×30 mL). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) gave 7.1 g of a colorless oily product, i.e., tert-butyl(cyclopent-3-ene-1-oxy)diphenylsilane, with a yield of 92.5%. 1 H NMR (400MHz, CDCl3) δ7.66 (ddd, J=13.9, 7.6, 1.5Hz, 4H), 7.44-7.30 (m, 6H), 5.65- 5.56 (m, 2H), 4.55 (tt, J=6.6, 4.3Hz, 1H), 2.47-2.33 (m, 4H), 1.06 (d, J=5.8Hz, 9H).

[0132] Step 2: Preparation of ((6-oxabicyclo[3.1.0]hexane-3-yl)oxy)(tert-butyl)diphenylsilane:

[0133]

[0134] The compound tert-butyl(cyclopent-3-en-1-oxy)diphenylsilane (6.5 g, 20.18 mmol) was dissolved in 100 mL of dichloromethane, and m-chloroperbenzoic acid (1.9 g, 26.23 mmol, 85%) was added portionwise in an ice bath. After the addition of the starting materials was complete, the ice bath was removed, and the reaction was continued at room temperature (20-25°C) for 18 hours. TLC indicated that the starting materials had reacted completely. 20 mL of saturated NaHCO₃ solution was added to the reaction system, and the mixture was allowed to stand for a while before the organic phase was separated. The organic phase was washed three times with saturated NaHCO₃ solution, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated. Purification by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) yielded 2.2 g of the oily product, the compound ((6-oxabicyclo[3.1.0]hexan-3-yl)oxy)(tert-butyl)diphenylsilane), in a yield of 32.2%. 1H NMR (400MHz, CDCl3) δ7.69-7.63 (m, 4H), 7.42-7.33 (m, 6H), 4.41 (ddd, J=6.7, 4.1, 0.7Hz, 1H ), 3.42 (d, J=8.6Hz, 2H), 2.09-1.98 (m, 2H), 1.86 (dd, J=15.2, 7.4Hz, 2H), 1.06-1.02 (m, 9H).

[0135] Step 3: Preparation of 4-((tert-butyldiphenylsilyl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentane-1-ol:

[0136]

[0137] The compound ((6-oxabicyclo[3.1.0]hexan-3-yl)oxy)(tert-butyl)diphenylsilane (86 mg, 0.254 mmol) was dissolved in 1.27 mL of ethanol, and triethylamine (128 mg, 1.28 mmol) and 1,2,3,4-tetrahydroisoquinoline (40.5 mg, 0.3048 mmol) were added. The reaction system was then refluxed for 48 hours. After cooling to room temperature, 5 mL of water and 20 mL of dichloromethane were added to the reaction system. After stagnating, the organic phase was separated. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated. Purification by column chromatography (petroleum ether:ethyl acetate = 10:1) yielded 55 mg of the product, 4-((tert-butyldiphenylsilyl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol, in a yield of 46.2%. LC-MS: 472.38 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.7-7.60(m, 4H), 7.48-7.35(m, 6H), 7.16-7.06(m, 3H ), 7.05-6.99 (m, 1H), 4.40 (s, 1H), 4.23 (s, 1H), 3.16 (s, 1H), 2.91 (d, J=5.1 Hz, 3H), 2.66 (d, J=63.2Hz, 2H), 2.15-1.99 (m, 2H), 1.93-1.82 (m, 2H), 1.58 (d, J=7.9Hz, 2H), 1.26 (ddd, J=9.6, 6.5, 2.7Hz, 1H), 1.07 (d, J=6.7Hz, 9H).

[0138] Step 4: Preparation of 4-((tert-butyldiphenylsilyl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentyl acetate:

[0139]

[0140] In an ice bath under nitrogen, sodium hydride (17 mg, 0.424 mmol) was dissolved in 1 mL of DMF (N,N-dimethylformamide), followed by the addition of 4-((tert-butyldiphenylsilyl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol (100 mg, 0.212 mmol). After half an hour, acetyl chloride (17 mg, 0.212 mmol) was added. After two hours, TLC indicated complete reaction of the starting materials. The reaction was quenched by the addition of 1 mL of saturated ammonium chloride solution. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent concentrated. Purification by column chromatography (petroleum ether:ethyl acetate = 2:1) gave 88 mg of the product, 4-((tert-butyldiphenylsilyl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentyl acetate, in an 81.4% yield. LC-MS: 514.45 [M+H] + .

[0141] Step 5: Preparation of 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl acetate:

[0142]

[0143] The compound 4-((tert-butyldiphenylsilyl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentyl acetate (315 mg, 0.613 mmol) was dissolved in 3 mL of THF (tetrahydrofuran), and 0.674 mL of a 1 mol / L tetrabutylammonium fluoride solution in tetrahydrofuran was added. The mixture was stirred at room temperature overnight. 5 mL of water and 20 mL of dichloromethane were added to the reaction system, and the mixture was allowed to stand for a while before the organic phase was separated. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated. Purification by column chromatography (dichloromethane:methanol = 20:1) gave 90 mg of the product, 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl acetate, in a yield of 54.5%. LC-MS: 276.24 [M+H]. + ; 1H NMR (400MHz, CDCl3) δ7.31-7.21 (m, 2H), 7.18 (d, J=7.4Hz, 1H), 7.07 (d, J=7 .4Hz, 1H), 5.59 (ddd, J=8.7, 5.4, 3.3Hz, 1H), 4.90-4.46 (m, 1H), 4.37 (s, 2H) , 4.10-4.00(m, 1H), 3.91-3.32(m, 2H), 3.16(s, 2H), 2.60-2.49(m, 1H), 2.38 -2.26 (m, 1H), 2.27-2.14 (m, 1H), 2.11-1.98 (m, 3H), 1.75 (d, J=15.1Hz, 1H).

[0144] Step 6: Preparation of 4-((6-((tert-butoxycarbonyl)(cyclobutyl)amino)pyrimidin-4-yl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentyl acetate:

[0145]

[0146] Compounds 6 (50 mg, 0.181 mmol) and 7 (51 mg, 0.181 mmol) were dissolved in 0.9 mL of anhydrous tetrahydrofuran under an ice bath and nitrogen atmosphere, followed by the addition of 0.18 mL of a 1 mol / L solution of potassium tert-butoxide in tetrahydrofuran. Two hours later, 1 mL of saturated ammonium chloride solution was added dropwise. 5 mL of water and 20 mL of ethyl acetate were added to the reaction system, and the mixture was allowed to stand for a while before the organic phase was separated. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated. Column chromatography (dichloromethane:methanol = 20:1) yielded 32 mg of the product, 4-((6-((tert-butoxycarbonyl)(cyclobutyl)amino)pyrimidin-4-yl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentyl acetate, in a yield of 54.5%. LC-MS: 523.42 [M+H]. + .

[0147] Step 7: Preparation of 4-((6-(cyclobutylamino)pyrimidin-4-yl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentyl acetate:

[0148]

[0149] 4-((6-((tert-Butoxycarbonyl)(cyclobutyl)amino)pyrimidin-4-yl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentyl acetate (90 mg, 0.212 mmol) was dissolved in 1 mL of dichloromethane, and 0.25 mL of trifluoroacetic acid was added. After two hours, TLC confirmed the complete reaction. 5 mL of 1,2-dichloroethane was added, and the solvent was evaporated to dryness. The crude product was directly used in the next reaction.

[0150] Step 8: Preparation of 4-((6-(cyclobutylamino)pyrimidin-4-yl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol:

[0151]

[0152] The crude compound 4-((6-(cyclobutylamino)pyrimidin-4-yl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentyl acetate (70 mg, 0.165 mmol) was dissolved in 1 mL of methanol, and potassium carbonate solution (57 mg, 0.414 mmol, dissolved in 1.5 mL of water) was added. After two hours, 5 mL of water and 20 mL of ethyl acetate were added to the reaction system. After standing, the organic phase was separated. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated. The product was purified by medium pressure preparative purification. LC-MS: 381.38 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ10.21 (s, 1H), 8.16 (d, J=20.7Hz, 1H), 7.36-7.29 (m, 1H), 7 .21 (d, J=7.3Hz, 1H), 7.11 (d, J=7.1Hz, 1H), 5.71 (s, 1H), 5.48 (s, 1H), 4.94 (s, 1H) ), 4.56 (d, J = 14.1Hz, 2H), 3.93-3.59 (m, 4H), 3.26 (s, 3H), 2.62 (d, J = 75.0Hz, 2H) , 2.45-2.33(m, 3H), 2.16(d, J=8.2Hz, 2H), 2.05-1.93(m, 2H), 1.91-1.73(m, 2H).

[0153] Example 2

[0154] Preparation of trans-1-(4-((6-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0155]

[0156] Step 1: Preparation of trans-3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxypyrrolidine-l-carboxylic acid tert-butyl ester:

[0157]

[0158] Compound 3-Boc-6-oxa-3-azabicyclo[3.1.0]hexane (1.50 g, 8.10 mmol, 1.0 eq) was dissolved in 40 mL water, compound 1, 2, 3, 4-tetrahydroisoquinoline (1.62 g, 12.15 mmol, 1.5 eq) was added, the reaction was reacted at 20 °C for 16 hours. After TLC detection of the completion of the reaction, the reaction liquid was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography to obtain (±)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxypyrrolidine-l-carboxylic acid tert-butyl ester 1.20 g, yield 46.5%; LCMS (ESI) [M+H] + = 319.11.

[0159] Step 2: Preparation of trans-4-(3,4-dihydroisoquinolin-2(lH)-yl)pyrrolidin-3-ol:

[0160]

[0161] Compound (±)-3-(3,4-dihydroisoquinolin-2(lH)-yl)-4-hydroxypyrrolidine-l- carboxylic acid tert-butyl ester (400 mg, 1.26 mmol, 1.0 eq) was dissolved in DCM (20 mL), TFA (5 mL) was added, the reaction was reacted at 20 °C overnight for 30 minutes. After TLC detection of the completion of the reaction, the reaction liquid was concentrated to obtain (±)-4-(3,4-dihydroisoquinolin-2(lH)-yl)pyrrolidin-3-ol crude product; LCMS (ESI) [M+H] + = 219.06.

[0162] Step 3: Preparation of trans-l-(4-((6-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxypyrrolidine-l-carbonyl)pyrimidin-4-yl)amino)piperidin-l-yl)ethan-l-one:

[0163]

[0164] (±)-4-(3,4-dihydroisoquinolin-2(1H)-yl)pyrrolidin-3-ol (274 mg, 1.26 mmol, 1.0 eq) was dissolved in DMF (N,N-dimethylformamide) (6 mL). 6-((1-acetylpiperidin-4-yl)amino)pyrimidine-4-carboxylic acid (332 mg, 1.26 mmol, 1.0 eq), T3P (1-propylphosphonic anhydride) (50% by mass in ethyl acetate, 1.60 g, 2.51 mmol, 2.0 eq), and TEA (triethylamine) (0.87 mL, 6.28 mmol, 5.0 eq) were added. The mixture was allowed to react at 20°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated and purified by preparative HPLC to obtain 150 mg of the title compound in a 25.7% yield. LCMS (ESI) [M+H] + =465.20; 1 H NMR (400MHz, Chloroform-d3) δ8.52 (d, J=8.6Hz, 1H), 7.09 (dtt, J=9.1, 6.2, 3.0Hz, 3H), 6.99 (dt, J=6.7, 3.3Hz, 1H), 6.84 (d, J=1 7.6Hz, 1H), 6.30 (d, J=145.5Hz, 1H), 4.47 (ddq, J=16.7, 11.3, 5.8, 4.5Hz, 2H), 4.26-4.04 (m, 2H), 3.98 (td, J=12.8, 7.0Hz, 1H), 3 .78 (dddd, J=53.3, 20.7, 12.8, 7.2Hz, 5H), 3.53 (dd, J=12.8, 5.6Hz, 1H), 3.21 (tq, J=14.4, 4.0Hz, 1H), 3.08 (dq, J=12.9, 6.7Hz, 1 H), 2.94 (dt, J=8.4, 4.1Hz, 1H), 2.82 (ddt, J=25.1, 11.0, 5.7Hz, 4H), 2.09 (d, J=2.2Hz, 3H), 2.02-1.95 (m, 2H), 1.56-1.36 (m, 2H).

[0165] Example 3

[0166] Preparation of 6-(cyclobutylamino)-N-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide:

[0167]

[0168] Step 1: Preparation of cyclopentyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4-(1,3-dihydroisoindolin-2-yl)acetate:

[0169]

[0170] 2-(3,4-Dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl acetate (50 mg, 0.182 mmol, 1.0 eq), phthalimide (26.80 mg, 0.182 mmol, 1.0 eq), and triphenylphosphine (71.50 mg, 0.273 mmol, 1.5 eq) were dissolved in anhydrous tetrahydrofuran (1 mL). The reaction mixture was stirred for 0.5 h under an ice bath and nitrogen atmosphere. Diethyl azodicarboxylate (47.5 mg, 0.273 mmol, 1.5 eq) was then added to the reaction mixture. The ice bath was removed and stirring continued for two hours. TLC analysis indicated complete reaction of the starting materials. Water (10 mL) and ethyl acetate (30 mL) were added to the reaction system, and the aqueous phase was extracted three times with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent concentrated. Purification by column chromatography (silica gel, dichloromethane:methanol=100:0 to 96:4) gave 65 mg of cyclopentyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4-(1,3-dihydroisoindolin-2-yl)acetate as a white solid. Yield: 89.2%. 1 H NMR (400MHz, CDCl3) δ7.87-7.80 (m, 2H), 7.75-7.68 (m, 2H), 7.15-7.07 (m, 3H), 7.06-6.98 (m, 1H), 5 .47 (ddd, J=7.7, 4.4, 3.0Hz, 1H), 4.81 (tt, J=10.9, 7.7Hz, 1H), 3.88-3.75 (m, 2H), 3.29-3.17 (m, 1H) , 3.02-2.94 (m, 1H), 2.91 (dd, J=11.3, 5.9Hz, 2H), 2.88-2.83 (m, 1H), 2.83-2.78 (m, 1H), 2.56 (dd, J =22.8, 11.5Hz, 1H), 2.30-2.18 (m, 1H), 2.09 (s, 3H), 1.92 (dd, J = 14.0, 7.9Hz, 1H); LC-MS (ESI) [M+H] + =405.27.38.

[0171] Step 2: Preparation of 4-amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentane-1-ol:

[0172]

[0173] Cyclopentyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4-(1,3-dihydroisoindolin-2-yl)acetate (160 mg, 0.398 mmol, 1.0 eq) was dissolved in ethanol (2 mL). Hydrazine hydrate (200 mg, 4 mmol, 10 eq) was added, and the mixture was heated to 85°C and stirred for half an hour. Solid precipitated. After cooling to room temperature, the filtrate was filtered and the solvent was concentrated. Preparative HPLC was used for separation and purification (C18, 10 mmol / L aqueous NH4HCO3 solution, acetonitrile). 50 mg of 4-amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol was obtained as a white solid in a yield of 54.3%. LC-MS (ESI) [M+H] + =232.28.

[0174] Step 3: Preparation of 6-(cyclobutylamino)-N-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide:

[0175]

[0176] 4-Amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol (20 mg, 0.086 mmol, 1.0 eq), 6-(cyclobutylamino)pyrimidine-4-carboxylic acid (16.6 mg, 0.086 mmol, 1.0 eq), and HATU (2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (47 mg, 0.1245 mmol, 1.5 eq) were dissolved in N,N-dimethylformamide (0.4 mL). N,N-diisopropylethylamine (33.0 mg, 0.258 mmol, 3.0 eq) was added, and the mixture was stirred under nitrogen for two hours. Water (10 mL) and ethyl acetate (20 mL) were added to the reaction system, and the aqueous phase was extracted three times with ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent concentrated. Preparative HPLC separation and purification (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) afforded 4.4 mg of 6-(cyclobutylamino)-N-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide in a 12.5% ​​yield. LC-MS (ESI) [M+H] + =408.20; 1H NMR (400MHz, CDCl3) δ8.40 (s, 1H), 8.09 (d, J=8.1Hz, 1H), 7.14-7.09 (m, 3H), 7.07 (s, 1H), 7.02 (d, J=5 .5Hz, 1H), 5.43 (s, 1H), 4.61 (dd, J=15.3, 7.9Hz, 1H), 4.43 (d, J=3.3Hz, 1H), 3.79 (s, 2H), 2.93 (s, 2H) , 2.91 (d, J = 4.0Hz, 1H), 2.83 (dd, J = 14.7, 5.8Hz, 2H), 2.48 (dd, J = 12.1, 6.4Hz, 3H), 2.19-2.11 (m, 1H) , 2.03 (dt, J=7.5, 5.5Hz, 2H), 1.96-1.90 (m, 2H), 1.84 (d, J=7.2Hz, 2H), 1.68 (dd, J=21.6, 9.2Hz, 2H).

[0177] Example 4

[0178] Preparation of 6-(((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide:

[0179]

[0180] Step 1: Preparation of 6-(((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide:

[0181]

[0182] 4-Amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol (38 mg, 0.164 mmol, 1.0 eq), 6-((1-acetylpiperidin-4-yl)amino)pyrimidine-4-carboxylic acid (43.2 mg, 0.164 mmol, 1.0 eq) and HATU (2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (94 mg, 0.246 mmol, 1.5 eq) were dissolved in N,N- To dimethylformamide (0.8 mL) was added N,N-diisopropylethylamine (64 mg, 0.492 mmol, 3.0 eq) and stirred under nitrogen for two hours. Water (10 mL) and ethyl acetate (20 mL) were added to the reaction system, and the aqueous phase was extracted three times with ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent concentrated. Preparative HPLC (C18, 10 mmol / L aqueous NH4HCO3 solution, acetonitrile) was used to separate and purify the product to give 6 mg of 6-(((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide in a yield of 7.6%. LC-MS (ESI) [M+H] + =479.36; 1 H NMR (400MHz, CDCl3) δ8.46 (s, 1H), 8.17 (d, J = 8.4Hz, 1H), 7.24-7.18 (m, 2H), 7.18-7.11 (m, 3H), 7.04 (d, J=6.6Hz, 1H), 4.65-4.54 (m, 3H), 4.12 (d, J=7.1Hz, 1H), 3.96 (s, 1H), 3.83 (d, J =13.9Hz, 1H), 3.22 (d, J = 11.8Hz, 1H), 3.05 (s, 2H), 2.79 (d, J = 10.6Hz, 1H), 2.55-2.47 (m, 1 H), 2.14 (s, 2H), 2.11 (s, 3H), 1.86 (s, 1H), 1.57 (s, 4H), 1.46 (s, 2H), 1.41 (d, J=8.0Hz, 2H).

[0183] Example 5

[0184] Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide:

[0185]

[0186] Step 1: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)-6-(oxetane-3-ylamino)pyrimidine-4-carboxamide:

[0187]

[0188] The compounds 4-amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol (5 mg, 0.0216 mmol, 1.0 eq), 6-(cyclobutylamino)pyrimidine-4-carboxylic acid (4.2 mg, 0.0216 mmol, 1.0 eq), and 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (12.3 mg, 0.0324 mmol, 1.5 eq) were dissolved in 0.1 mL of DMF. N,N-diisopropylethylamine (8.4 mg, 0.0648 mmol, 3.0 eq) was added, and the mixture was stirred under nitrogen for two hours. 2 mL of water and 10 mL of ethyl acetate were added to the reaction system, and the aqueous phase was extracted three times with ethyl acetate (3×10 mL). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent concentrated. Purification by preparative HPLC gave 1.2 mg of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide in a yield of 13.6%. 1 H NMR (400MHz, CD3OD) δ8.41 (d, J=1.1Hz, 1H), 7.15-7.08 (m, 4H), 7.05 (d, J=7.8Hz, 1H), 5.10 (s, 1H), 4.95 ( t, J=6.9Hz, 2H), 4.60 (t, J=6.4Hz, 2H), 4.53 (dd, J=15.9, 8.0Hz, 1H), 4.32 (dd, J=10.0, 5.3Hz, 1H), 3.84-3 .74 (m, 2H), 3.08-3.00 (m, 1H), 2.94 (t, J=5.8Hz, 2H), 2.82 (dd, J=11.8, 5.8Hz, 1H), 2.79-2.73 (m, 1H), 2. 48 (dt, J=13.2, 6.8Hz, 1H), 2.05 (dd, J=8.2, 5.7Hz, 2H), 1.68 (dt, J=12.4, 9.5Hz, 1H); LC-MS: 410.16[M+H] + .

[0189] Example 6

[0190] Preparation of trans-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidin-1-yl)(6-(oxetan-3-ylamino)pyrimidin-4-yl)methanone:

[0191]

[0192] Step 1: Preparation of trans-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidin-1-yl)(6-((oxetan-3-ylamino)pyrimidin-4-yl)methanone:

[0193]

[0194] The compound trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)pyrrolidin-3-ol (206 mg, 0.94 mmol, 1.0 eq) was dissolved in DMF (N,N-dimethylformamide) (5 mL). 6-(oxetan-3-ylamino)pyrimidine-4-carboxylic acid (184 mg, 0.94 mmol, 1.0 eq), T3P (1-propylphosphonic anhydride) (50% by mass solution in ethyl acetate, 1.20 g, 1.88 mmol, 2.0 eq), and TEA (triethylamine) (0.66 mL, 4.71 mmol, 5.0 eq) were added and reacted at 20°C for 1 hour. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC to obtain 36 mg of the target compound in a 9.7% yield. LCMS (ESI) [M+H] + =396.13; 1 H NMR (400MHz, CDCl3) δ8.53 (dd, J=4.6, 1.1Hz, 1H), 7.21-7.09 (m, 3H), 7.06-6.99 (m, 1H), 6.92 (d, J=14.3Hz, 1H ), 6.41 (d, J=50.9Hz, 1H), 5.08 (s, 1H), 4.99 (t, J=6.8Hz, 2H), 4.64 (dd, J=6.5, 3.0Hz, 1H), 4.57 (td, J=6.4, 2. 2Hz, 2H), 4.23 (ddd, J=18.8, 12.2, 7.1Hz, 1H), 4.14-3.90 (m, 4H), 3.78 (ddd, J=18.4, 12.5, 7.0Hz, 1H), 3.56 (d d, J=13.0, 6.0Hz, 1H), 3.30 (q, J=7.1Hz, 1H), 3.13 (dp, J=17.5, 5.8Hz, 2H), 2.99 (dq, J=14.6, 6.9, 6.5Hz, 2H).

[0195] Example 7

[0196] Preparation of cis-1-(4-((6-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0197]

[0198] Step 1: Preparation of trans-3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester:

[0199]

[0200] (COCl)2 (oxalyl chloride) (951 mg, 7.56 mmol, 1.2 eq) was dissolved in dichloromethane (10 mL). Under nitrogen protection at -78°C, DMSO (dimethyl sulfoxide) (540 mg, 6.93 mmol, 1.1 eq) was dissolved in dichloromethane (10 mL) and slowly added dropwise to the above solution. The reaction solution was reacted at -78°C for 25 minutes. The compound trans-3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 6.3 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL) and slowly added dropwise to the reaction solution. After the reaction solution was reacted at -78°C for 25 minutes, TEA (triethylamine) (3.2 g, 31.5 mmol, 5 eq) was added under nitrogen protection. The reaction solution was reacted at -78 degrees Celsius for 2 hours. After the reaction was completed by TLC and LCMS detection, the temperature was naturally raised to 0 degrees Celsius, and a saturated ammonium chloride solution (10 mL) was added to quench the reaction. The reaction solution was naturally warmed to room temperature, poured into 20 ml of water, extracted three times with dichloromethane, 20 ml each time, the organic phases were combined, washed once with 15 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain tert-butyl 3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxopyrrolidine-1-carboxylate (720 mg, yield 36%). LCMS (ESI) [M+1] + =317.12.

[0201] Step 2: Preparation of cis-3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

[0202]

[0203] tert-Butyl 3-(3,4-dihydroisoquinolin-2(lH)-yl)-4-oxopyrrolidine-l- carboxylate (700 mg, 2.21 mmol, 1.0 eq) was dissolved in tetrahydrofuran (11 mL) and L-selectride (3.31 mL, 3.31 mmol, 1.5 eq) was added slowly dropwise at -78 °C under nitrogen. The reaction was stirred at -78 °C for 3 h. TLC and LCMS indicated the reaction was complete. The reaction was quenched by slowly adding saturated ammonium chloride solution (10 mL) at -78 °C, and allowed to warm to room temperature. Water (20 mL) was added, and the reaction was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give cis-tert-butyl 3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxypyrrolidine-l-carboxylate (410 mg, 58% yield). LCMS (ESI) [M+1] + = 319.11.

[0204] Step 3: Preparation of cis-4-(3,4-dihydroisoquinolin-2(lH)-yl)pyrrolidin-3-ol

[0205]

[0206] tert-Butyl 3-(3,4-dihydroisoquinolin-2(lH)-yl)-4-oxopyrrolidine-l- carboxylate (700 mg, 2.21 mmol, 1.0 eq) was dissolved in tetrahydrofuran (11 mL) and L-selectride (3.31 mL, 3.31 mmol, 1.5 eq) was added slowly dropwise at -78 °C under nitrogen. The reaction was stirred at -78 °C for 3 h. TLC and LCMS indicated the reaction was complete. The reaction was quenched by slowly adding saturated ammonium chloride solution (10 mL) at -78 °C, and allowed to warm to room temperature. Water (20 mL) was added, and the reaction was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give cis-tert-butyl 3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxypyrrolidine-l-carboxylate (410 mg, 58% yield). LCMS (ESI) [M+1] + = 219.02.

[0207] Step 4: Preparation of cis-l-(4-((6-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxypyrrolidine-l-carbonyl)pyrimidin-4-yl)amino)piperidin-l-yl)ethanone

[0208]

[0209] Cis-4-(3,4-dihydroisoquinolin-2(1H)-yl)pyrrolidin-3-ol (90 mg, 0.41 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (2 mL). Under nitrogen, 6-((1-acetylpiperidin-4-yl)amino)pyrimidine-4-carboxylic acid (87 mg, 0.33 mmol, 0.8 eq), TEA (triethylamine) (207 mg, 2.05 mmol, 5.0 eq), and T3P (1-propylphosphonic anhydride) (50% by mass solution in ethyl acetate, 1.044 g, 0.82 mmol, 2.0 eq) were added to the reaction mixture. The reaction mixture was stirred at room temperature (20-25°C) for 3 hours. The reaction was complete as determined by TLC and LCMS. The reaction solution was poured into 10 mL of water and extracted three times with 20 mL of ethyl acetate each time. The ethyl acetate phases were combined, washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to give cis-1-(4-((6-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-ylethanone (2.5 mg, yield 1.3%). LCMS (ESI) [M+1] + =465.24; 1 H NMR (400MHz, CDCl3) δ8.57 (m, 1H), 7.22-7.08 (m, 3H), 7.07-6.99 (m, 1H), 6 .86(d, J=11.2Hz, 1H), 5.32(m, 1H), 4.55(d, J=13.2Hz, 1H), 4.46-4.27(m, 1H), 4.15-3.54 (m, 8H), 3.23 (t, J=12.7Hz, 1H), 3.10-2.89 (m, 4H), 2.89-2 .70 (m, 2H), 2.18-2.09 (m, 4H), 2.05 (d, J=12.5Hz, 1H), 1.51-1.33 (m, 2H).

[0210] Example 8

[0211] Preparation of N-(-3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide:

[0212]

[0213] Step 1: Preparation of tert-butyl cyclopent-3-en-1-ylcarbamate:

[0214]

[0215] 3-Cyclopentenamine hydrochloride (4.5 g, 37.625 mmol, 1.0 eq) was dissolved in dichloromethane (188 ml). Under nitrogen, di-tert-butyl dicarbonate (9.85 g, 45.151 mmol, 1.2 eq) and triethanolamine (23 mL, 165.552 mmol, 4.4 eq) were added. The reaction mixture was allowed to react overnight (10 h) at room temperature (18°C). After completion of the reaction, as determined by TLC and LCMS, water (30 mL) was added and the mixture was extracted with dichloromethane three times (100 ml each time). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 5.85 g of the intermediate tert-butyl cyclopent-3-en-1-ylcarbamate in an 85.0% yield. LCMS: [M+1] + =184.17; 1 H NMR (400MHz, DMSO-d6) δ6.97 (d, J=7.2Hz, 1H), 5.64 (s, 2H), 4.04 (dt, J=8.0, 4.6 Hz, 1H), 2.54 (d, J=8.2, 1.9Hz, 1H), 2.20-2.05 (m, 2H), 1.47 (s, 1H), 1.38 (s, 9H).

[0216] Step 2: Preparation of tert-butyl (6-oxabicyclo[3.1.0]hexan-3-yl)carbamate

[0217]

[0218] Dissolve tert-butyl cyclopent-3-en-1-ylcarbamate (5.85 g, 31.924 mmol, 1.0 eq) in dichloromethane (160 ml). Under nitrogen, add m-chloroperbenzoic acid (9.72 g, 47.885 mmol, 1.5 eq). The reaction mixture is allowed to react overnight at room temperature (18°C) for 10 hours. After completion of the reaction, as determined by TLC and LCMS, water (30 mL) is added and the mixture is extracted with dichloromethane three times, 100 ml each time. The mixture is dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is isolated by column chromatography (dichloromethane) to yield 800 mg of the intermediate tert-butyl (6-oxabicyclo[3.1.0]hex-3-yl)carbamate as a light yellow solid in a 12.6% yield. LCMS: [M+1] + =184.17; 1 H NMR (400MHz, DMSO-d6) δ6.79 (d, J=8.5Hz, 1H), 3.59-3.49 (m, 1H), 3.44 (s, 2H), 2.17 (dd, J=13.9, 7.6Hz, 2H), 1.48 (dd, J=13.8, 8.9Hz, 2H), 1.36 (s, 9H).

[0219] Step 3: Preparation of tert-butyl (3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)carbamate:

[0220]

[0221] The starting material (tert-butyl 6-oxabicyclo[3.1.0]hexan-3-yl)carbamate (150 mg, 0.754 mmol, 1.0 eq) was dissolved in water (4 mL). 1,2,3,4-tetrahydroisoquinoline (110 mg, 0.829 mmol, 1.1 eq) was added under nitrogen. The reaction mixture was allowed to react overnight at 80°C (10 h). After completion of the reaction, the mixture was analyzed by TLC and LCMS. Dichloromethane (30 mL) was added and the mixture was extracted three times with 30 mL each. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated by column chromatography (dichloromethane / methanol = 15 / 1) to afford 210 mg of the intermediate (tert-butyl 3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)carbamate as a pale yellow solid in an 84.0% yield. LCMS: [M+1] + =333.14;1H NMR (400MHz, DMSO-d6) δ7.16-6.96 (m, 4H), 6.82 (d, J=8.0Hz, 1H), 4.73 (d, J=5.0Hz, 1H), 4.06-3.98 (m, 1H), 3.96-3.85 (m, 1H), 3. 61 (s, 2H), 2.93-2.83 (m, 1H), 2.81-2.73 (m, 2H), 2.68-2.51 (m, 3H), 2.13 (dt, J=12.6, 6.6Hz, 1H), 1.79-1.61 (m, 2H), 1.38 (s, 9H).

[0222] Step 4: Preparation of 4-amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentane-1-ol:

[0223]

[0224] The starting material, tert-butyl (3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)carbamate (100 mg, 0.301 mmol, 1.0 eq), was dissolved in dichloromethane (4 ml). Trifluoroacetic acid (1 ml) was added under nitrogen, and the reaction mixture was allowed to react at room temperature (18°C) for 2 h. After completion of the reaction, as monitored by TLC and LCMS, 1,2-dichloroethane (5 mL) was added and the mixture was concentrated to yield 84 mg of the crude intermediate (4-amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol). The product was a yellow oily liquid with a yield of 100%. LCMS: [M+1] + =233.00.

[0225] Step 5: Preparation of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide

[0226]

[0227] (4-Amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol (35 mg, 0.150 mmol, 1.0 eq), 6-(oxetan-3-ylamino)pyrimidine-4-carboxylic acid (30 mg, 0.150 mmol, 1.0 eq) and HATU (2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (86 mg, 0.226 mmol, 1.5 eq) were dissolved in DMF (N,N-dimethylformamide) (1 mL), and DIEA (N,N-diisopropylethylamine) (0.13 ml, 0.7 54mmol, 5.0eq) was added to the mixture. Under nitrogen protection, the reaction solution was reacted at room temperature (18°C) for 10 hours. After completion of the reaction, the reaction solution was poured into 50 ml of water and extracted with ethyl acetate three times, each time with 15 ml. The ethyl acetate phases were combined, washed once with 20 ml of water and once with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and reversed to obtain 5.54 mg of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide in a yield of 9.0%. LCMS: [M+H] + =410.20; 1H NMR (400MHz, CDCl3) δ8.47 (d, J=1.2Hz, 1H), 8.21 (d, J=8.0Hz, 1H), 7.38 (brs, 1H), 7.22-7.1 2 (m, 3H), 7.07-7.00 (m, 1H), 6.88 (brs, 1H), 5.21 (brs, 1H), 5.05 (td, J=7.0, 1.8Hz, 2H), 4.6 2(ddd, J=12.4, 6.4, 4.2Hz, 4H), 4.02 (s, 2H), 3.24-2.98 (m, 6H), 2.55 (dt, J=12.9, 6.6Hz, 1H ), 2.21 (ddd, J=11.1, 7.1, 3.5Hz, 1H), 2.08 (dt, J=13.8, 8.2Hz, 1H), 1.88 (q, J=10.4Hz, 1H).

[0228] Example 9

[0229] Preparation of 6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide:

[0230]

[0231] Step 1: Preparation of 6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide:

[0232]

[0233] To a solution of (4-amino-2-(3,4-dihydroisoquinolin-2(lH)-yl)cyclopentan-l-ol (35 mg, 0.150 mmol, 1.0 eq), 6-((l-acetylpiperidin-4-yl)amino)-pyrimidine-4-carboxylic acid (40 mg, 0.150 mmol, 1.0 eq) and HATU (2-(7-oxabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (86 mg, 0.226 mmol, 1.5 eq) in DMF (N,N-dimethylformamide) (1 mL) was added DIEA (N,N-diisopropylethylamine) (0.13 ml, 0.754 mmol, 5.0 eq) and the reaction was stirred at room temperature (18 °C) for 10 h under nitrogen atmosphere. After completion of the reaction (TLC and LCMS), the reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (15 mL x 3), washed with water (20 mL x 1), brine (20 mL x 1), dried over sodium sulfate (10 min), filtered and concentrated. The residue was purified by reverse phase preparative HPLC to give 6-((l-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxycyclopentyl)pyrimidine-4-carboxamide 4.89 mg, yield 6.8 %. LCMS: [M+H] + = 479.27; 1 H NMR (400 MHz, CD3Cl) δ 8.50 (s, 1H), 8.26 (s, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.22-7.13 (m, 2H), 7.09 (d, J = 7.5 Hz, 1H), 4.93 (s, 1H), 4.49 (d, J = 16.8 Hz, 3H), 4.20 (br s, 1H), 3.81 (d, J = 13.5 Hz, 1H), 3.60 (s, 1H), 3.50 (s, 1H), 3.30-3.19 (m, 2H), 2.76 (s, 1H), 2.58 (s, 1H), 2.17-2.11 (m, 4H), 2.09 (d, J = 3.5 Hz, 3H), 1.99-1.91 (m, 2H), 1.88-1.55 (m, 4H), 1.43-1.24 (m, 2H).

