CDK inhibitor compound with lactam structure

Abstract

The invention relates to a compound as shown in a formula (I), a pharmaceutical composition containing the compound and application of the compound as shown in the formula (I) to prevention and / or treatment of cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Description

A lactam-structured CDK inhibitor compound TECHNICAL FIELD

[0001] The present application relates to a compound, in particular to a highly active CDK inhibitor containing a lactam structure and its use. BACKGROUND

[0002] Cell cycle-dependent kinases (CDKs) are a class of serine (Ser) / threonine (Thr) kinases, which can be divided into two categories: cell cycle-related (such as CDK1 / 2 / 4 / 6) and cell transcription-related (such as CDK7 / 9 / 12).

[0003] The most studied ones are CDK4 and CDK6, which play a key regulatory role in the cell division cycle, can form a CDK-cyclin complex with cyclin D, and are involved in cell growth, proliferation, dormancy or apoptosis. CDK4 / 6-cyclin D is a key pathway for the cell cycle to enter the S phase from the G1 phase, and when it is overexpressed, it leads to uncontrolled cell division cycle, and thus causes cancer. As represented by Palbociclib, the first CDK4 / 6 selective inhibitor launched by Pfizer, a number of CDK4 / 6 selective inhibitors have been approved for marketing, mainly for the treatment of HR+ / HER2- breast cancer.

[0004] Although CDK4 / 6 inhibitors have achieved great success, they still have obvious side effects in clinical practice, especially bone marrow suppression toxicity. Studies have shown that CDK6 is a key factor for the activation of hematopoietic stem cells, and CDK4 has relatively less impact on the hematopoietic system. Further studies have shown that CDK4 is highly expressed in tumors, while CDK6 is weakly expressed. In breast cancer, CDK4 may be a more important carcinogenic factor. Therefore, maintaining the activity of CDK4 while reducing the inhibition of CDK6 will help CDK inhibitors reduce clinical toxicity.

[0005] CDK2 is another important cell cycle regulator, which can bind to cyclin E or A, respectively, to play a role in the process of entering the S phase from the G1 phase and maintaining the S phase. When CDK4 / 6 is inhibited, CDK2-cyclin E is activated, compensating for the function of CDK4 / 6, which may be one of the main reasons for the resistance of CDK4 / 6 inhibitors.

[0006] In summary, by optimizing the selectivity, further improving the therapeutic effect and safety of existing CDK4 / 6 inhibitor-based treatments has important social significance. SUMMARY

[0007] The present application provides a new type of CDK inhibitor. The structure of this type is different from the existing CDK4 / 6 dual-target inhibitor, but has optimized activity and selectivity, thereby achieving the purpose of improving the antitumor efficacy and reducing the toxic side effects. Compared with the prior art, there is a major improvement.

[0008] In one aspect, the present application provides a compound represented by Formula I, an isotopic derivative or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0009] wherein:

[0010] R1 represents H, D, halogen, CN, C1-C3 alkyl, halo C1-C3 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy, 3-6 membered heterocycloalkyl;

[0011] Ar1 represents phenyl or 5-6 membered heteroaryl;

[0012] R2 each independently represents H, D, halogen, CN, OR a , NR a R a ’, N(R a )COR a ’, -CONR a R a ’, -C(O)R a , -C(O)OR a , -S(O)2R a , C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein said C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 0, 1, 2, 3 or 4 R 22 ;

[0013] 2 R2s together with the Ar1 ring atoms to which they are attached and the atoms therebetween can form a 5-8 membered ring, which can further contain 0, 1, 2 or 3 heteroatoms selected from N, O, S;

[0014] X, Y each independently represents CH or N;

[0015] R3 represents H, D, halogen, CN, C1-C6 alkyl or C1-C6 alkoxy, wherein said C1-C6 alkyl, C1-C6 alkoxy is optionally substituted with 0, 1, 2, 3 or 4 R 23 ;

[0016] V represents C(O), S(O), S(O)2 or S(O)(NR5);

[0017] W each independently represents CR4R4', C(O), NR5, O, S, S(O), S(O)2, or S(O)(NR5);

[0018] R4, R4' each independently represents H, D, halogen, CN, OR a , SR a , NR a R a ', N(R a )COR a ', CONR a R a ', -C(O)R a , -S(O)2R a , C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3, or 4 R 24 ;

[0019] R4, R4' attached to the same C can also form, together with the C atom to which they are attached, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O, or S, which ring can further comprise 0, 1, 2, or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3, or 4 R 30 ;

[0020] two R4attached to different C atoms can form, together with the atoms to which they are attached and the atoms between them, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O, or S, which ring can further comprise 0, 1, 2, or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3, or 4 R 30 ;

[0021] R5each independently represents H, D, -S(O)2R a , -S(O)R a , -C(O)R a , -CONR a R a ', -C(O)OR a , C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 0, 1, 2, 3, or 4 R 25 ;

[0022] R4and R5together with the atoms to which they are attached and the atoms therebetween can form a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O, or S, which ring can further include 0, 1, 2, or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3, or 4 R 30 substituted;

[0023] R 22 each independently D, oxo, halogen, OR a , NR a R a , N(R a )COR a , -C(O)R a , -C(O)OR a , CONR a R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl, or 4-8 membered heterocycloalkyl, which C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl can be optionally substituted with 0, 1, 2, 3, or 4 R a , NR a R a , C1-C2alkyl, or halogenated C1-C2alkyl; two R 22 , on the same atom or different atoms can form a 3-6 membered ring, which ring can further contain 0, 1, 2, or 3 heteroatoms selected from N, O, S;

[0024] R 23 , R 24 , R 25 , R 30 each independently D, oxo, halogen, CN, OR a , NR a R a , N(R a )COR a , CONR a R a , -C(O)R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl, or 4-8 membered heterocycloalkyl, which C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl can be optionally substituted with 0, 1, 2, 3, or 4 R a , NR a R a', C1-C2 alkyl or halo-C1-C2 alkyl substitution; two Rs on the same atom or different atoms 23 Two R atoms on the same atom or different atoms 24 Two R atoms on the same atom or different atoms 25 Or R 24 With R 25 It can form a 3-6 membered ring with the C atom and / or N atom it is connected to, and the ring may further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0025] R a and R a Each can independently represent H, D, C1-C3 alkyl, or C3-C6 cycloalkyl;

[0026] m can be 1, 2, or 3;

[0027] n can be 2, 3, 4, 5 or 6, and when n is 3, W is not simultaneously CH2.

[0028] In some embodiments of the present invention, Ar1 represents a 5-membered heteroaryl group; preferably, Ar1 represents pyrazolyl, imidazolyl, thiazolyl, or isothiazolyl.

[0029] In some embodiments of the present invention, V represents C(O) or S(O)2.

[0030] In some embodiments of the present invention, the two R2s do not form a ring.

[0031] In some embodiments of the present invention, the compound of formula I has the structure shown in formula II:

[0032] in:

[0033] R1 represents H, D, halogen, CN, C1-C3 alkyl, halo-C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C2 alkoxy.

[0034] Ar1 represents either a pyrazolyl group or a thiazolyl group;

[0035] R2 independently represents H, D, halogen, CN, and OR. a NR a R a '、N(R a )COR a '、-CONR a R a '、-C(O)R a -C(O)OR a -S(O)2R a, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 0, 1, 2, 3 or 4 R 22 substituents;

[0036] R3represents H, D, halogen, CN, C1-C6 alkyl or C1-C6 alkoxy, wherein said C1-C6 alkyl, C1-C6 alkoxy are optionally substituted with 0, 1, 2, 3 or 4 R 23 substituents;

[0037] W each independently represents CR4R4', C(O), NR5, O or S(O)2;

[0038] R4, R4' each independently represents H, D, halogen, CN, OR a , SR a , NR a R a ', N(R a )COR a ', CONR a R a ', C(O)R a , -S(O)2R a , C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 R 24 substituents;

[0039] R4, R4' attached to the same C can also form, together with the C atom to which they are attached, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 substituents;

[0040] two R4attached to different C atoms can form, together with the atoms to which they are attached and the atoms between them, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 substituents;

[0041] R5each independently represents H, D, -S(O)2R a , -S(O)Ra -C(O)R a -CONR a R a -C(O)OR a , C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 0, 1, 2, 3 or 4 R 25 ;

[0042] R4and R5together with the atoms to which they are attached and the atoms therebetween can form a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 ;

[0043] R 22 each independently represents D, oxo, halogen, OR a , NR a R a , N(R a )COR a , CONR a R a , -C(O)R a , -C(O)OR a , CONR a R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, OR a , NR a R a , C1-C2alkyl or halogenated C1-C2alkyl; two R 22 , on the same atom or on different atoms can form a 3-6 membered ring, which ring can further contain 0, 1, 2 or 3 heteroatoms selected from N, O, S;

[0044] R 23 , R 24 , R 25 , R 30 each independently represents D, oxo, halogen, CN, OR a , NR a Ra R a , -C(O)R a , -S(O)2R a , -S(O)2NR a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2, 3 or 4 R a , NR a R a , C1-C2alkyl or halogenated C1-C2alkyl; two R 23 on the same atom or on different atoms, two R 24 on the same atom or on different atoms, two R 25 on the same atom or on different atoms, or R 24 and R 25 may form, with the C and / or N atom to which they are attached, a 3-6 membered ring, which can further contain 0, 1, 2 or 3 heteroatoms selected from N, O, S;

[0045] R a and R a each independently represent H, D, C1-C3alkyl or C3-C6cycloalkyl;

[0046] m is 1, 2, 3 or 4;

[0047] n is 2, 3, 4, 5 or 6, and when n is 3, W is not simultaneously CH2.

[0048] In some embodiments of the application, R1represents H, D, halogen, CN, C1-C2alkyl, fluorinated C1-C2alkyl; preferably, R1represents F, Cl, CN, methyl, trifluoromethyl.

[0049] In some embodiments of the application, R2each independently represents H, D, halogen, CN, OR a , NR a R a , N(R a )COR a , C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 0, 1, 2, 3 or 4 R 22substituted; preferably, each R2independently represents halogen, C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 0, 1, 2 or 3 R 22 substituted.

[0050] In some embodiments of the application, each R2independently represents halogen, C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein said C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 0, 1, 2 or 3 R 22 substituted.

[0051] In some embodiments of the application, R3represents H, D, halogen, CN, methyl or methoxy.

[0052] In some embodiments of the application, each W independently represents CR4R4', NR5, O or S(O)2.

[0053] In some embodiments of the application, each R4, R4'independently represents H, D, halogen, CN, OR a , SR a , NR a R a ', N(R a )COR a ', -C(O)R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 R 24 substituted; R4, R4' attached on the same C can also form, together with the C atom to which they are attached, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 substituted; two R4attached on different C atoms can form, together with the atoms to which they are attached and the atoms between them, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 substituted.

[0054] In some embodiments of the application, each R4, R4' independently represents H, D, halogen, CN, OR a , SR a , NR a R a ', N(R a )COR a ', -S(O)2R a , C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 R 24 ; R4, R4' attached to the same C can also form, together with the C atom to which they are attached, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 ; two R4 attached to different C atoms can form, together with the atoms to which they are attached and the atoms between them, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 .

[0055] In some embodiments of the application, each R4, R4' independently represents H, halogen, CN, OR a , SR a , NR a R a ', N(R a )COR a ', -S(O)2R a , C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl are optionally substituted with 0, 1, 2 or 3 R 24 ; preferably, each R4, R4' independently represents H, halogen, CN, OR a , SR a , NR a R a ', N(R a )COR aH, halogen, CN, OR

[0056] In some embodiments of the application, R4, R4' each independently represent H, halogen, CN, OR a , SR a , NR a R a , N(R a )COR a , -C(O)R a , -S(O)2R a , C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl are optionally substituted with 0, 1, 2 or 3 R 24 ; preferably, R4, R4' each independently represent H, halogen, CN, OR a , SR a , NR a R a , N(R a )COR a , C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl are optionally substituted with 0, 1, 2 or 3 halogen or methyl.

[0057] In some embodiments of the application, R4, R4' attached to the same C can form with the C atom to which they are attached a C3-C6 aliphatic ring or a 4-8 membered heterocyclic ring, said C3-C6 aliphatic ring, 4-8 membered heterocyclic ring being optionally substituted with 0, 1, 2 or 3 R 30 ; preferably, R4, R4' attached to the same C can also form with the C atom to which they are attached a C3-C6 aliphatic ring or a 4-8 membered heterocyclic ring, said C3-C6 aliphatic ring, 4-8 membered heterocyclic ring being optionally substituted with 0, 1, 2 or 3 halogen or methyl.

[0058] In some embodiments of the application, R5 each independently represent H, -S(O)2R a , -C(O)R a , C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl are optionally substituted with 0, 1, 2 or 3 R 25 ; preferably, R5 each independently represent H, -S(O)2Ra -C(O)R a C1-C6alkyl, C3-C6cycloalkyl, or 4-8 membered heterocycloalkyl, which C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted with 0, 1, 2, or 3 halogen or methyl.

[0059] In some embodiments of the application, two R4attached to different atoms, or R4and R5, together with the atom to which they are attached and the atoms between them, can form a C3-C6aliphatic ring or a 4-8 membered heterocyclic ring, which C3-C6aliphatic ring, 4-8 membered heterocyclic ring can be substituted with 0, 1, 2, or 3 R 30 substituents.

[0060] In some embodiments of the application, two R4attached to different atoms, or R4and R5, together with the atom to which they are attached and the atoms between them, can form a 3-8 membered ring, which ring, if including unsaturated bonds, is preferably a 5-6 membered heteroaromatic ring, which 5-6 membered heteroaromatic ring can be substituted with 0, 1, 2, or 3 R 30 substituents.

[0061] In some embodiments of the application, R 22 each independently represents D, oxo, halogen, OR a , NR a R a , N(R a )COR a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl, or 4-8 membered heterocycloalkyl, which C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, OR a , NR a R a , C1-C2alkyl, or halogenated C1-C2alkyl.

[0062] In some embodiments of the application, R 22 each independently represents D, oxo, halogen, OR a , NR a R a , N(R a )COR a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl, or 4-8 membered heterocycloalkyl, which C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, OR a , NRa R a ', C1-C2 alkyl or halo-C1-C2 alkyl substitution; two Rs on the same atom or different atoms 22 It can form 3-6 membered rings with the atoms it is connected to, and the rings may further contain 0, 1, 2 or 3 heteroatoms selected from N, O, and S; preferably, R 22 Each can be independently represented as oxidized, halogenated, or OR. a NR a R a '、N(R a )COR a '、-S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C3-C6 cycloalkyl or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, or 3 halogens, OR a NR a R a '、C1-C2 alkyl substitution.

[0063] In some embodiments of the present invention, R 22 Each can be independently represented as oxidized, halogenated, or OR. a NR a R a '、N(R a )COR a '、-C(O)R a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C3-C6 cycloalkyl or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, or 3 halogens, OR a NR a R a '、C1-C2 alkyl substitution.

[0064] In some embodiments of the present invention, R 22 Each can be independently represented as D, oxo, halogen, or OR. a NR a R a '、N(R a )COR a '、-C(O)R a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NRa R a ', C1-C2 alkyl or halo-C1-C2 alkyl substitution; two Rs on the same atom or different atoms 22 It can form 3-6 membered rings with the atoms it is connected to, and the rings may further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0065] In some embodiments of the present invention, R 22 Each independently represents oxidative, halogenated, and OR. a NR a R a '、N(R a COR a '、CONR a R a '、-C(O)R a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C3-C6 cycloalkyl or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, or 3 halogens, OR a NR a R a '、C1-C2 alkyl substitution.

[0066] In some embodiments of the present invention, R 23 R 24 R 25 R 30 Each can be independently represented as D, oxo, halogen, CN, OR a NR a R a '、N(R a COR a '、-C(O)R a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NR a R a ', C1-C2 alkyl or halo-C1-C2 alkyl substitution; two Rs on the same atom or different atoms 23 Two R atoms on the same atom or different atoms 24 Two R atoms on the same atom or different atoms 25 Or R 24 With R 25It can form a 3-6 membered ring with the C atom and / or N atom it is connected to, and the ring may further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0067] In some embodiments of the present invention, R 23 R 24 R 25 R 30 Each can be independently represented as D, oxo, halogen, CN, OR a NR a R a '、N(R a COR a '、-S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NR a R a ', C1-C2 alkyl or halogenated C1-C2 alkyl substituted.

[0068] In some embodiments of the present invention, R 23 R 24 R 25 R 30 Each can be independently represented as D, oxo, halogen, CN, OR a NR a R a '、N(R a COR a '、-S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NR a R a ', C1-C2 alkyl or halo-C1-C2 alkyl substitution; two Rs on the same atom or different atoms 23 Two R atoms on the same atom or different atoms 24 Two R atoms on the same atom or different atoms 25 Or R 24 With R 25 It can form a 3-6 membered ring with the C atom and / or N atom it is connected to, and the ring may further contain 0, 1, 2 or 3 heteroatoms selected from N, O, and S; preferably, R 23 R24 25 30 each independently represents oxo, halogen, CN, OR a a R a a a a C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, OH, C1-C2alkyl; a a R a 23 24 25 30 each independently represents oxo, halogen, CN, OR a a R a C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, OH, C1-C2alkyl; 23 24 25 30 each independently is selected from oxo, F, Cl, CN, OR a a R a .

[0069] In some embodiments of the application, R 23 24 25 30 each independently represents oxo, halogen, CN, OR a a R a N(R a )COR a a a C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, OH, C1-C2alkyl; a a R a ​​​​​​​​​​​​​​​​​​​​​​​, C1-C2alkyl; preferably, R 23 , R 24 , R 25 , R 30 each independently represents oxo, halogen, CN, OR a , NR a R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, OH, C1-C2alkyl; more preferably, R 23 , R 24 , R 25 , R 30 each independently is selected from oxo, F, Cl, CN, OR a , NR a R a ’.

[0070] In some embodiments of the present application, R a and R a each independently represents H, D or C1-C3alkyl;

[0071] In another aspect, the present application provides a compound having the following structure, an isotopic derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0072] In another aspect, the present application provides use of the aforementioned compound or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer or pharmaceutical composition thereof in the manufacture of a medicament for the prevention and / or treatment of cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

[0073] In yet another aspect, the present application provides a method for the prevention and / or treatment of cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer and / or pharmaceutical composition thereof.

[0074] It is specifically noted that, herein, when referring to a “compound” of the structure of formula (x), stereoisomers, diastereomers, enantiomers, racemic mixtures and isotopic derivatives thereof are generally encompassed as well.

[0075] As is known to those of ordinary skill in the art, a salt, solvate, hydrate of a compound is an alternative form of the compound, which can be converted into the compound under certain conditions, and therefore, it is specifically noted that when a compound of the structure of formula (x) is referred to herein, it is meant to also include pharmaceutically acceptable salts thereof, and further solvates and hydrates thereof.

[0076] Similarly, when a compound is referred to herein, it is meant to also include prodrugs, metabolites, and nitroso derivatives thereof.

[0077] The pharmaceutically acceptable salts of the present application can be formed using inorganic or organic acids, for example, as follows: "Pharmaceutically acceptable salt" refers to salts of a compound, which are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the application, or separately by reacting the free base or free acid with a suitable reagent, as outlined below. For example, a free base function can be reacted with the appropriate acid. Examples of pharmaceutically acceptable, inorganic salts are salts of minerals acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts of organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or salts formed by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0078] The pharmaceutically acceptable salts of the present application can be prepared by conventional methods, e.g., by dissolving the compound of the present application in an organic solvent which is miscible with water, such as acetone, methanol, ethanol and acetonitrile, adding thereto an excess of an aqueous solution of an organic or inorganic acid, so that the salt precipitates from the resulting mixture, removing the solvent and the excess free acid therefrom, and isolating the precipitated salt.

[0079] The precursors or metabolites described herein can be precursors or metabolites known in the art, so long as the precursor or metabolite is converted in vivo to form the compound. For example, "prodrug" means those precursors of the compounds of the present application which, upon administration, are metabolized in reasonable medical judgment, to contact the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. The term "prodrug" means compounds which are rapidly converted in vivo to the parent compound of the above formula, for example, by hydrolysis in living animals, or N-demethylation of the compounds of the present application.

[0080] The "solvate" described herein means the physical association of one or more solvent molecules (whether organic or inorganic) with one of the compounds of the present application. The physical association can include hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules can be present in a regular or an orderly arrangement. Solvates can comprise stoichiometric or non-stoichiometric amounts of the solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods for solvation are known in the art.

[0081] The "stereoisomers" of the present application are divided into conformational isomers and configurational isomers, and the configurational isomers are further divided into cis-trans isomers and optical isomers (i.e. optical isomers). Conformational isomers refer to a kind of stereoisomerism phenomenon of organic molecules with certain configuration, in which the spatial arrangement of atoms or atomic groups is different due to the rotation or distortion of carbon-carbon single bond. Common examples include the chair conformation and boat conformation of cyclohexane structure. "Stereoisomers" refer to the compounds of the present application containing one or more asymmetric centers, which can exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers. The compounds of the present application have asymmetric centers, and each asymmetric center will produce two optical isomers. The scope of the present application includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds of the present application can exist in the form of tautomers, which have different hydrogen bonding sites by shifting one or more double bonds. For example, ketone and its enol form are ketone-enol tautomers. Each tautomer and its mixture is included in the compounds of the present application. All enantiomers, diastereomers, racemates, meso forms, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of the compounds of formula (x) are included in the scope of the present application.

[0082] The "isotopic derivatives" of the present application refer to the molecules in which the compounds are isotopically labeled. The isotopes commonly used for isotopic labeling are: 2 H and 3 H; carbon isotopes: 11 C, 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotopically labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. In particular, deuterium 3 H and carbon 13 C are more widely used because they are easy to label and convenient to detect. Certain heavy isotopes, such as heavy hydrogen (deuterium) 2Substitution of the compounds of the present application with isotopes such as deuterium can enhance metabolic stability, increase the half-lives of the compounds of the present application, and therefore provide a therapeutic advantage. Isotopically labeled compounds generally have the same physical and chemical properties as the non-labeled compounds, and are used in the same manner.

[0083] The present application also provides the use of the compounds of the present application for the manufacture of a medicament for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease.

[0084] In addition, the present application provides a pharmaceutical composition for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, a neurodegenerative disease, an attention-related disease, or an immune-mediated disease, comprising a compound of the present application as an active ingredient. The pharmaceutical composition can optionally comprise a pharmaceutically acceptable carrier.

[0085] In addition, the present application provides a method for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, a neurodegenerative disease, an attention-related disease, or an immune-mediated disease, comprising administering a compound of the present application to a mammal in need thereof.

[0086] Representative examples of the inflammatory disease, the autoimmune disease, and the immune-mediated disease can include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritides, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung diseases, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic lung inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (hives), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic rhinosinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0087] Representative examples of cancers or tumors can include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis cancer, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, larynx cancer, hypopharynx cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelocytic leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratocarcinoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, or plasmacytoma.

[0088] When the compound of the present application or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for treating cancer or tumor, the compound of the present application or a pharmaceutically acceptable salt thereof can provide an enhanced anticancer effect.

[0089] Representative examples of anti-cancer agents for treating cancer or tumor can include, but are not limited to, cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, goserelin analogs, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, sirolimus lipidate, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crotetuzumab, dabrafenib, dacotuzumab, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, seribantumab, sorafenib, sunitinib, telotristat, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, velpatasarin, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab ozogamicin, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, and anti-CTLA-4 antibodies, or any combination thereof.

[0090] When the compound of the present application or a pharmaceutically acceptable salt thereof is administered in combination with another therapeutic agent for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases, the compound of the present application or a pharmaceutically acceptable salt thereof can provide an enhanced therapeutic effect.

[0091] Representative examples of therapeutic agents for the treatment of inflammatory diseases, autoimmune diseases, and immune-mediated diseases can include, but are not limited to, steroidal drugs (e.g., prednisone, prednisolone, methylprednisolone, cortisone, hydrocortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFa agents (e.g., etanercept, infliximab, adalimumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, fexofenadine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one or more therapeutic agents selected from among them can be included in the pharmaceutical composition of the present application.

[0092] Other features of the present application will become apparent in the course of the procedures described in the exemplary embodiments which are given for illustration of the application and are not intended to be limiting thereof, the following examples were prepared, isolated and characterized using the methods disclosed herein.

[0093] The compounds of the present application can be prepared in a number of ways known to one skilled in the art of organic synthesis, either by adapting the methods described below or by using synthetic methods or by variations of synthetic methods known to those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in solvents appropriate to the reagents and materials employed and appropriate to the solvent used for the synthesis. One skilled in the art of organic synthesis will recognize that the sequence of steps can be modified, or the order of addition of reagents can be altered, or the raw materials can be modified, to achieve the desired compound of the present application. DETAILED DESCRIPTION

[0094] The terms used in the present application, including the specification and claims, are defined as follows, if not otherwise indicated. The conventional methods of mass spectrometry, nuclear magnetic, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used, if not otherwise indicated. In the present application, "or" or "and" means "and / or", if not otherwise indicated.

