Sulfoximine linker-containing degradation agent, intermediate thereof and use thereof

Abstract

Disclosed in the present invention are a Sulfoximine linker-containing degradation agent, an intermediate thereof and a use thereof. The Sulfoximine linker-containing degradation agent of the present invention is a compound as represented by formula I or a pharmaceutically acceptable salt thereof. The degradation agent of the present invention exhibits strong target protein degradation activity, favorable pharmacological efficacy, and good prospect for druggability.

Description

Degradation agents containing sulfoximine linkers, intermediates thereof, and uses

[0001] This application claims priority to Chinese Patent Application No. 2024107097177, filed on June 3, 2024, and Chinese Patent Application No. 2024114241581, filed on October 12, 2024. This application incorporates the entirety of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application relates to a degradation agent containing a sulfoximine linker, intermediates thereof, and uses. BACKGROUND

[0003] PROTAC (Proteolysis Targeting Chimera) is a hybrid bifunctional small molecule compound. Its structure contains two different ligands: one is an E3 ubiquitin ligase ligand, and the other is a target protein binding ligand, and the two ligands are connected by a connecting arm. PROTAC brings the target protein and the ubiquitin ligase E3 in the cell close together to form a target protein-PROTAC-E3 ternary complex, and then recruits E3 ligase to specific unnecessary proteins and marks ubiquitination protein tags, and then starts the powerful ubiquitination-proteasome system in the cell, specifically degrading the target protein, and thus achieving the effect of inhibiting the corresponding protein signaling pathway.

[0004] PROTAC exhibits unique advantages: 1. PROTAC does not need to bind to the target protein for a long time and with high intensity, and the degradation of the target protein is similar to a catalytic reaction, which can be recycled to bind and degrade the target protein, thereby reducing the systemic exposure of the drug and reducing the occurrence of toxic side effects; 2. After the target protein is degraded, it needs to be synthesized again to restore its function, so degrading the target protein shows a more efficient and persistent antitumor effect than inhibiting its activity, and is less likely to develop drug resistance due to target protein mutations; 3. For currently considered undruggable targets, such as transcription factors, scaffold proteins, and regulatory proteins, PROTAC also has therapeutic potential. By introducing ligands that can bind different target proteins into the PROTAC molecule, it is possible to apply PROTAC technology to the treatment of various diseases. Developing high-efficiency PROTAC drugs for the treatment of diseases related to target proteins has great significance.

[0005] The literature (J. Med. Chem. 2020, 63, 14243-14275) reported that the Sulfoximine (imine sulfoxide) functional group has been long overlooked in previous medicinal chemistry research. So far, several Sulfoximine N-H containing compounds have entered clinical trials and late-stage development. However, due to the reduced lipophilicity and membrane permeability of Sulfoximine and its analogs, the introduction of Sulfoximine moiety often has some unpredictability on the biological activity and drugability, which still has great challenges.

[0006] Therefore, the present application is proposed. SUMMARY

[0007] The present application provides a Sulfoximine-containing linker degrader and intermediates and applications thereof, which are completely different from the prior art. The Sulfoximine-containing linker degrader of the present application has good target protein degradation activity and good drug efficacy.

[0008] The present application provides a compound as shown in formula I or a pharmaceutically acceptable salt thereof:

[0009] R 1 is C 1-6 alkyl or C 3-6 cycloalkyl;

[0010] R 2 is C 1-6 alkylene or C 3-6 cycloalkylene;

[0011] Alternatively, R 1 and R 2 together with the sulfur atom to which they are attached form a ring A, which is a 4-11 membered heterocycloalkyl; the heteroatoms in the 4-11 membered heterocycloalkyl are independently one or more of N, S and O, in a number of 1, 2 or 3 (containing at least 1 S);

[0012] D is a target protein binding ligand;

[0013] E is an E3 ubiquitin ligase ligand.

[0014] In the compound as shown in formula I or a pharmaceutically acceptable salt thereof, the definitions of some groups can be as follows, and the definitions of other groups are described in any of the schemes in the present application.

[0015] In some schemes, R 1 , the alkyl of C 1-6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl, ethyl or isobutyl, for example methyl.

[0016] In some schemes, R 1 In the context, C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl.

[0017] In some schemes, R 2 In the context, C 1-6 The alkylene group can be methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, or tert-butylene, and may also be...

[0018] In some schemes, R 2 In the context, C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0019] In some schemes, the 4-11 member heterocyclic alkyl group in ring A is a 4, 5, or 6 member monocyclic heterocyclic alkyl group, or a 9, 10, or 11 member bicyclic heterospirocyclic alkyl group, with heteroatoms being N and / or S, and the number being 1 or 2. It may also be tetrahydro-2H-thiopyranyl, thiomorpholinyl, 2-thia-7-azaspiro[3.5]nonyl, 2-thiaspiro[3.5]nonyl, 3-thia-9-azaspiro[5.5]undecyl or 3-thiaspiro[5.5]undecyl.

[0020] Preferably, when ring A also contains N, ring A is connected to D through N atoms.

[0021] In some schemes, for n1, n2, n3, n4, n5, and n6 are independently 1, 2, or 3; X 1 and X 2 It can be -CH- or N independently.

[0022] In some schemes, for (like ), ( ).

[0023] In some schemes, D is the EGFR target protein binding ligand.

[0024] In some schemes, the EGFR target protein binding ligand has the structure shown in Formula D1:

[0025] Among them, L 1 and L 2independently absent or C 1-6 alkylene;

[0026] ring B is absent or 4-6 membered heterocycloalkyl; the heteroatoms in said 4-6 membered heterocycloalkyl are one or more of N, S, and O, in a number of 1, 2, or 3;

[0027] ring C is 4-12 membered heterocycloalkyl or 4-12 membered heterocycloalkyl substituted with one or more R a substituted 4-12 membered heterocycloalkyl; the heteroatoms in said 4-12 membered heterocycloalkyl and said 4-12 membered heterocycloalkyl substituted with one or more R a substituted 4-12 membered heterocycloalkyl are one or more of N, S, and O, in a number of 1, 2, 3, or 4;

[0028] R 3 is -O-C 1-6 alkyl or -O-C 3a alkyl substituted with one or more R 1-6 ,

[0029] each R 3a is independently halogen or deuterium; R 4 is C 1-6 alkyl, C 3-6 cycloalkyl, C 4a-1 alkyl substituted with one or more R 1-6 cycloalkyl substituted with one or more R 4a-2 alkyl, C 3-6 cycloalkyl substituted with one or more R 4a-3 substituted 5-6 membered heteroaryl, the heteroatoms in said 5-6 membered heteroaryl substituted with one or more R 4a-4 substituted 5-6 membered heteroaryl are one or more of N, S, and O, in a number of 1, 2, or 3;

[0030] each R 4a-1 , each R 4a-2 , each R 4a-3 , and each R 4a-4 is independently halogen, deuterium, or C 1-6 alkyl;

[0031] R 5 is halogen, C 1-6 alkyl, or C 1-6 alkyl substituted with one or more halogen;

[0032] R 6 is independently -P(=O)(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C 3-6 cycloalkyl)S(=O)2(C 1-6alkyl), -N(C 1-6 alkyl), -N(C 1-6 alkyl), -N(C 1-6 alkyl), or -N(C 3-6 cycloalkyl);

[0033] R 7 and R 8 are independently H, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl substituted by one or more halogens, or C 3-6 cycloalkyl substituted by one or more halogens, or R 7 and R 8 together with the atom to which they are attached form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted by one or more R a ; the heteroatom in said 5-6 membered heteroaryl is independently one or more of N, S and O, in a number of 1, 2 or 3;

[0034] each R a is independently halogen, C 1-6 alkyl, or -O-C 1-6 alkyl.

[0035] L 1 and L 2 , said C 1-6 alkylene can be methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, or t-butylene, and can also be methylene,

[0036] In ring B, said 4-6 membered heterocycloalkyl can be a 4-, 5-, or 6-membered monocyclic heterocycloalkyl, with the heteroatom being N, in a number of 1 or 2, and can also be azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, for example 1 is attached to L 1 , and 2 is attached to L 2 .

[0037] In ring C, said 4-12 membered heterocycloalkyl and said 4-12 membered heterocycloalkyl substituted by one or more R a may be a 4-6 membered monocyclic heterocycloalkyl or a 6-12 membered bicyclic spirocyclic heterocycloalkyl, with the heteroatom being N and / or O, in a number of 1 or 2, and can also be piperidinyl, piperazinyl, tetrahydrofuranyl, or 3,9-diazaspiro[5.5]undecanyl, for example 1 is attached to L 2 , and 2 is attached to phenyl.

[0038] each R3a Each R 4a-1 Each R 4a-2 Each R 4a-3 Each R 4a-4 R 5 and each R a In this context, the halogen is preferably F, Cl, Br, or I, for example, Cl or Br.

[0039] R 3 R 4 R 5 R 6 R 7 R 8 Each R 4a-1 Each R 4a-2 Each R 4a-3 Each R 4a-4 and each R a In the context, C 1-6 Alkyl group, the -OC 1-6 C in alkyl 1-6 Alkyl group, the one or more R 3a Replacement -OC 1-6 C in alkyl 1-6 Alkyl, the one or more R 4a-1 Replacement C 1-6 C in alkyl 1-6 Alkyl groups, the -P(=O)(C 1-6 C in alkyl)2 1-6 Alkyl groups, the -NHS(=O)2(C 1-6 C in alkyl) 1-6 alkyl groups, the N(C) 3-6 cycloalkyl)S(=O)2(C 1-6 C in alkyl) 1-6 alkyl groups, the -N(C) 1-6 alkyl)S(=O)2(C 1-6 C in alkyl) 1-6 alkyl groups and the -S(=O)2(C 1-6 C in alkyl) 1-6 The alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, for example, methyl or ethyl.

[0040] The one or more R 4a-1 Replacement C 1-6 The alkyl group can be

[0041] R 6 R 7 and R 8N(C 3-6 alkyl)S(=O)2(C 1-6 alkyl)S(=O)2(C 3-6 alkyl)S(=O)2(C 3-6 alkyl)S(=O)2(C 3-6 alkyl)S(=O)2(C 3-6 alkyl)S(=O)2(C

[0042] R 7 and R 8 together with the atom to which they are attached form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted by one or more R a , the 5-6 membered heteroaryl of the 5-6 membered heteroaryl and the 5-6 membered heteroaryl substituted by one or more R a , is preferably a 6 membered heteroaryl, the number of heteroatoms is 1 or 2, and is more preferably pyridyl, pyrimidinyl, pyrazinyl, for example denotes the formation of a ring with the phenyl ring here.

[0043] the 3-12 membered heterocycloalkyl substituted by one or more R a , can be a 4-6 membered monocyclic heterocycloalkyl substituted by halogen, and can also be 1 is attached to L 2 , and 2 is attached to phenyl.

[0044] preferably 1 is attached to R 2 , and 2 is attached to phenyl.

[0045] preferably 1 is attached to ring C, and 2 is attached to -NH-.

[0046] preferably

[0047] preferably

[0048] , in particular preferably 1 is attached to R 2 , and 2 is attached to phenyl.

[0049] Preferably, any one of the following structures:

[0050] In some embodiments, E is a CRBN-like ubiquitin ligase ligand.

[0051] In some embodiments, the CRBN-like ubiquitin ligase ligand is preferably of the structure of Formula E1:

[0052] X e1 is N or CR e2 ;

[0053] R e1 and R e2 are independently hydrogen, C 1-6 alkyl or halogen;

[0054] Y is a bond, -O-, -NH-, -(CH2) n7 - or -NHC(=O)-, and n7 is 1, 2, 3 or 4;

[0055] Ring E is C 6-10 aryl, 5-14 membered heteroaryl, C e3 aryl substituted by one or more R 6-10 , or 5-14 membered heteroaryl substituted by one or more R e3 ; the heteroatoms in said 5-14 membered heteroaryl and said 5-14 membered heteroaryl substituted by one or more R e3 are independently one or more of N, S or O, in a number of 1, 2, 3 or 4;

[0056] each R e3 is independently halogen, oxo, cyano, C 1-6 alkyl, C 1-6 alkyl substituted by one or more halogen, -O-C 1-6 alkyl or C 3-6 cycloalkyl;

[0057] Alternatively, R e3 on the same atom are taken together to form -(CH2) n7 -, and n7 is 1, 2, 3 or 4.

[0058] R e1 , R e2 and each R e3 , the halogen and the halogen in said C 1-6 alkyl substituted by one or more halogen are independently preferably F, Cl, Br or I, for example F.

[0059] R e1 , Re2 and each R e3 In the context, C 1-6 Alkyl groups, C groups substituted with one or more halogens 1-6 C in alkyl 1-6 alkyl groups and the -OC 1-6 C in alkyl 1-6 The alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, for example, methyl.

[0060] Each R e3 In the context, C 3-6 The cycloalkyl group is preferably cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0061] In ring E, the aforementioned C 6-10 The aryl group and the one or more R e3 Replacement C 6-10 C in aryl 6-10 The aryl group is preferably phenyl or naphthyl.

[0062] In ring E, the 5-14 member heteroaryl group and the group bounded by one or more R groups e3 The 5-14 membered heteroaryl group is preferably a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic fused heteroaryl group (5-6 membered heterocyclic benzophenyl, 5-6 membered heteroenylbenzophenyl, 5-6 membered heteroaryl benzo-6 membered heteroaryl, such as pyridine or pyrimidine), wherein the heteroatom is N and / or O, and the number is 1, 2 or 3, more preferably N. Position 1 is connected to Y, and position 2 is connected to N (N in the Sulfoximine group).

[0063] Preferably, E1 is E1-1, E1-2, E1-3, or E1-4:

[0064] In E1-1, It is a single key or does not exist;

[0065] X e2 It can be C or N;

[0066] Z 1 Z 2 Z 3 Z 4 and Z 5 Independent of N, CH or CR e3 And Z 1 Z 2 Z 3 Z4 and Z 5 are not simultaneously N; X e1 , Y, R e1 , and R e3 are each as previously described;

[0067] In formula E1-2, Z 10 is -CH2-, *-CH2-CH2-, *-CH=CH-, *-N=CH-, or *-C(=O)-, wherein the *-marked segment is attached to N;

[0068] Z 6 , Z 7 , Z 8 , and Z 9 are each independently N, CH, or CR e3 , and Z 6 , Z 7 , Z 8 , and Z 9 are not simultaneously N; X e1 , Y, R e1 , and R e3 are each as previously described;

[0069] In formula E1-3, Z

[0070] is a single bond or is absent; X e3 is N or C;

[0071] Z 11 is N, C, or -C(=O)-; Z 12 is CH2, CR e3 R e3 , CR e3 , O, NH, or NR e3 ; Z 13 is C or N;

[0072] Z 6 , Z 7 , Z 8 , and Z 9 are each independently N, CH, or CR e3 , and Z 6 , Z 7 , Z 8 , and Z 9 are not simultaneously N; X e1 , Y, R e1 , and R e3 are each as previously described;

[0073] In formula E1-4, Z 14 is N or C; Z 15 is CH or CR e3 ; Z6 , Z 7 , Z 8 , and Z 9 are independently N, CH or CR e3 , and Z 6 , Z 7 , Z 8 , and Z 9 are not simultaneously N; X e1 , R e1 , and R e3 .

[0074] preferably is each R e3 is independently halogen, C 1-6 alkyl or -O-C 1-6 alkyl, the 1-position is attached to X e1 , and the 2-position is attached to N.

[0075] preferably is each R e3 is independently halogen, C 1-6 alkyl or -O-C 1-6 alkyl, the 1-position is attached to X e1 , and the 2-position is attached to N.

[0076] preferably is each R e3 is independently C 1-6 alkyl, the 1-position is attached to X e1 , and the 2-position is attached to N.

[0077] preferably is the 1-position is attached to X e1 , and the 2-position is attached to N.

[0078] E1is preferably any one of the following structures:

[0079] In some embodiments, the compound of Formula I is any one of the following compounds:

[0080] The present application also provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as described above, and a pharmaceutically acceptable excipient.

[0081] The present application also provides use of a compound of Formula I, a pharmaceutically acceptable salt thereof or the pharmaceutical composition described above in the manufacture of a medicament for preventing or treating a lung cancer (e.g., lung adenocarcinoma).

[0082] The lung cancer is preferably non-small cell lung cancer or lung adenocarcinoma.

[0083] The present application also provides use of a compound of Formula I, a pharmaceutically acceptable salt thereof or the pharmaceutical composition described above in the manufacture of a medicament for preventing or treating a lung cancer (e.g., lung adenocarcinoma).

[0084] The lung cancer is preferably non-small cell lung cancer or lung adenocarcinoma.

[0085] The EGFR protein mutation is preferably selected from the following mutation points: Del19-T790M-C797S mutation, L858R-T790M-C797S mutation, Del19-C797S mutation, L858R-C797S mutation, L858R-T790M mutation, Del19 mutation and L858R mutation.

[0086] The present application also provides a method for treating or preventing a disease, comprising administering to a patient an effective amount of a compound of Formula I, a pharmaceutically acceptable salt thereof or the pharmaceutical composition described above, wherein the disease is a disease related to EGFR described above or a lung cancer described above.

[0087] The present application also provides a compound of Formula II or III or a salt thereof (e.g., for preparing a compound of Formula I):

[0088] E, R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , ring B and ring C are the same as defined above.

[0089] The compound of Formula II is preferably any one of the following compounds:

[0090] The salt of the compound of Formula II is preferably a hydrochloride salt or a trifluoroacetate salt.

[0091] The compound represented by Formula III is preferably any one of the following compounds:

[0092] The term "alkyl" refers to an alkyl group having a specified number of carbon atoms (e.g., C40, C50, C6 ... 1-6 Alkyl groups are saturated, linear or branched, and include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0093] The term "alkylene" refers to a divalent group that is attached to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "alkyl".

[0094] The term "(monocyclic)cycloalkyl" refers to a cycloalkyl group having a specified number of carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ... 3-6 Cyclic, saturated monovalent hydrocarbon groups, which are monocyclic. (Monocyclic)cycloalkyl groups include, but are not limited to: wait.

[0095] The term "cycloalkylene" refers to a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "cycloalkylene".

[0096] The term "heterocyclic alkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 4 to 14), a specified number of heteroatoms (e.g., 1, 2, 3, or 4), and a specified type of heteroatom (one or more of N, O, and S), and is either monocyclic or polycyclic (2-ring) spirocyclic. Heterocyclic alkyl groups are attached to the rest of the molecule via carbon atoms or heteroatoms. Heterocyclic alkyl groups include, but are not limited to: wait.

[0097] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6 to C5). 10 Aromatic groups are cyclic, unsaturated monovalent hydrocarbon groups, which can be monocyclic or polycyclic (e.g., two or three). In polycyclic cases, the monocyclic rings share two atoms and one bond, and (at least one ring / each ring) is aromatic. The aryl group is attached to the rest of the molecule via an aromatic or non-aromatic ring. Aromatic groups include, but are not limited to: phenyl, naphthyl, ... wait.

[0098] The term "heteroaryl" refers to a cyclic, unsaturated monovalent group of specified number of ring atoms (e.g., 5-14 membered), specified number of heteroatoms (e.g., 1, 2, or 3), specified kind of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic (2 or 3 rings), sharing two atoms and one bond between single rings, and (at least one ring / each ring) having aromaticity. The heteroaryl is attached to the rest of the molecule by a carbon atom or a heteroatom; the heteroaryl is attached to the rest of the molecule by a ring having a heteroatom or a ring not having a heteroatom; the heteroaryl is attached to the rest of the molecule by a ring having aromaticity or a ring not having aromaticity. Heteroaryl includes, but is not limited to: etc.

[0099] The term "therapeutically effective amount" refers to an amount of a compound administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by a person skilled in the art as appropriate.

[0100] The term "pharmaceutically acceptable excipient" refers to all substances, other than active pharmaceutical ingredients, contained in a pharmaceutical preparation, which are generally divided into two categories: excipients and additives. For details, please refer to the "People's Republic of China Pharmacopoeia (2020 Edition)", Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0101] The term "treatment" refers to eliminating the cause or alleviating the symptoms.

[0102] The term "prevention" refers to reducing the risk of developing a disease.

[0103] The term "patient" refers to any animal, usually a mammal, such as a human, in need of treatment or prevention of a disease. Mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0104] On the basis of common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e., to obtain each preferred example of the present application.

[0105] The reagents and raw materials used in the present application are commercially available.

[0106] The positive progress effect of the present application is that the Sulfoximine degrader of the present application has good protein degradation activity and good efficacy. DETAILED DESCRIPTION

[0107] The application will be further described in the following by way of examples without limiting the application to the examples described. The experimental methods in the following examples, unless otherwise specified, are carried out according to conventional methods and conditions, or according to the instructions of the commercial suppliers.

[0108] General procedure for preparing the compounds of the examples

[0109] The starting materials and reagents used in the present application are known products, which can be synthesized according to the methods known in the art, or can be obtained by purchasing commercial products. The commercial reagents used are not required to be further purified.

[0110] Room temperature refers to 20-30℃; unless otherwise specified, the reactions in the reaction examples are carried out under nitrogen atmosphere. Nitrogen atmosphere refers to that the reaction bottle is connected to a nitrogen balloon of about 1L.

[0111] The hydrogenation reaction is usually vacuumed and filled with hydrogen, and the operation is repeated for 3 times. Hydrogen atmosphere refers to that the reaction bottle is connected to a hydrogen balloon of about 1L.

[0112] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by a (BRUKER AVANCE III type, 400M) nuclear magnetic instrument, and the measuring solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broad singlet, d = doublet, t = triplet, m = multiplet. The coupling constant is listed as J value, measured in Hz.

[0113] The flash column chromatography uses an automatic column machine (FS-9200T) of Aijie, and the silica gel pre-packed column uses a pre-packed column of Sansite. The thin layer chromatography silica gel plate uses a Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specification of the product separated and purified by thin layer chromatography is 0.4mm-0.5mm.

[0114] The reverse phase preparative chromatography uses a Waters-3767 reverse phase preparative chromatograph

[0115] Preparation column: Waters SunFire, 250*19mm, 5mm or Xbridge Prep C18 or Gemini C18 21.2*250 5um; mobile phase: A: 0.05% ammonia-water solution; B: acetonitrile; detection wavelength: 254nm & 214nm; flow rate: 20ml / min.

[0116] LCMS was performed using a Waters ARC HPLC-QDA instrument.

[0117] Column: ACQUITY UPLC BEH C18 3.5um 3.0*50mm; Ion source: ESI; Mobile phase: A: 0.05% Ammonia in water; B: 0.05% Ammonia in acetonitrile; Detection wavelength: 254nm & 214nm; Run time: 1.5ml / min / 3.5min.

[0118] HPLC was performed using a Waters W2489 Instrument.

[0119] Column: Xbridge C18, 4.6*50mm; Mobile phase: A: 0.1% Ammonia in water; B: Acetonitrile; Detection wavelength: 254nm & 214nm; Run time: 9.0min.

[0120] Supercritical fluid chromatography (SFC) was performed using a Waters SFC 150 instrument.

[0121] Column: DAICEL Chiralpak AD-H

[0122] Mobile phase: A: Supercritical CO2; B: 0.05% Ammonia in methanol

[0123] Detection wavelength: 254nm & 214nm.

[0124] Synthesis of intermediates:

[0125] Intermediate 1

[0126] Intermediate 1 was prepared from the following steps:

[0127] Step A: Int-1a (3.0 g, 10.07 mmol) and dimethyl phosphine oxide (0.86 g, 11.08 mmol), potassium phosphate (6.4 g, 30.21 mmol), palladium acetate (0.23 g, 1.01 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (1.75 g, 0.3 mmol) were added to 1,4-dioxane (50 mL) and stirred at 100 °C for 4 hours under nitrogen protection. The reaction solution was filtered and concentrated, and then purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain Int-1b (2.3 g, yield 92.07%). ESI-MS (m / z): 248.1 (M+H) + .

[0128] Step B: Int-1b (1.1 g, 4.43 mmol), cyclopropylboronic acid (0.76 g, 8.86 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (0.33 g, 0.44 mmol), potassium carbonate (2.82 g, 19.93 mmol) were added into 1,4-dioxane (15 mL) and water (1.5 mL), stirred at 100 °C for 4 h under nitrogen protection. The reaction solution was filtered and concentrated, then purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) to give Int-1c (450 mg, yield 48.50%). ESI-MS (m / z): 209.2 (M+H) + .

[0129] Step C: Int-1c (450 mg, 2.15 mmol), 5-bromo-2,4-dichloropyrimidine (950 mg, 4.30 mmol), potassium carbonate (870 mg, 6.45 mmol) were added into N,N-dimethylformamide (5 mL), stirred at 100 °C for 6 h. Water was added to the reaction solution, and extracted with ethyl acetate. The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) to give Int-1 (400 mg, yield 46.42%). ESI-MS (m / z): 400.1 (M+H) + . 1 HNMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.50 (s, 1H), 8.18 (d, J = 6.8 Hz, 1H), 7.35 (d, J = 14.2 Hz, 1H), 7.26 (d, J = 10.0 Hz, 1H), 1.98 - 1.92 (m, 1H), 1.80 (d, J = 14.2 Hz, 6H), 0.97 (d, J = 10.6 Hz, 2H), 0.76 (d, J = 6.8 Hz, 2H).

[0130] Intermediate 2

[0131] Intermediate 2 was prepared from the following steps:

[0132] Step A: Int-2a (20.4 g, 193 mmol) was dissolved in dichloromethane (200 mL), triethylamine (39.2 g, 387 mmol, 54.0 mL) was added, di-tert-butyl dicarbonate (46.5 g, 213 mmol, 48.9 mL) was added dropwise at 0 °C, and the reaction was stirred at room temperature overnight. The reaction was washed with saturated aqueous ammonium chloride solution and saturated brine solution in turn, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to a white solid. The solid was dried in vacuum to obtain Int-2b (21.8 g, yield 55.57%). 1 H NMR (400 MHz, DMSO-d6) δ 3.62 - 3.52 (m, 4H), 2.55 - 2.47 (m, 6H), 1.40 (s, 9H).

[0133] Step B: Int-2b (20 g, 980 mmol) was dissolved in methanol (200 mL), iodobenzene acetate (66.3 g, 206 mmol) and ammonium acetate (12.1 g, 157 mmol) were added, and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain Int-2c (20 g, yield 86.77%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 3.84 (dt, J = 14.8, 4.9 Hz, 2H), 3.53 (dt, J = 13.2, 6.0 Hz, 2H), 3.03 - 2.92 (m, 4H), 1.41 (s, 9H).

[0134] Step C: Int-2c (8.5 g, 36.2 mmol), Int-2d (10.1 g, 30.2 mmol) were dissolved in dioxane (170 mL), t-BuXPhos-Pd-G3 (2.40 g, 3.02 mmol), t-BuXPhos (1.28 g, 3.02 mmol) and cesium carbonate (29.5 g, 90.6 mmol) were added to the reaction, and the reaction was replaced with nitrogen for 3 times and reacted at 100 °C for 3 hours. LC / MS showed that the reaction was complete. The reaction was concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain Int-2e (7.53 g, yield 49.76%) as a white solid. ESI-MS (m / z): 491.24 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 1.6 Hz, 1H), 7.35 (dd, J = 8.0, 2.0 Hz, 1H), 5.09 (dd, J = 12.8, 5.2 Hz, 1H), 4.07 - 3.98 (m, 2H), 3.56 (d, J = 11.6 Hz, 4H), 3.48 - 3.36 (m, 2H), 2.94 - 2.82 (m, 1H), 2.64 - 2.52 (m, 2H), 2.07 - 2.00 (m, 1H), 1.42 (s, 9H).

[0135] Step D: Int-2e (2 g, 4.08 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and the solution was cooled to 0 °C in an ice bath. Hydrochloric acid / dioxane solution (4.0 M, 10 mL) was added to the solution, and the reaction was stirred at room temperature for about 2 hours. LC / MS showed that the starting material was consumed. The reaction was concentrated under reduced pressure to give Int-2 (2.2 g, crude). Off-white solid. No further purification was needed. ESI-MS (m / z): 391.2 (M+H) + .

[0136] Intermediate 3

[0137] Intermediate 3 was prepared from the following steps:

[0138] Step A: Int-3a (22.5 g, 95.3 mmol) was dissolved in N,N-dimethylformamide (200 mL), and potassium carbonate (26.3 g, 190.6 mmol) and iodomethane (20.3 g, 143 mmol) were added to the solution. The reaction was stirred at 45 °C for 2 hours. TLC showed that the reaction was complete. The reaction was cooled to room temperature, and the solution was poured into water (300 mL). A solid was precipitated. The solid was collected by filtration and washed with water. The solid was dried under vacuum to give Int-3b (22 g, yield 92.29%).

[0139] Step B: Int-3b (22 g, 88 mmol), 1 -methyl-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)- 1H-pyrazole (22 g, 105.6 mmol), 1,1 '-bis(diphenylphosphino)ferrocene palladium(II) dichloride (3.2 g, 4.4 mmol), potassium carbonate (30.4 g, 220 mmol) were added into a mixture solvent of 1,4-dioxane (200 mL) and water (20 mL), stirred at 90 °C overnight under nitrogen atmosphere, LC / MS showed the reaction was complete. Cooled to room temperature, quenched by water, extracted by tetrahydrofuran, combined the organic phase, dried over anhydrous sodium sulfate, concentrated after filtration, purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-3c (12 g, yield 54.28%). ESI-MS (m / z): 251.9 (M+H) + .

[0140] Step C: Int-3c (6.2 g, 24.7 mmol) was dissolved in dimethyl sulfoxide (60 mL), added Int-3d (5.6 g, 37 mmol), potassium carbonate (10.2 g, 74.1 mmol), stirred at 120 °C overnight, LC / MS showed the reaction was complete. Cooled to room temperature, quenched by water, extracted by ethyl acetate, combined the organic phase, dried over anhydrous sodium sulfate, concentrated after filtration, the obtained crude was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-3e (4 g, yield 46.79%). ESI-MS (m / z): 418.0 (M+H) + . 1 H NMR (500 MHz, DMSO-d6) d 8.08 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H), 6.76 (s, 1H), 4.54 (t, J = 5.3 Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.33-3.26 (m, 4H), 2.64-2.55 (m, 2H), 1.70-1.63 (m, 2H), 1.53-1.43 (m, 1H), 1.30-1.21 (m, 2H).

[0141] Step D: Int-3e (1.0 g, 2.89 mmol) was dissolved in DCM (15 mL) at room temperature, and Dess-Martin Oxidizing reagent (1.59 g, 3.75 mmol) was added to the reaction solution under ice-bath condition. The reaction was stirred at room temperature for about 2 hours. LCMS showed the reaction was complete. Sodium carbonate solution was added to the reaction solution, and the organic layer was washed with sodium thiosulfate solution twice. After drying over anhydrous sodium sulfate, the crude product Int-3 (910 mg, crude product) was obtained by concentration under reduced pressure, which was used directly for the next step. ESI-MS (m / z): 345.2 [M+H] + .

[0142] Intermediate 4

[0143] Intermediate 4 was prepared from the following steps:

[0144] Step A: To a solution of Int-4a (25.0 g, 17.22 mmol) in acetic acid (500 mL) was added iodine (87.4 g, 34.44 mmol) in acetic acid (500 mL) dropwise. The reaction was stirred at 60 °C for 16 hours. LCMS showed the reaction was complete. The reaction was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 10 / 1) to give Int-4b (22.0 g, yield 47.13%). ESI-MS (m / z): 271.85 (M+H) + .

[0145] Step B: Int-4b (20.0 g, 7.38 mmol), dimethylphosphine oxide (8.6 g, 11.07 mmol), potassium phosphate (31.3 g, 14.76 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.3 g, 0.74 mmol), palladium acetate (1.65 g, 0.74 mmol) were added to 1,4-dioxane (250 mL) and stirred at 100 °C for 16 hours under nitrogen protection. The reaction was concentrated and purified by column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) to give Int-4c (16.1 g, yield 89.12%). ESI-MS (m / z): 222.12 (M+H) + .

[0146] Step C: A solution of Int-4c (5.0 g, 22.6 mmol) in N,N-dimethylformamide (35 mL) was added dropwise to a suspension of sodium hydride (3.62 g, 90.4 mmol, 60%) in tetrahydrofuran (25 mL) at 0 °C and stirred for 40 min. A solution of 5-bromo-2,4-dichloropyrimidine (10.3 g) in tetrahydrofuran (25 mL) was added dropwise to the reaction mixture and stirred at 25 °C for 4 h. LCMS showed the reaction was complete. The reaction mixture was poured into ice water and a solid precipitated, which was filtered and slurried with ethyl acetate / dichloromethane / methanol to give the product Int-4 (5.6 g, 60.04% yield). ESI-MS (m / z): 412.1 (M+H) + . 1 H NMR (400 MHz, Methanol-d4) δ 9.02 (dd, J = 9.5, 4.2 Hz, 1H), 8.90 - 8.81 (m, 2H), 8.51 (s, 1H), 8.25 (d, J = 9.5 Hz, 1H), 2.18 (s, 3H), 2.15 (s, 3H).

[0147] Intermediate 5

[0148] Intermediate 5 was prepared from the following steps:

[0149] Step A: Pinacol diborane (3.14 g, 12.38 mmol), Int-5a (2 g, 6.19 mmol), potassium acetate (1.82 g, 18.57 mmol) and DPPF palladium dichloride (226.43 mg, 0.309 mmol) were dissolved in 1,4-dioxane (25 mL) and stirred at 100 °C for 16 h. LC / MS showed the reaction was complete. The reaction mixture was cooled and 30 mL of petroleum ether was added and stirred for 10 min. A solid was generated and was filtered and dried to give Int-5b (1.6 g, 69.83% yield), ESI-MS (m / z): 371.2 [M+H] + .

[0150] Step B: Ammonium acetate (3.33 g, 43.22 mmol), sodium periodate (924.41 mg, 4.32 mmol), Int-5b (1.6 g, 4.32 mmol) were dissolved in a mixture of acetonitrile (20 mL) and water (10 mL) and stirred at 50 °C for 16 h. LC / MS showed the reaction was complete. A large amount of solid was generated and the reaction mixture was filtered, washed with water and dried to give white solid Int-5c (1.1 g, 88.35% yield), ESI-MS (m / z): 290.1 [M+H] + .

[0151] Step C: Int-5c (500 mg, 1.74 mmol), Int-2c (406.71 mg, 1.74 mmol), triethylamine (1.05 g, 10.41 mmol, 1.45 mL) and copper acetate (690.82 mg, 3.47 mmol) were dissolved in N,N-dimethylformamide (6 mL) and stirred at 40 °C for 16 hours. LC / MS showed the reaction was complete. The reaction was filtered through celite, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-5d (340 mg, yield 41.10 %), ESI-MS (m / z): 477.3 [M+H] + .

[0152] Step D: Int-5d (340 mg, 0.713 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated to give Int-5 (0.26 g, crude product) without further purification. ESI-MS (m / z): 377.3 [M+H] + .

[0153] Intermediate 6

[0154] Intermediate 6 was prepared by the following steps:

[0155] Step A: Compound Int-6a (5 g, 26.85 mmol), Int-6b (4.92 g, 26.85 mmol) and N,N-diisopropyl ethylamine (6.94 g, 53.7 mmol) were dissolved in isopropyl alcohol (50 mL). The reaction was stirred at 60 °C for 16 hours. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure, and the crude product was purified by silica gel column (eluent: petroleum ether / ethyl acetate (V / V) = 5 / 1) to give white solid Int-6 (3 g, yield 33.54 %). ESI-MS (m / z): 333.0 [M+H] + .

[0156] Intermediate 7

[0157] Intermediate 7 was prepared by the following steps:

[0158] Step A: To a solution of Int-7a (50 g, 344.8 mmol) in acetonitrile (30 mL) was added Selectfluor fluorinating agent (128 g, 344.8 mmol) at room temperature. The resulting mixture was stirred at 80 °C overnight. The reaction was concentrated, the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 100:1) to give Int-7b (40 g, yield 70%). ESI-MS (m / z): 163.9 (M+H) + .

[0159] Step B: Int-7b (40 g, 245.17 mmol) was dissolved in concentrated sulfuric acid (80 mL, 98%) at 0 °C, to which concentrated nitric acid (28 g, 65%) was added. The resulting mixture was stirred at 0 °C for 1 hour. LC / MS showed the reaction was complete. The reaction was poured into ice water (1000 mL) and stirred for 10 minutes. A large amount of solid was produced, which was filtered, washed with water and dried under vacuum to give Int-7c (54 g, crude). ESI-MS (m / z): 208.92 (M+H) + .

[0160] Step C: Int-7c (54 g, 259.43 mmol) was added to a solution of phosphorus oxychloride (250 mL), heated at 100 °C overnight. The reaction was concentrated, basified with saturated sodium bicarbonate solution, extracted with dichloromethane, the combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 20 / 1) to give Int-7d (10 g, yield 17%). ESI-MS (m / z): 227.0 (M+H) + .

[0161] Step D: Int-7d (10 g, 44.13 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriphosphaadamantane (20 g, 158.87 mmol), DPPF palladium dichloride (4 g, 5.29 mmol) and potassium phosphate (23 g, 110.32 mmol) were dissolved in 1,2-dichloroethane (250 mL) and water (50 mL), stirred at 80 °C overnight under nitrogen atmosphere. LC / MS showed the reaction was complete. The mixture was rotary evaporated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 20 / 1) to give Int-7e (6 g, yield 54%). ESI-MS (m / z): 206.89 (M+H) + .

[0162] Step E: Int-7e (6 g, 29.10 mmol) was dissolved in methanol (100 mL) at room temperature, palladium on carbon (1 g, 10 wt.%) was added, after replaced by hydrogen balloon, stirred at 25 °C for 5 h, the mixture was filtered through celite, the obtained filtrate was concentrated under reduced pressure to give Int-7f (3.9 g, yield 76%). ESI-MS (m / z): 176.95 (M+H) + .

[0163] Step F: To a solution of Int-7f (3.9 g, 22.13 mmol) in acetic acid (20 mL) was added iodine monochloride (4.7 g, 26.56 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. LC / MS showed the reaction was complete. Adjusted to PH = 8 with saturated sodium bicarbonate solution, extracted with dichloromethane, combined organic phase, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-7g (5.5 g, yield 82%). ESI-MS (m / z): 302.97 (M+H) + .