[0234] Example 10

[0235] Preparation of cis-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-4-hydroxypyrrolidin-l-yl)(6- (oxetan-3-ylamino)pyrimidin-4-yl)methanone:

[0236]

[0237] Step 1: Preparation of cis-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidin-1-yl)(6-(oxetan-3-ylamino)pyrimidin-4-yl)methanone:

[0238] Cis-4-(3,4-dihydroisoquinolin-2(1H)-yl)pyrrolidin-3-ol (90 mg, 0.41 mmol, 1.0 eq) was dissolved in DMF (N,N-dimethylformamide) (2 mL). Under nitrogen, 6-(oxetan-3-ylamino)pyrimidine-4-carboxylic acid (72 mg, 0.37 mmol, 0.9 eq), TEA (triethylamine) (207 mg, 2.05 mmol, 5.0 eq), and T3P (1-propylphosphonic anhydride) (50% by mass solution in ethyl acetate, 261 mg, 0.82 mmol, 2.0 eq) were added to the reaction solution. The reaction was stirred at room temperature (25-30°C) for 3 hours. After the reaction was complete, the reaction solution was poured into 10 mL of water and extracted with ethyl acetate three times with 20 mL each time. The ethyl acetate phases were combined, washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 5 minutes, filtered, concentrated, and purified by preparative HPLC (C18, 10 mmol / L aqueous solution, acetonitrile) to give cis-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidin-1-yl)(6-(oxetan-3-ylamino)pyrimidin-4-yl)methanone (2.2 mg, yield 1.3%). LCMS (ESI) [M+1] + =396.18; 1 H NMR (400MHz, CDCl3) δ8.59 (m, 1H), 7.22-7.09 (m, 3H), 7.07-6.99 (m, 1H), 6.96-6.86 (m, 1H), 5.83 (m, 1H), 5.20- 4.93 (m, 3H), 4.59 (q, J=5.8Hz, 2H), 4.46-4.28 (m, 1H), 4.14-3.46 (m, 7H), 3.11-2.89 (m, 4H), 2.88-2.69 (m, 1H).

[0239] Example 11

[0240] Preparation of 1-(4-((6-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0241]

[0242] Step 1: Preparation of 1-(4-((6-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0243]

[0244] (4-amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol (50 mg, 0.216 mmol, 1.0 eq), 1-(4-((6-chloropyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one (66 mg, 0.259 mmol, 1.2 eq), Brettphos (dicyclohexyl[3,6-dimethoxy-2′,4′,6′ -triisopropyl[1,1′-biphenyl]-2-yl]phosphine) (12 mg, 0.022 mmol, 0.1 eq), Brettphos-Pd-G3 (methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II)) (20 mg, 0.022 mmol, 0. 1 eq) and t-BuONa (sodium tert-butoxide) (31 mg, 0.323 mmol, 1.5 eq) were added to a sealed microwave tube. Under nitrogen protection, THF (tetrahydrofuran) (1.1 mL) was added, and the temperature was raised to 60°C under nitrogen protection for 4 h. After completion of the reaction, the reaction solution was poured into 5 mL of water and extracted with ethyl acetate three times, each time with 10 mL. The ethyl acetate phases were combined, washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, filtered, concentrated, and subjected to preparative HPLC to obtain 18.1 mg of 1-(4-((6-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one in a yield of 18.6%. LCMS: [M+H] + =451.26; 1H NMR (400MHz, CDCl3) δ8.06 (s, 1H), 7.24-7.12 (m, 3H), 7.05 (d, J=7.2Hz, 1H), 6.04 (brs, 1H), 5.5 9(brs, 1H), 5.35(s, 1H), 4.58(s, 1H), 4.46(d, J=13.7Hz, 1H), 4.29(s, 1H), 4.10-3.95(m, 2H), 3 .80 (d, J=14.9Hz, 2H), 3.23 (d, J=12.7Hz, 1H), 3.14 (s, 1H), 3.06-3.00 (m, 2H), 2.86 (t, J=12.5H z, 1H), 2.61-2.51 (m, 2H), 2.11 (s, 3H), 2.08-1.96 (m, 5H), 1.87-1.74 (m, 1H), 1.51-1.33 (m, 3H).

[0245] Example 12

[0246] Preparation of 6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide:

[0247]

[0248] Step 1: Preparation of tert-butyl (3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-carbonylcyclopentyl)carbamate:

[0249]

[0250] To a solution of oxalyl chloride (0.38 mL, 4.52 mmol, 3.0 eq) in DCM (1 mL) was added dropwise a solution of dimethylsulfoxide (DMSO) (0.44 mL, 6.02 mmol, 4.0 eq) in 1 mL of DCM at -78 °C. The reaction mixture was stirred for 1 h under anhydrous and oxygen-free conditions at -78 °C. Then, the starting material tert-butyl (3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxycyclopentyl)carbamate (500 mg, 1.51 mmol, 1.0 eq) was dissolved in DCM (5.5 mL) and added dropwise to the reaction system under nitrogen protection. The reaction was carried out at -78 °C for 4.5 h, and then triethylamine (1.68 mL, 12.05 mmol, 8.0 eq) was added at -78 °C for 0.5 h. After the reaction was completed (TLC and LCMS), the reaction was quenched with an aqueous solution of ammonium chloride (5 mL), extracted with DCM (30 mL) and water (5 mL) three times, 30 mL each time, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (DCM / MeOH = 15 / 1) to obtain the intermediate tert-butyl (3-(3,4-dihydroisoquinolin-2(lH)-yl)-4-oxocyclopentyl)carbamate (200 mg, yield 40.2%). LCMS (ESI) [M+1] = 331.32. +

[0251] Second step: Preparation of tert-butyl (3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxycyclopentyl)carbamate:

[0252]

[0253] The starting material tert-butyl (3-(3,4-dihydroisoquinolin-2(lH)-yl)-4-oxocyclopentyl)carbamate (200 mg, 0.61 mmol, 1.0 eq) was dissolved in THF (3 mL) under anhydrous and oxygen-free conditions at -78 °C, and lithium tri-sec-butylborohydride (L-seletride) (0.91 mL, 0.91 mmol, 1.5 eq) was added dropwise to the reaction system under nitrogen protection. The reaction was carried out at -78 °C for 5 h. After the reaction was completed (TLC and LCMS), the reaction was quenched with an aqueous solution of ammonium chloride (5 mL), extracted with DCM (30 mL) and water (5 mL) three times, 30 mL each time, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by preparative HPLC (C 18, 0.08% aqueous ammonium bicarbonate solution, acetonitrile) to obtain four compounds:

[0254] Compound a: tert-butyl (3-(3,4-dihydroisoquinolin-2(lH)-yl)-4-hydroxycyclopentyl)carbamate (34 mg, yield 16.9%). LCMS (ESI) [M+1] = 331.32.​+ =333.20;1H NMR (400MHz, DMSO-d6) δ7.15-7.00 (m, 4H), 6.65 (d, J=7.8Hz, 1H), 4.09 (d, J=5.3Hz, 1 H), 4.01-3.94 (m, 1H), 3.87-3.77 (m, 1H), 3.70 (d, J = 15.1Hz, 1H), 3.59 (d, J = 15.1Hz, 1H), 2.91-2.73 (m, 3H), 2.69-2.60 (m, 1H), 2.39 (ddd, J=11.2, 6.5, 4.0Hz, 1H), 2.23- 2.06 (m, 2H), 1.60 (td, J=11.8, 8.6Hz, 1H), 1.48 (dd, J=14.4, 4.9Hz, 1H), 1.38 (s, 9H).

[0255] Compound b: tert-butyl (3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)carbamate (8.0 mg, yield 4.0%). LCMS (ESI) [M+1] + =333.20; 1 H NMR (400MHz, DMSO-d6) δ7.13-7.01 (m, 4H), 6.93 (d, J = 7.7Hz, 1H), 4.17 (s, 1H), 4.08-3.96 (m, 1H), 3.87 (s, 1H), 3.68 (d, J = 15.1Hz, 1H), 3.58 (d , J=15.1Hz, 1H), 2.90-2.74(m, 3H), 2.69-2.57(m, 2H), 2.04-1.92(m, 2 H), 1.71-1.62 (m, 1H), 1.57 (ddd, J=13.0, 7.7, 4.2Hz, 1H), 1.38 (s, 9H).

[0256] LCMS (ESI) [M+1] of compounds c and d + =333.20, not separated.

[0257] Step 3: Preparation of 4-amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentane-1-ol:

[0258]

[0259] The raw material tert-butyl (3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)carbamate (34 mg, 0.10 mmol, 1.0 eq) was dissolved in dichloromethane (4 mL). Under nitrogen, trifluoroacetic acid (1 mL) was added and the reaction mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, 1,2-dichloroethane (5 mL) was added and the mixture was concentrated to obtain the crude intermediate 4-amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol. LCMS (ESI) [M+1] + =233.24.

[0260] Step 4: Preparation of 6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide:

[0261]

[0262] 4-Amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol (23.7 mg, 0.10 mmol, 1.0 eq), 6-((1-acetylpiperidin-4-yl)amino)pyrimidine-4-carboxylic acid (27 mg, 0.10 mmol, 1.0 eq) and HATU (2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (59 mg, 0.15 mmol, 1.5 eq) were dissolved in DMF (N,N-dimethylformamide) (1 mL), and DIEA (N,N-diisopropylethylamine) (0.09 ml, 0.51 mmol, 5.0 eq) was added. The reaction mixture was reacted at room temperature under nitrogen protection for 3 hours. After the reaction was complete, the reaction solution was poured into 10 mL of water and extracted with ethyl acetate three times with 10 mL each time. The ethyl acetate phases were combined, washed once with 20 mL of water and once with 20 mL of saturated brine, dried over anhydrous sodium sulfate for 3 minutes, filtered, and concentrated. The crude product was separated and purified by preparative HPLC (C18, 0.08% NH4HCO3 aqueous solution, acetonitrile) to obtain 6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide (14.6 mg, yield 29.9%). LCMS (ESI) [M+H] + =479.43; 1HNMR (400MHz, CD3Cl) δ8.50 (d, J=1.1Hz, 1H), 8.43 (d, J=9.0Hz, 1H), 7.20-7.09 (m, 4H), 7.05-6.98 (m, 1H), 5.21 (d, J=7 .8Hz, 1H), 4.66-4.50 (m, 2H), 4.31 (d, J=4.0Hz, 1H), 4.07 (brs, 1H), 3.91-3.80 (m, 2H), 3.75 (d, J=14.9Hz, 1H), 3.23 (d dd, J=14.2, 11.8, 2.8Hz, 1H), 2.99 (s, 1H), 2.93 (s, 2H), 2.89-2.70 (m, 3H), 2.56 (dt, J=12.8, 7.7Hz, 1H), 2.26-2.18 (m , 1H), 2.12 (s, 3H), 2.06 (d, J=13.3Hz, 1H), 1.94 (dd, J=14.6, 3.1Hz, 1H), 1.85 (s, 1H), 1.62 (s, 2H), 1.50-1.37 (m, 2H).

[0263] Example 13

[0264] Preparation of 6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide:

[0265]

[0266] Step 1: Preparation of 4-amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol:

[0267]

[0268] The raw material (tert-butyl (3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)carbamate (8 mg, 0.02 mmol, 1.0 eq)) was dissolved in dichloromethane (2 mL). Under nitrogen, trifluoroacetic acid (0.5 mL) was added and the reaction mixture was allowed to react at room temperature (20-25°C) for 1 hour. After completion of the reaction, 1,2-dichloroethane (3 mL) was added and the mixture was concentrated to obtain the crude intermediate (1R,2S,4S)-4-amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol. LCMS (ESI) [M+1] + =233.16.

[0269] Step 2: Preparation of 6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide:

[0270]

[0271] 4-Amino-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentan-1-ol (5.6 mg, 0.02 mmol, 1.0 eq), 6-((1-acetylpiperidin-4-yl)amino)pyrimidine-4-carboxylic acid (6.4 mg, 0.02 mmol, 1.0 eq) and HATU (2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (14 mg, 0.036 mmol, 1.5 eq) were dissolved in DMF (N,N-dimethylformamide) (1 mL), and DIEA (N,N-diisopropylethylamine) (16 mg, 0.120 mmol, 5.0 eq) was added. Under nitrogen protection, the reaction solution was reacted at room temperature (18° C.) for 3 hours. After the reaction was complete, the reaction solution was poured into 10 mL of water and extracted with ethyl acetate three times with 10 mL each time. The ethyl acetate phases were combined, washed once with 20 mL of water and once with 20 mL of saturated brine, dried over anhydrous sodium sulfate for 1 minute, filtered, and concentrated. The crude product was separated and purified by preparative HPLC (C18, 0.08% NH4HCO3 aqueous solution, acetonitrile) to obtain 6-((1-acetylpiperidin-4-yl)amino)-N-((1S,3S,4R)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)pyrimidine-4-carboxamide (3.1 mg, yield 27.0%). LCMS (ESI) [M+1] + =479.23; 1 H NMR (400MHz, CD3Cl) δ8.49 (s, 1H), 8.01 (d, J=7.5Hz, 1H), 7.22-7.10 (m, 4H), 7.05 (d, J=7.0Hz, 1H) , 5.49 (brs, 1H), 4.72-4.63 (m, 1H), 4.56 (d, J=13.6Hz, 1H), 4.47 (s, 1H), 4.07-3.90 (m, 2H), 3.84 (d , J=14.1Hz, 1H), 3.29-3.08 (m, 3H), 3.00 (s, 2H), 2.83 (t, J=12.5Hz, 1H), 2.51 (dd, J=14.6, 8.2Hz, 2H), 2.12 (s, 3H), 2.08-1.97 (m, 3H), 1.88-1.80 (m, 2H), 1.72-1.63 (m, 2H), 1.46 (d, J=11.7Hz, 2H).

[0272] Example 14

[0273] Preparation of 1 -(4-((6-((3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxycyclopentyl)oxy)pyrimidin-4-yl)amino)piperidin-l -yl)ethan- 1 -one:

[0274]

[0275] First step: Preparation of 4-((tert-butyldiphenylsilyl)oxy)-2-(3,4- dihydroisoquinolin-2(lH)-yl)cyclopentyl neopentanoate:

[0276]

[0277] To a solution of 4-((tert-butyldiphenylsilyl)oxy)-2-(3,4-dihydroisoquinolin-2(lH)- yl)cyclopentanol and DMAP (4-dimethylaminopyridine) (16 mg, 0.13 mmol, 0.1 eq) in dry acetonitrile (6 ml) was added triethylamine (258 mg, 2.55 mmol, 2.0 eq) under nitrogen. The solution was heated to 40 degrees Celsius and PvCl (trimethylacetyl chloride) (306 mg, 2.55 mmol, 2.0 eq) was added. After 1 hour at 60 degrees Celsius the reaction was complete as determined by TLC. The reaction was quenched by the addition of water and extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the crude product by flash chromatography (silica gel, EA:PE = 0 to 8%) gave 4-((tert-butyldiphenylsilyl)oxy)-2-(3,4-dihydroisoquinolin-2(lH)-yl)cyclopentyl neopentanoate (680 mg, 96.3% yield).

[0278] Second step: Preparation of 2-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxycyclopentyl neopentanoate:

[0279]

[0280] 4-((tert-Butyldiphenylsilyl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)neopentylcyclopentyl ester (430 mg, 0.78 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 ml), and tetrabutylammonium fluoride solution (1.0 molar solution in tetrahydrofuran, 1.6 ml, 1.55 mmol, 2.0 eq) was added. The reaction was allowed to react at room temperature overnight (16 h), and the reaction was monitored for completion by TLC and LCMS. The reaction solution was added with ethyl acetate and washed with water, and the aqueous phase was back-extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and then spin-dried to obtain crude 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl pivalate (513 mg) as a brown oil. The crude product was used directly in the next step. 1 H NMR (400MHz, CDCl3) δ7.15-7.06 (m, 3H), 7.01-6.96 (m, 1H), 5.20 (ddd, J=8.3, 5.0, 3.5Hz, 1H), 4 .37 (tt, J=5.2, 2.3Hz, 1H), 3.69 (s, 2H), 3.45 (s, 2H), 3.32 (ddd, J=9.8, 7.4, 4.9Hz, 1H), 2.85 (d q, J=22.6, 5.8Hz, 3H), 2.78-2.71 (m, 1H), 2.48 (ddd, J=15.1, 8.3, 5.4Hz, 1H), 2.19 (ddt, J=13.5 , 7.4, 2.4Hz, 1H), 1.86 (ddd, J=13.3, 9.8, 5.1Hz, 1H), 1.66 (dq, J=15.0, 2.7Hz, 1H), 1.23 (s, 9H).

[0281] Step 3: Preparation of 4-((6-((1-acetylpiperidin-4-yl)(tert-butoxycarbonyl)amino)pyrimidin-4-yl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-yl)cyclopentyl pivalate:

[0282]

[0283] To a solution of 2-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxycyclopentyl pivalate (452 mg of crude, 1.43 mmol, 1.0 eq) in tetrahydrofuran (3 ml) was added dropwise a suspension of sodium hydride (63 mg of sodium hydride 60% w / w plus 2 ml of tetrahydrofuran to form a suspension, 1.1 eq) in tetrahydrofuran (2 ml) at 0 °C under nitrogen. After stirring for half an hour, a solution of (l-acetylpiperidin-4-yl)(6-chloropyrimidin-4-yl)carbamic acid tert-butyl ester (253 mg, 0.71 mmol, 0.5 eq) in tetrahydrofuran (4 ml) was added. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched by the addition of saturated ammonium chloride solution. After extraction with ethyl acetate and drying, the solvent was removed by evaporation. Flash chromatography (silica gel, MeOH:DCM = 0 to 1%) gave 4-((6-((l-acetylpiperidin-4-yl)(tert-butoxycarbonyl)amino)pyrimidin-4-yl)oxy)-2-(3,4-dihydroisoquinolin-2(lH)-yl)cyclopentyl pivalate 140 mg. Two step yield 28.5%. LCMS (ESI) [M+H] = 636.17. +

[0284] Fourth step: Preparation of 4-((6-((l-acetylpiperidin-4-yl)amino)pyrimidin-4-yl)oxy)-2-(3,4-dihydroisoquinolin-2(lH)-yl)cyclopentyl pivalate:

[0285]

[0286] To a solution of 4-((6-((l-acetylpiperidin-4-yl)(tert-butoxycarbonyl)amino)pyrimidin-4-yl)oxy)-2-(3,4-dihydroisoquinolin-2(lH)-yl)cyclopentyl pivalate (55 mg, 0.087 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (0.5 ml). The reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored by TLC and LCMS. The reaction was evaporated to dryness to give crude 4-((6-((l-acetylpiperidin-4-yl)amino)pyrimidin-4-yl)oxy)-2-(3,4-dihydroisoquinolin-2(lH)-yl)cyclopentyl pivalate (80 mg) as a pale yellow oil which was used directly in the next step. LCMS (ESI) [M+H] = 536.48. +

[0287] Fifth step: Preparation of l-(4-((6-(((3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxycyclopentyl)oxy)pyrimidin-4-yl)amino)piperidin-l-yl)ethanone:

[0288]

[0289] ​​4-((6-((1-acetylpiperidin-4-yl)amino)pyrimidin-4-yl)oxy)-2-(3,4-dihydroisoquinolin-2(1H)-ylneopentylcyclopentyl ester (80 mg crude product, 0.087 mmol, 1.0 eq) was dissolved in anhydrous methanol (2 ml) and sodium methoxide (122 mg, 2.27 mmol, 26 eq) was added. The reaction was allowed to react at 50°C for 2 hours and monitored by LCMS. After completion of the reaction, 1N aqueous hydrochloric acid solution was added to adjust the pH to 7. The crude product was concentrated and the reaction was reversed to give 1-(4-((6-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxycyclopentyl)oxy)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one (10 mg). LCMS: LCMS (ESI) [M+H] + =452.24; 1 H NMR (400MHz, CDCl3) δ8.25 (d, J=0.8Hz, 1H), 7.18-7.07 (m, 3H), 7.06-7.00 (m, 1H), 5.65 (d, J=0. 9Hz, 1H), 5.45 (s, 1H), 4.74 (d, J = 7.9Hz, 1H), 4.51 (d, J = 13.6Hz, 1H), 4.35 (s, 1H), 3.94-3.69 (m, 4H), 3.22 (td, J=13.9, 12.7, 2.8Hz, 1H), 3.11 (dt, J=11.7, 6.3Hz, 1H), 3.04-2.76 (m, 5H), 2.51 (d dd, J=14.2, 8.0, 5.6Hz, 1H), 2.39-2.17 (m, 1H), 2.15-1.88 (m, 8H), 1.40 (qd, J=11.4, 4.3Hz, 2H).

[0290] Example 15

[0291] Preparation of trans-1-(4-((2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0292]

[0293] Step 1: Preparation of trans-1-(4-((2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)amino)piperidin-1-yl)ethanone:

[0294]

[0295] Dissolve l-(4-((2-chloropyrimidin-4-yl)amino)piperidin-l-yl)ethanone (30 mg, 0.118 mmol, 1.0 eq) and trans-4-(3,4-dihydroisoquinolin-2(lH)-yl)pyrrolidin-3-ol (26 mg, 0.118 mmol, 1.0 eq) in isopropanol (1 mL), add N,N-diisopropylethylamine (31 mg, 0.236 mmol, 2.0 eq), and heat the reaction to 100 degrees Celsius for 16 hours. Dry the reaction in vacuo and purify by reverse phase HPLC to give trans-l-(4-((2-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxypyrrolidin-l-yl)pyrimidin-4-yl)amino)piperidin-l-yl)ethanone 19 mg, 36.9% yield. LCMS: [M+l] = 437.3. + 1 HNMR (400 MHz, CD3Cl) δ 7.87 (d, J = 5.7 Hz, IH), 7.17-7.08 (m, 3H), 7.06-7.00 (m, IH), 5.74 (d, J = 6.0 Hz, IH), 4.81 (br s, IH), 4.59-4.45 (m, 2H), 4.09-3.76 (m, 6H), 3.58 (t, J = 9.6 Hz, IH), 3.50-3.39 (m, IH), 3.26-3.15 (m, 2H), 3.04-2.79 (m, 5H), 2.20-2.01 (m, 5H), 1.49-1.34 (m, 2H).

[0296] Example 16

[0297] Preparation of trans-l-(4-((l-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxypyrrolidin-l-carbonyl)piperidin-4-yl)amino)piperidin-l-yl)ethan-l-one:

[0298]

[0299] First Step: Preparation of trans-tert-butyl (l-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-4- hydroxypyrrolidin-l-carbonyl)piperidin-4-yl)carbamate:

[0300]

[0301] ​Compound trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)pyrrolidin-3-ol (500 mg, 2.30 mmol, 1.0 eq) and bis(trichloromethyl) carbonate (273 mg, 0.40 mmol, 0.4 eq) were dissolved in dichloromethane (10 mL), cooled to 0°C, and under nitrogen protection, tert-butyl piperidin-4-ylcarbamate (459 mg, 2.30 mmol, 1.0 eq) and N,N-diisopropylethylamine (890 mg, 6.90 mmol, 3.0 eq) were added, and the reaction was carried out at 0°C for 2 h. After completion of the reaction, the mixture was extracted with dichloromethane three times with 15 mL each time. The combined dichloromethane phases were washed once with 20 mL of water and once with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate for 10 minutes, filtered, and the concentrated crude product was purified by flash chromatography (silica gel, DCM:MeOH = 19:1) to obtain the title compound (420 mg, 41.2% yield) as a white solid. LCMS (ESI) [M+H] + =445.43; 1 H NMR (400MHz, DMSO-d6) δ8.87 (s, 1H), 7.06 (d, J = 20.3Hz, 4H), 6.84 (d, J = 7.6Hz, 1H), 5.19 (d, J = 4.0Hz, 1H), 4.30-4.07 (m, 1H), 3.74 (t, J = 11.4 Hz, 1H), 3.64-3.48 (m, 6H), 3.38 (s, 1H), 3.15-3.09 (m, 2H), 2.92 (s, 1H), 2.72 (dd, J=23.5, 11.3Hz, 6H), 1.69 (d, J=11.2Hz, 2H), 1.38 (s, 9H).

[0302] Step 2: Preparation of trans-(4-aminopiperidin-1-yl)(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidin-1-yl)methanone:

[0303]

[0304] tert-Butyl trans-(1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidine-1-carbonyl)piperidin-4-yl)carbamate (280 mg, 0.63 mmol, 1.0 eq) was dissolved in dichloromethane (3.2 mL), trifluoroacetic acid (0.8 mL) was added, and the mixture was stirred at room temperature (25°C) for 1 hour. After completion of the reaction, saturated sodium bicarbonate solution was added to adjust the pH to alkaline, and the mixture was extracted with dichloromethane three times with 10 mL each time. The mixture was dried over anhydrous sodium sulfate for 10 minutes, filtered, and concentrated to obtain the crude desired product (191 mg, 88.2% yield) as a yellow solid.

[0305] LCMS (ESI) [M+H] + =345.21.

[0306] Step 3: Preparation of trans-1-(4-((1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidine-1-carbonyl)piperidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0307]

[0308] The intermediate trans-(4-aminopiperidin-1-yl)(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypyrrolidin-1-yl)methanone (190 mg, 0.55 mmol, 1.0 eq) and 1-acetylpiperidin-4-one (78 mg, 0.55 mmol, 1.0 eq) were dissolved in tetrahydrofuran (2.5 mL) and stirred at room temperature (25°C) for 1 hour. Then, sodium triacetoxyborohydride (140 mg, 0.66 mmol, 1.1 eq) was added. After TLC analysis, the reaction was quenched by the addition of 2 mL of water and extracted three times with 15 mL of ethyl acetate each time. The ethyl acetate phases were combined, washed once with 20 mL of water and once with 20 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, and filtered. The crude product was separated and purified by preparative HPLC (C18, 10 mmol / L aqueous NH4HCO3 solution, acetonitrile) to obtain the title compound (98 mg, 37.8% yield). LCMS (ESI) [M+H] + =470.39; 1 H NMR (400MHz, CDCl3) δ7.15-7.06 (m, 3H), 7.02-6.98 (m, 1H), 4.47 (d, J=13.3Hz, 1H), 4.34 (q, J=6.2Hz, 1H), 3.84 (dd, J=20.3, 12.2Hz, 2H), 3.78-3.59 (m, 6H), 3.43 (dt, J= 16.1, 8.0Hz, 1H), 3.39-3.30 (m, 1H), 3.13-3.04 (m, 1H), 3.00 (dd, J=13.8, 7.4Hz, 1H) , 2.96-2.91(m, 1H), 2.91-2.62(m, 9H), 2.08(s, 3H), 1.88(s, 4H), 1.35-1.16(m, 4H).

[0309] Example 17

[0310] Preparation of trans-1-(4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-ylethanone:

[0311]

[0312] Step 1: Preparation of compound 6-chloropyrimidine-4-carbonyl chloride:

[0313]

[0314] Compound 4,6-dichloropyrimidine (570 mg, 3.83 mmol, 1.0 eq) was dissolved in 18 mL of EA, and (COCl)2(oxalyl chloride) (2.43 g, 19.13 mmol, 5.0 eq) and N,N-dimethylformamide (1.8 ml) were added. The reaction was incubated at 85°C for 2 hours. After completion of the reaction, monitored by TLC and LCMS, the reaction solution was quickly dried on a rotary evaporator, sealed, and used directly in the next step.

[0315] Step 2: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

[0316]

[0317] Dissolve tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (2.50 g, 12.56 mmol, 1.0 eq) in i-PrOH (isopropanol, 63 mL) and add 1,2,3,4-tetrahydroisoquinoline (1.67 g, 12.56 mmol, 1.0 eq). The reaction is incubated at 85°C for 18 h under nitrogen. After completion of the reaction, the solvent is dried by spin-drying, water (200 mL) is added, and the product is extracted with dichloromethane (3 times, 200 mL each). The product is dried over anhydrous sodium sulfate, filtered, and then spin-dried. This step exhibits regioisomerism, including trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester and trans-3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester. The crude mixture (3.40 g, 81.5% yield) was purified by chromatography (silica gel, ethyl acetate:petroleum ether = 15:85) two or three times to afford 1.7 g of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester, in a 41% yield. LCMS (ESI) [M+H] + =333.3; 1H NMR (400MHz, CDCl3) δ7.20-7.08 (m, 3H), 7.05-6.98 (m, 1H), 4.59-4.17 (m, 2H), 3.94 (d, J=14.6Hz, 1H), 3.68 (d, J=14.5Hz, 2H), 3.54 (td, J= 10.0, 5.0Hz, 1H), 3.03 (dt, J=10.9, 5.3Hz, 1H), 2.91 (t, J=5.6Hz, 2H), 2.80-2.47 (m, 4H), 1.82 (dd, J=12.7, 2.5Hz, 1H), 1.59-1.38 (m, 10H).

[0318] Step 3: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0319]

[0320] The compound trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.01 mmol, 1.0 eq) was dissolved in DCM (dichloromethane) (15 mL) and TFA (trifluoroacetic acid) (3.75 mL). The reaction was stirred at room temperature (20-25°C) for 2 hours. After the reaction was completed, the reaction solution was dried using a rotary evaporator and 1,2-dichloroethane was added three times to remove excess TFA. After drying, the solution was sealed and used directly in the third step. LCMS (ESI) [M+H] + =233.2.

[0321] Step 4: Preparation of trans-(6-chloropyrimidin-4-yl)(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone:

[0322]

[0323] Trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (570 mg, 3.23 mmol, 1.0 eq) was dissolved in DCM (dichloromethane) (8 ml) and TEA (triethylamine) (653 mg, 6.46 mmol, 2.0 eq). 6-Chloropyrimidine-4-carbonyl chloride was dissolved in dichloromethane (8 ml) and slowly added to the reaction mixture of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol under nitrogen. The reaction mixture was allowed to react in an ice bath for 2 hours, then slowly warmed to room temperature (20-25°C) and reacted for 1 hour. After completion of the reaction, the reaction mixture was monitored by TLC and LCMS. 100 ml of water was added to the reaction mixture, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The organic phase was concentrated and separated and purified by reverse phase HPLC (C18, 0.08% NH4HCO3 aqueous solution, acetonitrile) to obtain 900 mg of the compound trans-(6-chloropyrimidin-4-yl)(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone (900 mg, yield 56.3%). LCMS (ESI) [M+H] + =373.

[0324] Step 5: Preparation of trans-1-(4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-ylethanone:

[0325]

[0326] Trans-(6-chloropyrimidin-4-yl)(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone (110 mg, 0.30 mmol, 1.0 eq) and 1-acetylpiperidin-4-amine hydrochloride (64 mg, 0.36 mmol, 1.2 eq) were dissolved in ACN (acetonitrile) (2 ml). DIPEA (N,N-diisopropylethylamine) (153 mg, 1.18 mmol, 3.9 eq) was added under nitrogen. The reaction solution was reacted at 90 degrees Celsius for 3 hours and then slowly cooled to room temperature (20-25 degrees Celsius). After completion of the reaction, 20 ml of water was added to the reaction solution, which was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic phase was concentrated and separated and purified by preparative HPLC (C18, 0.08% NH4HCO3 aqueous solution, acetonitrile) to give trans-1-(4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-ylethanone (17 mg, yield 11.8%). 1H NMR (400MHz, CDCl3) δ8.54 (s, 1H), 7.20-7.07 (m, 3H), 7.06-6.96 (m, 1H), 6.70-6.57 (m, 1H), 5.50-5.30 (m, 1H), 4.82 (m, 1H), 4.55 (d, J=13.6Hz, 1H), 4.37-3.92 (m, 3H), 3.90-3. 72 (m, 3H), 3.31-3.16 (m, 1.5H), 3.16-3.03 (m, 1H), 3.03-2.58 (m, 6.5H), 2.23 (d, J=13. 0Hz, 0.5H), 2.16-1.97(m, 5.5H), 1.72-1.51(m, 1H), 1.49-1.34(m, 2H); LCMS(ESI)[M+H] + =479.26.

[0327] Example 18

[0328] Preparation of cis-1-(4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-ylethanone

[0329]

[0330] Step 1: Preparation of tert-butyl 4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopiperidine-1-carboxylate:

[0331]

[0332] (COCl)2 (oxalyl chloride) (688 mg, 5.40 mmol, 1.2 eq) was dissolved in DCM (dichloromethane) (8 mL) and cooled to -78°C. Under nitrogen, DMSO (dimethyl sulfoxide) (387 mg, 4.95 mmol, 1.1 eq) was dissolved in DCM (8 mL) and slowly added dropwise to the reaction mixture, followed by stirring at -78°C for 30 minutes. A solution of tert-butyl trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carboxylate (1.5 g, 4.5 mmol, 1.0 eq) in DCM (8 mL) was then slowly added to the reaction mixture and stirred for 30 minutes. Et3N (triethylamine) (2.27 g, 22.5 mmol, 5.0 eq) was then added, stirred for 30 minutes, and then naturally warmed to room temperature (15°C). The reaction mixture was quenched with saturated ammonium chloride and extracted three times with 15 mL of dichloromethane each time. The dichloromethane phases were combined. The mixture was washed once with 20 mL of water and once with 20 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, DCM:MeOH = 49:1) to obtain the title compound (1.00 g, yield 67.1%) as a yellow oil. LCMS (ESI) [M+H] + =331.

[0333] Step 2: Preparation of cis-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[0334]

[0335] Dissolve tert-butyl 4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopiperidine-1-carboxylate (1.00 g, 3.00 mmol, 1.0 eq) in THF (tetrahydrofuran) (15 mL) and cool to -78°C. Under nitrogen, slowly add L-selectride (lithium tri-sec-butylborohydride) in tetrahydrofuran (1 M, 3.7 mL, 3.70 mmol, 1.2 eq) dropwise to the reaction mixture, followed by stirring at -78°C for 3 hours. The reaction mixture is quenched with saturated ammonium chloride and extracted three times with 15 mL of ethyl acetate. The ethyl acetate phases are combined and washed once with 20 mL of water and once with 20 mL of saturated brine. The mixture is dried over anhydrous sodium sulfate for 10 minutes, filtered, and concentrated. The crude product is purified by flash chromatography (silica gel, DCM:MeOH = 49:1) to obtain the target intermediate (220 mg, 21.9% yield) as a yellow oil. LCMS (ESI) [M+H] + =333.18; 1H NMR (400MHz, CDCl3) δ7.15 (dd, J=6.3, 3.2Hz, 2H), 7.13-7.09 (m, 1H), 7.02 (dd, J=9.6, 7.2Hz, 1H), 5.30 (s, 1H), 4.12 (m, 1H) , 3.89 (s, 2H), 3.49 (s, 4H), 3.11-3.01 (m, 1H), 2.92 (s, 3H), 2.66 (s, 1H), 2.50 (s, 1H), 2.03 (d, J=10.6Hz, 1H), 1.47 (s, 9H).

[0336] Step 3: Preparation of cis-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-3-ol:

[0337]

[0338] TFA (trifluoroacetic acid) (0.25 mL) was slowly added dropwise to a DCM (dichloromethane) solution (1 mL) of cis-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.60 mmol, 1.0 eq), followed by stirring at room temperature (15°C) for 1 hour. The reaction mixture was made alkaline with saturated sodium bicarbonate solution and extracted with dichloromethane three times, each time using 5 mL. The dichloromethane phases were combined. The mixture was washed once with 5 mL of water and once with 5 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, DCM:MeOH = 49:1) to obtain the target intermediate (110 mg, 79.1% yield) as a yellow oil. LCMS (ESI) [M+H] + =233.04.