[0095] In the specification and claims, given chemical formulae or names shall encompass all stereoisomers and optical isomers and racemates thereof in which the above-mentioned isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the application. Multiple geometric isomers can also exist for C=C double bonds, C=N double bonds, ring systems, etc., in the described compounds, and all such stable isomers are contemplated in the present application. The present application describes the cis- and trans- (or E- and Z-) geometric isomers of the compounds of the application and they can be isolated in admixture or in separate isomer form. The compounds of the application can be isolated in optically active or racemic forms. All methods used in the making of the compounds of the application and intermediates made therein are considered to be part of the present application. When preparing enantiomeric or diastereomeric products, they can be separated by conventional methods, e.g., by chromatography or fractional crystallization. The end products of the application are obtained in free (neutral) or salt form, depending on the method conditions. Both the free form and the salts of these end products are within the scope of the present application. If desired, one form of a compound can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into the free compound or another salt; a mixture of isomeric compounds of the application can be separated into the individual isomers. The compounds of the application, their free forms and salts can exist in various tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged thereby. It is understood that all tautomeric forms which can exist are included within the present application.

[0096] In the present application, when a linking group is listed without indicating its direction of attachment, its direction of attachment is arbitrary, e.g. where L is -C(O)NH-, which can be attached to the phenyl and cyclohexyl groups in the order of reading from left to right to form or in the order of reading from left to right in reverse to form The combination of the linking group and the groups to which it is attached is only allowed if it results in a stable compound. In some preferred embodiments of the present application, the order of reading is from left to right.

[0097] Unless otherwise defined, the definitions of substituents of the present application are independent of each other and not interdependent, e.g. (by way of illustration and not exhaustive), in one aspect, for R a (or R a ') in one substituent, a definition is selected, it does not mean that the same R a (or R a ') in another substituent definition is the same. Specifically, when a definition is selected for R a (or R a) have the same definition. More specifically, for example (and this list is non-exhaustive) for NR a R a ) in R a (when R a ) is defined as hydrogen, it does not mean that R a R a ) in R a (when R a ) is defined as hydrogen. In another aspect, when there is more than one R a (when R a ) in a substituent, the R a (when R a ) are also independent of each other. For example, in the substituent -(CR a R a’ ) m -O-(CR a R a’ ) n -, where m+n is equal to or greater than 2, the m+n R a (when R a ) are independent of each other and can have the same or different meanings.

[0098] Unless otherwise defined, when a substituent is labeled "optionally substituted" the substituent is selected from, for example, alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclyl, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (where the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl such as -SO2NH2, substituted sulfonylamino, nitro, cyano, carboxy, carbamoyl such as -CONH2, substituted carbamoyl such as -CONHalkyl, -CONHaryl, -CONHarylalkyl or where the nitrogen has two substituents selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like, and substituted heterocyclyl.

[0099] The term "single bond" or "bond" or "direct bond" as used herein, unless otherwise defined, means the connection of two atoms by a saturated covalent bond. For example, when L represents a single bond, "A-L-B" means that A and B are connected by a saturated covalent bond, i.e. "A-B"; for another example, when L represents a single bond, "-CH2-L-NH-" means that -CH2- and -NH- are connected by a saturated covalent bond, i.e. "-CH2-NH-".

[0100] The term "alkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "Ci-C6alkyl" denotes alkyl groups with one to six carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g. n-propyl and isopropyl), butyl (e.g. n-butyl, isobutyl, t-butyl) and pentyl (e.g. n-pentyl, isopentyl, neopentyl). The alkyl group can be unsubstituted or substituted, when substituted it can be substituted at any available attachment point with one or more substituents preferably selected from deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In the present context, alkyl is preferably an alkyl group having 1 to 6, more preferably 1 to 4 carbon atoms.

[0101] The term "alkylene" as used herein is intended to include both branched and straight chain, saturated aliphatic hydrocarbon groups, including or not including cyclic alkyl groups, having the specified number of carbon atoms, which is a residue derived from the same carbon atom or two different carbon atoms of a parent alkane by removal of two hydrogen atoms. For example, "C0-C6alkylene" denotes alkylene groups with 0 (i.e. a bond), 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (e.g. -(CH2)3-, -(CHCH3)CH2-, -CH(CH2CH3)-), and the like. In the present context, alkylene is preferably an alkylene group having 0-6, 0-4, 0-3, 1-6, 1-4, 1-3 carbon atoms. In the present context, alkylene is preferably an alkylene group not including cyclic alkyl groups.

[0102] The term "cycloalkyl" refers to monocyclic, polycyclic or branched cyclic alkyl groups. For example, C3-C10cycloalkyl denotes cycloalkyl groups with 3 to 10 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. The cycloalkyl group can be unsubstituted or substituted, when substituted it can be substituted at any available attachment point with one or more substituents preferably selected from deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, heterocycloalkyl, aryl and heteroaryl. In the present context, cycloalkyl is preferably a cycloalkyl group having 3 to 6 carbon atoms. 12cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Herein, a cycloalkyl group can be a saturated or partially unsaturated carbocyclic ring, e.g., a 6-membered cycloalkyl group can include 0-2 double bonds, and a 12-membered cycloalkyl group can include 0-5 double bonds or triple bonds. Polycyclic, e.g., bicyclic and tricyclic, cycloalkyl groups include bridged, spiro, or fused ring cycloalkyl groups. A cycloalkyl group can be unsubstituted or substituted, and when substituted, can be substituted at any available attachment point with one or more substituents preferably selected from the group consisting of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In the application, a cycloalkyl group is preferably a C3-C8cycloalkyl group, more preferably a C3-C6cycloalkyl group, and even more preferably a C3-C4cycloalkyl group. 12 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Herein, a cycloalkyl group can be a saturated or partially unsaturated carbocyclic ring, e.g., a 6-membered cycloalkyl group can include 0-2 double bonds, and a 12-membered cycloalkyl group can include 0-5 double bonds or triple bonds. Polycyclic, e.g., bicyclic and tricyclic, cycloalkyl groups include bridged, spiro, or fused ring cycloalkyl groups. A cycloalkyl group can be unsubstituted or substituted, and when substituted, can be substituted at any available attachment point with one or more substituents preferably selected from the group consisting of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In the application, a cycloalkyl group is preferably a C3-C8cycloalkyl group, more preferably a C3-C6cycloalkyl group, and even more preferably a C3-C4cycloalkyl group.

[0103] Similarly, the term "heterocycloalkyl" refers to a monocyclic ring structure in which at least one carbon atom in the cycloalkyl ring structure is replaced with a heteroatom selected from the group consisting of N, O, S, and P. Herein, a heterocycloalkyl group can be a saturated or partially unsaturated heterocyclic ring, e.g., a 6-membered heterocycloalkyl group can include 0-2 double bonds, and a 12-membered heterocycloalkyl group can include 0-5 double bonds or triple bonds. The N atoms can optionally be quaternized, and the N and S atoms can optionally be oxidized (i.e., NO, SO, and SO2). It includes monocyclic, bicyclic, and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include spiro, fused, and bridged ring systems. A heterocycloalkyl group can be unsubstituted or substituted, and when substituted, can be substituted at any available attachment point with one or more substituents preferably selected from the group consisting of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In the application, a heterocycloalkyl group is preferably a 4-12 membered heterocycloalkyl group, more preferably a 4-8 membered heterocycloalkyl group.

[0104] In the application, the term "fused" refers to a polycyclic group formed by two or more ring structures sharing two adjacent atoms with each other.

[0105] In the application, the term "bridged" refers to a polycyclic group in which two rings in the system share more than two ring atoms.

[0106] In the application, the term "spiro" refers to a polycyclic group in which a single ring shares one carbon atom (called a spiro atom) with another ring.

[0107] The term "alkenyl" denotes straight-chained or branched hydrocarbon groups containing one or more double bonds and typically having a length of from 2 to 20 carbon atoms. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1 -methyl-2-buten-1 -yl, and the like. In the present context, alkenyl is preferably C2-C6 alkenyl.

[0108] The term "cycloalkenyl" refers to monocyclic or bicyclic cyclic alkenyl groups. Monocyclic cyclic alkenyl groups refer to C3-C8 cyclic alkenyl groups including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl. Branched cycloalkenyl groups such as 1 -methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyl groups include bridged, spiro, or fused cyclic alkenyl groups.

[0109] The term "alkynyl" denotes straight-chained or branched hydrocarbon groups containing one or more triple bonds and typically having a length of from 2 to 20 carbon atoms. For example, "C2-C6 alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1 -propynyl, 1 -butynyl, and the like. In the present context, alkynyl is preferably C2-C6 alkynyl.

[0110] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "Ci-C6alkoxy" (or alkyloxy) is intended to include Ci, C2, C3, C4, C5, C6alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propyloxy (e.g., n- propyloxy and isopropyloxy), and t-butyloxy. In the present context, alkoxy is preferably alkoxy having 1 to 6, more preferably having 1 to 4 carbon atoms. Similarly, "alkylthio" or "thioalkoxy" denotes an alkyl group as defined above attached through a sulfur bridge with the indicated number of carbon atoms; for example, methyl-S- and ethyl-S-. The alkoxy group can be unsubstituted or substituted, when substituted it can be substituted at any available attachment point with one or more substituents preferably selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0111] The term "carbonyl" refers to the organic functional group (C=0) connected by a double bond between a carbon and an oxygen atom.

[0112] The term "aryl," alone or in combination with other radicals, means a monocyclic, bicyclic, or tricyclic ring system having from 5 to 12 ring members in which at least one ring is aromatic and in which each ring in the system contains from 3 to 7 ring members. In certain embodiments of the application, "aryl" refers to aromatic ring systems including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" means an alkyl residue attached to an aryl ring, non-limiting examples of which include benzyl, phenethyl, and the like. A fused aryl group can be attached to another group at a suitable position on either the cycloalkyl ring or the aromatic ring. The dashed line drawn from the ring system indicates that the bond can be attached to any suitable ring atom. The aryl group can be unsubstituted or substituted, and when substituted, it can be substituted at any available point of attachment with one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0113] When the term "heterocycle" is used, it means fully saturated, partially unsaturated, and fully unsaturated ring structures containing heteroatoms, including heterocycloalkyl, heteroaromatic rings.

[0114] When the term "alicyclic" is used, it means fully saturated, partially unsaturated, and fully unsaturated ring structures containing no heteroatoms, including cycloalkyl, aromatic rings.

[0115] When the term "ring" is used, without further specific indication, it means fully saturated, partially unsaturated, and fully unsaturated ring structures containing heteroatoms or containing no heteroatoms, including cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic rings.

[0116] The term "heteroaryl" means a stable 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered polyaromatic heterocyclic ring that contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; it includes structures in which a cycloalkane or heterocycloalkane is fused to an aromatic ring such as a benzene ring or a heteroaromatic ring such as a pyridine ring, the point of attachment of the substituent being at the cycloalkane, heterocycloalkane, aromatic, or heteroaromatic ring. Nitrogen and sulfur heteroatoms can optionally be oxidized. The nitrogen atoms are substituted or unsubstituted (i.e., N or NR, where R is H or, if defined, another substituent). The heterocyclic rings can be attached to their side groups at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein can be substituted on carbon or nitrogen atoms if the resulting compound is stable. The nitrogen in the heterocyclic ring can optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocyclic ring exceeds 1, then these heteroatoms are not adjacent to one another. Preferably, the total number of S and O atoms in the heterocyclic ring is not more than 1. The heteroaryl group can be unsubstituted or substituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.Examples of aryl hetero groups include, but are not limited to, azetidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, imidazopyridinyl, indoleninyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, oxindolyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-l,2,5-thiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienopyridyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, lH-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, 1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.The term "heteroaryl" can also include biaryl structures formed from the above defined "aryl" groups with monocyclic "heteroaryl" groups, such as, but not limited to, "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", "-pyrimidylbiphenyl-"; wherein the present application also includes fused ring and spiro compounds containing, for example, the above heterocycles.

[0117] The term "substituted" as used herein means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that a stable compound results. Ring double bonds are as defined herein to be between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0118] In the present disclosure, one or more halogen can each independently be selected from fluorine, chlorine, bromine, and iodine.

[0119] "Halo" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" / "haloalkylene" is intended to include branched and straight-chain saturated aliphatic alkyl / alkylene groups having the specified number of carbon atoms substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptafluoropropyl. Examples of haloalkyl also include "fluoroalkyl" intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms. "Halo cycloalkyl" / "halo heterocycloalkyl" is intended to include cycloalkyl / heterocycloalkyl groups having the specified number of carbon atoms substituted with one or more halogens. In the present application, the halogen atom is preferably fluorine or chlorine, more preferably fluorine. In the present disclosure, a group is considered to be halogenated unless it is specifically indicated that the group cannot be substituted with halogen, or it can be inferred from the context that the group does not include halogen, or it is generally known in the art that the group is not suitable for halogenation.

[0120] "Haloalkoxy" or "haloalkyloxy" denotes an oxygen-bridged haloalkyl group as defined above having the specified number of carbon atoms. For example, "halo C1-C6alkoxy" is intended to include C1, C2, C3, C4, C5, C6haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" denotes a sulfur-bridged haloalkyl group as defined above having the specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0121] In the present disclosure, C x1 -C x2The expression indicates that the number of carbon atoms in the substituent group can be x1 to x2. For example, C0-C8 indicates that the group contains 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C1-C8 indicates that the group contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C2-C8 indicates that the group contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C3-C8 indicates that the group contains 3, 4, 5, 6, 7, or 8 carbon atoms; C4-C8 indicates that the group contains 4, 5, 6, 7, or 8 carbon atoms; C0-C6 indicates that the group contains 0, 1, 2, 3, 4, 5, or 6 carbon atoms; C1-C6 indicates that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms; C2-C6 indicates that the group contains 2, 3, 4, 5, or 6 carbon atoms; and C3-C6 indicates that the group contains 3, 4, 5, or 6 carbon atoms.

[0122] In this disclosure, when referring to cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), the expression "x1-x2 membered ring" is used, indicating that the number of ring atoms in the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; a 3-6 membered ring indicates that the cyclic group can be a 3, 4, 5, or 6 membered ring, and its number of ring atoms can be 3, 4, 5, or 6; a 3-8 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, or 8; a 3-9 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, 8, or 9 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; 8 or 9; 4-7 membered ring indicates that the cyclic group can be a 4, 5, 6, or 7 membered ring, and its number of ring atoms can be 4, 5, 6, or 7; 5-8 membered ring indicates that the cyclic group can be a 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 5, 6, 7, or 8; 5-12 membered ring indicates that the cyclic group can be a 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 5, 6, 7, 8, 9, 10, 11, or 12; 6-12 membered ring indicates that the cyclic group can be a 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 6, 7, 8, 9, 10, 11, or 12. The ring atoms can be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cyclic heteroatoms, for example heteroatoms selected from N, O and S.

[0123] Where there are nitrogen atoms (e.g., amines) on the compounds of the application, these can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to afford other compounds of the application. Thus, a shown and claimed nitrogen atom is considered to cover both the shown nitrogen and its N-oxide to afford derivatives of the application.

[0124] When any variable occurs more than one time in any constituent or formula for a compound, its definition in each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R's, said group can optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0125] The term "patient" as used herein means an organism being treated by the methods of the application. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, monkeys, horses, cows, pigs, canines, felines, etc.) and most preferably refers to humans.

[0126] The term "effective amount" as used herein means that amount of a drug or pharmaceutical agent (i.e., a compound of the application), which will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means that amount which results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder, compared to that which would occur in the absence of the administration of the above. An effective amount can be given in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope amounts effective to enhance normal physiological function.

[0127] The term "treatment" as used herein includes any effect that relieves, reduces, modulates, ameliorates, or eliminates a condition, disease, disorder, etc., or a symptom thereof.

[0128] The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, and / or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0129] The phrase "pharmaceutically acceptable carrier" or "pharmaceutically acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0130] The term "pharmaceutical composition" means a composition comprising a compound of the present application in combination with at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" means a medium generally accepted in the art for the delivery of a biologically active agent to an animal, particularly a mammal, including, i.e., an adjuvant, excipient, or vehicle, such as diluent, preserving, salt, buffer, dispersing, or dispersing agent, or solvent, depending on the formulation desired. The term "pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, ester, or other derivative of a compound of this application, which, upon administration to an animal, is capable of providing (directly or indirectly) the parent compound or an inhibitor.

[0131] Specific Pharmaceutical and Medical Terms

[0132] The term "acceptable", as used herein, means healthily not having an excessively deleterious effect on the general treatment goals of a prescribed component or active ingredient.

[0133] The term "cancer", as used herein, means an abnormal growth of cells that is uncontrolled and, under some conditions, can metastasize (spread). This type of cancer includes, but is not limited to, solid tumors (e.g., bladder, bowel, brain, breast, uterine, cardiac, kidney, lung, lymphatic tissue (lymphoma), ovarian, pancreatic, or other endocrine organ (e.g., thyroid), prostate, skin (melanoma), or blood (e.g., non-leukemic leukemia).

[0134] The term "co-administration" or its grammatical equivalents, as used herein, means the administration of two or more selected therapeutic agents to a single patient at the same time by the same or different routes of administration.

[0135] The term "enhance" or "enhancing", as used herein, means an intended result that can be an increase or prolongation in potency or duration. Thus, in the context of enhancing the therapeutic effect of a drug, the term "enhancing" means the ability of a drug to have an increased or prolonged potency or duration in the system. "Enhancing value", as used herein, means the ability to maximize the enhancement of another therapeutic agent in an ideal system.

[0136] The term "immune disease" refers to a disease or condition resulting from an adverse or deleterious reaction to an endogenous or exogenous antigen. The result is usually a dysfunction of cells, or destruction and dysfunction of organs or tissues from which the immune condition arises.

[0137] The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and house cats; laboratory animals such as rats, mice, and guinea pigs; and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred aspect, the mammal is a human.

[0138] The terms "treatment," "treatment regime," or "therapy," as used herein, include alleviating, inhibiting or ameliorating a disease symptom or condition; inhibiting the onset of a complication; ameliorating or preventing a metabolic syndrome; inhibiting the onset of a disease or condition, such as controlling the development of a disease or condition; relieving a disease or condition; causing a disease or condition to regress; relieving a complication caused by a disease or condition, or preventing and / or treating a sign caused by a disease or condition.

[0139] As used herein, an improvement in a disease, condition, or condition, refers to an improvement in the severity thereof, a delay in the onset thereof, a slowing of the progression thereof, or a reduction in the duration thereof, whether fixed or temporal, continuous or intermittent, attributable to or associated with the administration.

[0140] Examples

[0141] General procedure

[0142] When not included in a preparation route, the starting materials and reagents used in the present application are known products, which can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. The commercially available reagents used are not required to be further purified.

[0143] Room temperature refers to 20-30 °C.

[0144] Unless otherwise specified in the reaction examples, the reactions were carried out under a nitrogen atmosphere. The nitrogen atmosphere refers to the reaction flask being connected to a nitrogen balloon of about 1 L.

[0145] The hydrogenation reaction was usually carried out by vacuuming and filling hydrogen repeatedly for 3 times. The hydrogen atmosphere refers to the reaction flask being connected to a hydrogen balloon of about 1 L.

[0146] Microwave reaction uses Initiator + microwave reactor.

[0147] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR measurements are made on a (Bruker Ascend TM 500) NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent and tetramethylsilane (TMS) as the internal standard. The following abbreviations are used for multiplicity of NMR signals: s = singlet, br s = broad singlet, d = doublet, t = triplet, m = multiplet. Coupling constants are listed as J values, measured in Hz.

[0148] Preparative reverse phase chromatography uses a Thermo (UltiMate 3000) preparative reverse phase chromatograph. Flash column chromatography uses an Agilent (FS-9200T) automated column over machine, and silica gel pre-packed columns use a Taisite pre-packed column. Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, and the specifications used for thin layer chromatography separation and purification of products are 0.4mm-0.5mm.

[0149] LC-MS analysis method is as follows:

[0150] 1) Mass spectrometry method: Thermo Fisher MSQ PLUS mass spectrometer, ESI source, positive ion mode. Ion source parameters: drying gas temperature 350℃; drying gas flow rate 10L / min; MS Range: 120-1000.

[0151] 2) Liquid chromatography conditions: column: Waters XBridge (3.5μm, 50mm x 4.6mm); mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile solution, linear gradient elution according to the following Table 1; flow rate: 2mL / min; column temperature: 30℃; ultraviolet detection wavelength: 214nm, 254nm, 280nm; injection volume 2μL.

[0152] Table 1. Gradient elution conditions

[0153] HPLC analysis method is as follows:

[0154] Column: Waters XBridge phenyl (3.5μm, 150mm x 4.6mm); mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile solution, linear gradient elution according to the following Table 2; flow rate: 1mL / min; column temperature: 30℃; ultraviolet detection wavelength: 214nm, 254nm, 280nm; injection volume 2μL. ​

[0155] Table 2. Gradient elution conditions

[0156] The synthesis method of some intermediates in the invention is as follows:

[0157] Intermediate 1

[0158] Intermediate 1 is prepared from the following steps:

[0159] Step 1: Compound INT-1a (600 mg, 2.62 mmol), INT-1b (698.47 mg, 2.62 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (192.03 mg, 0.26 mmol), sodium carbonate (556.32 mg, 5.25 mmol) were dissolved in 1,4-dioxane (10 mL) / water (1 mL), protected by nitrogen, stirred at 90°C overnight, after the reaction was completed, the reaction solution was filtered through diatomite, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain yellow solid INT-1c (370 mg, yield 42%). ESI-MS (m / z): 333.4 [M+H] + .

[0160] Step 2: Compound INT-1c (340 mg, 1.02 mmol) was dissolved in dichloromethane (5 mL), cooled to 0°C in an ice water bath, and m-chloroperbenzoic acid (441.35 mg, 2.56 mmol) was added, and stirred at 0°C for four hours, after the reaction was completed, saturated sodium bicarbonate aqueous solution was added to quench the reaction, then extracted with dichloromethane (30 mL x 3), the combined organic phase was dried, concentrated under reduced pressure to obtain yellow oil INT-1 (340 mg, yield 91%). ESI-MS (m / z): 365.4 [M+H] + .

[0161] Intermediate 2

[0162] Intermediate 2 is prepared from the following steps:

[0163] Step 1: Dissolve INT-2a (2.00 g, 9.22 mmol) and zinc chloride (3.77 g, 27.65 mmol) in a mixture of 1,2-dichloroethane (15 mL) and tert-butanol (15 mL) and stir at 0 °C for 1 h. Then dissolve INT-2b (1.77 g, 9.22 mmol) and triethylamine (1.79 g, 13.83 mmol) in 1,2-dichloroethane (15 mL) and tert-butanol (15 mL) and add dropwise to the above reaction solution. Stir the reaction at 0 °C for 3 h. After the reaction is completed, filter the reaction solution, concentrate and dry the filtrate to obtain a crude product. Subject the crude product to column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target product INT-2 (2.00 g, yield 58.21%). ESI-MS (m / z): 373.7 [M+H] + .

[0164] Intermediate 3

[0165] Intermediate 3 is prepared by the following steps:

[0166] Step 1: Dissolve INT-1a (500 mg, 2.19 mmol), INT-3a (608.33 mg, 2.19 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (160.02 mg, 0.22 mmol), and sodium carbonate (463.60 mg, 4.37 mmol) in a mixture of 1,4-dioxane (10 mL) and water (1 mL) and stir the reaction at 80 °C for 6 h under nitrogen protection. After the reaction is completed, concentrate and dry the reaction solution and subject the residue to column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound INT-3b (430 mg, yield 57.10%). ESI-MS (m / z): 345.6 [M+H] + .

[0167] Step 2: Dissolve INT-3b (430 mg, 1.25 mmol) in dichloromethane (10 mL) and add m-chloroperoxybenzoic acid (557.74 mg, 2.75 mmol) to the above reaction solution. Stir the reaction at room temperature for 4 h. After the reaction is completed, add saturated sodium thiosulfate and saturated sodium bicarbonate solutions to the above reaction solution and extract. Dry and concentrate the organic phase to obtain the target compound INT-3 (380 mg, yield 80.86%). ESI-MS (m / z): 377.7 [M+H] + .

[0168] Intermediate 4

[0169] Intermediate 4 was prepared by the following steps:

[0170] Step 1 : Compound INT-4a (103 mg, 0.563 mmol), INT-1b (100 mg, 0.375 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (27.5 mg, 37.5 umol), sodium carbonate (119 mg, 1.13 mmol) were dissolved in 1,4-dioxane (10 mL) / water (1 mL), protected by nitrogen, stirred at 90 °C overnight, after the reaction was completed, the reaction solution was filtered through diatomite, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain yellow solid INT-4 (70 mg, yield 64%). ESI-MS (m / z): 287.6 [M+H] + .