[0164] Step G: To a solution of Int-7g (5.5 g, 18.21 mmol) and dimethyl phosphine oxide (2.84 g, 36.41 mmol) in 1,4-dioxane (100 mL) was added potassium phosphate (11.6 g, 54.63 mmol), then palladium acetate (820 mg, 3.64 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.2 g, 7.28 mmol) were added to the mixture. After replaced by nitrogen, stirred at 100 °C overnight. The mixture was filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) to give Int-7h (4.5 g, yield 99%). ESI-MS (m / z): 253.14 (M+H) + .

[0165] Step H: To a solution of Int-7h (5.0 g, 19.82 mmol) and 5-bromo-2,4-dichloropyrimidine (13.55 g, 59.46 mmol) in n-butanol (100 mL) was added N,N-diisopropylethylamine (7.7 g, 59.46 mmol) at room temperature. The obtained mixture was stirred at 120 °C overnight. LC / MS showed the reaction was complete. The reaction was concentrated, the obtained crude residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give Int-7 (4.5 g, yield 51%). ESI-MS (m / z): 443.1 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.57 (s, 1H), 8.49 (d, J = 12.2 Hz, 1H), 8.29 (dd, J = 9.3, 3.9 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 2.65 (d, J = 2.7 Hz, 3H), 2.02 (d, J = 13.4 Hz, 6H).

[0166] Intermediate 8

[0167] Intermediate 8 was prepared from the following steps:

[0168] Step A: Int-7a (50 g, 344.45 mmol) was dissolved in concentrated sulfuric acid (400 mL, 98%) at 0 °C, to which concentrated nitric acid (39.5 g, 65%) was added. The resulting mixture was stirred at 0 °C for 1 h. LC / MS showed the reaction was complete. The reaction was poured into ice water (1000 mL) and stirred for 10 min. A large amount of solid was produced, which was filtered, washed with water and dried under vacuum to give Int-8a (57 g, crude). ESI-MS (m / z): 190.92 (M+H) + .

[0169] Step B: Int-8a (57 g, 299.75 mmol) was added to a solution of phosphorus oxychloride (500 mL) and heated at 100 °C for 2 h. The reaction was concentrated, basified with saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give Int-8b (43 g, yield 69%). ESI-MS (m / z): 209.0 (M+H) + .

[0170] Step C: Int-8b (23 g, 110.26 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (34 g, 220.52 mmol), DPPF palladium dichloride (4.03 g, 22.05 mmol) and potassium carbonate (53.3 g, 385.91 mmol) were dissolved in 1,4-dioxane (500 mL) and water (50 mL) and stirred at 100 °C under nitrogen atmosphere overnight. The mixture was rotary evaporated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (V / V) = 15 / 1) to give Int-8c (15 g, yield 72.5%).

[0171] Step D: Int-8c (15 g, 74.92 mmol) was dissolved in methanol (200 mL) at room temperature, palladium on carbon (3 g, 10 wt.%) was added, and the reaction was stirred at 25 °C for 16 h after hydrogen balloon was replaced. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give Int-8d (12.0 g, yield 95%). ESI-MS (m / z): 173.1 (M+H) + .

[0172] Step E: To a solution of Int-8d (3.8 g, 22.06 mmol) in acetic acid (40 mL) was added iodine monochloride (4.3 g, 26.47 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. After the reaction was completed, it was adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted with dichloromethane, the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-8e (6.3 g, yield 95%).

[0173] Step F: To a solution of Int-8e (5.88 g, 19.72 mmol) and dimethyl phosphine oxide (3.08 g, 36.44 mmol) in 1,4-dioxane (100 mL) was added potassium phosphate (10.5 g, 49.30 mmol), then palladium acetate (885 mg, 3.94 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.28 g, 3.94 mmol) were added to the mixture. After nitrogen replacement, it was stirred at 100 °C overnight. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) to give Int-8f (2.9 g, yield 60%). ESI-MS (m / z): 249.4 (M+H) + .

[0174] Step G: To a solution of Int-8f (2.33 g, 9.38 mmol) and 5-bromo-2,4-dichloropyrimidine (8.55 g, 37.52 mmol) in n-butanol (50 mL) was added N,N-diisopropylethylamine (6.1 g, 46.9 mmol) at room temperature. The mixture was stirred at 120 °C overnight. LC / MS showed the reaction was complete. The reaction was concentrated, and the crude residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give Int-8 (3.2 g, yield 77%). ESI-MS (m / z): 439.1 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.67 - 8.51 (m, 2H), 8.39 (dd, J = 9.2, 4.0 Hz, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 2.96 (q, J = 7.6 Hz, 2H), 2.16 - 1.96 (m, 6H), 1.34 (t, J = 7.6 Hz, 3H).

[0175] Intermediate 9

[0176] Intermediate 9 was prepared from the following steps:

[0177] Step A: To a solution of Int-9a (5.0 g, 29.57 mmol) in acetonitrile (100 mL) was added propargyl amine hydrochloride (5 g, 73.92 mmol) and potassium carbonate (12.3 g, 88.71 mmol) at room temperature. The mixture was stirred at 80 °C overnight. LC / MS showed the reaction was complete. The reaction was concentrated, the residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 100 / 1) to give Int-9b (1.6 g, crude). ESI-MS (m / z): 204.11 (M+H) + .

[0178] Step B: Int-9b (1.6 g, 7.87 mmol) was dissolved in tetrahydrofuran (40 mL) and water (8 mL) at room temperature, iron powder (2.20 g, 39.35 mmol) and ammonium chloride (2.11 g, 39.35 mmol) were added to the reaction. The mixture was stirred at 25 °C overnight. LC / MS showed the reaction was complete. The mixture was filtered through celite, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give Int-9c (640 mg, yield 47%). ESI-MS (m / z): 173.96 (M+H) + .

[0179] Step C: To a solution of Int-9c (640 mg, 3.69 mmol) in acetic acid (20 mL) was added iodine monochloride (900 mg, 5.53 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, it was adjusted to PH = 8 with saturated sodium bicarbonate solution, extracted with dichloromethane, the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-9d (900 mg, yield 81%). ESI-MS (m / z): 299.79 (M+H) + .

[0180] Step D: To a solution of Int-9d (900 mg, 3.01 mmol) and dimethyl phosphine oxide (470 mg, 6.02 mmol) in 1,4-dioxane (20 mL) was added potassium phosphate (1.6 g, 7.52 mmol), then to the mixture was added palladium acetate (135 mg, 0.602 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (348 mg, 0.602 mmol). After nitrogen substitution, the mixture was stirred at 100 °C overnight. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) to give Int-9e (640 mg, yield 85%). ESI-MS (m / z): 250.1 (M+H) + .

[0181] Step E: To a solution of Int-9e (640 mg, 2.57 mmol) and 5-bromo-2,4-dichloropyrimidine (1.76 g, 7.71 mmol) in n-butanol (30 mL) was added N,N-diisopropylethylamine (996 mg, 7.71 mmol) at room temperature. The resulting mixture was stirred at 120 °C overnight. LC / MS showed the reaction was complete. The reaction was concentrated, the resulting crude residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give Int-9 (540 mg, yield 48%). ESI-MS (m / z): 440.08 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.83 (s, 1H), 8.61 - 8.53 (m, 2H), 8.12 (d, J = 9.4 Hz, 1H), 3.06 (q, J = 7.6 Hz, 2H), 2.10 (d, J = 13.5 Hz, 6H), 1.39 - 1.36 (m, 3H).

[0182] Intermediate 10

[0183] Intermediate 10 was prepared from the following steps:

[0184] Step A: Int-10a (300 mg, 0.99 mmol), Int-2c (231.17 mg, 0.99 mmol), cesium carbonate (707.17 mg, 2.17 mmol), t-BuXPhos (41.83 mg, 0.099 mmol) and t-BuXPhos Pd G3 (78.37 mg, 0.099 mmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and N,N-dimethylformamide (3 mL), and stirred at 80 °C for 16 h under nitrogen. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the combined organic phase was concentrated under reduced pressure to give Int-10b (310 mg, crude), which was used without further purification. ESI-MS (m / z): 458.2 [M+H] + .

[0185] Step B: Int-10b (310 mg, 0.68 mmol) was dissolved in dichloromethane (2 mL), then trifluoroacetic acid (1.49 g, 13.07 mmol, 1 mL) was added, and the reaction was stirred at room temperature for 2 h. LC / MS showed the reaction was complete. The reaction was concentrated to give Int-10 (210 mg, crude), which was used without further purification. ESI-MS (m / z): 358.3 [M+H] + .

[0186] Intermediate 11

[0187] Intermediate 11 was prepared from the following steps:

[0188] Step A: Ethyl cyanoacetate (179 g, 1585.11 mmol) was dissolved in methanol (800 mL), ammonium acetate (4.07 g, 52.84 mmol) was added, then Int-11a (100 g, 528.37 mmol) was added dropwise, and finally ammonia water (75 mL) was added, and stirred at 25 °C for 24 h. After the reaction was completed, 100 mL of concentrated hydrochloric acid was added, and a solid was precipitated, which was suction filtered, and the filter cake was washed with ethyl acetate to give Int-11b (94 g, yield 55.19%). ESI-MS (m / z): 323.1 [M+H] + .

[0189] Step B: Sulfuric acid (500 mL) and water (330 mL) were mixed, and Int-llb (94 g, 291.59 mmol) was added portionwise, and the temperature was gradually increased to 130 °C and stirred for 24 h. After the reaction was completed, it was concentrated under reduced pressure. Then it was dissolved in ethanol (900 mL) and reacted at 120 °C for 20 h. After the reaction was completed again, it was cooled. Then sodium bicarbonate (122.5 g, 1457.95 mmol) was added under ice bath, and water was added thereto, and dichloromethane was extracted, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15:1) to obtain Int-llc (100 g, yield 98%). ESI-MS (m / z): 348.3 [M+H] + .

[0190] Step C: Compound Int-llc (100 g, 287.8 mmol) was dissolved in tetrahydrofuran (1000 mL), and lithium aluminum hydride (21.87 g, 575.6 mmol) was added portionwise at 0 °C under nitrogen protection, and stirred at 25 °C overnight. LC / MS showed that the reaction was complete. Quenching was performed by slowly adding sodium sulfate decahydrate under stirring, filtered, washed with tetrahydrofuran, and concentrated to obtain compound Int-llc (70 g, crude). ESI-MS (m / z): 264.2 [M+H] + .

[0191] Step D: Compound Int-llc (70 g, 265.77 mmol) was dissolved in methanol (800 mL), and di-tert-butyl dicarbonate (58.0 g, 265.77 mmol) was added, and palladium hydroxide (11.2 g, 79.73 mmol) was added, and stirred at 40 °C under hydrogen for 12 h. Then the reaction solution was filtered through diatomite, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15:1) to obtain Int-11e (48 g, yield 66.26%).

[0192] Step E: Compound Int-11e (48 g, 175.58 mmol) was dissolved in dichloromethane (5000 mL), and triethylamine (71.07 g, 702.32 mmol, 97.62 mL) and methylsulfonic anhydride (61.17 g, 351.16 mmol) were added under cooling to 0 °C, and the reaction was stirred for 1 h. The reaction solution was quenched by slowly adding water, and dichloromethane was extracted, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound Int-11e (69 g, crude).

[0193] Step F: Compound Int-11e (69 g, 160.64 mmol) was dissolved in N,N- dimethylformamide (800 mL), sodium sulfide nonahydrate (18.52 g, 192.77 mmol) was added, and stirring was performed at 50 °C for 16 hours. LC / MS showed that the reaction was complete. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The obtained crude product was separated and purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (V / V) = 5:1) to obtain compound Int-11f (35 g, in a yield of 80.27%). ESI-MS (m / z): 272.1 [M+H] + . 1 H NMR (500 MHz, CDCl3) δ 3.35-3.27 (m, 4H), 2.57-2.47 (m, 4H), 1.71-1.61 (m, 4H), 1.38 (s, 9H), 1.37-1.32 (m, 4H).

[0194] Step G: Int-11f (35 g, 128.95 mmol) was dissolved in methanol (400 mL), iodobenzene acetate (124.6 g, 386.85 mmol) and ammonium acetate (39.76 g, 515.8 mmol) were added, and stirring was performed at 25 °C for 8 hours. The reaction solution was concentrated under vacuum, and the obtained crude product was separated and purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 15:1) to obtain compound Int-11 (26 g, in a yield of 66.67%). ESI-MS (m / z): 303.1 [M+H] + .

[0195] Intermediate 12

[0196] Intermediate 12 was prepared by the following steps:

[0197] Step A: Int-12a (2 g, 5.93 mmol) and Int-11 (1.79 g, 5.93 mmol) were dissolved in 1,4-dioxane (30 mL) under nitrogen protection, t-BuXPhos-Pd-G3 (471.3 mg, 0.59 mmol), t-BuXPhos (251.9 mg, 0.59 mmol), cesium carbonate (5.79 g, 17.8 mmol) were added. The reaction was stirred at 110 °C for 4 h. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, saturated aqueous ammonium chloride was added, and the mixture was extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (1 / 1, by volume)) to give Int-12b (2.75 g, 83.1% yield) as a white solid. ESI-MS (m / z): 559.4 [M+H] + .

[0198] Step B: Int-12b (2.75 g, 4.92 mmol) was dissolved in dichloromethane (20 mL), then HCl (4.0 M in 1,4-dioxane, 10 mL) was added at 0 °C. The reaction was stirred at room temperature for 4 h. White product precipitated out. LC / MS showed the reaction was complete. After filtration, the product was dried in vacuo to give Int-12 (2.8 g, crude) as a white solid. No further purification was needed. ESI-MS (m / z): 390.17 [M+H] + .

[0199] Intermediate 13

[0200] Intermediate 13 was prepared by the following steps:

[0201] Step A: Pinacol diboronic acid (3.14 g, 12.38 mmol), Int-13a (2 g, 6.19 mmol), potassium acetate (1.82 g, 18.57 mmol) and DPPF palladium dichloride (226.43 mg, 0.309 mmol) were dissolved in 1,4-dioxane (25 mL) under nitrogen protection, and the reaction was stirred at 100 °C for 16 h. LC / MS showed the reaction was complete. The reaction was cooled, 30 mL of petroleum ether was added and stirred for 10 min. Solid was generated, filtered and dried to give Int-13b (1.6 g, 69.83% yield). ESI-MS (m / z): 371.2 [M+H] + .

[0202] Step B: Ammonium acetate (3.33 g, 43.22 mmol) was added to sodium periodate (924.41 mg, 4.32 mmol) and Int-13b (1.6 g, 4.32 mmol) in a mixture solvent of acetonitrile (20 mL) and water (10 mL) and stirred at 50 °C for 16 h. LC / MS showed the reaction was complete. A large amount of solid was produced. The reaction mixture was filtered, washed with water and dried to give white solid Int-13c (1.1 g, yield 88.35 %), ESI-MS (m / z): 290.1 [M+H] + .

[0203] Step C: Int-13c (500 mg, 1.74 mmol), Int-2c (406.71 mg, 1.74 mmol), triethylamine (1.05 g, 10.41 mmol, 1.45 mL) and copper acetate (690.82 mg, 3.47 mmol) were dissolved in N,N-dimethylformamide (6 mL) and stirred at 40 °C for 16 h. LC / MS showed the reaction was complete. The reaction mixture was filtered through celite and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-13d (340 mg, yield 41.10 %), LC / MS (ESI m / z): 477.3 [M+H] + . + .

[0204] Step D: Int-13d (340 mg, 0.713 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1.49 g, 13.07 mmol, 1 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give Int-3 (0.26 g, crude), ESI-MS (m / z): 377.3 [M+H] + .

[0205] Intermediate 14

[0206] Intermediate 14 was prepared by the following steps:

[0207] Step A: Int-14a (2 g, 7.46 mmol) and Int-11 (2.26 g, 7.46 mmol) were dissolved in dimethyl sulfoxide (3 mL), t-BuXPhos-Pd-G3 (592.58 mg, 0.75 mmol), t-BuXPhos (316.77 mg, 0.75 mmol), cesium carbonate (7.29 g, 22.38 mmol) were added under nitrogen protection. The reaction was heated at 110 °C for 4 h. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, saturated aqueous ammonium chloride was added, and the mixture was extracted with dichloromethane. The organic phases were combined and washed with water and brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-14b (2.8 g, 76.66% yield) as a white solid. ESI-MS (m / z): 490.23 [M+H] + .

[0208] Step B: Int-14b (2.8 g, 5.76 mmol) was dissolved in dichloromethane (30 mL), then HCl (4.0 M in 1,4-dioxane, 10 mL) was added at 0 °C. The reaction was stirred at room temperature for 4 h. White product precipitated out. LC / MS showed the reaction was complete. After filtration, the product was dried in vacuo to give Int-14 (2 g, crude) as a white solid. No further purification was needed. ESI-MS (m / z): 390.17 [M+H] + .

[0209] Intermediate 15

[0210] Intermediate 15 was prepared from the following steps:

[0211] Step A: Int-10a (2 g, 6.58 mmol) and Int-11 (1.59 g, 5.26 mmol) were dissolved in 1,4-dioxane (15 mL) and N,N-dimethylformamide (15 mL), under nitrogen protection, t-BuXPhos-Pd-G3 (156 mg, 0.197 mmol), t-BuXPhos (279 mg, 0.658 mmol), cesium carbonate (4.29 g, 13.15 mmol) were added. The reaction was stirred at 80 °C for 16 h, LC / MS showed the reaction was complete. The reaction was cooled to room temperature, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with water and brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-15a (2.5 g, yield 72.32%) as a white solid. ESI-MS (m / z): 425.4 [M-100+H] + .

[0212] Step B: Int-14b (2.5 g, 4.76 mmol) was dissolved in dichloromethane (20 mL), then HCl (4.0 M in 1,4-dioxane, 10 mL) was added at 0 °C. The reaction was stirred at room temperature for 4 h, white product precipitated, LC / MS showed the reaction was complete. After filtration, the white solid was dried in vacuo to give Int-15 (2.1 g, crude) as a white solid. No further purification was needed. ESI-MS (m / z): 425.4 [M+H] + .

[0213] Intermediate 16

[0214] Intermediate 16 was prepared by the following steps:

[0215] Step A: Int-16a (3 g, 14.53 mmol) and acrylic acid (1.15 g, 15.98 mmol) were dissolved in acetic acid (10 mL) and water (40 mL), the reaction was stirred at 100 °C for 12 h, LC / MS showed the reaction was complete. After concentration under reduced pressure, Int-16b (4.0 g, crude) was obtained as a light yellow solid. No further purification was needed. ESI-MS (m / z): 280.0 [M+H] + .

[0216] Step B: Int-16b (4.0 g, 14.36 mmol) was dissolved in N,N-dimethylformamide (30 mL), and ammonia water (5.03 g, 143.6 mmol, 5.59 mL) was added thereto, followed by the addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.46 g, 14.36 mmol) at room temperature, and the reaction was allowed to proceed for 12 hours. After the reaction was completed by LC / MS, water was added to the reaction mixture, which was extracted with ethyl acetate, and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Int-16c (3.1 g, 77.77% yield). ESI-MS (m / z): 279.0 [M+H] + .

[0217] Step C: Int-16c (3.1 g, 11.17 mmol) was dissolved in acetonitrile (60 mL), and N,N'-carbonyldiimidazole (2.17 g, 13.40 mmol), triethylamine (1.86 mL, 13.40 mmol), and 4-dimethylaminopyridine (136.4 mg, 1.12 mmol) were added to the reaction mixture, followed by the reaction at 90°C for 48 hours. After the reaction was completed by LC / MS, the reaction mixture was cooled to room temperature, water was added thereto, which was extracted with ethyl acetate, and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Int-16d (1.3 g, 38.34% yield). ESI-MS (m / z): 305.0 [M+H] + .

[0218] Step D: Int-16d (1.0 g, 3.29 mmol) and Int-2c (771.9 mg, 3.29 mmol) were dissolved in 1,4-dioxane (8 mL) and N,N-dimethylformamide (8 mL), and t-BuXPhos-Pd-G3 (78 mg, 0.099 mmol), t-BuXPhos (139 mg, 0.329 mmol), and cesium carbonate (2.15 g, 6.59 mmol) were added to the reaction mixture under nitrogen, followed by the reaction at 80°C for 16 hours. After the reaction was completed by LC / MS, the reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride was added thereto, which was extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with water and brine, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (V / V)=1 / 1) to obtain Int-16e (1.2 g, 80.00% yield) as a white solid. ESI-MS (m / z): 457.2 [M+H] + .

[0219] Step E: Int-16e (1.2 g, 2.63 mmol) was dissolved in dichloromethane (10 mL), then HCl (4.0 M in 1,4-dioxane, 5 mL) was added at 0 °C. The reaction was stirred at room temperature for 2 h, and a white solid was precipitated. LC / MS showed the reaction was complete. After filtration, the white solid was dried in vacuum to give Int-16 (980 mg, crude) as a white solid. No further purification was needed. ESI-MS (m / z): 357.2 [M+H] + .

[0220] Intermediate 17

[0221] Intermediate 17 was prepared from the following steps:

[0222] Step A: Compound Int-17a (2 g, 10.04 mmol), Int-17b (3.25 g, 12.04 mmol) and N,N-diisopropyl ethylamine (3.89 g, 30.12 mmol) were dissolved in dimethyl sulfoxide (50 mL). The reaction was stirred at 120 °C for 5 h, and LCMS showed the reaction was complete. The reaction was cooled to room temperature, and saturated aqueous ammonium chloride was added. The mixture was extracted with dichloromethane twice, and the combined organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give Int-17c (3 g, yield 66.61%) as a yellow solid. LC / MS (ESI + m / z: 449.3 [M+H] + .

[0223] Step B: Int-17c (3 g, 6.69 mmol) was dissolved in dichloromethane (50 mL), and the reaction was cooled to 0 °C in an ice bath. HCl (4.0 M in 1,4-dioxane, 9 mL) was added dropwise. The reaction was stirred at room temperature for 4 h, and a white solid was precipitated. LCMS showed the reaction was complete. The solid was filtered, and the filter cake was rinsed with DCM. The white solid was dried in vacuum to give Int-17 (2 g, yield 85.82%) as a white solid. LC / MS (ESI + m / z: 349.2 [M+H] + .

[0224] Example 1

[0225] 5-((4-((1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0226] Example 1 was prepared by the following steps:

[0227] Step A: Int-2 (270 mg, 0.63 mmol, C) and Int-3 (217.81 mg, 0.63 mmol) were dissolved in dichloromethane (6 mL) at room temperature, and 3 drops of acetic acid were added dropwise. Sodium triacetoxyborohydride (268.11 mg, 1.27 mmol) was added portionwise. The reaction was stirred at room temperature for 2 hours. LC / MS showed that the reaction was complete. The reaction was quenched with water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, (V / V)) to obtain 1a (278 mg, yield 61.15%) as a light yellow solid. ESI-MS (m / z): 719.4 [M+H] + .

[0228] Step B: 1a (278 mg, 0.38 mmol), iron powder (108.00 mg, 1.93 mmol), and ammonium chloride (103.44 mg, 1.93 mmol) were dissolved in ethanol (6.00 mL) and water (1.2 mL) at room temperature. The reaction was stirred at 80 °C for 1 hour. LC / MS showed that the reaction was complete. The reaction was rotary evaporated, dissolved in dichloromethane / methanol = 15 / 1 (V / V), filtered through celite, and the resulting solution was evaporated under reduced pressure to obtain the crude product. The product 1b (158 mg, yield 59.31%) was obtained by purification by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, (V / V)). ESI-MS (m / z): 689.4 [M+H] + .

[0229] Step C: 1b (60 mg, 0.087 mmol) and Int-1 (45.37 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, to which p-toluenesulfonic acid (45.00 mg, 0.26 mmol) was added, and reacted at 100 °C for 16 hours. LC / MS showed the reaction was complete. After cooling to room temperature, the reaction was poured into sodium bicarbonate solution, the product was precipitated, filtered and dried, and the crude product was purified by thin layer preparative plate (dichloromethane / methanol = 10 / 1 (V / V)) to obtain a yellowish solid, which was compound 1 (43.7 mg, yield 47.17%). ESI-MS (m / z): 527.8 [M+2H] 2+ / 2; 1 H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.86 (s, 1H), 8.25 - 8.10 (m, 3H), 7.98 (s, 1H), 7.90 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.59 - 7.50 (m, 1H), 7.38 - 7.31 (m, 2H), 7.27 - 7.20 (m, 1H), 6.79 (s, 1H), 6.48 - 6.34 (m, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 1H), 3.57 - 3.37 (m, 4H), 3.14 - 2.99 (m, 4H), 2.94 - 2.83 (m, 3H), 2.66 - 2.55 (m, 3H), 2.48 - 2.43 (m, 4H), 2.06 - 1.99 (m, 1H), 1.83 - 1.70 (m, 8H), 1.64 - 1.54 (m, 1H), 1.38 - 1.26 (m, 2H), 0.93 - 0.85 (m, 2H), 0.53 - 0.43 (m, 2H).

[0230] Example 2

[0231] 5-((4-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0232] Example 2 was prepared from the following steps:

[0233] Step A: 1b (60 mg, 0.087 mmol) and Int-4 (46.72 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) to which p-toluenesulfonic acid (45.00 mg, 0.26 mmol) was added and reacted at 100 °C for 16 h. LC / MS showed the reaction was complete. Cooled to room temperature, the reaction was poured into sodium bicarbonate solution, the product precipitated, filtered and dried under vacuum. The resulting residue was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 2 as a light yellow solid (41.0 mg, yield 43.76%). ESI-MS (m / z): 533.8 [M+2H] 2+ / 2; 1 H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.11 (s, 1H), 8.86-8.82 (m, 1H), 8.83-8.79 (m, 2H), 8.44-8.39 (m, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.77-7.71 (m, 1H), 7.59-7.48 (m, 2H), 7.39-7.34 (m, 1H), 7.37-7.31 (m, 1H), 6.86-6.80 (m, 1H), 5.10 (dd, J = 12.8, 5.5 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.57-3.40 (m, 4H), 3.14-3.00 (m, 4H), 2.94-2.82 (m, 3H), 2.67-2.53 (m, 4H), 2.48-2.43 (m, 2H), 2.08-1.96 (m, 7H), 1.84-1.75 (m, 2H), 1.65-1.54 (m, 1H), 1.37-1.26 (m, 2H).

[0234] Example 3

[0235] 3-(5-((4-((1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0236] Example 3 was prepared from the following steps:

[0237] Step A: Int-3 (187.88 mg, 0.54 mmol) and Int-5 (205.38 mg, 0.54 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and 3 drops of acetic acid were added. The reaction was cooled to 0 °C in an ice bath, and sodium triacetoxyborohydride (231.27 mg, 1.09 mmol) was added in portions. The reaction was stirred at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction was quenched with water and extracted with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, (V / V)) to give 3a (0.12 g, yield 31.21%) as a light yellow solid. ESI-MS (m / z): 705.3 [M+H] + .

[0238] Step B: 3a (0.12 g, 0.17 mmol), iron powder (47.55 mg, 0.85 mmol) and ammonium chloride (45.55 mg, 0.85 mmol) were dissolved in ethanol (3 mL) and water (0.6 mL) at room temperature, and the reaction was stirred at 80 °C for 1 hour. LC / MS showed the product. The reaction was rotary evaporated, and the residue was dissolved in dichloromethane / methanol = 15 / 1 (V / V). The solution was filtered through celite, and the solvent was removed under reduced pressure to give the crude product. The product 3b (60 mg, yield 52.22%) was obtained by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, (V / V)). ESI-MS (m / z): 675.4 [M+H] + .

[0239] Step C: 3b (50 mg, 0.74 mmol), Int-1 (35.62 mg, 0.89 mmol) and p-toluenesulfonic acid (38.28 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (1 mL), and the reaction was stirred at 100 °C for 16 hours. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, and sodium bicarbonate aqueous solution was added to the reaction. The product was precipitated, filtered and rotary evaporated. The resulting residue was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 3 (8 mg, yield 10.08%) as a light yellow solid. ESI-MS (m / z): 520.6 [M+2H] 2+ / 2. 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.86 (s, 1H), 8.22 (s, 1H), 8.14 (s, 2H), 7.99 (s, 1H), 7.90 (s, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 14.6 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.79 (s, 1H), 6.40 (s, 1H), 5.10 - 5.02 (m, 1H), 4.35 (d, J = 17.3 Hz, 1H), 4.22 (d, J = 17.1 Hz, 1H), 3.87 - 3.72 (m, 6H), 3.46-3.33 (m, 2H), 3.26-3.21 (m, 2H), 3.11 - 2.97 (m, 4H), 2.94-2.90 (m, J = 13.8 Hz, 1H), 2.85-2.80 (m, 4H), 2.62-2.58 (m, 3H), 2.46-2.41 (m, 2H), 2.38-2.31 (m, 1H), 1.98-1.92 (m, 1H), 1.81-1.70 (m, 8H), 1.63-1.58 (m, 2H), 1.31-1.23 (m, 4H).

[0240] Example 4

[0241] N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dicarbonylpiperidin-3-yl)-1,3- dicarbonylisodiindol-5-yl)imino)-1-hydroxy-1l6-thiomorpholino)methyl)piperidin-1-yl)- 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl) methanesulfonamide

[0242] Example 4 was prepared from the following steps:

[0243] Step A: l b (80 mg, 0.11 mmol) and Int-6 (50.31 mg, 0.15 mmol) were dissolved in N,N- dimethylformamide (1.2 mL) at room temperature, to which p-toluenesulfonic acid (60.00 mg, 0.35 mmol) was added and reacted at 100 °C for 16 h. LCMS showed the reaction was complete. Cooled to room temperature, aqueous sodium bicarbonate solution was added to the reaction, the product precipitated, filtered and dried, the residue obtained was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 4 (49.0 mg, yield 39.81%). ESI-MS (m / z): 493.4 [M+2H] 2+ / 2.1 H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.29 (s, 1H), 8.47-8.42 (m, 1H), 8.14-8.07 (m, 2H), 8.02-7.96 (m, 1H), 7.89-7.84 (m, 1H), 7.82 (s, 1H), 7.76-7.70 (m, 1H), 7.61-7.56 (m, 1H), 7.37-7.28 (m, 3H), 7.06-6.99 (m, 1H), 6.90-6.81 (m, 1H), 6.78-6.74 (m, 1H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H), 3.86-3.81 (m, 3H), 3.77 (s, 3H), 3.56-3.39 (m, 4H), 3.10-2.99 (m, 4H), 2.97 (s, 3H), 2.93-2.83 (m, 3H), 2.63-2.52 (m, 4H), 2.46-2.40 (m, 2H), 2.06-2.00 (m, 1H), 1.80-1.73 (m, 2H), 1.61-1.52 (m, 1H), 1.34-1.25 (m, 2H).

[0244] Example 5

[0245] 5-((4-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0246] Example 5 was prepared from the following steps:

[0247] Step A: l b (70 mg, 0.10 mmol) and Int-7 (58.61 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, to which p-toluenesulfonic acid (52.50 mg, 0.31 mmol) was added, and reacted at 100 °C for 16 hours. LCMS showed the reaction was complete. Cooled to room temperature, aqueous sodium bicarbonate solution was added to the reaction, which produced a large amount of solid, the residue obtained after filtration was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system), to give yellow solid 5 (24.6 mg, yield 21.87%). ESI-MS (m / z): 549.3 [M+2H] 2+ / 2.1 H NMR (500 MHz, DMSO-d6) δ 11.96 (s, 1H), 11.11 (s, 1H), 8.41 - 8.28 (m, 1H), 8.27 - 8.11 (m, 3H), 7.98 - 7.87 (m, 1H), 7.79 - 7.68 (m, 2H), 7.61 - 7.44 (m, 2H), 7.40 - 7.29 (m, 2H), 6.76 (s, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.83 - 3.72 (m, 6H), 3.57 - 3.40 (m, 4H), 3.08 - 2.98 (m, 4H), 2.95 - 2.83 (m, 3H), 2.63 - 2.52 (m, 6H), 2.47 - 2.41 (m, 4H), 2.08 - 1.93 (m, 6H), 1.82 - 1.72 (m, 2H), 1.63 - 1.52 (m, 1H), 1.35 - 1.21 (m, 2H).

[0248] Example 6

[0249] 5-((4-(2-(1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)ethyl)-1-hydroxy-1l6-thioxomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0250] Example 6 was prepared by the following steps:

[0251] Step A: Int-3c (200 mg, 0.8 mmol) and 6a (250 mg, 0.96 mmol) were dissolved in dimethyl sulfoxide (3 mL), N,N-diisopropylethylamine (200 mg, 1.59 mmol) was added to the reaction solution. The reaction was carried out at 110 °C for 4 hours, LC / MS showed that the reaction was complete. The reaction was cooled to room temperature, saturated aqueous ammonium chloride was added, dichloromethane was extracted, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain yellow solid 6b (250 mg, yield 87.13%). ESI-MS (m / z): 361.1 [M+H] + .

[0252] Step B: 6b (250 mg, 0.69 mmol) was dissolved in dichloromethane (4 mL), and Dess-Martin Oxidizing Reagent (580 mg, 1.39 mmol) was added at 0 °C. The reaction was stirred at room temperature for 4 h, and LC / MS showed the reaction was complete. The reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, washed with aqueous sodium thiosulfate solution twice, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give 6c (200 mg, yield 80.45%) as a light yellow solid. ESI-MS (m / z): 359.4 [M+H] + .

[0253] Step C: Compound 6c (200 mg, 0.56 mmol) and Int-2 (120 mg, 0.28 mmol) were dissolved in N,N-dimethylformamide (2 mL), and two drops of glacial acetic acid were added. The reaction was cooled to 0 °C, and sodium triacetoxyborohydride (120 mg, 0.56 mmol) was added portionwise. The reaction was stirred at room temperature for 4 h, and LC / MS showed the reaction was complete. The reaction was poured into water, and the yellow product was precipitated, filtered, and dried under vacuum to give 6d (200 mg, yield 97.09%) as a yellow solid. ESI-MS (m / z): 733.3 [M+H] + .

[0254] Step D: 6d (200 mg, 0.27 mmol), iron powder (80 mg, 1.36 mmol), and ammonium chloride (80 mg, 1.36 mmol) were dissolved in a mixture of ethanol (5 mL) and water (1 mL). The reaction was stirred at 80 °C for 1 h, and LC / MS showed the reaction was complete. The reaction was concentrated, dissolved in dichloromethane, and filtered through celite. The filtrate was concentrated under reduced pressure, and the crude product was purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 10 / 1) to give 6e (120 mg, yield 62.56%) as a yellow solid. ESI-MS (m / z): 703.3 [M+H] + .

[0255] Step E: 6e (50 mg, 0.07 mmol), Int-1 (57 mg, 0.14 mmol), and p-toluenesulfonic acid (37 mg, 0.2 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction was stirred at 100 °C for 16 h, and LC / MS showed the reaction was complete. The reaction was cooled to room temperature, poured into saturated aqueous sodium bicarbonate solution, and a large amount of solid was produced. The residue was filtered and purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 15 / 1) to give 6 (18 mg, yield 23.48%) as a yellow solid. ESI-MS (m / z): 534.8 [M+2H]2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.85 (s, 1H), 8.26 - 8.07 (m, 3H), 7.98 (s, 1H), 7.89 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.55 (s, 1H), 7.40 - 7.31 (m, 2H), 7.23 (d, J = 14.4 Hz, 1H), 6.79 (s, 1H), 6.44 (s, 1H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.55 - 3.48 (m, 2H), 3.47 - 3.38 (m, 2H), 3.30 - 3.15 (m, 1H), 3.12 - 2.98 (m, 4H), 2.94 - 2.83 (m, 3H), 2.67 - 2.53 (m, 5H), 2.06 - 1.99 (m, 1H), 1.88 - 1.65 (m, 9H), 1.53 - 1.44 (m, 2H), 1.43 - 1.31 (m, 3H), 0.92 - 0.84 (m, 2H), 0.56 - 0.45 (m, 2H).

[0256] Example 7

[0257] 5-((4-(2-(4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(l-methyl-lH-pyrazol-4-yl)phenyl)piperazin-l-yl)ethyl)-l- hydroxy-l l6-thioxomorpholin-l-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-l,3-dione

[0258] Example 7 was prepared from the following steps:

[0259] Step A: Int-3c (1.0 g, 3.98 mmol) and 7a (621.88 mg, 4.78 mmol) were dissolved in dimethyl sulfoxide (20 mL). N,N-diisopropylethylamine (1.0 g, 7.96 mmol) was added to the reaction solution. The reaction was carried out at 110 °C for 4 hours, and LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and saturated ammonium chloride aqueous solution was added. The mixture was extracted with dichloromethane, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a yellow solid 7b (600 mg, yield 41.71%). ESI-MS (m / z): 362.1 [M+H] + .

[0260] Step B: Under nitrogen protection, oxalyl chloride (210 mg, 1.66 mmol) was dissolved in anhydrous dichloromethane (3 mL). The solution was cooled to -78 °C, and dimethyl sulfoxide (194.57 mg, 2.49 mmol) was slowly added dropwise. The mixture was stirred at -78 °C for 1 hour. Then, a solution of 7b (200 mg, 0.69 mmol) in dichloromethane (2 mL) was added dropwise. The mixture was then stirred at -78 °C. o The reaction was continued at C for 2 hours, then triethylamine (560 mg, 5.53 mmol) was added, and the reaction was continued at room temperature for 30 minutes. LC / MS showed that the reaction was complete. The reaction solution was extracted with saturated sodium bicarbonate aqueous solution and dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a pale yellow solid 7c (150 mg, yield 75.42%). ESI-MS (m / z): 360.1 [M+H] + .

[0261] Step C: Compound 7c (150 mg, 0.4 mmol) and Int-2 (83 mg, 0.2 mmol) were dissolved in N,N-dimethylformamide (2 mL), and two drops of glacial acetic acid were added dropwise. Under ice bath conditions, sodium triacetoxyborohydride (90 mg, 0.4 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 2 hours, and LC / MS showed complete reaction. The reaction solution was poured into water, and a yellow solid precipitated. The mixture was filtered, the filter cake was washed with water, and then dried under vacuum to give yellow solid 7d (150 mg, yield 96.15%). ESI-MS (m / z): 734.3 [M+H] + .