[0339] Step 4: Preparation of cis-1-(4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0340]

[0341] The compound cis-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-3-ol (51 mg, 0.22 mmol, 1.0 eq), 6-((1-acetylpiperidin-4-yl)amino)pyrimidine-4-carboxylic acid (58 mg, 0.22 mmol, 1.0 eq), and HATU (2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (125 mg, 0.33 mmol, 1.5 eq) were dissolved in DMF (N,N-dimethylformamide) solution (1.5 mL), and DIPEA (N,N-diisopropylethylamine) (85 mg, 0.66 mmol, 3.0 eq) was added, followed by stirring at room temperature (10-15° C.) for 1 hour. The reaction mixture was poured into 10 mL of water and extracted with ethyl acetate three times with 6 mL each time. The ethyl acetate phases were combined, washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 5 minutes, filtered, and concentrated. The crude product was separated and purified by preparative HPLC (C18, 10 mmol / L aqueous NH4HCO3 solution, acetonitrile) to obtain the title compound (12 mg, yield 11.4%). LCMS (ESI) [M+H] + =479.27; 1 H NMR (400MHz, DMSO-d6) δ8.63 (d, J=5.3Hz, 1H), 8.38 (s, 1H), 7.88 (s, 1H), 7.43 (t, J=5.5Hz, 1H), 7. 18(d, J=6.0Hz, 1H), 7.12-7.06(m, 3H), 7.04-6.97(m, 1H), 5.22-5.09(m, 1H), 5.09(s, 1H), 4.86(t , J=6.9Hz, 2H), 4.65 (t, J=6.4Hz, 2H), 4.09-3.89 (m, 1H), 3.73-3.55 (m, 3H), 3.49-3.38 (m, 1H), 2. 84 (t, J=5.4Hz, 2H), 2.76 (dt, J=11.2, 5.5Hz, 1H), 2.68 (dd, J=11.3, 6.1Hz, 1H), 2.58-2.52 (m, 2H).

[0342] Example 19

[0343] Preparation of cis-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-(oxetan-3-ylamino)pyrimidin-4-yl)methanone:

[0344]

[0345] Step 1: Preparation of cis-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-(oxetan-3-ylamino)pyrimidin-4-yl)methanone:

[0346] The compounds cis-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-3-ol (60 mg, 0.258 mmol, 1.0 eq), 6-(oxetan-3-ylamino)pyrimidine-4-carboxylic acid (50 mg, 0.258 mmol, 1.0 eq), and HATU (2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (147 mg, 0.387 mmol, 1.5 eq) were dissolved in DMF (N,N-dimethylformamide) solution (2 mL), and DIPEA (N,N-diisopropylethylamine) (100 mg, 0.774 mmol, 3 eq) was added, followed by stirring at room temperature (10-15° C.) for 1 hour. The reaction mixture was poured into 10 mL of water and extracted with 6 mL of ethyl acetate three times. The ethyl acetate phases were combined, washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 5 minutes, filtered, concentrated, and purified by preparative HPLC to afford 9 mg of the title compound in an 8.57% yield. LCMS: [M+H] = 410.16. 1 H NMR (400MHz, CDCl3) δ8.53 (d, J=4.3Hz, 1H), 7.18-7.07 (m, 3H), 7.02 (d, J=5.9Hz, 1H), 6.75 (d, J =15.1Hz, 1H), 6.12 (m, 1H), 5.00 (m, 3H), 4.77 (d, J = 13.3Hz, 1H), 4.56 (t, J = 6.1Hz, 2H), 4.25-4.0 7 (m, 2H), 3.95-3.75 (m, 2H), 3.17 (d, J = 14.0Hz, 1H), 3.00-2.94 (m, 1H), 2.89 (dd, J = 11.3, 5.6Hz , 2H), 2.75 (td, J=13.0, 2.7Hz, 1H), 2.56 (dd, J=8.4, 3.2Hz, 1H), 2.17-1.83 (m, 2H), 1.72 (m, 2H).

[0347] Example 20

[0348] Preparation of trans-N-(1-acetylpiperidin-4-yl)-2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)thiazole-5-carboxamide:

[0349]

[0350] Step 1: Preparation of N-(1-acetylpiperidin-4-yl)-2-chlorothiazole-5-carboxamide:

[0351]

[0352] 2-Chlorothiazole-5-carboxylic acid (200 mg, 1.23 mmol, 1.0 eq), 1-(4-aminopiperidin-1-yl)ethane-1-one (218 mg, 1.23 mmol, 1.0 eq) and HATU (2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (699 mg, 1.85 mmol, 1.5 eq) were dissolved in DMF (N,N-dimethylformamide) (1 mL), and DIEA (N,N-diisopropylethylamine) (475 mg, 3.69 mmol, 3.0 eq) was added. Under nitrogen protection, the reaction solution was reacted at room temperature (20-25°C) for 4 hours. After the reaction was complete, the reaction solution was poured into 50 mL of water and extracted with ethyl acetate three times with 50 mL each time. The ethyl acetate phases were combined, washed once with 30 mL of water and once with 30 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, filtered, and concentrated. The crude product was separated and purified by preparative HPLC (C18, 0.08% NH4HCO3 aqueous solution, acetonitrile) to obtain N-(1-acetylpiperidin-4-yl)-2-chlorothiazole-5-carboxamide (180 mg, yield 51.0%). LCMS (ESI) [M+1] + =288.18.

[0353] Step 2: Preparation of trans-N-(1-acetylpiperidin-4-yl)-2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)thiazole-5-carboxamide:

[0354]

[0355] The compound N-(1-acetylpiperidin-4-yl)-2-chlorothiazole-5-carboxamide (40 mg, 0.14 mmol, 1.0 eq) was dissolved in DMF (N,N-dimethylformamide) (0.7 mL). Under nitrogen protection, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (39 mg, 0.17 mmol, 1.2 eq) and DIEA (N,N-diisopropylethylamine) (0.05 mL, 0.28 mmol, 2.0 eq) were added. Under nitrogen protection, the reaction solution was reacted at 60°C overnight. After the reaction was completed, water (30 mL) was added and the mixture was extracted with ethyl acetate three times (10 mL each time). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by preparative HPLC (C18, 0.08% NH4HCO3 aqueous solution, acetonitrile) to obtain trans-N-(1-acetylpiperidin-4-yl)-2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)thiazole-5-carboxamide (23.69 mg, 35.3% yield). LCMS (ESI) [M+1] + =484.20; 1 H NMR (400MHz, CDCL3) δ7.60 (s, 1H), 7.20-7.10 (m, 3H), 7.07-7.01 (m, 1H), 5.77 (d, J=7.8Hz, 1H), 4. 60 (d, J=13.6Hz, 1H), 4.30 (dt, J=15.1, 7.7Hz, 2H), 4.19-4.10 (m, 1H), 4.01 (d, J=14.6Hz, 1H), 3.8 5-3.71 (m, 3H), 3.24-3.14 (m, 1H), 3.07 (td, J=12.8, 12.1, 4.3Hz, 2H), 2.97 (dd, J=13.7, 9.0Hz, 3H ), 2.80-2.67 (m, 3H), 2.11 (s, 3H), 2.04-1.94 (m, 3H), 1.55 (dqd, J=120.3, 12.1, 11.6, 4.3Hz, 4H).

[0356] Example 21

[0357] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(((6-phenylpyridin-2-yl)methyl)piperidin-3-ol:

[0358]

[0359] Step 1: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(((6-phenylpyridin-2-yl)methyl)piperidin-3-ol:

[0360]

[0361] Trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (50 mg, 0.215 mmol, 1.0 eq) and 6-phenylpyridinecarboxaldehyde (59 mg, 0.323 mmol, 1.5 eq) were dissolved in dry tetrahydrofuran (1 ml) and stirred at room temperature for 40 minutes. Sodium acetate borohydride (137 mg, 0.646 mmol, 3.0 eq) was then added. The mixture was reacted at room temperature (20-25°C) for 1 hour and then quenched with water. After extraction with ethyl acetate, the organic phase was dried by rotary evaporation and purified by preparative HPLC to yield 45 mg of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(((6-phenylpyridin-2-yl)methyl)piperidin-3-ol in a yield of 52.3%. LCMS: [M+1]+ = 400.26; 1 H NMR (400MHz, CDCl3) δ8.03-7.96 (m, 2H), 7.72 (t, J=7.7Hz, 1H), 7.60 (dd, J=7.8, 1.1Hz, 1H), 7.50-7.44 (m, 2H), 7.43-7.3 6 (m, 2H), 7.17-7.09 (m, 3H), 7.05-6.99 (m, 1H), 3.96 (d, J = 14.6Hz, 1H), 3.89-3.73 (m, 3H), 3.69 (d, J = 14.6Hz, 1H), 3.54 ( s, 1H), 3.34 (ddd, J=10.5, 4.6, 2.1Hz, 1H), 3.14-3.02 (m, 2H), 2.91 (t, J=5.8Hz, 2H), 2.66 (dt, J=11.9, 6.2Hz, 1H), 2.53- 2.41 (m, 1H), 2.24 (t, J=11.3Hz, 1H), 2.12 (t, J=10.1Hz, 1H), 1.83 (dd, J=12.3, 3.4Hz, 1H), 1.70 (qd, J=12.0, 3.9Hz, 1H).

[0362] Example 22

[0363] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-((1-methyl-4-phenyl-1H-imidazol-2-yl)methyl)piperidin-3-ol:

[0364]

[0365] Step 1: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-((1-methyl-4-phenyl-1H-imidazol-2-yl)methyl)piperidin-3-ol:

[0366]

[0367] Trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (50 mg, 0.215 mmol, 1.0 eq) and 1-methyl-4-phenyl-1H-imidazole-2-carbaldehyde (60 mg, 0.323 mmol, 1.5 eq) were dissolved in dry tetrahydrofuran (1 ml) and stirred at room temperature (20-25°C) for 40 minutes. Sodium acetate borohydride (137 mg, 0.646 mmol, 3.0 eq) was then added. After reacting at room temperature for 1 hour, the mixture was quenched with water. After extraction with ethyl acetate, the organic phase was dried by rotary evaporation. HPLC analysis yielded 38.3 mg of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-((1-methyl-4-phenyl-1H-imidazol-2-yl)methyl)piperidin-3-ol in a 44.2% yield. LCMS: [M+1]+ = 403.27; 1 H NMR (600MHz, CDCl3) δ7.75-7.70 (m, 2H), 7.37-7.33 (m, 2H), 7.21 (tt, J=7.2, 1.2Hz, 1H), 7.16-7.09 (m, 4H), 7.02 (dd, J=7.0 , 1.9Hz, 1H), 3.93 (d, J=14.6Hz, 1H), 3.74 (s, 3H), 3.73-3.66 (m, 4H), 3.58 (brs, 1H), 3.24 (ddd, J=10.7, 4.6, 2.1Hz, 1H), 3.0 4(dt, J=11.2, 5.4Hz, 1H), 2.96 (ddt, J=11.5, 4.5, 2.5Hz, 1H), 2.90 (t, J=5.9Hz, 2H), 2.66 (dt, J=11.8, 6.1Hz, 1H), 2.50-2. 44 (m, 1H), 2.17 (td, J=11.8, 2.6Hz, 1H), 2.10 (t, J=10.1Hz, 1H), 1.80 (dq, J=12.7, 3.0Hz, 1H), 1.57 (qd, J=12.2, 4.1Hz, 1H).

[0368] Implementation 23

[0369] Preparation of trans-1-(4-((6-((3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)pyrimidin-4-yl)amino)piperidin-1-yl)ethanone:

[0370]

[0371] Step 1: Preparation of 1-(4-((6-chloropyrimidin-4-yl)amino)piperidin-1-yl)ethanone:

[0372]

[0373] 4,6-Dichloropyrimidine (500 mg, 3.356 mmol, 1.0 eq) and 1-(4-aminopiperidin-1-yl)ethanone hydrochloride (600 mg, 3.356 mmol, 1.0 eq) were dissolved in isopropanol (15 ml) and N,N-diisopropylethylamine (1.3 g, 10.068 mmol, 3.0 eq) was added. Stir at 100 degrees Celsius for 1 hour. LCMS monitored the reaction completion. The solvent was dried and purified on a normal silica gel column (0-3% methanol / dichloromethane) to give 850 mg of 1-(4-((6-chloropyrimidin-4-yl)amino)piperidin-1-yl)ethanone. LCMS: [M+1] + =345.10.

[0374] Step 2: Preparation of trans-1-(4-((6-((3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)pyrimidin-4-yl)amino)piperidin-1-yl)ethanone:

[0375]

[0376] 1-(4-((6-chloropyrimidin-4-yl)amino)piperidin-1-yl)ethanone (50 mg, 0.197 mmol, 1.0 eq) and trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (46 mg, 0.197 mmol, 1.0 eq) were dissolved in isopropanol (1 mL), and N,N-diisopropylethylamine (51 mg, 0.394 mmol, 2.0 eq) was added. The mixture was heated and stirred at 100 degrees Celsius overnight (16 h). The solvent was evaporated to dryness, and 11 mg of trans-1-(4-((6-((3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)pyrimidin-4-yl)amino)piperidin-1-yl)ethanone was obtained by HPLC with a yield of 12.4%. LCMS: [M+1]+=451.31; 1H NMR (400 MHz, CDC13) δ 8.18 (d, J = 0.9 Hz, 1H), 7.19 - 7.09 (m, 3H), 7.06 - 6.98 (m, 1H), 5.51 (d, J = 1.1 Hz, 1H), 4.76 (d, J = 13.4 Hz, 1H), 4.57 - 4.38 (m, 3H), 3.94 (d, J = 14.6 Hz, 1H), 3.90 - 3.77 (m, 2H), 3.77 - 3.65 (m, 2H), 3.59 (td, J = 10.0, 4.8 Hz, 1H), 3.24 (dd, J = 14.0, 11.2 Hz, 1H), 3.02 (dt, J = 11.0, 5.3 Hz, 1H), 2.91 (t, J = 5.8 Hz, 2H), 2.89 - 2.83 (m, 1H), 2.81 - 2.62 (m, 4H), 2.20 - 1.99 (m, 5H), 1.91 (dd, J = 12.9, 3.4 Hz, 1H), 1.63 - 1.50 (m, 1H), 1.45 - 1.33 (m, 2H).

[0377] Example 24

[0378] Preparation of trans-4-(3,4-dihydroisoquinolin-2(lH)-yl)-l-(6-(phenylamino)pyrimidin-4- yl)piperidin-3-ol:

[0379]

[0380] First Step: Preparation of trans-l-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(lH)- yl)piperidin-3-ol:

[0381]

[0382] trans-4-(3,4-Dihydroisoquinolin-2(lH)-yl)piperidin-3-ol (156 mg, 0.671 mmol, 1.0 eq) and N,N-diisopropylethylamine (173 mg, 1.342 mmol, 2.0 eq) were dissolved in isopropanol (3.5 ml). The reaction was stirred at 100 °C for 30 minutes. The reaction was monitored by LCMS and was complete. The solvent was evaporated and the product was purified by normal phase silica gel column (0-3% methanol / dichloromethane) to give trans-l-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(lH)-yl)piperidin-3-ol 187 mg, 54.0% yield. LCMS: [M+l] = 345.10. + = 345.10.

[0383] Step 2: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(phenylamino)pyrimidin-4-yl)piperidin-3-ol:

[0384]

[0385] (3S,4S)-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (racemic) (113 mg, 0.328 mmol, 1.0 eq) was dissolved in isopropanol (2 ml). Aniline (46 mg, 0.493 mmol, 1.5 eq) and concentrated hydrochloric acid (36% by mass, 0.2 ml) were added. The mixture was heated at 100°C with stirring overnight (12 h). The pH was adjusted to 7 with 1N aqueous sodium hydroxide solution. The solvent was evaporated to dryness. Reverse-phase HPLC was used to obtain 38.7 mg of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(phenylamino)pyrimidin-4-yl)piperidin-3-ol in a 29.4% yield. LCMS: [M+1]+ = 403.27. 1 H NMR (600MHz, CDCl3) δ8.26 (d, J=1.0Hz, 1H), 7.41-7.35 (m, 2H), 7.30-7.26 (m, 2H), 7.17-7.09 (m, 4H), 7.04-7.00 (m, 1 H), 6.87-6.77 (m, 1H), 6.00 (d, J=1.1Hz, 1H), 4.71 (d, J=13.4Hz, 1H), 4.48-4.38 (m, 1H), 3.93 (d, J=14.5Hz, 1H), 3.74- 3.64 (m, 2H), 3.57 (td, J=10.0, 4.9Hz, 1H), 3.01 (dt, J=11.1, 5.4Hz, 1H), 2.90 (t, J=5.8Hz, 2H), 2.77 (td, J=12.9, 2.6 Hz, 1H), 2.71 (dd, J=12.7, 10.2Hz, 1H), 2.68-2.62 (m, 2H), 1.90 (dq, J=13.0, 2.8Hz, 1H), 1.54 (qd, J=12.5, 4.4Hz, 1H).

[0386] Example 25

[0387] Preparation of trans-1-(4-((5-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)thiazol-2-yl)amino)piperidin-1-yl)ethan-1-one:

[0388]

[0389] Step 1: Preparation of trans-(2-chlorothiazol-5-yl)(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone:

[0390]

[0391] 2-Chlorothiazole-5-carboxylic acid (200 mg, 1.223 mmol, 1.0 eq), trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (340 mg, 1.467 mmol, 1.2 eq) and HATU (2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (697 mg, 1.834 mmol, 1.5 eq) were dissolved in N,N-dimethylformamide (6.2 mL), and N,N-diisopropylethylamine (1.06 mL, 6.113 mmol, 5.0 eq) was added. The reaction solution was reacted at room temperature (18° C.) overnight under nitrogen protection. After completion of the reaction (TLC and LCMS), the reaction solution was poured into 50 mL of water and extracted with ethyl acetate three times with 50 mL each time. The ethyl acetate phases were combined, washed once with 30 mL of water and once with 30 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, filtered, concentrated, and filtered through a column to obtain 300 mg of trans-(2-chlorothiazol-5-yl)(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone in a yield of 65.1%. LCMS: [M+H] + =378.07.

[0392] Step 2: Preparation of trans-1-(4-((5-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)thiazol-2-yl)amino)piperidin-1-yl)ethan-1-one:

[0393]

[0394] To a solution of compound trans-(2-chlorothiazol-5-yl)(4-(3,4-dihydroisoquinolin-2(lH)-yl)-3- hydroxypiperidin-l-yl)methanone (60 mg, 0.159 mmol, 1.0 eq), l-(4-aminopiperidin-l-yl)ethan- 1-one (34 mg, 0.191 mmol, 1.2 eq), Brettphos (dicyclohexyl[3,6-dimethoxy-2',4',6'-triisopropyl[ 1, 1 '-biphenyl]-2-yl]phosphine) (8.6 mg, 0.016 mmol, 0.1 eq), Brettphos-Pd-G3 (methyl sulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-l,r-biphenyl)(2-amino-l,r-biphenyl-2-yl)palladium(II)) (14.5 mg, 0.016 mmol, 0.1 eq) in THF (tetrahydrofuran) (0.8 mL), t-BuONa (sodium tert-butoxide) (46 mg, 0.477 mmol, 3.0 eq) was added, and the reaction mixture was heated to 60 °C for 2.5 h. After completion of the reaction, the reaction mixture was poured into 10 mL of water, and extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with 10 mL of brine, dried over sodium sulfate (10 min), filtered, and concentrated to give a crude product. The crude product was purified by preparative HPLC to give the target molecule 2.1 mg in 2.7% yield. LCMS: [M+1] = 484.33. + 1 H NMR (400 MHz, CDC13) δ 7.44 (s, 1H), 7.21 - 7.10 (m, 3H), 7.07 - 7.02 (m, 1H), 5.55 (br s, 1H), 4.73 (d, J = 13.1 Hz, 1H), 4.64 (d, J = 13.5 Hz, 1H), 4.50 (d, J = 13.7 Hz, 1H), 4.16 - 4.00 (m, 1H), 3.89 - 3.77 (m, 2H), 3.72 (s, 2H), 3.28 - 3.18 (m, 1H), 3.15 (s, 1H), 3.02 (s, 2H), 2.94 - 2.81 (m, 4H), 2.20 (d, J = 13.0 Hz, 1H), 2.12 (s, 4H), 1.99 (d, J = 12.7 Hz, 1H), 1.71 - 1.57 (m, 3H), 1.53 - 1.41 (m, 2H).

[0395] Example 26

[0396] Preparation of trans-l-(4-((2-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-4-hydroxypiperidin-l- yl)pyrimidin-4-yl)amino)piperidin-l-yl)ethanone:

[0397] ​

[0398] Step 1: Preparation of 1-(4-((2-chloropyrimidin-4-yl)amino)piperidin-1-yl)ethanone:

[0399]

[0400] 2,4-Dichloropyrimidine (300 mg, 2.014 mmol, 1.0 eq) and 1-(4-aminopiperidin-1-yl)ethanone hydrochloride (395 mg, 2.215 mmol, 1.1 eq) were dissolved in acetonitrile (9 mL), and N,N-diisopropylethylamine (780 mg, 6.042 mmol, 3.0 eq) was added. The reaction solution was reacted at 90°C for 1 hour. After completion of the reaction, the reaction solution was spin-dried and filtered through a column to obtain 197 mg of 1-(4-((2-chloropyrimidin-4-yl)amino)piperidin-1-yl)ethanone in a yield of 38.5%. LCMS: [M+H] + =255.10,257.10; 1 H NMR (400MHz, CDCl3) δ8.00 (d, J=5.8Hz, 1H), 6.30 (d, J=5.9Hz, 1H), 5.37 (d, J=7.5Hz, 1H), 4.54 (d, J=13.7Hz, 1H), 4.06 (s, 1H), 3.90 -3.78 (m, 1H), 3.25 (ddd, J=14.2, 11.7, 2.9Hz, 1H), 2.85 (t, J=12.2Hz, 1H), 2.19-2.08 (m, 4H), 2.08-1.99 (m, 1H), 1.47-1.35 (m, 2H).

[0401] Step 2: Preparation of trans-1-(4-((2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypiperidin-1-yl)pyrimidin-4-yl)amino)piperidin-1-yl)ethanone:

[0402]

[0403] 1-(4-((2-chloropyrimidin-4-yl)amino)piperidin-1-yl)ethanone (30 mg, 0.118 mmol, 1.0 eq) and trans-3-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-4-ol (28 mg, 0.118 mmol, 1.0 eq) were dissolved in isopropanol (1 mL), and N,N-diisopropylethylamine (31 mg, 0.236 mmol, 2.0 eq) was added. The reaction solution was reacted at 100 degrees Celsius for 22 hours. The reaction solution was spin-dried and reverse-phase HPLC was used to obtain 18 mg of trans-1-(4-((2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-hydroxypiperidin-1-yl)pyrimidin-4-yl)amino)piperidin-1-yl)ethanone in a yield of 33.9%. LCMS: [M+1] + =451.3; 1 H NMR (400MHz, CDCl3) δ7.88 (d, J=5.8Hz, 1H), 7.18-7.09 (m, 3H), 7.05-6.99 (m, 1H), 5.67 (d, J=5.8Hz, 1H), 5.12 (dd , J=12.7, 4.9Hz, 1H), 4.90 (d, J=13.3Hz, 1H), 4.56-4.43 (m, 1H), 4.07-3.90 (m, 2H), 3.86-3.76 (m, 1H), 3.76-3.68 (m, 2H), 3.59 (tt, J=9.7, 4.7Hz, 1H), 3.29-3.18 (m, 1H), 3.04 (dt, J=11.0, 5.3Hz, 1H), 2.94-2.76 (m, 4H), 2.66 (t, J=11.5Hz, 3H), 2.18-1.99 (m, 5H), 1.89 (dd, J=12.6, 3.3Hz, 1H), 1.55 (qd, J=12.3, 4.4Hz, 1H), 1.46-1.33 (m, 2H).

[0404] Example 27

[0405] Preparation of trans-(6-(benzylthio)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0406]

[0407] Step 1: Preparation of trans-(6-(benzylthio)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0408]

[0409] 4-(Benzylthio)-6-chloropyrimidine (60 mg, 0.254 mmol, 1.2 eq) and trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (49 mg, 0.212 mmol, 1.0 eq) were dissolved in isopropanol (1 mL). DIEA (N,N-diisopropylethylamine) (55 mg, 0.424 mmol, 2.0 eq) was added, and the reaction mixture was incubated at 100°C for 1 hour. The reaction mixture was spin-dried and analyzed by reverse-phase HPLC to yield 40 mg of trans-1-(6-(benzylthio)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol in a yield of 43.7%. LCMS: [M+1] + =433.21; 1 H NMR (400MHz, CDCl3) δ8.45 (d, J=1.1Hz, 1H), 7.45-7.37 (m, 2H), 7.34-7.28 (m, 2H), 7.28-7.21 (m, 1H), 7.18-7.08 (m, 3H) , 7.05-6.97 (m, 1H), 6.41 (d, J=1.2Hz, 1H), 4.59 (dd, J=37.2, 12.8Hz, 2H), 4.41 (s, 2H), 3.92 (d, J=14.5Hz, 1H), 3.75-3.6 2 (m, 2H), 3.54 (td, J=10.1, 4.9Hz, 1H), 3.00 (dt, J=10.9, 5.3Hz, 1H), 2.90 (t, J=5.7Hz, 2H), 2.81 (td, J=13.1, 2.6Hz, 1H) , 2.73 (dd, J=12.8, 10.3Hz, 1H), 2.66 (qd, J=8.6, 6.0Hz, 2H), 1.90 (dq, J=12.9, 2.8Hz, 1H), 1.51 (qd, J=12.5, 4.4Hz, 1H).

[0410] Example 28

[0411] Preparation of trans-1-(4-((3-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)phenyl)amino)piperidin-1-yl)ethan-1-one:

[0412]

[0413] Step 1: Preparation of methyl 3-((1-acetylpiperidin-4-yl)amino)benzoate:

[0414]

[0415] The compounds methyl m-chlorobenzoate (500 mg, 2.93 mmol, 1.0 eq), 1-acetyl-4-aminopiperidine (626 mg, 3.52 mmol, 1.2 eq), Ruphos (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl) (41 mg, 0.09 mmol, 0.03 eq), Ruphos-Pd-G3 (methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl) After dissolving 1-(1-acetyl)palladium(II)) (74 mg, 0.09 mmol, 0.03 eq) in THF (tetrahydrofuran) (14 mL), t-BuONa (sodium tert-butoxide) (563 mg, 5.86 mmol, 2.0 eq) was added sequentially. The temperature was raised to 60°C for 1.5 hours. After the reaction, the reaction solution was poured into 20 mL of water and extracted with ethyl acetate three times with 15 mL each time. The ethyl acetate phases were combined, washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, filtered, and concentrated to obtain a crude product. The crude product was separated by column chromatography (silica gel, DCM:MeOH = 20:1 to 15:1) to obtain 180 mg of the intermediate methyl 3-((1-acetylpiperidin-4-yl)amino)benzoate, in a yield of 22.2%. LCMS (ESI+) [M+1] + =277.1.

[0416] Step 2: Preparation of 3-((1-acetylpiperidin-4-yl)amino)benzoic acid:

[0417]

[0418] Methyl 3-((1-acetylpiperidin-4-yl)amino)benzoate (180 mg, 0.65 mmol, 1.0 eq) was dissolved in MeOH (methanol) (3.2 mL), and 3.5 M (molar concentration) sodium hydroxide aqueous solution (29 mg, 0.72 mmol, 1.1 eq) was added. Under nitrogen protection, the reaction solution was reacted at rt (room temperature, 24 ° C) for 3 hours. The reaction was not completed by detection (TLC and LCMS), and the temperature was raised to 38 ° C for 4 hours. After the reaction was completed by detection (TLC and LCMS), the reaction solution was poured into 5 mL of water, extracted with ethyl acetate, and the aqueous phase was adjusted to pH 4 with 1 M (molar concentration) hydrochloric acid aqueous solution. The water was spin-dried and dried to obtain 154 mg of 3-((1-acetylpiperidin-4-yl)amino)benzoic acid with a yield of 90%.

[0419] Step 3: Preparation of trans-1-(4-((3-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)phenyl)amino)piperidin-1-yl)ethan-1-one:

[0420]

[0421] 3-((1-acetylpiperidin-4-yl)amino)benzoic acid (100 mg, 0.38 mmol, 1.0 eq), trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (89 mg, 0.38 mmol, 1.0 eq) and HATU (2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (218 mg, 0.57 mmol, 1.5 eq) were dissolved in DMF (N,N-dimethylformamide) (1.9 mL), and DIEA (N,N-diisopropylethylamine) (0.34 mL, 1.91 mmol, 5.0 eq) was added. Under nitrogen protection, the reaction solution was reacted at room temperature (24° C.) for 1.5 hours. After completion of the reaction (TLC and LCMS), the reaction solution was poured into 5 mL of water and extracted with ethyl acetate three times with 5 mL each time. The ethyl acetate phases were combined, washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 2 minutes, filtered, and concentrated. The crude product was separated and purified by preparative HPLC (C18, 0.08% aqueous NH4HCO3, MeCN) to obtain 25.4 mg of the product, trans-1-(4-((3-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-carbonyl)phenyl)amino)piperidin-1-yl)ethan-1-one, in a yield of 14.0%. LCMS (ESI) [M+H] + =477.4; 1 H NMR (400MHz, CDCl3) δ7.21-7.10 (m, 4H), 7.06-7.01 (m, 1H), 6.69 (d, J=7.4Hz, 1H), 6.63 (d, J=6.2 Hz, 2H), 5.17-4.80 (m, 1H), 4.50 (d, J=13.6Hz, 1H), 4.27-3.93 (m, 2H), 3.87-3.63 (m, 3H), 3.60-3. 44 (m, 2H), 3.26-3.15 (m, 1H), 3.08 (s, 1H), 2.96 (s, 2H), 2.85 (t, J=12.5Hz, 2H), 2.73 (s, 2H), 2.15 (s, 1H), 2.12 (s, 3H), 2.08-2.04 (m, 1H), 2.00-1.91 (m, 1H), 1.71-1.50 (m, 3H), 1.42-1.30 (m, 2H).

[0422] Example 29

[0423] Preparation of trans-1-(4-((4-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)phenyl)amino)piperidin-1-yl)ethan-1-one:

[0424]

[0425] Step 1: Preparation of trans-(4-bromophenyl)(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone:

[0426]

[0427] The compounds 4-bromobenzoic acid (200 mg, 1.00 mmol, 1.0 eq), trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (277 mg, 1.19 mmol, 1.2 eq) and HATU (2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (568 mg, 1.49 mmol, 1.5 eq) were dissolved in DMF (N,N-dimethylformamide) (9 mL), and DIEA (N,N-diisopropylethylamine) (0.86 mL, 4.98 mmol, 5.0 eq) was added. Under nitrogen protection, the reaction solution was reacted at room temperature (24°C) for 1.5 hours. After completion of the reaction, the reaction solution was poured into 15 mL of water and extracted with ethyl acetate three times with 15 mL each time. The ethyl acetate phases were combined, washed once with 20 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 2 minutes, filtered, and concentrated. The crude product was separated by column chromatography (DCM:MeOH = 20:1 to 10:1) to obtain the intermediate trans-(4-bromophenyl)(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone (410 mg, yield 99.3%). LCMS (ESI) [M+H] + =415.3.

[0428] Step 2: Preparation of trans-1-(4-((4-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)phenyl)amino)piperidin-1-yl)ethan-1-one:

[0429]

[0430] Trans-(4-bromophenyl)(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone (340 mg, 0.82 mmol, 1.0 eq), 1-acetyl-4-aminopiperidine (175 mg, 0.98 mmol, 1.2 eq), Ruphos(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl) (12 mg, 0.03 mmol, 0.03 eq), Ruphos-Pd-G3(methanesulfonic acid(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II)) (21 mg, 0.03 mmol, 0.03 eq) were dissolved in THF (tetrahydrofuran) After the addition of 4% t-butylfuran (4 mL), t-BuONa (sodium tert-butoxide) (158 mg, 1.64 mmol, 2.0 eq) was added in sequence, and the temperature was raised to 80°C for overnight reaction. After the reaction, the reaction solution was poured into 20 mL of water and extracted with ethyl acetate three times with 15 mL each time. The ethyl acetate phases were combined and washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, filtered and concentrated to obtain a crude product. The crude product was separated and purified by Prep-HPLC (C18, 0.08% NH4HCO3 aqueous solution, acetonitrile) to obtain the product trans-1-(4-((4-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-carbonyl)phenyl)amino)piperidin-1-yl)ethan-1-one (20.5 mg, yield 5.2%). LCMS (ESI) [M+H] + =477.4;1H NMR (400MHz, CDCl3) δ7.21-7.10 (m, 4H), 7.06-7.01 (m, 1H), 6.69 (d, J=7.4Hz, 1H), 6.63 (d, J=6.2 Hz, 2H), 5.17-4.80 (m, 1H), 4.50 (d, J=13.6Hz, 1H), 4.27-3.93 (m, 2H), 3.87-3.63 (m, 3H), 3.60-3. 44 (m, 2H), 3.26-3.15 (m, 1H), 3.08 (s, 1H), 2.96 (s, 2H), 2.85 (t, J=12.5Hz, 2H), 2.73 (s, 2H), 2.15 (s, 1H), 2.12 (s, 3H), 2.08-2.04 (m, 1H), 2.00-1.91 (m, 1H), 1.71-1.50 (m, 3H), 1.42-1.30 (m, 2H).

[0431] Example 30

[0432] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-fluorophenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0433]

[0434] Step 1: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-fluorophenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0435]

[0436] Dissolve trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (100 mg, 0.29 mmol, 1.0 eq) in isopropanol (1.5 mL). Add 4-fluoroaniline (64 mg, 0.58 mmol, 2.0 eq) and concentrated hydrochloric acid (36% by mass, 0.15 mL). Heat and stir at 100°C overnight (16 h). Adjust the pH to 7 with 1 M aqueous sodium hydroxide. The mixture was extracted with ethyl acetate three times with 5 mL each time. The ethyl acetate phases were combined, washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, and filtered. The crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, MeCN) to obtain trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-fluorophenyl)amino)pyrimidin-4-yl)piperidin-3-ol (17.8 mg, yield 14.7%). LCMS (ESI) [M+H] + =420.36; 1 H NMR (400MHz, CDCl3) δ8.24 (s, 1H), 7.27-7.23 (m, 2H), 7.18-7.04 (m, 5H), 7.03-6.99 (m, 1H), 6 .85 (s, 1H), 5.81 (s, 1H), 4.70 (d, J = 12.7Hz, 1H), 4.40 (d, J = 10.0Hz, 1H), 3.93 (d, J = 14.5Hz, 1H ), 3.68 (d, J=14.6Hz, 2H), 3.56 (td, J=10.0, 4.9Hz, 1H), 3.01 (dt, J=10.8, 5.3Hz, 1H), 2.90 (t , J=5.6Hz, 2H), 2.82-2.61 (m, 4H), 1.89 (dd, J=12.8, 3.1Hz, 1H), 1.53 (qd, J=12.5, 4.3Hz, 1H).

[0437] Example 31

[0438] Preparation of trans-1-(4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)thiazolo[4,5-c]pyridin-2-yl)amino)piperidin-1-yl)ethanone:

[0439]

[0440] Step 1: Preparation of 6-chlorothiazolo[4,5-c]pyridine-2(3H)-thione:

[0441]

[0442] A three-necked flask containing 4,6-dichloropyridin-3-amine (1.0 g, 6.14 mmol, 1.0 eq) and C2H5O(C=S)SK (potassium ethylxanthate) (1.47 g, 9.20 mmol, 1.5 eq) was replaced with nitrogen and anhydrous NMP (N-methylpyrrolidone) (40 mL) was added. The reaction was allowed to react overnight (16 h) at 145 degrees Celsius. LCMS and TLC monitored the completion of the reaction. After the reaction solution was cooled to room temperature, 1.2 mL of acetic acid was added. The reaction solution was poured into 200 mL of water and filtered. After washing the filter cake with a small amount of water, the solid was dried under vacuum to obtain a crude product of 6-chlorothiazolo[4,5-c]pyridine-2(3H)-thione (1.17 g, crude yield 94.4%) as a brown solid. LCMS (ESI) [M+H] + =203.02; 1 H NMR (400MHz, DMSO-d6) δ14.14 (s, 2H), 8.28 (d, J=0.6Hz, 1H), 7.94 (d, J=0.6Hz, 1H).