[0171] Intermediate 5

[0172] Intermediate 5 was prepared by the following steps:

[0173] Step 1 : Compound INT-4a (89 mg, 0.485 mmol), INT-3a (90 mg, 0.323 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (24.3 mg, 32.3 umol), sodium carbonate (103 mg, 0.97 mmol) were dissolved in 1,4-dioxane (10 mL) / water (1 mL), protected by nitrogen, stirred at 90 °C overnight, after the reaction was completed, the reaction solution was filtered through diatomite, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain yellow solid INT-5 (85 mg, yield 87%). ESI-MS (m / z): 299.8 [M+H] + .

[0174] Intermediate 6

[0175] Intermediate 6 was prepared by the following steps:

[0176] Step 1: Compound INT-6a (100 mg, 0.359 mmol), INT-3a (100 mg, 0.540 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (26.4 mg, 36.0 umol), sodium carbonate (114 mg, 1.08 mmol) were dissolved in 1,4-dioxane (10 mL) / water (1 mL), protected by nitrogen, stirred at 90 °C overnight, after the reaction was completed, the reaction liquid was filtered through diatomite, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain yellow solid INT-6b (90 mg, yield 83%). ESI-MS (m / z): 302.7 [M+H] + .

[0177] Step 2: INT-6b (70 mg, 0.232 mmol) was dissolved in dichloromethane (2 mL), m- chloroperoxybenzoic acid (80 mg, 0.464 mmol) was added to the reaction liquid at 0 °C, and the reaction was maintained at 0 °C for 8 hours. After the reaction was completed, saturated sodium thiosulfate and saturated sodium bicarbonate solution were added to the above reaction liquid, and then extracted. The organic phase was dried and concentrated to obtain the target compound INT-6 (40 mg, yield 51%). ESI-MS (m / z): 334.2 [M+H] + .

[0178] Intermediate 7

[0179] Intermediate 7 was prepared by the following steps:

[0180] Step 1: INT-2b (1.0 g, 5.20 mmol) was dissolved in 5 mL formic acid, and stirred at 100 °C for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain an oil, which was slurried with petroleum ether / ethyl acetate (10 / 1), suction filtered, and dried to obtain white solid INT-7 (1.0 g, yield 87%). ESI-MS (m / z): 221.2 [M+H] + .

[0181] Intermediate 8

[0182] Intermediate 8 was prepared by the following steps:

[0183] Step 1: Dissolve INT-2a (3 g, 13.12 mmol), INT-8a (3.65 g, 13.12 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (960.14 mg, 1.31 mmol), potassium carbonate (3.63 g, 26.24 mmol) in a mixed solvent of 1,4-dioxane (100 mL) and water (10 mL), and stir the reaction solution at 90 °C under nitrogen atmosphere for 12 hours. After the reaction is completed, filter and concentrate the reaction solution to obtain a crude product. The crude product is subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain the target product INT-8b (3.95 g, yield 87.42%). ESI-MS (m / z): 345.5 [M+H] + .

[0184] Step 2: Dissolve INT-8b (3.74 g, 10.86 mmol) in dichloromethane (40 mL), and add meta-chloroperoxybenzoic acid (4.85 g, 23.89 mmol) to the above reaction solution. Stir the reaction solution at room temperature for 4 hours. After the reaction is completed, add saturated sodium thiosulfate and sodium bicarbonate solution to quench the reaction. Extract the quenched reaction solution with dichloromethane, dry and concentrate the organic phase to obtain a crude product. The crude product is subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the target product INT-8c (1.8 g, yield 44.04%). ESI-MS (m / z): 377.5 [M+H] + .

[0185] Step 3: Dissolve INT-8c (1.8 g, 4.78 mmol), INT-2b (1.38 g, 7.17 mmol), trifluoroacetic acid (1.64 g, 14.35 mmol) in 1,4-dioxane (30 mL), and stir the reaction solution at 100 °C for 12 hours. After the reaction is completed, concentrate and dry the reaction solution to obtain a crude product. The crude product is subjected to column chromatography (dichloromethane / methanol = 10 / 1) to obtain the target compound INT-8 (1.53 g, yield 79.12%). ESI-MS (m / z): 405.1 [M+H] + .

[0186] Intermediate 9

[0187] Intermediate 9 is prepared by the following steps:

[0188] Step 1 : Compound INT-9a (108 mg, 0.647 mmol), INT-3a (150 mg, 0.539 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (39.4 mg, 53.9 umol), sodium carbonate (114 mg, 1.08 mmol) were dissolved in 1,4-dioxane (5 mL) / water (0.5 mL), protected by nitrogen, stirred at 90 °C overnight, after the reaction was completed, the reaction solution was filtered through diatomite, the filtrate was concentrated and purified by preparative plate (petroleum ether / ethyl acetate = 1 / 1) to obtain yellow solid INT-9 (100 mg, yield 65.6%). ESI-MS (m / z): 283.2 [M+H] +

[0189] Intermediate 10

[0190] Intermediate 10 was prepared by the following steps:

[0191] Step 1 : Compound INT-10a (439.52 mg, 2.70 mmol), INT-3a (500 mg, 1.80 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (131.53 mg, 179.76 umol), sodium carbonate (571.57 mg, 5.39 mmol) were dissolved in 1,4-dioxane (10 mL) / water (1 mL), protected by nitrogen, stirred at 90 °C overnight, after the reaction was completed, the reaction solution was filtered through diatomite, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain yellow solid INT-10 (400 mg, yield 79%). ESI-MS (m / z): 279.5 [M+H] + .

[0192] Intermediate 11

[0193] Intermediate 11 was prepared by the following steps:

[0194] Step 1 : Compound INT-11a (174.87 mg, 0.97 mmol), INT-4b (200 mg, 0.75 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (27.49 mg, 37.57 umol), sodium carbonate (159.3 mg, 1.5 mmol) were dissolved in 1,4-dioxane (5 mL) / water (0.5 mL), protected by nitrogen, stirred at 90 °C overnight, after the reaction was completed, the reaction solution was filtered through diatomite, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain yellow solid INT-11 (180 mg, yield 84%). ESI-MS (m / z): 283.5 [M+H] + .

[0195] Intermediate 12

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

[0197] Step 1 : Compound INT-12a (2 g, 17.37 mmol) was dissolved in acetone (20 mL), the temperature of the reaction system was reduced to 0 °C, then benzene sulfonyl chloride (3.37 g, 19.11 mmol) was slowly added and stirred for 0.5 h, finally sodium hydroxide (0.833 g, 20.85 mmol) was dissolved in water (5 mL) and slowly added to the reaction solution, the temperature was raised to room temperature and stirred overnight, after the reaction was completed, extracted with ethyl acetate, the organic phase was dried and concentrated to obtain yellow solid INT-12b (326 mg, yield 16%).

[0198] 1 H NMR (500 MHz, Chloroform-d) δ 6.58 (s, 1H), 3.84 - 3.78 (m, 2H), 3.78 - 3.72 (m, 2H), 3.34 (m, 2H), 2.76 - 2.68 (m, 2H).

[0199] Step 2: Compound INT-12b (157 mg, 1.37 mmol), compound INT-12c (250 mg, 1.14 mmol), potassium carbonate (473 mg, 3.42 mmol), cuprous iodide (109 mg, 0.57 mmol), N,N'-dimethylethylenediamine (109 mg, 0.57 mmol) were dissolved in 1,4-dioxane (4 mL), protected by nitrogen, the reaction solution was stirred at 120 °C for 24 h, after the reaction was completed, the reaction solution was filtered through diatomite, the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to obtain black solid INT-12 (110 mg, yield 46%). ESI-MS (m / z): 207.6 [M+H]+ .

[0200] Intermediate 13

[0201] Intermediate 13 was prepared by the following steps:

[0202] Step 1: Compound INT-13a (2.5 g, 19.06 mmol), sodium carbonate (6.6 g, 57.17 mmol) were dissolved in acetone (30 mL) and water (30 mL), p-toluenesulfonyl chloride (5.5 g, 28.58 mmol) was added at room temperature, then the temperature was raised to 60 °C and stirred overnight, after the reaction was completed, extracted with ethyl acetate, the organic phase was dried and concentrated to obtain yellow solid INT-13b (1 g, yield 40%).

[0203] 1 H NMR (500 MHz, Chloroform-d) δ 6.81 (s, 1H), 3.68 - 3.55 (m, 2H), 2.98 - 2.88 (m, 2H), 2.79 - 2.74 (m, 2H), 2.73 - 2.69 (m, 2H).

[0204] Step 2: Compound INT-13b (563 mg, 4.29 mmol), compound INT-12c (783 mg, 3.58 mmol), potassium carbonate (1.48 g, 10.73 mmol), cuprous iodide (681 mg, 3.58 mmol), N,N'-dimethylethylenediamine (315 mg, 3.58 mmol) were dissolved in 1,4-dioxane (8 mL), protected by nitrogen, and the reaction solution was stirred at 120 °C for 48 hr, after the reaction was completed, the reaction solution was filtered through diatomite, the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain black solid INT-13 (520 mg, yield 65%). ESI-MS (m / z): 223.6 [M+H] + .

[0205] Intermediate 14

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

[0207] Step 1: Dissolve INT-14a (3.8 g, 19.48 mmol), INT-8a (5.42 g, 19.48 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (1.43 g, 1.95 mmol), potassium carbonate (5.38 g, 38.96 mmol) in a mixed solvent of 1,4-dioxane (100 mL) and water (10 mL), the reaction solution was stirred at 100 degrees Celsius for 12 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated to obtain a crude product, and the crude product was subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain the target compound INT-14b (4.8 g, yield 79.28%). ESI-MS (m / z): 310.9 [M+H] + .

[0208] Step 2: Dissolve INT-14b (4.8 g, 15.44 mmol) in dichloromethane (100 mL), and add m-chloroperoxybenzoic acid (7.21 g, 35.32 mmol) to the above reaction solution. The reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, saturated sodium thiosulfate and sodium bicarbonate solution were added to quench the reaction. The quenched reaction solution was extracted with dichloromethane, and the organic phase was dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the target product INT-14c (3.1 g, yield 58.55%). ESI-MS (m / z): 343.3 [M+H] + .

[0209] Step 3: Dissolve INT-7 (2.67 g, 12.12 mmol) in N,N-dimethylformamide (50 mL), and add sodium hydride (484.83 mg, 12.12 mmol) to the above reaction solution under nitrogen atmosphere at 0 degrees Celsius. The reaction solution was reacted at 0 degrees Celsius for half an hour. INT-14c (2.77 g, 8.08 mmol) was added to the above reaction solution in batches, and the reaction solution was stirred at room temperature for 12 hours under nitrogen atmosphere. After the reaction was completed, water (50 mL) was added to the reaction solution to precipitate a white solid, and the white solid was filtered to obtain the target compound INT-14d (3.3 g, yield 89.77%). ESI-MS (m / z): 455.0 [M+H] + .

[0210] Fourth step: dissolve INT-14d (1 g, 2.20 mmol), trifluoroacetic acid (1.25 g, 10.99 mmol) in a mixed solution of 1,4-dioxane (30 mL) and water (1 mL), and stir the reaction solution at room temperature for 3 hours. After the reaction is completed, the reaction solution is alkalized with saturated aqueous sodium bicarbonate solution at 0°C and extracted with ethyl acetate. The organic phase is dried and concentrated to obtain a crude product. The crude product is subjected to column chromatography (dichloromethane / methanol = 20 / 1) to obtain the target compound INT-14 (540 mg, yield 66.25%). ESI-MS (m / z): 371.1 [M+H] + .

[0211] Intermediate 15

[0212] Intermediate 15 is prepared by the following steps:

[0213] First step: dissolve compound INT-15a (1 g, 8.12 mmol) in acetonitrile (10 mL), reduce the temperature of the reaction system to 0°C, then dissolve N-iodosuccinimide (2.19 g, 9.14 mmol) in acetonitrile (5 mL) and slowly add it to the reaction system, finally stir at 0°C for 0.5 hr. After the reaction is completed, add 4M HCl solution to the organic phase, wash the aqueous phase with ethyl acetate; adjust the pH of the aqueous phase to 9 by adding 4M NaOH solution, extract with ethyl acetate, combine and separate the organic phase, dry with anhydrous sodium sulfate, filter and rotary evaporate to obtain brown solid compound INT-15b.

[0214] Second step: dissolve compound INT-15b (400 mg, 1.61 mmol) and imidazole (131 mg, 1.93 mmol) in dichloromethane (8 mL), reduce the temperature of the reaction system to 0°C, then slowly add tert-butyldimethylsilyl chloride (363 mg, 2.41 mmol) to the reaction system, stir at room temperature overnight, after the reaction is completed, extract with ethyl acetate, concentrate the filtrate, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain yellow solid INT-15c (244 mg, yield 41%). ESI-MS (m / z): 364.3 [M+H] + .

[0215] Step 3: Compound INT-15c (244 mg, 671 umol), compound INT-15d (75 mg, 738 ummol), potassium carbonate (278 mg, 2.01 mmol), copper iodide (64 mg, 336 umol), N,N'-dimethylethylenediamine (60 mg, 671 umol) were dissolved in 1,4-dioxane (4 mL) under nitrogen protection. The reaction solution was stirred at 120 °C for 24 hr. After the reaction was completed, the reaction solution was filtered through diatomite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain black solid INT-15 (190 mg, yield 84%). ESI-MS (m / z): 336.9 [M+H] + .

[0216] Intermediate 16

[0217] Intermediate 16 was prepared by the following steps:

[0218] Step 1: Compound INT-16a (3 g, 20.81 mmol) was dissolved in pyridine (5 mL, 62.43 mmol), and then tert-butyl hydroperoxide (1 mL, 10.40 mmol) and iodine (2.9 g, 11.44 mmol) were added. The reaction solution was stirred at room temperature overnight. Dichloromethane (50 mL) was added to the reaction system, and the solid was removed by filtration. The filtrate was washed with saturated aqueous ammonium chloride solution (20 mL x 3), and then purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to obtain brown solid compound INT-16b (3 g, yield 53.4%). ESI-MS (m / z): 271.0 [M+H] + .

[0219] Step 2: Compound INT-16b (1 g, 3.70 mmol), compound INT-15d (749 mg, 7.41 mmol), potassium phosphate (1.57 g, 7.41 mmol), copper iodide (70.52 mg, 370.3 umol), N,N-dimethylethylenediamine (32.64 mg, 370.3 umol) were dissolved in 1,4-dioxane (5 mL) under nitrogen protection. The reaction solution was stirred at 120 °C overnight. After the reaction was completed, the reaction solution was filtered through diatomite. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain yellow solid INT-16c (410 mg, yield 45.5%). ESI-MS (m / z): 244.1 [M+H] + .

[0220] Step 3: Compound INT-16c (410 mg, 1.69 mmol) was dissolved in methanol (10 mL), platinum dioxide (38.3 mg, 0.17 mmol) and 4M hydrochloric acid / dioxane solution (1.26 mL, 5.06 mmol) were added, and the reaction was stirred at room temperature under H2atmosphere overnight. After the reaction was completed, water (5 mL) was added to the reaction system, and the solid was removed by filtration. The filtrate was concentrated to obtain yellow solid INT-16d (410 mg, yield 98%).

[0221] Step 4: Compound INT-16d (410 mg, 1.66 mmol) was dissolved in dichloromethane (10 mL), N,N-diisopropyl ethylamine (0.87 mL, 4.97 mmol) was added, and di-tert-butyl dicarbonate (543 mg, 2.49 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction liquid was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain red solid INT-16 (450 mg, yield 78%). ESI-MS (m / z): 348.1 [M+H] + .

[0222] Intermediate 17

[0223] Intermediate 17 was prepared by the following steps:

[0224] Step 1: INT-17a (10.00 g, 51.55 mmol), 4-methoxychlorobenzene (9.69 g, 61.86 mmol), potassium carbonate (9.26 g, 67.02 mmol) were dissolved in N,N-dimethylformamide (150 mL), and the reaction was stirred at room temperature under nitrogen protection for 12 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, and ethyl acetate (200 mL) was used for extraction. The organic phase was dried and concentrated, and then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound INT-17b (16.00 g, yield 98.80%). ESI-MS (m / z): 314.6 [M+H] + .

[0225] Second step: Dissolve INT-17b (16.16 g, 51.45 mmol) in tetrahydrofuran (160 mL), under nitrogen protection and at -78 degrees Celsius, add lithium diisopropylamide (2 M, 30.87 mL, tetrahydrofuran solution) drop by drop, and react at -78 degrees Celsius for 0.5 hours. Then, dissolve hexachloroethane (14.61 g, 61.73 mmol) in tetrahydrofuran (50 mL) at -78 degrees Celsius, and add to the above reaction solution drop by drop, and stir the reaction solution at -78 degrees Celsius for 2 hours. After the reaction is completed, quench with saturated ammonium chloride solution (80 mL), extract with ethyl acetate (200 mL), dry the organic phase, and concentrate to obtain a crude product. The crude product is subjected to column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound INT-17c (11.80 g, yield 65.80%).

[0226] Third step: Dissolve INT-17c (11.35 g, 32.56 mmol) in tetrahydrofuran (150 mL), under nitrogen protection and at 0 degrees Celsius, add isopropyl magnesium chloride (2 M, 40.70 mL, tetrahydrofuran solution) drop by drop, and react at 0 degrees Celsius for 0.5 hours. Then, add 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25.72 g, 162.81 mmol) to the above reaction solution at 0 degrees Celsius, and stir the reaction solution at 0 degrees Celsius for 2 hours. After the reaction is completed, quench with saturated aqueous ammonium chloride solution (100 mL) at 0 degrees Celsius, extract with ethyl acetate (200 mL), dry the organic phase, and concentrate to obtain a crude product. The crude product is subjected to column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound INT-17d (8.67 g, yield 76.37%). ESI-MS (m / z): 349.1 [M+H] + .

[0227] Fourth step: Dissolve INT-14a (5.11 g, 26.20 mmol), INT-17d (8.70 g, 24.95 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (1.83 g, 2.50 mmol), and potassium carbonate (6.90 g, 49.91 mmol) in a mixed solution of 1,4-dioxane (100 mL) and water (5 mL), and stir the reaction solution at 90 degrees Celsius under nitrogen protection for 12 hours. After the reaction is completed, cool to room temperature, filter the reaction solution, concentrate the filtrate to obtain a crude product, and subject the crude product to column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound INT-17e (6.50 g, yield 68.32%). ESI-MS (m / z): 381.0 [M+H] + .

[0228] Step 5: INT-17e (6.20 g, 16.26 mmol) was dissolved in dichloromethane (60 mL), and m-chloroperoxybenzoic acid (8.25 g, 40.65 mmol, 85%) was added at 0 °C under air atmosphere. The reaction was stirred at 0 °C for 4 h. After the reaction was completed, saturated aqueous sodium bicarbonate solution (40 mL) and aqueous sodium thiosulfate solution (40 mL) were added to quench the reaction, and dichloromethane (150 mL) was added to extract the organic phase. The organic phase was dried and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the target compound INT-17f (5.50 g, yield 81.84%). ESI-MS (m / z): 412.7 [M+H] + .

[0229] Step 6: INT-7 (2.64 g, 11.99 mmol) was dissolved in N,N-dimethylformamide (60 mL), and sodium hydride (813.01 mg, 20.33 mmol, 60%) was added at 0 °C under nitrogen protection. The reaction was stirred at 0 °C for 0.5 h. Then, INT-17f (4.20 g, 10.16 mmol) was added to the reaction at 0 °C, and the reaction was stirred at room temperature for 12 h. After the reaction was completed, water (50 mL) was added to quench the reaction, and ethyl acetate (150 mL) was added to extract the organic phase. The organic phase was dried and concentrated to obtain a crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain the target compound INT-17g (4.20 g, yield 78.66%). ESI-MS (m / z): 525.5 [M+H] + .

[0230] Step 7: INT-17g (4.20 g, 7.61 mmol) was dissolved in a mixed solution of 1,2-dichloroethane (10 mL) and trifluoroacetic acid (10 mL), and the reaction was carried out at 80 °C under nitrogen protection for 12 h. After the reaction was completed, the reaction was cooled to room temperature, saturated aqueous sodium bicarbonate solution (80 mL) was added to quench the reaction, and ethyl acetate (150 mL) was added to extract the organic phase. The organic phase was dried and concentrated to obtain a crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain the target compound INT-17 (1.92 g, yield 62.23%). ESI-MS (m / z): 403.8 [M+H] + .

[0231] Intermediate 18

[0232] Intermediate 18 was prepared by the following steps:

[0233] Step 1: Dissolve INT-18a (1 g, 4.12 mmol), INT-18b (873.9 mg, 4.12 mmol) and potassium carbonate (568.94 mg, 4.12 mmol) in N,N-dimethylformamide (10 mL), stir at 70 °C for 16 hours. After the reaction is completed, cool to room temperature, dilute the reaction solution with ethyl acetate (50 mL), then wash with saturated brine (50 mL x 3), dry the organic phase over anhydrous sodium sulfate, filter and concentrate to obtain a crude product, which is subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the target compound INT-18c (500 mg, yield 32%). ESI-MS (m / z): 374.4 [M+H] + .

[0234] Step 2: Dissolve INT-18c (500 mg, 1.34 mmol) in anhydrous tetrahydrofuran (10 mL), cool to -78 °C, slowly drop n-butyllithium (0.64 mL, 1.60 mmol, 2.5 M, n-heptane) under nitrogen atmosphere, after half an hour, start to drop INT-18d (497.08 mg, 2.68 mmol), continue to stir at -78 °C for 2 hours. After the reaction is completed, quench the reaction by adding saturated aqueous sodium chloride solution (10 mL), slowly rise to room temperature, extract the reaction solution with ethyl acetate (50 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain a crude product, which is subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the target compound INT-18e (300 mg, yield 53%). ESI-MS (m / z): 422.5 [M+H] + .

[0235] Step 3: Dissolve INT-18e (300 mg, 0.71 mmol), INT-14a (166.66 mg, 0.85 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (26.05 mg, 35.6 umol), sodium carbonate (150.93 mg, 1.42 mmol) in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL), stir the reaction solution at 80 °C for 16 hours under nitrogen atmosphere. After the reaction is completed, cool the reaction solution to room temperature, dilute with ethyl acetate (50 mL), filter and concentrate to obtain a crude product, which is subjected to column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the target compound INT-18f (100 mg, yield 30%). ESI-MS (m / z): 454.0 [M+H] + .

[0236] Fourth step: dissolve INT-18f (100 mg, 0.22 mmol) in dichloromethane (2 mL), cool to 0 °C, add m-chloroperoxybenzoic acid (95.03 mg, 0.55 mmol) to the above reaction solution, slowly raise the reaction solution to room temperature, and stir at room temperature for 4 hours. After the reaction is completed, quench the reaction with saturated aqueous sodium bicarbonate solution (10 mL). The quenched reaction solution is extracted with dichloromethane (30 mL x 3), the combined organic phases are dried over anhydrous sodium sulfate, concentrated and rotary evaporated to obtain the target product INT-18 (90 mg, yield 84%). ESI-MS (m / z): 485.9 [M+H] + .

[0237] Intermediate 19

[0238] Intermediate 19 is prepared by the following steps:

[0239] First step: dissolve compound INT-19a (1 g, 5.65 mmol) in dichloromethane (20 mL), slowly add diethylamine sulfide (1.49 mL, 11.3 mmol) dropwise under ice bath at 0 °C, after the dropwise addition is completed, raise to room temperature and stir overnight, monitor the reaction completion of the starting material by LCMS, directly purify the reaction solution by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain colorless oily compound INT-19b (820 mg, yield 68.1%).

[0240] Second step: dissolve INT-19b (100 mg, 503 umol), INT-4b (134 mg, 503 umol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (36.8 mg, 50.3 umol), sodium carbonate (106.5 mg, 1.01 mmol) in a mixed solvent of 1,4-dioxane (3 mL) and water (0.3 mL), stir the reaction solution under nitrogen atmosphere at 80 °C overnight. After the reaction is completed, cool to room temperature, filter and concentrate the reaction solution to obtain a crude product, which is subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain yellow oily compound INT-19 (100 mg, yield 65.7%). ESI-MS (m / z): 303.3 [M+H] + .

[0241] Intermediate 20

[0242] Intermediate 20 is prepared by the following steps:

[0243] Step 1: Compound INT-20a (600 mg, 2.57 mol), compound INT-15d (286 mg, 2.83 mmol), potassium carbonate (1.07 g, 7.72 mmol), cuprous iodide (245.16 mg, 1.29 mol), N, N-dimethylethylenediamine (226.95 mg, 2.57 mol) were dissolved in 1, 4-dioxane (5 mL) under nitrogen protection, and the reaction solution was stirred at 120 °C for 24 hours. After the reaction was completed, it was cooled to room temperature, filtered through diatomite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain INT-20 (320 mg, yield 60%). ESI-MS (m / z): 206.7 [M+H] + .