[0262] Step D: 7d (150 mg, 0.27 mmol), iron powder (80 mg, 1.36 mmol) and ammonium chloride (80 mg, 1.36 mmol) were dissolved in a mixed solution of ethanol (5 mL) and water (1 mL). The reaction was carried out at 80 °C for 1 h, LC / MS showed the reaction was complete. The reaction was concentrated, dissolved in dichloromethane, filtered with celite, and the filtrate was rotary evaporated to dryness. The resulting crude was purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 10 / 1) to give yellow solid 7e (80 mg, yield 55.61%). ESI-MS (m / z): 704.3 [M+H] + .

[0263] Step E: 7e (40 mg, 0.057 mmol), Int-1 (45 mg, 0.11 mmol) and p-toluenesulfonic acid (30 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (1 mL) at room temperature. The reaction was carried out at 100 °C for 16 h, LC / MS showed the reaction was complete. The reaction was poured into saturated aqueous sodium bicarbonate solution, a large amount of solid was produced, the resulting residue was purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 15 / 1) to give yellow solid 7 (17 mg, yield 27.69%). ESI-MS (m / z): 534.6 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) d 11.11 (s, 1H), 10.85 (s, 1H), 8.20 (s, 1H), 8.14 (s, 2H), 7.98 (s, 1H), 7.90 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.56 (s, 1H), 7.39 - 7.30 (m, 2H), 7.22 (dd, J = 14.4, 2.0 Hz, 1H), 6.79 (s, 1H), 6.43 (s, 1H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.55 - 3.48 (m, 2H), 3.47 - 3.39 (m, 2H), 3.32 - 3.25 (m, 1H), 3.15 - 3.07 (m, 2H), 3.03 - 2.90 (m, 3H), 2.90 - 2.77 (m, 5H), 2.74 - 2.67 (m, 2H), 2.65 - 2.52 (m, 6H), 2.06 - 1.99 (m, 1H), 1.82 - 1.77 (m, 1H), 1.75 (s, 3H), 1.73 (s, 3H), 0.91 - 0.85 (m, 2H), 0.54 - 0.46 (m, 2H).

[0264] Example 8

[0265] 5-((4-(2-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)ethyl)-1-hydroxy-1l6-thioxomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0266] Example 8 was prepared from the following steps:

[0267] Step A: 6e (70 mg, 0.1 mmol), Int-4 (82 mg, 0.2 mmol) and p-toluenesulfonic acid (51 mg, 0.3 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction was stirred at 100 °C for 16 h, LC / MS showed the reaction was complete. The reaction was poured into saturated aqueous sodium bicarbonate solution, a large amount of solid precipitated, filtered and dried. The resulting crude product was purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 15 / 1) to give yellow solid 8 (35 mg, yield 32.24%). ESI-MS (m / z): 540.2 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.10 (s, 1H), 8.82 (d, J = 14.9 Hz, 3H), 8.40 (s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.57 (s, 2H), 7.34 (dd, J = 13.4, 5.3 Hz, 2H), 6.82 (s, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.57 - 3.48 (m, 2H), 3.47 - 3.40 (m, 2H), 3.13 - 2.99 (m, 4H), 2.94 - 2.83 (m, 3H), 2.70 - 2.52 (m, 6H), 2.07 - 2.03 (m, 1H), 2.03 (s, 3H), 2.00 (s, 3H), 1.80 - 1.68 (m, 2H), 1.55 - 1.44 (m, 2H), 1.44 - 1.30 (m, 3H).

[0268] Example 9

[0269] 5-((4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)-1-hydroxy-1l6-thioxomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0270] Example 9 was prepared from the following steps:

[0271] Step A: 7e (40 mg, 0.056 mmol), Int-4 (47 mg, 0.11 mmol) and p-toluenesulfonic acid (30 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction was reacted at 100 °C for 16 hours, LC / MS showed the reaction was complete. The reaction was poured into saturated aqueous sodium bicarbonate solution, which produced a large amount of solid, the residue was purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 15 / 1) to give yellow solid 9 (13 mg, yield 20.94%). ESI-MS (m / z): 540.6 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.11 (s, 1H), 8.84 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 1.6 Hz, 2H), 8.45 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.37 - 7.31 (m, 2H), 6.83 (s, 1H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.55 - 3.48 (m, 3H), 3.48 - 3.44 (m, 3H), 3.15 - 3.08 (m, 4H), 3.01 - 2.93 (m, 3H), 2.90 - 2.81 (m, 5H), 2.73 - 2.68 (m, 2H), 2.62 - 2.55 (m, 4H), 2.03 (s, 3H), 2.00 (s, 3H).

[0272] Example 10

[0273] 5-((4-(3-(4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)propyl)-1-hydroxy-1l6-thioxomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0274] Example 10 was prepared by the following steps:

[0275] Step A: Int-3c (1 g, 3.98 mmol) and 10a (688 mg, 4.78 mmol) were dissolved in dimethyl sulfoxide (20 mL), and N, N-diisopropyl ethylamine (1 g, 7.96 mmol) was added to the reaction solution. The reaction was carried out at 110 °C for 4 hours, and LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride was added, and dichloromethane was used for extraction, and the organic phases were combined. After washing with saturated brine, anhydrous sodium sulfate was added for drying, and the mixture was filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain yellow solid 10b (1.1 g, yield 73.61%). ESI-MS (m / z): 376.2 [M+H] + .

[0276] Step B: Oxalyl chloride (676.2 mg, 1.07 mmol) was dissolved in anhydrous dichloromethane (10 ml) under nitrogen protection, and the solution was cooled to -78 °C. Dimethyl sulfoxide (416.23 mg, 5.33 mmol) was slowly added dropwise, and the mixture was stirred at -78 °C for 1 hour. A solution of 10b (400 mg, 1.07 mmol) in dichloromethane (3 mL) was added dropwise to the reaction solution, and the mixture was reacted at -78 °C for 2 hours. Triethylamine (1.08 g, 10.65 mmol) was added, and the mixture was reacted at room temperature for 30 minutes. LC / MS showed that the reaction was complete. Saturated aqueous sodium bicarbonate was added to the reaction solution, and dichloromethane was used for extraction. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain yellow solid 10c (300 mg, yield 75.40%). ESI-MS (m / z): 374.2 [M+H] + .

[0277] Step C: Compound 10c (300 mg, 0.80 mmol) and Int-2 (170 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (5 mL), two drops of glacial acetic acid were added, and sodium triacetoxyborohydride (168.81 mg, 0.8 mmol) was added portionwise under ice bath condition. The reaction was stirred at room temperature for 2 hours, LC / MS showed the reaction was complete. The reaction was poured into water, and a yellow solid was precipitated, which was filtered, the filter cake was washed with water, the obtained crude was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give yellow solid 10d (100 mg, yield 33.58%). ESI-MS (m / z): 748.3 [M+H] + .

[0278] Step D: 10d (100 mg, 0.13 mmol), iron powder (80 mg, 1.36 mmol) and ammonium chloride (80 mg, 1.36 mmol) were dissolved in a mixture of ethanol (5 mL) and water (1 mL). The reaction was stirred at 80 °C for 1 hour, LC / MS showed the reaction was complete. The reaction was concentrated, dissolved in dichloromethane and filtered through celite. The filtrate was rotary evaporated, the obtained crude was purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 10 / 1) to give yellow solid 10e (60 mg, yield 62.51%). ESI-MS (m / z): 718.3 [M+H] + .

[0279] Step E: 10e (30 mg, 0.042 mmol), Int-1 (34 mg, 0.083 mmol) and p-toluenesulfonic acid (30 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction was stirred at 100 °C for 16 hours, LC / MS showed the reaction was complete. The reaction was poured into saturated aqueous sodium bicarbonate solution, a large amount of solid was produced, which was filtered and the obtained residue was purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 10 / 1) to give yellow solid 10 (7.6 mg, yield 16.64%). ESI-MS (m / z): 541.6 [M+2H] 2+ / 2. 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.85 (s, 1H), 8.21 (s, 1H), 8.14 (s, 2H), 7.99 (s, 1H), 7.91 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.33 (dd, J = 12.7, 4.7 Hz, 2H), 7.22 (d, J = 14.5 Hz, 1H), 6.80 (s, 1H), 6.43 (s, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.55 - 3.48 (m, 2H), 3.48 - 3.41 (m, 2H), 3.05 - 2.97 (m, 3H), 2.94 - 2.81 (m, 7H), 2.62 - 2.52 (m, 5H), 2.42 - 2.34 (m, 3H), 2.06 - 1.95 (m, 2H), 1.82 - 1.78 (m, 1H), 1.75 (s, 3H), 1.73 (s, 3H), 1.66 - 1.58 (m, 2H), 0.91 - 0.87 (m, 2H), 0.53 - 0.46 (m, 2H).

[0280] Example 11

[0281] 5-((4-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)propyl)-1-hydroxy-1l6-thioxomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0282] Example 11 was prepared from the following steps:

[0283] Step A: 10e (30 mg, 0.042 mmol), Int-4 (34 mg, 0.08 mmol) and p-toluenesulfonic acid (30 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction was reacted at 100 °C for 16 h, LC / MS showed the reaction was complete. The reaction was poured into saturated aqueous sodium bicarbonate solution, a large amount of solid precipitated, filtered and dried. The crude product was purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 15 / 1) to give yellow solid 11 (6 mg, yield 12.99 %). ESI-MS (m / z): 547.1 [M+2H] 2+ / 2. 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.85 (s, 1H), 8.21 (s, 1H), 8.14 (s, 2H), 7.99 (s, 1H), 7.91 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.33 (dd, J = 12.7, 4.7 Hz, 2H), 7.22 (d, J = 14.5 Hz, 1H), 6.80 (s, 1H), 6.43 (s, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.55 - 3.48 (m, 2H), 3.48 - 3.41 (m, 2H), 3.05 - 2.97 (m, 3H), 2.94 - 2.81 (m, 7H), 2.62 - 2.52 (m, 5H), 2.42 - 2.34 (m, 3H), 2.06 - 1.95 (m, 2H), 1.82 - 1.78 (m, 1H), 1.75 (s, 3H), 1.73 (s, 3H), 1.66 - 1.58 (m, 2H), 0.91 - 0.87 (m, 2H), 0.53 - 0.46 (m, 2H).

[0284] Example 12

[0285] 5-((4-(((S)-1-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)methyl)-1-hydroxy-1l6-thioxomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindoline-1,3-dione

[0286] Example 12 was prepared by the following steps:

[0287] Step A: Int-2 (500 mg, 1.28 mmol) was dissolved in DCM (10 mL), cooled to 0 °C in an ice bath, 3 drops of acetic acid was added dropwise, sodium triacetoxyborohydride (814.29 mg, 3.84 mmol) was added portionwise, and the reaction was allowed to proceed at room temperature for about 2 hours. LC / MS showed that the reaction was complete. The reaction was concentrated, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 15 / 1) to give the product 12b (510 mg, yield: 69.42%) as a light yellow solid. Light yellow solid. ESI-MS (m / z): 474.3 [M-100+H] + .

[0288] Step B: 12b (510 mg, 0.89 mmol) was dissolved in DCM (4 mL) at room temperature, and a HC1 / dioxane solution (4 M, 3 mL) was added at 0 °C. The reaction was stirred at room temperature for 2 h. LC / MS showed the reaction was complete. The solvent was removed under reduced pressure to give the crude product 12c (360 mg, crude). It was used in the next step without further purification. ESI-MS (m / z): 474.3 [M+H] + .

[0289] Step C: 12c (343.78 mg, 0.72 mmol) and Int-1 (250 mg, 0.72 mmol) were dissolved in DCM (15 mL) at room temperature, and the reaction was cooled to 0 °C in an ice bath. A catalytic amount of acetic acid (3 drops) was added, followed by the addition of sodium triacetoxyborohydride (461.59 mg, 2.18 mmol) in portions. The reaction was stirred at room temperature for about 2 h. LC / MS showed the reaction was complete. The reaction was concentrated, and the residue was purified by column chromatography (DCM / methanol (V / V) = 15 / 1) to give the product 12d (100 mg, yield 7.18%) as a light yellow solid. ESI-MS (m / z): 802.4 [M+H] + .

[0290] Step D: 12d (100 mg, 0.12 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL) at room temperature, and iron powder (34.82 mg, 0.62 mmol) and ammonium chloride (33.35 mg, 0.62 mmol) were added to the reaction. The reaction was stirred at 80 °C for 1 h. LC / MS showed the reaction was complete. After cooling to room temperature, the reaction was concentrated, dissolved in DCM / methanol = 15 / 1, and filtered through diatomite. The resulting solution was concentrated under reduced pressure to give the crude product, which was purified by thin layer chromatography (DCM / methanol = 15 / 1) to give 12e (60 mg, yield 62.33%) as a yellow solid. ESI-MS (m / z): 772.4 [M+H] + .

[0291] Step E: 12e (30 mg, 0.039 mmol) and Int-4 (22.45 mg, 0.054 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (20.08 mg, 0.11 mmol) was added to the reaction. The reaction was stirred at 100 °C for 16 h. LC / MS showed the reaction was complete. After cooling to room temperature, an aqueous sodium bicarbonate solution was added to the reaction, and a large amount of solid was produced. The residue was filtered and purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 12 (10.7 mg, yield: 23.74%) as a light yellow solid. ESI-MS (m / z): 575.3 [M+2H]2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.67 (s, 1H), 11.12 (s, 1H), 8.90-8.77 (m, 2H), 8.48-8.39 (m, 1H), 8.27 (s, 1H), 8.24-8.19 (m, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.75-7.70 (m, 1H), 7.40-7.29 (m, 2H), 6.83 (s, 1H), 6.74-6.66 (m, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 3.81-3.74 (m, 6H), 3.10-2.98 (m, 6H), 2.93-2.82 (m, 4H), 2.68-2.53 (m, 4H), 2.49-2.43 (m, 4H), 2.42-2.31 (m, 3H), 2.28-2.23 (m, 1H), 2.06-1.97 (m, 7H), 1.92-1.83 (m, 1H), 1.81-1.72 (m, 4H), 1.60-1.52 (m, 1H), 1.45-1.38 (m, 1H), 1.36-1.27 (m, 2H).

[0292] Example 13

[0293] 5-((4-(((R)-1-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)methyl)-1-hydroxy-1l6-thioxomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0294] Example 13 was prepared from the following steps:

[0295] Step A: Int-2 (500 mg, 1.28 mmol) and 13a (331.73 mg, 1.66 mmol) were dissolved in dichloromethane (10 mL), cooled to 0 °C in an ice bath, and a catalytic amount of acetic acid (3 drops) was added. Sodium triacetoxyborohydride (814.29 mg, 3.84 mmol) was added portionwise, and the reaction was allowed to proceed at room temperature for about 2 hours. LC / MS showed that the reaction was complete. The reaction was concentrated, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 15 / 1) to give the product 13b (525 mg, yield 71.46%) as a light yellow solid. Light yellow solid. ESI-MS (m / z): 474.3 [M-100+H]+ .

[0296] Step B: 13b (525 mg, 0.91 mmol) was dissolved in dichloromethane (5 mL) at room temperature, hydrochloric acid / dioxane solution (4 M, 4 mL) was added at 0 °C, the reaction was stirred at room temperature for 2 hours. LC / MS showed the reaction was complete. The solvent was removed by evaporation under reduced pressure to obtain the crude product 13c (365 mg, crude). It was used in the next step without further purification. ESI-MS (m / z): 474.3 [M+H] + .

[0297] Step C: 13c (360 mg, 0.71 mmol, C) and Int-3 (291.69 mg, 0.85 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the reaction was cooled to 0 °C in an ice bath, a catalytic amount of acetic acid (4 drops) was added, and sodium triacetoxyborohydride (448.81 mg, 2.12 mmol) was added portionwise. The reaction was stirred at room temperature for about 2 hours. LC / MS showed that the reaction was complete, the reaction was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to obtain the product 13d (200 mg, yield 35.33%) as a light yellow solid. ESI-MS (m / z): 802.4 [M+H] + .

[0298] Step D: 13d (200 mg, 0.25 mmol) was dissolved in ethanol (4 mL) and water (0.8 mL) at room temperature, iron powder (69.64 mg, 1.25 mmol) and ammonium chloride (66.70 mg, 1.25 mmol) were added to the reaction, and the reaction was stirred at 80 °C for 1 hour. LC / MS showed that the reaction was complete. After cooling to room temperature, the reaction was concentrated, dissolved in dichloromethane / methanol = 15 / 1, and filtered through diatomite. The obtained solution was concentrated under reduced pressure to obtain the crude product, which was purified by thin layer chromatography (dichloromethane / methanol = 15 / 1) to obtain 13e (95 mg, yield 49.34%) as a yellow solid. ESI-MS (m / z): 772.4 [M+H] + .

[0299] Step E: 13e (50 mg, 0.065 mmol) and Int-F (34.74 mg, 0.084 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) to which p-toluenesulfonic acid (33.46 mg, 0.19 mmol) was added and reacted at 100 °C for 16 h. LC / MS showed the reaction was complete. Cooled to room temperature, aqueous sodium bicarbonate solution was added to the reaction, which resulted in a large amount of solid, the residue obtained after filtration was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give light yellow solid 13 (13.4 mg, yield 17.84%). ESI-MS (m / z): 575.2 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.12 (s, 1H), 8.88 - 8.74 (m, 3H), 8.43 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.75 - 7.70 (m, 1H), 7.61 - 7.52 (m, 1H), 7.39 - 7.29 (m, 2H), 6.83 (s, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 3.82 - 3.73 (m, 6H), 3.54 - 3.40 (m, 5H), 3.11 - 2.98 (m, 4H), 2.94 - 2.81 (m, 3H), 2.68 - 2.51 (m, 5H), 2.49 - 2.45 (m, 2H), 2.40 - 2.31 (m, 4H), 2.29 - 2.22 (m, 1H), 2.07 - 1.96 (m, 7H), 1.91 - 1.81 (m, 1H), 1.81 - 1.75 (m, 2H), 1.61 - 1.51 (m, 1H), 1.45 - 1.37 (m, 1H), 1.37 - 1.25 (m, 2H).

[0300] Example 14

[0301] 5-((4-(((S)-1-((1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)methyl)-1-hydroxy-1l6-thioxomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0302] Example 14 was prepared from the following steps:

[0303] Step A: 12e (30 mg, 0.039 mmol) and Int-1 (21.80 mg, 0.054 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) to which p-toluenesulfonic acid (20.08 mg, 0.11 mmol) was added and reacted at 100 °C for 16 h. LC / MS showed the reaction to be complete. The reaction was cooled to room temperature and an aqueous solution of sodium bicarbonate was added to the reaction which resulted in a large amount of solid which was filtered and the residue obtained was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain 14 as a yellow solid (10.6 mg, yield: 22.23%). ESI-MS (m / z): 569.5 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.86 (s, 1H), 8.28 - 8.20 (m, 1H), 8.18 - 8.12 (m, 2H), 8.01 - 7.97 (m, 1H), 7.89 (s, 1H), 7.76 - 7.70 (m, 1H), 7.59 - 7.52 (m, 1H), 7.36 - 7.30 (m, 2H), 7.27 - 7.20 (m, 1H), 6.80 (s, 1H), 6.45 - 6.39 (m, 1H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.54 - 3.43 (m, 5H), 3.11 - 2.97 (m, 4H), 2.93 - 2.82 (m, 3H), 2.66 - 2.55 (m, 5H), 2.48 - 2.42 (m, 2H), 2.40 - 2.28 (m, 4H), 2.25 - 2.18 (m, 1H), 2.05 - 1.98 (m, 1H), 1.89 - 1.70 (m, 10H), 1.59 - 1.50 (m, 1H), 1.44 - 1.36 (m, 1H), 1.35 - 1.27 (m, 2H), 0.92 - 0.85 (m, 2H), 0.53 - 0.46 (m, 2H).

[0304] Example 15

[0305] 5-((4-(((R)-1-((1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)methyl)-1-hydroxy-1l6-thioxomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0306] Example 15 was prepared from the following steps:

[0307] Step A: 13e (50 mg, 0.65 mmol) and Int-1 (33.74 mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) to which p-toluenesulfonic acid (33.46 mg, 0.19 mmol) was added and reacted at 100 °C for 16 h. LC / MS showed the reaction was complete. The reaction was cooled to room temperature and aqueous sodium bicarbonate solution was added to the reaction which resulted in a large amount of solid which was filtered and the residue obtained was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to get 15 as a yellow solid (10.5 mg, yield 14.13%). ESI-MS (m / z): 569.3 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.85 (s, 1H), 8.25 - 8.18 (m, 1H), 8.18 - 8.11 (m, 2H), 7.99 (s, 1H), 7.90 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.37 - 7.30 (m, 2H), 7.27 - 7.20 (m, 1H), 6.79 (s, 1H), 6.47 - 6.35 (m, 1H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.55 - 3.41 (m, 5H), 3.11 - 2.98 (m, 4H), 2.94 - 2.81 (m, 3H), 2.65 - 2.56 (m, 5H), 2.47 - 2.33 (m, 6H), 2.06 - 1.99 (m, 1H), 1.95 - 1.86 (m, 1H), 1.84 - 1.69 (m, 10H), 1.66 - 1.57 (m, 1H), 1.50 - 1.41 (m, 1H), 1.40 - 1.28 (m, 2H), 0.93 - 0.86 (m, 2H), 0.52 - 0.44 (m, 2H).

[0308] Example 16

[0309] 5-((4-((1-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)azetidin-3-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0310] Example 16 was prepared by the following steps:

[0311] Step A: Int-2 (500 mg, 1.17 mmol) and 16a (260.34 mg, 1.41 mmol) were dissolved in dichloromethane (10 mL) at room temperature, a catalytic amount of acetic acid (3 drops) was added, and sodium triacetoxyborohydride (1.24 g, 5.86 mmol) was added portionwise in an ice bath. The reaction was stirred at room temperature for 2 h, and LC / MS showed that the reaction was complete. Saturated sodium bicarbonate solution was added to the reaction, and dichloromethane was used to extract the mixture. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain white solid 16b (550 mg, yield 83.91%). ESI-MS (m / z): 559.63 [M+H] + .

[0312] Step B: 16b (550 mg, 0.99 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and trifluoroacetic acid (5 mL) was slowly added dropwise to the system in an ice bath. The reaction was stirred at room temperature for 2 h, and LC / MS showed that the reaction was complete. Methyl tert-butyl ether was added to the system, and a large amount of solid was precipitated. After filtration, the solid was dried to obtain white solid 16c (535 mg, yield 95%). ESI-MS (m / z): 449.63 [M+H] + .

[0313] Step C: 16c (610 mg, 1.06 mmol) and Int-3 (439.51 mg, 1.28 mmol) were dissolved in dichloromethane (10 mL), and a catalytic amount of acetic acid (3 drops) was added to the reaction in an ice bath, followed by the addition of sodium triacetoxyborohydride (1.13 g, 5.32 mmol) portionwise. The reaction was stirred at room temperature for 2 h, and LC / MS showed that the reaction was complete. Saturated sodium bicarbonate solution was added to quench the reaction, and dichloromethane was used to extract the mixture. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain white solid 16d (720 mg, yield 85.92%). ESI-MS (m / z): 787.88 [M+H] + .

[0314] Step D: 16d (630 mg, 0.79 mmol) was dissolved in ethanol (8 mL) and water (1.6 mL), iron powder (220.6 mg, 3.95 mmol) and ammonium chloride (211.28 mg, 3.95 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC / MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved with dichloromethane / methanol = 15 / 1, and then filtered with diatomite. The obtained solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain yellow solid 16e (520 mg, yield 85.81%). ESI-MS (m / z): 757.90 [M+H] + .

[0315] Step E: 16e (100 mg, 0.13 mmol), Int-4 (65.33 mg, 0.16 mmol), p-toluenesulfonic acid (68.16 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature, and the reaction was carried out at 100 °C for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and an aqueous sodium bicarbonate solution was added to the reaction solution to produce a large amount of solid. The obtained residue was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia water system) after filtration to obtain white solid 16 (3.3 mg, yield 2.21%). ESI-MS (m / z): 568.3 [M+2H] 2+ / 2. 1HNMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.13 (s, 1H), 8.85 (s, 1H), 8.82 (s, 1H), 8.44 (s, 1H), 8.40 (s, 2H), 8.28 (s, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 6.82 (s, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.49 - 3.48 (m, 5H), 3.36 - 3.34 (m, 4H), 3.08 - 3.04 (m, 2H), 2.99 - 2.95 (m, 2H), 2.92 - 2.88 (m, 1H), 2.87 - 2.82 (m, 2H), 2.80 - 2.75 (m, 2H), 2.71 - 2.67 (m, 2H), 2.63 - 2.56 (m, 4H), 2.36 - 2.31 (m, 2H), 2.03 (s, 3H), 2.01 (s, 3H), 1.74 - 1.68 (m, 2H), 1.33 - 1.28 (m, 2H).

[0316] Example 17

[0317] 5-((4-((1-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)azetidin-3-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0318] Example 17 is prepared from the following steps:

[0319] Step A: 16e (100 mg, 0.13 mmol), 17a (65.33 mg, 0.16 mmol) were dissolved in dioxane (1.5 mL) at room temperature, BrettPhos (14.16 mg, 0.026 mmol), BrettPhos Pd G3 (11.96 mg, 0.013 mmol) and cesium carbonate (128.97 mg, 0.39 mmol) were added successively, the reaction was carried out at 100 °C for 16 h under nitrogen atmosphere. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, washed with saturated brine, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia water system) to obtain 17 as a white solid (13.7 mg, yield 10.01%). ESI-MS (m / z): 519.5 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 11.22 (s, 1H), 11.12 (s, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.57 (s, 1H), 7.52 - 7.47 (m, 1H), 7.36 - 7.34 (m, 1H), 7.32 (dd, J = 8.1, 2.0 Hz, 1H), 7.01 - 6.97 (m, 1H), 6.78 (s, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.49 - 3.45 (m, 4H), 3.43 - 3.41 (m, 4H), 3.06 - 3.02 (m, 2H), 2.98 - 2.94 (m, 2H), 2.91 - 2.87 (m, 1H), 2.86 - 2.82 (m, 2H), 2.80 - 2.77 (m, 2H), 2.70 - 2.67 (m, 2H), 2.62 - 2.59 (m, 1H), 2.58 - 2.52 (m, 4H), 2.36 - 2.33 (m, 2H), 2.06 - 2.01 (m, 1H), 1.77 (s, 3H), 1.75 (s, 3H), 1.72 - 1.69 (m, 2H), 1.38 - 1.33 (m, 1H), 1.32 - 1.27 (m, 2H).

[0320] Example 18

[0321] 5-((4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0322] Example 18 was prepared from the following steps:

[0323] Step A: To Int-3c (1.5 g, 5.97 mmol) in dimethyl sulfoxide (15 mL) was added 18a (1.64 g, 11.94 mmol), potassium carbonate (4.95 g, 35.83 mmol) at room temperature. The reaction was stirred at 100 °C for 16 h. LC / MS showed the reaction was complete. The reaction was diluted with saturated brine solution. The organic phase was combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give 18b (1.6 g, yield 80.63%) as a yellow solid. ESI-MS (m / z): 332.35 [M+H] + .

[0324] Step B: 18b (1.0 g, 3.01 mmol) was dissolved in dichloromethane (15 mL) at room temperature. Dess-Martin reagent (1.91 g, 4.51 mmol) was added to the reaction mixture under ice bath. The reaction was stirred at room temperature for 2 h. LC / MS showed the reaction was complete. The reaction was diluted with saturated sodium bicarbonate solution. The organic phase was combined and washed with sodium thiosulfate solution. The organic phase was combined and dried over anhydrous sodium sulfate, filtered and concentrated to give 18c (760 mg, crude) as a yellow solid. ESI-MS (m / z): 330.34 [M+H] + .

[0325] Step C: 18c (420 mg, 1.51 mmol) and Int-2 (700 mg, 1.51 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and acetic acid (3 drops) was added to the mixture under ice bath. Sodium triacetylboration hydride (1.6 g, 7.55 mmol) was added portionwise. The reaction was stirred at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction was quenched by saturated sodium bicarbonate solution. The organic phase was extracted by ethyl acetate for three times. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 18d (835 mg, yield 84.68%) as a yellow solid. ESI-MS (m / z): 652.72 [M+H] + .

[0326] Step D: 18d (100 mg, 0.15 mmol) was dissolved in ethanol (4 mL) and water (0.8 mL) at room temperature. Iron powder (42.78 mg, 0.77 mmol) and ammonium chloride (40.97 mg, 0.77 mmol) were added to the reaction mixture. The reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated. The residue was dissolved in dichloromethane / methanol = 15 / 1 and filtered through celite. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 18e (90 mg, yield 94.33%) as a yellow solid. ESI-MS (m / z): 622.73 [M+H] + .

[0327] Step E: 18e (50 mg, 0.074 mmol), Int-4 (36.69 mg, 0.089 mmol), p-toluenesulfonic acid (38.28 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature. The reaction was stirred at 100 °C for 16 hours. The reaction was cooled to room temperature and 10 mL of saturated aqueous sodium bicarbonate solution was added. A yellow solid was precipitated. The crude product was obtained by filtration. The crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia water system) to give 18 (28.9 mg, yield 37.11%) as a white solid. ESI-MS (m / z): 526.8 [M+2H] 2+ / 2. 1HNMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.13 (s, 1H), 8.85 (d, J = 1.7 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.43 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.57 (s, 1H), 7.38 (d, J = 1.5 Hz, 1H), 7.36 (dd, J = 8.1, 1.9 Hz, 1H), 6.82 (s, 1H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.59 - 3.53 (m, 2H), 3.47 - 3.42 (m, 3H), 3.20 - 3.12 (m, 4H), 3.05 - 2.98 (m, 2H), 2.93 - 2.85 (m, 1H), 2.68 - 2.55 (m, 5H), 2.04 (s, 3H), 2.01 (s, 3H), 1.83 - 1.76 (m, 2H), 1.69 - 1.61 (m, 2H).

[0328] Example 19

[0329] 5-((4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2- ethyl-5-methoxyphenyl)piperidin-4-yl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6- dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0330] Example 19 was prepared by the following steps:

[0331] Step A: To 19a (1.0 g, 5.02 mmol) in dimethyl sulfoxide (15 mL) was added 19b (1.38 g, 10.04 mmol), potassium carbonate (4.16 g, 30.12 mmol) at room temperature. The reaction was stirred at 100 °C for 16 h. LC / MS showed the reaction was completed. The reaction mixture was added to saturated brine and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give yellow solid 19c (1.1 g, yield 78.16%). ESI-MS (m / z): 280.32 [M+H] + .

[0332] Step B: 19c (1.0 g, 3.57 mmol) was dissolved in tetrahydrofuran (15 mL) at room temperature, and Dess-Martin Oxidizing Reagent (2.27 g, 5.36 mmol) was added to the reaction system. The reaction was stirred at room temperature for 2 hours. LC / MS showed that the reaction was complete. Saturated sodium bicarbonate solution was added to quench the reaction, and the reaction was extracted with ethyl acetate three times. The organic phase was washed with sodium thiosulfate solution, and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give yellow solid 19d (900 mg, crude), which was used without further purification. ESI-MS (m / z): 278.30 [M+H] + .

[0333] Step C: 19d (700 mg, 1.51 mmol) and Int-2 (700 mg, 1.51 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and acetic acid (3 drops) was added to the reaction system under ice bath conditions. Sodium triacetylboration hydride (1.6 g, 7.55 mmol) was added portionwise. The reaction was stirred at room temperature for 2 hours. LC / MS showed that the reaction was complete. Saturated sodium bicarbonate solution was added to quench the reaction, and the reaction was extracted with ethyl acetate three times. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give yellow solid 19e (835 mg, yield 84.68%). ESI-MS (m / z): 652.72 [M+H] + .

[0334] Step D: 19e (100 mg, 0.15 mmol) was dissolved in ethanol (4 mL) and water (0.8 mL) at room temperature, and iron powder (42.78 mg, 0.77 mmol) and ammonium chloride (40.97 mg, 0.77 mmol) were added to the reaction solution. The reaction was stirred at 80°C for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, concentrated, dissolved in dichloromethane / methanol = 15 / 1, filtered through diatomite, and concentrated under reduced pressure to give the crude product. The product was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give yellow solid 19f (91 mg, yield 95.38%). ESI-MS (m / z): 622.73 [M+H] + .

[0335] Step E: 19f (50 mg, 0.08 mmol), Int-4 (49.69 mg, 0.12 mmol), p-toluenesulfonic acid (41.48 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) under nitrogen protection, and reacted at 100 °C for 16 hours. The reaction solution was cooled to room temperature, 10 mL of saturated aqueous sodium bicarbonate solution was added, and a yellow solid was precipitated. After suction filtration, the crude product was obtained, and purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia water system) to obtain white solid 19 (2.6 mg, yield 3.24%). ESI-MS (m / z): 500.8 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.64 (s, 1H), 11.12 (s, 1H), 8.87 (dd, J = 8.6, 1.8 Hz, 2H), 8.83 - 8.77 (m, 1H), 8.48 - 8.41 (m, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 7.92 - 7.86 (m, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.35 (dd, J = 8.1, 1.9 Hz, 1H), 6.80 (s, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.77 (s, 3H), 3.56 - 3.51 (m, 2H), 3.18 - 3.13 (m, 2H), 3.06 - 2.98 (m, 4H), 2.94 - 2.84 (m, 2H), 2.76 - 2.68 (m, 3H), 2.62 - 2.53 (m, 3H), 2.48 - 2.46 (m, 1H), 2.04 (s, 3H), 2.01 (s, 3H), 1.85 - 1.80 (m, 2H), 1.68 - 1.62 (m, 2H), 0.95 - 0.88 (m, 3H), 0.86 - 0.80 (m, 2H).

[0336] Example 20

[0337] 5-((4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindoline-1,3-dione

[0338] Example 20 was prepared from the following steps:

[0339] Step A: 18e (100 mg, 0.15 mmol), Int-8 (78.19 mg, 0.18 mmol), p-toluenesulfonic acid (76.56 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) and reacted at 100 °C for 16 hours. The reaction solution was cooled to room temperature, 10 mL of saturated aqueous sodium bicarbonate solution was added, and a yellow solid was precipitated. After suction filtration, the crude product was obtained, and purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia water system) to obtain white solid 20 (6 mg, yield 3.72%). ESI-MS (m / z): 539.4 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 12.24 (s, 1H), 11.13 (s, 1H), 8.42-8.37 (m, 1H), 8.37-8.32 (m, 1H), 8.30-8.23 (m, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.58-7.44 (m, 2H), 7.39 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.35 (dd, J = 8.1, 2.0 Hz, 1H), 6.78 (s, 1H), 5.11 (dd, J = 12.8, 5.5 Hz, 1H), 3.78 (s, 3H), 3.76 (s, 2H), 3.58-3.53 (m, 2H), 3.47-3.42 (m, 3H), 3.19-3.11 (m, 4H), 3.03-2.97 (m, 2H), 2.91-2.85 (m, 3H), 2.68-2.59 (m, 4H), 2.59-2.52 (m, 2H), 2.02 (s, 3H), 1.99 (s, 3H), 1.81-1.76 (m, 2H), 1.68-1.61 (m, 2H), 1.29 (t, J = 7.6 Hz, 3H).

[0340] Example 21

[0341] 5-((4-((1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-[1,4'-bipiperidin]-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindoline-1,3-dione

[0342] Example 21 was prepared from the following steps:

[0343] Step A: To Int-3c (1.0 g, 3.95 mmol) in dimethyl sulfoxide (15 mL) was added 21a (2.16 g, 7.96 mmol), potassium carbonate (3.3 g, 23.88 mmol) at room temperature. The reaction was stirred at 100 °C for 16 h. LC / MS showed the reaction was complete. The reaction was quenched by the addition of saturated brine solution. The organic phase was combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (1 / 1, by volume)) to give 21b (1.2 g, 70.19% yield) as a yellow solid. ESI-MS (m / z): 429.51 [M+H] + .

[0344] Step B: To 21b (1.0 g, 2.33 mmol) in tetrahydrofuran (15 mL) was added Dess-Martin periodinane (1.48 g, 3.49 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. LC / MS showed the reaction was complete. The reaction was quenched by the addition of saturated sodium bicarbonate solution. The organic phase was extracted with ethyl acetate for three times. The organic phase was washed with sodium thiosulfate solution. The organic phase was combined and dried over anhydrous sodium sulfate, filtered and concentrated to give 21c (737 mg, crude) as a yellow solid without further purification. ESI-MS (m / z): 427.5 [M+H] + .

[0345] Step C: To 21c (700 mg, 1.63 mmol) and Int-2 (958.88 mg, 2.45 mmol) in N,N- dimethylformamide (10 mL) was added acetic acid (3 drops) under ice bath. Sodium triacetoxyborohydride (1.04 g, 4.89 mmol) was added portionwise. The reaction was stirred at room temperature for 2 h. LC / MS showed the reaction was complete. The reaction was quenched by the addition of saturated sodium bicarbonate solution. The organic phase was extracted with ethyl acetate for three times. The organic phase was combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (20 / 1, by volume)) to give 21d (1.05 g, 80.33% yield) as a yellow solid. ESI-MS (m / z): 802.4 [M+H] + .

[0346] Step D: 21d (1.0 g, 1.25 mmol) was dissolved in ethanol (10 mL) and water (2 mL) at room temperature, iron powder (349.01 mg, 6.25 mmol) and ammonium chloride (334.31 mg, 6.25 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 h. LC / MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved with dichloromethane / methanol = 15 / 1, filtered with diatomite, and the obtained solution was concentrated under reduced pressure to obtain the crude product. Purification was performed by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain 21e (950 mg, yield 98.69%) as a yellow solid. ESI-MS (m / z): 772.4 [M+H] + .