[0443] Step 2: Preparation of 2,6-dichlorothiazolo[4,5-c]pyridine:

[0444]

[0445] A three-necked flask containing crude 6-chlorothiazolo[4,5-c]pyridine-2(3H)-thione (937 mg, 4.64 mmol, 1.0 eq) was replaced with nitrogen atmosphere. SO₂Cl₂ (sulfonyl chloride) (10 mL) was added and stirred at room temperature for 2 hours. The reaction was monitored for completion by LCMS. The reaction solution was poured into ice water and the pH was adjusted to 7 with 1 M aqueous sodium hydroxide solution. The product was extracted with ethyl acetate and dried by spin drying. Flash chromatography (silica gel, EA:PE = 0 to 1:20) afforded pure 2,6-dichlorothiazolo[4,5-c]pyridine (501 mg, 50.0% yield over two steps) as a white solid. LCMS (ESI) [M+H] +=204.84,206.83; 1 H NMR (400MHz, CDCl3) δ9.00 (d, J=0.8Hz, 1H), 7.79 (d, J=0.8Hz, 1H).

[0446] Step 3: Preparation of 1-(4-((6-chlorothiazolo[4,5-c]pyridin-2-yl)amino)piperidin-1-yl)ethanone:

[0447]

[0448] 2,6-Dichlorothiazolo[4,5-c]pyridine (1.00 g, 4.90 mmol, 1.0 eq) and 1-acetylpiperidin-4-amine hydrochloride (960 mg, 5.39 mmol, 1.1 eq) were dissolved in anhydrous acetonitrile (40 ml), and potassium carbonate (2.37 g, 17.16 mmol, 3.5 eq) was added. The reaction was stirred at 50°C under nitrogen for 20 hours. The reaction mixture was filtered, water was added, and the mixture was extracted with dichloromethane. The organic phase was dried and spin-dried. Flash chromatography (silica gel, MeOH:DCM = 0 to 1:24) afforded pure 1-(4-((6-chlorothiazolo[4,5-c]pyridin-2-yl)amino)piperidin-1-yl)ethanone (425 mg, 28.0% yield) as a white solid. 424 mg of the raw material was recovered. LCMS (ESI) [M+H] + =311.28,313.30.

[0449] Step 4: Preparation of trans-1-(4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)thiazolo[4,5-c]pyridin-2-yl)amino)piperidin-1-yl)ethanone:

[0450]

[0451] 1-(4-((6-chlorothiazolo[4,5-c]pyridin-2-yl)amino)piperidin-1-yl)ethanone (400 mg, 1.29 mmol, 1.0 eq), trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (309 mg, 1.42 mmol, 1.1 eq), RuPhos(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl) A microwave tube was loaded with RuPhosPdG3 (methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl) palladium(II)) (120 mg, 0.26 mmol, 0.2 eq), and sodium tert-butoxide (496 mg, 5.16 mmol, 4.0 eq) and replaced with nitrogen. Anhydrous dioxane (6.5 ml) was added, and the reaction was heated at 100 degrees Celsius for 40 hours. The reaction solution was filtered, water was added, and the product was extracted with dichloromethane. The organic phase was dried, spin-dried, and purified by flash chromatography (silica gel, MeOH:DCM = 0 to 1:24) to obtain the crude product. The product was then separated and purified by preparative HPLC (C18, 10 mmol / L aqueous NH4HCO3, MeCN) to afford pure trans-1-(4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)thiazolo[4,5-c]pyridin-2-yl)amino)piperidin-1-yl)ethanone (35 mg, 5.4% yield). LCMS (ESI) [M+H] + =507.41; 1 H NMR (400MHz, CDCl3) δ8.43 (s, 1H), 7.18-7.09 (m, 3H), 7.05-6.99 (m, 1H), 6.96 (s, 1H), 5.06 (s, 1H), 4.54 (d, J= 13.5Hz, 2H), 4.42 (ddd, J=12.6, 5.0, 2.0Hz, 1H), 4.09-3.92 (m, 2H), 3.89-3.79 (m, 1H), 3.77-3.66 (m, 3H), 3.2 6(ddd, J=14.1, 11.6, 2.9Hz, 1H), 3.04 (dt, J=10.9, 5.3Hz, 1H), 2.91 (t, J=5.9Hz, 3H), 2.88-2.71 (m, 3H), 2.71 -2.61 (m, 2H), 2.34-2.23 (m, 1H), 2.22-2.07 (m, 4H), 1.96-1.88 (m, 1H), 1.72-1.65 (m, 1H), 1.53-1.39 (m, 2H).

[0452] Example 32

[0453] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0454]

[0455] Step 1: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0456]

[0457] Dissolve trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (60 mg, 0.17 mmol, 1.0 eq) in isopropanol (1 mL). Add 4-methanesulfonylaniline (60 mg, 0.35 mmol, 2.0 eq) and concentrated hydrochloric acid (36% by mass, 0.1 mL). Heat and stir at 100°C overnight. Adjust the pH to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate three times with 5 mL each time. The ethyl acetate phases were combined, washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 2 minutes, and filtered. The crude product was purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to give trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol (15.6 mg, yield 18.7%). LCMS (ESI) [M+H] + =480.3; 1 H NMR (400MHz, CDCl3) δ8.35 (s, 1H), 793-7.85 (m, 2H), 7.62-7.55 (m, 2H), 7.19-7.08 (m, 3H), 7.05-7.01 (m, 1H), 6.90 (s, 1H), 6.05 (s, 1H), 4.76 (d, J = 13.4Hz, 1H), 4.48 (d, J = 12.9Hz, 1H) , 3.98 (d, J=14.6Hz, 1H), 3.89-3.66 (m, 2H), 3.63 (td, J=10.0, 4.8Hz, 1H), 3.13-3.01 (m, 4H) , 2.94 (t, J=5.8Hz, 2H), 2.88-2.68 (m, 4H), 1.95 (dd, J=12.8, 3.3Hz, 1H), 1.63-1.52 (m, 1H).

[0458] Example 33

[0459] Preparation of trans-4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)pyrimidin-4-yl)amino)benzonitrile:

[0460]

[0461] Step 1: Preparation of trans-4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)pyrimidin-4-yl)amino)benzonitrile:

[0462]

[0463] Dissolve trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (70 mg, 0.20 mmol, 1.0 eq) in isopropanol (1 mL). Add p-aminobenzonitrile (48 mg, 0.41 mmol, 2.0 eq) and concentrated hydrochloric acid (0.1 mL). Heat and stir at 100°C overnight. Adjust the pH to 8 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate three times with 5 mL each time. The ethyl acetate phases were combined, washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 2 minutes, and filtered. The crude product was separated and purified by Prep-HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to obtain trans-4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)pyrimidin-4-yl)amino)benzonitrile (11.3 mg, yield 13.1%). LCMS (ESI) [M+H] + =427.3; 1 H NMR (400MHz, CDCl3) δ8.35 (s, 1H), 7.61 (d, J=8.3Hz, 2H), 7.52 (d, J=8.3Hz, 2H), 7.20-7.10 (m, 3 H), 7.02 (d, J = 6.9Hz, 1H), 6.74 (s, 1H), 6.02 (s, 1H), 4.76 (d, J = 13.4Hz, 1H), 4.47 (d, J = 13.0Hz, 1H), 3.98 (d, J=14.6Hz, 1H), 3.89-3.68 (m, 2H), 3.62 (td, J=10.0, 4.9Hz, 1H), 3.05 (dd, J=11.1, 5.5Hz, 1H), 2.94 (t, J=5.7Hz, 2H), 2.89-2.67 (m, 4H), 1.95 (d, J=12.4Hz, 1H), 1.58-1.52 (m, 1H).

[0464] Example 34

[0465] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(m-benzylamino)pyrimidin-4-yl)piperidin-3-ol:

[0466]

[0467] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 3-methylaniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(m-benzylamino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 63.0%. LCMS (ESI) [M+H] + =417.4; 1 H NMR (400MHz, CDCl3) δ8.25 (d, J=0.9Hz, 1H), 7.32-7.21 (m, 1H), 7.19-7.05 (m, 5H), 7.04-6.93 (m, 2H), 6.75 (s, 1H), 5.96 (d, J = 1.0Hz, 1H), 4.71 (d, J = 13.5Hz, 1H), 4.42 (d, J = 11.3Hz, 1H), 3.94 (d, J = 14.6Hz , 1H), 3.69 (d, J=14.6Hz, 2H), 3.57 (td, J=10.0, 4.9Hz, 1H), 3.02 (dt, J=11.0, 5.3Hz, 1H), 2.91 (t, J=5 .8Hz, 2H), 2.84-2.62 (m, 4H), 2.37 (s, 3H), 1.90 (dd, J=12.8, 3.5Hz, 1H), 1.54 (qd, J=12.4, 4.3Hz, 1H).

[0468] Example 35

[0469] Preparation of trans-1-(6-((3-cyclopropylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0470]

[0471] The starting material trans- 1 -(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin- 2( 1 H)-yl)piperidin-3 -ol was used in the substitution reaction with 3 -cyclopropyl aniline according to the method of Example 33 to give the target molecule trans- 1 -(6-((3- cyclopropylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(lH)-yl)piperidin- 3 -ol in a yield of 45.8%. LCMS (ESI) [M+H] + = 442.3; 1 H NMR (400 MHz, Chloroform-d) δ 8.25 (d, J = 0.9 Hz, 1H), 7.28 - 7.22 (m, 1H), 7.17 - 7.09 (m, 3H), 7.09 - 7.05 (m, 1H), 7.03 - 6.99 (m, 1H), 6.94 (t, J = 2.0 Hz, 1H), 6.87 (dt, J = 7.7, 1.4 Hz, 1H), 6.70 (s, 1H), 5.97 (d, J = 1.1 Hz, 1H), 4.69 (d, J = 13.5 Hz, 1H), 4.43 (d, J = 13.0 Hz, 1H), 3.94 (d, J = 14.5 Hz, 1H), 3.75 - 3.65 (m, 2H), 3.57 (td, J = 10.0, 4.9 Hz, 1H), 3.02 (dt, J = 11.0, 5.3 Hz, 1H), 2.91 (t, J = 5.8 Hz, 2H), 2.83 - 2.61 (m, 4H), 1.94 - 1.85 (m, 2H), 1.54 (qd, J = 12.5, 4.4 Hz, 1H), 1.04 - 0.95 (m, 2H), 0.73 - 0.67 (m, 2H).

[0472] Example 36

[0473] Preparation of trans-3-((6-(4-(3,4-dihydroisoquinolin-2(lH)-yl)-3- hydroxypiperidin-l-yl)pyrimidin-4-yl)amino)benzonitrile:

[0474]

[0475] The starting material trans- 1 -(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin- 2( 1 H)-yl)piperidin-3 -ol was used in the substitution reaction with 3 -cyclopropyl aniline according to the method of Example 33 to give the target molecule trans- 1 -(6-((3- cyclopropylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(lH)-yl)piperidin- 3 -ol in a yield of 45.8%. LCMS (ESI) [M+H] + = 442.3; 1H NMR (400MHz, CDCl3) δ8.32 (s, 1H), 7.80 (t, J=1.9Hz, 1H), 7.66-7.57 (m, 1H), 7.44 (t, J=7.9Hz, 1H), 7.36 (dt, J=7. 6, 1.5Hz, 1H), 7.14 (dt, J=9.4, 3.3Hz, 3H), 7.07-6.99 (m, 1H), 6.67 (s, 1H), 5.90 (s, 1H), 4.73 (d, J=13.2Hz, 1H), 4 .46 (d, J=12.6Hz, 1H), 3.95 (d, J=14.6Hz, 1H), 3.87-3.66 (m, 2H), 3.60 (td, J=10.0, 4.9Hz, 1H), 3.03 (dt, J=11.0, 5.4Hz, 1H), 2.92 (t, J=5.7Hz, 2H), 2.87-2.64 (m, 4H), 1.93 (dd, J=12.9, 3.3Hz, 1H), 1.56 (qd, J=12.5, 4.3Hz, 1H).

[0476] Example 37

[0477] Preparation of trans-1-(6-((3-tert-butylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0478]

[0479] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 3-tert-butylaniline to obtain the target molecule, trans-1-(6-((3-tert-butylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 23%. LCMS (ESI) [M+H] + =458.4; 1H NMR (400MHz, CDCl3) δ8.25 (d, J=0.9Hz, 1H), 7.32 (t, J=7.9Hz, 1H), 7.26-7.24 (m, 1H), 7.21-7.17 (m, 1H), 7.16 -7.08 (m, 4H), 7.06-6.97 (m, 1H), 6.84 (s, 1H), 6.01 (s, 1H), 4.67 (d, J = 13.5Hz, 1H), 4.44 (d, J = 12.4Hz, 1H), 3. 93 (d, J=14.5Hz, 1H), 3.83-3.62 (m, 2H), 3.56 (td, J=10.1, 4.9Hz, 1H), 3.01 (dt, J=11.1, 5.3Hz, 1H), 2.90 (t, J =5.8Hz, 2H), 2.86-2.58 (m, 4H), 1.89 (dd, J=12.8, 3.4Hz, 1H), 1.54 (qd, J=11.8, 11.1, 3.6Hz, 1H), 1.33 (s, 9H).

[0480] Example 38

[0481] Preparation of trans-1-(6-((4-cyclopropylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0482]

[0483] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 4-cyclopropylaniline to obtain the target molecule, trans-1-(6-((4-cyclopropylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 22.3%. LCMS (ESI) [M+H] + =442.4; 1H NMR (400MHz, CDCl3) δ11.53 (s, 1H), 8.11 (s, 1H), 7.34-7.27 (m, 2H), 7.26-7.23 (m, 1H), 7.20 (dd, J =7.4, 1.7Hz, 1H), 7.16-7.11 (m, 3H), 7.07 (d, J = 7.4Hz, 1H), 5.77 (s, 1H), 4.48 (d, J = 14.8Hz, 1H), 4. 25 (d, J=14.8Hz, 2H), 3.90 (s, 2H), 3.58-3.26 (m, 4H), 3.22-2.79 (m, 4H), 2.11 (d, J=12.5Hz, 1H), 1 .91 (td, J=8.6, 4.4Hz, 1H), 1.68 (d, J=12.6Hz, 1H), 1.07-0.96 (m, 2H), 0.72 (dt, J=6.6, 4.7Hz, 2H).

[0484] Example 39

[0485] Preparation of trans-1-(6-((4-tert-butylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0486]

[0487] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 4-tert-butylaniline to obtain the target molecule, trans-1-(6-((4-tert-butylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 47.4%. LCMS (ESI) [M+H] + =458.4; 1 H NMR (400MHz, DMSO-d6) δ8.94 (s, 1H), 8.16 (s, 1H), 7.47-7.44 (m, 2H), 7.31-7.2 7(m, 2H), 7.07-7.03(m, 4H), 5.98(s, 1H), 4.70(s, 1H), 4.27(dd, J=39.2.Hz, 12 .0Hz, 2H), 3.81 (dd, J=26.8Hz, 14.8Hz, 2H), 3.59-3.57 (m, 1H), 2.90-2.79 (m, 5 H), 2.69-2.64 (m, 2H), 1.81 (d, J=10.4Hz, 1H), 1.49-1.42 (m, 1H), 1.27 (s, 9H).

[0488] Example 40

[0489] Preparation of trans- 1 -(6-([ 1, 1 '-biphenyl]-4-ylamino)pyrimidin-4-yl)-4-(3,4- dihydroisoquinolin-2( 1 H)-yl)piperidin-3 -ol:

[0490]

[0491] The starting material, trans- 1 -(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin- 2( 1 H)-yl)piperidin-3 -ol, was subjected to substitution reaction with 4-aminobiphenyl according to the method of Example 33 to give the target molecule, trans- 1 -(6-([ 1, 1 '- biphenyl]-4-ylamino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2( 1 H)-yl)piperidin-3 -ol, in a yield of 64.9%. LCMS (ESI) [M+H] + = 478.4; 1 H NMR (400 MHz, CDC13) δ 11.77 (s, 1H), 8.14 (s, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.62-7.57 (m, 2H), 7.46 (dd, J = 8.3, 6.8 Hz, 2H), 7.40-7.32 (m, 3H), 7.30-7.23 (m, 2H), 7.22-7.16 (m, 1H), 7.07 (d, J = 7.4 Hz, 1H), 5.92 (s, 1H), 4.52 (d, J = 14.8 Hz, 1H), 4.44-3.76 (m, 4H), 3.68-3.30 (m, 4H), 3.22-2.79 (m, 4H), 2.13 (d, J = 12.4 Hz, 1H), 1.79-1.60 (m, 1H).

[0492] Example 41

[0493] Preparation of trans- 1 -(6-((4-methylphenyl)amino)pyrimidin-4-yl)-4-(3,4- dihydroisoquinolin-2( 1 H)-yl)piperidin-3 -ol:

[0494]

[0495] The starting material, trans- 1 -(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin- 2( 1 H)-yl)piperidin-3 -ol, was subjected to substitution reaction with 4-methylaniline according to the method of Example 33 to give the target molecule, trans- 1 -(6-((4- methylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2( 1 H)-yl)piperidin-3 -ol, in a yield of 45.6%. LCMS (ESI) [M+H] +=416.45; 1 H NMR (400MHz, Chloroform-d) δ8.24 (d, J=1.0Hz, 1H), 7.21-7.08 (m, 7H), 7.05-6.96 (m, 1H), 6.66 (s, 1H), 5.89 (d, J=1.1Hz, 1H), 4.72 (d, J=13.4Hz, 1H), 4.39 (d, J=11.9Hz, 1H), 3.93 (d, J=14.6Hz, 1H), 3.69 (d, J=14.0Hz, 2H), 3.56 (td, J=10.0, 4.9Hz, 1H), 3.01 (dt, J=10.9, 5.3Hz, 1H), 2.91 (t, J=5.7H z, 2H), 2.81-2.60 (m, 4H), 2.36 (s, 3H), 1.89 (dd, J=13.0, 3.3Hz, 1H), 1.53 (qd, J=12.5, 4.4Hz, 1H).

[0496] Example 42

[0497] Preparation of trans-1-(6-((3-fluorophenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0498]

[0499] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 3-fluoroaniline to obtain the target molecule, trans-1-(6-((3-fluorophenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 49.6%. LCMS (ESI): [M+H] + =420.32; 1H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 8.25 (s, 1H), 7.78-7.71 (m, 1H), 7.32-7.23 (m, 2H), 7.11-7.05 (m, 3H), 7.03 (dd, J=5.9, 2.2Hz, 1H), 6.76-6.68 (m, 1H), 6.02 (s, 1H), 4.72 (d, J=4.0Hz, 1H), 4.33 (d, J=10.3Hz, 1H), 4.22 (d, J=12.4Hz, 1H), 3.80 (q, J=15.0Hz, 2H), 3.64-3.55 (m, 1H), 2.88 (dd, J=15.4 , 8.4Hz, 2H), 2.83-2.74 (m, 3H), 2.74-2.62 (m, 2H), 1.87-1.77 (m, 1H), 1.48 (qd, J=12.4, 4.1Hz, 1H).

[0500] Example 43

[0501] Preparation of trans-1-(6-((3-chlorophenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0502]

[0503] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 3-chloroaniline to obtain the target molecule, trans-1-(6-((3-chlorophenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 49.6%. LCMS (ESI) [M+H] + =436.30,438.31; 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, IH), 8.25 (s, IH), 7.95 (t, J = 2.0 Hz, IH), 7.48 - 7.39 (m, IH), 7.28 (t, J = 8.1 Hz, IH), 7.13 - 6.99 (m, 4H), 6.95 (ddd, J = 7.9, 2.0, 0.8 Hz, IH), 6.01 (s, IH), 4.71 (d, J = 4.0 Hz, IH), 4.33 (d, J = 10.8 Hz, IH), 4.22 (d, J = 11.4 Hz, IH), 3.80 (q, J = 15.0 Hz, 2H), 3.64 - 3.54 (m, IH), 2.98 - 2.84 (m, 2H), 2.76 (dt, J = 9.7, 6.4 Hz, 3H), 2.74 - 2.62 (m, 2H), 1.88 - 1.76 (m, IH), 1.48 (qd, J = 12.4, 4.1 Hz, IH).

[0504] Example 44

[0505] Preparation of trans-l-(6-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-4- (3,4-dihydroisoquinolin-2(lH)-yl)piperidin-3-ol:

[0506]

[0507] The starting material, trans-l-(6-chloropyrimidin-4-yl)-4-(3,4- dihydroisoquinolin-2(lH)-yl)piperidin-3-ol, was subjected to a substitution reaction with 3-(methylsulfonyl)aniline according to the method of Example 33 to give the target molecule, trans-l-(6-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-4-(3,4- dihydroisoquinolin-2(lH)-yl)piperidin-3-ol, in a yield of 7.8%. LCMS (ESI) [M+H] + = 480.29; 1H NMR (400 MHz, CDC13) δ 8.31 (d, J = 8.0 Hz, IH), 8.00 (s, IH), 7.74 (d, J = 8.0 Hz, IH), 7.62 (d, J = 7.9 Hz, IH), 7.54 (t, J = 7.9 Hz, IH), 7.19 - 7.09 (m, 3H), 7.06 7.00 (m, IH), 6.95 (s, IH), 5.98 (s, IH), 4.70 (d, J = 12.7 Hz, IH), 4.48 (d, J = 10.2 Hz, IH), 3.87 (dd, J = 94.3, 14.6 Hz, 3H), 3.63 (td, J = 9.9, 4.8 Hz, IH), 3.09 (s, 3H), 3.06 - 2.99 (m, IH), 2.94 (t, J = 5.5 Hz, 2H), 2.78 (ddd, J = 20.9, 16.4, 7.8 Hz, 4H), 1.94 (d, J = 9.8 Hz, IH), 1.60 - 1.52 (m, IH).

[0508] Example 45

[0509] Preparation of trans- 1 -(6-((4-( 1 -chloro-3 -hydroxypropan-2-yl)phenyl)amino)pyrimidin-4-yl)- 4-(3,4-dihydroisoquinolin-2( 1 H)-yl)piperidin-3 -ol:

[0510]

[0511] The starting material trans- 1 -(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2( 1 H)- yl)piperidin-3 -ol was subjected to a substitution reaction with 4-(oxetan-3 -yl)aniline according to the method of Example 33 to give the target molecule trans- 1 -(6-((4-( 1 -chloro-3 - hydroxypropan-2-yl)phenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2( 1 H)-yl)piperidin- 3 -ol in a yield of 23.7%. LCMS (ESI) [M+H] + = 494.32; 1H NMR (400MHz, CDCl3) δ8.25 (s, 1H), 7.26 (s, 4H), 7.19-7.07 (m, 3H), 7.02 (d, J=6.0Hz, 1H), 6.76 (s, 1H), 5.99 (s, 1H), 4.74 (d, J=12.4Hz, 1H), 4.42 (d, J=10.3Hz, 1H), 3.99 (d, J=5.9Hz, 2H), 3.94 (d, J=14.8Hz, 1H), 3.90-3.85 (m, 1H), 3.8 1 (dd, J=11.0, 6.3Hz, 1H), 3.69 (d, J=14.5Hz, 1H), 3.58 (td, J=10.0, 4.9Hz, 1H), 3.24-3.15 (m, 1H), 3.01 (dd, J=10.8 , 5.2Hz, 1H), 2.91 (t, J=5.3Hz, 2H), 2.83-2.72 (m, 2H), 2.71-2.62 (m, 2H), 1.91 (d, J=10.2Hz, 1H), 1.62-1.50 (m, 1H).

[0512] Example 46

[0513] Preparation of trans-1-(6-((2-methylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0514]

[0515] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 2-methylaniline to obtain the target molecule, trans-1-(6-((2-methylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 17.2%. LCMS (ESI) [M+H] + =416.36; 1H NMR (400MHz, CDCl3) δ8.24 (s, 1H), 7.33 (d, J = 7.3Hz, 1H), 7.28 (d, J = 7.8Hz, 1H), 7.23 (d, J = 7.7Hz, 1H), 7.20- 7.08 (m, 4H), 7.06-6.98 (m, 1H), 6.41 (s, 1H), 5.64 (s, 1H), 4.69 (d, J=12.8Hz, 1H), 4.36 (d, J=9.6Hz, 1H), 3.9 2(d, J=14.5Hz, 1H), 3.68 (d, J=14.4Hz, 2H), 3.55 (td, J=10.0, 4.9Hz, 1H), 3.01 (dt, J=10.9, 5.3Hz, 1H), 2.90 (t, J=5.6Hz, 2H), 2.80-2.58 (m, 4H), 2.27 (s, 3H), 1.88 (dd, J=12.8, 3.2Hz, 1H), 1.52 (qd, J=12.4, 4.3Hz, 1H).

[0516] Example 47

[0517] Preparation of trans-1-(6-((3-methoxyphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0518]

[0519] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 3-methoxyaniline to obtain the target molecule, trans-1-(6-((3-methoxyphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 30.2%. LCMS (ESI) [M+H] + =432.4; 1H NMR (400MHz, CDCl3) δ8.28 (s, 1H), 7.33-7.28 (m, 1H), 7.19-7.12 (m, 3H), 7.05-7.03 (m, 1H), 6.92-6.87 (m, 3H), 6.75-6.72 (d, J=7.4Hz, 1H), 6.03 (s, 1H), 4.76-4.73 (d, J=13.6Hz, 1H), 4.48-4.45 (d, J=10.0Hz, 1H), 4 .00-3.96 (d, J=14.4Hz, 1H), 3.84 (s, 3H), 3.76-3.72 (d, J=14.8Hz, 1H), 3.64-3.58 (m, 1H), 3.07-3.03 (m, 1 H), 2.96-2.94 (t, J=5.6Hz, 2H), 2.85-2.70 (m, 4H), 196-1.92 (dd, J=3.2Hz, 12.8Hz, 1H), 1.63-1.53 ​​(m, 1H).

[0520] Example 48

[0521] Preparation of trans-1-(6-((3-trifluoromethylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0522]

[0523] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 3-aminobenzotrifluoride to obtain the target molecule, trans-1-(6-((3-trifluoromethylphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 20.6%. LCMS (ESI) [M+H] + =470.3; 1H NMR (400 MHz, CDC13) δ 8.33 (s, IH), 7.64 (s, IH), 7.58-7.56 (d, J = 8.4 Hz, IH), 7.52-7.48 (t, J = 7.6 Hz, IH), 7.39-7.38 (d, J = 7.6 Hz, IH), 7.19-7.12 (m, 3H), 7.05-7.03 (m, IH), 6.78 (s, IH), 5.97 (s, IH), 4.74-4.71 (d, J = 13.6 Hz, IH), 4.50-4.48 (d, J = 9.6 Hz, IH), 4.00-3.96 (d, J = 14.4 Hz, IH), 3.75-3.72 (d, J = 14.8 Hz, IH), 3.65-3.59 (m, IH), 3.09-3.03 (m, IH), 2.96-2.93 (t, J = 5.6 Hz, 2H), 2.88-2.68 (m, 4H), 1.97-1.93 (dd, J = 3.2 Hz, 12.8 Hz, IH), 1.63-1.54 (m, IH).

[0524] Example 49

[0525] Preparation of trans-4-(3,4-dihydroisoquinolin-2(lH)-yl)-l-(6-((4- morpholinophenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0526]

[0527] The starting material, trans-l-(6-chloropyrimidin-4-yl)-4-(3,4- dihydroisoquinolin-2(lH)-yl)piperidin-3-ol, was subjected to a substitution reaction with 4-morpholinophenylamine according to the method of Example 33 to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(lH)-yl)-l-(6-((4-morpholinophenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 69.8%. LCMS (ESI) [M+H] + = 487.5; 1H NMR (400MHz, DMSO-d6) δ8.77 (s, 1H), 8.12 (s, 1H), 7.39-7.37 (d, J=9.2Hz, 1H), 7.10-7.07 (m, 3H), 7.04-7.02 (m, 1H), 6.91-6.88 (d, J=9.2Hz, 1H), 5.88 (s, 1H), 4.69-4.68 (d, J=4.0Hz, 1H), 4.31-4.28 (d, J=3.6Hz, 1H), 4. 22-4.19 (d, J=12.4Hz, 1H), 3.86-3.79 (m, 2H), 3.75-3.73 (t, J=4.8Hz, 4H), 3.60-3.55 (m, 1H), 3.05-3.03 (t, J =4.8Hz, 4H), 2.91-2.78 (m, 5H), 2.68-2.61 (t, J = 10.0Hz, 2H), 1.81-1.78 (d, J = 3.2Hz, 1H), 1.48-1.44 (m, 1H).

[0528] Example 50

[0529] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-morpholinylphenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0530]

[0531] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 2-(morpholinyl)aniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-morpholinylphenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 20.57%. LCMS (ESI) [M+H] + =487.4; 1H NMR (400MHz, CDCl3) δ8.33 (s, 1H), 7.77-7.75 (d, J=7.6Hz, 1H), 7.33 (s, 1H), 7.18-7.15 (m, 5H), 7.10- 7.03 (m, 2H), 6.11 (s, 1H), 4.80-4.77 (d, J=13.2Hz, 1H), 4.52-4.49 (dd, J=2.8Hz, 12.8Hz, 1H), 3.99-3 .95(d, J=14.4Hz, 1H), 3.90-3.88(t, J=4.4Hz, 4H), 3.76-3.71(m, 2H), 3.66-3.60(m, 1H), 3.08-3.03( m, 1H), 2.95-2.91 (m, 6H), 2.86-2.67 (m, 4H), 1.97-1.93 (dd, J=3.2Hz, 12.8Hz, 1H), 1.64-1.57 (m, 1H).

[0532] Example 51

[0533] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-cyclopropylphenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0534]

[0535] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 2-cyclopropylaniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-cyclopropylphenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 28.2%. LCMS (ESI) [M+H] + =442.3; 1H NMR (400MHz, CDCl3) δ8.29 (s, 1H), 7.46-7.44 (d, J=0.8Hz, 8.0Hz, 1H), 7.27-7.23 (td, J=1.6Hz, 7.2Hz, 1H), 7.17 -7.08 (m, 5H), 7.05-7.02 (m, 1H), 6.80 (s, 1H), 5.89 (s, 1H), 4.74-4.71 (d, J=13.2Hz, 1H), 4.45-4.42 (dd, J=2.4Hz , 12.4Hz, 1H), 3.97-3.93 (d, J=14.4Hz, 1H), 3.72-3.69 (m, 2H), 3.62-3.56 (m, 1H), 3.05-3.01 (m, 1H), 2.94-2.91 (t, J=6.0Hz, 2H), 2.82-2.64 (m, 4H), 1.95-1.88 (m, 2H), 1.58-1.54 (m, 1H), 1.02-0.98 (m, 2H), 0.72-0.68 (m, 2H).

[0536] Example 52

[0537] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0538]

[0539] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 4-trifluoromethylaniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 74%. LCMS (ESI) [M+H] + =442.3; 1H NMR (400MHz, TFA-d6) δ8.52 (s, 1H), 8.01-7.99 (d, J=8.0Hz, 2H), 7.67-7.65 (d, J=8 .0Hz, 2H), 7.57-7.48(m, 2H), 7.44-7.43(d, J=7.6Hz, 1H), 7.34-7.29(m, 1H), 6.35( s, 1H), 5.10 (s, 1H), 4.95-4.70 (m, 3H), 4.60-4.53 (m, 1H), 4.12-4.10 (d, J=11.2Hz, 2H), 3.91-3.38 (m, 5H), 2.66-2.58 (t, J=16.8Hz, 1H), 2.26-2.21 (t, J=10.4Hz, 1H).

[0540] Example 53

[0541] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-fluorophenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0542]

[0543] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 2-fluoroaniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-fluorophenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 43.4%. LCMS (ESI) [M+H] + =420.32; 1 H NMR (400MHz, CDCl3) δ8.30 (s, 1H), 7.76 (td, J=8.0, 1.5Hz, 1H), 7.21-6.97 (m, 7H), 6.63 ( s, 1H), 5.91 (s, 1H), 4.73 (d, J=13.5Hz, 1H), 4.53-4.38 (m, 1H), 3.94 (d, J=14.5Hz, 1H), 3. 85-3.65 (m, 2H), 3.59 (td, J=10.0, 4.9Hz, 1H), 3.02 (dt, J=11.0, 5.3Hz, 1H), 2.91 (t, J=5 .8Hz, 2H), 2.86-2.61 (m, 4H), 1.91 (dq, J=12.9, 2.9Hz, 1H), 1.55 (qd, J=12.5, 4.4Hz, 1H).

[0544] Example 54

[0545] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-chlorophenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0546]

[0547] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 2-chloroaniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-chlorophenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 17.1%. LCMS (ESI) [M+H] + =436.30,438.30; 1 H NMR (400MHz, CDCl3) δ8.32 (d, J=1.0Hz, 1H), 7.85 (dd, J=8.2, 1.5Hz, 1H), 7.43 (dd, J=8.0, 1.5Hz, 1H), 7.32-7.26 (m , 1H), 7.13 (dtd, J=9.0, 5.9, 2.3Hz, 3H), 7.08-6.98 (m, 2H), 6.79 (s, 1H), 5.96 (d, J=1.0Hz, 1H), 4.73 (d, J=13.4Hz, 1 H), 4.45 (d, J=12.8Hz, 1H), 3.95 (d, J=14.5Hz, 1H), 3.86-3.66 (m, 2H), 3.59 (td, J=10.0, 4.9Hz, 1H), 3.03 (dt, J=11. 0, 5.3Hz, 1H), 2.91 (t, J=5.8Hz, 2H), 2.85-2.63 (m, 4H), 1.92 (dq, J=12.8, 2.8Hz, 1H), 1.56 (qd, J=12.5, 4.4Hz, 1H).

[0548] Example 55

[0549] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-methoxyphenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0550]

[0551] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 4-methoxyaniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-methoxyphenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 14%. LCMS (ESI) [M+H] + =432.4; 1 H NMR (400MHz, CDCl3) δ8.21 (d, J=0.9Hz, 1H), 7.23-7.07 (m, 5H), 7.05-6.98 (m, 1H), 6.98-6.88 (m, 2H) , 6.75 (s, 1H), 5.72 (d, J = 1.0Hz, 1H), 4.72 (d, J = 13.4Hz, 1H), 4.36 (d, J = 12.6Hz, 1H), 3.94 (d, J = 14.6 Hz, 1H), 3.84 (s, 3H), 3.75-3.65 (m, 2H), 3.56 (td, J=10.0, 5.0Hz, 1H), 3.02 (dt, J=10.9, 5.2Hz, 1H), 2.91 (t, J=5.7Hz, 2H), 2.81-2.62 (m, 4H), 1.90 (dd, J=12.9, 3.5Hz, 1H), 1.55 (td, J=12.5, 4.3Hz, 1H).

[0552] Example 56

[0553] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-tert-butylphenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0554]

[0555] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 2-tert-butylaniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-tert-butylphenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 13.7%. LCMS (ESI) [M+H] + =458.4; 1H NMR (400MHz, CDCl3) δ8.22 (d, J=0.9Hz, 1H), 7.53-7.44 (m, 1H), 7.25 (d, J=2.9Hz, 3H), 7.17 -7.08 (m, 3H), 7.01 (d, J=6.0Hz, 1H), 5.48 (s, 1H), 4.69 (s, 1H), 4.29 (s, 1H), 3.94 (d, J=14.6 Hz, 1H), 3.69 (d, J=14.8Hz, 2H), 3.55 (td, J=10.0, 4.9Hz, 1H), 3.02 (dt, J=10.9, 5.3Hz, 1H) , 2.91 (t, J=5.7Hz, 2H), 2.81-2.57 (m, 4H), 1.89 (dd, J=12.8, 3.3Hz, 1H), 1.67-1.45 (m, 1H).