[0244] Intermediate 21

[0245] Intermediate 21 was prepared by the following steps:

[0246] Step 1: Compound INT-21a (100 mg, 0.47 mmol), INT-4b (111.11 mg, 0.47 mmol), 1, 1-bis (diphenylphosphino) ferrocene palladium dichloride (15.27 mg, 21 umol), potassium carbonate (161.88 mg, 1.25 mmol) were dissolved in 1, 4-dioxane (3 mL) / water (0.3 mL) under nitrogen protection, and stirred at 90 °C overnight. After the reaction was completed, it was cooled to room temperature, filtered through diatomite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain INT-21b (40 mg, yield 27%). ESI-MS (m / z): 343.0 [M+H] + .

[0247] Step 2: Compound INT-21b (40 mg, 0.17 mmol), 4-dimethylaminopyridine (14.21 mg, 0.17 mmol) were dissolved in acetic anhydride (3 mL), and then the mixture was stirred at 60 °C for 3 hours. After the reaction was completed, it was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added to quench the reaction, and then extracted with dichloromethane (10 mL x 3). After the combined organic phases were dried, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to obtain compound INT-21c (42 mg, yield 93%). ESI-MS (m / z): 385.2 [M+H] + .

[0248] Step 3: Compound INT-21c (42 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and the solution was cooled to 0 °C in an ice water bath. Meta-chloroperoxybenzoic acid (37.62 mg, 0.22 mmol) was added, and the mixture was stirred at 0 °C for 4 h. After the reaction was completed, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was dried and concentrated under reduced pressure to give INT-21 (45 mg, 99% yield). ESI-MS (m / z): 417.0 [M+H] + .

[0249] Intermediate 22

[0250] Intermediate 22 was prepared by the following steps:

[0251] Step 1: Compound INT-22a (300 mg, 1.2 mmol) was dissolved in N,N- dimethylformamide (5 mL), followed by the addition of tert-butyldimethylsilyl chloride (200 mg, 1.33 mmol) and imidazole (246 mg, 3.61 mmol) sequentially. The reaction mixture was stirred at room temperature for 6 h. After the reaction was completed, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (20 mL), and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-22b (300 mg, 69% yield) as a white solid. ESI-MS (m / z): 364.1 [M+H] + .

[0252] Step 2: Compound INT-22b (300 mg, 826 umol) and INT-15d (92 mg, 908 umol) were dissolved in 1,4-dioxane (5 mL), followed by the addition of cuprous iodide (16 mg, 83 umol), N,N-dimethylethylenediamine (8 mg, 83 umol), and potassium phosphate (351 mg, 1.65 mol) sequentially. The reaction mixture was stirred at 120 °C under a nitrogen atmosphere for 12 h. After the reaction was completed, the reaction was cooled to room temperature, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-22 (245 mg, 88% yield). ESI-MS (m / z): 337.4 [M+H] + .

[0253] Intermediate 23

[0254] Intermediate 23 was prepared by the following steps:

[0255] Step 1: Dissolve INT-23b (500 mg, 1.33 mmol), INT-23a (319.82 mg, 1.72 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (96.97 mg, 132.53 umol), sodium carbonate (280.93 mg, 2.65 mmol) in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL), the reaction solution was stirred at 90 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (50 mL), filtered and concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain the target compound INT-23 (380 mg, yield 71%). ESI-MS (m / z): 401.4 [M+H] + .

[0256] Intermediate 24

[0257] Intermediate 24 was prepared by the following steps:

[0258] Step 1: Dissolve compound INT-24a (700 mg, 3.51 mol), compound INT-12c (765 mg, 3.51 mmol), potassium carbonate (1.45 g, 10.49 mmol), cuprous iodide (332 mg, 1.75 mol), N,N'-dimethylethylenediamine (154 mg, 1.57 mol) in 1,4-dioxane (5 mL), protect it under nitrogen, and stir the reaction solution at 120 °C for 24 hours. After the reaction was completed, it was cooled to room temperature, filtered through diatomite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain INT-24b (900 mg, yield 88%). ESI-MS (m / z): 291.9 [M+H] + .

[0259] Step 2: Dissolve compound INT-24b (170 mg, 0.58 mol), potassium carbonate (0.24 g, 1.75 mmol) in dichloromethane (5 mL), then reduce the temperature of the reaction system to 0 °C, and add benzyl chloroformate (0.15 g, 0.875 mol), finally stir the reaction system at room temperature overnight. After the reaction was completed, add saturated sodium bicarbonate solution (5 mL) to quench the reaction, extract with dichloromethane, dry and concentrate the organic phase to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 4) to obtain the target product INT-24c (230 mg, yield 92%). ESI-MS (m / z): 426.2 [M+H] +.

[0260] Step 3: Compound INT-24c (200 mg, 0.54 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phase was dried, concentrated, and the residue was purified by preparative chromatography to obtain compound INT-24d (175 mg, yield 99%) as a white solid. ESI-MS (m / z): 326.4 [M+H] + .

[0261] Step 4: Compound INT-24d (175 mg, 0.54 mmol), N,N-diisopropylethylamine (208 mg, 1.61 mmol), acetic anhydride (82 mg, 0.86 mmol) were dissolved in dichloromethane (2 mL), the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phase was dried, concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain the target product INT-24e (120 mg, yield 60%). ESI-MS (m / z): 368.5 [M+H] + .

[0262] Step 5: Compound INT-24e (120 mg, 0.32 mmol) was dissolved in methanol (2 mL), then palladium on carbon (43.45 mg, 0.41 mmol) was added, and finally the reaction system was stirred in hydrogen overnight. After the reaction was completed, the reaction solution was filtered through diatomite, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain INT-24 (180 mg, yield 94%). ESI-MS (m / z): 233.4 [M+H] + .

[0263] Intermediate 25

[0264] Intermediate 25 was prepared by the following steps:

[0265] Step 1 : Compound INT-25a (548.53 mg, 2.74 mmol), INT-12c (600.00 mg, 2.74 mmol), N, N-dimethylethylenediamine (24.15 mg, 0.27 mmol), cesium fluoride (1.04 g, 6.85 mmol), cuprous iodide (52.17 mg, 0.27 mmol) were dissolved in tetrahydrofuran (10 mL), the reaction was stirred at 60 °C for 12 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, the reaction was filtered, the filtrate was concentrated to obtain a crude product, and column chromatography (dichloromethane / methanol = 10 / 1) was used to obtain the target compound INT-25 (650.00 mg, yield 81.44%). ESI-MS (m / z): 236.6 [M+H-56] + .

[0266] Intermediate 26

[0267] Intermediate 26 was prepared by the following steps:

[0268] Step 1 : Compound INT-26a (700 mg, 2.61 mmol), INT-12c (571.32 mg, 2.61 mmol), cuprous iodide (49.68 mg, 0.26 mmol), 1,2-bis(methylamino)ethane (22.99 mg, 0.26 mmol), potassium carbonate (721.03 mg, 5.22 mmol) were dissolved in 1,4-dioxane (20 mL), stirred at 120 °C for 48 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, the reaction was filtered through diatomite, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain compound INT-26 (500 mg, yield 53%). ESI-MS (m / z): 360.6 [M+H] + .

[0269] Intermediate 27

[0270] Intermediate 27 was prepared by the following steps:

[0271] First step: dissolve INT-18a (1 g, 4.12 mmol), INT-27a (766.72 mg, 4.12 mmol) and potassium carbonate (568.94 mg, 4.12 mmol) in N,N-dimethylformamide (10 mL), stir at 70 degrees Celsius for 16 hours. After the reaction is completed, cool to room temperature, dilute the reaction solution with ethyl acetate (50 mL), then wash with saturated brine (50 mL x 3), dry the organic phase over anhydrous sodium sulfate, filter and concentrate to obtain a crude product, and the crude product is subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the target compound INT-27b (750 mg, yield 52%). ESI-MS (m / z): 348.2 [M+H] + .

[0272] Second step: dissolve INT-27b (600 mg, 1.72 mmol) in anhydrous tetrahydrofuran (10 mL), cool to -78 degrees Celsius, slowly drop n-butyllithium (0.75 mL, 1.90 mmol, 2.5 M) under nitrogen atmosphere, after half an hour, start to drop INT-18d (641.1 mg, 3.45 mmol), continue to stir at -78 degrees Celsius for 2 hours. After the reaction is completed, quench the reaction by adding saturated aqueous sodium chloride solution (10 mL), slowly rise to room temperature, extract the reaction solution with ethyl acetate (50 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain a crude product, and the crude product is subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the target compound INT-27c (600 mg, yield 88%). ESI-MS (m / z): 396.3 [M+H] + .

[0273] Third step: dissolve INT-27c (300 mg, 0.76 mmol), INT-14a (177.64 mg, 0.91 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (27.76 mg, 37.94 umol), sodium carbonate (160.97 mg, 1.52 mmol) in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL), stir the reaction solution at 80 degrees Celsius under nitrogen atmosphere for 16 hours. After the reaction is completed, cool the reaction solution to room temperature, dilute with ethyl acetate (50 mL), filter and concentrate to obtain a crude product, and the crude product is subjected to column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the target compound INT-27d (150 mg, yield 46%). ESI-MS (m / z): 428.4 [M+H] + .

[0274] Fourth Step: Dissolve INT-27d (150 mg, 0.35 mmol) in dichloromethane (2 mL), cool to 0 °C, and add meta-chloroperoxybenzoic acid (151.21 mg, 0.87 mmol) to the reaction mixture. Slowly raise the reaction mixture to room temperature and stir at room temperature for 4 hours. After the reaction is completed, quench the reaction with saturated aqueous sodium bicarbonate solution (10 mL). Extract the quenched reaction mixture with dichloromethane (30 mL x 3), dry the combined organic phase over anhydrous sodium sulfate, and concentrate in vacuo to give the target product INT-27 (150 mg, yield 93%). ESI-MS (m / z): 460.1 [M+H] + .

[0275] Intermediate 28

[0276] Intermediate 28 is prepared by the following steps:

[0277] First Step: Dissolve compound INT-28a (3 g, 18.3 mmol) and INT-28b (5 g, 23.8 mmol) in a mixture solvent of 1,4-dioxane (30 mL) and water (3 mL), then sequentially add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (670 mg, 914 umol) and sodium carbonate (3.9 g, 36.6 mmol), and stir the reaction mixture at 100 °C under a nitrogen atmosphere for 12 hours. After the reaction is completed, cool to room temperature, filter the reaction mixture through diatomite, concentrate the filtrate in vacuo, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound INT-28c (1.7 g, yield 56%) as a yellow oil. ESI-MS (m / z): 168.2 [M+H] + .

[0278] Second Step: Dissolve compound INT-28c (1.7 g, 10.4 mmol) in methanol (20 mL), then add palladium on carbon (2 g, 50%-60% water-wet paste), and stir the reaction mixture at room temperature under a hydrogen atmosphere for 16 hours. After the reaction is completed, filter the reaction mixture through diatomite, concentrate the filtrate in vacuo, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-28d (770 mg, yield 44%) as a white solid. ESI-MS (m / z): 170.0 [M+H] + .

[0279] Step 3: Compound INT-28d (430 mg, 2.54 mmol) was dissolved in N,N- dimethylformamide (5 mL), N-bromosuccinimide (678 mg, 3.81 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound INT-28e (501 mg, yield 80%) as a white solid. ESI-MS (m / z): 248.2 [M+H] + .

[0280] Step 4: Compound INT-28e (400 mg, 1.61 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), isopropyl alcohol pinacol borate (600 mg, 3.22 mmol) was added, and the reaction mixture was stirred at -78°C for 10 minutes. Subsequently, n-butyllithium (709 uL, 2.5 M in hexanes) was slowly added dropwise to the reaction mixture, and the reaction mixture was further stirred at -78°C for 2 hours. After the reaction was completed, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL), slowly warmed to room temperature, extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-28f (220 mg, yield 46%). ESI-MS (m / z): 296.4 [M+H] + .

[0281] Step 5: Compound INT-1a (95 mg, 415 umol) and INT-28f (147 mg, 498 umol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (0.3 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (31 mg, 42 umol) and N,N-diisopropylethylamine (108 mg, 830 umol) were sequentially added, and the reaction mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain compound INT-28g (20 mg, yield 13%). ESI-MS (m / z): 362.0 [M+H] + .

[0282] Step 6: INT-28g (20 mg, 55 umol) was dissolved in dichloromethane (3 mL), m-chloroperoxybenzoic acid (30 mg, 138 umol) was added to the reaction solution at 0 °C, and the reaction mixture was stirred at 0 °C for 8 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction, and ethyl acetate (20 mL x 3) was used for extraction. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound INT-28 (10 mg, yield 46%). ESI-MS (m / z): 393.8 [M+H] + .

[0283] Intermediate 29

[0284] Intermediate 29 was prepared by the following steps:

[0285] Step 1: Compound INT-29a (650 mg, 4.74 mmol) was dissolved in acetonitrile (10 mL), the temperature of the reaction system was reduced to 0 °C, then N-iodosuccinimide (1.12 g, 4.98 mmol) was dissolved in acetonitrile (10 mL) and slowly added to the reaction system, and finally stirred at 0 °C for 0.5 hours. After the reaction was completed, saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution were added to quench the reaction (10 mL), and ethyl acetate was used for extraction. The separated organic phase was combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 2) to obtain compound INT-29b (800 mg, yield 64%).

[0286] Step 2: Compound INT-29b (200 mg, 0.76 mol), compound INT-15d (115 mg, 1.14 mmol), potassium carbonate (315 mg, 2.28 mmol), cuprous iodide (72.39 mg, 0.38 mol), N, N'-dimethylethylenediamine (67.02 mg, 0.76 mol) were dissolved in 1, 4-dioxane (5 mL), and the reaction was stirred at 120 °C for 24 hours under nitrogen protection. After the reaction was completed, the reaction was cooled to room temperature, and the reaction was filtered through diatomite. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to obtain INT-29c (160 mg, yield 89%). ESI-MS (m / z): 237.6 [M+H] + .

[0287] Step 3: Compound INT-29c (80 mg, 0.39 mmol) was dissolved in dichloromethane (2 mL), the temperature of the reaction system was reduced to 0 °C, and then tert-butyldimethylsilyl chloride (76.55 mg, 0.51 mmol) was slowly added to the reaction system, and stirred at room temperature overnight. After the reaction was completed, it was extracted with ethyl acetate, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 4) to obtain yellow solid INT-29 (100 mg, yield 84%). ESI-MS (m / z): 351.4 [M+H] + .

[0288] Intermediate 30

[0289] Intermediate 30 was prepared by the following steps:

[0290] Step 1: Compound INT-4 (1.6 g, 5.57 mmol), 4-dimethylaminopyridine (680.73 mg, 5.57 mmol) were dissolved in acetic anhydride (3 mL), and stirred at 80 °C for 2 hours. After the reaction was completed, it was cooled to room temperature, concentrated, diluted with dichloromethane (100 mL), and the organic phase was washed with saturated aqueous sodium bicarbonate solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound INT-30 (1.1 g, yield 59%). ESI-MS (m / z): 329.0 [M+H] + .

[0291] Intermediate 31

[0292] Intermediate 31 was prepared by the following steps:

[0293] Step 1: Compound INT-4a (1 g, 5.45 mmol), INT-31a (3.09 g, 8.18 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (398.91 mg, 545.18 umol), sodium carbonate (1.73 g, 16.36 mmol) were dissolved in 1,4-dioxane (10 mL) / water (1 mL), protected by nitrogen, and stirred at 90 °C overnight. After the reaction was completed, it was cooled to room temperature, filtered through diatomite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain the target compound INT-31 (2.1 g, yield 96%). ESI-MS (m / z): 397.8 [M+H] + .

[0294] Intermediate 32

[0295] Intermediate 32 was prepared by the following steps:

[0296] Step 1: Compound INT-32a (300 mg, 1.08 mmol) and INT-15d (121 mg, 1.19 mmol) were dissolved in 1,4-dioxane (5 mL), and cuprous iodide (21 mg, 108 umol), N,N-dimethylethylenediamine (10 mg, 108 umol) and potassium phosphate (460 mg, 2.17 mol) were added successively. The reaction mixture was stirred at 120 °C under nitrogen atmosphere for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was filtered through diatomite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound INT-32 (130 mg, yield 48%). ESI-MS (m / z): 250.9 [M+H] + .

[0297] Intermediate 33

[0298] Intermediate 33 was prepared by the following steps:

[0299] Step 1: INT-33a (1.50 g, 6.52 mmol) was dissolved in a mixture of tetrahydrofuran (10 mL) and methanol (10 mL) at room temperature, and sodium borohydride (493.40 mg, 13.04 mmol) was then added. The reaction solution was stirred at room temperature under nitrogen protection for 4 hours. After the reaction was completed, water (40 mL) was added to quench the reaction, and ethyl acetate (30 mL x 3) was used for extraction. The organic phase was dried and concentrated to obtain INT-33b (1.50 g, yield 99.13%), ESI-MS (m / z): 231.8 [M+H] + .

[0300] Step 2: INT-33b (1.00 g, 4.31 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (344.78 mg, 8.62 mmol, purity 60%) was added at 0 °C under nitrogen protection. The reaction solution was stirred at 0 °C under nitrogen protection for 0.5 hours. Then, iodomethane (3.06 g, 21.55 mmol) was added to the above reaction solution, and the reaction solution was stirred at room temperature under nitrogen protection for 12 hours. After the reaction was completed, water (40 mL) was added to quench the reaction, and ethyl acetate (40 mL x 3) was used for extraction. The organic phase was dried and concentrated to obtain INT-33c (850 mg, yield 80.15%).

[0301] Step 3: Dissolve INT-33c (400.00 mg, 1.63 mmol), INT-15d (493.07 mg, 4.88 mmol), cuprous iodide (30.96 mg, 0.16 mmol), N,N-dimethylethylenediamine (14.33 mg, 0.16 mmol), potassium carbonate (449.36 mg, 3.25 mmol) in 1,4-dioxane (10 mL), and stir the reaction solution at 110 °C for 12 hours under nitrogen protection. After the reaction is completed, filter the reaction solution, and concentrate the filtrate to obtain a crude product. Subject the crude product to column chromatography (dichloromethane / methanol = 10 / 1) to obtain the target product INT-33d (350.00 mg, in a yield of 80.86%).

[0302] Step 4: Dissolve INT-33d (250.00 mg, 0.94 mmol), reduced iron powder (262.21 mg, 4.69 mmol), ammonium chloride (251.13 mg, 4.69 mmol) in a mixed solution of ethanol (10 mL) and water (2 mL), and stir the reaction solution at 80 °C for 12 hours under nitrogen protection. After the reaction is completed, filter the reaction solution, and concentrate the filtrate to obtain a crude product. Subject the crude product to column chromatography (dichloromethane / methanol = 10 / 1) to obtain the target product INT-33 (180 mg, in a yield of 81.14%). ESI-MS (m / z): 237.2 [M+H] + .

[0303] Intermediate 34

[0304] Intermediate 34 is prepared by the following steps:

[0305] Step 1: Dissolve INT-18a (0.5 g, 2.06 mmol), INT-34a (383.36 mg, 2.06 mmol), and potassium carbonate (284.48 mg, 2.06 mmol) in N,N-dimethylformamide (10 mL), and stir the reaction solution at 70 °C for 16 hours. After the reaction is completed, cool to room temperature, dilute the reaction solution with ethyl acetate (50 mL), wash with saturated brine (50 mL x 3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. Subject the crude product to column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the target compound INT-34b (480 mg, in a yield of 66%). ESI-MS (m / z): 348.2 [M+H] + .

[0306] Second step: dissolve INT-34b (430 mg, 1.23 mmol) in anhydrous tetrahydrofuran (10 mL), cool to 0 °C, slowly drop isopropyl magnesium chloride (1.85 mL, 2 mol / L in THF) under nitrogen atmosphere, after half an hour, start to drop 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (641.1 mg, 3.45 mmol), continue to stir at 0 °C for 1 hour, slowly rise to room temperature and continue to react for 16 hours. After the reaction is completed, quench the reaction by adding saturated aqueous ammonium chloride solution (10 mL), slowly rise to room temperature, extract the reaction liquid with ethyl acetate (50 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain a crude product, which is subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the target compound INT-34c (200 mg, yield 40%). ESI-MS (m / z): 396.1 [M+H] + .

[0307] Third step: dissolve INT-34c (200 mg, 0.51 mmol), INT-14a (118.43 mg, 0.61 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (18.51 mg, 25.3 μmol), sodium carbonate (107.24 mg, 1.01 mmol) in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL), stir the reaction liquid at 90 °C under nitrogen atmosphere for 16 hours. After the reaction is completed, cool the reaction liquid to room temperature, dilute with ethyl acetate (50 mL), filter and concentrate to obtain a crude product, which is subjected to column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the target compound INT-34d (150 mg, yield 69%). ESI-MS (m / z): 428.1 [M+H] + .

[0308] Fourth step: dissolve INT-34d (150 mg, 0.35 mmol) in dichloromethane (2 mL), cool to 0 °C, add meta-chloroperoxybenzoic acid (151.21 mg, 0.87 mmol) to the above reaction liquid, slowly rise to room temperature, and stir at room temperature for 4 hours. After the reaction is completed, quench the reaction by adding saturated aqueous sodium bicarbonate solution (10 mL). Extract the quenched reaction liquid with dichloromethane (30 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate and dry to obtain the target product INT-34 (150 mg, yield 93%). ESI-MS (m / z): 460.0 [M+H] + .

[0309] Intermediate 35

[0310] Intermediate 35 was prepared from the following steps:

[0311] Step 1: INT-18a (0.5 g, 2.06 mmol), INT-35a (383.36 mg, 2.06 mmol) and potassium carbonate (284.48 mg, 2.06 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 70 °C for 16 hours. After the reaction was completed, it was cooled to room temperature and diluted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the target compound INT-35b (500 mg, yield 69%). ESI-MS (m / z): 347.9 [M+H] + .

[0312] Step 2: INT-35b (490 mg, 1.41 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and cooled to 0 °C. Isopropylmagnesium chloride (2.11 mL, 2 mol / L in THF) was slowly added dropwise under a nitrogen atmosphere. After half an hour, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (666.93 mg, 4.22 mmol) was added dropwise. The reaction was continued to stir at 0 °C for 1 hour and then slowly warmed to room temperature and continued to react for 16 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction. The reaction was slowly warmed to room temperature and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the target compound INT-35c (100 mg, yield 17%). ESI-MS (m / z): 396.3 [M+H] + .

[0313] Step 3: INT-35c (100 mg, 0.25 mmol), INT-14a (59.21 mg, 0.30 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (9.25 mg, 12.65 μmol) and sodium carbonate (53.62 mg, 0.51 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL). The reaction was stirred at 90 °C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the target compound INT-35d (80 mg, yield 73%). ESI-MS (m / z): 427.8 [M+H]+ .

[0314] Fourth Step: Dissolve INT-35d (80 mg, 0.19 mmol) in dichloromethane (2 mL), cool to 0 °C, add m-chloroperoxybenzoic acid (80.65 mg, 0.47 mmol) to the reaction mixture, slowly raise the temperature to room temperature, and stir at room temperature for 4 hours. After the reaction is completed, quench the reaction with saturated aqueous sodium bicarbonate solution (10 mL). Extract the quenched reaction mixture with dichloromethane (20 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to dryness to obtain the target product INT-35 (80 mg, yield 93%). ESI-MS (m / z): 459.7 [M+H] + .

[0315] Intermediate 36

[0316] Intermediate 36 is prepared by the following steps:

[0317] First Step: Dissolve compound INT-36a (1.0 g, 4.12 mmol) and compound INT-18b (874 mg, 4.12 mmol) in N,N-dimethylformamide (10 mL), then add potassium carbonate (1.14 g, 8.23 mmol), and stir the reaction mixture at 70 °C for 12 hours. After the reaction is completed, cool the reaction mixture to room temperature, dilute with saturated brine (50 mL), extract with ethyl acetate (30 mL x 3), combine the organic phases, dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound INT-36b (374 mg, yield 24%). ESI-MS (m / z): 373.9 [M+H] + .

[0318] Second Step: Dissolve compound INT-36a (189 mg, 505 μmol) in anhydrous tetrahydrofuran (5 mL), then slowly add n-butyllithium (606 μL, 2.5 mol / L in hexanes) dropwise under a nitrogen atmosphere, stir the reaction mixture at -78 °C for 30 minutes, then add isopropyl pinacol borate (282 mg, 1.51 mmol), and continue to stir the reaction mixture at -78 °C for 2 hours. After the reaction is completed, quench the reaction with saturated aqueous ammonium chloride solution (20 mL), extract with ethyl acetate (20 mL x 3), combine the organic phases, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude compound INT-36b (122 mg, yield 71%). ESI-MS (m / z): 340.3 [M+H] + .

[0319] Step 3: Compound INT-36b (108 mg, 318 pmol) and INT-4a (76 mg, 414 pmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (0.3 mL), then [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (23 mg, 32 pmol) and sodium carbonate (67 mg, 637 pmol) were added successively, and the reaction mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the reaction solution was filtered through diatomite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-36 (77 mg, yield 55%). ESI-MS (m / z): 442.0 [M+H] + .