[0347] Step E: 21e (50 mg, 0.065 mmol), Int-4 (32.07 mg, 0.078 mmol), p-toluenesulfonic acid (33.46 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature, and the reaction was carried out at 100 °C for 16 h under nitrogen protection. The reaction solution was cooled to room temperature, and 10 mL of saturated aqueous sodium bicarbonate solution was added. A yellow solid was precipitated, which was filtered to obtain the crude product. Purification was performed by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia water system) to obtain 20 (6.1 mg, yield 8.2%) as a white solid. ESI-MS (m / z): 575.4 [M+2H] 2+ / 2. 1HNMR(500MHz,DMSO-d6)δ12.67(s,1H),11.12(s,1H),8.84(d,J=1.8Hz,1H),8.81(d,J=1.8Hz,1H),8.42(s,1H),8.31(s,1H),8.27(s,1H),7.98 (s,1H),7.79(s,1H),7.73(d,J=8.1Hz,1H),7.56(s,1H),7.36(d,J=1.7Hz,1H),7.33(dd,J=8.1,2.0Hz,1H),6.81(s,1H),5.10(dd,J=12.8,5.5H z,1H),3.80(s,3H),3.76(s,3H),3.52–3.48(m,4H),3.15–3.09(m,3H), 3.02–2.92(m,5H),2.90–2.78(m,4H),2.62–2.56(m,3H),2.35–2.30(m,3 H),2.19–2.14(m,2H),2.03(s,3H),2.00(s,3H),1.83–1.78(m,2H),1.7 5–1.70(m,2H),1.66–1.59(m,2H),1.47–1.43(m,1H),1.13–1.07(m,2H).

[0348] Example 22

[0349] 5-((4-((1'-(4-((5-bromo-4-((5-(dimethylphospho)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-piperidin]-4-yl)methyl)-1-hydroxy-116-thiomorpholine-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isodihydroindole-1,3-dione

[0350] Example 22 was prepared by the following steps:

[0351] Step A: At room temperature, 22b (1.99 g, 10.04 mmol) and potassium carbonate (4.16 g, 30.12 mmol) were added to 15 mL of dimethyl sulfoxide (DMSO) containing 22a (1.0 g, 5.02 mmol). The reaction was carried out at 100 °C for 16 hours. LC / MS showed that the reaction was complete. Saturated brine was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a yellow solid 22c (1.8 g, yield 94.98%). ESI-MS (m / z): 377.48 [M+H]+ .

[0352] Step B: To a solution of 22c (1.0 g, 2.65 mmol) in tetrahydrofuran (15 mL) was added Dess-Martin periodinane (1.68 g, 3.97 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction was quenched by the addition of saturated sodium bicarbonate solution. The reaction was extracted with ethyl acetate for three times. The organic phase was washed with sodium thiosulfate solution. The organic phase was combined and dried over anhydrous sodium sulfate, filtered and concentrated to give 22d (850 mg, crude) as a yellow solid. ESI-MS (m / z): 375.46 [M+H] + .

[0353] Step C: To a solution of 22d (850 mg, 2.27 mmol) and Int-2 (700 mg, 1.51 mmol) in N,N-dimethylformamide (10 mL) was added acetic acid (3 drops) and sodium triacetylboration hydride (1.6 g, 7.55 mmol) portion wise at room temperature. The reaction was stirred at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction was quenched by the addition of saturated sodium bicarbonate solution. The reaction was extracted with ethyl acetate. The organic phase was combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 22e (1.13 g, yield 77.32%) as a yellow solid. ESI-MS (m / z): 749.87 [M+H] + .

[0354] Step D: To a solution of 22e (500 mg, 0.67 mmol) in ethanol (10 mL) and water (2 mL) was added iron powder (187.1 mg, 3.35 mmol) and ammonium chloride (179.19 mg, 3.35 mmol) at room temperature. The reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated. The residue was dissolved in dichloromethane / methanol = 15 / 1 and filtered through celite. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 22f (470 mg, yield 97.92%) as a yellow solid. ESI-MS (m / z): 719.89 [M+H] + .

[0355] Step E: To a solution of 22f (50 mg, 0.069 mmol), Int-4 (34.39 mg, 0.083 mmol), p-toluenesulfonic acid (35.88 mg, 0.21 mmol) in N,N-dimethylformamide (1.5 mL) was heated at 100 °C for 16 h. The reaction was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added and a yellow solid precipitated. The crude product was obtained after filtration and purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia in water) to give 22 as a white solid (13.8 mg, yield 18.13%). ESI-MS (m / z): 549.3 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 12.64 (s, 1H), 11.12 (s, 1H), 8.87 (d, J = 1.8 Hz, 1H), 8.85 (d, J = 1.9 Hz, 1H), 8.30 (s, 1H), 8.27 (s, 2H), 7.93 - 7.87 (m, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 7.36 - 7.35 (m, 1H), 7.34 - 7.31 (m, 1H), 6.80 (s, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.77 (s, 3H), 3.39 - 3.38 (m, 4H), 3.04 - 2.93 (m, 7H), 2.91 - 2.79 (m, 4H), 2.73 - 2.67 (m, 2H), 2.64 - 2.55 (m, 2H), 2.49 - 2.47 (m, 2H), 2.35 - 2.31 (m, 2H), 2.26 - 2.20 (m, 2H), 2.04 (s, 3H), 2.01 (s, 3H), 1.87 - 1.82 (m, 2H), 1.75 - 1.70 (m, 2H), 1.67 - 1.60 (m, 2H), 1.49 - 1.44 (m, 1H), 1.15 - 1.08 (m, 2H), 0.96 - 0.89 (m, 3H).

[0356] Example 23

[0357] 5-((4-((1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-[1,4'-bipiperidin]-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0358] Example 23 was prepared from the following steps:

[0359] Step A: 21e (100 mg, 0.13 mmol), Int-8 (68.35 mg, 0.15 mmol), p-toluenesulfonic acid (66.92 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) and reacted at 100 °C for 16 hours. The reaction was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added. A yellow solid precipitated, which was filtered to give the crude product. Purification by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) gave yellow solid 23 (5.2 mg, yield 3.38%). ESI-MS (m / z): 588.0 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 12.24 (s, 1H), 11.14 (s, 1H), 8.48 - 8.43 (m, 2H), 8.37 - 8.33 (m, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 7.83 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.60 - 7.52 (m, 1H), 7.51 - 7.45 (m, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.36 (d, J = 1.7 Hz, 1H), 7.34 (dd, J = 8.1, 1.9 Hz, 1H), 6.79 (s, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 2H), 3.14 - 3.10 (m, 2H), 3.02 - 2.98 (m, 2H), 2.96 - 2.92 (m, 2H), 2.90 - 2.88 (m, 2H), 2.87 - 2.84 (m, 2H), 2.63 - 2.57 (m, 3H), 2.56 - 2.53 (m, 1H), 2.35 - 2.32 (m, 2H), 2.17 - 2.11 (m, 2H), 2.03 (s, 3H), 2.00 (s, 3H), 1.83 - 1.78 (m, 2H), 1.75 - 1.70 (m, 2H), 1.64 - 1.58 (m, 2H), 1.48 - 1.43 (m, 1H), 1.29 (t, J = 7.6 Hz, 3H), 1.13 - 1.07 (m, 2H).

[0360] Example 24

[0361] 5-((4-((1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-[1,4'-bipiperidin]-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindoline-1,3-dione

[0362] Example 24 was prepared from the following steps:

[0363] Step A: 21e (50 mg, 0.065 mmol), Int-9 (34.25 mg, 0.078 mmol), p-toluenesulfonic acid (33.46 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide solution (1.5 mL) and reacted at 100 °C for 16 h. The reaction solution was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added. A yellow solid precipitated, and the crude product was obtained after suction filtration. Purification by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia water system) gave yellow solid 24 (1.3 mg, yield 1.69%). ESI-MS (m / z): 589.5 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 12.08 (s, 1H), 11.12 (s, 1H), 9.63 (s, 1H), 8.52 (s, 1H), 8.37 (s, 2H), 8.21 (s, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.73 (s, 1H), 7.51 - 7.46 (m, 1H), 7.35 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 6.77 (s, 1H), 5.12 - 5.08 (m, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.13 - 3.06 (m, 4H), 3.02 - 2.97 (m, 4H), 2.97 - 2.90 (m, 4H), 2.90 - 2.79 (m, 5H), 2.65 - 2.52 (m, 6H), 2.07 (s, 3H), 2.05 (s, 3H), 1.82 - 1.78 (m, 2H), 1.74 - 1.70 (m, 2H), 1.62 - 1.58 (m, 2H), 1.48 - 1.42 (m, 2H), 1.34 (t, J = 7.6 Hz, 3H), 1.13 - 1.08 (m, 2H), 0.87 - 0.83 (m, 1H).

[0364] Example 25

[0365] 5-((4-((1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2- ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)- [1,4'-bipiperidin]-4-yl)methyl)-1-hydroxy-1 l6-thioxomorpholin-1-ylidene)amino)- 2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0366] Example 25 was prepared from the following steps:

[0367] Step A: 22f (100 mg, 0.14 mmol), Int-8 (73.29 mg, 0.17 mmol), p-toluenesulfonic acid (71.76 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) and reacted at 100 °C for 16 h. The reaction was cooled to room temperature and saturated aqueous sodium bicarbonate solution was added. A yellow solid precipitated and was collected by suction filtration to give the crude product. Purification by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia water system) gave 25 as a yellow solid (6.0 mg, 3.81% yield). ESI-MS (m / z): 588.0 [M+2H] 2+ / 2. 1HNMR (500 MHz, DMSO-d6) δ 11.82 (s, 1H), 11.13 (s, 1H), 8.57 (d, J = 8.9 Hz, 1H), 8.40 - 8.34 (m, 1H), 8.31 - 8.26 (m, 1H), 8.21 (s, 1H), 8.03 (s, 1H), 7.88 (d, J = 9.3 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.36 (d, J = 1.7 Hz, 1H), 7.33 (dd, J = 8.1, 1.9 Hz, 1H), 6.75 (s, 1H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 3.76 (s, 3H), 3.40 (s, 3H), 3.02 - 2.88 (m, 11H), 2.88 - 2.82 (m, 3H), 2.70 - 2.60 (m, 4H), 2.59 - 2.54 (m, 2H), 2.40 - 2.36 (m, 1H), 2.35 - 2.32 (m, 2H), 2.31 - 2.26 (m, 2H), 2.00 (s, 3H), 1.98 (s, 3H), 1.83 - 1.78 (m, 2H), 1.75 - 1.69 (m, 2H), 1.62 - 1.56 (m, 2H), 1.46 - 1.42 (m, 1H), 1.32 (t, J = 7.6 Hz, 3H), 1.13 - 1.06 (m, 2H), 0.79 - 0.75 (m, 2H).

[0368] Example 26

[0369] 5-((4-((1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidin]-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindoline-1,3-dione

[0370] Example 26 was prepared from the following steps:

[0371] Step A: 22f (50 mg, 0.069 mmol), Int-9 (36.73 mg, 0.083 mmol), p-toluenesulfonic acid (35.88 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature and reacted at 100 °C for 16 hours. The reaction solution was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added, and a yellow solid was precipitated. After suction filtration, the crude product was obtained, and purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia water system) to obtain a yellow solid 26 (1.9 mg, yield 2.41%). ESI-MS (m / z): 563.5 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 11.65 (s, 1H), 11.14 (s, 1H), 9.91 (s, 1H), 8.45 (s, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.40-7.30 (m, 2H), 6.75 (s, 1H), 5.17-5.07 (m, 1H), 3.84 (s, 1H), 3.77 (s, 4H), 3.10-2.80 (m, 12H), 2.70-2.60 (m, 3H), 2.46-2.38 (m, 2H), 2.38-2.32 (m, 2H), 2.30-2.16 (m, 4H), 2.10-1.98 (m, 6H), 1.86-1.78 (m, 2H), 1.77-1.69 (m, 2H), 1.66-1.56 (m, 2H), 1.50-1.44 (m, 1H), 1.44-1.33 (m, 3H), 1.32-1.20 (m, 3H), 1.17-1.08 (m, 2H), 0.81-0.70 (m, 2H).

[0372] Example 27

[0373] 3-(5-((4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0374] Example 27 was prepared by the following steps:

[0375] Step A: 3b (100 mg, 0.15 mmol), 27a (56.22 mg, 0.18 mmol), p-toluenesulfonic acid (76.55 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature and reacted at 100 °C for 16 hours. The reaction solution was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added, and a yellow solid was precipitated. After suction filtration, the crude product was obtained, and purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia water system) to obtain yellow solid 27 (50 mg, yield 34.64%). ESI-MS (m / z): 477.9 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 11.22 (s, 1H), 10.97 (s, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.10 (d, J = 5.4 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J = 5.0 Hz, 1H), 7.61 - 7.45 (m, 4H), 7.15 (s, 1H), 7.06 (s, 1H), 6.99 (s, 1H), 6.79 (s, 1H), 4.35 (d, J = 17.6 Hz, 1H), 4.23 (d, J = 17.2 Hz, 1H), 3.81 (dd, J = 20.7, 5.2 Hz, 6H), 3.07 (s, 2H), 3.48 - 3.42 (m, 2H), 3.00 (s, 3H), 2.85 (s, 3H), 2.57 (d, J = 9.2 Hz, 3H), 2.43 (s, 3H), 2.15 (s, 1H), 1.97 (s, 1H), 1.82 - 1.70 (m, 9H), 1.59 - 1.51 (m, 1H), 1.31 - 1.25 (m, 2H).

[0376] Example 28

[0377] 3-(5-((4-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0378] Example 28 was prepared from the following steps:

[0379] Step A: 3b (70 mg, 0.10 mmol), Int-4 (51.36 mg, 0.12 mmol) and p-toluenesulfonic acid (53.58 mg, 0.30 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature, stirred at 100 °C for 16 hours, LC / MS showed the reaction was complete. The reaction was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, a solid precipitated, after suction filtration, the crude product was obtained, purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain 28 (8.0 mg, yield 7.19%). ESI-MS (m / z): 526.8 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.67 (s, 1H), 10.98 (s, 1H), 8.93 (s, 1H), 8.83 (dd, J = 17.2, 1.7 Hz, 3H), 8.43 (s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.59 - 7.51 (m, 3H), 7.16 (s, 1H), 7.07 (dd, J = 8.2, 1.7 Hz, 1H), 6.82 (s, 1H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 4.23 (d, J = 17.1 Hz, 1H), 3.82 (s, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.09 (d, J = 10.9 Hz, 3H), 3.04 - 2.99 (m, 3H), 2.92 - 2.83 (m, 4H), 2.64 - 2.56 (m, 4H), 2.44 (d, J = 6.8 Hz, 2H), 2.39 - 2.34 (m, 1H), 2.09 - 2.07 (m, 1H), 2.05 (s, 1H), 2.01 (d, J = 14.4 Hz, 6H), 1.81 - 1.76 (m, 2H), 1.61 - 1.57 (m, 1H).

[0380] Example 29

[0381] 3-(4-((4-((1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0382] Example 29 was prepared from the following steps:

[0383] Step A: Int-10 (210 mg, 0.59 mmol, C) and Int-3 (202.35 mg, 0.59 mmol) were dissolved in dichloromethane (5 mL) at room temperature, 3 drops of acetic acid was added, sodium triacetoxyborohydride (186.81 mg, 0.88 mmol) was added in portions, after that, the reaction was stirred at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction was quenched by water, dichloromethane was added to extract. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a light yellow solid 29a (310 mg, crude product). ESI-MS (m / z): 686.4 [M+H] + .

[0384] Step B: 29a (200 mg, 0.29 mmol), iron powder (48.87 mg, 0.87 mmol) and ammonium chloride (46.80 mg, 0.87 mmol) were dissolved in ethanol (5.00 mL) and water (1.0 mL) at room temperature, and the reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was complete. After cooling to room temperature, the reaction was rotary evaporated, dissolved in dichloromethane / methanol = 15 / 1, filtered by celite, and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give product 29b (80 mg, yield 41.83%). ESI-MS (m / z): 656.4 [M+H] + .

[0385] Step C: 29b (80 mg, 0.12 mmol) and Int-1 (58.65 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, p-toluenesulfonic acid (63.02 mg, 0.37 mmol) was added, and the reaction was stirred at 100 °C for 16 hours. LC / MS showed the reaction was complete. After cooling to room temperature, sodium bicarbonate solution was added dropwise to the reaction, dichloromethane / methanol = 15 / 1 was added to extract, and the organic phase was washed with brine twice. The solvent was removed under reduced pressure to give a crude product, which was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a light yellow solid, which was compound 29 (35 mg, yield 25.32%). ESI-MS (m / z): 510.4 [M+2H] 2+ / 2. 1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.14 (s, 2H), 7.99 (s, 1H), 7.90 (s, 1H), 7.56 (s, 1H), 7.23 (d, J = 14.3 Hz, 1H), 6.80 (s, 1H), 6.63 (d, J = 10.8 Hz, 2H), 6.41 (s, 1H), 4.11 (dd, J = 12.7, 5.0 Hz, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.10 - 3.05 (m, 2H), 3.02 - 2.95 (m, 2H), 2.91 - 2.87 (m, 2H), 2.84 - 2.76 (m, 5H), 2.44 (d, J = 6.8 Hz, 2H), 2.15 - 2.08 (m, 4H), 2.04 - 1.99 (m, 4H), 1.74 (d, J = 13.6 Hz, 6H), 1.63-1.55 (m, 1H), 1.36 - 1.28 (m, 2H), 0.92 - 0.86 (m, 2H), 0.52 - 0.47 (m, 2H).

[0386] Example 30

[0387] 3-(5-((4-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0388] Example 30 was prepared by the following steps:

[0389] Step A: To 30a (5.0 g, 25.10 mmol) in dimethyl sulfoxide (75 mL) was added 30b (3.47 g, 30.12 mmol), potassium carbonate (20.45 g, 62.76 mmol) at room temperature. The reaction was stirred at 100 °C for 16 h. LC / MS showed the reaction was complete. The reaction was washed with saturated brine. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give yellow solid E-162c (4.6 g, yield 62.25 %). ESI-MS (m / z): 294.35 [M+H] + .

[0390] Step B: 30c (1.2 g, 4.08 mmol), iron powder (2.28 g, 40.77 mmol) and ammonium chloride (2.18 mg, 40.77 mmol) were dissolved in a mixture of ethanol (10 mL) and water (2 mL). The reaction was stirred at 80 °C for 2 h. LC / MS showed the reaction was complete. The reaction was concentrated, dissolved in dichloromethane and filtered through celite. The filtrate was concentrated and the crude product was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 10 / 1) to give 30d (1 g, yield 92.78%) as a yellow solid. ESI-MS (m / z): 265.18 [M+H] + .

[0391] Step C: 30d (1 g, 3.78 mmol), Int-4 (2.03 g, 4.92 mmol) and p-toluenesulfonic acid (977.0 mg, 5.67 mmol) were dissolved in DMF (20 mL). The reaction was stirred at 100 °C for 16 h. LC / MS showed the reaction was complete. The reaction was cooled to room temperature and poured into saturated aqueous sodium bicarbonate solution. The product was precipitated and filtered to give a yellow solid. The crude product was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give 30e (1 g, yield 41.27%) as a yellow solid. ESI-MS (m / z): 640.17 [M+H] + .

[0392] Step D: Oxalyl chloride (1.17 g, 13.9 mmol) was dissolved in anhydrous dichloromethane (10 mL) and cooled to -78 °C. Dimethyl sulfoxide (1.09 g, 13.92 mmol) was added slowly to the reaction. The reaction was stirred for 1 h at -78 °C. A solution of 30e (1 g, 1.39 mmol) in dichloromethane (10 mL) was added dropwise. The reaction was stirred for another 2 h at -78 °C. Triethylamine (2.82 g, 27.83 mmol) was added and the reaction was stirred for 30 min at room temperature. LC / MS showed the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to the reaction. The reaction was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give 30f (300 mg, yield 33.77%) as a yellow solid. ESI-MS (m / z): 638.16 [M+H] + .

[0393] Step E: Compound Int-5 (20 mg, 0.05 mmol) and 30f (57.82 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (1 mL), two drops of glacial acetic acid were added to the reaction under ice bath condition, sodium triacetoxyborohydride (22.58 mg, 0.1 mmol) was added portion wise. The reaction was stirred at room temperature for 4 hours, LC / MS showed the reaction was complete. The reaction was poured into water, the yellow product precipitated, filtered, the filter cake was washed with water and dried in vacuum. The crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 30 (1.7 mg, yield 3.17%). ESI-MS (m / z): 501.1 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.98 (s, 1H), 8.87 (d, J = 1.9 Hz, 1H), 8.85 (d, J = 1.9 Hz, 1H), 8.81 (s, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 7.89 (d, J = 9.7 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.16 (s, 1H), 7.06 (d, J = 1.8 Hz, 1H), 6.81 (s, 1H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.38 - 4.34 (m, 1H), 4.25 - 4.21 (m, 1H), 3.77 (s, 3H), 3.02 - 2.97 (m, 4H), 2.89 - 2.83 (m, 3H), 2.72 - 2.67 (m, 2H), 2.63 - 2.56 (m, 2H), 2.43 - 2.41 (m, 2H), 2.39 - 2.35 (m, 2H), 2.03 (s, 3H), 2.01 (s, 3H), 1.85 - 1.81 (m, 2H), 1.63 - 1.60 (m, 1H), 1.31 - 1.26 (m, 2H), 0.95 - 0.90 (m, 3H).

[0394] Example 31

[0395] 5-((9-((1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3- hydroxy-3l6-thia-9-azaspiro[5.5]undec-3-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3- yl)isoindole-1,3-dione

[0396] Example 31 was prepared from the following steps:

[0397] Step A: Int-12 (300 mg, 0.65 mmol, C) and Int-3 (397.67 mg, 1.15 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and 3 drops of acetic acid was added dropwise. Sodium triacetoxyborohydride (407.91 mg, 1.92 mmol) was added portionwise. After completion of the reaction (LC / MS), the reaction was quenched with water and extracted with dichloromethane. The organic phase was combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. Purification by column chromatography (dichloromethane / methanol (V / V) = 15 / 1) gave 31a (500 mg, yield 66.03%) as a yellow solid. ESI-MS (m / z): 787.4 [M+H] + .

[0398] Step B: 31a (500 mg, 0.64 mmol), iron powder (212.91 mg, 3.81 mmol) and ammonium chloride (203.93 mg, 3.81 mmol) were dissolved in ethanol (10.00 mL) and water (2.0 mL) at room temperature, and the reaction was carried out at 80 °C for 1 h. After completion of the reaction (LC / MS), the reaction was cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in dichloromethane / methanol = 15 / 1, and filtered through celite. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give 31b (170 mg, yield 35.35%) as a yellow solid. ESI-MS (m / z): 758.4 [M+H] + .

[0399] Step C: 31b (80 mg, 0.11 mmol) and Int-1 (55.05 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, and p-toluenesulfonic acid (54.60 mg, 0.32 mmol) was added. The reaction was carried out at 100 °C for 16 h. After completion of the reaction (LC / MS), the reaction was cooled to room temperature, and sodium bicarbonate solution was added dropwise. The reaction mixture was extracted with dichloromethane / methanol = 15 / 1, and the organic phase was washed with brine twice. The organic phase was combined and concentrated under reduced pressure to give the crude product, which was purified by reverse phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 31 (25.2 mg, yield 21.05%) as a yellow solid. ESI-MS (m / z): 561.8 [M+2H] 2+ / 2. 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.86 (s, 1H), 8.24 - 8.11 (m, 3H), 7.98 (s, 1H), 7.89 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.37 - 7.30 (m, 2H), 7.23 (dd, J = 14.5, 2.2 Hz, 1H), 6.80 (s, 1H), 6.48 - 6.35 (m, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.48 - 3.37 (m, 5H), 3.09 - 3.03 (m, 2H), 2.93 - 2.84 (m, 1H), 2.65 - 2.52 (m, 3H), 2.48 - 2.42 (m, 1H), 2.39 - 2.30 (m, 4H), 2.27 - 2.21 (m, 2H), 2.06 - 1.99 (m, 1H), 1.94 - 1.78 (m, 5H), 1.77 - 1.71 (m, 7H), 1.66 - 1.57 (m, 3H), 1.54 - 1.44 (m, 2H), 1.35 - 1.24 (m, 2H), 0.92 - 0.86 (m, 2H), 0.54 - 0.44 (m, 2H).

[0400] Example 32

[0401] 5-((9-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3l6-thia-9-azaspiro[5.5]undec-3- ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0402] Example 32 was prepared from the following steps:

[0403] Step A: 31b (80 mg, 0.11 mmol) and Int-9 (60.55 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, to which p-toluenesulfonic acid (54.60 mg, 0.32 mmol) was added, and the reaction was carried out at 100 °C for 16 hours. LC / MS showed that the reaction was complete. After cooling to room temperature, sodium bicarbonate solution was slowly added dropwise to the reaction, and after extraction with dichloromethane / methanol = 15 / 1, washing with brine twice, the organic phase was combined, and the solvent was removed under reduced pressure to obtain a yellow solid, which was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain compound 32 (12.0 mg, yield 9.68%). ESI-MS (m / z): 581.0 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.09 (s, 1H), 11.10 (s, 1H), 9.60 (s, 1H), 8.59 - 8.44 (m, 1H), 8.35 - 8.26 (m, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.78 - 7.68 (m, 2H), 7.55 - 7.43 (m, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.1, 2.1 Hz, 1H), 6.79 (s, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 3.76 (d, J = 6.5 Hz, 6H), 3.48 - 3.35 (m, 5H), 3.09 - 2.96 (m, 4H), 2.93 - 2.83 (m, 1H), 2.62 - 2.52 (m, 3H), 2.40 - 2.27 (m, 4H), 2.26 - 2.20 (m, 2H), 2.12 - 1.98 (m, 7H), 1.94 - 1.78 (m, 4H), 1.77 - 1.70 (m, 2H), 1.68 - 1.56 (m, 3H), 1.53 - 1.44 (m, 2H), 1.34 (t, J = 7.6 Hz, 3H), 1.33 - 1.22 (m, 2H).

[0404] Example 33

[0405] 3-(4-((9-((1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3,6-thia-9-azaspiro[5.5]undec-3-ylidene)amino)phenyl)piperidine-2,6-dione

[0406] Example 33 was prepared from the following steps:

[0407] Step A: 33a (2.0 g, 7.46 mmol) and Int-11 (2.26 g, 7.46 mmol) were dissolved in dimethyl sulfoxide (3 mL) under nitrogen protection, t-BuXPhos-Pd-G3 (592.58 mg, 0.75 mmol), t-BuXPhos (316.77 mg, 0.75 mmol), cesium carbonate (7.29 g, 22.38 mmol) were added. The reaction was stirred at 110 °C for 4 h. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, added saturated aqueous ammonium chloride solution, dichloromethane was added to extract the mixture, the organic phase was combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give 33b (2.8 g, yield 76.66%) as a white solid. ESI-MS (m / z): 490.23 [M+H] + .

[0408] Step B: 33b (2.8 g, 5.76 mmol) was dissolved in dichloromethane (20 mL), HCl (4.0 M, 1,4-dioxane) (10 mL) was added dropwise under ice bath condition. The reaction was stirred at room temperature for 4 h. LC / MS showed the reaction was complete. A white product was precipitated. The reaction was filtered and dried in vacuo to give 33c (2 g, yield 80.10%) as a light white solid. No further purification was needed. ESI-MS (m / z): 390.17 [M+H] + .

[0409] Step C: Compound Int-3 (678.66 mg, 1.74 mmol) and 33c (500 mg, 1.45 mmol) were dissolved in N,N-dimethylformamide (10 mL), two drops of glacial acetic acid were added dropwise under ice bath condition, sodium triacetoxyborohydride (615 mg, 2.90 mmol) was added portionwise. The reaction was stirred at room temperature for 2 h. LC / MS showed the reaction was complete. The reaction was poured into water, a yellow product was precipitated. The reaction was filtered and dried in vacuo to give 33d (700 mg, yield 67.16%) as a yellow solid. ESI-MS (m / z): 718.33 [M+H] + .

[0410] Step D: 33d (700 mg, 0.98 mmol), iron powder (272.3 mg, 4.88 mmol) and ammonium chloride (260.8 mg, 4.88 mmol) were dissolved in ethanol (10.00 mL) and water (2.0 mL) at room temperature, and the mixture was stirred at 80 °C for 1 h. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, and was rotary evaporated to dryness. The residue was dissolved in dichloromethane / methanol = 15 / 1, and was filtered through celite. The filtrate was evaporated to dryness under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) to give product 33e (500 mg, yield 72.54 %). ESI-MS (m / z): 688.36 [M+H] + .

[0411] Step E: 33e (50 mg, 0.073 mmol) and Int-9 (34.94 mg, 0.087 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, and p-toluenesulfonic acid (37.54 mg, 0.22 mmol) was added. The mixture was stirred at 100 °C for 16 h. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, and sodium bicarbonate solution was added dropwise. The mixture was extracted with dichloromethane / methanol = 15 / 1, and the organic phase was washed with brine twice. The combined organic phase was evaporated to dryness under reduced pressure. The residue was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 33 as a yellow solid (15.1 mg, yield 19.55 %). ESI-MS (m / z): 526.4 [M+2H] 2+ / 2. 1H NMR (500 MHz, DMSO) δ 10.84 (s, 1H), 10.79 (s, 1H), 8.18 (d, J = 7.4 Hz, 2H), 7.98 (s, 1H), 7.88 (s, 1H), 7.55 (s, 1H), 7.23 (dd, J = 14.4, 2.0 Hz, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.80 (s, 1H), 6.43 (s, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.74 (dd, J = 11.2, 5.0 Hz, 1H), 3.26 - 3.21 (m, 7H), 3.06 (d, J = 10.9 Hz, 2H), 2.62 - 2.55 (m, 2H), 2.39 - 2.31 (m, 4H), 2.25 (d, J = 6.8 Hz, 2H), 2.16 - 2.10 (m, 1H), 2.04 - 1.98 (m, 1H), 1.89 - 1.78 (m, 5H), 1.75 (s, 3H), 1.73 (s, 3H), 1.65 - 1.58 (m, 3H), 1.50 - 1.44 (m, 2H), 1.35 - 1.22 (m, 3H), 0.92 - 0.87 (m, 2H), 0.52 - 0.46 (m, 2H).

[0412] Example 34

[0413] 3-(4-((9-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2- ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H- pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3,6-thia-9- azaspiro[5.5]undec-3-ylidene)amino)phenyl)piperidine-2,6-dione

[0414] Example 34 was prepared from the following steps:

[0415] Step A: 33e (50 mg, 0.073 mmol) and Int-9 (32.03 mg, 0.073 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, to which p-toluenesulfonic acid (37.54 mg, 0.22 mmol) was added and reacted at 100 °C for 16 h. LC / MS showed the reaction was complete. Upon cooling to room temperature, the reaction was added dropwise to sodium bicarbonate solution, a large amount of solid precipitated, which was filtered and dried under vacuum, the crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 33 (15.1 mg, yield 19.55%) as a yellow solid. ESI-MS (m / z): 546.2 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO) δ 12.08 (s, 1H), 10.79 (s, 1H), 9.61 (s, 1H), 8.54 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.75 (s, 1H), 7.48 (s, 2H), 7.03 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.79 (s, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.75 - 3.72 (m, 1H), 3.27 - 3.22 (m, 7H), 3.06 - 3.02 (m, 2H), 3.01 - 2.97 (m, 2H), 2.61 - 2.55 (m, 2H), 2.38 - 2.32 (m, 4H), 2.25 (d, J = 6.8 Hz, 2H), 2.15 - 2.11 (m, 1H), 2.08 (s, 3H), 2.05 (s, 3H), 2.04 - 1.99 (m, 1H), 1.89 - 1.84 (m, 2H), 1.83 - 1.78 (m, 2H), 1.76 - 1.71 (m, 2H), 1.64 - 1.58 (m, 3H), 1.50 - 1.45 (m, 2H), 1.34 (t, J = 7.6 Hz, 3H), 1.30 - 1.23 (m, 2H).

[0416] Example 35

[0417] 3-(5-((4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2- ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-1- carbonylisindolin-2-yl)piperidine-2,6-dione

[0418] Example 35 was prepared from the following steps:

[0419] Step A: 30c (1.0 g, 3.40 mmol) was dissolved in tetrahydrofuran (15 mL) at room temperature, and dixemartin oxidant (2.16 g, 5.10 mmol) was added to the reaction under ice bath. The reaction was stirred at room temperature for 2 hours. LC / MS showed the reaction was completed. The reaction was quenched by adding saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 35a (980 mg, crude) as a yellow solid, which was used for the next step without further purification. ESI-MS (m / z): 292.33 [M+H] + .

[0420] Step B: Compound 35a (400 mg, 1.37 mmol) and Int-5 (564.97 mg, 1.37 mmol) were dissolved in N,N-dimethylformamide (10 mL), and three drops of glacial acetic acid were added to the reaction under ice bath. Sodium triacetoxyborohydride (1.45 g, 6.84 mmol) was added portionwise. The reaction was stirred at room temperature for 2 hours. LC / MS showed the reaction was completed. The reaction was poured into water, and a yellow product was precipitated. The product was filtered and dried under vacuum to give 35b (300 mg, 33.59% yield) as a yellow solid. ESI-MS (m / z): 652.76 [M+H] + .

[0421] Step C: 35b (300 mg, 0.46 mmol), iron powder (128.34 mg, 2.30 mmol) and ammonium chloride (122.92 mg, 2.30 mmol) were dissolved in ethanol (5.00 mL) and water (1.0 mL) at room temperature. The reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was completed. The reaction was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane / methanol = 15 / 1, and the solution was filtered through celite. The solvent was evaporated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 35c (271 mg, 94.68% yield). ESI-MS (m / z): 622.78 [M+H] + .

[0422] Step D: 35c (100 mg, 0.16 mmol) and 35d (60.91 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, to which p-toluenesulfonic acid (82.95 mg, 0.48 mmol) was added and reacted at 100 °C for 16 h. LC / MS showed the reaction was complete. Upon cooling to room temperature, the reaction was added dropwise to sodium bicarbonate solution, a large amount of solid precipitated, which was filtered and dried under vacuum. The crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 35 (8.5 mg, yield 5.81%) as a yellow solid. ESI-MS (m / z): 451.9 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 10.99 (s, 1H), 8.46 - 8.41 (m, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.58 - 7.53 (m, 2H), 7.42 (s, 1H), 7.35 - 7.29 (m, 1H), 7.18 - 7.16 (m, 1H), 7.09 (d, 2H), 6.78 (s, 1H), 5.07 (dd, J = 13.2, 4.9 Hz, 1H), 4.36 (d, J = 17.1 Hz, 1H), 4.23 (d, J = 17.1 Hz, 1H), 3.76 (s, 3H), 3.06 - 2.96 (m, 5H), 2.95 - 2.82 (m, 4H), 2.70 - 2.65 (m, 2H), 2.63 - 2.56 (m, 2H), 2.55 - 2.54 (m, 1H), 2.44 - 2.41 (m, 2H), 2.40 - 2.30 (m, 2H), 2.00 - 1.96 (m, 1H), 1.86 - 1.82 (m, 2H), 1.79 (s, 3H), 1.76 (s, 3H), 1.65 - 1.59 (m, 1H), 1.32 - 1.23 (m, 3H), 1.06 (t, J = 7.4 Hz, 3H).

[0423] Example 36

[0424] 3-(5-((9-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)-3-hydroxy-3,6-thia-9-azaspiro[5.5]undec-3- ylidene)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0425] Example 36 was prepared from the following steps:

[0426] Step A: Compound 30f (50 mg, 0.078 mmol) and Int-13 (52 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1 mL), and two drops of glacial acetic acid were added to the reaction under ice bath condition, followed by the addition of sodium triacetoxyborohydride (33 mg, 0.16 mmol) in portions. The reaction was stirred at room temperature for 4 hours, and LC / MS showed the reaction was complete. The reaction was poured into water, and the yellow product precipitated, which was filtered, washed with water, and dried in vacuum. The resulting crude was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 36 (6.0 mg, 7.1% yield). ESI-MS (m / z): 534.5 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.98 (s, 1H), 8.86 (dd, J = 9.7, 1.8 Hz, 2H), 8.84 - 8.77 (m, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.88 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.14 (s, 1H), 7.08 - 7.04 (m, 1H), 6.81 (s, 1H), 5.06 (dd, J = 13.3, 5.1 Hz, 1H), 4.35 (d, J = 17.1 Hz, 1H), 4.22 (d, J = 17.2 Hz, 1H), 3.77 (s, 3H), 3.00 - 2.95 (m, 2H), 2.92 - 2.87 (m, 1H), 2.64 - 2.56 (m, 2H), 2.37 - 2.30 (m, 5H), 2.23 - 2.18 (m, 2H), 2.03 (s, 3H), 2.01 (s, 3H), 1.91 - 1.86 (m, 2H), 1.84 - 1.74 (m, 5H), 1.70 - 1.59 (m, 4H), 1.50 - 1.45 (m, 2H), 1.31 - 1.21 (m, 3H), 0.95 - 0.89 (m, 3H).

[0427] Example 37

[0428] 3-(4-((4-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)-1-hydroxy-1H-pyrrolidin-1-ylidene)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0429] Example 37 was prepared from the following steps:

[0430] Step A: Compound 30f (52.7 mg, 0.082 mmol) and Int-13 (20 mg, 0.048 mmol) were dissolved in N,N-dimethylformamide (1 mL), and two drops of glacial acetic acid were added to the reaction under ice bath condition, followed by the addition of sodium triacetoxyborohydride (33 mg, 0.16 mmol) in portions. The reaction was stirred at room temperature for 4 hours, and LC / MS showed the reaction was complete. The reaction was poured into water, and the yellow product precipitated, which was filtered, washed with water, and dried in vacuum. The resulting crude was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 37 (6.0 mg, 6.0% yield). ESI-MS (m / z): 491.4 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.93 (s, 1H), 8.86 (dd, J = 9.2, 1.8 Hz, 2H), 8.82 (s, 1H), 8.41 (s, 1H), 8.32 (s, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.35 (s, 1H), 6.81 (s, 1H), 6.63 (d, J = 10.8 Hz, 2H), 4.11 (dd, J = 12.4, 5.0 Hz, 1H), 3.77 (s, 3H), 3.04 - 2.96 (m, 4H), 2.92 - 2.85 (m, 2H), 2.84 - 2.75 (m, 2H), 2.72 - 2.66 (m, 2H), 2.44 - 2.40 (m, 2H), 2.12 - 2.07 (m, 1H), 2.04 (s, 3H), 2.01 (s, 3H), 1.86 - 1.80 (m, 2H), 1.67 - 1.57 (m, 2H), 1.34 - 1.24 (m, 3H), 0.93 (t, J = 7.0 Hz, 3H).