[0556] Example 57

[0557] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-methoxyphenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0558]

[0559] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 2-methoxyaniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-methoxyphenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 35.16%. LCMS (ESI) [M+H] + =432.4; 1H NMR (400MHz, Chloroform-d) δ8.30 (s, 1H), 7.75 (d, J=7.8Hz, 1H), 7.17-7.10 (m, 3H), 7.09-6.96 (m, 4H), 6.93 (dd, J=8 .0, 1.5Hz, 1H), 6.00 (s, 1H), 4.74 (d, J=13.6Hz, 1H), 4.45 (d, J=12.9Hz, 1H), 4.04-3.92 (m, 1H), 3.88 (s, 3H), 3.82 (br s, 1H), 3.73 (d, J=14.7Hz, 1H), 3.62 (td, J=10.0, 4.9Hz, 1H), 3.05 (dt, J=10.9, 5.3Hz, 1H), 2.9 6-2.94 (m, 2H), 2.83-2.73 (m, 4H), 1.92 (dd, J=13.0, 3.4Hz, 1H), 1.56 (qd, J=12.4, 4.4Hz, 1H).

[0560] Example 58

[0561] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-trifluoromethylphenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0562]

[0563] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 2-trifluoromethylaniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-trifluoromethylphenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 14.7%. LCMS (ESI) [M+H] + =470.3; 1H NMR (400MHz, CDCl3) δ8.32 (s, 1H), 7.77-7.75 (d, J=8.0Hz, 1H), 7.71-7.69 (d, J=7.60Hz, 1H), 7.61-7.57 (t , J=8.0Hz, 1H), 7.29-7.26 (m, 1H), 7.18-7.12 (m, 3H), 7.05-7.03 (m, 1H), 6.66 (s, 1H), 5.91 (s, 1H), 4.79-4. 75 (d, J=14.0Hz, 1H), 4.43-4.41 (d, J=10.0Hz, 1H), 4.0-3.96 (d, J=14.8Hz, 1H), 3.79-3.72 (m, 2H), 3.64-3 .58 (m, 1H), 3.08-3.03 (m, 1H), 2.85-2.70 (m, 4H), 1.96-1.92 (dd, J=3.6Hz, 12.8Hz, 1H), 1.65-1.53 ​​(m, 2H).

[0564] Example 59

[0565] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(pyridin-3-ylamino)pyrimidin-4-yl)piperidin-3-ol:

[0566]

[0567] Step 1: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(pyridin-3-ylamino)pyrimidin-4-yl)piperidin-3-ol:

[0568]

[0569] At room temperature (20°C), under nitrogen protection, the raw material trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (50 mg, 0.15 mmol, 1.0 eq) was dissolved in dioxane (1,4-dioxane) (3 mL), and 3-aminopyridine (68 mg, 0.73 mmol, 5.0 eq), Pd(OAc) (palladium acetate) (6.0 mg, 0.029 mmol, 0.2 eq), BINAP (1,1′-binaphthyl-2,2′-bis(diphenylphosphine)) (36.0 mg, 0.058 mmol, 0.4 eq), and Cs2CO3 (cesium carbonate) (94.0 mg, 0.29 mmol, 2.0 eq) were added, and the mixture was heated and stirred at 110°C for 12 hours. The reaction was complete after LCMS analysis. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered, and concentrated. The crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to obtain the target compound, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(pyridin-3-ylamino)pyrimidin-4-yl)piperidin-3-ol (20 mg, 34.3% yield). LCMS (ESI) [M+H] + =403.3; 1 H NMR (400MHz, CDCl3) δ8.60-8.59 (d, J=2.4Hz, 1H), 8.40-8.39 (dd, J=1.2Hz, 4.8Hz, 1H), 8.32 (s, 1H), 7.89-7.86 (m, 1 H), 7.36-7.28 (m, 1H), 7.19-7.13 (m, 3H), 7.06-7.03 (m, 1H), 6.71 (s, 1H), 5.93 (s, 1H), 4.75-4.72 (d, J=13.2Hz, 1H) , 4.75-4.72 (d, J=12.4Hz, 1H), 4.03-3.99 (d, J=14.8Hz, 1H), 3.79-3.75 (d, J=10.0Hz, 1H), 3.67-3.61 (m, 1H), 3.1-3 .06 (m, 1H), 2.99-2.96 (t, J=5.6Hz, 1H), 2.87-2.76 (m, 4H), 1.98-1.94 (dd, J=3.6Hz, 16.8Hz, 1H), 1.64-1.57 (m, 1H).

[0570] Example 60

[0571] Preparation of trans-4-(3,4-dihydroisoquinolin-2(19-H)-yl)-1-(6-(pyridin-4-ylamino)pyrimidin-4-yl)piperidin-3-ol:

[0572]

[0573] Following the method of Example 59, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 4-aminopyridine to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(pyridin-4-ylamino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 51.4%. LCMS (ESI) [M+H] + =403.3; 1 H NMR (400MHz, CDCl3) δ8.47-8.46 (d, J=6.4Hz, 2H), 8.39 (s, 1H), 7.44-7.42 (d, J=6.4Hz, 2H), 7.20-7.1 3(m, 3H), 7.05-6.96(m, 2H), 6.14(s, 1H), 4.78-4.75(d, J=13.2Hz, 1H), 4.57-4.54(d, J=10.4Hz, 1H), 3.99-3.95 (d, J=14.4Hz, 1H), 3.75-3.71 (d, J=14.8Hz, 1H), 3.67-3.60 (m, 1H), 3.08-3.02 (m, 1H), 2.9 5-2.92 (t, J=5.6Hz, 1H), 2.91-2.79 (m, 2H), 2.76-2.67 (m, 2H), 1.99-1.95 (m, 1H), 1.64-1.54 (m, 1H).

[0574] Example 61

[0575] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(pyridin-2-ylamino)pyrimidin-4-yl)piperidin-3-ol:

[0576]

[0577] Following the method of Example 59, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 2-aminopyridine to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(pyridin-2-ylamino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 51.4%. LCMS (ESI) [M+H] + =403.36; 1H NMR (400 MHz, CDC13) δ 8.47-8.46 (d, J = 6.4 Hz, 2H), 8.39 (s, 1H), 7.44-7.42 (d, J = 6.4 Hz, 2H), 7.20-7.13 (m, 3H), 7.05-6.96 (m, 2H), 6.14 (s, 1H), 4.78-4.75 (d, J = 13.2 Hz, 1H), 4.57-4.54 (d, J = 10.4 Hz, 1H), 3.99-3.95 (d, J = 14.4 Hz, 1H), 3.75-3.71 (d, J = 14.8 Hz, 1H), 3.67-3.60 (m, 1H), 3.08-3.02 (m, 1H), 2.95-2.92 (t, J = 5.6 Hz, 1H), 2.91-2.79 (m, 2H), 2.76-2.67 (m, 2H), 1.99-1.95 (m, 1H), 1.64-1.54 (m, 1H).

[0578] Example 62

[0579] Preparation of trans-4-(3,4-dihydroisoquinolin-2(lH)-yl)-l-(6-((4- chlorophenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0580]

[0581] The target molecule, trans-4-(3,4-dihydroisoquinolin-2(lH)-yl)-l-(6-((4- chlorophenyl)amino)pyrimidin-4-yl)piperidin-3-ol, was obtained by the method of Example 33 using the starting material, trans-l-(6-chloropyrimidin-4-yl)-4-(3,4- dihydroisoquinolin-2(lH)-yl)piperidin-3-ol, for substitution reaction with 4- chloroaniline in a yield of 88.9%. LCMS (ESI) [M+H] + = 436.3; 1 H NMR (400 MHz, CDC13) δ 8.47-8.46 (d, J = 6.4 Hz, 2H), 8.39 (s, 1H), 7.44-7.42 (d, J = 6.4 Hz, 2H), 7.20-7.13 (m, 3H), 7.05-6.96 (m, 2H), 6.14 (s, 1H), 4.78-4.75 (d, J = 13.2 Hz, 1H), 4.57-4.54 (d, J = 10.4 Hz, 1H), 3.99-3.95 (d, J = 14.4 Hz, 1H), 3.75-3.71 (d, J = 14.8 Hz, 1H), 3.67-3.60 (m, 1H), 3.08-3.02 (m, 1H), 2.95-2.92 (t, J = 5.6 Hz, 1H), 2.91-2.79 (m, 2H), 2.76-2.67 (m, 2H), 1.99-1.95 (m, 1H), 1.64-1.54 (m, 1H).

[0582] Example 63

[0583] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0584]

[0585] Following the method of Example 59, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 4-aminotetrahydropyran to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 10.2%. LCMS (ESI) [M+H] + =410.33; 1 H NMR (400MHz, CDCl3) δ8.16 (s, 1H), 7.19-7.08 (m, 3H), 7.06-6.98 (m, 1H), 5.50 (s, 1H), 4.7 2 (dd, J=24.8, 10.6Hz, 2H), 4.43 (dd, J=12.6, 2.8Hz, 1H), 3.97 (dd, J=20.8, 13.3Hz, 3H), 3. 74 (dd, J=35.1, 11.2Hz, 3H), 3.71-3.51 (m, 3H), 3.08-2.97 (m, 1H), 2.91 (t, J=5.6Hz, 2H), 2 .83-2.60 (m, 4H), 2.01 (d, J=11.9Hz, 2H), 1.91 (dd, J=12.8, 2.8Hz, 1H), 1.62-1.43 (m, 3H).

[0586] Example 64

[0587] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-(oxetan-3-yl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0588]

[0589] Following the method of Example 59, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 4-(oxetan-3-yl)aniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-(oxetan-3-yl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 17.6%. LCMS (ESI) [M+H]+ = 458.36; 1 H NMR (400 MHz, CDC13) δ 8.26 (s, IH), 7.41 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.17-7.08 (m, 3H), 7.01 (d, J = 5.9 Hz, IH), 6.83 (s, IH), 5.96 (s, IH), 5.09 (dd, J = 8.3, 6.0 Hz, 2H), 4.78 (dd, J = 17.3, 10.9 Hz, 3H), 4.39 (d, J = 9.8 Hz, IH), 4.29-4.19 (m, IH), 3.93 (d, J = 14.6 Hz, IH), 3.68 (d, J = 14.6 Hz, 2H), 3.57 (td, J = 10.0, 4.9 Hz, IH), 3.05-2.96 (m, IH), 2.90 (t, J = 5.5 Hz, 2H), 2.80-2.62 (m, 4H), 1.95-1.86 (m, IH), 1.61-1.45 (m, IH).

[0590] Example 65

[0591] Preparation of trans-4-(3,4-dihydroisoquinolin-2(lH)-yl)-l-(6-((2- (methylsulfonyl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0592]

[0593] The starting material, trans-l-(6-chloropyrimidin-4-yl)-4-(3,4- dihydroisoquinolin-2(lH)-yl)piperidin-3-ol, was subjected to a substitution reaction with 2-(methylsulfonyl)aniline according to the method of Example 33 to give the target molecule, trans-4-(3,4-dihydroisoquinolin-2(lH)-yl)-l-(6-((2- (methylsulfonyl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 7.9%. LCMS (ESI) [M+H] + = 480.33; 1H NMR (400MHz, CDCl3) δ8.38 (d, J=17.0Hz, 2H), 8.24 (d, J=8.1Hz, 1H), 7.94 (dd, J=8.0, 1.5Hz, 1H), 7.67-7.53 (m, 1H), 7.22-7.10 (m, 4H), 7.01 (dd, J=8.0, 5.6Hz, 1H), 5.98 (s, 1H), 4.52-4.72 (m, 2H), 3.95 (d, J=14.5Hz, 1H), 3.7 1 (d, J=14.5Hz, 2H), 3.61 (td, J=10.1, 4.9Hz, 1H), 3.07 (s, 3H), 3.03 (dd, J=11.0, 5.3Hz, 1H), 2.91 (dd, J=11.2, 5.7Hz, 2H), 2.88-2.80 (m, 1H), 2.79-2.72 (m, 1H), 2.71-2.62 (m, 2H), 1.95 (dd, J=12.9, 3.1Hz, 1H), 1.25 (m, 1H).

[0594] Example 66

[0595] Preparation of trans-1-(6-([1,1′-biphenyl]-2-ylamino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0596]

[0597] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and [1,1′-biphenyl]-2-amine to obtain the target molecule, trans-1-(6-([1,1′-biphenyl]-2-ylamino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 52.8%. LCMS (ESI): [M+H] + =478.40; 1H NMR (400MHz, DMSO-d6) δ8.27 (s, 1H), 7.99 (s, 1H), 7.48 (d, J=7.8Hz, 1H), 7.40-7 .34(m, 6H), 7.33-7.23(m, 2H), 7.13-6.99(m, 4H), 5.58(s, 1H), 4.66(s, 1H), 4.14 (dd, J=29.9, 10.3Hz, 2H), 3.79 (q, J=14.8Hz, 2H), 3.51-3.44 (m, 1H), 2.95-2.68 ( m, 5H), 2.67-2.52 (m, 2H), 1.74 (d, J=10.6Hz, 1H), 1.36 (dd, J=20.8, 11.8Hz, 1H).

[0598] Example 67

[0599] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((3-(pyrrolidin-1-yl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0600]

[0601] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 3-pyrrolidin-1-aniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((3-(pyrrolidin-1-yl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 44.8%. LCMS (ESI) [M+H] + =471.37; 1 H NMR (400MHz, Chloroform-d) δ11.32 (s, 1H), 8.12 (s, 1H), 7.27 (dt, J=16.3, 7.5Hz, 3H), 7.19 ( d, J=7.4Hz, 1H), 7.07 (d, J=7.5Hz, 1H), 6.60-6.49 (m, 2H), 6.44 (s, 1H), 5.91 (s, 1H), 4.53 (d, J =14.8Hz, 1H), 4.34 (d, J = 14.8Hz, 1H), 3.97 (s, 2H), 3.68-3.23 (m, 9H), 3.14 (d, J = 16.8Hz, 1H) , 2.96 (dd, J=25.8, 13.3Hz, 2H), 2.14 (d, J=12.7Hz, 1H), 2.08-2.00 (m, 4H), 1.80-1.62 (m, 1H).

[0602] Example 68

[0603] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(thiazol-2-amino)pyrimidin-4-yl)piperidin-3-ol:

[0604]

[0605] Following the method of Example 59, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 2-aminothiazole to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(thiazol-2-amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 48.96%. LCMS (ESI) [M+H] + =409.3; 1 H NMR (400MHz, Chloroform-d) δ8.43 (s, 1H), 7.41 (d, J=3.3Hz, 1H), 7.15 (dt, J=10.3, 3.6Hz , 3H), 7.03 (d, J=6.9Hz, 1H), 6.88 (d, J=3.7Hz, 1H), 6.23 (s, 1H), 4.74 (d, J=13.5Hz, 1H), 4 .58(d, J=12.8Hz, 1H), 4.03(d, J=14.8Hz, 1H), 3.79(d, J=14.7Hz, 1H), 3.70-3.67(m, 1H), 3.10-3.08 (m, 1H), 2.98 (s, 2H), 2.93-2.74 (m, 4H), 2.02-1.94 (m, 1H), 1.66-1.54 (m, 1H).

[0606] Example 69

[0607] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0608]

[0609] Following the method of Example 59, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 2-aminothiazole to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 42.8%. LCMS (ESI) [M+H] + =407.6; 1 H NMR (400MHz, Chloroform-d) δ8.24 (d, J=1.0Hz, 1H), 7.51 (d, J=2.0Hz, 1H), 7.15-7.10 (m, 3H), 7.06-6.97 (m, 1H), 6.39 (br s, 1H), 6.16 (d, J = 1.9Hz, 1H), 5.57 (d, J = 1.1Hz, 1H), 4.62 (d, J = 13.4Hz, 1H), 4.4 6(d, J=12.6Hz, 1H), 3.94 (d, J=14.5Hz, 1H), 3.76 (s, 3H), 3.70 (d, J=14.9Hz, 2H), 3.56 (td, J=10.0, 4.8Hz, 1H), 3.02 (dt, J=11.0, 5.2Hz, 1H), 2.91 (t, J=5.8Hz, 2H ), 2.85-2.58 (m, 4H), 1.90 (dd, J=12.9, 3.3Hz, 1H), 1.52 (qd, J=12.5, 4.4Hz, 1H).

[0610] Example 70

[0611] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(4-(trifluoromethyl)phenoxy)pyrimidin-4-yl)piperidin-3-ol:

[0612]

[0613] Step 1: Preparation of 4-chloro-6-(4-(trifluoromethyl)phenoxy)pyrimidine:

[0614]

[0615] p-Trifluoromethylphenol (0.326 g, 2.01 mmol), 4,6-dichloropyrimidine (0.3 g, 2.01 mmol), and potassium carbonate (0.292 g, 2.11 mmol) were dissolved in acetone (5 mL). The reaction mixture was stirred at room temperature (20-25°C) for 3 h. TLC (pure PE) confirmed the reaction was complete. The mixture was extracted with ethyl acetate three times, each time using 20 mL. The ethyl acetate phases were combined, washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, filtered, and the crude product was recrystallized from petroleum ether at 0°C to yield 4-chloro-6-(4-(trifluoromethyl)phenoxy)pyrimidine (0.37 g, 66.9% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ 8.59 (s, 1H), 7.73 (d, J=8.6Hz, 2H), 7.28 (d, J=8.5Hz, 2H), 7.02 (s, 1H).

[0616] Step 2: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(4-(trifluoromethyl)phenoxy)pyrimidin-4-yl)piperidin-3-ol:

[0617]

[0618] 4-Chloro-6-(4-(trifluoromethyl)phenoxy)pyrimidine (40 mg, 0.145 mmol), trans-4-(3, dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (37 mg, 0.16 mmol) and 2-isopropylethylamine (37 mg, 0.291 mmol) were dissolved in isopropanol (0.8 mL), and the reaction solution was stirred at 100°C for 3 h. The mixture was extracted with ethyl acetate three times, each time with 10 mL. The ethyl acetate phases were combined, washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, and filtered. The crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to obtain trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(4-(trifluoromethyl)phenoxy)pyrimidin-4-yl)piperidin-3-ol (45.8 mg, yield 66%). LCMS (ESI) [M+H] + =471.4; 1H NMR (400MHz, CDCl3) δ8.31 (s, 1H), 7.67 (d, J=8.4Hz, 2H), 7.25 (d, J=11.2Hz, 2H), 7.19-7 .09 (m, 3H), 7.03 (d, J = 6.7Hz, 1H), 6.11 (s, 1H), 4.74 (d, J = 13.5Hz, 1H), 4.57 (d, J = 12.7Hz , 1H), 3.99 (d, J=14.5Hz, 1H), 3.75 (d, J=14.7Hz, 1H), 3.64-3.62 (m, 1H), 3.08-3.05 (m, 1 H), 2.95 (s, 2H), 2.88-2.72 (m, 4H), 1.97 (d, J=12.8Hz, 1H), 1.60 (td, J=12.4, 4.4Hz, 1H).

[0619] Example 71

[0620] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(2-(trifluoromethyl)phenoxy)pyrimidin-4-yl)piperidin-3-ol:

[0621]

[0622] Following the method of Example 70, a substitution reaction was completed using o-trifluoromethylphenol and 4,6-dichloropyrimidine, followed by a substitution reaction with trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(2-(trifluoromethyl)phenoxy)pyrimidin-4-yl)piperidin-3-ol, in a yield of 60.1%. LCMS (ESI) [M+H] + =471.4; 1H NMR (400MHz, CDCl3) δ8.28 (s, 1H), 7.70 (d, J=7.8Hz, 1H), 7.59 (t, J=7.9Hz, 1H), 7.33 (t, J=7.7Hz, 1H) , 7.24 (s, 1H), 7.16-7.11 (m, 3H), 7.07-7.00 (m, 1H), 6.15 (s, 1H), 4.72 (d, J=13.1Hz, 1H), 4.61 (d, J=12 .6Hz, 1H), 3.99 (d, J=14.5Hz, 1H), 3.74 (d, J=14.6Hz, 2H), 3.64 (td, J=10.0, 4.9Hz, 1H), 3.06 (dd, J=11 .1, 5.5Hz, 1H), 2.95-2.91 (m, 2H), 2.90-2.64 (m, 4H), 2.04-1.91 (m, 1H), 1.60 (qd, J=12.5, 4.4Hz, 1H).

[0623] Example 72

[0624] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)piperidin-3-ol:

[0625]

[0626] Following the method of Example 70, a substitution reaction was completed using m-trifluoromethylphenol and 4,6-dichloropyrimidine, followed by a substitution reaction with trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)piperidin-3-ol, in a yield of 52.53%. LCMS (ESI) [M+H] + =471.4; 1H NMR (400MHz, CDCl3) δ8.30 (s, 1H), 7.58-7.45 (m, 2H), 7.40 (s, 1H), 7.33 (d, J=7.9Hz, 1H), 7.18-7.14 (m, 3H), 7.04 (d, J=6.6Hz, 1H), 6.10 (s, 1H), 4.74 (d, J=13.2Hz, 1H), 4. 56 (d, J=12.9Hz, 1H), 4.04 (d, J=13.6Hz, 1H), 3.80 (d, J=10.0Hz, 1H), 3.67 (s, 1H), 3. 10 (s, 1H), 2.99 (s, 2H), 2.91-2.80 (m, 4H), 1.98 (d, J=12.8Hz, 1H), 1.69-1.53 ​​(m, 1H).

[0627] Example 73

[0628] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((3-morpholinylphenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0629]

[0630] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 3-morpholinoaniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((3-morpholinophenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 21.5%. LCMS (ESI) [M+H] + =487.39; 1 H NMR (400MHz, CDCl3) δ11.20 (s, 1H), 8.12 (s, 1H), 7.34 (t, J=8.1Hz, 1H), 7.26 -7.18 (m, 2H), 7.15 (d, J=7.4Hz, 1H), 7.05 (d, J=7.5Hz, 1H), 6.94-6.79 (m, 3H ), 5.86 (s, 1H), 4.68-4.25 (m, 2H), 4.06-3.77 (m, 6H), 3.71-3.45 (m, 3H), 3.3 9-3.08 (m, 7H), 2.95 (s, 2H), 2.16 (d, J=12.2Hz, 1H), 1.72 (d, J=12.6Hz, 1H).

[0631] Example 74

[0632] Preparation of trans-1-(6-([1,1′-biphenyl]-3-ylamino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0633]

[0634] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 3-aminobiphenyl to obtain the target molecule, trans-1-(6-([1,1′-biphenyl]-3-ylamino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 45.1%. LCMS (ESI) [M+H] + =478.38; 1 H NMR (400MHz, CDCl3) δ8.28 (s, 1H), 7.61-7.57 (m, 2H), 7.50-7.42 (m, 4H), 7.40-7.33 (m, 2H), 7.33-7.23 (m, 2H), 7.15-7.02 (m, 3H), 7.04-6.96 (m, 1H), 6.05 (s, 1H), 4.68 (d, J=13.4Hz, 1H), 4.46 (dd, J=13.4, 4. 9Hz, 1H), 3.92 (d, J=14.5Hz, 1H), 3.68 (d, J=14.6Hz, 1H), 3.58 (td, J=10.0, 4.8Hz, 1H), 3.00 (dt, J=10.9 , 5.3Hz, 1H), 2.89 (t, J=5.8Hz, 2H), 2.83-2.60 (m, 4H), 2.00-1.80 (m, 2H), 1.54 (qd, J=12.5, 4.3Hz, 1H).

[0635] Example 75

[0636] Preparation of trans-1-(6-(cyclobutylamino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0637]

[0638] Step 1: Preparation of 6-chloro-N-cyclobutylpyrimidin-4-amine:

[0639]

[0640] Cyclobutylamine (200 mg, 2.81 mmol, 1.0 eq) was dissolved in acetone (5 mL), and 4,6-dichloropyrimidine (420 mg, 2.81 mmol, 1.0 eq) and potassium carbonate (580 mg, 4.21 mmol, 2.0 eq) were added. The mixture was stirred at room temperature overnight (16 h). The compound was filtered and the filtrate was concentrated. 20 mL of water was added to the system, and the mixture was extracted with ethyl acetate three times, each time with 5 mL. The ethyl acetate phases were combined, washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, filtered, and concentrated. The crude product was separated and purified by column chromatography (PE:EA = 0-20%) to obtain 6-chloro-N-cyclobutylpyrimidin-4-amine (208 mg, 40.3% yield) as a yellow solid. LCMS (ESI) [M+H] + =184.1.

[0641] Step 2: Preparation of trans-1-(6-(cyclobutylamino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0642]

[0643] Dissolve 6-chloro-N-cyclobutylpyrimidin-4-amine (50 mg, 0.272 mmol, 1.0 eq) in isopropanol (2 mL), add trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (69 mg, 0.299 mmol, 1.1 eq) and N,N-diisopropylethylamine (70 mg, 0.544 mmol, 2.0 eq). Heat and stir at 100°C overnight (16 h). Adjust the pH to 7 with 1N aqueous sodium hydroxide. Extract with ethyl acetate three times, each time with 5 mL. The ethyl acetate phases were combined, washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, and filtered. The crude product was separated and purified by Prep-HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to obtain trans-1-(6-(cyclobutylamino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (16.8 mg, yield 16.3%). LCMS (ESI) [M+H] + =380.4; 1H NMR (400MHz, CDCl3) δ7.97 (s, 1H), 7.08-7.01 (m, 4H), 6.94 (d, J=6.8Hz, 1H), 5.54 (s, 1H), 4.64 (s, 1H), 4.22 (d, J=10.8Hz, 2H), 3.81-3.73 ( m, 2H), 3.55 (s, 1H), 2.89-2.74 (m, 5H), 2.67-2.55 (m, 2H), 2.25 (d, J=8.0Hz, 2H), 1.91-1.76 (m, 3H), 1.68-1.59 (m, 2H), 1.45-1.42 (m, 1H).

[0644] Example 76

[0645] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0646]

[0647] Following the method of Example 59, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 2-aminothiazole to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 3.6%. LCMS (ESI) [M+H] + =406.33; 1 H NMR (400MHz, Chloroform-d) δ8.25 (s, 1H), 7.17-7.09 (m, 3H), 7.04-6.99 (m, 1H), 6.82 (s, 1 H), 6.66 (s, 1H), 6.43 (s, 1H), 4.64 (t, J=12.8Hz, 2H), 3.93 (d, J=14.5Hz, 1H), 3.69 (d, J=14. 6Hz, 1H), 3.61 (dd, J=9.9, 5.0Hz, 1H), 3.56 (s, 3H), 3.01 (dt, J=10.7, 5.3Hz, 1H), 2.90 (t, J =5.8Hz, 2H), 2.86-2.62 (m, 5H), 1.90 (dd, J=13.2, 3.4Hz, 1H), 1.55 (qd, J=12.5, 4.3Hz, 1H).

[0648] Example 77

[0649] Preparation of trans-1-(6-((3,5-difluorophenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0650]

[0651] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 3,5-difluoroaniline to obtain the target molecule, trans-1-(6-((3,5-difluorophenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 46.8%. LCMS (ESI) [M+H] + =438.3; 1 H NMR (400MHz, CDCl3) δ8.31 (s, 1H), 7.22-7.09 (m, 4H), 7.04-7.00 (m, 1H), 6.98-6.92 (m, 2H), 6.51 (td, J=8.9 , 2.1Hz, 1H), 5.98 (s, 1H), 4.71 (d, J=13.4Hz, 1H), 4.48 (dd, J=11.9, 4.8Hz, 1H), 3.94 (d, J=14.5Hz, 1H), 3.70 (d, J=14.6Hz, 1H), 3.59 (td, J=10.0, 4.8Hz, 1H), 3.02 (dt, J=11.1, 5.4Hz, 1H), 2.91 (t, J=5.8Hz, 2H), 2.81 (d dd, J=21.7, 11.0, 2.4Hz, 2H), 2.74-2.64 (m, 2H), 1.92 (dd, J=12.9, 3.4Hz, 1H), 1.55 (qd, J=12.5, 4.3Hz, 1H).

[0652] Example 78

[0653] Preparation of trans-1-(6-((3,4-difluorophenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0654]

[0655] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 3,4-difluoroaniline to obtain the target molecule, trans-1-(6-((3,4-difluorophenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 29.3%. LCMS (ESI) [M+H] + =438.34; 1 H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 7.32-7.22 (m, 1H), 7.19-7.09 (m, 4H), 7.04-6.92 (m, 3H), 5.85 (s, 1H), 4.69 (d, J = 13.4Hz, 1H), 4.49-4.39 (m, 1H), 3.94 (d, J = 14.5Hz, 1H), 3.69 (d, J = 14.5Hz, 1H) , 3.58 (td, J=10.0, 4.8Hz, 1H), 3.02 (dt, J=11.0, 5.4Hz, 1H), 2.91 (t, J=5.8Hz, 2H), 2.83-2.73 (m, 2H), 2.67 (td, J=9.9, 9.3, 3.3Hz, 2H), 1.91 (dd, J=12.9, 3.4Hz, 1H), 1.54 (qd, J=12.5, 4.4Hz, 1H).

[0656] Example 79

[0657] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((3,4,5-trifluorophenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0658]

[0659] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 3,4,5-trifluoroaniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((3,4,5-trifluorophenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 33.9%. LCMS (ESI) [M+H] + =456.32; 1H NMR (400MHz, CDCl3) δ8.29 (s, 1H), 7.18-7.05 (m, 5H), 7.03-7.00 (m, 1H), 6.89 (s, 1H), 5.87 ( s, 1H), 4.71 (d, J = 13.4Hz, 1H), 4.50-4.42 (m, 1H), 3.95 (d, J = 14.5Hz, 1H), 3.71 (d, J = 14.6Hz, 1H), 3.59 (td, J=10.0, 4.9Hz, 1H), 3.03 (dt, J=11.0, 5.3Hz, 1H), 2.92 (t, J=5.8Hz, 2H), 2.86 -2.75 (m, 2H), 2.75-2.64 (m, 2H), 1.93 (dd, J=12.9, 3.3Hz, 1H), 1.55 (qd, J=12.5, 4.3Hz, 1H).

[0660] Example 80

[0661] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-(pyrrolidin-1-yl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol

[0662]

[0663] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 2-(pyrrolidin-1-yl)aniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-(pyrrolidin-1-yl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 4.2%. LCMS (ESI) [M+H] + =471.5; 1H NMR (400MHz, CDCl3) δ8.25 (s, 1H), 7.37 (dd, J=8.0Hz, 0.8Hz, 1H), 7.17-7.08 (m, 4H), 7.01 (dd, J=7.2Hz , 2.4Hz, 1H), 6.97 (d, J = 7.2Hz, 1H), 6.91 (t, J = 7.2Hz, 1H), 6.65 (s, 1H), 5.79 (s, 1H), 4.69 (d, J = 12.8Hz, 1H), 4.42 (d, J=9.6Hz, 1H), 3.93 (d, J=14.8Hz, 1H), 3.70-3.66 (m, 1H), 3.60-3.54 (m, 1H), 3.16-3.14 (m, 4H), 3.04-2.99 (m, 1H), 2.90 (t, J=5.6Hz, 2H), 2.79-2.61 (m, 4H), 1.91-1.88 (m, 5H), 1.60-1.49 (m, 1H).

[0664] Example 81

[0665] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(oxetan-3-ylamino)pyrimidin-4-yl)piperidin-3-ol

[0666]

[0667] Following the method of Example 59, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 3-oxetanamine to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-(oxetan-3-ylamino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 11.2%. LCMS (ESI) [M+H] + =382.40; 1H NMR (400MHz, Chloroform-d) δ8.17 (s, 1H), 7.19-7.09 (m, 3H), 7.06-6.99 (m, 1H), 5.42 (s, 1H) , 5.21 (d, J=6.9Hz, 1H), 5.06-4.95 (m, 2H), 4.91-4.89 (m, 1H), 4.72 (d, J=13.5Hz, 1H), 4.57-4. 54 (m, 2H), 4.48-4.41 (m, 1H), 3.95 (d, J=14.5Hz, 1H), 3.84-3.66 (m, 2H), 3.60-3.59 (m, 1H), 3 .04-3.01 (m, 1H), 2.93-2.90 (m, 2H), 2.84-2.63 (m, 4H), 1.96-1.87 (m, 1H), 1.57-1.53 ​​(m, 1H).

[0668] Example 82

[0669] Preparation of trans-1-(6-(cyclohexylamino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0670]

[0671] Following the method of Example 59, the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, was subjected to a substitution reaction with cyclohexylamine to obtain the target molecule, trans-1-(6-(cyclohexylamino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 23.7%. LCMS (ESI) [M+H] + =408.37; 1H NMR (400MHz, CDCl3) δ8.13 (s, 1H), 7.18-7.09 (m, 3H), 7.05-7.00 (m, 1H), 5.47 (s, 1H), 4.88 (bs, 1H), 4. 76 (d, J=13.5Hz, 1H), 4.49-4.40 (m, 1H), 3.95 (d, J=14.5Hz, 1H), 3.77-3.66 (m, 2H), 3.68-3.59 (m, 1H), 3 .44(bs, 1H), 3.04-3.01(m, 1H), 2.91(t, J=5.8Hz, 2H), 2.81-2.71(m, 2H), 2.71-2.63(m, 2H), 2.04-1.96 (m, 2H), 1.92-1.89 (m, 1H), 1.78-1.74 (m, 3H), 1.59-1.57 (m, 1H), 1.47-1.34 (m, 2H), 1.30-1.18 (m, 3H).

[0672] Example 83

[0673] Preparation of trans-1-(6-(benzo[d][1,3]dioxazol-4-ylamino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol

[0674]

[0675] Following the method of Example 59, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and benzo[d][1,3]dioxazol-4-amine to obtain the target molecule, trans-1-(6-(benzo[d][1,3]dioxazol-4-ylamino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 28.2%. LCMS (ESI): [M+H] + =446.5; 1H NMR (400MHz, DMSO-d6) δ8.69 (s, 1H), 8.12 (s, 1H), 7.18 (d, J=8.2Hz, 1H), 7.11-7.00 (m, 4H ), 6.80 (t, J=8.0Hz, 1H), 6.68 (d, J=7.6Hz, 1H), 6.02 (s, 2H), 5.94 (s, 1H), 4.69 (d, J=2.5H z, 1H), 4.30 (d, J=9.0Hz, 1H), 4.21 (d, J=11.4Hz, 1H), 3.80 (q, J=15.0Hz, 2H), 3.58-3.54 ( m, 1H), 2.92-2.73 (m, 5H), 2.69-2.60 (m, 2H), 1.79 (dd, J=10.2Hz, 1H), 1.49-1.40 (m, 1H).

[0676] Example 84

[0677] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0678]

[0679] Following the method of Example 59, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 2-trifluoromethoxyaniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 31.3%. LCMS (ESI) [M+H] + =486.5; 1H NMR (400MHz, Chloroform-d) δ8.32 (d, J=1.0Hz, 1H), 7.92 (dd, J=8.5, 1.6Hz, 1H), 7.35-7.28 (m, 2H), 7.18 -7.07 (m, 4H), 7.06-6.99 (m, 1H), 6.59 (s, 1H), 5.97 (d, J = 1.0Hz, 1H), 4.75 (d, J = 13.5Hz, 1H), 4.46 (d, J = 12 .5Hz, 1H), 3.95 (d, J=14.5Hz, 1H), 3.72-3.68 (m, 2H), 3.60 (td, J=10.0, 4.9Hz, 1H), 3.03 (dt, J=11.0, 5.3H z, 1H), 2.92 (t, J=5.8Hz, 2H), 2.86-2.75 (m, 2H), 2.73-2.65 (m, 2H), 1.94-1.90 (m, 1H), 1.65-1.52 (m, 1H).