[0320] Intermediate 37

[0321] Intermediate 37 was prepared by the following steps:

[0322] Step 1: Compound INT-37a (500 mg, 2.11 mmol) and INT-15d (213.29 mg, 2.11 mmol) were dissolved in 1,4-dioxane (6 mL), and cuprous iodide (40.18 mg, 210.96 pmol), N,N-dimethylethylenediamine (18.6 mg, 210.96 pmol) and potassium phosphate (895.59 mg, 4.22 mol) were added successively, and the reaction mixture was stirred at 120 °C for 12 h under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the reaction solution was filtered through diatomite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound INT-37b (362 mg, yield 81%).

[0323] Step 2: INT-37b (250 mg, 1.19 mmol) was dissolved in formic acid (1 mL) and stirred at 100 °C for 1 h. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure to obtain an oil, which was slurried with petroleum ether / ethyl acetate (10 / 1), suction filtered and dried to obtain white solid INT-37 (250 mg, yield 87%). ESI-MS (m / z): 239.3 [M+H] + .

[0324] Intermediate 38

[0325] Intermediate 38 was prepared by the following steps:

[0326] Step 1: Compound INT-38a (500 mg, 2.15 mmol) and INT-15d (282 mg, 2.79 mmol) were dissolved in 1,4-dioxane (5 mL), and cuprous iodide (41 mg, 215 μmol), N,N-dimethylethylenediamine (19 mg, 215 μmol) and potassium phosphate (911 mg, 4.29 mmol) were added successively. The reaction mixture was stirred at 120 °C under nitrogen atmosphere for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction solution was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound INT-38b (440 mg, yield 99%). ESI-MS (m / z): 207.2 [M+H] + .

[0327] Step 2: INT-38b (200 mg, 970 μmol) was dissolved in 5 mL of formic acid and stirred at 100 °C for 1 h. After the reaction was completed, it was concentrated under reduced pressure to obtain an oil. The oil was slurried with petroleum ether / ethyl acetate (10 / 1), suction filtered, and dried to obtain compound INT-38c (227 mg, yield 99%). ESI-MS (m / z): 235.2 [M+H] + .

[0328] Step 3: Sodium hydride (42 mg, 1.06 mmol) was dissolved in N,N-dimethylformamide (5 mL), and the temperature of the reaction solution was reduced to 0 °C. INT-36c (227 mg, 970 μmol) was added, and the reaction mixture was stirred at 0 °C for 30 min. Then, INT-17f (364 mg, 881 μmol) was added, and the reaction solution was stirred at 0 °C for 12 h. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (30 mL x 3), and dried with anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-38d (450 mg, yield 95%). ESI-MS (m / z): 539.9 [M+H] + .

[0329] Fourth step: Compound INT-38d (450 mg, 834 pmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (476 mg, 4.17 mmol) was added. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound INT-38 (310 mg, yield 89%). ESI-MS (m / z): 418.7 [M+H] + .

[0330] Intermediate 39

[0331] Intermediate 39 was prepared by the following steps:

[0332] First step: INT-39a (23.00 g, 60.97 mmol) was dissolved in tetrahydrofuran (230 mL), lithium diisopropylamide (2 M, 38.11 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection and at -78 °C, and the reaction was carried out at -78 °C for 0.5 hours. Then, hexachloroethane (28.87 g, 121.94 mmol) was dissolved in tetrahydrofuran (50 mL) and added dropwise to the above reaction solution at -78 °C, and the reaction was stirred at -78 °C for 2 hours. After the reaction was completed, saturated ammonium chloride solution (80 mL) was added to quench, and ethyl acetate (400 mL) was extracted. The organic phase was dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound INT-39b (22.00 g, yield 87.65%).

[0333] Second Step: Dissolve INT-39b (22.00 g, 53.44 mmol) in tetrahydrofuran (220 mL), add isopropylmagnesium chloride (2 M, 61.46 mL, tetrahydrofuran solution) drop by drop under nitrogen protection and at 0 °C, and react the reaction solution at 0 °C for 0.5 h. Then, add 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25.33 g, 160.32 mmol) to the above reaction solution at 0 °C, and stir the reaction solution at 0 °C for 2 h. After the reaction is completed, quench the reaction by adding saturated aqueous ammonium chloride solution (100 mL) at 0 °C, extract with ethyl acetate (400 mL), dry the organic phase, and concentrate to obtain a crude product. Subject the crude product to column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound INT-39c (21.00 g, yield 95.44%). ESI-MS (m / z): 411.8 [M+H] + .

[0334] Third Step: Dissolve INT-39c (20.00 g, 48.58 mmol), INT-14a (11.37 g, 58.29 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (1.78 g, 2.43 mmol), and sodium carbonate (10.30 g, 97.15 mmol) in a mixed solution of 1,4-dioxane (200 mL) and water (10 mL), stir the reaction solution at 90 °C under nitrogen protection for 12 h. After the reaction is completed, cool to room temperature, filter the reaction solution, concentrate to obtain a crude product, and subject the crude product to column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound INT-39d (15.60 g, yield 72.27%). ESI-MS (m / z): 444.1 [M+H] + .

[0335] Fourth Step: Dissolve INT-39d (15.00 g, 33.76 mmol) in dichloromethane (150 mL), add meta-chloroperoxybenzoic acid (15.76 g, 77.64 mmol, purity 85%) at 0 °C under air atmosphere, and stir the reaction solution at 0 °C for 4 h. After the reaction is completed, quench the reaction by adding saturated aqueous sodium bicarbonate solution (10 mL) and aqueous sodium thiosulfate solution (100 mL), extract with dichloromethane (350 mL), dry the organic phase, and concentrate to obtain a crude product. Subject the crude product to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the target compound INT-39 (15.30 g, yield 95.15%). ESI-MS (m / z): 477.7 [M+H] + .

[0336] Intermediate 40

[0337] Intermediate 40 was prepared from the following steps:

[0338] Step 1: Compound INT-40a (500 mg, 2.11 mmol) and INT-15d (234.62 mg, 2.32 mmol) were dissolved in 1,4-dioxane (6 mL), cuprous iodide (401.77 mg, 2.11 mmol), N,N-dimethylethylenediamine (185.96 mg, 2.11 mmol) and potassium carbonate (874.7 mg, 6.33 mol) were added successively, and the reaction mixture was stirred at 120 °C under nitrogen atmosphere for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was filtered through diatomite, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound INT-40b (312 mg, yield 70%). ESI-MS (m / z): 211.6 [M+H] + .

[0339] Step 2: INT-40b (200 mg, 0.95 mmol) was dissolved in formic acid (1 mL) and stirred at 100 °C for 1 hour. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure to obtain an oil, which was slurried with petroleum ether / ethyl acetate (10 / 1), suction filtered and dried to obtain white solid INT-40 (200 mg, yield 88%). ESI-MS (m / z): 239.2 [M+H] + .

[0340] The synthesis method of the compound of the example in the present application is as follows:

[0341] Example 1

[0342] 4-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0343] Example 1 was prepared from the following steps:

[0344] Compound INT-1 (60 mg, 0.16 mmol) and INT-2b (47.8 mg, 0.24 mmol) were dissolved in 2,2,2-trifluoroethanol (2 mL), and one drop of trifluoroacetic acid was added. The reaction mixture was reacted under microwave irradiation at 100 °C for 2 hours. After the reaction was completed, the filtrate was concentrated, and the crude product was purified by preparative liquid chromatography to obtain compound 1 (29.68 mg, yield 37%) as a white solid. ESI-MS (m / z): 477.4 [M+H] + .

[0345] 1 H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.76 (s, 1H), 8.29 (s, 1H), 8.01 (s, 1H), 7.81 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.9 Hz, 2H), 4.81 (s, 1H), 4.20 (s, 2H), 4.14 (s, 2H), 4.02 - 3.94 (m, 2H), 3.76 - 3.67 (m, 2H), 1.09 (s, 6H).

[0346] Example 2

[0347] 4-(4-((4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0348] Example 2 was prepared from the following steps:

[0349] First step: INT-1a (400 mg, 1.75 mmol), 2a (483 mg, 1.75 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (128 mg, 0.17 mmol), sodium carbonate (370.88 mg, 3.50 mmol) were dissolved in a mixed solution of 1,4-dioxane (10 mL) and water (1 mL), and the reaction solution was stirred at 80 °C for 6 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated and dried, and column chromatography (petroleum ether / ethyl acetate = 3 / 1) was performed to obtain the target product 2b (400.00 mg, yield 66.80%). ESI-MS (m / z): 343.7 [M+H] + .

[0350] Second Step: 2b (330 mg, 0.96 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (489.37 mg, 2.41 mmol) was added to the above reaction solution. The reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, the above reaction solution was extracted with saturated sodium thiosulfate and saturated sodium bicarbonate solution. The organic phase was dried and concentrated to obtain the target compound 2c (320 mg, yield 88.68%). ESI-MS (m / z): 392.7 [M+H] + .

[0351] Third Step: 2c (100.00 mg, 0.27 mmol), INT-2b (61.63 mg, 0.32 mmol), trifluoroacetic acid (30.47 mg, 0.27 mmol) were dissolved in 1,4-dioxane (5 mL) to obtain a solution, and the reaction solution was stirred at 100 degrees Celsius for four hours. After the reaction was completed, the reaction solution was concentrated and rotary evaporated, and the target compound 2 (18 mg, yield 13.85%) was obtained by reverse phase column chromatography. ESI-MS (m / z): 487.2 [M+H] + .

[0352] 1 H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.80 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 7.80 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 9.0 Hz, 2H), 5.34 (q, J = 9.0 Hz, 2H), 4.20 (s, 2H), 4.01 - 3.96 (m, 2H), 3.75 - 3.71 (m, 2H).

[0353] Example 3

[0354] 4-(4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0355] Example 3 was prepared by the following steps:

[0356] A solution of INT-3 (80 mg, 0.21 mmol), INT-2b (49.03 mg, 0.26 mmol), trifluoroacetic acid (24.24 mg, 0.21 mmol) in 1,4-dioxane (5 mL) was stirred at 100 °C for 4 h. After the reaction was completed, the reaction mixture was concentrated and dried, and the target compound 3 (23 mg, yield 14.45%) was obtained by reverse phase column chromatography. ESI-MS (m / z): 489.3 [M+H] + .

[0357] 1 H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.76 (s, 1H), 8.33 (s, 1H), 8.04 (s, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 8.9 Hz, 2H), 4.63-4.57 (m, 1H), 4.20 (s, 2H), 4.01-3.97 (m, 4H), 3.73-3.71 (m, 2H), 3.52-3.44 (m, 2H), 2.00-1.95 (m, 4H).

[0358] Example 4

[0359] 4-(4-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0360] Example 4 was prepared by the following steps:

[0361] First step: Compound INT-2 (150 mg, 0.40 mmol) and 4a (228 mg, 0.60 mmol) were dissolved in a mixed solution of 1,4-dioxane (5 mL) and water (0.5 mL), and 1,1'-bis (di-cyclohexylphosphino) ferrocene palladium dichloride (31 mg, 0.04 mmol) and cesium carbonate (162 mg, 0.80 mmol) were added in turn. The reaction mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. After the reaction was completed, the reaction mixture was filtered with celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 4b (140 mg, yield 59%). ESI-MS (m / z): 588.5 [M+H] + .

[0362] Step 2: Compound 4b (140 mg, 0.24 mmol) was dissolved in hydrochloric acid in dioxane (2 mL). The reaction mixture was stirred in an ice water bath for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative chromatography to obtain compound 4 (8 mg, yield 7%). ESI-MS (m / z): 488.6 [M+H] + .

[0363] 1 H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.75 (s, 1H), 8.28 (s, 1H), 8.02 (s, 1H), 7.82 - 7.75 (m, 2H), 7.39 - 7.32 (m, 2H), 4.41 - 4.33 (m, 1H), 4.20 (s, 2H), 3.98 (dd, J = 6.0, 4.1 Hz, 2H), 3.75 - 3.69 (m, 2H), 3.08 - 3.01 (m, 2H), 2.65 - 2.55 (m, 2H), 1.99 - 1.92 (m, 2H), 1.86 - 1.76 (m, 2H).

[0364] Example 5

[0365] 4-(4-((6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)morpholin-3-one

[0366] Example 5 was prepared from the following steps:

[0367] Compound 4 (60 mg, 0.12 mmol) was dissolved in methanol (2 mL), and formaldehyde (11 mg, 0.37 mmol) was added to the reaction. The reaction mixture was stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (52 mg, 0.24 mmol) was added to the reaction. The reaction mixture was continuously stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with saturated aqueous ammonium chloride solution (5 mL) and extracted with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative chromatography to obtain compound 5 (3 mg, yield 5%). ESI-MS (m / z): 502.1 [M+H] + .

[0368] 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.75 (s, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 7.85 - 7.76 (m, 2H), 7.42 - 7.33 (m, 2H), 4.33 - 4.27 (m, 1H), 4.20 (s, 2H), 4.04 - 3.94 (m, 2H), 3.78 - 3.69 (m, 2H), 2.90 - 2.83 (m, 2H), 2.20 (s, 3H), 2.10 - 1.96 (m, 6H).

[0369] Example 6

[0370] 4-(4-((5-chloro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0371] Example 6 was prepared by the following steps:

[0372] Compound INT-4 (27 mg, 94 umol), INT-2b (27 mg, 121 umol), tris(dibenzylideneacetone)dipalladium(0) (8.6 mg, 9.4 umol), potassium phosphate (60 mg, 282 umol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (5.4 mg, 9.4 umol) were dissolved in 1,4-dioxane (3 mL) / water (0.3 mL), protected by nitrogen, stirred at 110 °C overnight, after the reaction was completed, the reaction solution was filtered through diatomite, the residue was purified by preparative chromatography to obtain compound 6 (15 mg, yield 36%). ESI-MS (m / z): 443.3 [M+H] + .

[0373] 1 H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.56 (s, 1H), 8.52 (s, 1H), 8.23 (s, 1H), 7.82 - 7.76 (m, 2H), 7.35 - 7.29 (m, 2H), 4.82 (s, 1H), 4.19 (s, 2H), 4.14 (s, 2H), 3.97 (dd, J = 6.0, 4.1 Hz, 2H), 3.71 (dd, J = 5.9, 4.2 Hz, 2H), 1.10 (s, 6H).

[0374] Example 7

[0375] 4-(4-((5-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0376] Example 7 was prepared from the following steps:

[0377] Compound INT-5 (30 mg, 101 umol), INT-2b (29 mg, 150 umol), tris(dibenzylideneacetone)dipalladium(0) (9.2 mg, 10.1 umol), potassium phosphate (64 mg, 300 umol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (5.8 mg, 10.1 umol) were dissolved in 1,4-dioxane (3 mL) / water (0.3 mL), protected by nitrogen, stirred at 110 °C overnight, after the reaction was completed, the reaction solution was filtered through diatomite, the residue was purified by preparative chromatography to obtain compound 7 (8 mg, yield 18%). ESI-MS (m / z): 455.1 [M+H] + .

[0378] 1 H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.63 (s, 1H), 8.52 (s, 1H), 8.27 (s, 1H), 7.81-7.74 (m, 2H), 7.35-7.30 (m, 2H), 4.59 (ddd, J = 15.7, 9.0, 7.1 Hz, 1H), 4.19 (s, 2H), 3.99 (ddd, J = 12.9, 6.3, 3.7 Hz, 4H), 3.73-3.69 (m, 2H), 3.51-3.43 (m, 2H), 2.02 (td, J = 9.0, 7.8, 3.9 Hz, 4H).

[0379] Example 8

[0380] 2-((4-(3-oxomorpholino)phenyl)amino)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile

[0381] Example 8 was prepared from the following steps:

[0382] Sodium hydride (11 mg, 270 umol) was dissolved in a solution of N,N,-dimethylformamide (2 mL), the temperature of the reaction was reduced to 0 °C and INT-7 (25 mg, 116 umol) was added, maintained at 0 °C and stirred for one hour, finally INT-6 (30 mg, 90 umol) was added, the reaction was stirred at room temperature overnight. After the end of the reaction, the reaction was concentrated and dried and chromatographed on a reverse phase column to the target compound 8 (4 mg, yield 10%). ESI-MS (m / z): 445.3 [M+H] +

[0383] 1 H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.86 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.63 (p, J = 8.4 Hz, 1H), 4.20 (s, 2H), 4.02 - 3.96 (m, 4H), 3.73 (dd, J = 6.0, 4.2 Hz, 2H), 3.48 (td, J = 11.5, 4.9 Hz, 2H), 2.01 (td, J = 10.9, 9.6, 3.9 Hz, 4H).

[0384] Example 9 and Example 10

[0385] 4-(4-((4-(1-(2-chloro-4-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one and

[0386] 4-(4-((4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0387] Example 9 and Example 10 were prepared from the following steps:

[0388] First step: Dissolve INT-8 (150 mg, 0.37 mmol), 9a (58.82 mg, 0.37 mmol), potassium phosphate (157.49 mg, 0.74 mmol) in dimethyl sulfoxide (5 mL), the reaction solution is stirred at 100 degrees Celsius for 12 hours. After the reaction is completed, add water to quench the reaction and extract with ethyl acetate. The organic phase is dried and concentrated to obtain the crude product, which is subjected to column chromatography (dichloromethane / methanol = 20 / 1) to obtain the target compound 9b (170 mg, yield 84.41%). ESI-MS (m / z): 542.4 [M+H] + .

[0389] Second step: Dissolve 9b (50 mg, 0.09 mmol), methylamine hydrochloride (12.44 mg, 0.18 mmol) in 1,2-dichloroethane (3 mL), the reaction solution is stirred at room temperature for 1 hour. Then add sodium triacetoxyborohydride (29.28 mg, 0.14 mmol) to the above reaction solution, and stir the reaction solution at room temperature for 12 hours. After the reaction is completed, add saturated sodium bicarbonate solution to quench the reaction and extract with dichloromethane, dry and concentrate the organic phase to obtain the crude product, which is subjected to reverse phase column chromatography (acid method) to obtain the target products 9 (20 mg, yield 38.92%) and 10 (5 mg, yield 9.96%). 9: ESI-MS (m / z): 544.7 [M+H] + ; 10: ESI-MS (m / z): 557.8 [M+H] + .

[0390] 9: 1 H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.83 (s, 1H), 8.61 (s, 1H), 8.26 (s, 1H), 7.84-7.78 (m, 2H), 7.70-7.64 (m, 2H), 7.48 (dd, J = 8.2, 1.8 Hz, 1H), 7.39-7.34 (m, 2H), 5.51 (s, 1H), 4.62-4.59 (m, 2H), 4.20 (s, 2H), 3.98-3.96 (m, 2H), 3.73-3.71 (m, 2H).

[0391] 10: 1H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.83 (s, 1H), 8.61 (s, 1H), 8.26-8.25 (m, 1H), 7.84-7.79 (m, 2H), 7.71-7.65 (m, 2H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H), 7.38-7.35 (m, 2H), 4.20 (s, 2H), 4.00-3.96 (m, 2H), 3.78 (s, 2H), 3.74-3.70 (m, 2H), 2.32 (s, 3H).

[0392] Example 11

[0393] 2-(4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1,2-thiazinane 1,1-dioxide

[0394] Example 11 was prepared by the following steps:

[0395] First step: dissolve 11a (500 mg, 3.70 mmol) in N,N-dimethylformamide (10 mL), replace nitrogen, and then add sodium hydride (192.33 mg, 4.81 mmol) at 0°C. Stir the reaction solution at 0°C for half an hour. Then add 11b (521.88 mg, 3.70 mmol) to the above reaction solution, and stir the reaction solution at room temperature for 12 hours under a nitrogen atmosphere. After the reaction is completed, extract with ethyl acetate, dry the organic phase, concentrate, and perform column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target product 11c (750 mg, yield 79.12%).

[0396] Second step: dissolve 11c (300 mg, 1.17 mmol) and Raney nickel (100 mg, 1.71 mmol) in methanol (10 mL), and stir the reaction solution under a hydrogen atmosphere for 12 hours. After the reaction is completed, filter and concentrate the reaction solution to obtain the target product 11d (260 mg, yield 98.15%). ESI-MS (m / z): 227.3 [M+H] + .

[0397] Step 3: Compound 11d (40 mg, 0.11 mmol), INT-3 (24.05 mg, 0.11 mmol), trifluoroacetic acid (12.12 mg, 0.11 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction was stirred at 100 °C for 12 h. After the reaction was completed, the reaction was concentrated and dried, and the target product 11 (15 mg, yield 26.91%) was obtained by reverse phase column chromatography. ESI-MS (m / z): 523.6 [M+H] + .

[0398] 1 H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.76 (s, 1H), 8.33 (s, 1H), 8.05 (s, 1H), 7.78 (d, J = 10.0 Hz, 2H), 7.31 (d, J = 10.0, 2H), 4.63-4.57 (m, 1H), 4.01-3.97 (m, 2H), 3.63–3.61 (m, 2H), 3.51–3.45 (m, 2H), 3.30–3.27 (m, 2H), 2.18-2.13 (m, 2H), 2.02-1.98 (m, 4H), 1.85–1.79 (m, 2H).

[0399] Example 12

[0400] 1-(4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)imidazolidin-2-one

[0401] Example 12 was prepared by the following steps:

[0402] Step 1: Compound INT-12c (500 mg, 2.28 mmol) and 12a (590 mg, 6.85 mmol) were dissolved in 1,4-dioxane (8 mL), and cuprous iodide (44 mg, 0.23 mmol), potassium phosphate (970 mg, 4.57 mmol) and N,N-dimethylethylenediamine (20 mg, 0.23 mmol) were added in turn. The reaction mixture was stirred at 120 °C for 48 h under a nitrogen atmosphere. After the reaction was completed, the reaction was filtered with diatomite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 12b (283 mg, yield 70%). ESI-MS (m / z): 178.2 [M+H] + .

[0403] Second Step: Compound 12b (20 mg, 0.11 mmol) and compound INT-3 (30 mg, 0.08 mmol) were dissolved in isopropanol (2 mL), trifluoroacetic acid (1 mg, 0.01 mmol) was added. The reaction mixture was stirred under microwave condition at 100 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by preparative chromatography to give compound 12 (28 mg, yield 75%) as a yellow solid. ESI-MS (m / z): 474.4 [M+H] + .

[0404] 1 H NMR (500 MHz, DMSO-d6) d 10.05 (s, 1H), 8.70 (s, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 6.88 (s, 1H), 4.64 - 4.55 (m, 1H), 4.02 - 3.94 (m, 2H), 3.88 - 3.80 (m, 2H), 3.51 - 3.44 (m, 2H), 3.42 - 3.38 (m, 2H), 2.05 - 1.94 (m, 4H).

[0405] Example 13

[0406] 6,6-dimethyl-4-(4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0407] Example 13 was prepared from the following steps:

[0408] First Step: Compound INT-12c (300 mg, 1.37 mmol) and 13a (266 mg, 2.05 mmol) were dissolved in 1,4-dioxane (5 mL), cuprous iodide (26 mg, 0.14 mmol), potassium phosphate (582 mg, 2.74 mmol) and N,N’-dimethylethylenediamine (12 mg, 0.14 mmol) were added successively. The reaction mixture was stirred under nitrogen atmosphere at 120 °C for 48 hours. After the reaction was completed, the reaction solution was filtered with celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate) to give compound 13b (283 mg, yield 93%). ESI-MS (m / z): 221.8 [M+H]+ .

[0409] Second Step: Compound 13b (15 mg, 0.07 mmol) and compound INT-3 (20 mg, 0.05 mmol) were dissolved in isopropanol (2 mL), trifluoroacetic acid (1 mg, 0.01 mmol) was added. The reaction mixture was stirred under microwave condition at 100 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by preparative chromatography to obtain compound 13 (10 mg, yield 37%) as a white solid. ESI-MS (m / z): 517.5 [M+H] + .

[0410] 1 H NMR (500 MHz, DMSO-d6) d 10.25 (s, 1H), 8.76 (s, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 4.64 - 4.55 (m, 1H), 4.17 (s, 2H), 4.02 - 3.94 (m, 2H), 3.60 (s, 2H), 3.52 - 3.43 (m, 2H), 2.05 - 1.96 (m, 4H), 1.32 (s, 6H).

[0411] Example 14

[0412] 4-(4-((5-fluoro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0413] Example 14 was prepared from the following steps:

[0414] First Step: Compound INT-9 (50 mg, 177 umol), INT-2b (44 mg, 230 umol), Brettphos Pd G3 (8 mg, 8.8 umol), Brettphos (9.5 mg, 17.7 umol), cesium carbonate (173 mg, 530 umol) were dissolved in 1,4-dioxane (5 mL), protected by nitrogen, stirred at 110 °C overnight, after the reaction was completed, the reaction solution was filtered through diatomite, and the residue was purified by preparative chromatography to obtain compound 14 (2.14 mg, yield 2.8%). ESI-MS (m / z): 438.8 [M+H] + .