[0431] Example 38

[0432] 3-(4-((9-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6- yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4- yl)methyl)-3-hydroxy-3,6-thia-9-azaspiro[5.5]undec-3-ylidene)amino)phenyl)piperidine-2,6-dione

[0433] Example 38 was prepared from the following steps:

[0434] Step A: 33e (50 mg, 0.073 mmol) and Int-7 (32.25 mg, 0.073 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, to which p-toluenesulfonic acid (37.54 mg, 0.22 mmol) was added and reacted at 100 °C for 16 h. LC / MS showed the reaction was complete. Upon cooling to room temperature, the reaction was added dropwise to sodium bicarbonate solution, a large amount of solid precipitated, which was filtered and dried under vacuum, the crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 38 (29.2 mg, yield 36.32%) as a yellow solid. ESI-MS (m / z): 547.7 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO) δ 11.95 (s, 1H), 10.79 (s, 1H), 8.32 (s, 1H), 8.21 (s, 3H), 7.93 (s, 1H), 7.73 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.76 (s, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.75 - 3.72 (m, 1H), 3.26 - 3.22 (m, 7H), 3.02 (d, J = 11.1 Hz, 2H), 2.59 (d, J = 2.5 Hz, 3H), 2.56 - 2.53 (m, 1H), 2.41 - 2.35 (m, 4H), 2.27 (d, J = 6.7 Hz, 2H), 2.15 - 2.10 (m, 1H), 2.05 - 2.01 (m, 1H), 2.00 (s, 3H), 1.98 (s, 3H), 1.89 - 1.84 (m, 2H), 1.83 - 1.78 (m, 2H), 1.73 (d, J = 11.4 Hz, 2H), 1.65 - 1.58 (m, 3H), 1.51 - 1.46 (m, 2H), 1.30 - 1.23 (m, 2H).

[0435] Example 39

[0436] 3-(4-((9-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3l6-thia-9-azaspiro[5.5]undec-3-ylidene)amino)phenyl)piperidine-2,6-dione

[0437] Example 39 was prepared from the following steps:

[0438] Step A: 33e (100 mg, 0.16 mmol), Int-4 (71.98 mg, 0.17 mmol) and p-toluenesulfonic acid (37 mg, 0.2 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction was stirred at 100 °C for 16 h. LC / MS showed the reaction was complete. The reaction was poured into saturated aqueous sodium bicarbonate solution, the product precipitated and was filtered and dried. The resulting crude product was purified by preparative thin layer chromatography (dichloromethane / methanol (V / V) = 15 / 1) to give yellow solid 39 (65.9 mg, yield 42.18%). ESI-MS (m / z): 533.5 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 10.79 (s, 1H), 8.82 (dd, J = 17.2, 1.8 Hz, 3H), 8.41 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.57 (s, 1H), 7.53 (s, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.83 (s, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.75 - 3.71 (m, 1H), 3.26 - 3.23 (m, 4H), 3.11 - 3.03 (m, 3H), 2.69 - 2.55 (m, 4H), 2.39 - 2.32 (m, 4H), 2.28 - 2.22 (m, 2H), 2.15 - 2.11 (m, 1H), 2.03 (s, 3H), 2.00 (s, 3H), 1.89 - 1.83 (m, 2H), 1.83 - 1.78 (m, 2H), 1.76 - 1.71 (m, 2H), 1.64 - 1.57 (m, 3H), 1.51 - 1.46 (m, 2H), 1.33 - 1.26 (m, 2H).

[0439] Example 40

[0440] 3-(4-((9-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3,6-thia-9-azaspiro[5.5]undec-3-ylidene)amino)phenyl)piperidine-2,6-dione

[0441] Example 40 was prepared from the following steps:

[0442] Step A: 33e (50 mg, 0.073 mmol), 40a (27.57 mg, 0.087 mmol) and p-toluenesulfonic acid (37.54 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction was stirred at 100 °C for 16 h, LC / MS showed the reaction was complete. The reaction was poured into saturated aqueous sodium bicarbonate solution, the product precipitated and was filtered and dried. The resulting crude product was purified by preparative thin layer chromatography (dichloromethane / methanol (V / V) = 15 / 1) to give yellow solid 39 (32.8 mg, yield 46.17%). ESI-MS (m / z): 484.5 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 11.21 (s, 1H), 10.79 (s, 1H), 8.43 (s, 1H), 8.23 (d, J = 6.4 Hz, 2H), 8.10 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.58 (s, 1H), 7.50 (dd, J = 14.1, 9.0 Hz, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 6.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.80 (s, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.74 (dd, J = 11.1, 4.9 Hz, 1H), 3.26 - 3.19 (m, 7H), 3.08 - 3.04 (m, 2H), 2.62 - 2.55 (m, 2H), 2.37 - 2.29 (m, 4H), 2.25 - 2.21 (m, 2H), 2.16 - 2.10 (m, 1H), 2.04 - 1.99 (m, 1H), 1.90 - 1.79 (m, 4H), 1.77 (s, 3H), 1.75 (s, 3H), 1.73 - 1.69 (m, 1H), 1.64 - 1.57 (m, 3H), 1.49 - 1.44 (m, 2H), 1.31 - 1.23 (m, 2H).

[0443] Example 41

[0444] 3-(5-((9-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6- yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4- yl)methyl)-3-hydroxy-3,6-thia-9-azaspiro[5.5]undec-3-ylidene)amino)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione

[0445] Example 41 was prepared from the following steps:

[0446] Step A: Int-13 (100 mg, 0.22 mmol) and Int-3 (116 mg, 0.34 mmol) were dissolved in dichloromethane (3 mL) at room temperature, and the mixture was cooled to 0 °C in an ice bath. A catalytic amount of acetic acid (3 drops) was added, followed by the addition of sodium triacetoxyborohydride (143.03 mg, 0.67 mmol) in portions. The reaction was stirred at room temperature for about 2 hours. LC / MS showed that the reaction was complete. The reaction was concentrated, and the residue was purified by thin layer chromatography (dichloromethane / methanol (V / V) = 15 / 1) to give product 41a (52 mg, yield 29.91%) as a yellow solid. ESI-MS (m / z): 773.5 [M+H] + .

[0447] Step B: 41a (52 mg, 0.067 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL) at room temperature. Iron powder (18.79 mg, 0.34 mmol) and ammonium chloride (17.99 mg, 0.34 mmol) were added to the reaction mixture, and the mixture was stirred at 80 °C for 1 hour. LC / MS showed that the reaction was complete. After cooling to room temperature, the reaction was concentrated, and the residue was dissolved in dichloromethane / methanol = 15 / 1. The solution was filtered through diatomite and concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (dichloromethane / methanol = 15 / 1) to give 41b (30 mg, yield 60.02%) as a yellow solid. ESI-MS (m / z): 743.4 [M+H] + .

[0448] Step C: 41b (30 mg, 0.040 mmol) and Int-7 (23.29 mg, 0.052 mmol) were dissolved in N,N-dimethylformamide (0.7 mL), and p-toluenesulfonic acid (13.91 mg, 0.081 mmol) was added to the mixture. The mixture was stirred at 100 °C for 16 hours. LC / MS showed that the reaction was complete. After cooling to room temperature, an aqueous sodium bicarbonate solution was added to the reaction mixture, and a large amount of solid was produced. The residue was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 41 (2.6 mg, yield: 5.54%) as a yellowish solid. ESI-MS (m / z): 576.5 [M+2H] 2+ / 2. 1H NMR (500 MHz, DMSO-d6) δ 12.78 (s, 1H), 11.80 (s, 1H), 9.31 - 9.19 (m, 2H), 9.06 - 8.99 (m, 2H), 8.80 - 8.69 (m, 1H), 8.55 (s, 1H), 8.44 - 8.29 (m, 3H), 7.96 (d, J = 1.8 Hz, 1H), 7.87 (dd, J = 8.2, 1.8 Hz, 1H), 7.58 (s, 1H), 5.88 (dd, J = 13.3, 5.1 Hz, 1H), 5.17 (d, J = 17.0 Hz, 1H), 5.04 (d, J = 17.1 Hz, 1H), 4.63 - 4.56 (m, 6H), 3.87 - 3.80 (m, 3H), 3.77 - 3.68 (m, 2H), 3.45 - 3.36 (m, 6H), 3.21 - 3.12 (m, 6H), 3.07 - 3.02 (m, 2H), 2.86 - 2.76 (m, 8H), 2.74 - 2.59 (m, 5H), 2.58 - 2.52 (m, 2H), 2.48 - 2.39 (m, 4H), 2.32 - 2.26 (m, 2H).

[0449] Example 42

[0450] 3-(4-((4-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1-hydroxy-1H-pyrrolidin-1-ylidene)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0451] Example 42 was prepared by the following steps:

[0452] Step A: 29b (100 mg, 0.152 mmol), Int-4 (62.92 mg, 0.152 mmol) and p-toluenesulfonic acid (78.78 mg, 0.457 mmol) were dissolved in N,N-dimethylformamide (2 mL) and the reaction was stirred at 90 °C for 16 hours. LC / MS showed the reaction was complete. The reaction was cooled to room temperature and an aqueous solution of sodium bicarbonate was added to the reaction, which produced a large amount of solid. The residue was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 42 (51 mg, yield 30.79%) as a light yellow solid. ESI-MS (m / z): 516.3 [M+2H] 2+ / 2. 1H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.02 (s, 1H), 10.92 (s, 1H), 8.83 (dd, J = 16.6, 1.8 Hz, 2H), 8.42 (s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.57 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 6.83 (s, 1H), 6.63 (d, J = 10.8 Hz, 2H), 4.29 - 4.22 (m, 1H), 4.11 (dd, J = 12.6, 5.0 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.09 (d, J = 11.0 Hz, 2H), 3.03 - 2.97 (m, 2H), 2.92 - 2.86 (m, 2H), 2.84 - 2.75 (m, 2H), 2.64 - 2.57 (m, 2H), 2.44 (d, J = 7.0 Hz, 2H), 2.15 - 2.06 (m, 2H), 2.04 - 1.97 (m, 7H), 1.81 - 1.75 (m, 2H), 1.62 - 1.54 (m, 2H), 1.36 - 1.28 (m, 3H).

[0453] Example 43

[0454] 5-((9-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6- yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin- 4-yl)methyl)-3-hydroxy-3l6-thia-9-azaspiro[5.5]undec-3-ylidene)amino)-2-(2,6-dicarbonylpiperidin- 3-yl)isoindole-1,3-dione

[0455] Example 43 was prepared from the following steps:

[0456] Step A: 31b (48.5 mg, 0.06 mmol) and Int-9 (36.95 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, to which p-toluenesulfonic acid (22 mg, 0.12 mmol) was added, and reacted at 100 °C for 16 hours. LC / MS showed that the reaction was complete. After cooling to room temperature, sodium bicarbonate solution was slowly added dropwise to the reaction, and after extraction with dichloromethane / methanol = 15 / 1, washed with brine twice, the organic phases were combined, and the solvent was removed under reduced pressure to obtain a crude product which was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain compound 43 (8.6 mg, yield 11.41%) as a yellow solid. ESI-MS (m / z): 583.8 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 11.10 (s, 1H), 8.46 - 8.38 (m, 4H), 7.95 - 7.84 (m, 1H), 7.75 - 7.69 (m, 2H), 7.62 - 7.45 (m, 2H), 7.35 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.1, 2.0 Hz, 1H), 6.75 (s, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 3.81 - 3.71 (m, 6H), 3.03 - 2.96 (m, 3H), 2.93 - 2.82 (m, 2H), 2.61 - 2.50 (m, 7H), 2.35 - 2.29 (m, 4H), 2.24 - 2.19 (m, 3H), 2.06 - 1.99 (m, 2H), 1.99 (s, 3H), 1.96 (s, 3H), 1.93 - 1.86 (m, 2H), 1.85 - 1.79 (m, 3H), 1.75 - 1.69 (m, 2H), 1.64 - 1.58 (m, 3H), 1.51 - 1.44 (m, 3H).

[0457] Example 44

[0458] 5-((4-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0459] Example 44 was prepared from the following steps:

[0460] Step A: 1b (60 mg, 0.087 mmol) and Int-4 (46.72 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) to which p-toluenesulfonic acid (45.00 mg, 0.26 mmol) was added and reacted at 100 °C for 16 h. LC / MS showed the reaction was complete. Cooled to room temperature, the reaction was poured into sodium bicarbonate solution, the product precipitated, filtered and dried under vacuum. The resulting residue was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 2 as a light yellow solid (41.0 mg, yield 43.76%). ESI-MS (m / z): 533.8 [M+2H] 2+ / 2; 1 H NMR (500 MHz, DMSO-d6) δ 12.10 (s, 1H), 11.11 (s, 1H), 9.61 (s, 1H), 8.60 - 8.50 (m, 1H), 8.36 - 8.26 (m, 1H), 8.23 (s, 1H), 7.95 - 7.88 (m, 1H), 7.81 - 7.68 (m, 2H), 7.55 - 7.40 (m, 2H), 7.39 - 7.29 (m, 2H), 6.78 (s, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.77 (d, J = 8.4 Hz, 6H), 3.58 - 3.39 (m, 4H), 3.11 - 2.96 (m, 5H), 2.94 - 2.83 (m, 3H), 2.66 - 2.54 (m, 3H), 2.48 - 2.40 (m, 4H), 2.12 - 1.94 (m, 7H), 1.83 - 1.72 (m, 2H), 1.64 - 1.52 (m, 2H), 1.39 - 1.26 (m, 5H).

[0461] Example 45

[0462] 5-((4-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-fluoropiperidin-4-yl)methyl)-1-hydroxy-1l6-thiomorpholin-1-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0463] Example 45 was prepared from the following steps:

[0464] Step A: Int-3c (1.13 g, 4.51 mmol) was dissolved in dimethyl sulfoxide (60 mL), 45a (600 mg, 4.51 mmol) and sodium bicarbonate (1.89 g, 22.53 mmol) were added, stirred at 120 °C overnight, LC / MS showed the reaction was complete. Cooled to room temperature, quenched with water, extracted with dichloromethane, combined organic phase, dried over anhydrous sodium sulfate, filtered and concentrated, the obtained crude was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give 45b (1.0 g, yield 60.91%). ESI-MS (m / z): 365.3 (M+H) + .

[0465] Step B: 45b (300 mg, 0.82 mmol) was dissolved in DCM (15 mL), Dess-Martin periodinane (523.8 mg, 1.24 mmol) was added under ice bath, the reaction was stirred at room temperature for about 2 hours, LCMS showed the reaction was complete. Sodium carbonate solution was added to the reaction, the organic layer was washed with sodium thiosulfate solution twice, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product 45c (310 mg, crude), which was used directly in the next step. ESI-MS (m / z): 363.2 [M+H] + .

[0466] Step C: 45c (100 mg, 0.27 mmol) and Int-3 (107.74 mg, 0.27 mmol) were dissolved in dichloromethane (5 mL), a catalytic amount of acetic acid (3 drops) was added, the reaction was stirred at room temperature for 1 hour. Cooled to 0 °C under ice bath, sodium triacetoxyborohydride (116.98 mg, 0.55 mmol) was added in portions, the reaction was stirred at room temperature for about 2 hours. LC / MS showed the reaction was complete, the reaction was concentrated, the residue was purified by thin layer chromatography plate (dichloromethane / methanol (V / V) = 15 / 1) to give the product 45d (100 mg, yield 49.18%) as a yellow solid. ESI-MS (m / z): 737.4 [M+H] + .

[0467] Step D: 45d (100 mg, 0.13 mmol) was dissolved in ethanol (3 mL) and water (0.6 mL), iron powder (37.90 mg, 0.68 mmol) and ammonium chloride (36.30 mg, 0.68 mmol) were added to the reaction, and the reaction was stirred at 80 °C for 1 h. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated, dissolved in dichloromethane / methanol = 15 / 1, filtered through celite, and the resulting solution was concentrated under reduced pressure to give the crude product, which was purified by thin layer chromatography plate (dichloromethane / methanol = 15 / 1) to give 45e (56 mg, yield 58.38%) as a yellow solid. ESI-MS (m / z): 707.4 [M+H] + .

[0468] Step E: 45e (53 mg, 0.075 mmol) and Int-4 (43.32 mg, 0.105 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), p-toluenesulfonic acid (38.74 mg, 0.22 mmol) was added to the reaction, and the reaction was stirred at 100 °C for 16 h. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, and aqueous sodium bicarbonate solution was added to the reaction to produce a large amount of solid, which was filtered and the resulting residue was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 45 (21.9 mg, yield: 26.70%) as a light yellow solid. ESI-MS (m / z): 542.8 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.11 (s, 1H), 8.90 - 8.74 (m, 3H), 8.51 - 8.38 (m, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.82 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.62 - 7.44 (m, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 8.1, 2.0 Hz, 1H), 6.85 (s, 1H), 5.10 (dd, J = 12.8, 5.5 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.58 - 3.44 (m, 4H), 3.21 - 3.03 (m, 4H), 2.98 - 2.89 (m, 2H), 2.90 - 2.80 (m, 5H), 2.63 - 2.52 (m, 2H), 2.07 - 1.96 (m, 7H), 1.97 - 1.78 (m, 4H).

[0469] Example 46

[0470] 5-((9-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3- hydroxy-3l6-thia-9-azaspiro[5.5]undec-3-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindoline-1,3-dione

[0471] Example 46 was prepared from the following steps:

[0472] Step A: 31b (60 mg, 0.079 mmol) and Int-9 (45.79 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, to which p-toluenesulfonic acid (40.95 mg, 0.24 mmol) was added, and reacted at 100 °C for 16 hours. LC / MS showed the reaction was complete. Cooled to room temperature, slowly added sodium bicarbonate solution to the reaction, extracted with dichloromethane / methanol = 15 / 1, washed with brine twice, combined the organic phase, and the solvent was removed under reduced pressure to obtain the crude product which was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain compound 46 (35.5 mg, yield 39.13%) as a yellow solid. ESI-MS (m / z): 567.8 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.10 (s, 1H), 8.86 - 8.76 (m, 3H), 8.41 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.60 - 7.47 (m, 2H), 7.35 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.2, 2.0 Hz, 1H), 6.83 (s, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.47 - 3.35 (m, 4H), 3.10 - 3.03 (m, 2H), 2.93 - 2.84 (m, 1H), 2.65 - 2.52 (m, 4H), 2.39 - 2.27 (m, 4H), 2.26 - 2.20 (m, 2H), 2.06 - 1.97 (m, 7H), 1.94 - 1.87 (m, 2H), 1.86 - 1.79 (m, 2H), 1.77 - 1.70 (m, 2H), 1.67 - 1.57 (m, 3H), 1.53 - 1.45 (m, 2H), 1.34 - 1.23 (m, 2H).

[0473] Example 47

[0474] 5-((9-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3l6-thia-9-azaspiro[5.5]undec-3- ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0475] Example 47 was prepared by the following steps:

[0476] Step A: 31b (80 mg, 0.106 mmol) and 17a (46.78 mg, 0.148 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, p-toluenesulfonic acid (54.60 mg, 0.317 mmol) was added, and the reaction was reacted at 100 °C for 16 hours. LC / MS showed that the reaction was complete. After cooling to room temperature, sodium bicarbonate solution was slowly added dropwise to the reaction, and after extraction with dichloromethane / methanol = 15 / 1, the organic phase was washed with brine twice, the organic phase was combined, and the solvent was removed under reduced pressure. The crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain compound 47 (27.5 mg, yield 24.85%) as a yellow solid. ESI-MS (m / z): 519.0 [M+2H] 2+ / 2. 1H NMR (500 MHz, DMSO-d6) δ 11.22 (s, 1H), 11.11 (s, 1H), 8.48 - 8.37 (m, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.54 - 7.46 (m, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.32 (dd, J = 8.1, 2.0 Hz, 1H), 7.03 - 6.90 (m, 2H), 6.80 (s, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.48 - 3.37 (m, 4H), 3.10 - 3.03 (m, 2H), 2.94 - 2.82 (m, 1H), 2.63 - 2.52 (m, 4H), 2.38 - 2.29 (m, 4H), 2.23 (d, J = 7.1 Hz, 2H), 2.06 - 1.98 (m, 1H), 1.93 - 1.79 (m, 4H), 1.77 (s, 3H), 1.75 (s, 3H), 1.74 - 1.70 (m, 1H), 1.66 - 1.58 (m, 3H), 1.53 - 1.44 (m, 2H), 1.32 - 1.21 (m, 2H).

[0477] Example 48

[0478] 5-((9-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)-3-hydroxy-3l6-thia-9-azaspiro[5.5]undec-3- ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0479] Example 48 is prepared from the following steps:

[0480] Step A: Compound Int-12 (226 mg, 0.49 mmol) and 35a (292 mg, 0.68 mmol) were dissolved in dichloromethane (10 mL), three drops of glacial acetic acid were added dropwise under ice bath condition, sodium triacetoxyborohydride (322 mg, 1.52 mmol) was added portionwise. The reaction was stirred at room temperature for 2 hours, LC / MS showed the reaction was complete. The reaction was poured into water, dichloromethane was used to extract, the organic phase was combined, dried over anhydrous sodium sulfate, filtered and rotary evaporated to get the crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give yellow solid 48a (170 mg, yield 30.43%). ESI-MS (m / z): 735.4 [M+H] + .

[0481] Step B: 48a (170 mg, 0.23 mmol), iron powder (64.59 mg, 1.16 mmol) and ammonium chloride (61.87 mg, 1.16 mmol) were dissolved in ethanol (5.00 mL) and water (1.0 mL) at room temperature, and the reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was complete. Cooled to room temperature, the reaction was rotary evaporated to dryness, dissolved in dichloromethane / methanol = 15 / 1, filtered through celite, the solvent was removed under reduced pressure to get the crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give product 48b (130 mg, yield 79.72%). ESI-MS (m / z): 705.4 [M+H] + .

[0482] Step C: 48b (65 mg, 0.092 mmol) and Int-4 (53.27 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, p-toluenesulfonic acid (47.64 mg, 0.27 mmol) was added, and the reaction was stirred at 100 °C for 16 hours. LC / MS showed the reaction was complete. Cooled to room temperature, the reaction was added dropwise into sodium bicarbonate solution, a large amount of solid precipitated, filtered and dried under vacuum, the crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid compound 48 (28.0 mg, yield 27.81%). ESI-MS (m / z): 541.8 [M+2H] 2+ / 2. 1H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 11.10 (s, 1H), 8.89 - 8.78 (m, 3H), 8.29 (s, 1H), 8.27 (s, 1H), 7.93 - 7.85 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 2.1 Hz, 2H), 7.32 (dd, J = 8.1, 2.0 Hz, 1H), 6.81 (s, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 3.77 (s, 3H), 3.51 - 3.38 (m, 4H), 3.02 - 2.93 (m, 2H), 2.93 - 2.83 (m, 1H), 2.73 - 2.64 (m, 2H), 2.63 - 2.51 (m, 2H), 2.49 - 2.43 (m, 2H), 2.39 - 2.27 (m, 4H), 2.21 (d, J = 7.1 Hz, 2H), 2.07 - 1.98 (m, 7H), 1.94 - 1.87 (m, 2H), 1.86 - 1.76 (m, 4H), 1.69 - 1.57 (m, 3H), 1.52 - 1.46 (m, 2H), 1.31 - 1.21 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0483] Example 49

[0484] 5-((9-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2- ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)-3-hydroxy-3,6-thia-9-azaspiro[5.5]undec-3- yl)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-1,3-dione

[0485] Example 49 was prepared by the following steps:

[0486] Step A: 48b (65 mg, 0.092 mmol) and 49a (40.81 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, to which p-toluenesulfonic acid (47.64 mg, 0.27 mmol) was added and reacted at 100 °C for 16 hours. LC / MS showed the reaction was complete. Cooled to room temperature, the reaction was added dropwise to sodium bicarbonate solution, a large amount of solid precipitated, filtered and dried in vacuum, the obtained crude was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system), to give compound 49 as a yellow solid (28.0 mg, yield 27.81%). ESI-MS (m / z): 493.0 [M+2H]2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 11.10 (s, 1H), 8.48 - 8.37 (m, 1H), 8.12 (s, 1H), 8.10 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.54 (ddd, J = 14.1, 7.7, 1.6 Hz, 1H), 7.42 (s, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.13 - 7.08 (m, 1H), 6.77 (s, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 3.75 (s, 3H), 3.47 - 3.38 (m, 4H), 3.01 - 2.93 (m, 2H), 2.94 - 2.83 (m, 1H), 2.71 - 2.63 (m, 2H), 2.60 - 2.50 (m, 3H), 2.39 - 2.29 (m, 4H), 2.21 (d, J = 7.0 Hz, 2H), 2.06 - 1.99 (m, 1H), 1.94 - 1.81 (m, 4H), 1.82 - 1.73 (m, 9H), 1.67 - 1.58 (m, 3H), 1.53 - 1.46 (m, 2H), 1.31 - 1.21 (m, 2H), 1.05 (t, J = 7.5 Hz, 3H).

[0487] Example 50

[0488] 3-(4-((9-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)-3-hydroxy-3,6- thiaspiro[5.5]undec-3-ylidene)amino)phenyl)piperidine-2,6-dione

[0489] Example 50 is prepared from the following steps:

[0490] Step A: Compound Int-14 (200 mg, 0.51 mmol) and 35a (195 mg, 0.67 mmol) were dissolved in dichloromethane (10 mL), three drops of glacial acetic acid were added dropwise under ice bath condition, sodium triacetoxyborohydride (217 mg, 1.03 mmol) was added portionwise. The reaction was stirred at room temperature for 2 hours, LC / MS showed the reaction was complete. The reaction was poured into water, dichloromethane was used to extract, the organic phase was combined, dried over anhydrous sodium sulfate, filtered and rotary evaporated to get the crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give yellow solid 50a (100 mg, yield 29.25%). ESI-MS (m / z): 666.5 [M+H] + .

[0491] Step B: 50a (100 mg, 0.15 mmol), iron powder (41.94 mg, 0.75 mmol) and ammonium chloride (40.17 mg, 0.75 mmol) were dissolved in ethanol (5.00 mL) and water (1.0 mL) at room temperature, and the reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was complete. After cooling to room temperature, the reaction was rotary evaporated to dryness, dissolved in dichloromethane / methanol = 15 / 1, and filtered through celite. The solvent was removed by evaporation under reduced pressure to give the crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give product 50b (50 mg, yield 52.36%). ESI-MS (m / z): 637.5 [M+H] + .

[0492] Step C: 50b (50 mg, 0.078 mmol) and Int-4 (45.42 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, p-toluenesulfonic acid (40.62 mg, 0.27 mmol) was added, and the reaction was stirred at 100 °C for 16 hours. LC / MS showed the reaction was complete. After cooling to room temperature, the reaction was added dropwise to a sodium bicarbonate solution, and a large amount of solid precipitated. The solid was filtered and dried under vacuum. The crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid compound 50 (29.3 mg, yield 36.45%). ESI-MS (m / z): 507.3 [M+2H] 2+ / 2. 1HNMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.80 (s, 1H), 8.89 - 8.79 (m, 3H), 8.29 (s, 1H), 8.27 (s, 1H), 7.89 (d, J = 9.5 Hz, 1H), 7.36 (s, 1H), 7.07 - 7.00 (m, 2H), 6.95 - 6.89 (m, 2H), 6.81 (s, 1H), 3.77 (s, 3H), 3.74 (dd, J = 11.1, 4.9 Hz, 1H), 3.28 - 3.17 (m, 4H), 2.96 (d, J = 10.8 Hz, 2H), 2.73 - 2.58 (m, 3H), 2.49 - 2.44 (m, 3H), 2.38 - 2.30 (m, 4H), 2.21 (d, J = 7.1 Hz, 2H), 2.17 - 2.07 (m, 1H), 2.07 - 1.98 (m, 7H), 1.91 - 1.74 (m, 6H), 1.68 - 1.56 (m, 3H), 1.51 - 1.44 (m, 2H), 1.31 - 1.18 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H).

[0493] Example 51

[0494] 3-(4-((9-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)-3-hydroxy-3,6-thia-9-azaspiro[5.5]undec-3-ylidene)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0495] Example 51 was prepared from the following steps:

[0496] Step A: Compound Int-15 (200 mg, 0.47 mmol) and 35a (178 mg, 0.61 mmol) were dissolved in dichloromethane (10 mL), three drops of glacial acetic acid were added dropwise under ice bath condition, and sodium triacetoxyborohydride (199 mg, 0.94 mmol) was added portionwise. The reaction was stirred at room temperature for 2 hours, LC / MS showed the reaction was complete. The reaction was poured into water, dichloromethane was used to extract, the organic phase was combined, dried over anhydrous sodium sulfate, filtered and rotary evaporated to give the crude product which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give yellow solid 51a (120 mg, yield 36.38%). ESI-MS (m / z): 702.4 [M+H] + .

[0497] Step B: 51a (120 mg, 0.17 mmol), iron powder (47.74 mg, 0.85 mmol) and ammonium chloride (45.73 mg, 0.85 mmol) were dissolved in ethanol (5.00 mL) and water (1.0 mL) at room temperature, and the mixture was reacted at 80 °C for 1 h. LC / MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was rotary evaporated to dryness, dissolved in dichloromethane / methanol = 15 / 1, filtered through celite, and the solvent was removed under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to obtain product 51b (60 mg, yield 52.23%). ESI-MS (m / z): 672.4 [M+H] + .

[0498] Step C: 51b (60 mg, 0.089 mmol) and Int-4 (51.59 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, and p-toluenesulfonic acid (46.14 mg, 0.27 mmol) was added thereto, and the mixture was reacted at 100 °C for 16 h. LC / MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was added dropwise to a sodium bicarbonate solution, and a large amount of solid was precipitated, which was filtered and dried under vacuum. The obtained crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid, which was compound 51 (20.4 mg, yield 21.58%). ESI-MS (m / z): 525.3 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.91 (s, 1H), 8.90-8.78 (m, 3H), 8.29 (s, 1H), 8.27 (s, 1H), 7.89 (d, J = 9.5 Hz, 1H), 7.36 (s, 1H), 6.81 (s, 1H), 6.65-6.59 (m, 2H), 4.10 (dd, J = 12.7, 5.2 Hz, 1H), 3.77 (s, 3H), 3.42-3.35 (m, 2H), 3.00-2.93 (m, 2H), 2.85-2.74 (m, 1H), 2.72-2.65 (m, 2H), 2.56-2.50 (m, 1H), 2.50-2.43 (m, 4H), 2.37-2.31 (m, 4H), 2.21 (d, J = 7.0 Hz, 2H), 2.15-2.07 (m, 1H), 2.02 (d, J = 14.3 Hz, 7H), 1.91-1.73 (m, 6H), 1.69-1.57 (m, 3H), 1.52-1.45 (m, 2H), 1.31-1.21 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H).

[0499] Example 52

[0500] 3-(4-((9-(((3S,5S)-5-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)tetrahydrofuran-3-yl)methyl)-3-hydroxy-3lambda 6 - thia-9-azaspiro[5.5]undec-3-ylidene)amino)phenyl)piperidine-2,6-dione

[0501] Example 52 was prepared by the following steps:

[0502] Step A: Int-18 (300 mg, 0.84 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (209 mg, 1.01 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), potassium phosphate (534 mg, 2.52 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (40 mg, 0.084 mmol) and methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl-2-yl)palladium(II) (71 mg, 0.084 mmol) were added portionwise at 25 °C, stirred at 100 °C for 3 hours under nitrogen atmosphere. LCMS showed the reaction was complete. The reaction was cooled to room temperature, water and ethyl acetate were added. The organic phase was separated, washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the resulting solution was filtered and concentrated under reduced pressure, then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 52b (220 mg, yield 65.04%). ESI-MS (m / z): 404.1 [M+H] + .

[0503] Step B: 52a (220 mg, 0.56 mmol) and triethylamine (165 mg, 1.64 mmol) were dissolved in dichloromethane (4 mL), methanesulfonic anhydride (114 mg, 0.65 mmol) was added portionwise to the solution at 0 °C, the reaction was stirred at 25 °C for 1 hour under nitrogen atmosphere. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure to give 52b (230 mg, crude), which was used directly for the next step. ESI-MS (m / z): 482.3 [M+H] + .

[0504] Step C: Int-14 (180 mg, 0.46 mmol) and 52b (223 mg, 0.46 mmol) were dissolved in acetonitrile (5 mL), and triethylamine (467.62 mg, 4.62 mmol) and potassium iodide (77 mg, 0.46 mmol) were added to the solution at 25 °C, respectively. The reaction was stirred at 80 °C for 16 hours under nitrogen atmosphere. LCMS showed the reaction was complete. The reaction was reduced to room temperature, and water was added to the reaction. Ethyl acetate was extracted. The organic phase was combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The reaction was concentrated under reduced pressure, and purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 52c (100 mg, yield 27.96%). ESI-MS (m / z): 775.3 [M+H] + .

[0505] Step D: 52c (100 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL) and methanol (0.5 mL), and p-toluenesulfonic acid (111 mg, 0.65 mmol) was added at 0 °C. The reaction was stirred at 25 °C for 4 hours. LCMS showed the reaction was complete. The reaction was rotary evaporated under reduced pressure to give 52d (100 mg, crude product), which was used directly for the next step. ESI-MS (m / z): 675.7 [M+H] + .

[0506] Step E: 52d (100 mg, 0.15 mmol) and 17a (52 mg, 0.16 mmol) were dissolved in 1,4-dioxane (3 mL), and cesium carbonate (145 mg, 0.45 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (16 mg, 0.03 mmol), and methane sulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (13 mg, 0.015 mmol) were added to the solution at 25 °C, respectively. The reaction was stirred at 90 °C for 16 hours under nitrogen atmosphere. LCMS showed the reaction was complete. The reaction was reduced to room temperature, and water was added to the reaction. Ethyl acetate was extracted twice. The organic phase was combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The reaction was concentrated under reduced pressure, and purified by column chromatography (eluent: dichloromethane / methanol = 5 / 1) and preparative column to give 52 (11.3 mg, yield 7.99%). ESI-MS (m / z): 477.9 [M+2H] 2+ / 2. 1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),10.79(s,1H),8.40(s,3H),8.22–8.12(m,2H),7.80–7.62(m,2H),7.58 –7.46(m,1H),7.43(d,J=5.8Hz,1H),7.16–7.07(m,1H),7.08–6.94(m,3H),6.91(d,J=8.3Hz,2H),5.07–4.85 (m,1H),3.85(d,J=7.2Hz,6H),3.74(dd,J=11.2,5.1Hz,1H),3.57(d,J=2.5Hz,0H),3.22(d,J=10.3Hz,3H),2 .70–2.54(m,2H),2.35(dd,J=17.2,9.8Hz,3H),2.19–1.94(m,2H),1.79(t,J=13.4Hz,9H),1.64–1.37(m,5H).

[0507] Example 53

[0508] 5-((9-((1-(4-((5-bromo-4-((5-(dimethylphospho)-2-ethylquinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3λ 6 -Thia-9-azaspiro[5.5]undecane-3-ylidene)amino)-2-(2,6-dicarbonylpiperidin-3-yl)isodihydroindole-1,3-dione

[0509] Example 53 was prepared by the following steps:

[0510] Step A: At room temperature, 31b (25 mg, 0.03 mmol) and 47a (19 mg, 0.04 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (11 mg, 0.07 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC / MS showed that the reaction was complete. After cooling to room temperature, sodium bicarbonate solution was slowly added dropwise to the reaction mixture. After extraction with dichloromethane / methanol (15 / 1), the mixture was washed twice with brine. The organic phases were combined, and the solvent was removed by vacuum distillation. The crude product was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a yellow solid, compound 53 (8.6 mg, yield 11.41%). ESI-MS (m / z): 580.5 [M+2H] 2+ / 2. 1H NMR(500MHz,DMSO-d6)δ12.22(s,1H),11.10(s,1H),8.46–8.38(m,2H),8.35–8.29(m,1H),8.30–8.24(m,1H),8.19(s,1H),7.93(s,1H),7.82(s ,1H),7.72(d,J=8.1Hz,1H),7.50–7.43(m,1H),7.39(d,J=8.9Hz,1H),7.35(d,J=2.0Hz,1H),7.32(dd,J=8.1,2.1Hz,1H),6.80(s,1H),5.09(dd ,J=12.9,5.5Hz,1H),4.18–4.05(m,3H),3.79–3.74(m,3H),3.16(s,3H) ,3.09–3.02(m,2H),2.92–2.83(m,3H),2.62–2.52(m,7H),2.37–2.29(m ,3H),2.26–2.20(m,2H),2.06–1.97(m,6H),1.94–1.79(m,6H),1.77–1. 70(m,2H),1.67–1.57(m,3H),1.53–1.45(m,2H).1.28(t,J=7.6Hz,3H).

[0511] Example 54

[0512] 3-(4-((4-((4-(1-(4-((5-bromo-4-((5-(dimethylphospho)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)methyl)-1-hydroxytetrahydro-2H-1λ 6 -thiaran-1-yl)amino)phenyl)piperidin-2,6-dione

[0513] Example 54 was prepared by the following steps:

[0514] Step A: 54a (2 g, 15.13 mmol), iodobenzene acetate (9.74 g, 30.25 mmol), and ammonium acetate (2.33 g, 30.25 mmol) were dissolved in methanol (30 mL). The reaction was carried out at 25 °C for 2 hours, and LC / MS showed that the reaction was complete. The reaction solution was concentrated, dissolved in dichloromethane, and filtered through a diatomaceous earth filter. The filtrate was evaporated to dryness under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give a yellow oily substance 54b (1.9 g, yield 76.95%). LC / MS (ESI) was then performed. + m / z: 164.1 [M+H] +.

[0515] Step B: 54b (300 mg, 1.12 mmol), Int-14a (183 mg, 1.12 mmol), cesium carbonate (1.09 g, 3.36 mmol), t-BuXPhos (48 mg, 0.11 mmol) and t-BuXPhos Pd G3 (89 mg, 0.11 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 110 °C for 4 h under nitrogen. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, quenched with water, extracted with dichloromethane, the organic phases were combined and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give the product 54c (50 mg, yield 12.75%). ESI-MS (m / z): 351.1 [M+H] + .