[0680] Example 85

[0681] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((3-methoxypyridin-4-yl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0682]

[0683] Following the method of Example 59, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 4-amino-3-methoxypyridine to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((3-methoxypyridin-4-yl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 39.3%. LCMS (ESI): [M+H] + =433.4; 1H NMR (400MHz, DMSO-d6) δ8.54 (s, 1H), 8.43 (d, J=5.4Hz, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 8.05 ( d, J=5.4Hz, 1H), 7.13-6.99 (m, 4H), 6.62 (s, 1H), 4.71 (d, J=4.1Hz, 1H), 4.37 (d, J=10.4Hz, 1H ), 4.25 (d, J = 14.0Hz, 1H), 3.95 (s, 3H), 3.80 (q, J = 15.0Hz, 2H), 3.57 (dt, J = 13.7, 4.5Hz, 1H) , 2.96-2.84 (m, 2H), 2.83-2.63 (m, 5H), 1.82 (d, J=10.0Hz, 1H), 1.48 (dt, J=12.1, 8.4Hz, 1H).

[0684] Example 86

[0685] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((6-(pyrrolidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0686]

[0687] Step 1: Preparation of 6-(pyrrolidin-1-yl)pyridin-2-amine:

[0688]

[0689] 2-Amino-6-bromopyridine (200 mg, 1.16 mmol, 1.0 eq), tetrahydropyrrole (164 mg, 2.31 mmol, 2.0 eq), and Cs2CO3 (cesium carbonate) (565 mg, 1.73 mmol, 1.5 eq) were dissolved in NMP (N-methylpyrrolidone) (8 mL) and reacted at 200°C under microwave conditions for 0.5 hours. The reaction solution was poured into 20 mL of water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the crude product was separated and purified by flash chromatography (silica gel, dichloromethane) to obtain the target compound 6-(pyrrolidin-1-yl)pyridin-2-amine (406 mg, crude) as a brown liquid. LCMS (ESI) [M+H] + =164.10.

[0690] Step 2: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((6-(pyrrolidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0691]

[0692] Trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (50 mg, 0.14 mmol, 1.0 eq), 6-(pyrrolidin-1-yl)pyridin-2-amine (71 mg, 0.43 mmol, 3.0 eq), Pd(OAc)2 (palladium acetate) (7 mg, 0.03 mmol, 0.2 eq), BINAP (1,1′-binaphthyl-2,2′-bisdiphenylphosphine) (36 mg, 0.06 mmol, 0.4 eq) and Cs2CO3 (cesium carbonate) (94 mg, 0.29 mmol, 2.0 eq) were dissolved in 1,4-dioxane (1 mL) and reacted at 110°C under nitrogen protection for 17 hours. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic phase was concentrated, and the crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to obtain the target compound, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((6-(pyrrolidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)piperidin-3-ol (12.4 mg, 18.1%). LCMS (ESI) [M+H] + =472.48; 1 H NMR (400MHz, DMSO-d6) δ9.32 (s, 1H), 8.16 (s, 1H), 7.78 (s, 1H), 7.34 (t, J=8.0Hz, 1H), 7.10-7 .05 (m, 3H), 7.05-7.01 (m, 1H), 6.38 (d, J = 7.8Hz, 1H), 5.92 (d, J = 8.0Hz, 1H), 4.66-4.33 (m, 2H) , 3.80 (q, J=15.0Hz, 2H), 3.57 (tt, J=9.4, 4.5Hz, 1H), 3.43 (t, J=6.0Hz, 4H), 2.94-2.85 (m, 2H ), 2.82-2.64 (m, 5H), 1.98-1.90 (m, 4H), 1.79 (d, J=12.8Hz, 1H), 1.48 (qd, J=12.2, 4.2Hz, 1H).

[0693] Example 87

[0694] Preparation of trans-1-(6-((2,3-difluorophenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0695]

[0696] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 2,3-difluoroaniline to obtain the target molecule, trans-1-(6-((2,3-difluorophenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 21.8%. LCMS (ESI) [M+H] + =438.4; 1 H NMR (400MHz, CDCl3) δ8.32 (s, 1H), 7.62 (ddt, J=8.4, 6.8, 1.7Hz, 1H), 7.17-7.00 (m, 5H), 6.9 1-6.89 (m, 1H), 6.69 (s, 1H), 5.94 (s, 1H), 4.73 (d, J=13.5Hz, 1H), 4.51-4.40 (m, 1H), 3.96 (d, J=14.6Hz, 1H), 3.81-3.69 (m, 2H), 3.60 (td, J=10.1, 4.9Hz, 1H), 3.03 (dt, J=11.0, 5.4Hz, 1H ), 2.92 (t, J=5.8Hz, 2H), 2.85-2.67 (m, 4H), 1.94-1.91 (m, 1H), 1.56 (qd, J=12.5, 4.4Hz, 1H).

[0697] Example 88

[0698] Preparation of trans-1-(6-((3-fluoro-2-methoxyphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0699]

[0700] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 3-fluoro-2-methoxyaniline to obtain the target molecule, trans-1-(6-((3-fluoro-2-methoxyphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 57.5%. LCMS (ESI) [M+H] + =450.5; 1H NMR (400MHz, DMSO-d6) δ8.43 (s, 1H), 8.20 (s, 1H), 8.05 (d, J=8.4Hz, 1H), 7.05-7.08 ( m, 3H), 7.0-7.05 (m, 2H), 6.90-6.83 (m, 1H), 6.38 (s, 1H), 4.69 (d, J=4.0Hz, 1H), 4.36- 4.24(m, 2H), 3.84-3.82(m, 4H), 3.78-3.75(m, 1H), 3.61-3.54(m, 1H), 2.93-2.85(m, 2H), 2.82-2.79(m, 3H), 2.70-2.65(m, 2H), 1.82(d, J=10.3Hz, 1H), 1.52-1.41(m, 1H).

[0701] Example 89

[0702] Preparation of trans-1-(6-((2,3-dichlorophenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0703]

[0704] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, with 2,3-dichloroaniline to obtain the target molecule, trans-1-(6-((2,3-dichlorophenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 44.2%. LCMS (ESI) [M+H] + =470.4; 1 H NMR (400MHz, DMSO-d6) δ8.61 (s, 1H), 8.16 (s, 1H), 7.94 (dd, J=6.6, 3.1Hz, 1H), 7.38-7 .26 (m, 2H), 7.05 (dd;, J=18.3, 3.8Hz, 3H), 7.03 (d, J=3.7Hz, 1H), 6.26 (s, 1H), 4.71 (d , J=4.0Hz, 1H), 4.35-4.22 (m, 2H), 3.81 (q, J=15.1Hz, 2H), 3.65-3.53 (m, 1H), 3.09-2. 61 (m, 5H), 2.68 (dd, J=13.5, 8.4Hz, 2H), 1.82 (d, J=13.7Hz, 1H), 1.47 (d, J=8.2Hz, 1H).

[0705] Example 90

[0706] Preparation of trans-1-(6-((2-ethoxyphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0707]

[0708] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 2-ethoxyaniline to obtain the target molecule, trans-1-(6-((2-ethoxyphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 55.6%. LCMS (ESI) [M+H] + =446.1; 1 H NMR (400MHz, DMSO-d6) δ8.15 (s, 1H), 8.04-7.92 (m, 2H), 7.13-7.05 (m, 3H), 7.04-6.99 (m, 2H), 6.98 (ddd, J=9. 6, 7.2, 1.6Hz, 1H), 6.89 (td, J=7.7, 1.6Hz, 1H), 6.19 (s, 1H), 4.68 (d, J=4.0Hz, 1H), 4.29 (dd, J=42.2, 10.9Hz, 2 H), 4.09 (q, J=7.0Hz, 2H), 3.80 (q, J=15.1Hz, 2H), 3.57 (tt, J=9.3, 4.5Hz, 1H), 2.90-2.86 (m, 1H), 2.84-2.75 (m , 4H), 2.64 (dd, J=14.6, 8.1Hz, 2H), 1.80 (d, J=9.9Hz, 1H), 1.46 (td, J=12.1, 8.3Hz, 1H), 1.36 (t, J=7.0Hz, 3H).

[0709] Example 91

[0710] Preparation of trans-1-(6-(2-(2,2,2-trifluoroethoxyphenyl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0711]

[0712] The starting material trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin- 2(1H)-yl)piperidin-3-ol was used in the substitution reaction with 2-(2,2,2- trifluoroethoxy)aniline according to the method of Example 33 to give the target molecule trans-1-(6-((2,2,2-trifluoroethoxy)amino)pyrimidin-4-yl)-4-(3,4- dihydroisoquinolin-2(1H)-yl)piperidin-3-ol in a yield of 48.2%. LCMS (ESI) [M+H] + = 500.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 8.9 Hz, 2H), 7.83 (dd, J = 7.6, 1.9 Hz, 1H), 7.17 (dd, J = 7.8, 1.3 Hz, 1H), 7.10 - 6.99 (m, 6H), 6.07 (s, 1H), 4.77 (q, J = 8.9 Hz, 2H), 4.68 (d, J = 4.0 Hz, 1H), 4.28 (dd, J = 41.2, 11.4 Hz, 2H), 3.80 (q, J = 15.0 Hz, 2H), 3.55 (dt, J = 14.1, 4.7 Hz, 1H), 2.90 - 2.84 (m, 1H), 2.82 - 2.75 (m, 4H), 2.68 - 2.60 (m, 2H), 1.79 (d, J = 9.9 Hz, 1H), 1.45 (dt, J = 11.7, 8.2 Hz, 1H).

[0713] Example 92

[0714] Preparation of trans-1-(6-((2,2,2-trifluoroethoxy)amino)pyrimidin-4-yl)-4-(3,4- dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0715]

[0716] The starting material trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin- 2(1H)-yl)piperidin-3-ol was used in the substitution reaction with 5-fluoro-2- methoxyaniline according to the method of Example 33 to give the target molecule trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((5-fluoro-2- methoxyphenyl)amino)pyrimidin-4-yl)piperidin-3-ol in a yield of 29.5%). LCMS (ESI) [M+H] + = 450.4; 1H NMR (400MHz, CDCl3) δ8.35 (s, 1H), 7.96 (dd, J=10.7, 3.1Hz, 1H), 7.19-7.09 (m, 3H), 7.05-6.98 (m, 2H), 6.80 ( dd, J=8.9, 5.0Hz, 1H), 6.66 (td, J=8.4, 3.0Hz, 1H), 5.97 (s, 1H), 4.72 (d, J=13.5Hz, 1H), 4.51 (d, J=11.4Hz, 1H ), 3.95 (d, J=14.6Hz, 1H), 3.88 (s, 3H), 3.79-3.67 (m, 2H), 3.61 (td, J=10.0, 4.8Hz, 1H), 3.03 (dt, J=11.0, 5.4 Hz, 1H), 2.91 (t, J=5.8Hz, 2H), 2.87-2.64 (m, 4H), 1.92 (dd, J=12.9, 3.2Hz, 1H), 1.56 (qd, J=12.6, 4.4Hz, 1H).

[0717] Example 93

[0718] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-fluoro-2-methoxyphenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0719]

[0720] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 4-fluoro-2-methoxyaniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-fluoro-2-methoxyphenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 39.1%. LCMS (ESI) [M+H] + =450.37; 1H NMR (400MHz, CDCl3) δ8.28 (s, 1H), 7.70 (dd, J=8.6, 6.1Hz, 1H), 7.21-7.06 (m, 3H), 7.06-6.94 (m, 1H) , 6.76-6.60 (m, 3H), 5.86 (s, 1H), 4.72 (d, J = 13.4Hz, 1H), 4.43 (d, J = 10.0Hz, 1H), 3.94 (d, J = 14.5Hz, 1 H), 3.86 (s, 3H), 3.69 (d, J=14.6Hz, 2H), 3.58 (td, J=10.0, 4.9Hz, 1H), 3.02 (dt, J=10.9, 5.3Hz, 1H), 2.91 (t, J=5.6Hz, 2H), 2.82-2.63 (m, 4H), 1.90 (dd, J=12.8, 3.3Hz, 1H), 1.54 (qd, J=12.4, 4.3Hz, 1H).

[0721] Example 94

[0722] Preparation of trans-1-(6-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol:

[0723]

[0724] Following the method of Example 59, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 5-amino-1,4-benzodioxane to obtain the target molecule, trans-1-(6-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)pyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, in a yield of 6.5%. LCMS (ESI) [M+H] + =460.4; 1H NMR (400MHz, DMSO-d6) δ8.15 (d, J=2.8Hz, 2H), 7.50 (d, J=7.6Hz, 1H), 7.08-7. 03 (m, 4H), 6.76 (t, J=8.0Hz, 1H), 6.56 (d, J=7.6Hz, 1H), 6.16 (s, 1H), 4.69 (d, J =3.6Hz, 1H), 4.30-4.20(m, 6H), 3.86-3.75(m, 2H), 3.59-3.54(m, 1H), 2.90-2 .78 (m, 5H), 2.65 (t, J=10.0Hz, 2H), 1.79 (d, J=10.4Hz, 1H), 1.47-1.44 (m, 1H).

[0725] Example 95

[0726] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-(pyrrolidin-1-yl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol:

[0727]

[0728] Following the method of Example 33, a substitution reaction was carried out using the starting material, trans-1-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol, and 4-(pyrrolidin-1-yl)aniline to obtain the target molecule, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(6-((4-(pyrrolidin-1-yl)phenyl)amino)pyrimidin-4-yl)piperidin-3-ol, in a yield of 14.7%. LCMS (ESI) [M+H] + =471.6; 1 H NMR (400MHz, CDCl3) δ8.18 (s, 1H), 7.33-7.26 (m, 3H), 7.21 (d, J=6.8Hz, 1H), 7 .12(d, J=8.8Hz, 2H), 6.67(d, J=8.8Hz, 2H), 5.87(s, 1H), 4.76-4.42(m, 4H), 4. 02-3.96(m, 1H), 3.76-3.61(m, 3H), 3.33(s, 3H), 3.24-3.10(m, 4H), 2.98(td, J =11.4Hz, 2.0Hz, 1H), 2.26-2.24(m, 1H), 2.07-2.03(m, 4H), 1.88-1.85(m, 1H).

[0729] Example 96

[0730] Preparation of trans-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-((1-(2-methoxyethyl)piperidin-4-yl)amino)pyrimidin-4-yl)methanone:

[0731]

[0732] Step 1: Preparation of tert-butyl (1-(2-methoxyethyl)piperidin-4-yl)carbamate:

[0733]

[0734] At 20°C, tert-butylpiperidin-4-ylcarbamate (500 mg, 2.49 mmol, 1.0 eq) was dissolved in acetonitrile (10 mL) under nitrogen. 1-Bromo-2-methoxyethane (382 mg, 2.75 mmol, 1.1 eq) and potassium carbonate (1 g, 7.49 mmol, 3.0 eq) were added, and the mixture was stirred at 80°C for 16 hours. After completion of the reaction, as determined by LCMS, the mixture was cooled to room temperature, filtered, and concentrated. The crude product was separated by column chromatography (silica gel, gradient elution using pure DCM followed by a mixed solvent of DCM:MeOH = 95:5 (volume ratio)). The title compound, tert-butyl (1-(2-methoxyethyl)piperidin-4-yl)carbamate (545 mg, 84.5% yield), was obtained as a white solid. LCMS: [M+H] + =1.49.

[0735] The second step is the preparation of 1-(2-methoxyethyl)piperidin-4-amine:

[0736]

[0737] Dissolve tert-butyl (1-(2-methoxyethyl)piperidin-4-yl)carbamate (550 mg, 2.13 mmol, 1.0 eq) in a solution of hydrochloric acid in 1,4-dioxane (3 mL, 4 M), stir at room temperature (25°C) for 1 hour, and extract with dichloromethane (3 x 20 mL). The organic phase is washed once with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent is concentrated to give the crude product, 1-(2-methoxyethyl)piperidin-4-amine (520 mg crude), as a yellow oil. LC-MS (ESI): [M+H] + =159.16.

[0738] The third step is the preparation of trans-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-((1-(2-methoxyethyl)piperidin-4-yl)amino)pyrimidin-4-yl)methanone:

[0739]

[0740] At room temperature (20°C), under nitrogen, the raw material trans-(6-chloropyrimidin-4-yl)(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone (70 mg, 0.19 mmol, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and 1-(2-methoxyethyl)piperidin-4-amine (89 mg, 0.56 mmol, 3.0 eq), palladium acetate (9 mg, 0.04 mmol, 0.2 eq), BINAP (1,1′-binaphthyl-2,2′-bis(diphenylphosphine)) (47 mg, 0.08 mmol, 0.4 eq), and cesium carbonate (306 mg, 0.94 mmol, 5.0 eq) were added, and the mixture was heated and stirred at 100°C for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with dichloromethane (5 mL), filtered, and concentrated. The crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to obtain the compound trans-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-((1-(2-methoxyethyl)piperidin-4-yl)amino)pyrimidin-4-yl)methanone (7.2 mg, 7.8%). LCMS: [M+H] + =495.64; 1 H NMR (400MHz, CDCl3) δ8.52 (d, J=6.0Hz, 1H), 7.19-7.09 (m, 3H), 7.05-6.99 (m, 1H), 6.57 (d, J=16.6Hz, 1H), 5.03 (d, J=9.3Hz, 1H), 5.05-5.01 (m, 1H), 4.72 (d, J=14.0Hz, 1H), 4.32-4.13 (m, 1H), 3.95 (d, J=1 4.6Hz, 2H), 3.76-3.67(m, 2H), 3.52(t, J=5.5Hz, 2H), 3.36(s, 3H), 3.12-2.81(m, 7H), 2.73-2.64(m, 2 H), 2.61 (t, J=5.4Hz, 2H), 2.32-2.15 (m, 2H), 2.12-1.97 (m, 3H), 1.91-1.80 (m, 1H), 1.64-1.56 (m, 2H).

[0741] Example 97

[0742] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(-6-(trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)pyrimidin-4-yl)methanone:

[0743]

[0744] Step 1: Preparation of 4-carbonyl-6-chloropyrimidine chloride:

[0745]

[0746] 6-Hydroxypyrimidine-4-carboxylic acid (100 mg, 0.71 mmol, 1.0 eq) was dissolved in ethyl acetate (3 mL). Oxalyl chloride (453 mg, 3.57 mmol, 5.0 eq) and N,N-dimethylformamide (0.001 mL) were added at 0°C. The mixture was stirred at 80°C under nitrogen for 1 hour. The reaction was complete by TLC, and the product was dried to give crude 4-carbonyl-6-chloropyrimidine chloride as a black solid.

[0747] Step 2: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(-6-(trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)pyrimidin-4-yl)methanone

[0748]

[0749] Trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (265 mg, 1.14 mmol, 1.6 equiv.) and 4-carbonyl-6-chloropyrimidine chloride (126 mg, 0.71 mmol, 1.0 equiv.) were dissolved in dichloromethane (3 mL) at 0°C, and triethylamine (504 mg, 4.98 mmol, 7.0 equiv.) was added, and the mixture was stirred at 20°C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to give trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-(trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)pyrimidin-4-yl)methanone (26.4 mg, yield 6.5%). LCMS (ESI) [M+H] + =569.7; 1H NMR (400MHz, CDCl3) δ8.60-8.57 (m, 1H), 7.19-7.10 (m, 6H), 7.07-7.01 (m, 2H), 6.89-6.81 (m, 1H), 5.13-4.53 (m, 3H), 4.27-3.92 (m, 4H), 3.84-3.55 (m, 5H), 3.21-2.59 (m, 15H), 2.09-1.94 (m, 2H), 1.87 (d, J=12.8Hz, 1H).

[0750] Example 98

[0751] Preparation of 1-cyclopropyl-2-(2-((6-(trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonan-7-yl)ethane-1,2-dione:

[0752]

[0753] The first step is the preparation of tert-butyl (7-(2-(2-cyclopropyl-2-oxyacetyl)-7)-azaspiro[3.5]nonyl-2-yl)carbamate:

[0754]

[0755] At room temperature (20°C), under nitrogen, tert-butyl 7-azaspiro[3.5]nonane-2-carbamate (220 mg, 0.94 mmol, 1.0 equiv.), 2-cyclopropyl-2-oxoacetic acid (107 mg, 0.94 mmol, 1.0 equiv.) and 1-propylphosphonic anhydride (1.2 g, 1.88 mmol, 2.0 equiv.) were dissolved in N,N-dimethylformamide (5 mL). Triethylamine (475 mg, 4.70 mmol, 5.0 equiv.) was added and the mixture was heated to 25°C and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature (20-25°C), filtered, and concentrated. The crude product was separated by column chromatography (silica gel, gradient elution from pure DCM to DCM:MeOH = 20:1). The title compound (tert-butyl 7-(2-(2-cyclopropyl-2-oxoacetyl)-7)-azaspiro[3.5]nonyl-2-yl)carbamate (300 mg, yield: 94.8%) was obtained as a brown oil. LCMS: [M+H] + =326.20.

[0756] Step 2: Preparation of 1-(2-amino-7-azaspiro[3.5]nonane-7-yl)-2-cyclopropylethane-1,2-dione:

[0757]

[0758] Tert-butyl (7-(2-(2-cyclopropyl-2-oxoacetyl)-7)-azaspiro[3.5]nonan-2-yl)carbamate (300 mg, 0.89 mmol, 1.0 equiv.) was dissolved in a solution of hydrochloric acid in 1,4-dioxane (4 mL, 4 M), stirred at room temperature (25°C) for 1 hour, and extracted with dichloromethane (3 x 20 mL). The organic phase was washed once with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was concentrated to give the crude product, 1-(2-amino-7-azaspiro[3.5]nonan-7-yl)-2-cyclopropylethane-1,2-dione (300 mg, crude), as a yellow oil. LCSM (ESI): [M+H] + =237.23.

[0759] Step 3: Preparation of 1-cyclopropyl-2-(2-((6-(trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonane-7-yl)ethane-1,2-dione:

[0760]

[0761] At room temperature 20 ° C, under nitrogen protection, the raw material trans-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone (100 mg, 0.27 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (2 mL), and 1-(2-amino-7-azaspiro[3.5]nonan-7-yl)-2-cyclopropylethane-1,2- Diketone (190 mg, 0.81 mmol, 3.0 equiv.), palladium acetate (12 mg, 0.05 mmol, 0.2 eq), BINAP (1,1′-binaphthyl-2,2′-bisdiphenylphosphine) (67 mg, 0.11 mmol, 0.4 equiv.), cesium carbonate (437 mg, 1.34 mmol, 5.0 equiv.), heated with stirring at 100°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with dichloromethane (5 mL), filtered, and concentrated. The crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to obtain the title compound, 1-cyclopropyl-2-(2-((6-(trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonan-7-yl)ethane-1,2-dione (2.7 mg, yield: 1.8%). LCMS: [M+H] + =573.67;1 H NMR (400 MHz, CDC13) δ 8.55-8.53 (m, 1H), 7.19-7.09 (m, 3H), 7.03 (d, J = 5.5 Hz, 1H), 6.55-6.51 (m, 1H), 5.34 (s, 1H), 5.09-4.65 (m, 1H), 4.45-4.11 (m, 2H), 4.03-3.81 (m, 2H), 3.78-3.45 (m, 5H), 3.40-3.35 (m, 1H), 3.33-3.26 (m, 1H), 3.07-3.01 (m, 1H), 3.01-2.78 (m, 4H), 2.74-2.62 (m, 2H), 2.54-2.43 (m, 2H), 2.36-2.25 (m, 1H), 2.04-1.94 (m, 1H), 1.89-1.79 (m, 1H), 1.81-1.71 (m, 5H), 1.30-1.21 (m, 2H), 1.17-1.09 (m, 2H).

[0762] Example 99

[0763] Preparation of trans-1-cyclopropyl-2-(4-((6-(4-(3,4-dihydroisoquinolin-2(lH)-yl)-3- hydroxypiperidine- 1 -carbonyl)pyrimidin-4-yl)amino)piperidin- 1 -yl)ethane- 1,2-dione:

[0764]

[0765] First Step: Preparation of tert-butyl (l-(2-(2-cyclopropyl-2-oxoacetyl)piperidin-4- yl)carbamate:

[0766]

[0767] Tert-butyl 4-amino piperidine (500 mg, 2.50 mmol, 1.0 equiv.), 2-cyclopropyl-2- oxoacetic acid (313 mg, 2.75 mmol, 1.1 equiv.), T3P (1 -propylphosphonic anhydride) (50% in EA, 3.18 g, 4.99 mmol, 2.0 equiv.) and TEA (triethylamine) (1.26 g, 12.48 mmol, 5.0 equiv.) were dissolved in DMF (N,N-dimethylformamide) (12 mL) and reacted at 20 °C for 1 hour. The reaction solution was extracted with ethyl acetate, and the organic phase was concentrated. The crude product was separated and purified by flash chromatography (silica gel, DCM:MeOH = 100:1) to obtain the title compound (703 mg, 95%) as an orange solid. LCMS (ESI) [M+H-56] = 241.12. + = 241.12.

[0768] Step 2: Preparation of 1-(4-aminopiperidin-1-yl)-2-cyclopropylethane-1,2-dione:

[0769]

[0770] Tert-butyl (1-(2-(2-cyclopropyl-2-oxoacetyl)piperidin-4-yl)carbamate (250 mg, 0.84 mmol, 1.0 equiv.) was dissolved in a solution of hydrochloric acid in 1,4-dioxane (3 mL, 4 M) and reacted at 20°C for 1 hour. The reaction solution was concentrated to give the crude title compound (168 mg) as a yellow solid. LCMS (ESI) [M+H] + =197.13;

[0771] Step 3: Preparation of trans-1-cyclopropyl-2-(4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)ethane-1,2-dione:

[0772]

[0773] trans-(6-chloropyrimidin-4-yl)(4-(3,4-dihydroisoquinolin-2(1H)-yl)-5-hydroxyazepin-1-yl)methanone (80 mg, 0.22 mmol, 1.0 equiv.), 1-(4-aminopiperidin-1-yl)-2-cyclopropylethane-1,2-dione (84 mg, 0.43 mmol, 2.0 equiv.), Pd(OAc)2 (palladium acetate) (10 mg, 0 1,1′-binaphthyl-2,2′-bis(diphenylphosphine) (53 mg, 0.04 mmol, 0.2 equiv.), BINAP (1,1′-binaphthyl-2,2′-bis(diphenylphosphine)) (53 mg, 0.09 mmol, 0.4 equiv.), and Cs2CO3 (cesium carbonate) (350 mg, 1.07 mmol, 5.0 equiv.) were dissolved in 1,4-dioxane (2 mL) and reacted at 110°C under nitrogen for 17 hours. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 in water, MeCN) to give the title compound (2.0 mg, 1.7%). LCMS (ESI) [M+H] + =533.6; 1H NMR (400 MHz, CDC13) δ 8.62-8.46 (m, IH), 7.19-7.10 (m, 3H), 7.06-6.99 (m, IH), 6.69-6.56 (m, IH), 5.46-5.20 (m, IH), 4.71 (d, J = 12.0 Hz, IH), 4.49 (d, J = 13.5 Hz, IH), 4.33-4.08 (m, 2H), 4.00 (d, J = 14.6 Hz, IH), 3.86-3.67 (m, 3H), 3.28-3.14 (m, IH), 3.14-2.56 (m, 8H), 2.34 (tt, J = 7.9, 4.6 Hz, IH), 2.21-2.06 (m, 2H), 2.06-1.97 (m, IH), 1.89 (d, J = 12.5 Hz, IH), 1.51 (pd, J = 12.0, 4.1 Hz, 3H), 1.31-1.21 (m, 2H), 1.19-1.11 (m, 2H).

[0774] Example 100

[0775] Preparation of (trans-4-(3,4-dihydroisoquinolin-2(lH)-yl)-3-hydroxypiperidin-l- yl)(6-((l-methylpiperidin-4-yl)amino)pyrimidin-4-yl)methanone:

[0776]

[0777] Preparation of (trans-4-(3,4-dihydroisoquinolin-2(lH)-yl)-3-hydroxypiperidin-l- yl)(6-((l-methylpiperidin-4-yl)amino)pyrimidin-4-yl)methanone:

[0778]

[0779] At room temperature (20°C), under nitrogen protection, the raw material trans-(6-chloropyrimidin-4-yl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone (80 mg, 0.22 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (2 mL), and 1-methylpiperidin-4-amine hydrochloride (74 mg, 0.64 mmol, 3.0 equiv.), palladium acetate (10 mg, 0.04 mmol, 0.2 equiv.), BINAP (1,1′-binaphthyl-2,2′-bisdiphenylphosphine) (53 mg, 0.08 mmol, 0.4 equiv.), and cesium carbonate (350 mg, 1.07 mmol, 5.0 equiv.) were added, and the mixture was heated at 70°C with stirring for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and diluted with dichloromethane (5 mL), filtered, and concentrated. The crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to obtain the title compound (7.6 mg, 7.8%). LCMS: [M+H] + =451.37; 1 H NMR (400MHz, CDCl3) δ8.66-8.43 (m, 1H), 7.20-7.09 (m, 3H), 7.07-6.98 (m, 1H), 6 .64-6.45(m, 1H), 5.29-4.64(m, 2H), 4.35-4.09(m, 1H), 4.05-3.83(m, 2H), 3.74 -3.67(m, 2H), 3.13-2.96(m, 2H), 2.94-2.89(m, 2H), 2.87-2.80(m, 2H), 2.79-2. 53(m, 3H), 2.31(s, 3H), 2.20-2.11(m, 2H), 2.09-1.97(m, 3H), 1.73-1.49(m, 4H).

[0780] Example 101

[0781] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-(anilino)pyrimidin-4-yl)methanone:

[0782]

[0783] Step 1: Preparation of methyl 6-(phenylamino)pyrimidine-4-carboxylate:

[0784]

[0785] Methyl 6-chloro-pyrimidine-4-carboxylate (200 mg, 1.16 mmol), aniline (109.93 mg, 1.16 mmol), and DIPEA (299.59 mg, 2.32 mmol) were dissolved in IPA (isopropyl alcohol) (2.5 mL). The reaction was stirred at 90°C for 16 h. TLC confirmed the reaction was complete. The mixture was extracted with ethyl acetate three times, each time using 20 mL. The combined ethyl acetate phases were washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, and filtered. The crude product was column-filtered with PE:EA = 2:1 to yield methyl 6-(phenylamino)pyrimidine-4-carboxylate (0.237 g, 89%) as a white solid. 1 H NMR (400MHz, CDCl3) δ8.86 (s, 1H), 7.49-7.35 (m, 5H), 7.24-7.20 (m, 1H), 3.98 (s, 3H).

[0786] Step 2: Preparation of 6-(anilino)pyrimidine-4-carboxylic acid:

[0787]

[0788] Methyl 6-(phenylamino)pyrimidine-4-carboxylate (187 mg, 0.815 mmol) was dissolved in THF (4 mL), and then a 2 M aqueous lithium hydroxide solution (0.83 mL, 1.63 mmol) was added. The reaction mixture was stirred at room temperature (20-25°C) for 2 h. TLC indicated the reaction was complete. 1 M hydrochloric acid was added to adjust the pH to 4-5, and solid precipitated. After filtration, the filter cake was washed with 2 mL of water. Pure 6-(phenylamino)pyrimidine-4-carboxylic acid (136 mg, 78%) was obtained as a white solid. LCMS (ESI) [M+H] + =279.0;

[0789] Step 3: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-(anilino)pyrimidin-4-yl)methanone:

[0790]

[0791] 6-(Phenylamino)pyrimidine-4-carboxylic acid (140 mg, 0.65 mmol), T3P (1-propylphosphonic anhydride) (0.82 g, 1.3 mmol, 50% by mass in ethyl acetate), trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (151 mg, 0.65 mmol), and Et3N (triethylamine) (0.329 g, 3.25 mmol) were dissolved in DMF (3 mL). The reaction solution was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. Extraction was performed with ethyl acetate three times, each time using 10 mL. The ethyl acetate phases were combined, washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, filtered, and the crude product was separated and purified by preparative HPLC (C18, 10 mmol / L aqueous NH4HCO3, acetonitrile) to obtain the title compound (144 mg, 75%). LCMS (ESI) [M+H] + =430.4; 1 H NMR (400MHz, DMSO-d6) δ9.81 (d, J=7.3Hz, 1H), 8.64 (dd, J=9.0, 1.2Hz, 1H), 7.67 (dd, J=8.0 , 3.7Hz, 2H), 7.38-7.34 (m, 2H), 7.17-7.00 (m, 5H), 6.86 (dd, J=6.2, 1.2Hz, 1H), 4.79 (dd, J =38.2, 3.9Hz, 1H), 4.61-4.27(m, 1H), 4.00-3.70(m, 3H), 3.67-3.61(m, 1H), 3.04(t, J=12. 5Hz, 0.5H), 2.99-2.72(m, 4H), 2.71-2.57(m, 1.5H), 2.01-1.69(m, 1H), 1.54-1.50(m, 1H).

[0792] Example 102

[0793] Preparation of trans-1-(4-((4-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)ethan-1-one:

[0794]

[0795] Step 1: Preparation of methyl 6-((1-acetylpiperidin-3-yl)amino)pyrimidine-4-carboxylate:

[0796]

[0797] The starting material 2-chloro-5-trifluoromethylisonicotinic acid methyl ester (300 mg, 1.26 mmol, 1.0 equiv.) was added to acetonitrile (3 mL), then 1-acetylpiperidin-4-amine hydrochloride (268 mg, 1.51 mmol, 1.5 equiv.), DIPEA (N,N-diisopropylethylamine) (487 mg, 3.78 mmol, 3.0 equiv.) were added, stirred at 90 °C for 12 h. After the reaction was detected to be completed by LCMS, cooled to room temperature 28 °C, added water (5 mL), extracted with dichloromethane:methanol (V / V = 10 / 1) (5 mL x 3) three times, combined the organic phase, filtered, concentrated, the crude product was separated and purified by flash chromatography (silica gel, dichloromethane:methanol (V / V = 8 / 1)) to give the title compound methyl 6-((1-acetylpiperidin-3-yl)amino)pyrimidine-4-carboxylate (150 mg, 34%) as a yellow solid. LCMS (ESI) [M+H] + = 346.35.

[0798] Second step: Preparation of 2-((1-acetylpiperidin-4-yl)amino)-5- (trifluoromethyl)isonicotinic acid:

[0799]

[0800] The starting material methyl 6-((1-acetylpiperidin-3-yl)amino)pyrimidine-4-carboxylate (150 mg, 0.43 mmol, 1.0 equiv.) was added to water (1 mL), methanol (1.0 mL) and tetrahydrofuran (1.0 mL) at room temperature 28 °C, added lithium hydroxide (42 mg, 1.74 mmol, 1.1 equiv.), stirred at room temperature 28 °C for 1 h, after the reaction was detected to be completed by TLC (dichloromethane:methanol (V / V = 10 / 1)), the reaction was concentrated to 1 mL, adjusted to pH = 1-2 with 1 M (molar concentration) hydrochloric acid, the crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile), freeze-dried to give the title compound (30 mg, yield 21%) as a white solid. LCMS (ESI) [M+H] + = 332.3; 1 H NMR (400 MHz, MeOD-d4) δ 8.31 (s, 1H), 6.89 (d, J = 4.0 Hz, 1H), 4.46 (dd, J = 1.6 Hz, 13.2 Hz, 1H), 4.11 (br s, 1H), 3.95 (dd, J = 1.2 Hz, 13.6 Hz, 1H), 2.96-2.89 (m, 1H), 2.14 (s, 3H), 2.12-2.03 (m, 2H), 1.54-1.43 (m, 2H).