[0415] 1 H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.53 (d, J = 2.8 Hz, 1H), 8.45 (d, J = 1.8 Hz, 1H), 8.13 (s, 1H), 7.83 - 7.77 (m, 2H), 7.34 - 7.27 (m, 2H), 4.59 (p, J = 9.1, 8.3 Hz, 1H), 4.19 (s, 2H), 4.02 - 4.00 (m, 1H), 3.99 - 3.95 (m, 3H), 3.72 - 3.68 (m, 2H), 3.51 - 3.45 (m, 2H), 2.05 - 1.98 (m, 4H).

[0416] Example 15

[0417] 5-(4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one

[0418] Example 15 was prepared by the following steps:

[0419] First step: Compound 15a (1.0 g, 5.02 mmol) and N,N-dimethylformamide dimethyl acetal (598.2 mg, 5.02 mmol) were dissolved in methanol (10 mL) and reacted at 80 °C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain yellow solid 15b (1 g, yield 78%). ESI-MS (m / z): 255.6 [M+H] + .

[0420] Second step: Compound 15b (1.0 g, 3.93 mmol) and 15c (741.91 mg, 3.93 mmol) were dissolved in ethanol (10 mL) and reacted at room temperature for 16 hours. P-toluenesulfonic acid monohydrate (374.03 mg, 1.97 mmol) was added to the above reaction solution, and reacted at 80 °C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain yellow solid 15d (0.5 g, yield 52%). ESI-MS (m / z): 244.2 [M+H] + .

[0421] Step 3: Compound 15d (500 mg, 2.06 mmol), p-iodoaniline (585.23 mg, 2.67 mmol), potassium carbonate (852.23 mg, 6.18 mmol), cuprous iodide (39.15 mg, 0.21 mmol), N,N'-dimethylethylenediamine (36.24 mg, 0.42 mmol) were dissolved in 1,4-dioxane (10 mL) under nitrogen protection. The reaction was stirred at 120 °C for 16 hours. After the reaction was completed, the reaction was filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain yellow solid 15e (400 mg, yield 58%). ESI-MS (m / z): 335.5 [M+H] + .

[0422] Step 4: INT-3 (50 mg, 0.13 mmol), 15e (57.75 mg, 0.17 mmol) were dissolved in isopropanol (2 mL), and a drop of trifluoroacetic acid was added. The reaction was reacted at 100 °C for 2 hours under microwave irradiation. After the reaction was completed, the reaction was concentrated and dried to obtain a yellow solid crude 15f (70 mg, yield 83%). ESI-MS (m / z): 631.0 [M+H] + .

[0423] Step 5: Compound 15f (70 mg, 111 umol) was dissolved in trifluoroacetic acid (1 mL) and reacted at 100 °C for 3 hours. After the reaction was completed, the reaction was concentrated, and the residue was purified by reverse phase preparative chromatography to obtain compound 15 (25.5 mg, yield 45%). ESI-MS (m / z): 511.3 [M+H] + .

[0424] 1 H NMR (500 MHz, DMSO-d6) d 10.17 (s, 1H), 8.74 (s, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.81-7.75 (m, 4H), 4.91 (s, 2H), 4.65-4.54 (m, 1H), 4.03-3.94 (m, 2H), 3.51-3.45 (m, 2H), 2.06-1.96 (m, 4H).

[0425] Example 16

[0426] 4-(4-((5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0427] Example 16 was prepared by the following steps:

[0428] First Step: Compound INT-10 (50 mg, 179.38 umol), INT-2b (44.82 mg, 233.19 umol), Brettphos Pd G3 (8.13 mg, 8.97 umol), Cesium carbonate (175.34 mg, 538.14 umol), Brettphos (9.63 mg, 17.94 umol) were dissolved in 1,4-dioxane (5 mL) under nitrogen protection, stirred at 100 °C overnight, after the reaction was completed, the reaction solution was filtered through diatomite, the residue was purified by reverse phase preparative chromatography to obtain white solid compound 16 (34.87 mg, yield 44%). ESI-MS (m / z): 435.2 [M+H] + .

[0429] 1 H NMR (500 MHz, DMSO-d6) d 9.77 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.83 - 7.72 (m, 2H), 7.36 - 7.24 (m, 2H), 4.61 - 4.51 (m, 1H), 4.19 (s, 2H), 4.05 - 3.91 (m, 4H), 3.79 - 3.68 (m, 2H), 3.54 - 3.46 (m, 2H), 2.34 (s, 3H), 2.08 - 1.94 (m, 4H).

[0430] Example 17

[0431] 4-(4-((4-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0432] Example 17 was prepared by the following steps:

[0433] First Step: Compound 17a (500 mg, 2.40 mmol) and compound 17b (650 mg, 3.6 mmol) were dissolved in N,N,-dimethylformamide (20 mL), and cesium carbonate (1.57 g, 4.81 mmol) was added. The reaction mixture was heated and stirred at 100 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 mL). The organic phase was washed with water (40 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compounds 17c (143 mg, yield 21%, ESI-MS (m / z): 293.4 [M+H] + ) and 17d (300 mg, yield 42%, ESI-MS (m / z): 293.4 [M+H] + .

[0434] Second Step: Compound 17d (143 mg, 0.49 mmol) and compound INT-2 (166 mg, 0.45 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), and Pd(dcpf)Cl2 (35 mg, 0.04 mmol) and sodium carbonate (94 mg, 0.90 mmol) were added in turn. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered with diatomite, and the filtrate was concentrated. The residue was purified by preparative chromatography to obtain compound 17 (5 mg, yield 3%) as a white solid. ESI-MS (m / z): 503.3 [M+H] + .

[0435] 1 H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.79 (s, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.34 (d, J = 8.8 Hz, 2H), 4.57 - 4.48 (m, 1H), 4.19 (s, 2H), 4.00 - 3.94 (m, 4H), 3.73 - 3.69 (m, 2H), 3.55 - 3.47 (m, 2H), 2.50 (s, 3H), 2.11 - 2.01 (m, 2H), 1.87 - 1.80 (m, 2H).

[0436] Example 18

[0437] 4-(4-((4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0438] Example 18 was prepared by the following steps:

[0439] First Step: Compound 17d (300 mg, 1.03 mmol), INT-la (196 mg, 0.86 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (63 mg, 0.08 mmol), sodium carbonate (182 mg, 1.71 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). The reaction mixture was heated and stirred at 70 °C under nitrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered with celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 18a (135 mg, yield 45%). ESI-MS (m / z): 359.5 [M+H] + .

[0440] Second Step: 18a (135 mg, 0.38 mmol) was dissolved in dichloromethane (3 mL), and m-chloroperoxybenzoic acid (192 mg, 0.94 mmol) was added to the reaction solution at 0 °C and maintained at 0 °C for 8 hours. After the reaction was completed, saturated sodium thiosulfate and saturated sodium bicarbonate solution were added to the above reaction solution, extracted, and the organic phase was dried and concentrated to obtain compound 18b (147 mg, yield 99%). ESI-MS (m / z): 391.3 [M+H] + .

[0441] Third Step: Compound 18b (20 mg, 0.05 mmol) and compound INT-2b (12 mg, 0.06 mmol) were dissolved in isopropanol (2 mL), and trifluoroacetic acid (1 mg, 0.01 mmol) was added. The reaction mixture was stirred under microwave conditions at 100 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by preparative chromatography to obtain white solid compound 18 (3 mg, yield 12%). ESI-MS (m / z): 503.4 [M+H] + .

[0442] 1H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.77 (s, 1H), 7.96 (s, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.37 - 7.32 (m, 2H), 4.48 - 4.41 (m, 1H), 4.19 (s, 2H), 3.99 - 3.94 (m, 4H), 3.72 - 3.69 (m, 2H), 3.48 - 3.42 (m, 2H), 2.32 (s, 3H), 1.98 - 1.92 (m, 4H).

[0443] Example 19 and Example 20

[0444] 4-(4-((4-(1-(3-hydroxy-3-methylcyclohexyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0445] Example 19 and Example 20 were prepared by the following steps:

[0446] First step: Compound INT-8 (220 mg, 544.09 umol), 19a (124.21 mg, 1.09 mmol), triphenylphosphine (185.52 mg, 707.32 umol) were dissolved in anhydrous tetrahydrofuran (5 mL), diisopropyl azodicarboxylate (143.03 mg, 707.32 umol) was added dropwise at 0 °C under nitrogen protection, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution three times. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain yellow solid 19b (180 mg, yield 66%). ESI-MS (m / z): 501.1 [M+H] + .

[0447] Second step: Compound 19b (50 mg, 99.91 umol) was dissolved in anhydrous tetrahydrofuran (2 mL), methyl magnesium bromide (3 M, 49.95 uL, 149.86 umol) was added dropwise at 0 °C under nitrogen protection, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined. The organic phase was concentrated and purified by reverse phase preparative chromatography to obtain white solid compounds 19 (9.93 mg, yield 19%) and 20 (3.27 mg, yield 6%). ESI-MS (m / z): 517.6 [M+H] + .

[0448] 1 H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.75 (s, 1H), 8.31 (s, 1H), 8.02 (s, 1H), 7.87 - 7.75 (m, 2H), 7.41 - 7.32 (m, 2H), 4.64 (s, 1H), 4.50 - 4.37 (m, 1H), 4.20 (s, 2H), 4.02 - 3.94 (m, 2H), 3.76 - 3.69 (m, 2H), 2.01 - 1.85 (m, 3H), 1.78 - 1.72 (m, 1H), 1.68 - 1.57 (m, 2H), 1.47 - 1.37 (m, 2H), 1.21 (s, 3H).

[0449] 1 H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.75 (s, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.83 - 7.76 (m, 2H), 7.44 - 7.33 (m, 2H), 4.65 - 4.50 (m, 1H), 4.37 (s, 1H), 4.20 (s, 2H), 4.02 - 3.93 (m, 2H), 3.76 - 3.69 (m, 2H), 2.07 - 1.96 (m, 1H), 1.95 - 1.89 (m, 1H), 1.83 - 1.73 (m, 2H), 1.69 - 1.54 (m, 3H), 1.35 - 1.27 (m, 1H), 1.18 (s, 3H).

[0450] Example 21

[0451] 4-(4-((4-(1-(3-hydroxycyclohexyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0452] Example 21 was prepared from the following steps:

[0453] Step 1 : Compound 19b (30 mg, 59.94 umol) was dissolved in anhydrous tetrahydrofuran (2 mL), sodium borohydride (4.54 mg, 119.88 umol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated and purified by reverse phase preparative chromatography to obtain white solid compound 21 (4.82 mg, yield 16%). ESI-MS (m / z): 503.3 [M+H] + .

[0454] 1 H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.76 (s, 1H), 8.29 (s, 1H), 8.02 (s, 1H), 7.83-7.76 (m, 2H), 7.39-7.33 (m, 2H), 4.82 (s, 1H), 4.43-4.32 (m, 1H), 4.20 (s, 2H), 4.02-3.95 (m, 2H), 3.77-3.69 (m, 2H), 3.62-3.52 (m, 1H), 2.26-2.17 (m, 1H), 2.01-1.93 (m, 1H), 1.90-1.85 (m, 1H), 1.83-1.75 (m, 1H), 1.70-1.58 (m, 2H), 1.43-1.32 (m, 1H), 1.22-1.11 (m, 1H).

[0455] Example 22

[0456] 4-(4-((4-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0457] Example 22 was prepared from the following steps:

[0458] Step 1 : Compound 22a (500 mg, 2.48 mmol) was dissolved in dichloromethane (8 mL), methyl sulfonic anhydride (1.30 g, 7.45 mmol) and N,N-diisopropyl ethylamine (1.61 g, 12.42 mmol) were added in turn, and the reaction mixture was stirred at 0 °C for 4 hours. After the reaction was completed, the reaction solution was washed with saturated aqueous ammonium chloride solution (20 mL x 3), the organic phase was dried with anhydrous sodium sulfate, concentrated, and the crude product of compound 22b (690 mg, yield 99%) was obtained. ESI-MS (m / z): 280.5 [M+H] +.

[0459] Step 2: Compound 22b (42 mg, 0.15 mmol) and compound INT-8 (40 mg, 0.10 mmol) were dissolved in acetonitrile (2 mL), and cesium carbonate (65 mg, 0.20 mmol) was added. The reaction mixture was stirred at 100 °C for 8 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (10 mL). The organic phase was washed with water (10 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 22c (20 mg, yield 35%). ESI-MS (m / z): 588.6 [M+H] + .

[0460] Step 3: Compound 22c (20 mg, 0.03 mmol) was dissolved in 1,4-dioxane (1 mL), and hydrochloric acid 1,4-dioxane solution (4 M, 2 mL) was added. The reaction mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, concentrated, and the residue was purified by preparative chromatography to obtain compound 22 as a white solid (3 mg, yield 18%). ESI-MS (m / z): 488.6 [M+H] + .

[0461] 1 H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.75 (s, 0H), 8.37 (s, 1H), 8.00 (s, 0H), 7.85-7.76 (m, 2H), 7.43-7.33 (m, 2H), 4.34-4.28 (m, 1H), 4.20 (d, J = 2.2 Hz, 2H), 4.01-3.94 (m, 2H), 3.76-3.69 (m, 2H), 3.19-3.14 (m, 1H), 2.87-2.78 (m, 2H), 2.12-2.07 (m, 1H), 1.96-1.88 (m, 1H), 1.73-1.66 (m, 1H), 1.55-1.46 (m, 1H).

[0462] Example 23

[0463] 5-hydroxy-1-(4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidin-2-one

[0464] Example 23 was prepared from the following steps:

[0465] First Step: Compound INT-12c (500 mg, 2.28 mmol), 23a (789 mg, 6.85 mmol), cuprous iodide (43.5 mg, 228.3 umol), N,N-dimethylethylenediamine (20.12 mg, 228.3 umol), potassium phosphate (969.2 mg, 4.57 mmol) were dissolved in 1,4-dioxane (5 mL) under nitrogen protection, stirred at 110 °C overnight. After the reaction was completed, the reaction solution was filtered through diatomite, and the filtrate was purified by column chromatography (DCM:MeOH ~ 20:1) to obtain compound 23b (400 mg, yield 85%). ESI-MS (m / z): 207.2 [M+H] + .

[0466] Second Step: Compound 23b (36 mg, 172.7 umol), INT-3 (50 mg, 132.8 umol), TFA (1.5 mg, 13.3 umol) were dissolved in isopropanol (2 mL), and reacted at 100 °C for 2 hours under microwave. After the reaction was completed, the reaction solution was purified by reverse phase preparation to obtain compound 23 (23.33 mg, yield 35%) as a white solid. ESI-MS (m / z): 503.3 [M+H] + .

[0467] 1 H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.75 (s, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.79-7.73 (m, 2H), 7.28-7.20 (m, 2H), 5.15 (d, J = 3.6 Hz, 1H), 4.65-4.55 (m, 1H), 4.11-4.05 (m, 1H), 4.01-3.99 (m, 1H), 3.99-3.96 (m, 1H), 3.72 (dd, J = 12.0, 3.8 Hz, 1H), 3.51-3.42 (m, 3H), 2.54-2.52 (m, 1H), 2.38-2.31 (m, 1H), 2.03-1.95 (m, 5H), 1.87-1.80 (m, 1H).

[0468] Example 24

[0469] 4-(2-fluoro-4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0470] Example 24 was prepared from the following steps:

[0471] First Step: Compound 24a (500 mg, 2.11 mmol), compound INT-15d (234 mg, 2.32 mmol), potassium carbonate (874 mg, 6.33 mmol), cuprous iodide (401 mg, 2.11 mmol), N,N'-dimethylethylenediamine (185 mg, 2.11 mmol) were dissolved in 1,4-dioxane (4 mL) under nitrogen protection, the reaction solution was stirred at 120 °C for 24 hours. After the reaction was completed, the reaction solution was filtered through diatomite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain brown solid INT-24b (312 mg, yield 70%). ESI-MS (m / z): 211.6 [M+H] + .

[0472] Second Step: INT-3 (30 mg, 80 umol), 24b (22 mg, 103 umol), trifluoroacetic acid (9 mg, 80 umol) were dissolved in isopropanol (2 mL), the reaction solution was stirred at 120 °C for four hours under microwave. After the reaction was completed, the reaction solution was concentrated and dried, and the target compound 24 (12 mg, yield 29%) was obtained by reversed phase column chromatography. ESI-MS (m / z): 507.3 [M+H] + .

[0473] 1 H NMR (500 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.83 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 7.89 (dd, J = 13.0, 2.3 Hz, 1H), 7.59 (dd, J = 8.9, 2.3 Hz, 1H), 7.42 (t, J = 8.7 Hz, 1H), 4.60 (dt, J = 9.9, 4.6 Hz, 1H), 4.23 (s, 2H), 4.03 - 3.93 (m, 4H), 3.66 (t, J = 5.1 Hz, 2H), 3.48 (td, J = 11.1, 3.9 Hz, 2H), 2.00 (td, J = 11.1, 9.9, 4.0 Hz, 4H).

[0474] Example 25

[0475] 4-(4-((4-(1-(2-amino-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0476] Example 25 was prepared by the following steps:

[0477] First Step: Dissolve INT-8b (800 mg, 2.32 mmol), hydrochloric acid (4 M, 15 mL) in a mixed solution of 1,4-dioxane (10 mL) and water (1 mL), and stir the reaction solution at 60 degrees Celsius for 12 hours. After the reaction is completed, concentrate and dry the reaction solution to obtain a crude product, and subject the crude product to column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target product 25a (430 mg, yield 71.12%). ESI-MS (m / z): 261.4 [M+H] + .

[0478] Second Step: Dissolve 25a (200 mg, 0.77 mmol), 25b (231.65 mg, 0.92 mmol), cesium carbonate (751.20 mg, 2.31 mmol) in acetonitrile (10 mL), and stir the reaction solution at room temperature for 4 hours. After the reaction is completed, concentrate and dry the reaction solution to obtain a crude product, and subject the crude product to column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target product 25c (230 mg, yield 82.82%). ESI-MS (m / z): 362.6 [M+H] + .

[0479] Third Step: Dissolve 25c (240 mg, 0.66 mmol) in dichloromethane (10 mL), and add metachloroperbenzoic acid (296.66 mg, 1.46 mmol) to the above reaction solution, and stir the reaction solution at room temperature for 6 hours. After the reaction is completed, add saturated sodium bicarbonate and aqueous sodium thiosulfate solution to quench the reaction, and extract the organic phase with dichloromethane. Dry and concentrate the organic phase to obtain a crude product. Subject the crude product to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the target product 25d (220 mg, yield 84.21%). ESI-MS (m / z): 394.9 [M+H] + .

[0480] Fourth step: 25d (210 mg, 0.53 mmol), INT-2b (153.93 mg, 0.80 mmol), trifluoroacetic acid (182.62 mg, 1.60 mmol) were dissolved in 1,4-dioxane (10 mL), the reaction was stirred at 100 Celsius for 12 hours. After the reaction was completed, the reaction was concentrated and dried, and column chromatography (dichloromethane / methanol = 10 / 1) was carried out to obtain the target product 25e (230 mg, yield 85.23%). ESI-MS (m / z): 506.3 [M+H] + .

[0481] Fifth step: 25e (50 mg, 0.98 mmol), Raney nickel (84.75 mg, 0.99 mmol) were dissolved in methanol, the reaction was stirred at room temperature for 12 hours under hydrogen atmosphere. After the reaction was completed, the reaction was filtered, concentrated and reversed phase column chromatography to obtain the target product 25 (25 mg, yield 53.15%). ESI-MS (m / z): 476.4 [M+H] + .

[0482] 1 H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.76 (s, 1H), 8.31 (s, 1H), 8.02 (s, 1H), 7.80 (d, J = 10.0 Hz, 2H), 7.36 (d, J = 10.0 Hz, 2H), 4.20 (s, 2H), 4.08 (s, 2H), 3.99-3.97 (m, 2H), 3.73-3.71 (m, 2H), 1.59 (s, 2H), 1.00 (s, 6H).

[0483] Example 26

[0484] 4-(4-((4-(1-((1-hydroxycyclopentyl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0485] Example 26 was prepared by the following steps:

[0486] Step 1 : INT-8 (65 mg, 0.16 mmol), 26a (15.78 mg, 0.16 mmol), cesium carbonate (157.13 mg, 0.48 mmol) were dissolved in acetonitrile (5 mL), the reaction was stirred at 80 °C for 12 hours. After the reaction was completed, the reaction was filtered and concentrated to dryness and the target product 26 (15 mg, yield 18.57%) was obtained by reverse phase column chromatography. ESI-MS (m / z): 503.0 [M+H] + .

[0487] 1 H NMR (500 MHz, DMSO-d6) d 8.75 (s, 1H), 8.31 (s, 1H), 8.00 (s, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.9 Hz, 2H), 4.74 (s, 1H), 4.25 (s, 2H), 4.20 (s, 2H), 3.99 - 3.96 (m, 2H), 3.74 - 3.70 (m, 2H), 1.71 - 1.61 (m, 4H), 1.56 - 1.46 (m, 4H).

[0488] Example 27

[0489] 3-chloro-4-(4-(2-((4-(3-oxomorpholino)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzamide

[0490] Example 27 was prepared by the following steps:

[0491] Step 1 : INT-8 (50 mg, 0.12 mmol), 27a (32.19 mg, 0.19 mmol), potassium phosphate (52.50 mg, 0.25 mmol) were dissolved in N,N-dimethylformamide (3 mL), the reaction was stirred at 80 °C for 12 hours. After the reaction was completed, the reaction was filtered and concentrated to dryness and the target product 27 (30 mg, yield 43.48%) was obtained by reverse phase column chromatography. ESI-MS (m / z): 558.4 [M+H] + .

[0492] 1H NMR (500 MHz, DMSO-de) d 10.36 (s, 1H), 8.84 (s, 1H), 8.74 (s, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 8.20 (d, J = 1.9 Hz, 1H), 8.03 (dd, J = 8.3, 1.9 Hz, 1H), 7.83 (t, J = 8.3 Hz, 3H), 7.69 (s, 1H), 7.40 - 7.35 (m, 2H), 4.20 (s, 2H), 4.00 - 3.96 (m, 2H), 3.75 - 3.71 (m, 2H).

[0493] Example 28

[0494] 4-hydroxy-1-(4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidin-2-one

[0495] Example 28 was prepared by the following steps:

[0496] First step: Compound INT-12c (500 mg, 2.28 mmol), 28a (789 mg, 6.85 mmol), cuprous iodide (43.5 mg, 228.3 umol), N,N-dimethylethylenediamine (20.12 mg, 228.3 umol), potassium phosphate (969.2 mg, 4.57 mmol) were dissolved in 1,4-dioxane (5 mL), protected by nitrogen, stirred at 110 °C overnight, after the reaction was completed, the reaction liquid was filtered through diatomite, and the filtrate was purified by column chromatography (DCM:MeOH ~ 20:1) to obtain compound 28a (300 mg, yield 64%). ESI-MS (m / z): 207.2 [M+H] + .

[0497] Second step: Compound 28b (36 mg, 172.7 umol), INT-3 (50 mg, 132.8 umol), TFA (1.5 mg, 13.3 umol) were dissolved in isopropanol (2 mL), and reacted at 100 °C for 2 hours by microwave, after the reaction was completed, the reaction liquid was purified by reverse phase preparation to obtain compound 28 (12.66 mg, yield 19%), white solid. ESI-MS (m / z): 503.1 [M+H] + .

[0498] 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.75 (s, 1H), 8.32 (s, 1H), 8.03 (s, 1H), 7.80 - 7.72 (m, 2H), 7.28 - 7.20 (m, 2H), 5.08 (d, J = 3.6 Hz, 1H), 4.60 (p, J = 8.0 Hz, 1H), 4.09 (s, 1H), 3.99 (dt, J = 11.6, 3.4 Hz, 2H), 3.77 - 3.68 (m, 1H), 3.56 - 3.44 (m, 3H), 2.62 (dd, 1H), 2.29 (dd, 1H), 2.05 - 1.97 (m, 5H), 1.88 - 1.78 (m, 1H).

[0499] Example 29

[0500] 4-(4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1,4-oxazepan-5-one

[0501] Example 29 was prepared from the following steps:

[0502] First Step: A solution of INT-3 (42 mg, 112 umol), INT-12 (30 mg, 145 umol), trifluoroacetic acid (13 mg, 112 umol) in isopropanol (2 mL) was stirred at 120 °C for four hours under microwave. After the reaction was completed, the reaction was concentrated and dried, and the target compound 29 (25 mg, yield 44%) was obtained by reverse phase column chromatography. ESI-MS (m / z): 503.2 [M+H] + .