[0516] Step C: 54c (50 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL), and Dess-Martin periodinane (91 mg, 0.21 mmol) was added under ice bath. The reaction was stirred at 25 °C for 2 h, LCMS showed the reaction was complete. To the reaction was added sodium thiosulfate aqueous solution, extracted with dichloromethane, the organic phases were combined and washed with saturated sodium bicarbonate aqueous solution and saturated brine, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product 54d (50.0 mg, crude product), which was used directly in the next step.

[0517] Step D: 54d (50 mg, 0.14 mmol) and Int-17 (55 mg, 0.16 mmol) were dissolved in dichloromethane (63 mL) at room temperature, acetic acid (3 drops) was added under ice bath, sodium triacetoxyborohydride (61 mg, 0.29 mmol) was added portionwise. The reaction was stirred at room temperature for 2 h, LC / MS showed the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 10 / 1) to give yellow solid 54e (30 mg, yield 30.7%), ESI-MS (m / z): 681.4 [M+H] + .

[0518] Step E: 54e (30 mg, 0.044 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL) at room temperature, iron powder (12 mg, 0.22 mmol) and ammonium chloride (12 mg, 0.22 mmol) were added to the reaction, and the reaction was stirred at 80 °C for 1 h. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated, dissolved in dichloromethane / methanol = 15 / 1, and concentrated under reduced pressure to give the crude product 54f (28 mg, crude). ESI-MS (m / z): 651.4 [M+H] + .

[0519] Step F: 54f (28 mg, 0.043 mmol), Int-4 (18 mg, 0.043 mmol), p-toluenesulfonic acid (15 mg, 0.086 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, and the reaction was stirred at 100 °C for 16 h. The reaction was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added, and a yellow solid precipitated. After suction filtration, the crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 54 (8.5 mg, yield 13.31%). ESI-MS (m / z): 514.7 [M+H] + . 1 HNMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.80 (d, J = 3.2 Hz, 1H), 8.87 (d, J = 1.8 Hz, 1H), 8.86 (s, 1H), 8.82 (s, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.38 (s, 1H), 7.02 (dd, J = 10.6, 8.5 Hz, 2H), 6.91 (t, J = 8.3 Hz, 2H), 6.81 (s, 1H), 3.77 (s, 3H), 3.73 (dd, J = 11.0, 5.6 Hz, 1H), 3.46 - 3.36 (m, 3H), 3.31 - 3.29 (m, 1H), 3.29 - 3.25 (m, 1H), 3.24 - 3.15 (m, 3H), 3.05 - 2.98 (m, 2H), 2.75 - 2.68 (m, 2H), 2.64 - 2.61 (m, 1H), 2.48 - 2.43 (m, 2H), 2.40 - 2.24 (m, 5H), 2.20 - 2.16 (m, 1H), 2.15 - 2.06 (m, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 1.99 - 1.78 (m, 4H), 1.63 - 1.45 (m, 5H), 0.92 (t, J = 6.8 Hz, 3H).

[0520] Example 55

[0521] 1-(5-((4-((1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1-hydroxy-1H-1,2,3-triazol-5-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl 2-(dimethylphosphoryl)benzoate 6 -1,1-dimethylethyl 2-(dimethylphosphoryl)-3-oxo-2,3-dihydro-1H-isoindole-5-carboxylate

[0522] Example 55 was prepared by the following steps:

[0523] Step A: Int-16 (500 mg, 1.40 mmol) and Int-3 (482 mg, 1.40 mmol) were dissolved in dichloromethane (10 mL), a catalytic amount of acetic acid (3 drops) was added to the reaction under ice bath condition, then sodium triacetylborohydride (594 mg, 2.80 mmol) was added portionwise. The reaction was stirred at room temperature for 2 hours, LC / MS showed the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction, dichloromethane was used to extract the reaction. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated, the obtained crude was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 55a (600 mg, yield 62.49%) as a white solid, ESI-MS (m / z): 685.3 [M+H] + .

[0524] Step B: 55a (600 mg, 0.87 mmol) was dissolved in ethanol (8 mL) and water (1.6 mL), iron powder (147 mg, 2.63 mmol) and ammonium chloride (141 mg, 2.63 mmol) were added to the reaction, the reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated, dissolved in dichloromethane / methanol = 15 / 1, filtered by celite, the obtained solution was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 55b (310 mg, yield 54.03%) as a yellow solid. ESI-MS (m / z): 655.4 [M+H] + .

[0525] Step C: 55b (80 mg, 0.12 mmol), Int-1 (49 mg, 0.12 mmol), p-toluenesulfonic acid (63 mg, 0.37 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature and reacted at 100 °C for 16 hours. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, and an aqueous solution of sodium bicarbonate was added to the reaction, which resulted in a large amount of solid. The residue obtained after filtration was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give white solid 55 (31.0 mg, yield 25%). ESI-MS (m / z): 510.8 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.43 (s, 1H), 8.21-8.13 (m, 3H), 7.97 (s, 1H), 7.90 (s, 1H), 7.56 (s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.25-7.20 (m, 1H), 7.04 (d, J = 2.6 Hz, 1H), 6.96 (dd, J = 8.6, 2.6 Hz, 1H), 6.79 (s, 1H), 6.41 (s, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.72-3.67 (m, 1H), 3.57 (dd, J = 12.2, 6.2 Hz, 1H), 3.43-3.31 (m, 2H), 3.10-3.05 (m, 2H), 3.01-2.95 (m, 2H), 2.89-2.80 (m, 2H), 2.75-2.67 (m, 2H), 2.60 (t, J = 10.9 Hz, 2H), 2.44 (d, J = 6.9 Hz, 3H), 1.82-1.77 (m, 3H), 1.74 (d, J = 13.5 Hz, 6H), 1.62-1.55 (m, 1H), 1.37-1.27 (m, 2H), 0.92-0.87 (m, 2H), 0.51-0.46 (m, 2H).

[0526] Example 56

[0527] 1-(2-chloro-5-((4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1-hydroxy-1H-pyrazol-5-yl)methyl)thio)morpholine-4-carboxylic acid 6 - thiomorpholine-1-ylidene)amino)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0528] Example 56 was prepared from the following steps:

[0529] Step A: At room temperature, 55b (80 mg, 0.12 mmol), 17a (39 mg, 0.12 mmol), and p-toluenesulfonic acid (63 mg, 0.37 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and reacted at 100 °C for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and an aqueous sodium bicarbonate solution was added to the reaction solution, producing a large amount of solid. The residue obtained after filtration was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid 56 (68.0 mg, yield 58.98%). ESI-MS (m / z): 467.9 [M+2H] 2+ / 2. 1 HNMR(500MHz,DMSO-d6)δ11.21(s,1H),10.43(s,1H),8.43(s,1H),8.24(s,1H),8.10(s,1H),7.97(s,1H),7.86(s,1H),7.58(s, 1H),7.50(dd,J=14.0,8.7Hz,1H),7.35(d,J=8.6Hz,1H),7.04(d,J=2.6Hz,1H),7.01–6.92(m,3H),6.79(s,1H),3.82(s,3H),3.7 8(s,3H),3.72–3.67(m,1H),3.59(dd,J=12.3,6.0Hz,1H),3.41-3.37(m,3H),3.10-3.05(m,2H),3.01-2.95(m,2H),2.89-2.81(m ,2H),2.76–2.68(m,2H),2.58(t,J=10.8Hz,2H),2.42(d,J=7.0Hz,2H),1.80-1.72(m,8H),1.62-1.55(m,1H),1.33–1.21(m,3H).

[0530] Example 57

[0531] 1-(5-((4-((1-(4-((5-bromo-4-((5-(dimethylphospho)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1-hydroxy-1λ 6 -Thiomorpholine-1-yl)amino)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0532] Example 57 was prepared by the following steps:

[0533] Step A: 55b (100 mg, 0.15 mmol), Int-4 (63 mg, 0.15 mmol), p-toluenesulfonic acid (79 mg, 0.46 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature and reacted at 100 °C for 16 hours. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, and an aqueous solution of sodium bicarbonate was added to the reaction, which produced a large amount of solid. The residue obtained after filtration was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give white solid 57 (57.0 mg, yield 35.85%). ESI-MS (m / z): 516.8 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 12.66 (s, 1H), 10.44 (s, 1H), 8.82 (dd, J = 17.9, 1.7 Hz, 3H), 8.41 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.57 (s, 1H), 7.55 - 7.49 (m, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 2.6 Hz, 1H), 6.97 (dd, J = 8.6, 2.6 Hz, 1H), 6.82 (s, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.71 - 3.67 (m, 1H), 3.60-3.57 (m, 1H), 3.10-3.05 (m, 2H), 3.02-2.95 (m, 3H), 2.88-2.85 (m f, 2H), 2.76 - 2.68 (m, 2H), 2.60 (t, J = 10.7 Hz, 2H), 2.44 (d, J = 7.0 Hz, 2H), 2.01 (d, J = 14.4 Hz, 6H), 1.83 - 1.73 (m, 3H), 1.62-1.55 (m, 2H), 1.36 - 1.25 (m, 3H).

[0534] Example 58 3-(4-((9-((1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidin]-4-yl)methyl)-3-hydroxy-3lambda 6 -thia-9-azaspiro[5.5]undecan-3-ylidene)amino)phenyl)piperidine-2,6-dione

[0535] Example 58 was prepared from the following steps:

[0536] Step A: 22b (440.7 mg, 1.17 mmol) and Int-14 (500 mg, 1.17 mmol) were dissolved in dichloromethane (10 mL) at room temperature, acetic acid (3 drops) was added to the solution, sodium triacetylborohydride (1.24 g, 5.87 mmol) was added portionwise at room temperature. The reaction was stirred at room temperature for 2 hours. LC / MS showed the reaction was completed. The reaction was quenched by saturated sodium bicarbonate solution, extracted by ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 58a (330 mg, yield 37.54%) as a yellow solid. ESI-MS (m / z): 749.4 [M+H] + .

[0537] Step B: 58a (330 mg, 0.44 mmol) was dissolved in ethanol (5 mL) and water (1 mL) at room temperature, iron powder (123 mg, 2.20 mmol) and ammonium chloride (118 mg, 2.20 mmol) were added to the solution, the reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was completed. The reaction was cooled to room temperature, concentrated, dissolved in dichloromethane / methanol = 15 / 1, filtered by celite, the filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 58b (200 mg, yield 63.13%) as a yellow solid. ESI-MS (m / z): 719.4 [M+H] + .

[0538] Step C: 58b (100 mg, 0.14 mmol), Int-4 (69 mg, 0.17 mmol), p-toluenesulfonic acid (72 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature, the reaction was stirred at 100 °C for 16 hours. The reaction was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, a yellow solid was precipitated, which was filtered to give the crude product. The crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 58 (23.4 mg, yield 15.36%) as a yellow solid. ESI-MS (m / z): 548.8 [M+2H] 2+ / 2. 1HNMR(500MHz,DMSO-d6)δ12.65(s,1H),10.80(s,1H),8.87(s,1H),8.85(s,1H),8.84–8.75(m,1H),8.32–8.25(m,3H),7.9 4–7.85(m,1H),7.38(s,1H),7.05–7.00(m,2H),6.94–6.89(m,2H),6.80(s,1H),4.37–3.90(m,8H),3.77(s,3H),3.75–3.72 (m,1H),3.29–3.19(m,4H),3.05–2.94(m,4H),2.72–2.60(m,3H),2.49–2.44(m,3H),2.34–2.27(m,5H),2.17–2.10(m,3H) ,2.04(s,3H),2.01(s,3H),1.89–1.76(m,6H),1.72–1.56(m,6H),1.48–1.42(m,2H),1.18–1.07(m,2H),0.94–0.90(m,2H).

[0539] Example 59

[0540] 3-(4-((9-((1-(4-((5-bromo-4-((5-(dimethylphospho)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3λ 6 -Thia-9-azaspiro[5.5]undecane-3-ylidene)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0541] Example 59 was prepared by the following steps:

[0542] Step A: Compounds Int-3 (372 mg, 1.08 mmol) and Int-14 (500 mg, 1.08 mmol) were dissolved in dichloromethane (10 mL). Under ice bath conditions, two drops of glacial acetic acid were added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (1.15 g, 5.41 mmol) in portions. The reaction was allowed to proceed at room temperature for 2 hours, and LC / MS showed that the reaction was complete. The reaction solution was poured into water, and a yellow product precipitated. The product was filtered and dried under vacuum to give a yellow solid 59a (137 mg, yield 16.79%). ESI-MS (m / z): 754.4 [M+H] + .

[0543] Step B: 59a (137 mg, 0.18 mmol), iron powder (51 mg, 0.91 mmol) and ammonium chloride (49 mg, 0.91 mmol) were dissolved in ethanol (2.5 mL) and water (0.5 mL) at room temperature, and reacted at 80 °C for 1 h. LC / MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was rotary evaporated, dissolved in dichloromethane / methanol = 15 / 1, filtered with celite, and the solvent was removed by reduced pressure to obtain the crude product. Purification by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) gave the product 59b (100 mg, yield 76.02%). ESI-MS (m / z): 724.4 [M+H] + .

[0544] Step C: 59b (50 mg, 0.069 mmol) and Int-4 (34 mg, 0.083 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, and p-toluenesulfonic acid (36 mg, 0.21 mmol) was added thereto, and reacted at 100 °C for 16 h. LC / MS showed that the reaction was complete. After cooling to room temperature, sodium bicarbonate solution was slowly added dropwise to the reaction solution, extracted with dichloromethane / methanol = 15 / 1, washed with brine twice, combined the organic phase, and the solvent was removed by reduced pressure to obtain the crude product. Purification by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) gave compound 59 as a yellow solid (9.3 mg, yield 12.14%). ESI-MS (m / z): 548.8 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 10.92 (s, 1H), 8.84 (s, 1H), 8.81 (s, 1H), 8.41 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.57 (s, 1H), 6.83 (s, 1H), 6.62 (s, 1H), 6.60 (s, 1H), 4.13 - 4.07 (m, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.09 - 3.05 (m, 2H), 2.85 - 2.74 (m, 2H), 2.66 - 2.54 (m, 3H), 2.36 - 2.30 (m, 4H), 2.25 - 2.21 (m, 2H), 2.12 - 2.08 (m, 1H), 2.03 (s, 3H), 2.00 (s, 3H), 1.99 - 1.95 (m, 2H), 1.91 - 1.78 (m, 5H), 1.77 - 1.69 (m, 3H), 1.62 - 1.59 (m, 2H), 1.50 - 1.46 (m, 2H), 1.33 - 1.26 (m, 3H).

[0545] Example 60

[0546] 3-(4-((9-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3λ 6 - thia-9-azaspiro[5.5]undecan-3-ylidene)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0547] Example 60 was prepared by the following steps:

[0548] Step A: 59b (50 mg, 0.069 mmol) and 60a (26 mg, 0.083 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, p-toluenesulfonic acid (36 mg, 0.21 mmol) was added, and the reaction was reacted at 100 °C for 16 hours. LC / MS showed that the reaction was complete. After cooling to room temperature, sodium bicarbonate solution was slowly added dropwise to the reaction, and after extraction with dichloromethane / methanol = 15 / 1, the organic phase was washed with brine twice, the organic phase was combined, and the solvent was removed under reduced pressure. The crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain compound 60 (4.2 mg, yield 6.01%) as a yellow solid. ESI-MS (m / z): 502.4 [M+2H] 2+ / 2. 1H NMR (500 MHz, DMSO-d6) δ 11.22 (s, 1H), 10.92 (s, 1H), 8.50 - 8.39 (m, 1H), 8.32 - 8.20 (m, 2H), 8.10 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.59 (s, 1H), 7.54 - 7.46 (m, 1H), 7.03 - 6.90 (m, 2H), 6.79 (s, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 4.12 - 4.08 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.37 - 3.30 (m, 4H), 3.11 - 3.02 (m, 2H), 2.84 - 2.75 (m, 1H), 2.63 - 2.55 (m, 2H), 2.55 - 2.51 (m, 1H), 2.39 - 2.31 (m, 4H), 2.27 - 2.22 (m, 2H), 2.13 - 2.05 (m, 1H), 2.01 - 1.95 (m, 1H), 1.91 - 1.80 (m, 4H), 1.78 (s, 3H), 1.75 (s, 3H), 1.73 - 1.71 (m, 1H), 1.64 - 1.57 (m, 3H), 1.51 - 1.45 (m, 2H), 1.33 - 1.22 (m, 3H).

[0549] Example 61

[0550] 3-(4-((4-((1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidin]-4-yl)methyl)-1-hydroxy-1λ 6 -thioxomorphin-1-ylideneamino)-2,6-difluorophenyl)piperidine-2,6-dione

[0551] Example 61 was prepared from the following steps:

[0552] Step A: 22b (191 mg, 0.51 mmol) and Int-10 (200 mg, 0.51 mmol) were dissolved in dichloromethane (10 mL) at room temperature, acetic acid (3 drops) was added to the solution, sodium triacetylboration hydride (538 mg, 2.54 mmol) was added portionwise at ice bath. The reaction was stirred at room temperature for 2 hours, LC / MS showed the reaction was complete, the reaction was quenched by saturated sodium bicarbonate solution, extracted by ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 61a (80 mg, yield 21.98%) as a yellow solid, ESI-MS (m / z): 717.4 [M+H] + .

[0553] Step B: 61a (80 mg, 0.11 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL) at room temperature, iron powder (31 mg, 0.56 mmol) and ammonium chloride (30 mg, 0.56 mmol) were added to the solution, the reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated, dissolved in dichloromethane / methanol = 15 / 1, concentrated under reduced pressure to give the crude product 61b (75 mg, crude product). ESI-MS (m / z): 687.5 [M+H] + .

[0554] Step E: 61b (75 mg, 0.11 mmol), Int-4 (54 mg, 0.13 mmol), p-toluenesulfonic acid (56 mg, 0.33 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature, the reaction was stirred at 100 °C for 16 hours, the reaction was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, a yellow solid was precipitated, the crude product was obtained by suction filtration, purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 61 (22.3 mg, yield 19.02%) as a yellow solid. ESI-MS (m / z): 532.7 [M+2H] 2+ / 2. 1HNMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.92 (s, 1H), 8.88 (d, J = 1.9 Hz, 1H), 8.86 (d, J = 1.9 Hz, 1H), 8.84 - 8.77 (m, 1H), 8.31 (s, 1H), 8.28 (s, 1H), 7.93 - 7.88 (m, 1H), 7.40 (s, 1H), 6.81 (s, 1H), 6.64 (s, 1H), 6.62 (s, 1H), 4.13 - 4.08 (m, 1H), 3.78 (s, 3H), 3.56 - 3.50 (m, 1H), 3.47 - 3.38 (m, 4H), 3.29 - 3.26 (m, 1H), 3.11 - 3.05 (m, 2H), 3.01 - 2.95 (m, 3H), 2.92 - 2.85 (m, 3H), 2.84 - 2.72 (m, 4H), 2.54 - 2.52 (m, 1H), 2.49 - 2.45 (m, 2H), 2.39 - 2.34 (m, 2H), 2.14 - 2.07 (m, 2H), 2.04 (s, 3H), 2.01 (s, 3H), 1.99 - 1.94 (m, 2H), 1.90 - 1.61 (m, 6H), 1.50 - 1.39 (m, 2H), 0.95 - 0.89 (m, 3H).

[0555] Example 62

[0556] 3-(5-((9-((1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidin]-4-yl)methyl)-3-hydroxy-3λ 6 -thia-9-azaspiro[5.5]undecan-3-ylidene)amino)-1-carboxysiindolin-2-yl)piperidin-2,6-dione

[0557] Example 62 was prepared from the following steps:

[0558] Step A: 22b (203 mg, 0.54 mmol) and Int-13 (200 mg, 0.45 mmol) were dissolved in dichloromethane (10 mL), acetic acid (3 drops) was added to the solution under ice bath, and sodium triacetylboration hydride (477 mg, 2.25 mmol) was added portionwise. The reaction was stirred at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction was quenched by saturated sodium bicarbonate solution, and extracted by ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 62a (195 mg, yield 53.91%) as a yellow solid. ESI-MS (m / z): 805.4 [M+H] + .

[0559] Step B: 62a (80 mg, 0.11 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL) at room temperature, iron powder (31 mg, 0.56 mmol) and ammonium chloride (30 mg, 0.56 mmol) were added to the solution, and the reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated, and dissolved in dichloromethane / methanol = 15 / 1, and concentrated under reduced pressure to give the crude product 62b (75 mg, crude product). ESI-MS (m / z): 387.9 [M+2H] 2+ / 2.

[0560] Step E: 62b (50 mg, 0.065 mmol), Int-4 (32 mg, 0.077 mmol), p-toluenesulfonic acid (33 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature, and the reaction was stirred at 100 °C for 16 hours. The reaction was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added. A yellow solid was precipitated, which was filtered to give the crude product. The crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 62 (3.9 mg, yield 5.25%) as a yellow solid. ESI-MS (m / z): 575.5 [M+2H] 2+ / 2. 1HNMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.97 (s, 1H), 8.89-8.87 (m, 1H), 8.87-8.85 (m, 1H), 8.84-8.79 (m, 1H), 8.31 (s, 1H), 8.28 (s, 1H), 7.93-7.88 (m, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 7.14 (s, 1H), 7.06-7.04 (m, 1H), 6.81 (s, 1H), 5.08-5.05 (m, 1H), 4.37-4.33 (m, 1H), 4.24-4.20 (m, 1H), 3.78 (s, 3H), 3.11-3.00 (m, 4H), 2.94-2.87 (m, 2H), 2.79-2.70 (m, 3H), 2.62-2.56 (m, 2H), 2.48-2.45 (m, 2H), 2.40-2.21 (m, 8H), 2.20-2.09 (m, 4H), 2.04 (s, 3H), 2.01 (s, 3H), 1.99-1.96 (m, 2H), 1.91-1.75 (m, 10H), 1.64-1.59 (m, 2H), 1.50-1.43 (m, 3H), 0.95-0.90 (m, 3H).

[0561] Example 63

[0562] 3-(5-((9-((1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3λ 6 -thia-9-azaspiro[5.5]undecan-3-ylidene)amino)-1-carboxysiindolin-2-yl)piperidin-2,6-dione

[0563] Example 63 was prepared from the following steps:

[0564] Step A: 41b (50 mg, 0.067 mmol), Int-4 (33 mg, 0.081 mmol), p-toluenesulfonic acid (35 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) and reacted at 100 °C for 16 hours. The reaction was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and a yellow solid precipitated. After suction filtration, the crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 63 (11.3 mg, yield 14.85%). ESI-MS (m / z): 560.8 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 10.97 (s, 1H), 8.85-8.84 (m, 1H), 8.81-8.80 (m, 1H), 8.41 (s, 1H), 8.35-8.31 (m, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.57 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.14 (s, 1H), 7.07-7.04 (m, 1H), 6.83 (s, 1H), 5.08-5.03 (m, 1H), 4.37-4.33 (m, 1H), 4.24-4.20 (m, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.10-3.05 (m, 3H), 2.95-2.86 (m, 2H), 2.61-2.57 (m, 3H), 2.36-2.32 (m, 4H), 2.25-2.22 (m, 2H), 2.03 (s, 3H), 2.00 (s, 3H), 1.92-1.85 (m, 3H), 1.84-1.77 (m, 3H), 1.75-1.71 (m, 2H), 1.65-1.58 (m, 4H), 1.51-1.44 (m, 3H), 1.31-1.27 (m, 2H).

[0565] Example 64

[0566] 3-(5-((9-((1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3lambda 6 -thia-9-azaspiro[5.5]undecan-3-ylidene)amino)-1-carboxyisoindolin-2-yl)piperidin-2,6-dione

[0567] Example 64 was prepared by the following steps:

[0568] Step A: At room temperature, 41b (50 mg, 0.067 mmol), Int-1 (32 mg, 0.081 mmol), and p-toluenesulfonic acid (35 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain yellow solid 64 (6.5 mg, yield 8.64%). ESI-MS (m / z): 554.0 [M+2H] 2+ / 2. 1 HNMR(500MHz,DMSO-d6)δ10.97(s,1H),10.85(s,1H),8.27(s,1H),8.19(s ,1H),8.14(s,1H),7.98(s,1H),7.88(s,1H),7.56(s,1H),7.53(d,J=8.2Hz ,1H),7.25–7.21(m,1H),7.14(s,1H),7.06–7.04(m,1H),6.80(s,1H),6.4 9–6.40(m,1H),5.08–5.04(m,1H),4.37–4.33(m,1H),4.24–4.20(m,1H),3. 83(s,3H),3.77(s,3H),3.09–3.03(m,3H),2.95–2.86(m,2H),2.62–2.57( m,3H),2.36–2.31(m,4H),2.25–2.22(m,2H),2.01–1.94(m,2H),1.92–1.84 (m,3H),1.83–1.78(m,3H),1.75(s,3H),1.73(s,3H),1.63–1.59(m,3H),1 .49–1.45(m,2H),1.34–1.25(m,3H),0.90–0.87(m,2H),0.51–0.47(m,2H).

[0569] Example 65

[0570] 3-(4-((9-((1-(4-((5-bromo-4-((5-(dimethylphospho)-3-fluoro-2-methylquinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3λ 6- (2, 6-difluorophenyl) piperidin-2, 6-dione

[0571] Example 65 was prepared from the following steps:

[0572] Step A: 59b (40 mg, 0.055 mmol) and Int-7 (29 mg, 0.066 mmol) were dissolved in N, N-dimethylformamide (1.2 mL) at room temperature, to which p-toluenesulfonic acid (29 mg, 0.16 mmol) was added, and reacted at 100 °C for 16 hours. LC / MS showed that the reaction was complete. After cooling to room temperature, sodium bicarbonate solution was added dropwise to the reaction solution slowly, and after extraction with dichloromethane / methanol = 15 / 1, it was washed with brine twice, the organic phase was combined, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by a reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain compound 65 (3.3 mg, yield 5.23%) as a yellow solid. ESI-MS (m / z): 556.0 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 11.95 (s, 1H), 10.91 (s, 1H), 8.40-8.28 (m, 2H), 8.24-8.18 (m, 2H), 7.93 (s, 1H), 7.73 (s, 1H), 7.60-7.47 (m, 2H), 6.76 (s, 1H), 6.62 (s, 1H), 6.60 (s, 1H), 4.12-4.08 (m, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.07-2.97 (m, 3H), 2.82-2.76 (m, 1H), 2.65-2.57 (m, 4H), 2.56-2.52 (m, 3H), 2.41-2.27 (m, 5H), 2.25-2.20 (m, 2H), 2.12-2.07 (m, 1H), 2.00 (s, 3H), 1.97 (s, 3H), 1.91-1.80 (m, 4H), 1.75-1.70 (m, 2H), 1.68-1.53 (m, 4H), 1.51-1.45 (m, 2H), 1.32-1.24 (m, 3H).

[0573] Example 66 3-(4-((9-((1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidin]-4-yl)methyl)-3-hydroxy-3lambda 6- (2, 6-difluorophenyl) piperidin-2, 6-dione

[0574] Example 66 was prepared from the following steps:

[0575] Step A: 22b (159 mg, 0.42 mmol) and Int-15 (150 mg, 0.35 mmol) were dissolved in dichloromethane (6 mL) at room temperature, acetic acid (3 drops) was added to the solution, sodium triacetylborohydride (149 mg, 0.71 mmol) was added portionwise under ice bath condition. The reaction was stirred at room temperature for 2 hours, LC / MS showed the reaction was complete, the reaction was quenched by saturated sodium bicarbonate solution, extracted by ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 66a (130 mg, yield 46.98%) as a yellow solid, ESI-MS (m / z): 785.4 [M+H] + .

[0576] Step B: 66a (45 mg, 0.057 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL) at room temperature, iron powder (16 mg, 0.29 mmol) and ammonium chloride (15 mg, 0.29 mmol) were added to the solution, the reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated, dissolved in dichloromethane / methanol = 15 / 1, concentrated under reduced pressure to give the crude product 66b (40 mg, crude product). ESI-MS (m / z): 378.7 [M-100+H] + / 2.

[0577] Step C: 66b (40 mg, 0.053 mmol), Int-4 (26 mg, 0.064 mmol), p-toluenesulfonic acid (27 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, the reaction was stirred at 100 °C for 16 hours, the reaction was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, a yellow solid was precipitated, the crude product was obtained by suction filtration, purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 66 (3.3 mg, yield 5.45%) as a yellow solid. ESI-MS (m / z): 566.0 [M+2H] 2+ / 2. 1HNMR (500 MHz, DMSO-d6) δ 12.64 (s, 1H), 10.91 (s, 1H), 8.88-8.87 (m, 1H), 8.86-8.85 (m, 1H), 8.81 (s, 1H), 8.35-8.31 (m, 1H), 8.28 (s, 1H), 8.27 (s, 1H), 7.93-7.88 (m, 1H), 7.37 (s, 1H), 6.80 (s, 1H), 6.62 (s, 1H), 6.60 (s, 1H), 4.11-4.08 (m, 1H), 3.77 (s, 3H), 3.04-2.98 (m, 3H), 2.94-2.86 (m, 3H), 2.84-2.75 (m, 2H), 2.74-2.65 (m, 3H), 2.49-2.45 (m, 3H), 2.42-2.36 (m, 2H), 2.32-2.25 (m, 4H), 2.22-2.17 (m, 2H), 2.14-2.10 (m, 2H), 2.04 (s, 3H), 2.01 (s, 3H), 1.86-1.79 (m, 5H), 1.70-1.56 (m, 7H), 1.49-1.44 (m, 3H), 1.14-1.02 (m, 3H), 0.94-0.90 (m, 3H).

[0578] Example 67 3-(4-((9-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3λ 6 -thia-9-azaspiro[5.5]undec-3-ylidene)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0579] Example 67 was prepared from the following steps:

[0580] Step A: Dissolve 67a (200 mg, 0.59 mmol), Int-11 (215 mg, 0.71 mmol), cesium carbonate (578 mg, 1.77 mmol), t-BuXPhos (25 mg, 0.059 mmol) and t-BuXPhos Pd G3 (47 mg, 0.059 mmol) in 1,4-dioxane (3 mL) and stir the reaction at 110 °C for 4 h under nitrogen. LC / MS shows the reaction is complete. Cool the reaction to room temperature, quench with water, extract with dichloromethane, combine the organic layers, and concentrate under reduced pressure to give the crude product. Purify the crude product by column chromatography (eluting with petroleum ether / ethyl acetate = 1 / 1) to give the product 67b (200 mg, 60.42% yield). ESI-MS (m / z): 560.24 [M+H] + .

[0581] Step B: Dissolve 67b (200 mg, 0.36 mmol) in dichloromethane (5 mL), then add HCl (4.0 M in 1,4-dioxane solution) (1 mL) and stir the reaction at room temperature for 2 h. A white solid is produced. LC / MS shows the reaction is complete. Concentrate the reaction to give the crude product 67c (170 mg, crude), which is used without further purification. ESI-MS (m / z): 460.19 [M+H] + .

[0582] Step C: Dissolve 67c (170 mg, 0.34 mmol) and Int-3 (191 mg, 0.55 mmol) in dichloromethane (6 mL), then add acetic acid (3 drops) and sodium triacetoxyborohydride (157 mg, 0.74 mmol) portionwise under ice bath. Stir the reaction at room temperature for 2 h. LC / MS shows the reaction is complete. Quench the reaction with saturated sodium bicarbonate solution and extract with ethyl acetate. Dry the combined organic layers over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by column chromatography on silica gel (eluting with dichloromethane / methanol (V / V) = 20 / 1) to give yellow solid 67d (32 mg, 10.98% yield). ESI-MS (m / z): 788.34 [M+H] + .

[0583] Step D: 67d (32 mg, 0.04 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL) at room temperature, iron powder (12 mg, 0.2 mmol) and ammonium chloride (11 mg, 0.2 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC / MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved with dichloromethane / methanol = 15 / 1, and concentrated under reduced pressure to obtain the crude product 67e (30 mg, crude product). ESI-MS (m / z): 758.37 [M+H] + .

[0584] Step E: 67e (30 mg, 0.039 mmol), 67f (15 mg, 0.05 mmol), p-toluenesulfonic acid (14 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, and the reaction was carried out at 100 °C for 16 hours. The reaction solution was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added, and a yellow solid was precipitated. After suction filtration, the crude product was obtained, and purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain yellow solid 67 (13.0 mg, yield 31.34%). ESI-MS (m / z): 519.5 [M+H] + . 1HNMR (500 MHz, DMSO-d6) δ 11.22 (s, 1H), 11.08 (s, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.58 (s, 1H), 7.50 (dd, J = 13.8, 8.2 Hz, 1H), 6.99 (s, 1H), 6.83 (dd, J = 14.1, 6.6 Hz, 2H), 6.80 (s, 1H), 6.67 (d, J = 6.6 Hz, 1H), 5.34 - 5.29 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.66 (s, 3H), 3.10 - 3.03 (m, 3H), 2.93 - 2.84 (m, 2H), 2.73 - 2.66 (m, 1H), 2.64 - 2.62 (m, 1H), 2.61 - 2.55 (m, 2H), 2.36 - 2.29 (m, 4H), 2.24 - 2.20 (m, 2H), 2.01 - 1.96 (m, 1H), 1.93 - 1.87 (m, 2H), 1.84 - 1.79 (m, 2H), 1.77 (s, 3H), 1.76 - 1.75 (m, 1H), 1.75 (s, 3H), 1.73 - 1.70 (m, 1H), 1.67 - 1.56 (m, 4H), 1.49 - 1.45 (m, 2H), 1.30 - 1.21 (m, 3H).

[0585] Example 68 3-(5-((9-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3-hydroxy-3λ 6 -thia-9-azaspiro[5.5]undecan-3-ylidene)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0586] Example 68 was prepared from the following steps:

[0587] Step A: Dissolve 68a (200 mg, 0.59 mmol), Int-11 (215 mg, 0.71 mmol), cesium carbonate (578 mg, 1.77 mmol), t-BuXPhos (25 mg, 0.059 mmol) and t-BuXPhos Pd G3 (47 mg, 0.059 mmol) in 1,4-dioxane (3 mL) and stir the reaction at 110 °C for 4 h under nitrogen. LC / MS shows the reaction is complete. Cool the reaction to room temperature, quench with water, extract with dichloromethane, combine the organic layers, and concentrate under reduced pressure to give the crude product. Purify the crude product by column chromatography (eluting with petroleum ether / ethyl acetate = 1 / 1) to give the product 68b (200 mg, 60.42% yield). ESI-MS (m / z): 560.24 [M+H] + .

[0588] Step B: Dissolve 68b (200 mg, 0.36 mmol) in dichloromethane (5 mL), then add HCl (4.0 M in 1,4-dioxane solution) (1 mL) and stir the reaction at room temperature for 2 h. A white solid is produced. LC / MS shows the reaction is complete. Concentrate the reaction to give the crude product 68c (172 mg, crude), which is used without further purification. ESI-MS (m / z): 460.2 [M+H] + .

[0589] Step C: Dissolve 68c (172 mg, 0.34 mmol) and Int-3 (191 mg, 0.55 mmol) in dichloromethane (6 mL), then add acetic acid (3 drops) and sodium triacetoxyborohydride (157 mg, 0.74 mmol) portionwise while stirring under ice bath. Stir the reaction at room temperature for 2 h. LC / MS shows the reaction is complete. Quench the reaction with saturated sodium bicarbonate solution and extract with ethyl acetate. Dry the combined organic layers over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by column chromatography on silica gel (eluting with dichloromethane / methanol (V / V) = 20 / 1) to give yellow solid 68d (100 mg, 37.03% yield). ESI-MS (m / z): 788.3 [M+H] + .

[0590] Step D: Dissolve 68d (100 mg, 0.13 mmol) in ethanol (4 mL) and water (0.8 mL), add iron powder (36 mg, 0.63 mmol) and ammonium chloride (34 mg, 0.63 mmol) to the reaction mixture, and react at 80 °C for 1 h. LC / MS shows the reaction is complete. Cool to room temperature, concentrate the reaction, dissolve in dichloromethane / methanol = 15 / 1, and concentrate under reduced pressure to give the crude product 68e (80 mg, crude). ESI-MS (m / z): 758.4 [M+H] + .

[0591] Step E: Dissolve 68e (80 mg, 0.10 mmol), 68f (40 mg, 0.12 mmol), p-toluenesulfonic acid (36 mg, 0.20 mmol) in N,N-dimethylformamide (1.2 mL), and react at 100 °C for 16 h. Cool the reaction mixture to room temperature, add saturated aqueous sodium bicarbonate solution, and precipitate a yellow solid. Filter under suction to give the crude product, and purify by reverse-phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 68 (25.0 mg, yield 22.6%). ESI-MS (m / z): 519.5 [M+H] + . 1HNMR (500 MHz, DMSO-d6) δ 11.22 (s, 1H), 11.08 (s, 1H), 8.43 (s, 1H), 8.23 (s, 2H), 8.10 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.58 (s, 1H), 7.50 (dd, J = 14.2, 9.0 Hz, 1H), 6.99 (s, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.80 (s, 1H), 6.76 (d, J = 1.9 Hz, 1H), 6.67 (dd, J = 8.3, 1.9 Hz, 1H), 5.30 (dd, J = 12.8, 5.5 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.29 (s, 3H), 3.25 - 3.23 (m, 1H), 3.22 - 3.14 (m, 3H), 3.09 - 3.04 (m, 2H), 2.93 - 2.85 (m, 1H), 2.73 - 2.66 (m, 1H), 2.65 - 2.62 (m, 1H), 2.59 (d, J = 7.7 Hz, 2H), 2.35 - 2.27 (m, 4H), 2.25 - 2.20 (m, 2H), 2.03 - 1.97 (m, 1H), 1.88 - 1.80 (m, 4H), 1.77 (s, 3H), 1.76 - 1.75 (m, 1H), 1.75 (s, 3H), 1.73 - 1.71 (m, 1H), 1.64 - 1.58 (m, 3H), 1.50 - 1.45 (m, 2H), 1.31 - 1.23 (m, 2H).

[0592] Example 69 3-(4-((4-((4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)methyl)-1-hydroxytetrahydro-2H-1 6 - thiopyran-1-ylidene)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0593] Example 69 was prepared from the following steps:

[0594] Step A: 54b (129 mg, 0.79 mmol), Int-10a (200 mg, 0.66 mmol), cesium carbonate (643 mg, 1.97 mmol), t-BuXPhos (28 mg, 0.066 mmol) and t-BuXPhos Pd G3 (52 mg, 0.066 mmol) were dissolved in 1,4-dioxane (3 mL) and stirred at 100 °C for 4 h under nitrogen atmosphere. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, quenched with water, extracted with dichloromethane, the organic phases were combined and concentrated under reduced pressure to give the crude product which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give the product 69a (100 mg, yield 39.35%). ESI-MS (m / z): 387.1 [M+H] + .