[0801] Step 3: Preparation of trans-1-(4-((4-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3- hydroxypiperidine-1-carbonyl)-5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1- yl)ethan-1-one:

[0802]

[0803] The starting material 2-((1-acetylpiperidin-4-yl)amino)-5-(trifluoromethyl)isonicotinic acid (30 mg, 0.114 mmol, 1.0 equiv.) was added to DMF (N,N-dimethylformamide) (1 mL), followed by HATU (52 mg, 0.137 mmol, 1.2 equiv.), triethylamine (23 mg, 0.228 mmol, 2.0 equiv.), and a solution of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (32 mg, 0.137 mmol, 1.20 equiv.) in DMF (1 mL) after stirring for 5 min at room temperature 28 °C for 3 h. After the reaction was completed by LCMS detection, the crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile), and freeze-dried to obtain the title compound (8 mg, yield: 12.8%). LCMS (ESI) [M+H]+=546.3. 1 H NMR (400 MHz, CD3OD) δ 8.35 (t, J = 4.8 Hz, 1H), 7.10-7.05 (m, 4H), 6.49-6.40 (m, 1H), 4.78-4.60 (m, 1H), 4.45 (d, J = 13.2 Hz, 1H), 4.14 (br s, 1H), 3.98-3.88 (m, 3H), 3.82-3.48 (m, 2H), 3.20-2.98 (m, 2H), 2.95-2.87 (m, 4H), 2.83-2.64 (m, 2H), 2.14 (s, 3H), 2.07-1.85 (m, 3H), 1.68-1.38 (m, 3H).

[0804] Example 103

[0805] Preparation of trans-1-(4-((((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3- hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethan-1-one:

[0806]

[0807] Step 1: Preparation of tert-butyl ((1-acetylpiperidin-4-yl)methyl)carbamate:

[0808]

[0809] The starting material, tert-butyl N-(4-piperidinylmethyl)carbamate (500 mg, 2.33 mmol, 1 equiv.), was dissolved in dichloromethane (10 ml). Under nitrogen, TEA (triethylamine) (354 mg, 3.50 mmol, 1.5 equiv.) and acetic anhydride (240 mg, 2.35 mmol, 1.01 equiv.) were added at 0°C. After reacting for 2 hours at room temperature (20-25°C), the reaction was quenched by adding water. Extraction with dichloromethane was performed, and the organic phase was dried, concentrated, and purified by flash chromatography (silica gel, MeOH:DCM = 0-3%) to afford tert-butyl ((1-acetylpiperidin-4-yl)methyl)carbamate (580 mg, 97% yield) as a light yellow oil. LCMS (ESI) [M+1] + =257.31.

[0810] Step 2: Preparation of 1-(4-(aminomethyl)piperidin-1-yl)ethanone hydrochloride:

[0811]

[0812] Dissolve the starting material, tert-butyl ((1-acetylpiperidin-4-yl)methyl)carbamate (100 mg, 0.390 mmol, 1 equiv.) in dioxane (1 ml), and add a 4M (molar concentration) hydrochloric acid solution in dioxane (1 ml). The reaction is stirred at room temperature (20-25°C) for 2 hours, and the reaction is monitored for completion by TLC. The solution is spin-dried to give the product, 1-(4-(aminomethyl)piperidin-1-yl)ethanone hydrochloride (103 mg crude), as a white solid. LCMS (ESI) [M+1] + =157.14.

[0813] Step 3: Preparation of methyl 6-((((1-acetylpiperidin-4-yl)methyl)amino)amino)pyrimidine-4-carboxylate:

[0814]

[0815] 1-(4-(Aminomethyl)piperidin-1-yl)ethanone hydrochloride (103 mg crude product, 0.390 mmol, 1.2 equiv.) and methyl 6-chloropyrimidine-4-carboxylate (56 mg, 0.325 mmol, 1 equiv.) were dissolved in acetonitrile (3 ml) (suspension), and DIPEA (N,N-diisopropylethylamine) (169 mg, 1.31 mmol, 4.03 equiv.) was added and stirred at 90°C for 2 hours. After completion of the reaction, as monitored by LCMS, the solvent was evaporated to dryness and the product was purified by flash chromatography (silica gel, MeOH:DCM = 0-4%) to give methyl 6-((((1-acetylpiperidin-4-yl)methyl)amino)amino)pyrimidine-4-carboxylate (152 mg) as a light yellow oil. LCMS (ESI) [M+1] + =293.3.

[0816] Step 4: Preparation of 6-((((1-acetylpiperidin-4-yl)methyl)amino)pyrimidine-4-carboxylic acid:

[0817]

[0818] The starting material, methyl 6-((((1-acetylpiperidin-4-yl)methyl)amino)amino)pyrimidine-4-carboxylate (152 mg, 0.520 mmol, 1 equiv.), was dissolved in a mixture of tetrahydrofuran (2.4 ml) and water (0.6 ml), and LiOH (lithium hydroxide) (25 mg, 1.044 mmol, 2.01 equiv.) was added. The reaction was stirred at room temperature (20-25°C) for 1 hour. TLC monitored the reaction completion. 1 M (molar concentration) hydrochloric acid was added to adjust the pH to 5-6, and the solvent was evaporated to give the crude product 6-((((1-acetylpiperidin-4-yl)methyl)amino)pyrimidine-4-carboxylic acid, which was used directly in the next step. LCMS (ESI) [M+1] + =279.0.

[0819] Step 5: Preparation of trans-1-(4-((((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethanone:

[0820]

[0821] The reactant, 6-(((1-acetylpiperidin-4-yl)methyl)amino)pyrimidine-4-carboxylic acid (190 mg, 0.512 mmol, 1 equiv.), was dissolved in DMF (N,N-dimethylformamide) (2.5 ml). EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (150 mg, 0.782 mmol, 1.53 equiv.) and HOAt (N-hydroxy-7-azabenzotriazole) (106 mg, 0.779 mmol, 1.52 equiv.) were added. After stirring for 5 minutes, a DMF solution (2.5 ml) of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (200 mg, 0.517 mmol, 1.01 equiv.) was added. The reaction was stirred at room temperature for 1 hour. The solvent was dried by vortexing, and the crude product was purified by flash chromatography (silica gel, MeOH:DCM = 0-10%), followed by prep-HPLC reverse column purification (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to obtain the product (66.5 mg, 26.4% yield). LCMS (ESI) [M+1] + =493.5; 1 H NMR (400MHz, Chloroform-d) δ 8.59-8.46 (m, 1H), 7.21-7.08 (m, 3H), 7.07-6.98 (m, 1H), 6.68-6.56 (m, 1H), 5.77-5.38 (m, 1H), 5.09-4.54 (m, 2H), 4.3 1-4.10(m, 1H), 4.02-3.59(m, 5H), 3.44-3.17(m, 2H), 3.11-2.79(m, 6H), 2 .77-2.45(m, 3H), 2.12-2.08(m, 3H), 2.03-1.58(m, 5H), 1.31-1.08(m, 2H).

[0822] Example 104

[0823] Preparation of trans-1-(4-((6-(-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-phenylpyrimidin-4-yl)amino)piperidin-1-ylethanone:

[0824]

[0825] Step 1: Preparation of tert-butyl ((1-acetylpiperidin-4-yl)methyl)carbamate:

[0826]

[0827] The raw materials 6-(((1-acetylpiperidin-4-yl)amino)-2-chloropyrimidine-4-carboxylic acid methyl ester (100 mg, 0.320 mmol, 1 equiv.), phenylboronic acid (35 mg, 0.0303 mmol, 0.09 equiv.) and Na2CO3 (sodium carbonate) (49 mg, 0.462 mmol, 1.45 equiv.) were weighed and placed in a microwave tube, which was sealed and replaced with nitrogen. The solvent acetonitrile (1 0.2 ml) and water (0.3 ml, deoxygenated with nitrogen in advance). Microwave at 150 degrees Celsius for 30 minutes. LCMS monitored the reaction completion. The reaction solution was filtered and dried, and the crude product was purified by medium-pressure reverse-phase column chromatography (C18, 0.05% formic acid in water, MeCN) to obtain the product 6-((1-acetylpiperidin-4-yl)amino)-2-phenylpyrimidine-4-carboxylic acid (70 mg, 64.3% yield) as a light yellow solid. LCMS (ESI) [M+1] + =340.9; 1 H NMR (400MHz, DMSO-d6) δ8.44 (s, 1H), 8.36-8.27 (m, 2H), 7.50-7.41 (m, 3H), 7.35 (brs, 1H), 6.85 (s, 1H), 4.24 (d, J =13.1Hz, 2H), 3.86-3.77(m, 1H), 3.24-3.22(s, 1H), 2.88(t, J=12.2Hz, 1H), 2.08-1.88(m, 5H), 1.52-1.20(m, 2H).

[0828] Step 2: Preparation of trans-1-(4-((6-(-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-phenylpyrimidin-4-yl)amino)piperidin-1-ylethanone:

[0829]

[0830] The reactant, 6-((1-acetylpiperidin-4-yl)amino)-2-phenylpyrimidine-4-carboxylic acid (70 mg, 0.206 mmol, 1 equiv.), was dissolved in DMF (N,N-dimethylformamide) (2 ml). EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (59 mg, 0.308 mmol, 1.5 equiv.) and HOAt (N-hydroxy-7-azabenzotriazole) (42 mg, 0.309 mmol, 1.5 equiv.) were added. After stirring for 5 minutes, a DMF solution (1 ml) of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (58 mg, 0.250 mmol, 1.21 equiv.) was added. The reaction was stirred at room temperature for 1 hour. The solvent was dried by vortexing, and the crude product was purified by preparative HPLC reverse column (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to obtain the title compound (37.9 mg, yield: 34.8%). LCMS (ESI) [M+1] + =555.6; 1 H NMR (400MHz, CDCl3) δ8.39-8.29(m, 2H), 7.52-7.40(m, 3H), 7.20-7.10(m, 3H), 7.08- 7.02(m, 1H), 6.65-6.48(m, 1H), 5.45-5.22(m, 1H), 5.13-4.72(m, 1H), 4.59-4.34(m, 2 H), 4.17(brs, 1H), 4.05-3.94(m, 1H), 3.93-3.69(m, 4H), 3.31-3.17(m, 1H), 3.17-3.0 0 (m, 2H), 2.98-2.63 (m, 6H), 2.29-1.98 (m, 5H), 1.92-1.69 (m, 2H), 1.53-1.38 (m, 2H).

[0831] Example 105

[0832] Preparation of trans-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-((2-methoxyphenyl)amino)pyrimidin-4-yl)methanone:

[0833]

[0834] Step 1: Preparation of methyl 6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylate:

[0835]

[0836] The raw material methyl 6-chloropyrimidine-4-carboxylate (500 mg, 28.97 mmol, 1.0 equiv.) was added to dioxane (10 mL), followed by 2-methoxyaniline (428 mg, 34.77 mmol, 1.2 equiv.), Pd(OAc)2 (palladium acetate) (65 mg, 2.9 mmol, 0.1 equiv.), BINAP (binaphthyl diphenyl phosphine) (361 mg, 5.79 mmol, 0.2 equiv.), and Cs2CO3 (cesium carbonate) (2.36 g, 72.43 mmol, 2.5 equiv.), and the mixture was stirred at 110°C for 16 h under nitrogen protection. After completion of the reaction, the mixture was cooled to room temperature (25°C) and water (20 mL) was added. The mixture was extracted three times with dichloromethane (30 mL x 3). The organic phases were combined, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 3)) to obtain the title compound (178 mg, 23.7%) as a yellow solid. LCMS (ESI) [M+H] + =260.2.

[0837] Step 2: Preparation of 6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylic acid:

[0838]

[0839] The starting material, methyl 6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylate (178 mg, 6.87 mmol, 1.0 equiv.), was added to water (3 mL) and tetrahydrofuran (3.0 mL) at 25°C. Lithium hydroxide (57.7 mg, 13.74 mmol, 2.0 equiv.) was added and stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated to remove the organic solvent and the pH was adjusted to 3 with 1 M hydrochloric acid. The system was extracted three times with dichloromethane:methanol (V / V=10 / 1) (30 mL x 5). The organic phases were combined, dried, filtered, and concentrated to give the crude product, 6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylic acid (180 mg, crude), as a yellow solid. LCMS (ESI) [M+H] + =246.1.

[0840] Step 3: Preparation of trans-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-((2-methoxyphenyl)amino)pyrimidin-4-yl)methanone:

[0841]

[0842] The starting material 6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylic acid (180 mg, 7.34 mmol, 1.0 equiv.) was added to DMF (N,N-dimethylformamide) (3 mL), followed by HATU (335 mg, 8.81 mmol, 1.2 equiv.), triethylamine (285 mg, 22 mmol, 3.0 equiv.), and trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (205 mg, 8.81 mmol, 1.2 equiv.), and the mixture was stirred at room temperature at 25°C for 16 h. After completion of the reaction, the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / L NH4HCO3 in water, MeCN) and lyophilized to obtain trans-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-((2-methoxyphenyl)amino)pyrimidin-4-yl)methanone (60.2 mg, 17.8%). LCMS (ESI) [M+H]+ = 460.4; 1 H NMR (400MHz, DMSO-d6) δ9.14 (d, J=7.2Hz, 1H), 8.56 (dd, J=8.4Hz, 0.8Hz, 1H), 7 .84(d, J=7.2Hz, 1H), 7.17-7.03(m, 6H), 6.99-6.95(m, 1H), 6.87(s, 1H), 4.79(d d, J=34.4Hz, 4.0Hz, 1H), 4.50-4.33(m, 1H), 3.86-3.80(m, 5H), 3.76-3.60(m, 2 H), 3.06-2.79(m, 6H), 2.67-2.58(m, 1H), 1.87-1.73(m, 1H), 1.55-1.44(m, 1H).

[0843] Example 106

[0844] Preparation of trans-1-(3-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0845]

[0846] Step 1: Preparation of tert-butyl (1-acetylpiperidin-3-yl)carbamate:

[0847]

[0848] Compound 3-tert-butoxycarbonylaminopiperidine (1.2 g, 6.0 mmol, 1.0 equiv.) was dissolved in DCM (20 mL) and cooled to 0 °C in an ice water bath. Et3N (1.5 mL, 10.8 mmol, 1.8 equiv.) was added, followed by acetyl chloride (0.6 mL, 8.4 mmol, 1.4 equiv.). The reaction was stirred at 0 °C to room temperature overnight for 15 h. After LCMS indicated the reaction was complete, the mother liquor was concentrated, diluted with ethyl acetate (30 mL), washed with 0.5 N HC1 (15 mL), water (30 mL), and saturated brine (30 mL), dried over anhydrous sodium sulfate for 10 min, filtered, and concentrated to give tert-butyl (1-acetylpiperidin-3-yl)carbamate (800 mg, 55%) as a yellow solid. LCMS (ESI) [M+H] + = 243.3; 1 H NMR (400 MHz, DMSO-d6) δ 6.96 - 6.83 (m, 1H), 4.19 - 3.70 (m, 1H), 3.60 (t, J = 12.4 Hz, 1H), 3.32 - 3.02 (m, 2H), 2.98 - 2.90 (m, 1H), 1.98 - 1.91 (m, 3H), 1.81 - 1.79 (m, 1H), 1.71 - 1.63 (m, 1H), 1.40 - 1.38 (m, 9H), 1.35 - 1.23 (m, 2H).

[0849] Second Step: Preparation of 1-(3-aminopiperidin-1-yl)ethan-1-one:

[0850]

[0851] The starting material tert-butyl (1-acetylpiperidin-3-yl)carbamate (800 mg, 3.31 mmol, 1.0 equiv.) was dissolved in methanol (10 mL) at room temperature, and 4 M HC1 / dioxane (10 mL) was added. The reaction was stirred at room temperature for 14 h. After LCMS indicated the reaction was complete, the mother liquor was concentrated to give the title compound 1-(3-aminopiperidin-1-yl)ethan-1-one (700 mg, 94.5%) as a white oily solid.

[0852] Third Step: Preparation of methyl 6-((1-acetylpiperidin-3-yl)amino)pyrimidine-4- carboxylate:

[0853]

[0854] The starting material, methyl 6-chloro-pyrimidine-4-carboxylate (100 mg, 0.58 mmol, 1.0 equiv.), was added to acetonitrile (3 mL), followed by the addition of 1-(3-aminopiperidin-1-yl)ethan-1-one (155 mg, 0.87 mmol, 1.5 eq) and (N,N-diisopropylethylamine) (224 mg, 1.74 mmol, 3.0 equiv.), and the mixture was stirred at 90°C for 12 h. After completion of the reaction, as determined by LCMS, the mixture was cooled to room temperature (18°C), water (5 mL) was added, and the mixture was extracted three times with dichloromethane:methanol (V / V=10 / 1) (5 mL×3). The organic phases were combined, filtered, and concentrated. The crude product was separated and purified by flash chromatography (silica gel, dichloromethane:methanol (V / V=8 / 1)) to afford the title compound as a yellow solid (80 mg, 49.6%). LCMS (ESI) [M+H]+=279.28.

[0855] Step 4: Preparation of 6-((1-acetylpiperidin-3-yl)amino)pyrimidine-4-carboxylic acid:

[0856]

[0857] The raw material methyl 6-((1-acetylpiperidin-3-yl)amino)pyrimidine-4-carboxylate (150 mg, 0.54 mmol, 1.0 equiv.) was added to water (1 mL) and methanol (1.0 mL) at room temperature (28°C), and lithium hydroxide (52 mg, 2.16 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated to 1 mL and the pH was adjusted to 1-2 with 1 M hydrochloric acid. The aqueous phase was lyophilized to obtain the title compound (153 mg, yield >90%) as a yellow solid.

[0858] Step 5: Preparation of trans-1-(3-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0859]

[0860] The starting material 6-((1-acetylpiperidin-3-yl)amino)pyrimidine-4-carboxylic acid (130 mg, 0.49 mmol, 1.0 equiv.) was added to DMF (N,N-dimethylformamide) (3 mL), followed by T3P (1-propylphosphonic anhydride) (mass fraction 50% in ethyl acetate) (623 mg, 0.98 mmol, 2.0 equiv.), triethylamine (99 mg, 0.98 mmol, 2.0 equiv.), trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (136 mg, 0.59 mmol, 1.20 equiv.) and stirred at room temperature 25 °C for 14 h. After the reaction was detected to be completed by LCMS, water (5 mL) was added, and dichloromethane:methanol (V / V = 10 / 1) (5 mL x 3) was extracted three times, the organic phase was combined, filtered, concentrated, and the crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile), and freeze-dried to obtain the title compound (4 mg, yield: 1.7%). LCMS (ESI) [M+H]+= 479.3; 1 H NMR (400 MHz, MeOD-d4) δ 8.54-8.47 (m, 1H), 7.12-7.06 (m, 4H), 6.66-6.64 (m, 1H), 4.73-4.70 (m, 1H), 4.57-4.53 (m, 1H), 4.26-4.05 (m, 1H), 4.01-3.71 (m, 7H), 3.27-3.13 (m, 2H), 3.06-2.87 (m, 6H), 2.77-2.74 (m, 2H), 2.15-2.03 (m, 5H), 1.91-1.80 (m, 2H), 1.72-1.58 (m, 3H).

[0861] Example 107

[0862] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)methanone:

[0863]

[0864] First step: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)methanone:

[0865]

[0866] trans-(6-chloropyrimidin-4-yl)(4-(3,4-dihydroisoquinolin-2(1H)-yl)-5-hydroxyazepin-1-yl)methanone (50 mg, 0.13 mmol, 1.0 equiv.), 1-methylsulfonylpiperidin-4-amine hydrochloride (58 mg, 0.27 mmol, 2.0 equiv.), Pd(OAc)2 (palladium acetate) (CAS: 462-08-8) (6 mg, 0.03 mmol, 0.2 equiv.) v.), BINAP (1,1′-binaphthyl-2,2′-bis(diphenylphosphine)) (CAS: 98327-87-8) (34 mg, 0.05 mmol, 0.4 equiv.), and Cs2CO3 (cesium carbonate) (CAS: 534-17-8) (219 mg, 0.67 mmol, 5.0 equiv.) were dissolved in 1,4-dioxane (1,4-dioxane) (1 mL) and reacted at 80°C under nitrogen for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by preparative HPLC (C18, 10 mmol / L aqueous NH4HCO3 solution, acetonitrile) to give the title compound (23.1 mg, 33.5%). LCMS (ESI) [M+H] + =515.35; 1 H NMR (400MHz, CDCl3) δ 8.60-8.49 (m, 1H), 7.19-7.10 (m, 3H), 7.07-6.99 (m, 1H), 6.67-6.53 (m, 1H), 5.37-5.13 (m, 1H), 4.71 (d, J = 13.3Hz, 1H), 4.34-3.66 (m, 8H), 3.13-2.86 (m, 7H), 2.82 (s, 3H), 2.79-2.60 (m, 2H), 2.15 (d, J=13.0Hz, 2H), 2.06-1.83 (m, 2H), 1.65-1.57 (m, 2H).

[0867] Example 108

[0868] Preparation of trans-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-((3-(pyrrolidin-1-yl)phenyl)amino)pyrimidin-4-yl)methanone:

[0869]

[0870] Step 1: Preparation of trans-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-((3-(pyrrolidin-1-yl)phenyl)amino)pyrimidin-4-yl)methanone:

[0871]

[0872] Trans-(6-chloropyrimidin-4-yl)(4-(3,4-dihydroisoquinolin-2(1H)-yl)-5-hydroxyazepin-1-yl)methanone (50 mg, 0.13 mmol, 1.0 equiv.), 3-pyrrolidine-1-aniline (44 mg, 0.27 mmol, 2.0 equiv.), Pd(OAc)2 (palladium acetate) (6 mg, 0.03 mmol, 0.2 equiv.), BINAP (1,1′-binaphthyl-2,2′-bisdiphenylphosphine) (33 mg, 0.05 mmol, 0.4 equiv.) and Cs2CO3 (cesium carbonate) (87 mg, 0.27 mmol, 2.0 equiv.) were dissolved in 1,4-dioxane (1 mL) and reacted at 80°C under nitrogen protection for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to obtain the title compound (14.0 mg, 21.0%). LCMS (ESI) [M+H] + =499.42; 1 H NMR (400MHz, CDCl3) δ8.65-8.61 (m, 1H), 7.25-7.19 (m, 1H), 7.18-7.09 (m, 4H), 7. 05-6.94(m, 2H), 6.61-6.57(m, 1H), 6.48-6.41(m, 2H), 5.05-4.67(m, 1H), 4.22-4 .02(m, 1H), 4.00-3.83(m, 2H), 3.77-3.62(m, 2H), 3.35-3.23(m, 4H), 3.09-3.00( m, 1H), 2.992.55 (m, 6H), 2.05-1.98 (m, 4H), 1.99-1.94 (m, 1H), 1.88-1.80 (m, 1H).

[0873] Example 109

[0874] Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)methanone:

[0875]

[0876] Step 1: Preparation of methyl 6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-4-carboxylate:

[0877]

[0878] 4-Aminotetrahydropyran (141 mg, 1.39 mmol, 1.2 equiv.) and methyl 6-chloropyrimidine-4-carboxylate (200 mg, 1.1 δ mmol, 1 equiv.) were dissolved in acetonitrile (4 mL). DIPEA (N,N-diisopropylethylamine) (600 mg, 4.64 mmol, 4.0 equiv.) was added and stirred at 70°C for 4 hours. After completion of the reaction, as monitored by LCMS, the solvent was evaporated to dryness and the product was purified by flash chromatography (silica gel, MeOH:DCM = 0-4%) to afford methyl 6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-4-carboxylate (180 mg, 65.5% yield) as a yellow oil. LCMS (ESI) [M+H] + =238.19.

[0879] Step 2: Preparation of 6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-4-carboxylic acid:

[0880]

[0881] The raw material, methyl 6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-4-carboxylate (180 mg, 0.76 mmol, 1.0 equiv.), was dissolved in methanol (1.5 mL) and a 3.5 M aqueous NaOH solution (0.15 mL) was added. The reaction was stirred at room temperature (20-25 degrees) for 2 hours. TLC monitored the reaction completion. 1 M hydrochloric acid was added to adjust the pH to 5-6, and the solvent was evaporated to obtain the crude product 6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-4-carboxylic acid, which was used directly in the next step. LCMS (ESI) [M+H] + =224.16.

[0882] Step 3: Preparation of trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)methanone:

[0883]

[0884] The reactant, 6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-4-carboxylic acid (70 mg, 0.31 mmol, 1 equiv.), was dissolved in DMF (N,N-dimethylformamide) (1.5 ml). A 50% mass fraction of T3P (1-n-propylphosphonic anhydride) in ethyl acetate (400 mg, 0.63 mmol, 2.0 equiv.) and Et3N (triethylamine) (159 mg, 1.57 mmol, 5.0 equiv.) were added. Then, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (72.8 mg, 0.31 mmol, 1.0 equiv.) was added. The reaction was stirred at room temperature (20-25°C) for 1 hour. The solvent was dried by rotary evaporation, and the crude product was purified by preparative HPLC reverse phase column (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to give the product trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)methanone (55.2 mg, 40.2% yield). LCMS (ESI) [M+H] + =438.47; 1 H NMR (400MHz, CDCl3) δ8.62-8.46(m, 1H), 7.20-7.08(m, 3H), 7.08-6.98(m, 1H ), 6.67-6.49(m, 1H), 5.24-4.58(m, 2H), 4.31-4.14(m, 1H), 4.03-3.96(m, 3H) , 3.81-3.69(m, 2H), 3.60-3.46(m, 2H), 3.12-2.98(m, 2H), 2.95-2.87(m, 2H) , 2.79-2.58(m, 2H), 2.07-1.96(m, 3H), 1.94-1.78(m, 1H), 1.77-1.50(m, 5H).

[0885] Example 110

[0886] Preparation of trans-tert-butyl 4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidine-1-carboxylate:

[0887]

[0888] Step 1: Preparation of methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)pyrimidine-4-carboxylate:

[0889]

[0890] Methyl 6-chloropyrimidine-4-carboxylate (1 g, 5.80 mmol, 1.0 equiv.), 1-tert-butoxycarbonyl-4-aminopiperidine hydrochloride (1.65 g, 6.95 mmol, 1.2 equiv.), and DIPEA (N,N-diisopropylethylamine) (3.00 g, 23.18 mmol, 4.0 equiv.) were dissolved in MeCN (acetonitrile) (30 mL) and reacted at 90°C for 15 hours. The reaction mixture was concentrated, and the crude product was purified by flash chromatography (silica gel, PE:EA = 3:2) to yield the title compound (1.82 g, 93.4%) as a yellow solid. LCMS (ESI) [M+H] + =337.31;

[0891] Step 2: Preparation of 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)pyrimidine-4-carboxylic acid:

[0892]

[0893] Methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)pyrimidine-4-carboxylate (1.8 g, 5.35 mmol, 1.0 equiv.) and LiOH (lithium hydroxide) (0.26 g, 10.70 mmol, 2.0 equiv.) were dissolved in THF (tetrahydrofuran) (27 mL) and H2O (water) (9 mL) and reacted at 20°C for 1 hour. The reaction solution was concentrated, diluted with dichloromethane / methanol (3:1), filtered, and the filtrate was concentrated to obtain the crude title compound (2.14 g, yield not calculated) as a yellow solid. LCMS (ESI) [M+H] + =323.2;

[0894] Step 3: Preparation of trans-4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester:

[0895]

[0896] 6-((1-(tert-Butoxycarbonyl)piperidin-4-yl)amino)pyrimidine-4-carboxylic acid (2.1 g, 6.51 mmol, 1.0 equiv.), trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (2.09 g, 8.99 mmol, 1.38 equiv.), T3P (1-n-propylphosphonic anhydride) in ethyl acetate (mass fraction 50%) (8.29 g, 13.03 mmol, 2.0 equiv.) and TEA (triethylamine) (3.30 g, 32.57 mmol, 5.0 equiv.) were dissolved in DMF (N,N-dimethylformamide) (30 mL) and reacted at 20°C for 17 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was concentrated. The crude product was separated and purified by flash chromatography (silica gel, DCM:MeOH = 20:1) to obtain the crude title compound (0.98 g, 28.0%) as a yellow solid. 30 mg of the crude title compound was separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous NH4HCO3, acetonitrile) to obtain the title compound (19.4 mg). LCMS (ESI) [M+H] + =537.6; 1 H NMR (400MHz, CDCl3) δ8.57-8.51(m, 1H), 7.19-7.08(m, 3H), 7.06-6.99(m, 1H), 6.63-6.54(m, 1H), 5.17-4.66(m, 2H), 4.32-3.84(m, 6H), 3.77-3.62(m, 2H), 3.17-2.80(m, 7H), 2.79-2.54(m, 2H), 2.08-1.81(m, 3H), 1.76-1.65(m, 1H), 1.47(s, 9H), 1.44-1.35(m, 2H).

[0897] Example 111

[0898] Preparation of trans-1-(4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-methylpyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0899]

[0900] Step 1: Preparation of ethyl 6-((1-acetylpiperidin-4-yl)amino)-2-methylpyrimidine-4-carboxylate:

[0901]

[0902] Ethyl 6-chloro-2-methylpyrimidine-4-carboxylate (200 mg, 1 mmol, 1 equiv.), 1-acetylpiperidin-4-amine hydrochloride (240 mg, 1.2 mmol, 1.2 equiv.), palladium acetate (22.4 mg, 0.1 mmol, 0.1 equiv.), BINAP (1,1′-binaphthyl-2,2′-bisdiphenylphosphine) (124.5 mg, 0.2 mmol, 0.2 equiv.), and cesium carbonate (814.55 mg, 2.5 mmol, 2.5 equiv.) were dissolved in 1,4-dioxane (5 ml). The atmosphere was replaced with nitrogen three times, and the mixture was heated and stirred at 110° C. overnight (16 h). Extract with ethyl acetate three times, each time with 10 mL. The combined ethyl acetate phases were washed once with 10 mL of water and once with 10 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate for 10 minutes and filtered. The crude product was purified by column chromatography using DCM:MeOH = 100:1 to obtain ethyl 6-((1-acetylpiperidin-4-yl)amino)-2-methylpyrimidine-4-carboxylate (130 mg, 42.6%) as a white solid. LCMS (ESI) [M+H] + =307.3.

[0903] Step 2: Preparation of 6-((1-acetylpiperidin-4-yl)amino)-2-methylpyrimidine-4-carboxylic acid:

[0904]

[0905] Ethyl 6-((1-acetylpiperidin-4-yl)amino)-2-methylpyrimidine-4-carboxylate (120 mg, 0.392 mmol, 1 equiv.) was dissolved in THF (4 mL), followed by the addition of aqueous LiOH (lithium hydroxide) solution (0.39 mL, 0.78 mmol, 2 M (molar concentration), 2 equiv.). The reaction mixture was stirred at room temperature (20-25°C) for 2 h. TLC indicated the reaction was complete. 1 M (molar concentration) hydrochloric acid was added to adjust the pH to 6-7, and the mixture was directly spin-dried to give the crude product, 6-((1-acetylpiperidin-4-yl)amino)-2-methylpyrimidine-4-carboxylic acid (200 mg), as a white solid. LCMS (ESI) [M+H] + =279.0.

[0906] Step 3: Preparation of trans-1-(4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-methylpyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0907]

[0908] To a solution of 6-((1-acetylpiperidin-4-yl)amino)-2-methylpyrimidine-4-carboxylic acid (200 mg, 0.718 mmol, 1 equiv.), HATU (0.4 g, 1.08 mmol, 1.5 equiv.), trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (200 mg, 0.862 mmol, 1.2 equiv.) and DIPEA (0.278 g, 2.16 mmol, 3 equiv.) in DMF (3.5 mL) was stirred at room temperature (20-25 °C) for 2 h. LCMS showed the reaction was completed. The reaction mixture was extracted with ethyl acetate for three times, 10 mL each time, combined the ethyl acetate phase, washed with 10 mL water once, 10 mL saturated brine once, dried over sodium sulfate for 10 min, filtered, the crude product was separated and purified by prep-HPLC (C18, 10 mmol / L NH4HCO3 in water, acetonitrile) to give the title compound (75.3 mg, 21.3%). LCMS (ESI) [M+H] + = 494.0; 1 H NMR (400 MHz, Chloroform-d) δ 7.20 - 7.09 (m, 3H), 7.06 - 6.99 (m, 1H), 6.41 - 6.37 (m, 1H), 5.19 - 4.93 (m, 1H), 4.65 (d, J = 13.4 Hz, 1H), 4.53 (d, J = 13.7 Hz, 1H), 4.22 - 4.03 (m, 2H), 3.94 (d, J = 14.5 Hz, 1H), 3.82 (d, J = 14.0 Hz, 1H), 3.71 (d, J = 14.9 Hz, 2H), 3.31 - 3.11 (m, 1H), 3.14 - 2.98 (m, 2H), 2.98 - 2.78 (m, 3H), 2.77 - 2.55 (m, 2H), 2.51 (d, J = 4.6 Hz, 3H), 2.12 (d, J = 1.8 Hz, 4H), 2.07 - 1.94 (m, 2H), 1.668 - 1.616 (m, 1H), 1.41 (q, J = 12.3, 11.7 Hz, 2H).

[0909] Example 112

[0910] Preparation of trans-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6- (piperidin-4-ylamino)pyrimidin-4-yl)methanone:

[0911]

[0912] Step 1: Preparation of trans-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-(piperidin-4-ylamino)pyrimidin-4-yl)methanone:

[0913]

[0914] tert-Butyl trans-4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidine-1-carboxylate (30 mg, 0.06 mmol, 1.0 equiv.) was dissolved in DCM (dichloromethane) (0.4 mL), followed by the addition of TFA (trifluoroacetic acid) (0.1 mL) and the reaction was allowed to react at 20°C for 0.5 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution and concentrated. The crude product was separated and purified by preparative HPLC (C18, 10 mmol / L aqueous NH4HCO3 solution, acetonitrile) to give the title compound (17.42 mg, 71.4%). LCMS (ESI) [M+H] + =437.5; 1 H NMR (400MHz, DMSO-d6) δ8.46-8.32 (m, 1H), 7.61 (t, J=7.7Hz, 1H), 7.13-7.01 (m, 4H ), 6.51 (s, 1H), 4.79 (dd, J=35.1, 3.9Hz, 1H), 4.40 (dd, J=56.4, 12.7Hz, 1H), 3.93 ( m, 1H), 3.87-3.56 (m, 5H), 2.98 (d, J=12.5Hz, 2H), 2.93-2.87 (m, 1H), 2.85-2.75 (m , 4H), 2.69-2.53(m, 4H), 1.92-1.69(m, 3H), 1.57-1.43(m, 1H), 1.41-1.27(m, 2H).

[0915] Example 113

[0916] Preparation of 1-(4-((6-(trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)-2-methoxyethan-1-one:

[0917]

[0918] Step 1: Preparation of 1-(4-((6-(trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)-2-methoxyethane-1-one:

[0919]

[0920] At room temperature (25° C.) under nitrogen, the starting material (trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-(piperidin-4-ylamino)pyrimidin-4-yl)methanone (30 mg, 0.07 mmol, 1.0 equiv.) was dissolved in DMF (N,N-dimethylformamide) (1.5 mL). 2-Methoxyacetic acid (6 mg, 0.07 mmol, 1.0 equiv.), HATU (2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (39 mg, 0.10 mmol, 1.5 equiv.) and DIPEA (N,N-diisopropylethylamine) (27 mg, 0.20 mmol, 3.0 equiv.) were added, and the mixture was stirred at room temperature (25° C.) for 4 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (5 mL) and concentrated. The crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to obtain the title compound (12.5 mg, 35.8%). LCMS: [M+H] + =509.62; 1 H NMR (400MHz, CDCl3) δ8.64-8.44(m, 1H), 7.21-7.10(m, 3H), 7.07-7.00(m, 1H), 6.72-6.54(m, 1H ), 5.33-4.97(m, 1H), 4.87-4.36(m, 2H), 4.31-4.19(m, 1H), 4.18-4.10(m, 2H), 4.07-4.00(m, 1H) , 3.96-3.87(m, 1H), 3.83-3.71(m, 2H), 3.49-3.39(m, 3H), 3.25-3.07(m, 2H), 3.05-2.92(m, 3H) , 2.91-2.59(m, 4H), 2.17-2.06(m, 2H), 2.05-1.83(m, 2H), 1.76-1.65(m, 2H), 1.51-1.37(m, 2H).