[0503] 1 H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.75 (s, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.81 - 7.70 (m, 2H), 7.25 - 7.12 (m, 2H), 4.60 (p, J = 8.0 Hz, 1H), 3.99 (dt, J = 11.6, 3.5 Hz, 2H), 3.87 - 3.74 (m, 6H), 3.52 - 3.42 (m, 2H), 2.84 - 2.76 (m, 2H), 2.00 (h, J = 4.7, 4.0 Hz, 4H).

[0504] Example 30

[0505] 4-(5-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)morpholin-3-one

[0506] Example 30 was prepared from the following steps:

[0507] First Step: Compound 30a (400 mg, 1.82 mmol), compound INT-15d (202 mg, 2.01 mmol), potassium carbonate (753 mg, 5.45 mmol), cuprous iodide (173 mg, 0.91 mmol), N,N'-dimethylethylenediamine (80 mg, 0.91 mmol) were dissolved in 1,4-dioxane (4 mL) under nitrogen protection, the reaction solution was stirred at 120 °C for 24 hrs, after the reaction was completed, the reaction solution was filtered through diatomite, the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain brown solid 30b (312 mg, yield 70%). ESI-MS (m / z): 211.6 [M+H] + .

[0508] Second Step: INT-3 (30 mg, 80 umol), 30b (20 mg, 103 umol), trifluoroacetic acid (9 mg, 80 umol) were dissolved in isopropanol (2 mL), the reaction solution was stirred at 120 °C for four hours under microwave. After the reaction was completed, the reaction solution was concentrated and dried and subjected to reverse phase column chromatography to obtain the target compound 30 (7 mg, yield 17%). ESI-MS (m / z): 490.6 [M+H] + .

[0509] 1 H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.84 - 8.74 (m, 2H), 8.34 (s, 1H), 8.24 (dd, J = 9.0, 2.8 Hz, 1H), 8.04 (s, 1H), 7.95 (d, J = 9.0 Hz, 1H), 4.65 - 4.54 (m, 1H), 4.26 (s, 2H), 4.03 - 3.92 (m, 6H), 3.48 (ddd, J = 11.6, 8.6, 6.5 Hz, 2H), 2.00 (tt, J = 5.3, 2.9 Hz, 4H).

[0510] Example 31

[0511] 4-(4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1,4-thiazepan-5-one 1,1-dioxide

[0512] Example 31 was prepared by the following steps:

[0513] First Step: Dissolve INT-3 (35 mg, 93 umol), INT-13 (27 mg, 121 umol), trifluoroacetic acid (5.3 mg, 46.5 umol) in isopropanol (2 mL), the reaction was stirred at 120 °C for four hours. After the reaction was completed, the reaction was concentrated and dried, and column chromatography (dichloromethane:methanol = 10:1) was performed to obtain the target compound 31a (30 mg, yield 62%). ESI-MS (m / z): 519.7 [M+H] + .

[0514] Second Step: Dissolve 31a (30 mg, 58 umol) in dichloromethane (2 mL), add m-chloroperoxybenzoic acid (25 mg, 144 umol) to the reaction, and react at room temperature for 4 hours. After the reaction was completed, saturated sodium thiosulfate and saturated sodium bicarbonate solution were added to the above reaction, and dichloromethane was extracted, and the reaction was concentrated and dried, and reversed phase column chromatography was performed to obtain the target compound 31 (15 mg, yield 47%). ESI-MS (m / z): 551.5 [M+H] + .

[0515] 1 H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.76 (s, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.82-7.69 (m, 2H), 7.37-7.25 (m, 2H), 4.66-4.53 (m, 1H), 4.15-4.05 (m, 2H), 3.99 (dt, J = 11.5, 3.4 Hz, 2H), 3.54-3.41 (m, 6H), 2.99-2.89 (m, 2H), 2.00 (td, J = 10.2, 9.0, 4.2 Hz, 4H).

[0516] Example 32

[0517] 4-(4-((4-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0518] Example 32 was prepared by the following steps:

[0519] First step: Compound INT-8 (30 mg, 74.19 umol), 32a (19.93 mg, 111.29 umol), was dissolved in acetonitrile (2 mL), cesium carbonate (72.52 mg, 222.58 umol) was added, and the reaction was carried out at 90 °C for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride three times. The organic phase was concentrated and purified by reverse phase preparative chromatography to obtain white solid 32 (8.72 mg, yield 23%). ESI-MS (m / z): 502.7 [M+H] + .

[0520] 1 H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.76 (s, 1H), 8.28 (s, 1H), 8.02 (s, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.9 Hz, 2H), 4.20 (s, 2H), 4.15 (d, J = 7.2 Hz, 2H), 4.01 - 3.95 (m, 2H), 3.87 - 3.79 (m, 2H), 3.75 - 3.69 (m, 2H), 3.29 - 3.22 (m, 2H), 2.14 - 2.03 (m, 1H), 1.43 - 1.36 (m, 2H), 1.32 - 1.21 (m, 2H).

[0521] Example 33

[0522] 4-(4-((4-(1-(2-hydroxycyclopentyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)morpholin-3-one

[0523] Example 33 was prepared by the following steps:

[0524] Step 1 : Compound INT-8 (30 mg, 74.19 umol), 33a (9.36 mg, 111.29 umol) were dissolved in acetonitrile (2 mL), cesium carbonate (72.52 mg, 222.58 umol) was added, the reaction was carried out at 90 °C for 16 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution three times. The organic phase was concentrated and purified by reverse phase preparative chromatography to obtain white solid 33 (16.1 mg, yield 44%). ESI-MS (m / z): 489.1 [M+H] + .

[0525] 1 H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.76 (s, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 8.9 Hz, 2H), 5.18 (s, 1H), 4.58 - 4.46 (m, 1H), 4.27 - 4.17 (m, 3H), 4.01 - 3.94 (m, 2H), 3.77 - 3.69 (m, 2H), 2.24 - 2.14 (m, 1H), 2.07 - 1.94 (m, 2H), 1.84 - 1.72 (m, 2H), 1.63 - 1.53 (m, 1H).

[0526] Example 34

[0527] 4-(4-((4-(1-(1-isopropylpiperidin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0528] Example 34 was prepared from the following steps:

[0529] Step 1 : Compound 22 (10 mg, 0.02 mmol) was dissolved in dichloromethane (2 mL), acetone (6 mg, 0.10 mmol) was added, the reaction mixture was stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (9 mg, 0.04 mmol) was added to the reaction mixture, the reaction mixture was continued to stir at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, concentrated, and the residue was purified by preparative chromatography to obtain white solid compound 34 (0.5 mg, yield 5%). ESI-MS (m / z): 530.5 [M+H] + .

[0530] Example 35

[0531] 4-(4-((4-(1-cyclohexyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0532] Example 35 was prepared by the following steps:

[0533] First Step: Compound 35a (300 mg, 3.0 mmol) was dissolved in dichloromethane (6 mL), methylsulfonic anhydride (1.57 g, 8.99 mmol) and N,N-diisopropyl ethylamine (1.94 g, 14.98 mmol) were added successively, the reaction mixture was stirred at 0 °C for 4 hours. After the reaction was completed, the reaction liquid was washed with saturated aqueous ammonium chloride solution (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, concentrated to obtain compound 35b (533 mg, yield 99%).

[0534] Second Step: Compound 35b (14 mg, 0.08 mmol) and compound INT-8 (20 mg, 0.05 mmol) were dissolved in acetonitrile (2 mL), cesium carbonate (32 mg, 0.10 mmol) was added. The reaction mixture was stirred at 100 °C for 8 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, the residue was dissolved in dichloromethane (10 mL), the organic phase was washed with water (10 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by preparative chromatography to obtain white solid compound 35 (3 mg, yield 13%). ESI-MS (m / z): 487.5 [M+H] + .

[0535] 1 H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.75 (s, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.84-7.73 (m, 2H), 7.41-7.33 (m, 2H), 4.35-4.27 (m, 1H), 4.20 (s, 2H), 4.00-3.95 (m, 2H), 3.75-3.70 (m, 2H), 2.09-2.00 (m, 2H), 1.86-1.71 (m, 4H), 1.45-1.37 (m, 2H), 1.29-1.19 (m, 2H).

[0536] Example 36

[0537] 4-(4-((4-(1-((1-(aminomethyl)cyclobutyl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0538] Example 36 was prepared by the following steps:

[0539] First Step: Compound 36a (500 mg, 4.34 mmol) was dissolved in dichloromethane (8 mL), di-tert-butyl dicarbonate (1.42 g, 6.51 mmol) and N,N-diisopropyl ethylamine (1.68 g, 13.02 mmol) were added successively. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction liquid was washed with saturated aqueous ammonium chloride solution (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain compound 36b (934 mg, yield 99%). ESI-MS (m / z): 215.2 [M+H] + .

[0540] Second Step: Compound 36b (500 mg, 2.32 mmol) was dissolved in dichloromethane (8 mL), methyl sulfonic anhydride (1.21 g, 6.97 mmol) and N,N-diisopropyl ethylamine (1.50 g, 11.61 mmol) were added successively, and the reaction mixture was stirred at 0°C for 4 hours. After the reaction was completed, the reaction liquid was washed with saturated aqueous ammonium chloride solution (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain compound 36c (681 mg, yield 99%). ESI-MS (m / z): 294.0 [M+H] + .

[0541] Third Step: Compound 36c (22 mg, 0.07 mmol) and compound INT-8 (20 mg, 0.05 mmol) were dissolved in acetonitrile (2 mL), cesium carbonate (33 mg, 0.10 mmol) was added. The reaction mixture was stirred at 100°C for 8 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, the residue was dissolved in dichloromethane (10 mL), the organic phase was washed with water (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 36d (15 mg, yield 51%). ESI-MS (m / z): 602.7 [M+H] + .

[0542] Fourth step: Compound 36d (15 mg, 0.03 mmol) was dissolved in 1,4-dioxane (1 mL), hydrochloric acid in dioxane (4 M, 2 mL) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phase was dried, concentrated, and the residue was purified by preparative chromatography to obtain compound 36 as a white solid (3 mg, yield 24%). ESI-MS (m / z): 502.0 [M+H] + .

[0543] 1 H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.75 (d, J = 3.5 Hz, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.82 - 7.75 (m, 2H), 7.39 - 7.33 (m, 2H), 4.30 (s, 2H), 4.20 (s, 2H), 3.97 (dd, J = 6.0, 4.2 Hz, 2H), 3.72 (dd, J = 6.0, 4.2 Hz, 2H), 2.43 (s, 2H), 1.89 (dd, J = 11.2, 7.1 Hz, 2H), 1.78 (dt, J = 13.1, 4.8 Hz, 2H), 1.69 (ddd, J = 10.3, 7.5, 5.0 Hz, 2H).

[0544] Example 37

[0545] 4-(4-((4-(1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0546] Example 37 was prepared from the following steps:

[0547] First step: Compound 37a (200 mg, 1.54 mmol), N,N-diisopropylethylamine (0.8 mL, 4.61 mmol) were dissolved in dichloromethane (5 mL), methanesulfonic anhydride (400.97 mg, 2.3 mmol) was added at 0 °C, and the reaction was allowed to proceed at room temperature for 16 hours. After the reaction was completed, the reaction was diluted with dichloromethane and washed with saturated aqueous ammonium chloride solution three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oil 37b (250 mg, yield 78%) as a crude product.

[0548] 1HNMR (500 MHz, DMSO-d6) δ 4.92 (ddd, J = 10.5, 5.8, 4.7 Hz, 1H), 3.71 (ddd, J = 12.1, 5.0, 3.1 Hz, 1H), 3.64 - 3.53 (m, 1H), 3.20 (s, 3H), 1.95 (ddd, J = 12.5, 4.5, 1.6 Hz, 2H), 1.60 - 1.51 (m, 1H), 1.46 (dd, J = 12.6, 10.6 Hz, 1H), 1.17 (d, J = 3.1 Hz, 6H).

[0549] Second Step: Compound INT-8 (30 mg, 74.19 umol), 37b (23.18 mg, 111.29 mmol), was dissolved in acetonitrile (2 mL), cesium carbonate (72.52 mg, 222.58 umol) was added, and the reaction was carried out at 90 °C for 16 hours. After the reaction was completed, the reaction liquid was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride three times. The organic phase was concentrated and purified by reverse phase preparative chromatography to obtain white solid 37 (10.33 mg, yield 26%). ESI-MS (m / z): 517.6 [M+H] + .

[0550] 1 H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.76 (s, 1H), 8.34 (s, 1H), 8.04 (s, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 8.9 Hz, 2H), 4.86 - 4.73 (m, 1H), 4.20 (s, 2H), 4.03 - 3.92 (m, 2H), 3.83 - 3.67 (m, 4H), 1.99 - 1.79 (m, 4H), 1.27 (s, 3H), 1.21 (s, 3H).

[0551] Example 38

[0552] 4-(4-((4-(1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0553] Example 38 was prepared from the following steps:

[0554] First Step: Dissolve INT-3 (50 mg, 132 umol), INT-15 (53 mg, 159 umol), trifluoroacetic acid (15 mg, 132 umol) in isopropanol (2 mL), and stir the solution under microwave at 120 °C for four hours. After the reaction is completed, concentrate and dry the reaction solution to obtain the target compound 38a. ESI-MS (m / z): 633.2 [M+H] + .

[0555] Second Step: Dissolve 38a (70 mg, 110 umol) in dichloromethane (2 mL), and reduce the reaction temperature to 0 °C, and add 4M HCl to the reaction solution and stir for 4 hours. After the reaction is completed, add sodium bicarbonate solution to the above reaction solution to adjust the solution pH = 8, concentrate and dry the reaction solution, and purify by reverse phase column chromatography to obtain the target compound 38 (9 mg, yield 15%). ESI-MS (m / z): 536.6 [M+H] + .

[0556] 1 H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.79 (s, 1H), 8.36 (s, 1H), 8.07 (d, J = 12.1 Hz, 2H), 7.73 (dd, J = 8.7, 2.5 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 4.66 (s, 2H), 4.61 - 4.54 (m, 1H), 4.30 (d, J = 16.3 Hz, 1H), 4.20 (d, J = 16.4 Hz, 1H), 4.00 (ddt, J = 14.5, 6.7, 3.9 Hz, 4H), 3.81 (d, J = 11.8 Hz, 1H), 3.57 - 3.43 (m, 3H), 2.01 (td, J = 10.4, 9.1, 4.0 Hz, 4H).

[0557] Example 39

[0558] 4-(2-(hydroxymethyl)-4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0559] Example 39 is prepared from the following steps:

[0560] Step 1 : 38a (70 mg, 110 umol) was dissolved in dichloromethane (2 mL) and the reaction temperature was reduced to 0 °C, and 4M HC1 was added to the reaction and stirred for 4 hours, after the reaction was completed, the above reaction solution was added to the sodium bicarbonate solution to adjust the solution PH = 8, the reaction solution was concentrated and dried by reverse phase column chromatography to obtain the target compound 39 (12 mg, yield 20%). ESI-MS (m / z): 518.6 [M+H] + .

[0561] 1 H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.76 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 5.31 (s, 1H), 4.62 - 4.53 (m, 1H), 4.43 (d, J = 32.5 Hz, 1H), 4.21 (dd, J = 19.7, 14.5 Hz, 3H), 3.98 (td, J = 9.6, 8.9, 4.8 Hz, 4H), 3.71 (s, 1H), 3.47 (qd, J = 7.7, 7.2, 5.1 Hz, 3H), 2.01 (dp, J = 8.2, 4.0 Hz, 4H).

[0562] Example 40

[0563] 4-(2-methyl-4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0564] Example 40 was prepared by the following steps:

[0565] First Step: Compound 40a (600 mg, 2.57 mmol), compound INT-15d (286 mg, 2.83 mmol), potassium carbonate (1.07 g, 7.72 mmol), cuprous iodide (245 mg, 1.29 mmol), N,N'-dimethylethylenediamine (226 mg, 2.57 mmol) were dissolved in 1,4-dioxane (10 mL) under nitrogen protection. The reaction solution was stirred at 120 °C for 24 hr. After the reaction was completed, the reaction solution was filtered through diatomite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain brown solid 40b (320 mg, yield 66%). ESI-MS (m / z): 206.7 [M+H] + .

[0566] Second Step: INT-3 (35 mg, 93 umol), 40b (25 mg, 120 umol), trifluoroacetic acid (11 mg, 93 umol) were dissolved in isopropanol (2 mL). The reaction solution was stirred at 100 °C for four hours under microwave. After the reaction was completed, the reaction solution was concentrated and dried, and then subjected to reverse phase column chromatography to obtain the target compound 40 (22 mg, yield 47%). ESI-MS (m / z): 503.4 [M+H] + .

[0567] 1 H NMR (500 MHz, DMSO-d6) d 10.20 (s, 1H), 8.76 (s, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.72 (s, 1H), 7.64 (dd, J = 8.6, 2.5 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 4.58 (tt, J = 10.3, 5.2 Hz, 1H), 4.20 (d, J = 15.3 Hz, 2H), 4.04 - 3.95 (m, 4H), 3.68 (s, 1H), 3.48 (td, J = 11.5, 3.5 Hz, 3H), 2.15 (s, 3H), 2.00 (ddd, J = 15.5, 6.4, 3.5 Hz, 4H).

[0568] Example 41 and Example 42

[0569] 4-(4-((5-chloro-4-(1-(3-hydroxycyclopentyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0570] Example 41 and Example 42 were prepared by the following steps:

[0571] Step 1: Compound INT-14 (50 mg, 134.85 umol), 41a (27.0 mg, 269.69 umol), triphenylphosphine (53.05 mg, 202.27 umol) were dissolved in anhydrous tetrahydrofuran (5 mL), diisopropyl azodicarboxylate (40.9 mg, 202.27 umol) was added dropwise at 0 °C under nitrogen protection, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution three times. The organic phase was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain yellow oil 41b (50 mg, yield 81%). ESI-MS (m / z): 453.4 [M+H] + .

[0572] Step 2: Compound 41b (50 mg, 110.4 umol) was dissolved in anhydrous tetrahydrofuran (2 mL), and sodium borohydride (8.35 mg, 220.8 umol) was added at 0 °C. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined. The organic phase was concentrated and purified by reverse phase preparative chromatography to obtain white solid compounds 41 (6.25 mg, yield 12%) and 42 (1.17 mg, yield 2%). ESI-MS (m / z): 455.2 [M+H] + .

[0573] 1 H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.69 (s, 1H), 8.51 (s, 1H), 8.25 (s, 1H), 7.89-7.70 (m, 2H), 7.38-7.28 (m, 2H), 5.03-4.80 (m, 2H), 4.26-4.21 (m, 1H), 4.19 (s, 2H), 4.02-3.94 (m, 2H), 3.74-3.67 (m, 2H), 2.45-2.35 (m, 1H), 2.19-2.12 (m, 1H), 2.10-2.02 (m, 1H), 1.93-1.87 (m, 1H), 1.84-1.72 (m, 2H).

[0574] 1H NMR (500 MHz, DMSO-de) d 9.82 (s, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.25 (s, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 5.14 - 5.01 (m, 1H), 4.84 - 4.75 (m, 2H), 4.19 (s, 2H), 3.99 - 3.96 (m, 3H), 3.74 - 3.69 (m, 2H), 2.32 - 2.25 (m, 1H), 2.18 - 2.13 (m, 1H), 2.11 - 2.03 (m, 2H), 1.96 - 1.87 (m, 2H).

[0575] Example 43

[0576] 4-(4-((5-chloro-4-(4-(1-isopropyl-1H-pyrazol-5-yl)phenyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0577] Example 43 was prepared by the following steps:

[0578] First Step: Compound 43a (2 g, 10.05 mmol) and N,N-dimethylformamide dimethyl acetal (1.44 g, 12.06 mmol) were dissolved in toluene (20 mL) and reacted at 100 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was directly concentrated to obtain a crude yellow solid 43b (2.5 g, yield 97%). ESI-MS (m / z): 254.4, 256.4 [M+H] + .

[0579] Second Step: Compound 43b (2.5 g, 9.84 mmol) and isopropylhydrazine hydrochloride (1.63 g, 14.76 mmol) were dissolved in ethanol (25 mL) and reacted at 90 °C for 16 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain yellow oil 43c (2 g, yield 76%). ESI-MS (m / z): 265.5, 267.5 [M+H] + .

[0580] Step 3: Compound 43c (500 mg, 1.89 mmol), bis(pinacolato)diboron (718.29 mg, 2.83 mmol), potassium acetate (370.14 mg, 3.77 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (137.98 mg, 0.19 mmol) were dissolved in 1,4-dioxane (10 mL) under nitrogen atmosphere. The reaction was stirred at 100 °C for 16 h. After the reaction was completed, the reaction was filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give yellow oil 43d (520 mg, yield 88%). ESI-MS (m / z): 313.7 [M+H] + .

[0581] Step 4: 43d (200 mg, 0.64 mmol), INT-4a (176.25 mg, 0.196 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (46.87 mg, 64.06 umol) and sodium carbonate (135.79 mg, 1.28 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL) under nitrogen atmosphere. The reaction was stirred at 90 °C for 16 h. After the reaction was completed, the reaction was filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give yellow oil 43e (150 mg, yield 70%). ESI-MS (m / z): 333.1 [M+H] + .

[0582] Step 5: Compound 43e (80 mg, 179.38 umol), INT-2b (59.99 mg, 312.11 umol), Brettohos Pd G3 (10.88 mg, 12.0 umol), cesium carbonate (234.67 mg, 720.26 umol), Brettphos (12.89 mg, 24.01 umol) were dissolved in 1,4-dioxane (5 mL) under nitrogen atmosphere. The reaction was stirred at 100 °C for 16 h. After the reaction was completed, the reaction was filtered through celite. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) and reverse phase preparative chromatography to give white solid compound 43 (10.7 mg, yield 9%). ESI-MS (m / z): 489.0 [M+H] + .

[0583] 1H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.67 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 8.9 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 1.8 Hz, 1H), 7.31 (d, J = 8.9 Hz, 2H), 6.41 (d, J = 1.7 Hz, 1H), 4.67 - 4.53 (m, 1H), 4.18 (s, 2H), 4.01 - 3.91 (m, 2H), 3.76 - 3.67 (m, 2H), 1.41 (d, J = 6.5 Hz, 6H).

[0584] Example 44

[0585] 4-(4-((4-(1-(5-azaspiro[2.5]octan-8-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0586] Example 44 was prepared by the following steps:

[0587] First step: Compound 44a (300 mg, 1.33 mmol) was dissolved in ethanol (5 mL), sodium borohydride (76 mg, 2.0 mmol) was added at 0 °C. After the reaction was complete, the reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated to give compound 44b (302 mg, yield 99%).

[0588] Second step: Compound 44b (302 mg, 1.32 mmol) was dissolved in dichloromethane (8 mL), methyl sulfonic anhydride (690 mg, 3.96 mmol) and N,N-diisopropyl ethylamine (853 mg, 6.60 mmol) were added in turn, the reaction mixture was stirred at 0 °C for 4 hours. After the reaction was complete, the reaction solution was washed with saturated aqueous ammonium chloride solution (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, concentrated to give compound 44c (403 mg, yield 99%).

[0589] Step 3: Compound 44c (68 mg, 0.22 mmol) and compound INT-8 (60 mg, 0.15 mmol) were dissolved in acetonitrile (2 mL), and cesium carbonate (97 mg, 0.30 mmol) was added. The reaction mixture was stirred at 100 °C for 8 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (10 mL). The organic phase was washed with water (10 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 44d (20 mg, yield 22%). ESI-MS (m / z): 614.3 [M+H] + .

[0590] Step 4: Compound 44d (20 mg, 0.03 mmol) was dissolved in 1,4-dioxane (1 mL), and hydrochloric acid in dioxane (4 M, 2 mL) was added. The reaction mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, concentrated, and the residue was purified by preparative chromatography to obtain white solid compound 44 (3 mg, yield 18%). ESI-MS (m / z): 513.8 [M+H] + .

[0591] 1 H NMR (500 MHz, DMSO-d6) d 10.24 (s, 1H), 8.75 (s, 1H), 8.27 (s, 1H), 8.02 (s, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 5.41 (s, 1H), 4.29 (t, J = 7.1 Hz, 2H), 4.20 (s, 2H), 4.01 - 3.94 (m, 2H), 3.76 - 3.68 (m, 2H), 3.09 (d, J = 2.7 Hz, 2H), 2.66 (t, J = 5.7 Hz, 2H), 2.40 (t, J = 7.2 Hz, 2H), 1.86 (s, 2H).

[0592] Example 45

[0593] 4-(4-((5-chloro-4-(1-(2-hydroxycyclopentyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0594] Example 45 was prepared from the following steps:

[0595] Step 1 : Compound INT-14 (50 mg, 134.85 umol), 33a (17.01 mg, 202.27 umol), was dissolved in acetonitrile (2 mL), cesium carbonate (131.81 mg, 404.54 umol) was added, and the reaction was stirred at 90 °C for 16 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution three times. The organic phase was concentrated and purified by reverse phase preparative chromatography to give 45 (12.16 mg, yield 19%) as a white solid. ESI-MS (m / z): 455.3 [M+H] + .