[0595] Step B: 69a (100 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), and Dess-Martin periodinane (164 mg, 0.39 mmol) was added under ice bath. The reaction was stirred at 25 °C for 2 h, LCMS showed the reaction was complete. To the reaction was added sodium thiosulfate aqueous solution, extracted with dichloromethane, the organic phases were combined and washed with saturated sodium bicarbonate aqueous solution and saturated brine, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product 69b (84.5 mg, crude), which was used directly in the next step.

[0596] Step C: 69b (50 mg, 0.13 mmol) and Int-17 (50 mg, 0.14 mmol) were dissolved in dichloromethane (6 mL) under room temperature, acetic acid (3 drops) was added under ice bath, sodium triacetoxyborohydride (61 mg, 0.29 mmol) was added portionwise. The reaction was stirred at room temperature for 2 h, LC / MS showed the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 10 / 1) to give yellow solid 69c (40 mg, yield 42.90%), ESI-MS (m / z): 703.3 [M+H] + .

[0597] Step D: 69c (40 mg, 0.056 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL) at room temperature, iron powder (12 mg, 0.22 mmol) and ammonium chloride (12 mg, 0.22 mmol) were added to the reaction, and the reaction was stirred at 80 °C for 1 h. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated, dissolved in dichloromethane / methanol = 15 / 1, and concentrated under reduced pressure to give the crude product 69d (30 mg, crude). ESI-MS (m / z): 687.4 [M+H] + .

[0598] Step E: 69d (30 mg, 0.044 mmol), Int-4 (27 mg, 0.065 mmol), p-toluenesulfonic acid (15 mg, 0.087 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, and the reaction was stirred at 100 °C for 16 h. The reaction was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added, and a yellow solid precipitated. The crude product was obtained by suction filtration, and purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 69 (10.0 mg, yield 21.32%). ESI-MS (m / z): 531.5 [M+H] + . 1 HNMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.91 (d, J = 3.3 Hz, 1H), 8.87 (d, J = 1.9 Hz, 1H), 8.86 (s, 1H), 8.81 (s, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 6.81 (s, 1H), 6.62 - 6.58 (m, 2H), 4.11 - 4.07 (m, 1H), 3.77 (s, 3H), 3.58 - 3.50 (m, 3H), 3.26 - 3.24 (m, 1H), 3.03 - 2.99 (m, 2H), 2.82 - 2.74 (m, 2H), 2.73 - 2.67 (m, 2H), 2.34 - 2.27 (m, 3H), 2.22 - 2.17 (m, 2H), 2.15 - 2.07 (m, 4H), 2.03 (s, 3H), 2.01 (s, 3H), 1.94 - 1.89 (m, 2H), 1.88 - 1.82 (m, 3H), 1.64 - 1.47 (m, 7H), 0.95 - 0.90 (m, 3H).

[0599] Example 70 3-(4-((4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-1-hydroxytetrahydro-2H-1λ 6 - thiopyran-1-ylidene)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0600] Example 70 was prepared by the following steps:

[0601] Step A: Int-17 (300 mg, 0.78 mmol) and 70a (136 mg, 1.17 mmol) were dissolved in dichloromethane (5 mL) at room temperature, acetic acid (3 drops) was added to the mixture under ice bath, sodium triacetylboration hydride (330 mg, 1.56 mmol) was added portionwise. The reaction was stirred at room temperature for 2 hours, LCMS showed the reaction was complete. The reaction was quenched by saturated sodium bicarbonate solution, extracted by ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 10 / 1) to give yellow solid 70b (340 mg, yield 97.24 %), ESI-MS (m / z): 449.3 [M+H] + .

[0602] Step B: 70b (340 mg, 0.76 mmol), iodobenzene acetate (448 mg, 1.52 mmol) and ammonium acetate (117 mg, 1.52 mmol) were dissolved in methanol (5 mL). The reaction was stirred at 25 °C for 2 hours, LCMS showed the reaction was complete. The reaction was concentrated, dissolved in dichloromethane and filtered through celite. The filtrate was concentrated under reduced pressure, the crude product was purified by thin layer preparative plate (dichloromethane / methanol = 10 / 1) to give yellow solid 70c (160 mg, yield 44.02 %). LC / MS (ESI + )m / z: 480.3 [M+H] + .

[0603] Step C: 70c (160 mg, 0.33 mmol), Int-10a (122 mg, 0.40 mmol), cesium carbonate (217 mg, 0.67 mmol), t-BuXPhos (14.0 mg, 0.03 mmol) and t-BuXPhos Pd G3 (27 mg, 0.03 mmol) were dissolved in 1,4-dioxane (3 mL) and stirred at 110 °C for 4 h under nitrogen. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, quenched with water, extracted with dichloromethane, the organic phases were combined and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give the white product 70d (150 mg, yield 63.98%). ESI-MS (m / z): 703.3 [M+H] + .

[0604] Step D: 70d (150 mg, 0.21 mmol) was dissolved in ethanol (4 mL) and water (0.8 mL) at room temperature, iron powder (60 mg, 1.07 mmol) and ammonium chloride (57 mg, 1.07 mmol) were added to the reaction, which was stirred at 80 °C for 1 h. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated, dissolved in dichloromethane / methanol = 15 / 1 and concentrated under reduced pressure to give the crude product 70e (120 mg, crude). ESI-MS (m / z): 673.3 [M+H] + .

[0605] Step F: 70e (40 mg, 0.059 mmol), Int-17a (28 mg, 0.089 mmol), p-toluenesulfonic acid (20 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, which was stirred at 100 °C for 16 h. The reaction was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and a yellow solid precipitated. The crude product was obtained by suction filtration and purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 70 (25 mg, yield 43.71%). ESI-MS (m / z): 514.7 [M+2H] 2+ / 2. 1HNMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 10.92 (s, 1H), 8.43 (s, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.55 (dd, J = 12.9, 7.7 Hz, 1H), 7.43 (s, 1H), 7.32 (s, 1H), 7.11 (t, J = 7.1 Hz, 1H), 6.77 (s, 1H), 6.63 (d, J = 10.9 Hz, 2H), 4.11 (dd, J = 12.6, 5.0 Hz, 1H), 3.75 (s, 3H), 3.57 - 3.49 (m, 2H), 3.41 - 3.36 (m, 3H), 3.05 - 2.98 (m, 2H), 2.85 - 2.74 (m, 2H), 2.73 - 2.66 (m, 3H), 2.62 - 2.52 (m, 7H), 2.34 - 2.24 (m, 1H), 2.16 - 2.05 (m, 2H), 2.04 - 1.91 (m, 6H), 1.90 - 1.81 (m, 2H), 1.78 (s, 3H), 1.75 (s, 3H), 1.64 - 1.51 (m, 2H), 1.06 (t, J = 7.5 Hz, 3H).

[0606] Example 71 (4-((4-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-1- hydroxytetrahydro-2H-1λ 6 - thien-1-ylidene)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0607] Example 71 was prepared from the following steps:

[0608] Step A: 70e (40.0 mg, 0.059 mmol), Int-4 (37 mg, 0.089 mmol), p-toluenesulfonic acid (20 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) and reacted at 100 °C for 16 h. The reaction was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added. A yellow solid precipitated, which was filtered off and purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 71 (25 mg, yield 37.28%). ESI-MS (m / z): 525.8 [M+2H] 2+ / 2. 1HNMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.92 (s, 1H), 8.86 (d, J = 8.6 Hz, 2H), 8.81 (s, 1H), 8.28 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 9.1 Hz, 1H), 7.37 (s, 1H), 6.81 (s, 1H), 6.63 (d, J = 11.0 Hz, 2H), 4.11 (dd, J = 12.4, 4.7 Hz, 1H), 3.77 (s, 3H), 3.56 - 3.47 (m, 3H), 3.40 - 3.36 (m, 3H), 3.06 - 2.95 (m, 3H), 2.83 - 2.75 (m, 2H), 2.74 - 2.63 (m, 4H), 2.56 - 2.52 (m, 4H), 2.48 - 2.44 (m, 2H), 2.33 - 2.26 (m, 1H), 2.15 - 2.07 (m, 2H), 2.04 (s, 3H), 2.01 (s, 3H), 2.00 - 1.93 (m, 4H), 1.90 - 1.80 (m, 2H), 1.64 - 1.52 (m, 2H), 0.92 (t, J = 6.7 Hz, 3H).

[0609] Example 72 3-(4-((4-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-1-hydroxytetrahydro-2H-1λ 6 - thiopyran-1-ylidene)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0610] Example 72 was prepared from the following steps:

[0611] Step A: 70e (40.0 mg, 0.059 mmol), Int-7 (40 mg, 0.089 mmol), p-toluenesulfonic acid (20 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) and reacted at 100 °C for 16 h. The reaction was cooled to room temperature and saturated aqueous sodium bicarbonate solution was added. A yellow solid precipitated and was collected by suction filtration to give the crude product. Purification by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) gave 72 as a yellow solid (25 mg, 34.26% yield). ESI-MS (m / z): 541.3 [M+2H] 2+ / 2. 1HNMR (500 MHz, DMSO-d6) δ 11.27 (s, 1H), 10.92 (s, 1H), 9.86 (s, 1H), 8.67 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.35 (s, 1H), 6.72 (s, 1H), 6.63 (d, J = 11.1 Hz, 2H), 4.11 (dd, J = 12.5, 5.0 Hz, 1H), 3.75 (s, 3H), 3.59 - 3.46 (m, 4H), 3.12 - 2.94 (m, 5H), 2.93 - 2.87 (m, 1H), 2.84 - 2.75 (m, 2H), 2.74 - 2.59 (m, 8H), 2.33 - 2.24 (m, 1H), 2.23 - 2.13 (m, 3H), 2.12 - 2.05 (m, 2H), 2.04 - 1.99 (m, 4H), 1.96 (s, 3H), 1.92 (s, 3H), 1.87 - 1.74 (m, 3H), 1.61 - 1.43 (m, 2H), 1.17 - 1.10 (m, 1H), 0.76 - 0.63 (m, 3H).

[0612] Example 73 3-{5-[(4-{[1-(4-{[5-bromo-4-({5-[dimethyl(oxido- lambda 5 - methylphospho]-3-fluoro-2-methylquinolin-6-yl}amino)pyrimidin-2-yl]amino}-5- methoxy-2-(1-methylpyrazol-4-yl)phenyl)hexahydropyridin-4-yl]methyl}-1-oxido-1 lambda 6 -1,4-thiaazacyclohexan-1-ylidene)amino]-2-chlorophenyl}hexahydropyridine-2,6-dione

[0613] Example 73 was prepared from the following steps:

[0614] Step A: To a solution of 73a (5 g, 21.69 mmol) in tetrahydrofuran (60 mL) was added dropwise lithium diisopropylamide (2.0 M in tetrahydrofuran) (11.93 mL) at -65 °C, the reaction solution was stirred at this temperature for 1 hour, then 3-bromopropionic acid ethyl ester (4.71 g, 26.03 mmol) in tetrahydrofuran (15 mL) was added dropwise into it over 10 min. The resulting solution was stirred at -65 °C for 30 min, and then allowed to warm to room temperature naturally. LCMS showed the reaction was complete. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, concentration gave the product 73b (4.7 g, yield 65.53%). ESI-MS (m / z): 331.5 [M+H]+ .

[0615] Step B: To a solution of 73b (4.7 g, 14.22 mmol) in tetrahydrofuran (60 mL) and water (20 mL) was added lithium hydroxide (1.02 g, 42.65 mmol), the reaction was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. The reaction was diluted with water, extracted with EA twice, the aqueous phase was adjusted to pH 4-5 with 1 N HC1, extracted with ethyl acetate twice, the organic phase was combined, washed with brine, filtered and the organic phase was concentrated to give 73c (4.1 g, yield 95.32%) as a colorless oily liquid. ESI-MS (m / z): 303.6 [M+H] + .

[0616] Step C: 73c (4 g, 13.22 mmol) was dissolved in toluene (50 mL), then concentrated sulfuric acid (98% (AR)) (1.30 g, 13.22 mmol, 0.7 mL) was added, the reaction was stirred at 100 °C for 3 hours. LCMS showed the reaction was complete. The reaction was concentrated, the crude product was neutralized with saturated sodium bicarbonate solution after concentration, extracted with ethyl acetate, the organic phase was concentrated to give the crude product 73d (2.3 g, yield 57.50%). ESI-MS (m / z): 303.6 [M+H] + .

[0617] Step D: 73d (1.2 g, 3.97 mmol), Int-2c (929.36 mg, 3.97 mmol), cesium carbonate (2.58 g, 7.93 mmol), t-BuXphos (168.17 mg, 0.39 mmol) and t-BuXPhos-Pd-G3 (94.48 mg, 0.11 mmol) were dissolved in a mixed solvent of dioxane (6 mL) and N,N-dimethylformamide (6 mL), the reaction was stirred at 80 °C for 16 hours under nitrogen atmosphere. LCMS showed that the product was generated. The reaction was cooled, quenched with water, extracted with ethyl acetate, the organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 73e (1.3 g, yield 71.89%) after purification by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1). ESI-MS (m / z): 456.2 [M+H] + .

[0618] Step E: Dissolve 73e (1.2 g, 2.63 mmol) in dichloromethane (20 mL), then add HC1 (4.0 M in 1,4-dioxane, 10 mL) at 0 °C. Stir at room temperature for 4 h, white product precipitates, LC / MS shows the reaction is complete. Filter and dry in vacuum to get pale yellow solid 73f (0.7 g, crude). No further purification is needed. ESI-MS (m / z): 356.8 [M+H] + .

[0619] Step F: Dissolve 73f (0.5 g, 1.41 mmol, C) and Int-3 (483.88 mg, 1.41 mmol) in dichloromethane (8 mL) at room temperature, cool to 0 °C in ice bath, add 3 drops of acetic acid, add sodium triacetoxyborohydride (595.61 mg, 2.81 mmol) portion wise, stir at room temperature for 2 h. LC / MS shows the reaction is complete. Quench the reaction with water, extract with dichloromethane. Dry the combined organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, the crude product is purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, (V / V)) to get pale yellow solid 73g (710 mg, yield 73.85%). ESI-MS (m / z): 684.3 [M+H] + .

[0620] Step G: Dissolve 73g (700 mg, 1.02 mmol), iron powder (57.14 mg, 1.02 mmol) and ammonium chloride (54.72 mg, 1.02 mmol) in ethanol (6.00 mL) and water (1.2 mL) at room temperature, stir at 80 °C for 1 h. LC / MS shows the reaction is complete. Spin dry the reaction, dissolve in dichloromethane / methanol = 15 / 1 (V / V), filter over celite, evaporate the solvent under reduced pressure to get the crude product, purify by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, (V / V)) to get product 73h (500 mg, yield 74.7%). ESI-MS (m / z): 654.3 [M+H]+.

[0621] Step H: 73h (100 mg, 0.15 mmol) and Int-7 (67.81 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) to which p-toluenesulfonic acid (78.96 mg, 0.46 mmol) was added and reacted at 100 °C for 16 h. LC / MS showed the reaction was complete. Upon cooling to room temperature, the reaction was poured into sodium bicarbonate solution and the product precipitated, which was filtered and dried under vacuum. The resulting residue was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 73 as a light yellow solid (7.0 mg, yield 4.19%). ESI-MS (m / z): 531.8 [M+2H] 2+ / 2; 1 H NMR (500 MHz, DMSO-d6) δ 11.95 (s, 1H), 10.90 (s, 1H), 8.36 - 8.31 (m, 1H), 8.25 - 8.19 (m, 3H), 7.93 (s, 1H), 7.74 (s, 1H), 7.52 (s, 2H), 7.25 (d, J = 8.5 Hz, 1H), 6.91 (dd, J = 8.5, 2.6 Hz, 1H), 6.88 (d, J = 2.5 Hz, 1H), 6.75 (s, 1H), 4.09 (dd, J = 11.9, 5.0 Hz, 1H), 3.77 (d, J = 10.5 Hz, 6H), 3.06 - 3.01 (m, 2H), 2.99 - 2.95 (m, 2H), 2.87 - 2.81 (m, 3H), 2.79 - 2.70 (m, 2H), 2.61 - 2.57 (m, 4H), 2.55 - 2.52 (m, 4H), 2.42 (d, J = 7.0 Hz, 2H), 1.99 (d, J = 13.3 Hz, 6H), 1.80 - 1.74 (m, 3H), 1.62 - 1.54 (m, 2H), 1.32 - 1.25 (m, 2H).

[0622] Example 74 3-{2-chloro-5-[(4-{[1-(4-{[5-chloro-4-({2-[dimethyl(oxido- lambda 5 -1,4-thiazinanyl-1-ylidene)amino]phenyl}hexahydropyridin-2,6-dione 6 -1,4-thiazinanyl-1-ylidene)amino]phenyl}hexahydropyridin-2,6-dione

[0623] Example 74 was prepared from the following steps:

[0624] Step A: 73h (100 mg, 0.15 mmol), 17a (48.32 mg, 0.15 mmol), p-toluenesulfonic acid (78.96 mg, 0.46 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) under nitrogen protection, and reacted at 100 °C for 16 hours. The reaction solution was cooled to room temperature, 10 mL of saturated aqueous sodium bicarbonate solution was added, and a yellow solid was precipitated. After suction filtration, the crude product was obtained, and purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia water system) to obtain yellow solid 74 (19 mg, yield 12.91%). ESI-MS (m / z): 468.1 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 11.21 (s, 1H), 10.90 (s, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.85 (d, J = 4.2 Hz, 1H), 7.58 (s, 1H), 7.50 (dd, J = 14.1, 8.9 Hz, 1H), 7.24 (dd, J = 8.5, 2.9 Hz, 1H), 6.98 (d, J = 7.0 Hz, 1H), 6.91 (dd, J = 8.5, 2.6 Hz, 1H), 6.89 - 6.86 (m, 1H), 6.79 (s, 1H), 4.09 (dd, J = 12.1, 5.0 Hz, 1H), 3.80 (d, J = 20.1 Hz, 6H), 3.30 - 3.26 (m, 1H), 3.11 - 3.05 (m, 2H), 3.01 - 2.93 (m, 3H), 2.87 - 2.80 (m, 2H), 2.79 - 2.69 (m, 1H), 2.65 - 2.56 (m, 2H), 2.41 (d, J = 6.9 Hz, 2H), 2.26 - 2.22 (m, 1H), 2.02 - 1.96 (m, 1H), 1.80 - 1.73 (m, 8H), 1.62 - 1.56 (m, 2H), 1.32 - 1.25 (m, 3H).

[0625] Example 75 3-{4-[(4-{[1-(4-{[5-chloro-4-({2-[dimethyl(oxido- lambda 5 -1,4-thiazin-1-ylidene)amino]-2-ethyl-5-methoxyphenyl}hexahydropyridin-4- yl]methyl}-1-oxo-1 lambda 6 -1,4-thiazin-1-ylidene)amino]-2,6-difluorophenyl}hexahydropyridine-2,6-dione

[0626] Example 75 was prepared from the following steps:

[0627] Step A: 35a (245.40 mg, 0.84 mmol) and Int-10 (200 mg, 0.56 mmol) were dissolved in dichloromethane (3 mL) at room temperature, a catalytic amount of acetic acid (3 drops) was added to the solution under ice bath, and sodium triacetylborohydride (237.22 mg, 1.12 mmol) was added portionwise. The reaction was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction was quenched by the addition of saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 10 / 1) to give 75a (100 mg, yield 28.2%) as a yellow solid. ESI-MS (m / z): 634.2 [M+H] + .

[0628] Step B: 75a (100 mg, 0.16 mmol) was dissolved in ethanol (4 mL) and water (0.8 mL) at room temperature, iron powder (44.06 mg, 0.79 mmol) and ammonium chloride (42.21 mg, 0.79 mmol) were added to the solution, and the reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated, and dissolved in dichloromethane / methanol = 15 / 1, and concentrated under reduced pressure to give the crude product 75b (120 mg, crude). ESI-MS (m / z): 604.2 [M+H] + .

[0629] Step C: 75b (40 mg, 0.066 mmol), 17a (31.42 mg, 0.099 mmol), p-toluenesulfonic acid (22.82 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, and the reaction was stirred at 100 °C for 16 hours. The reaction was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added. A yellow solid precipitated, which was filtered to give the crude product. The crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 75 (19.3 mg, yield 31.33%) as a yellow solid. ESI-MS (m / z): 442.4 [M+2H] 2+ / 2. 1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 10.92 (s, 1H), 8.43 (s, 1H), 8.11 (d, J = 12.1 Hz, 2H), 7.55 (dd, J = 13.6, 7.2 Hz, 1H), 7.42 (s, 1H), 7.31 (s, 1H), 7.11 (t, J = 7.2 Hz, 1H), 6.78 (s, 1H), 6.63 (d, J = 10.8 Hz, 2H), 4.11 (dd, J = 12.6, 5.0 Hz, 1H), 3.75 (s, 3H), 3.47 - 3.37 (m, 4H), 3.03 - 2.95 (m, 4H), 2.92 - 2.85 (m, 2H), 2.83 - 2.75 (m, 1H), 2.71 - 2.63 (m, 2H), 2.58 - 2.52 (m, 3H), 2.44 - 2.38 (m, 2H), 2.14 - 2.05 (m, 1H), 2.01 - 1.94 (m, 1H), 1.87 - 1.80 (m, 2H), 1.78 (s, 3H), 1.75 (s, 3H), 1.65 - 1.56 (m, 1H), 1.34 - 1.27 (m, 2H), 1.06 (t, J = 7.5 Hz, 3H).

[0630] Example 76

[0631] 5-[(9-{[1-(4-{[5-bromo-4-({5-[dimethyl(oxido- lambda 5 - phosphono]quinoxalin-6-yl}amino)pyrimidin-2-yl]amino}-2-ethyl-5- methoxyphenyl)-4-fluorohexahydropyridin-4-yl]methyl}-3-oxo-3lambda 6 -9-aza-3-thiaspiro[5.5]undec-3-ylidene)amino]-2-(2,6-dioxohexahydropyridin-3- yl)isoindole-1,3-dione

[0632] Example 76 was prepared from the following steps:

[0633] Step A: 76a (3.0 g, 12.86 mmol) was dissolved in dichloromethane (30 mL) at room temperature, and Dess-Martin oxidizing reagent (8.18 g, 19.29 mmol) was added to the reaction system. The reaction was stirred at room temperature for 4 hours. LCMS showed that the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution to the system, and extracted with dichloromethane three times. The organic phase was washed with sodium thiosulfate solution, and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 76b (2.8 g, crude) as a colorless oil, which was used without further purification.

[0634] Step B: 76b (300 mg, 0.65 mmol) was dissolved in dichloromethane (5 mL) at room temperature, N, N-diisopropylethylamine (84.56 mg, 0.65 mmol, 0.11 mL) was added under ice-bath cooling, after 5 minutes, catalytic equivalent of glacial acetic acid (39.29 mg, 0.70 mmol) was added dropwise, 76b (302.61 mg, 1.31 mmol) was added to the reaction solution, and the reaction was allowed to proceed for about 1 hour, and the temperature was lowered to 0°C, and sodium triacetylborohydride (416.00 mg, 1.96 mmol) was added in portions. The reaction was allowed to proceed at room temperature for about 1 hour, and LCMS showed that the reaction was complete. Water was added to the reaction solution, and the organic phase was separated by extraction with dichloromethane, and the combined organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain 76c (250 mg, yield 56.71%) as a yellow solid. ESI-MS (m / z): 674.4 [M+H] + .

[0635] Step C: 76c (250 mg, 0.37 mmol) was dissolved in dichloromethane (4 mL) at room temperature, and the temperature was lowered to 0°C under ice-bath cooling, and hydrochloric acid / dioxane solution (4.0 M, 2 mL) was added thereto, and the reaction was allowed to proceed at room temperature for about 2 hours. LCMS showed the product. Directly concentrated under reduced pressure to obtain 76d (200 mg, crude) as a light yellow solid. No further purification was needed. ESI-MS (m / z): 574.4 [M+H] + .

[0636] Step D: 76d (200 mg, 0.35 mmol) and Int-17a (69.44 mg, 0.35 mmol) were dissolved in dimethyl sulfoxide (5 mL) at room temperature, and sodium bicarbonate (146.44 mg, 1.74 mmol) was added to the reaction solution, and the reaction was allowed to proceed with stirring at 120°C for 4 hours. LCMS showed that the reaction was complete. Water was added to the reaction solution, and then extracted with dichloromethane / methanol = 15 / 1, and then concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) to obtain 76e (50 mg, yield 19.05%) as a light yellow solid. ESI-MS (m / z): 753.4 [M+H] + .

[0637] Step E: 76e (50 mg, 0.066 mmol), iron powder (18.54 mg, 0.33 mmol) and ammonium chloride (17.76 mg, 0.33 mmol) were dissolved in ethanol (2.0 mL) and water (0.4 mL) at room temperature, and the mixture was reacted at 80 °C for 1 h. LCMS showed that the reaction was complete. After cooling to room temperature, the reaction solution was rotary evaporated to dryness, dissolved in dichloromethane / methanol = 15 / 1, filtered with celite, and the solvent was removed under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) to obtain 76f (25 mg, yield 52.07%) as a light yellow solid. ESI-MS (m / z): 362.3 [M+2H] 2+ / 2.

[0638] Step F: 76f (25 mg, 0.035 mmol) and Int-4 (18.55 mg, 0.045 mmol) were dissolved in N,N-dimethylformamide (1.0 mL) at room temperature, and p-toluenesulfonic acid (17.87 mg, 0.11 mmol) was added thereto, and the mixture was reacted at 100 °C for 16 h. LC / MS showed that the reaction was complete. After cooling to room temperature, sodium bicarbonate solution was slowly added dropwise to the reaction solution, extracted with dichloromethane / methanol = 15 / 1, washed with brine twice, combined the organic phase, and the solvent was removed under reduced pressure to obtain the crude product, which was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain compound 76 (4.0 mg, yield 10.42%) as a yellow solid. ESI-MS (m / z): 550.8 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 11.11 (s, 1H), 8.89-8.85 (m, 2H), 8.85-8.77 (m, 1H), 8.47-8.44 (m, 2H), 8.29 (d, J = 13.8 Hz, 2H), 7.94-7.86 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.41-7.30 (m, 3H), 6.84 (s, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 3.78 (s, 3H), 2.97-2.80 (m, 6H), 2.63-2.52 (m, 5H), 2.02 (d, J = 14.4 Hz, 7H), 1.97-1.77 (m, 10H), 1.66-1.60 (m, 2H), 1.53-1.46 (m, 2H), 1.32-1.20 (m, 6H), 0.92 (t, J = 7.5 Hz, 3H).

[0639] Example 77

[0640] 3-[4-({9-[1-(4-{[5-bromo-4-({5-[dimethyl(oxido- lambda 5 -9-aza-3-thiaspiro[5.5]undec-3-ylidene}amino)-2,6-difluorophenyl]hexahydropyridine- 2,6-dione 6 -9-aza-3-thiaspiro[5.5]undec-3-ylidene}amino)-2,6-difluorophenyl]hexahydropyridine- 2,6-dione

[0641] Example 77 was prepared from the following steps:

[0642] Step A: Compound 19c (343.39 mg, 1.23 mmol) and Int-15 (350 mg, 0.82 mmol) were dissolved in N,N-dimethylformamide (2 mL), two drops of glacial acetic acid were added, and the reaction was cooled to 0 °C. Sodium triacetoxyborohydride (871.69 mg, 4.11 mmol) was added in portions. The reaction was stirred at room temperature for 4 h. LC / MS showed the reaction was complete. The reaction was poured into water, and yellow product precipitated. The solid was collected by filtration, washed with water, and dried in vacuum to give yellow solid 77a (87 mg, yield 15.38%). ESI-MS (m / z): 687.8 [M+H] + .

[0643] Step B: 77a (50 mg, 0.072 mmol), iron powder (20.3 mg, 0.36 mmol) and ammonium chloride (19.44 mg, 0.36 mmol) were dissolved in a mixture of ethanol (1 mL) and water (0.2 mL). The reaction was stirred at 80 °C for 1 h. LC / MS showed the reaction was complete. The reaction was concentrated, dissolved in dichloromethane, and filtered through celite. The filtrate was concentrated under reduced pressure. The crude product was purified by thin layer preparative plate (dichloromethane / methanol (V / V) = 10 / 1) to give yellow solid 77b (42 mg, yield 87.83%). ESI-MS (m / z): 657.81 [M+H] + .

[0644] Step C: 77b (20 mg, 0.030 mmol), Int-4 (15.05 mg, 0.036 mmol) and p-toluenesulfonic acid (15.71 mg, 0.090 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction was heated at 100 °C for 16 h, LCMS showed the reaction was complete. Cooled to room temperature, the reaction was poured into saturated aqueous sodium bicarbonate solution, which produced a large amount of solid, the residue was obtained after filtration was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 77 (2.8 mg, yield 8.82%). ESI-MS (m / z): 518.4 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 10.92 (s, 1H), 8.89-8.87 (m, 1H), 8.86-8.85 (m, 1H), 8.82 (s, 1H), 8.37 (s, 1H), 8.30 (s, 1H), 8.27 (s, 1H), 7.93-7.88 (m, 1H), 7.37 (s, 1H), 6.81 (s, 1H), 6.64 (s, 1H), 6.61 (s, 1H), 4.12-4.09 (m, 1H), 3.77 (s, 3H), 3.54-3.53 (m, 3H), 3.35-3.33 (m, 4H), 3.03-2.99 (m, 2H), 2.84-2.75 (m, 2H), 2.73-2.68 (m, 2H), 2.49-2.45 (m, 3H), 2.42-2.35 (m, 2H), 2.16-2.06 (m, 2H), 2.04 (s, 3H), 2.01 (s, 3H), 1.90-1.82 (m, 5H), 1.65-1.58 (m, 4H), 1.53-1.48 (m, 2H), 0.96-0.89 (m, 3H).

[0645] Example 78 3-[4-({9-[1-(4-{[5-chloro-4-({2-[dimethyl(oxido- lambda 5 -9-azaspiro[5.5]undec-3-ylidene}amino)-2,6-difluorophenyl]hexahydropyridine- 2,6-dione 6 -9-azaspiro[5.5]undec-3-ylidene}amino)-2,6-difluorophenyl]hexahydropyridine- 2,6-dione

[0646] Example 78 was prepared from the following steps:

[0647] Step A: 77b (20 mg, 0.030 mmol), 17a (11.53 mg, 0.036 mmol) and p-toluenesulfonic acid (15.71 mg, 0.090 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction was stirred at 100 °C for 16 h. LCMS showed the reaction was complete. The reaction was cooled to room temperature and poured into saturated aqueous sodium bicarbonate solution, which resulted in a large amount of solid. The residue was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 78 as a yellow solid (2.7 mg, 9.38% yield). ESI-MS (m / z): 469.4 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.92 (s, 1H), 8.44 - 8.38 (m, 2H), 8.13 (s, 1H), 8.11 (s, 1H), 7.57 - 7.53 (m, 1H), 7.43 (s, 1H), 7.34 - 7.30 (m, 1H), 7.14 - 7.11 (m, 1H), 6.77 (s, 1H), 6.63 (s, 1H), 6.61 (s, 1H), 4.12 - 4.09 (m, 1H), 3.76 (s, 3H), 3.04 - 3.00 (m, 3H), 2.84 - 2.75 (m, 3H), 2.72 - 2.64 (m, 4H), 2.40 - 2.35 (m, 2H), 2.14 - 2.06 (m, 2H), 2.01 - 1.96 (m, 2H), 1.91 - 1.82 (m, 7H), 1.78 (s, 3H), 1.76 (s, 3H), 1.64 - 1.56 (m, 5H), 1.51 - 1.48 (m, 2H), 1.09 - 1.03 (m, 4H).

[0648] Example 79 3-{5-[(9-{[1-(4-{[5-bromo-4-({5-[dimethyl(oxido- lambda 5 - phosphorlyl)quinolin-6-yl}amino)pyrimidin-2-yl]amino}-2-ethyl-5- methoxyphenyl)hexahydropyridin-4-yl]methyl}-3-oxo-3- lambda 6 -9-aza-3-thiaspiro[5.5]undec-3-ylidene)amino]-3-methyl-2- oxonaphtho[d]imidazol-1-yl}hexahydropyridine-2,6-dione

[0649] Example 79 was prepared from the following steps:

[0650] Step A: 68c (200 mg, 0.41 mmol) and 35a (176.8 mg, 0.60 mmol) were dissolved in dichloromethane (6 mL), acetic acid (3 drops) was added, and sodium triacetylborohydride (427.28 mg, 2.02 mmol) was added portionwise at room temperature under ice bath. The reaction was stirred at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction was quenched by saturated sodium bicarbonate solution, and extracted by ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 79a (130 mg, yield 43.81%) as a yellow solid. ESI-MS (m / z): 735.89 [M+H] + .

[0651] Step B: 79a (80 mg, 0.18 mmol) was dissolved in ethanol (1.5 mL) and water (0.3 mL) at room temperature, iron powder (30.36 mg, 0.54 mmol) and ammonium chloride (29.07 mg, 0.54 mmol) were added, and the reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated, and dissolved in dichloromethane / methanol = 15 / 1, and concentrated under reduced pressure to give the crude product 79b (75 mg, crude product). ESI-MS (m / z): 706.91 [M+H] + .

[0652] Step C: 79b (75 mg, 0.11 mmol), Int-4 (52.61 mg, 0.13 mmol), p-toluenesulfonic acid (54.89 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) at room temperature, and the reaction was stirred at 100 °C for 16 hours. The reaction was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added. A yellow solid was precipitated, which was filtered to give the crude product. The crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 79 (1.8 mg, yield 1.55%) as a yellow solid. ESI-MS (m / z): 554.3 [M+2H] 2+ / 2. 1HNMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 11.08 (s, 1H), 8.89-8.86 (m, 1H), 8.86-8.84 (m, 1H), 8.30 (s, 1H), 8.27 (s, 1H), 7.92-7.88 (m, 1H), 7.36 (s, 1H), 7.20 (s, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.81 (s, 1H), 6.76 (s, 1H), 6.69-6.65 (m, 2H), 5.34-5.30 (m, 2H), 3.77 (s, 3H), 3.29 (s, 3H), 3.25-3.24 (m, 1H), 2.99-2.95 (m, 2H), 2.93-2.84 (m, 3H), 2.72-2.66 (m, 3H), 2.64-2.63 (m, 1H), 2.61-2.58 (m, 1H), 2.37-2.30 (m, 5H), 2.23-2.19 (m, 2H), 2.04 (s, 3H), 2.01 (s, 3H), 1.99-1.97 (m, 3H), 1.86-1.77 (m, 6H), 1.64-1.59 (m, 3H), 1.51-1.43 (m, 5H).

[0653] Example 80 3-{4-[(9-{[1-(4-{[5-bromo-4-({5-[dimethyl(oxido- lambda 5 -9-azaspiro[5.5]undec-3-ylidene)amino]-3-methyl-2-oxido- benz[d]imidazol-1-yl}hexahydropyridin-2,6-dione 6 -9-azaspiro[5.5]undec-3-ylidene)amino]-3-methyl-2-oxido- benz[d]imidazol-1-yl}hexahydropyridin-2,6-dione

[0654] Example 80 was prepared from the following steps:

[0655] Step A: 67c (200 mg, 0.41 mmol) and 35a (176.8 mg, 0.61 mmol) were dissolved in dichloromethane (6 mL), acetic acid (3 drops) was added, and sodium triacetylborohydride (427.28 mg, 2.02 mmol) was added portionwise at room temperature under ice bath. The reaction was stirred at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction was quenched by saturated sodium bicarbonate solution, and extracted by ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 80a (202 mg, yield 68.08%) as a yellow solid. ESI-MS (m / z): 736.4 [M+H] + .

[0656] Step B: 80a (106 mg, 0.14 mmol) was dissolved in ethanol (1.5 mL) and water (0.3 mL) at room temperature, iron powder (40.22 mg, 0.72 mmol) and ammonium chloride (38.52 mg, 0.72 mmol) were added, and the reaction was stirred at 80 °C for 1 hour. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated, and dissolved in dichloromethane / methanol = 15 / 1, and concentrated under reduced pressure to give the crude product 80b (100 mg, crude product). ESI-MS (m / z): 706.5 [M+H] + .

[0657] Step C: 80b (100 mg, 0.11 mmol), Int-4 (69.8 mg, 0.17 mmol), p-toluenesulfonic acid (73.18 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature, and the reaction was stirred at 100 °C for 16 hours. The reaction was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added. A yellow solid was precipitated, which was filtered to give the crude product. The crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 80 (3.3 mg, yield 2.16%) as a white solid. ESI-MS (m / z): 541.5 [M+2H] 2+ / 2. 1HNMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 11.09 (s, 1H), 8.87 (m, 1H), 8.85 (m, 1H), 8.82 (s, 1H), 8.41 (m, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 7.89 (m, 1H), 7.36 (s, 1H), 6.86 - 6.79 (m, 3H), 6.70 - 6.65 (m, 1H), 5.34 - 5.29 (m, 1H), 3.77 (s, 3H), 3.66 (s, 3H), 3.32 - 3.26 (m, 6H), 2.99 - 2.94 (m, 2H), 2.90 - 2.85 (m, 1H), 2.72 - 2.65 (m, 3H), 2.65 - 2.56 (m, 2H), 2.49 - 2.45 (m, 2H), 2.38 - 2.30 (m, 4H), 2.23 - 2.19 (m, 2H), 2.03 (s, 3H), 2.01 (s, 3H), 1.93 - 1.87 (m, 2H), 1.83 - 1.76 (m, 4H), 1.67 - 1.60 (m, 3H), 1.51 - 1.45 (m, 2H), 1.28 - 1.22 (m, 2H), 0.97 - 0.89 (m, 3H).