[0921] Example 114

[0922] Preparation of trans-1-(4-((6-(-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)(methyl)amino)piperidin-1-ylethanone:

[0923]

[0924] Step 1: Preparation of methyl 6-((1-acetylpiperidin-4-yl)(methyl)amino)pyrimidine-4-carboxylate:

[0925]

[0926] The starting materials, N-1-acetyl-4-methylaminopiperidine (450 mg, 2.883 mmol, 1 equiv.) and methyl 6-chloropyrimidine-4-carboxylate (597 mg, 3.459 mmol, 1.2 equiv.), were dissolved in acetonitrile (15 ml). DIPEA (N,N-diisopropylethylamine) (1.49 g, 11.53 mmol, 4 equiv.) was added at 25°C, and the mixture was stirred at 90°C for 18 hours. After completion of the reaction, as monitored by LCMS, the solvent was evaporated to dryness and the product was purified by flash chromatography (silica gel, MeOH:DCM = 0-4%) to afford methyl 6-((1-acetylpiperidin-4-yl)(methyl)amino)pyrimidine-4-carboxylate (900 mg, yield not calculated) as a light yellow oil. LCMS (ESI) [M+1] + =293.3.

[0927] Step 2: Preparation of 6-((1-acetylpiperidin-4-yl)(methyl)amino)pyrimidine-4-carboxylic acid:

[0928]

[0929] The starting material, methyl 6-((1-acetylpiperidin-4-yl)(methyl)amino)pyrimidine-4-carboxylate (850 mg, 2.908 mmol, 1 equiv.), was dissolved in acetonitrile (15 ml) and TMSOK (potassium trimethylsilanol) (450 mg, 3.4876 mmol, 1.2 equiv.) was added. Stirring was carried out at room temperature at 25 degrees for 1 hour. The reaction was monitored for completion by TLC. The reaction solution was filtered and the filter cake was collected. After the filter cake was dissolved in water, 1 M (molar concentration) hydrochloric acid was added to adjust the pH to 5-6. The solution was spin-dried and dissolved in dichloromethane and methanol. Solid impurities were removed by filtration, and the filtrate was concentrated to give 6-((1-acetylpiperidin-4-yl)(methyl)amino)pyrimidine-4-carboxylic acid (900 mg crude product) as a white solid, which was used directly in the next step. LCMS (ESI) [M+1] + =279.3.

[0930] Step 3: Preparation of trans-1-(4-((6-(-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)(methyl)amino)piperidin-1-ylethanone:

[0931]

[0932] The reactant, 6-((1-acetylpiperidin-4-yl)(methyl)amino)pyrimidine-4-carboxylic acid (100 mg, 0.359 mmol, 1 equiv.), was dissolved in DMF (N,N-dimethylformamide) (2 ml). HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (205 mg, 0.539 mmol, 1.5 equiv.) and DIPEA (N,N-diisopropylethylamine) (140 mg, 1.077 mmol, 3 equiv.) were added. After stirring for 5 minutes, trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (100 mg, 0.4308 mmol, 1.2 equiv.) was added. The reaction was stirred at room temperature (25°C) for 1 hour. The reaction was monitored by LCMS, indicating the disappearance of the starting material. The reaction mixture was quenched with water and extracted several times with dichloromethane:methanol = 10:1, followed by concentration to obtain the crude product. The crude product was purified twice by preparative TLC (1 mm, DCM:MeOH = 10:1, THF:Acetone = 1:1), followed by preparative HPLC with reversed-phase column chromatography (C18, 10 mmol / L aqueous NH4HCO3, acetonitrile) to obtain the product (60 mg, 100% purity, 33.9% yield). LCMS (ESI) [M+1] + =493.3; 1 H NMR (400MHz, DMSO-d6) δ8.51 (dd, J=9.5, 1.1Hz, 1H), 7.11-7.06 (m, 3H), 7.05-7.01 (m, 1 H), 6.80-6.65 (m, 1H), 4.88-4.69 (m, 1H), 4.44-4.29 (m, 2H), 3.98-3.80 (m, 1H), 3.79-3. 74(m, 2H), 3.67-3.60(m, 2H), 3.30-3.27(m, 1H), 3.19-3.17(m, 1H), 3.04-2.95(m, 1H), 2 .93-2.75(m, 8H), 2.69-2.56(m, 2H), 2.03(s, 3H), 1.90-1.67(m, 2H), 1.67-1.45(m, 4H).

[0933] Example 115

[0934] Preparation of trans-1-(4-(2-((6-(-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)ethanone:

[0935]

[0936] Step 1: Preparation of tert-butyl ((2-acetylpiperidin-4-yl)ethyl)carbamate:

[0937]

[0938] The starting material, tert-butyl N-(4-piperidinylethyl)carbamate (500 mg, 2.19 mmol, 1 equiv.), was dissolved in dichloromethane (15 ml). TEA (triethylamine) (670 mg, 6.57 mmol, 3 equiv.) and acetic anhydride (223 mg, 2.19 mmol, 1 equiv.) were added at 25°C. After reacting overnight at room temperature at 25°C, the reaction was quenched by adding water. Extraction with dichloromethane was performed, and the organic phase was dried and concentrated to give the crude product, tert-butyl ((2-acetylpiperidin-4-yl)ethyl)carbamate (650 mg, not included in the crude yield), as a light yellow oil. LCMS (ESI) [M+1] + =271.3.

[0939] Step 2: Preparation of 1-(4-(2-aminoethyl)piperidin-1-yl)ethanone trifluoroacetate:

[0940]

[0941] The starting material, tert-butyl ((2-acetylpiperidin-4-yl)ethyl)carbamate (600 mg crude, 2.219 mmol, 1 equiv.) was dissolved in dichloromethane (9 ml) and trifluoroacetic acid (3 ml) was added. The reaction was stirred at room temperature (25°C) for 1 hour. TLC monitored the reaction completion. The reaction solution was directly concentrated to obtain the product, 1-(4-(2-aminoethyl)piperidin-1-yl)ethanone trifluoroacetate (700 mg crude), as a white solid. LCMS (ESI) [M+1] + =171.2.

[0942] Step 3: Preparation of methyl 6-((2-(1-acetylpiperidin-4-yl)ethyl)amino)pyrimidine-4-carboxylate:

[0943]

[0944] 1-(4-(2-Aminoethyl)piperidin-1-yl)ethanone trifluoroacetate (650 mg crude, 2.288 mmol, 1 equiv.) and methyl 6-chloropyrimidine-4-carboxylate (474 ​​mg, 2.746 mmol, 1.2 equiv.) were dissolved in acetonitrile (12 ml), and DIPEA (N,N-diisopropylethylamine) (1.18 g, 9.154 mmol, 4 equiv.) was added. The mixture was stirred at 90°C for 18 hours. After completion of the reaction, as monitored by LCMS, the solvent was evaporated to dryness and the product was purified by flash chromatography (silica gel, MeOH:DCM = 0-4%) to afford methyl 6-((2-(1-acetylpiperidin-4-yl)ethyl)amino)pyrimidine-4-carboxylate (1 g, yield not calculated) as a light yellow oil. LCMS (ESI) [M+1] + =307.2;

[0945] Step 4: Preparation of 6-((2-(1-acetylpiperidin-4-yl)ethyl)amino)pyrimidine-4-carboxylic acid:

[0946]

[0947] The starting material, methyl 6-((2-(1-acetylpiperidin-4-yl)ethyl)amino)pyrimidine-4-carboxylate (900 mg, 2.928 mmol, 1 equiv.), was dissolved in acetonitrile (15 ml), and TMSOK (potassium trimethylsilanol) (450 mg, 3.514 mmol, 1.2 equiv.) was added. The mixture was stirred at room temperature at 25°C for 1 hour. The reaction was monitored for completion by TLC. The reaction mixture was filtered, and the filter cake was collected. The filter cake was dissolved in water, and 1 M hydrochloric acid was added to adjust the pH to 5-6. The solution was then spin-dried and dissolved in dichloromethane and methanol. Solid impurities were removed by filtration, and the filtrate was concentrated to yield 6-((2-(1-acetylpiperidin-4-yl)ethyl)amino)pyrimidine-4-carboxylic acid (580 mg crude product) as a pale yellow solid, which was used directly in the next step.

[0948] Step 5: Preparation of trans-1-(4-(2-((6-(-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)ethanone:

[0949]

[0950] The reactant 6-((2-(l-acetylpiperidin-4-yl)ethyl)amino)pyrimidine-4-carboxylic acid (100 mg, 0.341 mmol, 1 equiv.) was dissolved in DMF (N,N-dimethylformamide) (2 ml), and HATU (2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (195 mg, 0.515 mmol, 1.5 equiv.) and DIPEA (N,N-diisopropylethylamine) (130 mg, 1.023 mmol, 3 equiv.) were added. After stirring for 5 minutes, trans-4-(3,4-dihydroisoquinolin-2(lH)-yl)piperidin-3-ol (96 mg, 0.4092 mmol, 1.2 equiv.) was added. The reaction was stirred at room temperature (20-25 °C) for 1 hour. The reaction was monitored by LCMS, and the starting material disappeared. The reaction solution was quenched by adding water and extracted with dichloromethane:methanol = 10: 1 several times, followed by concentration to obtain a crude product. The crude product was purified by preparative TLC twice (1 mm, DCM:MeOH = 10: 1, THF:acetone = 1: 1), and then purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile) to obtain the title compound product (52 mg, yield 30%). LCMS (ESI) [M+1] + = 507.8; 1 H NMR (400 MHz, DMSO-d6) δ 8.51-8.47 (m, 1H), 7.71-7.63 (m, 1H), 7.11-7.01 (m, 4H), 6.59-6.53 (m, 1H), 4.76 (dd, J = 35.9, 3.8 Hz, 1H), 4.56-4.41 (m, 2H), 3.89-3.55 (m, 5H), 3.37-3.36 (m, 1H), 3.04-2.88 (m, 3H), 2.86-2.76 (m, 4H), 2.69-2.53 (m, 2H), 1.97 (s, 3H), 1.84-1.70 (m, 3H), 1.62-1.51 (m, 1H), 1.50-1.45 (m, 3H), 1.08-1.01 (m, 1H), 0.98-0.94 (m, 1H).

[0951] Example 116

[0952] Preparation of trans-(6-((l-(cyclopropanecarbonyl)piperidin-4-yl)amino)pyrimidin-4-yl)(4-(3,4-dihydroisoquinolin-2(lH)-yl)-3-hydroxypiperidin-l-yl)methanone:

[0953]

[0954] Step 1: Preparation of trans-(6-((1-(cyclopropanecarbonyl)piperidin-4-yl)amino)pyrimidin-4-yl)(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone:

[0955]

[0956] trans-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)(6-(piperidin-4-ylamino)pyrimidin-4-yl)methanone (150 mg, 0.07 mmol, 1.0 equiv.) was dissolved in DMF (N,N-dimethylformamide) (1.5 mL), followed by the addition of Cs2CO3 (cesium carbonate) (45 mg, 0.14 mmol, 2.0 equiv.) and cyclopropylcarbonyl chloride (7 mg, 0.07 mmol, 1.0 equiv.). The mixture was allowed to react at 20°C for 0.5 h. The reaction mixture was filtered and the filtrate was concentrated. The crude product was separated and purified by preparative HPLC (C18, 10 mmol / L aqueous NH4HCO3 solution, acetonitrile) to obtain the title compound (22.07 mg, 63.6%). LCMS (ESI) [M+H] + =505.6; 1 H NMR (400MHz, DMSO-d6) δ8.49-8.38 (m, 1H), 7.70-7.61 (m, 1H), 7.12-7.01 (m, 4H), 6.53 (s, 1H), 4.86-4.72 (m, 1H), 4.53-4.05 (m, 4H), 3.89-3.56(m, 4H), 3.31-3.20(m, 1H), 3.08-2.72(m, 7H), 2.68-2.55(m, 1H), 2.07-1.69(m, 4H), 1.56-1.19(m, 3H), 0.81-0.63(m, 4H).

[0957] Example 117

[0958] Preparation of trans-1-(4-((2-chloro-6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0959]

[0960] Step 1: Preparation of 6-((1-acetylpiperidin-4-yl)amino)-2-chloropyrimidine-4-carboxylic acid:

[0961]

[0962] The starting material 6-((1-acetylpiperidin-4-yl)amino)-2-chloropyrimidine-4- carboxylic acid methyl ester (500 mg, 1.60 mmol, 1.0 equiv.) was added to water (1.6 mL), tetrahydrofuran (3.0 mL) and methanol (3.0 mL), lithium hydroxide (76.6 mg, 3.20 mmol, 2.0 equiv.) was added, stirred at room temperature (25-30 degrees) for 1 h, after the reaction was completed by LCMS detection, the reaction liquid was concentrated to remove the organic solvent, adjusted to pH = 3 with 1M (molar concentration) hydrochloric acid, the system was extracted with dichloromethane:methanol (V / V = 10 / 1) (30 mL x 5) three times, the organic phase was combined, dried, filtered, and concentrated to obtain the crude product 6-((1-acetylpiperidin-4-yl)amino)-2-chloropyrimidine-4-carboxylic acid (1.5 g, crude) as a yellow solid. LCMS (ESI) [M+H] + = 299.2.

[0963] Second step: preparation of trans-1-(4-((2-chloro-6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3- hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0964]

[0965] The starting material 6-((1-acetylpiperidin-4-yl)amino)-2-chloropyrimidine-4- carboxylic acid (1.4 g, 7.34 mmol, 1.0 equiv.) was added to DMF (N,N-dimethylformamide) (10 mL), then HATU (CAS: 148893-10-1) (1.78 g, 4.69 mmol, 1.0 equiv.), N,N-diisopropylethylamine (1.82 g, 14.06 mmol, 3.0 equiv.) were added, stirred at room temperature 25°C for 2 h. After the reaction was completed by LCMS detection, the system was removed after the solvent, a solid was precipitated, filtered and dried to obtain the crude product 4 g. 180 mg of the crude product was separated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 aqueous solution, acetonitrile), and freeze-dried to obtain the compound trans-1-(4-((2-chloro-6-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3- hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one (18 mg). LCMS (ESI) [M+H]+ = 513.5; 1H NMR (400MHz, DMSO-d6) δ8.28-8.12(m, 1H), 7.10-7.02(m, 4H), 6.78-6.47(m, 1H) , 4.83-4.74(m, 1H), 4.46-4.21(m, 2H), 4.05(s, 1H), 3.86-3.77(m, 3H), 3.72-3.5 8(m, 2H), 3.23-3.17(m, 1H), 3.03(t, J=12.0Hz, 1H), 2.91-2.78(m, 6H), 2.68-2. 58 (m, 1H), 2.01 (s, 3H), 1.94-1.73 (m, 3H), 1.55-1.34 (m, 2H), 1.31-1.22 (m, 1H).

[0966] Example 118

[0967] Preparation of trans-1-(4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-(dimethylamino)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0968]

[0969] Step 1: Preparation of trans-1-(4-((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-(dimethylamino)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[0970]

[0971] The starting material, trans-1-(4-((2-chloro-6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one (2 g, 3.9 mmol, 1 equiv.), was added to n-butanol (10 mL), followed by dimethylamine hydrochloride (3.5 g, 42.92 mmol, 11 equiv.). The mixture was stirred in a microwave oven at 120°C for 1 h. After completion of the reaction, the crude product was separated and purified by preparative HPLC (C18, 10 mmol / L aqueous NH4HCO3 solution, acetonitrile), and lyophilized to obtain the title compound (7.16 mg, 0.4% yield). LCMS(ESI)[M+H]+=522.6;1H NMR (400MHz, CD3OD) δ7.11-7.08 (m, 3H), 7.06-7.03 (m, 1H), 5.83 (d, J=8.0Hz, 1H), 4.76-4.52 (m, 3H), 4.38 (d, J=13.6Hz, 1H), 4.0 7-3.76 (m, 5H), 3.13-3.11 (m, 6H), 3.07-2.64 (m, 8H), 2.12-2.11 (m, 4H), 2.04-1.87 (m, 2H), 1.72-1.65 (m, 1H), 1.51-1.40 (m, 2H).

[0972] Example 119

[0973] trans-1-(4-((6-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)thio)piperidin-1-yl)ethan-1-one

[0974]

[0975] Step 1: Preparation of methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)thio)pyrimidine-4-carboxylate:

[0976]

[0977] Compound 4-mercapto-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.38 mmol, 1.0 equiv.) and methyl 6-chloropyrimidine-4-carboxylate (285.8 mg, 1.66 mmol, 1.2 equiv.) were dissolved in acetonitrile (7.0 mL), replaced with nitrogen three times, and then DIEA (N,N-diisopropylethylamine) (535 mg, 4.14 mmol, 3.0 equiv.) was added. The reaction system was stirred at 90 °C for 16 h. TLC detection showed that the reaction was complete. Water (30 mL) was added to the reaction system, extracted with ethyl acetate three times (3 x 20 mL), the organic phase was combined, washed with saturated sodium chloride solution (20 mL) once, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated. Purification by column chromatography (PE:EA = 70:30) gave 430 mg of methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)thio)pyrimidine-4-carboxylate, a gray solid, with a yield of 88.3%. LCMS (ESI): m / z = 354.29; 1 HNMR (400MHz, ) δ 9.10 (d, J = 1.3 Hz, 1H), 7.88 (d, J = 1.3 Hz, 1H), 4.21-4.04 (m, 1H), 3.89 (s, 3H), 3.86-3.76 (m, 2H), 3.07 (s, 2H), 2.10-1.97 (m, 2H), 1.61-1.48 (m, 2H), 1.40 (s, 9H).

[0978] Second step: Preparation of methyl 6-(piperidin-4-ylthio)pyrimidine-4-carboxylate:

[0979]

[0980] Compound methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)thio)pyrimidine-4-carboxylate (405 mg, 1.15 mmol, 1.0 equiv.) was dissolved in dichloromethane (6.0 mL), and then trifluoroacetic acid (1.5 mL) was added. The reaction was stirred at 16 °C for 1 h, and TLC detection showed that the reaction was complete. The solvent was rotary evaporated to give 280 mg of methyl 6-(piperidin-4-ylthio)pyrimidine-4-carboxylate, a yellow oil, with a yield of 96.5%. LCMS (ESI): m / z = 254.16 1 HNMR (400MHz, DMSO) δ 9.11 (d, J = 1.2 Hz, 1H), 7.93 (d, J = 1.3 Hz, 1H), 4.24-4.13 (m, 1H), 3.90 (s, 3H), 3.37-3.27 (m, 2H), 3.19-3.06 (m, 2H), 2.29-2.18 (m, 2H), 1.88-1.77 (m, 2H).

[0981] Step 3: Preparation of methyl 6-((l-acetylpiperidin-4-yl)thio)pyrimidine-4- carboxylate:

[0982]

[0983] Compound methyl 6-(piperidin-4-ylthio)pyrimidine-4-carboxylate (300 mg, 1.18 mmol, 1 equiv.) was added dropwise to sodium hydride (56.8 mg, 1.42 mmol, 1.2 equiv., 60%) in N,N-dimethylformamide (6 mL) and stirred for 0.5 h under ice bath condition. At this temperature, acetyl chloride (111.5 mg, 1.42 mmol, 1.2 equiv.) was added and stirred for another 0.5 h at 16 °C. TLC indicated the reaction was complete. The reaction was slowly added to saturated ammonium chloride solution (1 mL) under ice bath condition and extracted with ethyl acetate three times (3 x 20 mL). The organic phase was combined and washed with saturated sodium chloride solution (20 mL) once, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (PE:EA = 70:30) to give 45 mg of methyl 6-((l-acetylpiperidin-4-yl)thio)pyrimidine-4-carboxylate as a light yellow solid with a yield of (12.9%). LCMS (ESI): m / z = 296.15.

[0984] Step 4: Preparation of 6-((l-acetylpiperidin-4-yl)thio)pyrimidine-4-carboxylic acid:

[0985]

[0986] Compound methyl 6-((l-acetylpiperidin-4-yl)thio)pyrimidine-4-carboxylate (45 mg, 0.152 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (0.1 mL) and lithium hydroxide (7.3 mg, 0.304 mmol, 2.0 equiv., 1 M (molar concentration) aqueous solution with 0.3 mL H2O) was added dropwise. It was stirred for 1 h at 16 °C and TLC indicated the reaction was complete. The pH was adjusted to about 5 with 1 M (molar concentration) hydrochloric acid solution and extracted with ethyl acetate three times (3 x 20 mL). The organic phase was combined and washed with saturated sodium chloride solution (20 mL) once, dried over anhydrous sodium sulfate, filtered and concentrated to give 35 mg of 6-((l-acetylpiperidin-4-yl)thio)pyrimidine-4-carboxylic acid as a light yellow solid with a yield of (81.9%). LCMS (ESI): m / z = 282.2.

[0987] Step 5: Preparation of trans-l-(4-((6-4-(3,4-dihydroisoquinolin-2(lH)-yl)-3- hydroxypiperidine-l-carbonyl)pyrimidin-4-yl)thio)piperidin-l-yl)ethan-l-one:

[0988]

[0989] Compound 6-((1-acetylpiperidin-4-yl)thio)pyrimidine-4-carboxylic acid (35 mg, 0.124 mmol, 1.0 equiv.), trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (28.8 mg, 0.124 mmol, 1.0 equiv.) and HATU (2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (70.7 mg, 0.186 mmol, 1.5 equiv.) were added to DMF (N,N-dimethylformamide) (0.4 mL), and DIEA (N,N-diisopropylethylamine) (48 mg, 0.372 mmol, 3.0 equiv.) was added. The mixture was stirred at 16° C. for 1 h. The reaction of the starting material was determined to be complete by TLC. Water (15 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (3 × 15 mL). The combined organic phases were washed once with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was concentrated and purified by preparative HPLC (C18, 10 mmol / L aqueous NH4HCO3 solution, acetonitrile) to afford 4.7 mg of the title compound in a 7.7% yield. LCMS (ESI): m / z = 496.5. 1 HNMR (400MHz, CDCl3) δ8.91 (dd, J=6.8, 1.3Hz, 1H), 7.41-7.33 (m, 1H), 7.1 8-7.01(m, 4H), 5.08-4.73(m, 1H), 4.37-4.27(m, 1H), 4.26-4.04(m, 2H), 4. 02-3.91(m, 1H), 3.85-3.66(m, 4H), 3.41-3.29(m, 1H), 3.17-2.91(m, 5H), 2 .85-2.61(m, 3H), 2.22-2.09(m, 5H), 2.04-1.95(m, 1H), 1.72-1.68(m, 3H).

[0990] Example 120

[0991] 1-(4-((6-(trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-methoxypyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one

[0992]

[0993] Step 1: Preparation of methyl 6-((1-acetylpiperidin-4-yl)amino)-2-chloropyrimidine-4-carboxylate:

[0994]

[0995] Methyl 2,6-dichloropyrimidine-4-carboxylate (2 g, 9.66 mmol), 1-acetylpiperidin-4-amine hydrochloride (1.9 g, 10.63 mmol), and N,N-diisopropylethylamine (4.99 g, 38.65 mmol) were dissolved in acetonitrile (50 ml). The mixture was stirred at 25°C for 2 h. The mixture was extracted with ethyl acetate three times, each time with 50 mL of ethyl acetate. The combined ethyl acetate phases were washed once with 20 mL of water and once with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate for 10 minutes and filtered. The crude product was purified by column chromatography using DCM:MeOH = 100:1 to obtain methyl 6-((1-acetylpiperidin-4-yl)amino)-2-chloropyrimidine-4-carboxylate (2.8 g, 92%) as a white solid. LCMS (ESI) [M+H] + =313.2.

[0996] Step 2: Preparation of 6-((1-acetylpiperidin-4-yl)amino)-2-chloropyrimidine-4-carboxylic acid:

[0997]

[0998] Methyl 6-((1-acetylpiperidin-4-yl)amino)-2-methylpyrimidine-4-carboxylate (200 mg, 0.639 mmol) was dissolved in THF (4 mL), and then a 2M (molar concentration) aqueous solution of lithium hydroxide (0.64 mL, 1.28 mmol, 2 equiv.) was added. The reaction solution was stirred at room temperature (25°C) for 2 h. TLC indicated that the reaction was complete. 1M (molar concentration) hydrochloric acid was added to adjust the pH to 6-7, and the mixture was directly spin-dried to obtain the crude product 6-((1-acetylpiperidin-4-yl)amino)-2-chloropyrimidine-4-carboxylic acid (400 mg) as a white solid. LCMS (ESI) [M+H] + =299.2.

[0999] Step 3: Preparation of 1-(4-((2-((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-6-(trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[1000]

[1001] 6-((1-acetylpiperidin-4-yl)amino)-2-chloropyrimidine-4-carboxylic acid (380 mg, 1.27 mmol), HATU (2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (725.5 mg, 1.91 mmol), trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (265 mg, 1.14 mmol), and DIPEA (N,N-diisopropylethylamine) (0.822 g, 6.36 mmol) were dissolved in DMF (N,N-dimethylformamide) (5 mL), and the reaction solution was stirred at room temperature (25°C) for 2 h. LCMS showed that the reaction was complete. The mixture was extracted with ethyl acetate three times with 20 mL each time. The ethyl acetate phases were combined, washed once with 10 mL of water and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, and filtered. The crude product was purified by column chromatography using DCM:MeOH = 20:1 to afford 1-(4-((2-((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-6-(trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one (200 mg) as a white solid. LCMS (ESI) [M+H] + =613.3.

[1002] Step 4: Preparation of 1-(4-((6-(trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-methoxypyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one:

[1003]

[1004] (4-((2-((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-6-(trans-4-(3,4- dihydroisoquinolin-2(lH)-yl)-3-hydroxypiperidin-l-ylcarbonyl)pyrimidin-4- yl)amino)piperidin-l-yl)ethan-l-one (130 mg, 0.212 mmol) was dissolved in methanol (4 mL), then sodium methoxide (114.6 mg, 0.84 mmol,) was added. The reaction was stirred at 60 °C for 4 h. LCMS showed the reaction was complete. The reaction was extracted with ethyl acetate for three times, 10 mL each time, the ethyl acetate phase was combined, washed with 10 mL water once, 10 mL saturated brine once, dried over sodium sulfate for 10 min, filtered, the crude product was purified by preparative HPLC (C18) to give 1-(4-((6-(trans-4-(3,4-dihydroisoquinolin-2(lH)-yl)-3- hydroxypiperidin-l-ylcarbonyl)-2-methoxypyrimidin-4-yl)amino)piperidin-l- yl)ethan-l-one (42.61 mg, 39%). LCMS (ESI) [M+H]+=509.3; ¾ NMR (400 MHz, CDC13) δ 7.16 - 7.11 (m, 3 H), 7.04 - 7.02 (m, 1 H), 6.28 (d, J=18.1 Hz, 1 H), 5.10 (d, J=13.1 Hz, 0.3 H), 5.03 - 4.99 (m, 1 H), 4.77 (d, J=13.2 Hz, 0.7 H), 4.56 (d, J=13.7 Hz, 1 H), 4.33 - 4.18 (m, 1 H), 3.95 (d, J=10.5 Hz, 4 H), 3.92 - 3.71 (m, 4 H), 3.25 (t, J=12.9 Hz, 1 H), 3.07 - 3.05 (m, 1 H), 2.97 - 2.93 (m, 3 H), 2.84 (t, J=12.7 Hz, 2 H), 2.72...

Claims

1. A compound represented by formula (II) B, its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs: in, R 1 、R 2 Each occurrence is independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; X is N; Y is selected from -(chemical bond), -O-, -S-, -CO-, -C(R 6 )F-, -CF2-, -SO-, -SO2-, -(CH2) p N(R 6 )-、-N(R 6 )(CH2) p -、-S(O)N(R 6 )-、-S(O)2N(R 6 )-、-N(R 6 )SO-、-N(R 6 )S(O)2-、-C(O)N(R 6 )-、-N(R 6 )C(O)-、-CH(R 6 )-; wherein p=0, 1, 2 or 3; R 6 is selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclic group; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently selected from halogen, hydroxyl, thiol, amino, cyano, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 3-6 substituted by cycloalkyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; Z is selected from -(chemical bond) and -CO-; G 1 is independently selected at each occurrence from hydrogen and halogen; G 2 is hydroxyl group; G 3 is optionally substituted The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R 16 Replaced by, where R 16 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, -R 9 、-OR 9 、-SR 9 、SO(R 9 )、-SO2(R 9 ), -COOR 9 、-NH(R 9 )、-N(R 9 )(R 10 ),-CONHR 9 、-CON(R 9 )(R 10 )、-SONH(R 9 )、-SON(R 9 )(R 10 )、SO2NH(R 9 )、-SO2N(R 9 )(R 10 ); where R 9 、R 10 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 3-6 One or more substituted C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; G 4 Selected from the following groups: optionally substituted C 1-12 Alkyl, optionally substituted C 1-12 Alkenyl, optionally substituted C 1-12 Alkynyl, optionally substituted C 3-12 Cycloalkyl, optionally substituted 4-10 membered heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted 5-10 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R 17 Replacement, R 17 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, carbonyl, -R 11 、-OR 11 、-SR 11 、-NH(R 11 )、-N(R 11 )(R 11 ), Among them, R 11 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 3-6 One or more substituted C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; D is independently selected at each occurrence from a bond, -CH2-, -C(=O)-, -NH-, -N(CH3)-, -O-, -S-, and f is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7 or 8; m＝0； B is N; n=1,E is -C(R 13 )R 13 -, R 13 Each occurrence is independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl; o＝1； The H ring is surrounded by one or more R 15 Independently substituted benzene ring, where R 15 Each occurrence is independently selected from hydrogen, halogen, optionally substituted -R 14 ; Among them, R 14 Each occurrence is independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently selected from halogen, C 1-6 Alkyl, C 3-6 substituted by a cycloalkyl substituent; Among them, the C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-12 Alkenyl and C 1-12 Alkynyl does not include C1 alkenyl and C1 alkynyl.

2. The compound according to claim 1, its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein R 1 、R 2 Each occurrence is independently selected from hydrogen and halogen.

3. The compound according to claim 1, its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein R 1 、R 2 Each occurrence is independently one of hydrogen, halogen, and methyl.

4. The compound according to claim 1, its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein R 1 and R 2 For hydrogen.

5. The compound according to any one of claims 1 to 4, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: Y is selected from -(chemical bond), -O-, -S-, -CO-, -C(R 6 )F-, -CF2-, -SO-, -SO2-, -(CH2) p N(R 6 )-、-N(R 6 )(CH2) p -、-S(O)N(R 6 )-、-S(O)2N(R 6 )-、-N(R 6 )SO-、-N(R 6 )S(O)2-、-C(O)N(R 6 )-、-N(R 6 )C(O)-、-CH(R 6 )-, wherein p=0, 1, 2 or 3; R 6 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group.

6. The compound according to any one of claims 1 to 4, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: Z is -CO-.

7. The compound according to any one of claims 1 to 4, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: G 1 It's hydrogen.

8. The compound according to any one of claims 1 to 4, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: Z is a chemical bond.

9. The compound according to any one of claims 1 to 4, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: G 4 Selected from the following groups: optionally substituted C 3-12 Cycloalkyl, optionally substituted 4-10 membered heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R 17 Replacement, R 17 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, carbonyl, -R 11 、-OR 11 、-SR 11 、-NH(R 11 )、-N(R 11 )(R 11 ), Among them, R 11 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 3-6 One or more substituted C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; D is independently selected from a bond, -CH2-, -C(=O)-, -NH-, -N(CH3)-, -O-, -S- at each occurrence, and f is independently selected from 0, 1 or 2 at each occurrence.

10. The compound according to any one of claims 1 to 4, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: G 4 Selected from: Wherein, there are one or more R 17 Substitution is at any substitutable site of the group.

11. The compound according to any one of claims 1 to 4, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: The H ring is surrounded by one or more R 15 Independently substituted benzene ring, wherein R 15 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl.

12. The compound according to claim 1, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: The compound has the following structure:

13. The compound according to claim 1, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, in, R 13 Each occurrence is independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl; R 15 Selected from hydrogen, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl.

14. The compound according to claim 13, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: R 13 Each occurrence is independently selected from hydrogen and halogen.

15. The compound according to claim 13, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: R 15 is selected from hydrogen and halogen.

16. The compound according to claim 13, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: G 1 It's hydrogen.

17. The compound according to claim 13, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: R 1 、R 2 Each occurrence is independently selected from hydrogen, halogen and methyl.

18. The compound according to claim 13, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: Z is ― (chemical bond).

19. The compound according to claim 13, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: Z is -CO-.

20. The compound according to claim 13 or 19, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: R 16 Each occurrence is independently selected from hydrogen, halogen, -R 9 、-OR 9 、-SR 9 、-SO(R 9 )、-NH(R 9 )、-N(R 9 )(R 10 ), where R 9 、R 10 Each occurrence is independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-6 One or more substituted C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 3-6 cycloalkyl, phenyl and 5-6 membered heteroaryl.

21. The compound according to claim 13 or 19, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: R 16 Each occurrence is independently selected from hydrogen, halogen, methyl, methoxy.

22. The compound according to claim 13 or 19, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: R 16 Each occurrence is independently selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-pentyloxy, isopentyl, trifluoromethyl, methoxy, amino, methylamino, dimethylamino, phenyl, pyridyl, -OCF3, -SCH(CH3)2, -S(O)CH(CH3)2.

23. The compound of claim 13, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: Y is selected from -(chemical bond), -NH-, -O-, -S-, -SO-, -SO2-, -N(CH3)-, -S(O)NH-, -S(O)2NH-, -NHSO- and -NHS(O)2-.

24. The compound of claim 13, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: Y is selected from -(chemical bond), -S-, -O- and -NH-.

25. The compound of claim 13, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: G 4 Selected from Wherein, there are one or more R 17 The substituent is located at any substitutable position of the group.

26. The compound of claim 25, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: R 17 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, carbonyl, -R 11 、-OR 11 、-SR 11 、 27. The compound according to claim 26, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: R 17 for 28. The compound of claim 26, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: R 11 Each occurrence is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, C 1-6 One or more optionally substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl.

29. The compound of claim 28, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: R 11 Each occurrence is independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 One or more optionally substituted C 1-6 Alkyl or phenyl.

30. The compound of claim 27, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: R 11 is selected from trifluoromethyl, difluoromethyl, trifluoroethyl, difluoroethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, a 4-6 membered heterocyclyl and a phenyl group.

31. The compound of claim 13, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, wherein: G 4 To be R 17 Substituted C 1-6 Alkyl; the R 17 Selected from halogen, methoxy.

32. A pharmaceutical composition comprising the compound according to any one of claims 1 to 31, and its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, and pharmaceutically acceptable excipients.

33. Use of the compound according to any one of claims 1 to 31, or its stereoisomers, tautomers, pharmaceutically acceptable salts or isotope-labeled analogs, in the preparation of a medicament for treating a disease mediated by PRMT5.

34. The use according to claim 33, wherein The diseases mediated by PRMT5 are cancer-related diseases, including skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, bone cancer, neuroblastoma, rectal cancer, familial adenomatous polyposis carcinoma, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, medullary thyroid cancer, papillary thyroid cancer, renal parenchymal cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary cancer, melanoma, glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma lymphoma, Burkitt lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myeloma, liposarcoma, fibrosarcoma, Ewing sarcoma, or plasmacytoma.

35. The use according to claim 33, wherein The disease mediated by PRMT5 is a tumor-related disease.

36. The use according to claim 33, wherein The disease mediated by PRMT5 is a cancer-related disease, and the cancer includes hereditary non-polyposis colorectal cancer, adenocarcinoma or brain tumor.

37. The use according to claim 33, wherein The disease mediated by PRMT5 is a cancer-related disease, and the cancer includes brain cancer, lung cancer or kidney cancer.

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