[0658] Example 81 9-{[1-(4-{[5-bromo-4-({5-[dimethyl(oxido- lambda 5 - phosphono]quinoxalin-6-yl}amino)pyrimidin-2-yl]amino}-2-ethyl-5- methoxyphenyl)hexahydropyridin-4-yl]methyl}-3-{[3-(2,4-dioxohexahydropyrimidin- 1-yl)-1-methylindazol-6-yl]hydrazono}-3lambda 6 -9-aza-3-thiaspiro[5.5]undecan-3-one

[0659] Example 81 was prepared from the following steps:

[0660] Step A: 81a (500 mg, 1.55 mmol), Int-11 (375.51 mg, 1.24 mmol), cesium carbonate (1.01 g, 3.10 mmol), t-BuXPhos (65.91 mg, 0.15 mmol) and t-BuXPhos Pd G3 (61.64 mg, 0.077 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 100 °C for 4 h under nitrogen atmosphere. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, quenched with water, extracted with dichloromethane, the organic phases were combined and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give yellow solid 81b (527 mg, yield 62.45%). ESI-MS (m / z): 544.68 [M+H] + .

[0661] Step B: 81b (200 mg, 0.37 mmol) was dissolved in dichloromethane (3 mL), then hydrochloric acid (4.0 M in 1,4-dioxane) (1.5 mL) was added, and the reaction was stirred at room temperature for 2 h. Yellow solid was produced. LC / MS showed the reaction was complete. The reaction was concentrated to give the crude product 81c (200 mg, crude), which was used without further purification. ESI-MS (m / z): 444.68 [M+H] + .

[0662] Step C: 81c (200 mg, 0.42 mmol) and 35a (182.7 mg, 0.63 mmol) were dissolved in dichloromethane (5 mL), and acetic acid (3 drops) was added to the solution under ice bath condition, then sodium triacetoxyborohydride (441.52 mg, 2.08 mmol) was added portionwise. The reaction was stirred at room temperature for 2 h, LC / MS showed the reaction was complete, then the reaction was quenched by the addition of saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give yellow solid 81d (180 mg, yield 60.01%). ESI-MS (m / z): 720.89 [M+H] + .

[0663] Step D: 81d (110 mg, 0.15 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL) at room temperature, iron powder (42.67 mg, 0.76 mmol) and ammonium chloride (40.87 mg, 0.76 mmol) were added to the reaction, and the reaction was stirred at 80 °C for 1 h. LC / MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated, dissolved in dichloromethane / methanol = 15 / 1, and concentrated under reduced pressure to give the crude product 81e (100 mg, crude). ESI-MS (m / z): 690.91 [M+H] + .

[0664] Step E: 81e (100 mg, 0.15 mmol), Int-4 (71.77 mg, 0.17 mmol), p-toluenesulfonic acid (74.88 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature, and the reaction was stirred at 100 °C for 16 h. The reaction was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added, and a yellow solid precipitated. After suction filtration, the crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 81 (10.7 mg, yield 6.68%). ESI-MS (m / z): 534.0 [M+2H] 2+ / 2. 1 HNMR (500 MHz, DMSO-d6) δ 12.64 (s, 1H), 10.53 (s, 1H), 8.88-8.86 (m, 1H), 8.86-8.84 (m, 1H), 8.84-8.76 (m, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 7.93-7.87 (m, 1H), 7.44 (d, 1H), 7.36 (s, 1H), 6.98 (s, 1H), 6.82-6.78 (m, 2H), 3.90-3.89 (m, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.31-3.25 (m, 4H), 3.00-2.94 (m, 2H), 2.76-2.72 (m, 2H), 2.71-2.65 (m, 2H), 2.49-2.45 (m, 2H), 2.38-2.29 (m, 4H), 2.23-2.18 (m, 2H), 2.03 (s, 3H), 2.01 (s, 3H), 1.94-1.74 (m, 7H), 1.68-1.60 (m, 3H), 1.51-1.45 (m, 2H), 1.33-1.17 (m, 3H), 0.96-0.88 (m, 3H).

[0665] Example 82 3-(4-{[4-({4-[1-(4-{[5-bromo-4-({5-[dimethyl(oxido- lambda 5 - phosphono] -3 -fluoro-2-methylquinolin-6-yl} amino)pyrimidin-2-yl] amino}-2- ethyl-5-methoxyphenyl)hexahydropyridin-4-yl]piperazin-1-yl}methyl)-1- oxido-1 lambda 6 - thianylidene]amino}-2,6-difluorophenyl)hexahydropyridine-2,6-dione

[0666] Example 82 was prepared from the following steps:

[0667] Step A: 69d (37 mg, 0.054 mmol), Int-7 (35.85 mg, 0.081 mmol), p-toluenesulfonic acid (18.55 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) and reacted at 100 °C for 16 h. The reaction was cooled to room temperature and saturated aqueous sodium bicarbonate solution was added. A yellow solid precipitated and was collected by suction filtration to give the crude product which was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 82 (15.8 mg, yield 26.54%). ESI-MS (m / z): 548.3 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 11.27 (s, 1H), 10.91 (s, 1H), 8.66 (s, 1H), 8.27 (d, J = 53.3 Hz, 1H), 8.17 (s, 1H), 7.94 (d, J = 9.5 Hz, 2H), 7.33 (s, 1H), 6.71 (s, 1H), 6.65 - 6.51 (m, 2H), 4.14 - 4.07 (m, 1H), 3.75 (s, 3H), 3.60 - 3.47 (m, 6H), 3.31 - 3.20 (m, 5H), 2.94 - 2.85 (m, 2H), 2.83 - 2.73 (m, 1H), 2.64 (d, J = 1.9 Hz, 3H), 2.63 - 2.59 (m, 2H), 2.58 - 2.52 (m, 3H), 2.43 - 2.31 (m, 3H), 2.29 - 2.23 (m, 1H), 2.21 - 2.15 (m, 2H), 2.14 - 2.05 (m, 3H), 2.05 - 1.99 (m, 2H), 1.96 (s, 3H), 1.93 (s, 3H), 1.86 - 1.76 (m, 2H), 1.64 - 1.42 (m, 4H), 0.69 (t, J = 15.9 Hz, 3H).

[0668] Example 83 3-(4-{[4-({4-[1-(4-{[5-bromo-4-({5-[dimethyl(oxido- lambda 5 - phosphono] -2-ethylquinolin-6-yl} amino) pyrimidin-2-yl] amino} -2-ethyl-5- methoxyphenyl) hexahydropyridin-4-yl] piperazin-1-yl} methyl)-1-oxido-1 lambda 6 - thianecarbonyl] amino} -2,6-difluorophenyl) hexahydropyridine-2,6-dione

[0669] Example 83 was prepared from the following steps:

[0670] Step A: 69d (37 mg, 0.054 mmol), Int-8 (35.53 mg, 0.081 mmol), p-toluenesulfonic acid (18.55 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) and reacted at 100 °C for 16 h. The reaction was cooled to room temperature and saturated aqueous sodium bicarbonate solution was added. A yellow solid precipitated and was collected by suction filtration to give the crude product which was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 83 (15.4 mg, yield 25.96%). ESI-MS (m / z): 545.4 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) d 11.77 (s, 1H), 10.91 (s, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 6.75 (s, 1H), 6.65 - 6.57 (m, 2H), 4.13 - 4.06 (m, 1H), 3.75 (s, 3H), 3.59 - 3.50 (m, 6H), 3.28 - 3.21 (m, 4H), 2.98 - 2.89 (m, 4H), 2.84 - 2.73 (m, 2H), 2.69 - 2.63 (m, 2H), 2.42 - 2.33 (m, 3H), 2.32 - 2.24 (m, 3H), 2.21 - 2.17 (m, 1H), 2.15 - 2.04 (m, 4H), 1.99 (s, 3H), 1.97 (s, 3H), 1.93 - 1.89 (m, 1H), 1.86 - 1.80 (m, 2H), 1.63 - 1.48 (m, 4H), 1.31 (t, J = 7.6 Hz, 3H), 0.81 - 0.70 (m, 3H).

[0671] Example 84 3-(4-{[4-({4-[1-(4-{[5-bromo-4-({5-[dimethyl(oxido-λ 5 -Phosphono]-2-ethylquinazolin-6-yl}amino)pyrimidin-2-yl]amino}-2-ethyl-5- methoxyphenyl)hexahydropyridin-4-yl]methyl)-1-oxo-1λ 6 -Phosphono]-2-ethylquinazolin-6-yl}amino)pyrimidin-2-yl]amino}-2,6- difluorophenyl)hexahydropyridine-2,6-dione

[0672] Example 84 was prepared from the following steps:

[0673] Step A: 69d (37.00 mg, 0.054 mmol), Int-9 (35.61 mg, 0.081 mmol), p- toluenesulfonic acid (18.55 mg, 0.11 mmol) were dissolved in N,N- dimethylformamide (1.2 mL) and reacted at 100 °C for 16 h. The reaction was cooled to room temperature and saturated aqueous sodium bicarbonate solution was added. A yellow solid precipitated out. The crude product was obtained after suction filtration. Purification was carried out by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 84 as a yellow solid (11.3 mg, 19.03% yield). ESI-MS (m / z): 546.9 [M+2H] 2+ / 2. 1H NMR (500 MHz, DMSO-d6) δ 11.57 (s, 1H), 10.92 (s, 1H), 9.90 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.86 (s, 1H), 7.29 (s, 1H), 6.73 (s, 1H), 6.63 - 6.56 (m, 2H), 4.13 - 4.07 (m, 1H), 3.75 (s, 3H), 3.54 - 3.50 (m, 4H), 3.29 - 3.24 (m, 3H), 3.07 - 3.02 (m, 2H), 2.95 - 2.89 (m, 2H), 2.84 - 2.75 (m, 2H), 2.65 (t, J = 10.9 Hz, 3H), 2.43 - 2.34 (m, 3H), 2.30 - 2.21 (m, 3H), 2.20 - 2.16 (m, 1H), 2.15 - 2.10 (m, 2H), 2.10 - 2.07 (m, 1H), 2.03 (s, 3H), 2.01 (s, 3H), 1.93 - 1.88 (m, 1H), 1.87 - 1.79 (m, 2H), 1.64 - 1.45 (m, 5H), 1.37 (t, J = 7.6 Hz, 3H), 1.09 - 1.03 (m, 1H), 0.89 - 0.83 (m, 1H), 0.78 - 0.65 (m, 3H).

[0674] Example 85

[0675] 3-(4-{[4-({4-[1-(4-{[5-bromo-4-({4-cyclopropyl-2-[dimethyl(oxido- lambda 5 - methylphospho]phenyl}amino)pyrimidin-2-yl]amino}-2-ethyl-5- methoxyphenyl)hexahydropyridin-4-yl]piperazin-1-yl}methyl)-1- oxido-1 lambda 6 - thian-1-ylidene]amino}-2,6-difluorophenyl)hexahydropyridine-2,6- dione

[0676] Example 85 is prepared from the following steps:

[0677] Step A: 69d (37.00 mg, 0.054 mmol), Int-1 (32.37 mg, 0.081 mmol), p-toluenesulfonic acid (18.55 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) and reacted at 100 °C for 16 hours. The reaction solution was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added, and a yellow solid precipitated. After suction filtration, the crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain yellow solid 85 (14.7 mg, yield 25.7%). ESI-MS (m / z): 526.9 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.68 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.39 (s, 1H), 7.27 (d, J = 12.2 Hz, 1H), 6.91 (s, 1H), 6.77 (s, 1H), 6.63 - 6.57 (m, 2H), 4.12 - 4.07 (m, 1H), 3.74 (s, 3H), 3.51 - 3.46 (m, 4H), 3.29 - 3.26 (m, 3H), 3.03 - 2.97 (m, 2H), 2.84 - 2.75 (m, 2H), 2.73 - 2.67 (m, 2H), 2.40 - 2.34 (m, 2H), 2.33 - 2.27 (m, 2H), 2.21 - 2.16 (m, 1H), 2.14 - 2.07 (m, 3H), 2.06 - 1.95 (m, 3H), 1.94 - 1.83 (m, 4H), 1.76 (s, 3H), 1.73 (s, 3H), 1.64 - 1.47 (m, 5H), 1.04 - 1.00 (m, 2H), 0.98 - 0.93 (m, 2H), 0.68 - 0.62 (m, 2H).

[0678] Example 86 3-(4-{[4-({4-[1-(4-{[5-chloro-4-({2-[dimethyl(oxido- lambda 5 - methylphospho]phenyl}amino)pyrimidin-2-yl]amino}-2-ethyl-5- methoxyphenyl)hexahydropyridin-4-yl]piperazin-1-yl}methyl)-1- oxido-1 lambda 6 - thian-1-ylidene]amino}-2,6-difluorophenyl)hexahydropyridine-2,6- dione

[0679] Example 86 was prepared from the following steps:

[0680] Step A: 69d (37.00 mg, 0.054 mmol), 17a (25.54 mg, 0.081 mmol), p-toluenesulfonic acid (18.55 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) and reacted at 100 °C for 16 hours. The reaction solution was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added, and a white solid precipitated. After suction filtration, the crude product was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain 86 as a white solid (21.3 mg, yield 40.50%). ESI-MS (m / z): 483.9 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 10.91 (s, 1H), 8.44 (s, 1H), 8.11 (d, J = 6.3 Hz, 2H), 7.55 (dd, J = 13.5, 8.2 Hz, 1H), 7.43 (s, 1H), 7.36 - 7.29 (m, 1H), 7.11 (t, J = 7.3 Hz, 1H), 6.77 (s, 1H), 6.64 - 6.57 (m, 2H), 4.13 - 4.07 (m, 1H), 3.75 (s, 3H), 3.59 - 3.48 (m, 3H), 3.28 - 3.21 (m, 4H), 3.04 - 2.98 (m, 2H), 2.87 - 2.75 (m, 2H), 2.73 - 2.62 (m, 3H), 2.42 - 2.33 (m, 3H), 2.32 - 2.26 (m, 2H), 2.22 - 2.17 (m, 1H), 2.15 - 2.07 (m, 3H), 2.06 - 1.94 (m, 3H), 1.93 - 1.84 (m, 3H), 1.78 (s, 3H), 1.75 (s, 3H), 1.64 - 1.46 (m, 5H), 1.06 (t, J = 7.6 Hz, 3H).

[0681] Example 87 3-{4-[(9-{[1-(4-{[5-bromo-4-({5-[dimethyl(oxido- lambda 5 - methylphospho]quinoxalin-6-yl}amino)pyrimidin-2-yl]amino}-2-ethyl-5- methoxyphenyl)-4-fluorohexahydropyridin-4-yl]methyl}-3-oxo-3lambda 6 -9-aza-3-thiaspiro[5.5]undec-3-ylidene)amino]-2,6-difluorophenyl}hexahydropyridine- 2,6-dione

[0682] Example 87 was prepared from the following steps:

[0683] Step A: Int-15 (700 mg, 1.65 mmol) was dissolved in dichloromethane (5 mL) at room temperature, N,N-diisopropylethylamine (212.62 mg, 1.65 mmol, 0.30 mL) was added under ice-bath condition, after 5 minutes, catalytic equivalent of glacial acetic acid (98.79 mg, 1.65 mmol) was added dropwise, 76b (760.93 mg, 3.29 mmol) was added into the reaction solution, the reaction was carried out at room temperature for about 1 hour, then the temperature was lowered to 0 °C, sodium triacetyl borohydride (697.35 mg, 3.29 mmol) was added in batches. The reaction was carried out at room temperature for about 1 hour, LCMS showed that the reaction was complete. Water was added to the reaction solution, the organic phase was combined after dichloromethane extraction, dried over anhydrous sodium sulfate, rotary evaporation under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain yellow solid 87a (430 mg, yield 40.79%). ESI-MS (m / z): 641.4 [M+H] + .

[0684] Step B: 87a (430 mg, 0.67 mmol) was dissolved in dichloromethane (4 mL) at room temperature, and the temperature was lowered to 0 °C under ice-bath condition, hydrochloric acid / dioxane solution (4.0 M, 2 mL) was added, the reaction was carried out at room temperature for about 2 hours. LCMS showed the product. Directly rotary evaporation under reduced pressure to obtain light yellow solid 87b (320 mg, crude). No further purification was needed. ESI-MS (m / z): 541.4 [M+H] + .

[0685] Step C: 87b (320 mg, 0.60 mmol) and Int-17a (120.00 mg, 0.60 mmol) were dissolved in dimethyl sulfoxide (5 mL) at room temperature, N,N-diisopropylethylamine (778.6 mg, 6.02 mmol, 1.05 mL) was added into the reaction solution, the reaction was carried out at 120 °C for 8 hours. LCMS showed that part of the starting material was not completely reacted. Water was added to the reaction solution, rotary evaporation under reduced pressure after dichloromethane / methanol = 15 / 1 extraction, purification by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) to obtain light yellow solid 87c (150 mg, yield 34.59%). ESI-MS (m / z): 720.4 [M+H] + .

[0686] ​Step D: 87c (150 mg, 0.21 mmol), iron powder (58.19 mg, 1.04 mmol) and ammonium chloride (55.73 mg, 1.04 mmol) were dissolved in ethanol (4.0 mL) and water (0.8 mL) at room temperature, and the mixture was reacted at 80 °C for 1 h. LCMS showed that the reaction was complete. After cooling to room temperature, the reaction solution was rotary evaporated, dissolved in dichloromethane / methanol = 15 / 1, filtered with celite, and the solvent was removed by reduced pressure to obtain the crude product. Purification by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) gave 87d (85 mg, yield 59.13%) as a light yellow solid. ESI-MS (m / z): 345.9 [M+2H] 2+ / 2.

[0687] Step E: 87d (82 mg, 0.12 mmol) and Int-4 (63.76 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (1.0 mL) at room temperature, and p-toluenesulfonic acid (61.41 mg, 0.36 mmol) was added thereto. The mixture was reacted at 100 °C for 16 h. LC / MS showed that the reaction was complete. After cooling to room temperature, sodium bicarbonate solution was slowly added dropwise to the reaction solution, extracted with dichloromethane / methanol = 15 / 1, washed with brine twice, combined the organic phase, and the solvent was removed by reduced pressure to obtain the crude product. Purification by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) gave compound 87 (24.7 mg, yield 19.30%) as a yellow solid. ESI-MS (m / z): 534.3 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.91 (s, 1H), 8.89-8.84 (m, 2H), 8.84-8.78 (m, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 7.90 (d, J = 9.7 Hz, 1H), 7.39 (s, 1H), 6.84 (s, 1H), 6.64-6.58 (m, 2H), 4.10 (dd, J = 12.7, 5.2 Hz, 1H), 3.78 (s, 3H), 3.38-3.33 (m, 4H), 2.95-2.88 (m, 2H), 2.86-2.75 (m, 3H), 2.62-2.51 (m, 4H), 2.49-2.45 (m, 5H), 2.15-2.07 (m, 1H), 2.04 (s, 3H), 2.01 (s, 3H), 1.99-1.76 (m, 9H), 1.64-1.57 (m, 2H), 1.52-1.45 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H).

[0688] Example 88 3-[4-({4-[9-(4-{[5-bromo-4-({5-[dimethyl(oxido- lambda 5 - phosphono] -3-fluoro-2-methylquinolin-6-yl} amino) pyrimidin-2-yl] amino} -2- ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undec-3-yl]-1-oxo-1 lambda 6 - thian-1-ylidene} amino) -2,6-difluorophenyl] hexahydropyridine-2,6-dione

[0689] Example 88 was prepared by the following steps:

[0690] Step A: 88a (1.5 g, 5.16 mmol, C) and 19a (1.03 g, 5.16 mmol) were dissolved in dimethyl sulfoxide (20 mL) at room temperature, cesium carbonate (5.04 g, 15.47 mmol) was added to the reaction solution, and the reaction was stirred at 110 °C for 3 hours. LCMS showed that the reaction was complete. Water was added to the reaction solution, and a large amount of solid was produced. After extraction with dichloromethane / methanol = 15 / 1 and rotary evaporation, purification by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 5 / 1) gave 88b (1.6 g, yield 71.55%) as a light yellow solid. ESI-MS (m / z): 434.3 [M+H] + .

[0691] Step B: 88b (1.6 g, 3.69 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and the solution was cooled to 0 °C in an ice bath. Hydrochloric acid / dioxane solution (4.0 M, 10 mL) was added, and the reaction was allowed to proceed at room temperature for about 2 hours. LCMS showed the product. Direct rotary evaporation under reduced pressure gave 88c (1.1 g, crude) as a light yellow solid. No further purification was needed. ESI-MS (m / z): 334.2 [M+H] + .

[0692] Step C: 88c (350 mg, 0.95 mmol) was dissolved in dichloromethane (5 mL), N, N- diisopropylethylamine (122.29 mg, 0.95 mmol, 0.16 mL) was added under ice bath, after 5 min, catalytic equivalent of glacial acetic acid (56.82 mg, 0.95 mmol) was added dropwise, 70a (186.89 mg, 1.61 mmol) was added into the reaction, the reaction was carried out at room temperature for about 1 h, then the temperature was lowered to 0 °C, sodium triacetoxyborohydride (401.09 mg, 1.89 mmol) was added in portions. The reaction was carried out at room temperature for about 1 h, LCMS showed that the reaction was complete. Water was added to the reaction, dichloromethane was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and then rotary evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain yellow solid 88d (380 mg, yield 92.62%). ESI-MS (m / z): 434.3 [M+H] + .

[0693] Step D: 88d (252 mg, 0.58 mmol), iodobenzene acetate (374.39 mg, 1.16 mmol) and ammonium acetate (89.60 mg, 1.16 mmol) were dissolved in methanol (4 mL). The reaction was carried out at 25 °C for 2 h, LCMS showed that the reaction was complete. The reaction was concentrated, dissolved in dichloromethane, and filtered through celite. The filtrate was rotary evaporated under reduced pressure to obtain the crude product, which was purified by thin layer preparative plate (dichloromethane / methanol = 15 / 1) to obtain yellow solid 88e (120 mg, yield 44.44%). ESI-MS (m / z): 465.4 [M+H]+.

[0694] Step E: 88e (152.79 mg, 0.33 mmol), Int-10a (100 mg, 0.33 mmol), cesium carbonate (214.29 mg, 0.66 mmol), t-BuXPhos (13.96 mg, 0.033 mmol) and t-BuXPhos Pd G3 (13.06 mg, 0.016 mmol) were dissolved in 1,4-dioxane (3 mL) and N, N-dimethylformamide (3 mL), the reaction was stirred at 80 °C for 6 h under nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction was cooled to room temperature, quenched with water, extracted with dichloromethane, the organic phases were combined, concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to obtain white solid 88f (110 mg, yield 48.63%). ESI-MS (m / z): 688.4 [M+H]+.

[0695] Step F: 88f (110 mg, 0.16 mmol), iron powder (44.66 mg, 0.80 mmol) and ammonium chloride (42.77 mg, 0.80 mmol) were dissolved in ethanol (2.0 mL) and water (0.4 mL) at room temperature, and the mixture was reacted at 80 °C for 1 h. LCMS showed that the reaction was complete. After cooling to room temperature, the reaction solution was rotary evaporated to dryness, dissolved in dichloromethane / methanol = 15 / 1, filtered through celite, and the solvent was removed under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) to obtain 88g (82 mg, yield 77.94%) as a light yellow solid. ESI-MS (m / z): 658.5 [M+H] + .

[0696] Step G: 88g (82 mg, 0.13 mmol) and Int-7 (71.89 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (1.0 mL) at room temperature, and p-toluenesulfonic acid (64.40 mg, 0.37 mmol) was added thereto, and the mixture was reacted at 100 °C for 16 h. LC / MS showed that the reaction was complete. After cooling to room temperature, sodium bicarbonate solution was slowly added to the reaction solution, extracted with dichloromethane / methanol = 15 / 1, washed with brine twice, combined the organic phase, and the solvent was removed under reduced pressure to obtain the crude product, which was purified by reverse phase column (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain compound 88 (40.0 mg, yield 29.83%) as a yellow solid. ESI-MS (m / z): 533.9 [M+2H] 2+ / 2. 1 H NMR (500 MHz, DMSO-d6) d 11.36 (s, 1H), 10.91 (s, 1H), 8.60 (d, J = 12.3 Hz, 1H), 8.26-8.15 (m, 2H), 7.98 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.29 (s, 1H), 6.78 (s, 1H), 6.66-6.58 (m, 2H), 4.10 (dd, J = 12.7, 5.2 Hz, 1H), 3.75 (s, 3H), 3.58-3.49 (m, 2H), 3.42-3.32 (m, 5H), 2.84-2.67 (m, 6H), 2.63 (d, J = 2.7 Hz, 2H), 2.54-2.51 (m, 1H), 2.49-2.43 (m, 4H), 2.25-2.15 (m, 2H), 2.14-2.04 (m, 1H), 2.03-1.92 (m, 10H), 1.57-1.47 (m, 7H), 0.79-0.64 (m, 3H).

[0697] Example 89

[0698] 3-(4-{[4-({1-[1-(4-{[5-chloro-4-({2-[dimethyl(oxido-λ 5 -1,4-oxazepan-1-yl]amino}-2,6-difluorophenyl)hexahydropyridin-2,6-dione 6 -1,4-oxazepan-1-yl]amino}-2,6-difluorophenyl)hexahydropyridin-2,6-dione

[0699] Example 89 was prepared from the following steps:

[0700] Step A: 61b (50 mg, 0.073 mmol), 17a (34.52 mg, 0.11 mmol), p-toluenesulfonic acid (37.61 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) and reacted at 100 °C for 16 h. The reaction was cooled to room temperature and saturated aqueous sodium bicarbonate solution...

Claims

1. A compound of Formula I: ###0001### or a pharmaceutically acceptable salt thereof. R 1 is C 1-6 alkyl or C 3-6 cycloalkyl; R 2 is C 1-6 alkylene or C 3-6 cycloalkylene; or R 1 and R 2 together with the sulfur atom to which they are attached form a ring A, said ring A being a 4-11 membered heterocycloalkyl; the heteroatoms in said 4-11 membered heterocycloalkyl being independently one or more of N, S, and O, in a number of 1, 2, or 3; D is a target protein binding ligand; E is an E3 ubiquitin ligase ligand.

2. The compound as shown in formula I or pharmaceutically acceptable salt thereof according to claim 1, wherein, which satisfies one or more of the following conditions: (1)R 1 In the context, C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, for example, methyl, ethyl, or isobutyl, e.g., methyl; (2)R 1 In the context, C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, for example, cyclopropyl or cyclobutyl; (3) R 2 In particular, the C 1-6 The alkylene group of the alkyl group is a methylene group, an ethylene group, a n-propylene group, an i-propylene group, a n-butylene group, a sec-butylene group, an i-butylene group or a t-butylene group, and can also be a (4) R 2 In particular, the C 3-6 The cycloalkylene group of the cycloalkylene group of R1is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene. and (5) in ring A, the 4-11 membered heterocycloalkyl is a 4, 5 or 6 membered monocyclic heterocycloalkyl, or a 9, 10 or 11 membered bicyclic heterospirocycloalkyl, the heteroatom is N and / or S, the number is 1 or 2, and can also be tetrahydro-2H-thiopyranyl, thiomorpholinyl, 2-thia-7-azaspiro[3.5]nonanyl, 2-thiaspiro[3.5]nonanyl, 3-thia-9-azaspiro[5.5]undecanyl or 3-thiaspiro[5.5]undecanyl; Preferably, when ring A also contains N, the ring A is connected to D through the N atom.

3. The compound as shown in formula I or pharmaceutically acceptable salt thereof according to claim 1, wherein, For n1, n2, n3, n4, n5, and n6 are independently 1, 2, or 3; X 1 and X 2 is independently -CH- or N.

4. The compound as shown in formula I or pharmaceutically acceptable salt thereof according to claim 1, wherein, For Preferably Preferably 5. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, according to Formula I, D is an EGFR target protein binding ligand; and / or, E is a CRBN class ubiquitin ligase ligand.

6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 5, wherein, The EGFR target protein binding ligand is a structure shown in formula D1: wherein L 1 and L 2 are independently absent or C 1-6 alkylene; ring B is absent or a 4-6 membered heterocycloalkyl; the heteroatom in the 4-6 membered heterocycloalkyl is one or more of N, S and O, the number is 1, 2 or 3; The ring C is a 4-12 membered heterocyclic alkyl group or is surrounded by one or more R groups. a Substituted 4-12-membered heterocyclic alkyl groups; the 4-12-membered heterocyclic alkyl groups and the groups substituted with one or more R groups. a The heteroatoms in the substituted 4-12-membered heterocyclic alkyl groups are one or more of N, S and O, and the number is 1, 2, 3 or 4; R 3 -O-C 1-6 alkyl or -O-C 3a alkyl substituted by one or more R 1-6 alkyl, Each R 3a Independently halogen or deuterium; R 4 alkyl, C 1-6 cycloalkyl, C 3-6 alkyl substituted by one or more R 4a-1 cycloalkyl, C 1-6 alkyl substituted by one or more R 4a-2 cycloalkyl, C 3-6 heteroaryl, said 5-6 membered heteroaryl being substituted by one or more R 4a-3 heteroaryl, said 5-6 membered heteroaryl being substituted by one or more R 4a-4 heteroaryl, said 5-6 membered heteroaryl being substituted by one or more R each R 4a-1 , each R 4a-2 , each R 4a-3 , and each R 4a-4 is independently halogen, deuterium, or C 1-6 1-6alkyl; R 5 halogen, C 1-6 alkyl, or C 1-6 alkyl substituted by one or more halogens; R 6 independently -P(=O)(C 1-6 alkyl), -NHS(=O)2(C 1-6 alkyl), -N(C 3-6 cycloalkyl)S(=O)2(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), or -S(=O)2(C 3-6 cycloalkyl); R 7 and R 8 are independently H, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl or C 3-6 cycloalkyl substituted by one or more halogen, or R 7 and R 8 together with the atom to which they are attached form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted by one or more R a ; the heteroatoms in said 5-6 membered heteroaryl are independently one or more of N, S and O, in a number of 1, 2 or 3; each R is independently halogen, C a independently halogen, C 1-6 alkyl or -O-C 1-6 alkyl; The CRBN ubiquitin ligase ligand is a structure shown in formula E1: X e1 is N or CR e2 ; R e1 and R e2 are independently hydrogen, C 1-6 alkyl or halogen; Y is a bond, -O-, -NH-, -(CH2) n7 - or -NHC(=O)-, n7 is 1, 2, 3 or 4; E is C 6-10 aryl, 5-14 membered heteroaryl, C e3 substituted with 1 or more R 6-10 aryl, or 5-14 membered heteroaryl substituted with 1 or more R e3 substituted with 1 or more R e3 the heteroatoms in said 5-14 membered heteroaryl and said 5-14 membered heteroaryl substituted with 1 or more R each R is independently halo, oxo, cyano, C e3 independently halo, oxo, cyano, C 1-6 independently halo, oxo, cyano, C 1-6 independently halo, oxo, cyano, C 1-6 independently halo, oxo, cyano, C 3-6 independently halo, oxo, cyano, C or, R together with R e3 form, together with the atoms to which they are attached, -(CH2) n7 n7 is 1, 2, 3 or 4.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, having Formula I, which satisfies one or more of the following conditions: (1) in formula D1, L 1 and L 2 wherein the C 1-6 alkylene is methylene, ethylene, n-propylene, i-propylene, n-butylene, sec-butylene, i-butylene or t-butylene, and can also be methylene, (2) In formula D1, in ring B, the 4-6 membered heterocycloalkyl is a 4-, 5- or 6- membered monocyclic heterocycloalkyl, the heteroatom is N, the number is 1 or 2, which can be azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl, for example 1 is connected to L 1 2 is connected to L 2 connected; (3) in formula D1, in ring C, the 4-12 membered heterocycloalkyl group and the 4-12 membered heterocycloalkyl group substituted by 1 or more R a The substituted 4-12 membered heterocycloalkyl group is a 4-6 membered monocyclic heterocycloalkyl group or a 6-12 membered bicyclic spirocyclic heterocycloalkyl group, the heteroatom is N and / or O, the number is 1 or 2, which can be piperidinyl, piperazinyl, tetrahydrofuranyl or 3,9-diazaspiro[5.5]undecanyl, for example 1 is attached to L 2 attached at the 2-position to the phenyl group; (4) in formula D1, each R 3a , each R 4a-1 , each R 4a-2 , each R 4a-3 , each R 4a-4 , R 5 and each R a , the halogen is F, Cl, Br or I, for example Cl or Br; (5) In formula D1, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , each R 4a-1 , each R 4a-2 , each R 4a-3 , each R 4a-4 , and each R a , the C 1-6 alkyl of the -O-C 1-6 alkyl, the C 1-6 alkyl of the -O-C 3a alkyl substituted with one or more R 1-6 , the C 1-6 alkyl of the alkyl substituted with one or more R 4a-1 , the C 1-6 alkyl of the alkyl substituted with one or more R 1-6 , the C 1-6 alkyl of the -P(=O)(C 1-6 alkyl)2, the C 1-6 alkyl of the -NHS(=O)2(C 1- alkyl), the C 3-6 alkyl of the N(C 1-6 cycloalkyl)S(=O)2(C 1-6 alkyl), the C 1-6 alkyl of the -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), and the C 1-6 alkyl of the -S(=O)2(C 1-6 alkyl) are independently methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, or t-butyl, preferably methyl or ethyl. (6) In the formula D1, R 6 , R 7 , and R 8 , the cycloalkyl group of the cycloalkyl group of the alkyl group of N(C 3-6 , the cycloalkyl group of the cycloalkyl group of the alkyl group of N(C 1-6 , the cycloalkyl group of the cycloalkyl group of the alkyl group of N(C 3-6 , the cycloalkyl group of the cycloalkyl group of the alkyl group of N(C 3-6 , the cycloalkyl group of the cycloalkyl group of the alkyl group of N(C 3-6 , the cycloalkyl group of the cycloalkyl group of the alkyl group of N(C 3-6 is preferably a cyclopropane group, a cyclobutane group, a cyclopentane group, or a cyclohexane group; (7) in formula D1, when R 7 and R 8 together with the atoms to which they are attached form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted by one or more R a , the 5-6 membered heteroaryl of said 5-6 membered heteroaryl and of said 5-6 membered heteroaryl substituted by one or more R a , is independently a 6 membered heteroaryl, the heteroatom(s) being N, in number 1 or 2, and is further preferably pyridyl, pyrimidinyl, pyrazinyl, for example represents a ring formed by the benzene ring and the ring A here; (8) In equation E1, R e1 R e2 and each R e3 In the context of halogens and C substituted with one or more halogens, 1-6 The halogen in the alkyl group is independently F, Cl, Br or I, for example F; (9) in the formula E1, each R e3 C 3-6 The cycloalkyl is cyclopropane, cyclobutane, cyclopentane or cyclohexane. (10) In E1, in ring E, the C 6-10 The aryl group and the one or more R e3 Replacement C 6-10 C in aryl 6-10 The aryl group can be phenyl or naphthyl independently; In formula (11) E1, in ring E, the 5-14 member heteroaryl group and the group surrounded by one or more R e3 The 5-14 membered heteroaryl group is independently a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic fused heteroaryl group, and the heteroatom is N and / or O, with 1, 2 or 3 atoms, preferably N, and is preferred. 1 is connected to Y, and 2 is connected to N.

8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, having Formula I, wherein which satisfies one or more of the following conditions: (1) in formula D1, Preferably 1 is attached to R 2 attached to the phenyl group, 2 is attached to the phenyl group; (2) in formula D1, For 1 is connected to ring C, and 2 is connected to -NH-; (3) in formula D1, For (4) in formula D1, For (5) In Formula E1, E1is E1-1, E1-2, E1-3, or E1-4: in formula E1-1, is a single bond or absent; X e2 is C or N; Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are independently N, CH or CR e3 , and Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are not simultaneously N; X e1 , Y, R e1 and R e3 are as defined in claim 6; In E1-2, Z 10 The values ​​are -CH2-, *-CH2-CH2-, *-CH=CH-, *-N=CH-, or *-C(=O)-, where the * segment is connected to N; Z 6 , Z 7 , Z 8 and Z 9 are independently N, CH or CR e3 , and Z 6 , Z 7 , Z 8 and Z 9 are not simultaneously N; X e1 , Y, R e1 and R e3 are as defined in claim 6; in formula E1-3, is a single bond or is absent; X e3 is N or C; Z 11 is N, C or -C(=0)-; Z 12 is CH2, CR e3 R e3 , CR e3 , O, NH or NR e3 ; Z 13 is C or N; Z 6 , Z 7 , Z 8 and Z 9 are independently N, CH or CR e3 , and Z 6 , Z 7 , Z 8 and Z 9 are not simultaneously N; X e1 , Y, R e1 and R e3 are as defined in claim 6; in formula E1-4, Z 14 is N or C; Z 15 is CH or CR e3 ; Z 6 , Z 7 , Z 8 and Z 9 are independently N, CH or CR e3 , and Z 6 , Z 7 , Z 8 and Z 9 are not simultaneously N; X e1 , R e1 and R e3 are each as defined in claim 6.

9. The compound of claim 6, or a pharmaceutically acceptable salt thereof, having Formula I, which is (1) and / or (2): (1) middle: For 1 is attached to R 2 attached at the 2-position to the phenyl group; For either of the following structures: (2) E1 is any one of the following structures:

10. The compound as shown in formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The compound as shown in Formula I is any one of the following compounds:

11. A pharmaceutical composition, characterized by, which comprises the compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, and a pharmaceutical adjuvant.

12. Use of the compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-10 or the pharmaceutical composition according to claim 11 in the preparation of a medicament for preventing or treating cancer or for preventing or treating a disease related to EGFR. The cancer is preferably lung cancer, further preferably non-small cell lung cancer or lung adenocarcinoma. The disease related to EGFR is preferably a disease caused by a mutation in the EGFR protein. The mutation in the EGFR protein is preferably selected from the following mutation points: Del19-T790M-C797S mutation, L858R-T790M-C797S mutation, Del19-C797S mutation, L858R-C797S mutation, L858R-T790M mutation, Del19 mutation and L858R mutation.

13. A compound of Formula II or III: ###00010### or a salt thereof. E, R 1 E, R 2 E, R 3 E, R 4 L, R 1 L, R 2 ring B and ring C are each as defined in any one of claims 1 to 10; The compound as shown in Formula II is preferably any one of the following compounds: The salt of the compound of formula II is preferably a hydrochloride or a trifluoroacetate. The compound as shown in formula III is preferably any one of the following compounds:

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