[0596] 1 H NMR (500 MHz, DMSO-d6) d 9.83 (s, 1H), 8.60 (s, 1H), 8.51 (s, 1H), 8.28 (s, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 5.17 (s, 1H), 4.57 - 4.45 (m, 1H), 4.29 - 4.22 (m, 1H), 4.19 (s, 2H), 3.99 - 3.94 (m, 2H), 3.75 - 3.68 (m, 2H), 2.23 - 2.14 (m, 1H), 2.07 - 1.96 (m, 2H), 1.82 - 1.75 (m, 2H), 1.63 - 1.55 (m, 1H).

[0597] Example 46

[0598] 4-(4-((5-chloro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0599] Example 46 was prepared from the following steps:

[0600] First Step: Compound INT-4a (200 mg, 1.09 mmol) and 4a (617 mg, 1.64 mmol) were dissolved in a mixed solution of 1,4-dioxane (5 mL) and water (0.5 mL), and 1,1'-bis (di-cyclohexylphosphino) ferrocene palladium dichloride (80 mg, 0.11 mmol) and sodium carbonate (347 mg, 3.27 mmol) were added successively. The reaction mixture was stirred at 90 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered with celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 46a (327 mg, yield 75%). ESI-MS (m / z): 398.3 [M+H] + .

[0601] Second Step: Compound 46a (100 mg, 0.25 mmol) and INT-2b (53 mg, 0.28 mmol) were dissolved in 1,4-dioxane (5 mL), and Brettohos Pd G3 (23 mg, 0.03 mmol), cesium carbonate (164 mg, 0.51 mmol), Brettphos (27 mg, 0.05 umol) were added successively. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered with celite, and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 46b (50 mg, yield 36%). ESI-MS (m / z): 555.4 [M+H] + .

[0602] Third Step: Compound 46b (50 mg, 0.09 mmol) was dissolved in a 1,4-dioxane solution of hydrochloric acid (4 M, 2 mL). The reaction mixture was stirred for 2 hours under an ice water bath. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative chromatography to obtain compound 46 (7 mg, yield 17%). ESI-MS (m / z): 454.1 [M+H] + .

[0603] 1H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.58 (s, 1H), 8.51 (s, 1H), 8.26 (s, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 4.51 - 4.41 (m, 1H), 4.19 (s, 2H), 3.99 - 3.94 (m, 2H), 3.73 - 3.69 (m, 2H), 3.18 - 3.13 (m, 2H), 2.77 - 2.69 (m, 2H), 2.07 - 2.01 (m, 2H), 1.99 - 1.90 (m, 2H).

[0604] Example 47

[0605] 4-(4-((5-fluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0606] Example 47 was prepared by the following steps:

[0607] First Step: INT-1b (150 mg, 0.56 mmol), INT-9a (113 mg, 0.68 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (41.2 mg, 56.36 umol) and sodium carbonate (119.5 mg, 1.13 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), the reaction was stirred at 100 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction was filtered through celite, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain yellow solid 47b (40 mg, yield 26.2%). ESI-MS (m / z): 271.2 [M+H] + .

[0608] Second Step: Compound 47b (40 mg, 147.8 umol), INT-2b (59 mg, 305.7 umol), Brettohos Pd G3 (10.66 mg, 11.8 umol), Cesium carbonate (230 mg, 705 umol), Brettohos (12.6 mg, 23.5 umol) were dissolved in 1,4-dioxane (5 mL) under nitrogen atmosphere, stirred at 100 °C for 16 hours. After the reaction was completed, the reaction solution was filtered through diatomite, and the residue was purified by reverse phase preparative chromatography to obtain white solid compound 47 (61 mg, yield 60.8%). ESI-MS (m / z): 427.5 [M+H] + .

[0609] 1 H NMR (500 MHz, DMSO-d6) d 9.73 (s, 1H), 8.52 (d, J = 2.9 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.09 (d, J = 1.3 Hz, 1H), 7.82 - 7.77 (m, 2H), 7.32 - 7.27 (m, 2H), 4.81 (s, 1H), 4.19 (s, 2H), 4.15 (s, 2H), 3.97 (dd, J = 6.0, 4.1 Hz, 2H), 3.70 (dd, J = 5.9, 4.2 Hz, 2H), 1.10 (s, 6H).

[0610] Example 48

[0611] 4-(4-((4-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)thiazol-5-yl)-5-chloropyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0612] Example 48 was prepared from the following steps:

[0613] Step 1: Dissolve INT-7 (48.94 mg, 0.22 mmol) in anhydrous N,N-dimethylformamide (2 mL), cool to 0 °C, and add sodium hydride (9.63 mg, 0.24 mmol) to the reaction mixture under nitrogen atmosphere. The reaction mixture is stirred at 0 °C for half an hour. Add INT-18 (90 mg, 0.18 mmol) in anhydrous N,N-dimethylformamide (1 mL) to the reaction mixture, and stir the reaction mixture at room temperature for 12 hours under nitrogen atmosphere. After the reaction is completed, quench the reaction by adding saturated aqueous ammonium chloride solution (10 mL), and extract the reaction mixture with ethyl acetate (10 mL x 3). Wash the combined organic phase with saturated brine (10 mL x 3), dry and concentrate to obtain compound 48a (60 mg, yield 54%). ESI-MS (m / z): 597.8 [M+H] + .

[0614] Step 2: Dissolve compound 48a (60 mg, 0.1 mmol) in dichloromethane (1 mL), and add trifluoroacetic acid (0.5 mL) at room temperature. Continue to stir the reaction mixture at room temperature for 3 hours. After the reaction is completed, add triethylamine (2 mL), and concentrate the reaction mixture under reduced pressure. Purify the residue by preparative chromatography to obtain compound 48 (23.21 mg, yield 46%). ESI-MS (m / z): 498.2 [M+H] + .

[0615] 1 H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.44 (s, 1H), 8.38 (s, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.32 (d, J = 8.9 Hz, 2H), 4.19 (s, 2H), 4.00 - 3.95 (m, 2H), 3.74 - 3.70 (m, 2H), 3.68 - 3.60 (m, 2H), 3.57 - 3.50 (m, 2H), 3.27 - 3.21 (m, 2H), 1.75 - 1.67 (m, 2H), 1.67 - 1.60 (m, 2H).

[0616] Example 49

[0617] 4-(4-((5-(difluoromethyl)-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0618] Example 49 is prepared by the following steps:

[0619] Step 1 : Compound INT-19 (50 mg, 0.165 mmol) and INT-2b (41 mg, 0.21 mmol) were dissolved in isopropanol (2 mL), p-toluenesulfonic acid (8.5 mg, 49.5 umol) was added, the reaction mixture was stirred under microwave conditions at 90 °C for 2 hours. After the reaction was completed, the reaction liquid was purified by preparative chromatography to obtain compound 49 (26.24 mg, yield 34.6%). ESI-MS (m / z): 459.3 [M+H] + .

[0620] 1 H NMR (500 MHz, DMSO-d6) d 10.04 (s, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 8.02 (s, 1H), 7.85-7.80 (m, 2H), 7.36-7.32 (m, 2H), 7.20 (t, J = 54.4 Hz, 1H), 4.80 (s, 1H), 4.20 (s, 2H), 4.13 (s, 2H), 4.00-3.95 (m, 2H), 3.74-3.68 (m, 2H), 1.10 (s, 6H).

[0621] Example 50

[0622] 4-(4-((5-chloro-4-(1-((1-hydroxycyclopentyl)methyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0623] Example 50 was prepared by the following steps:

[0624] Step 1 : INT-14 (35.00 mg, 0.09 mmol), 50a (9.26 mg, 0.09 mmol), cesium carbonate (61.51 mg, 0.19 mmol) were dissolved in acetonitrile (5 mL), the reaction liquid was stirred at 80 degrees Celsius under nitrogen protection for 12 hours. After the reaction was completed, the reaction liquid was filtered and concentrated to obtain a crude product. The crude product was subjected to reverse phase column chromatography to obtain the target compound 50 (15 mg, yield 33.89%). ESI-MS (m / z): 469.3 [M+H] + .

[0625] 1H NMR (500 MHz, DMSO-de) δ 9.83 (s, 1H), 8.58 (s, 1H), 8.51 (s, 1H), 8.23 (s, 1H), 7.81 - 7.76 (m, 2H), 7.35 - 7.31 (m, 2H), 4.73 (s, 1H), 4.26 (s, 2H), 4.19 (s, 2H), 3.98-3.96 (m, 2H), 3.72-3.70 (m, 2H), 1.72-1.63 (m, 4H), 1.56-1.45 (m, 4H).

[0626] Example 51

[0627] 4-(4-((4-(1-(3-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0628] Example 51 was prepared by the following steps:

[0629] First Step: Compound 51a (200 mg, 0.93 mmol), N,N-diisopropylethylamine (0.48 mL, 2.79 mmol) were dissolved in dichloromethane (5 mL), methanesulfonic anhydride (242.46 mg, 1.39 mmol) was added at 0 °C, and the reaction was allowed to proceed at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated aqueous ammonium chloride solution (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target compound 51b (220 mg, yield 80%).

[0630] Second Step: Compound INT-8 (30 mg, 74.19 umol), 51b (32.65 mg, 111.29 umol) were dissolved in acetonitrile (2 mL), cesium carbonate (72.52 mg, 222.58 umol) was added, and the reaction was allowed to proceed at 90 °C for 16 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (10 mL), washed with saturated brine (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 51c (30 mg, yield 67%) by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2). ESI-MS (m / z): 601.9 [M+H] + .

[0631] Step 3: Compound 51c (30 mg, 49.87 umol) was dissolved in dichloromethane (1 mL), hydrochloric acid 1,4-dioxane solution (49.87 uL, 199.46 umol, 4 M) was added at room temperature. The reaction mixture was continued to stir at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase preparative chromatography to obtain compound 51 (1.84 mg, yield 7%). ESI-MS (m / z): 502.0 [M+H] + .

[0632] 1 H NMR (500 MHz, DMSO-d6) d 10.24 (s, 1H), 8.75 (s, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.84 - 7.74 (m, 2H), 7.36 (d, J = 8.8 Hz, 2H), 4.20 (s, 2H), 4.06 - 3.99 (m, 1H), 3.99 - 3.95 (m, 2H), 3.75 - 3.70 (m, 2H), 3.08 - 2.94 (m, 2H), 2.64 - 2.53 (m, 1H), 2.24 (t, J = 11.7 Hz, 1H), 1.98 - 1.80 (m, 3H), 0.57 (d, J = 6.5 Hz, 3H).

[0633] Example 52

[0634] 4-(2-methyl-4-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0635] Example 52 was prepared from the following steps:

[0636] Step 1: Compound INT-la (200 mg, 0.87 mmol), 4a (363.06 mg, 0.96 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (64.01 mg, 87 umol), potassium carbonate (363.72 mg, 2.62 mmol) were dissolved in 1,4-dioxane (5 mL) / water (0.5 mL), protected by nitrogen, stirred at 90 °C overnight, after the reaction was completed, cooled to room temperature, the reaction liquid was filtered through diatomite, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 52a (243 mg, yield 55%). ESI-MS (m / z): 444.3 [M+H] + .

[0637] Second Step: Compound 52a (213 mg, 0.48 mmol) was dissolved in dichloromethane (5 mL), and the solution was cooled to 0 °C in an ice water bath. m-Chloroperoxybenzoic acid (207.20 mg, 1.20 mmol) was added, and the solution was stirred at 0 °C for four hours. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (30 mL x 3). The organic phase was combined, dried, and concentrated under reduced pressure to obtain 52b (100 mg, yield 43%). ESI-MS (m / z): 476.8 [M+H] + .

[0638] Third Step: A solution of 52b (83 mg, 175 umol), INT-20 (30 mg, 145 umol), trifluoroacetic acid (16.6 mg, 145.4 umol) in isopropanol (2 mL) was stirred at 100 °C for two hours. After the reaction was completed, the reaction was concentrated and dried, and the residue was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain the target compound 52c (30 mg, yield 34%). ESI-MS (m / z): 601.9 [M+H] + .

[0639] Fourth Step: Compound 52c (30 mg, 50 umol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 0 °C for two hours. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried, concentrated, and the residue was purified by preparative chromatography to obtain white solid compound 52 (4 mg, yield 16%). ESI-MS (m / z): 501.2 [M+H] + .

[0640] 1 H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.69 (s, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.66 (s, 1H), 7.57 (dd, J = 8.5, 2.5 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 4.31 (d, J = 11.9 Hz, 1H), 4.14 (d, J = 15.3 Hz, 2H), 3.92 (q, J = 5.4 Hz, 2H), 3.61 (s, 2H), 3.40 (s, 1H), 2.99 (d, J = 12.3 Hz, 2H), 2.54 (t, J = 12.4 Hz, 2H), 2.09 (s, 3H), 1.92 (d, J = 12.0 Hz, 2H), 1.75 (qd, J = 12.1, 4.3 Hz, 2H).

[0641] Example 53

[0642] 4-(4-((5-chloro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)-1,4-thiazepan-5-one 1,1-dioxide

[0643] Example 53 was prepared by the following steps:

[0644] First Step: Compound INT-4 (46.5 mg, 0.16 mmol) and compound INT-13 (30 mg, 0.13 mmol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium (12.63 mg, 13 umol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15.72 mg, 27 umol) and potassium phosphate (85.94 mg, 0.41 mmol) were added successively. The reaction mixture was stirred at 120 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the reaction solution was filtered with celite, and the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain compound 53a (50 mg, yield 51%). ESI-MS (m / z): 473.2 [M+H] + .

[0645] Second Step: Compound 53a (50 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL), and the ice water bath was cooled to 0 °C, and m-chloroperoxybenzoic acid (45.61 mg, 0.26 mmol) was added, and stirred at 0 °C for four hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added to quench the reaction, and extracted with dichloromethane (10 mL x 3), and the combined organic phase was dried, and the residue was concentrated under reduced pressure, and purified by preparative chromatography to obtain white solid compound 53 (6 mg, yield 11%). ESI-MS (m / z): 505.5 [M+H] + .

[0646] 1H NMR (500 MHz, DMSO-de) d 9.81 (s, 1H), 8.56 (s, 1H), 8.51 (s, 1H), 8.22 (s, 1H), 7.78-7.73 (m, 2H), 7.31-7.24 (m, 2H), 4.81 (s, 1H), 4.14 (s, 2H), 4.11-4.03 (m, 2H), 3.50-3.41 (m, 4H), 2.99-2.90 (m, 2H), 1.10 (s, 6H).

[0647] Example 54

[0648] 4-(4-((4-(1-((1-(hydroxymethyl)cyclobutyl)methyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0649] Example 54 was prepared by the following steps:

[0650] First Step: 54a (500.00 mg, 4.30 mmol), N,N-diisopropylethylamine (1.11 g, 8.61 mmol) were dissolved in dichloromethane (10 mL), p-toluenesulfonyl chloride (820.64 mg, 4.30 mmol) was dissolved in dichloromethane (5 mL) and added dropwise to the above reaction solution under room temperature and nitrogen protection, and the reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, and ethyl acetate (150 mL) was extracted. The organic phase was dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the target compound 54b (38 mg, yield 3.27%).

[0651] Second Step: 54b (26.74 mg, 0.10 mmol), INT-8 (40.00 mg, 0.10 mmol), cesium carbonate (64.46 mg, 0.20 mmol) were dissolved in acetonitrile, and the reaction solution was stirred at 80 degrees Celsius under nitrogen protection for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was subjected to reverse phase column chromatography to obtain the target compound 54 (15 mg, yield 30.18%). ESI-MS (m / z): 502.9 [M+H] + .

[0652] 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.76 (s, 1H), 8.26 (s, 1H), 8.00 (s, 1H), 7.82 - 7.78 (m, 2H), 7.38 - 7.34 (m, 2H), 4.83 (t, J = 5.1 Hz, 1H), 4.28 (s, 2H), 4.20 (s, 2H), 3.99 - 3.97 (m, 2H), 3.73 - 3.71 (m, 2H), 3.29-3.28 (m, 2H), 1.93-1.87 (m, 2H), 1.82 - 1.71 (m, 4H).

[0653] Example 55

[0654] 4-(4-((4-(1-((1-(aminomethyl)cyclobutyl)methyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1,4-thiazepan-5-one 1,1-dioxide

[0655] Example 55 was prepared by the following steps:

[0656] First Step: INT-14b (800 mg, 2.32 mmol) and hydrochloric acid-dioxane (4 mol / L, 1.16 mL) were dissolved in a mixed solution of 1,4-dioxane (10 mL) and water (2 mL), and the reaction solution was stirred at 60 °C under nitrogen protection for 12 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (60 mL) was added to adjust the pH of the reaction solution to about 7, dichloromethane (150 mL) was extracted, and the organic phase was dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography (dichloromethane / methanol = 10 / 1) to obtain 55a (430 mg, yield 71.12%). ESI-MS (m / z): 259.4 [M-H] - .

[0657] Second Step: Compound 36c (211 mg, 720 umol) and compound 55a (125 mg, 480 umol) were dissolved in acetonitrile (3 mL), and cesium carbonate (313 mg, 960 umol) was added. The reaction mixture was stirred at 80 °C for 8 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), washed with water (10 mL x 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (ethyl acetate) to obtain compound 55b (140 mg, yield 63%). ESI-MS (m / z): 458.1 [M+H] + .

[0658] Third Step: Compound 55b (140 mg, 306 umol) was dissolved in dichloromethane (3 mL), cooled to 0 °C in an ice water bath, and m-chloroperoxybenzoic acid (155 mg, 765 umol) was added. The reaction solution was stirred at 0 °C for 4 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (10 mL) was added to quench the reaction, and dichloromethane (30 mL x 3) was added for extraction. The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of compound 55c (149 mg, yield 99%). ESI-MS (m / z): 490.5 [M+H] + .

[0659] Fourth Step: Compound 55c (149 mg, 304 umol) and compound INT-13 (102 mg, 461 umol) were dissolved in isopropanol (2 mL), and trifluoroacetic acid (4 mg, 38 umol) was added. The reaction mixture was stirred at 100 °C under microwave conditions for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography (ethyl acetate) to obtain compound 55d (140 mg, yield 73%). ESI-MS (m / z): 632.8 [M+H] + .

[0660] Fifth Step: Compound 55d (140 mg, 222 umol) was dissolved in dichloromethane (3 mL), cooled to 0 °C in an ice water bath, and m-chloroperoxybenzoic acid (113 mg, 554 umol) was added. The reaction solution was stirred at 0 °C for 4 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (10 mL) was added to quench the reaction, and dichloromethane (30 mL x 3) was added for extraction. The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of compound 55e (147 mg, yield 99%). ESI-MS (m / z): 664.6 [M+H] + .

[0661] Step 6: Compound 55e (20 mg, 32 umol) was dissolved in 1,4-dioxane (1 mL), and hydrochloric acid 1,4-dioxane solution (4 mol / L, 2 mL) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain a white solid formate salt of compound 55 (3 mg, yield 17%). ESI-MS (m / z): 563.5 [M+H] + .

[0662] 1 H NMR (500 MHz, DMSO-d6) d 10.23 (s, 1H), 8.75 (s, 1H), 8.36 (s, 2H), 8.31 (s, 1H), 8.01 (s, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 4.32 (s, 2H), 4.11 - 4.06 (m, 2H), 3.44 (d, J = 7.0 Hz, 6H), 2.96 - 2.93 (m, 2H), 1.92 - 1.87 (m, 2H), 1.81 - 1.71 (m, 4H), 1.05 (t, J = 7.0 Hz, 2H).

[0663] Example 56

[0664] 4-(4-((5-chloro-4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0665] Example 56 was prepared by the following steps:

[0666] Step 1 : Compound 46 (83 mg, 183 umol) was dissolved in methanol (3 mL), and formaldehyde aqueous solution (37% solution, 0.02 mL) was added. The reaction mixture was stirred at room temperature for 30 min. Then sodium triacetoxyborohydride (78 mg, 366 umol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 8 h. After the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction, and dichloromethane (20 mL x 3) was added to extract the product. The organic phase was combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography to obtain compound 56 (13 mg, yield 15%) as a white solid. ESI-MS (m / z): 468.4 [M+H] + .

[0667] 1 H NMR (500 MHz, DMSO-d6) d 9.82 (s, 1H), 8.60 (s, 1H), 8.51 (s, 1H), 8.26 (s, 1H), 7.81-7.75 (m, 2H), 7.35-7.29 (m, 2H), 4.32-4.26 (m, 1H), 4.19 (s, 2H), 4.00-3.94 (m, 2H), 3.73-3.68 (m, 2H), 2.90-2.83 (m, 2H), 2.21 (s, 3H), 2.07-1.99 (m, 6H).

[0668] Example 57

[0669] 4-(5-((5-chloro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholin-3-one

[0670] Example 57 was prepared by the following steps:

[0671] First Step: Compound INT-30 (70 mg, 0.21 mmol) and INT-16 (96 mg, 0.28 mmol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium (19 mg, 0.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25 mg, 0.42 mmol), potassium phosphate (135 mg, 0.6 mmol) were added successively. The reaction mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and filtered with celite. The filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 57a (50 mg, yield 36%). ESI-MS (m / z): 640.1 [M+H] + .

[0672] Second Step: Compound 57a (50 mg, 0.08 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.6 mL) was added at 0 °C. The reaction mixture was stirred for 1 h under ice water bath. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain compound 57b (40 mg, yield 94.8%).

[0673] Third Step: Compound 57b (40 mg, 0.07 mmol) was dissolved in a mixed solvent of methanol (3 mL) and water (0.6 mL), and lithium hydroxide monohydrate (15.5 mg, 0.37 mmol) was added. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was purified by preparative chromatography to obtain compound 57 (10.41 mg, yield 28.2%). ESI-MS (m / z): 498.0 [M+H] + .

[0674] 1 H NMR (500 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.49 (s, 1H), 8.39 (s, 1H), 8.12 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 4.78 (s, 1H), 4.19 (q, J = 16.5 Hz, 3H), 4.11 (s, 1H), 4.02 - 3.93 (m, 2H), 3.76 - 3.59 (m, 3H), 3.47 - 3.41 (m, 1H), 2.99 - 2.90 (m, 1H), 2.87 - 2.80 (m, 1H), 2.66 - 2.59 (m, 2H), 1.09 (s, 6H), 0.94 (d, J = 6.5 Hz, 1H).

[0675] Example 58

[0676] 4-(4-((4-(1-((3-methylazetidin-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0677] Example 58 was prepared by the following steps:

[0678] First Step: Dissolve 58a (150 mg, 0.75 mmol), triethylamine (174.04 mg, 1.72 mmol) in dichloromethane (8 mL), add methylsulfonic anhydride (199.74 mg, 1.15 mmol) to the above solution at room temperature under air atmosphere, the reaction solution is reacted at room temperature for 4 hours. After the reaction is completed, quench the reaction by adding water (30 mL), extract with dichloromethane (60 mL), dry and concentrate the organic phase, and then directly use it in the next step reaction (160 mg, yield 99.90%).

[0679] Second Step: Dissolve 58b (110.54 mg, 0.40 mmol), INT-8 (80.00 mg, 0.20 mmol), cesium carbonate (128.93 mg, 0.40 mmol) in N,N-dimethylformamide (5 mL), stir the reaction solution at 90 degrees Celsius under nitrogen protection for 12 hours. After the reaction is completed, cool to room temperature, quench the reaction by adding water (30 mL), extract with ethyl acetate (70 mL), dry and concentrate the organic phase to obtain the crude product which is directly used in the next step reaction. ESI-MS (m / z): 588.2 [M+H] + .

[0680] Third Step: Dissolve 58c (100.00 mg, 0.17 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL) at 0 degrees Celsius under air atmosphere, stir the reaction solution at 0 degrees Celsius for 4 hours. After the reaction is completed, quench the reaction by adding saturated aqueous sodium bicarbonate solution (50 mL), extract with dichloromethane (100 mL), dry and concentrate the organic phase to obtain the crude product. The crude product is subjected to reverse phase column chromatography to obtain the target compound 58 (25 mg, yield 30.13%). ESI-MS (m / z): 488.4 [M+H] + .

[0681] 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.76 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 8.04 (s, 1H), 7.82 - 7.77 (m, 2H), 7.39 - 7.34 (m, 2H), 4.44 (s, 2H), 4.20 (s, 2H), 4.00 - 3.96 (m, 2H), 3.79 (d, J = 9.2 Hz, 2H), 3.74 - 3.70 (m, 2H), 3.40 (d, J = 9.1 Hz, 2H), 1.13 (s, 3H).

[0682] Example 59

[0683] 4-(4-((5-bromo-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0684] Example 59 was prepared from the following steps:

[0685] First Step: Sodium hydride (11 mg, 270 umol, 60% purity) was dissolved in a solution of N,N-dimethylformamide (1 mL) under nitrogen protection, the temperature of the reaction solution was reduced to 0 °C, then INT-7 (24 mg, 107 umol) was added, maintained at 0 °C and stirred for one hour, finally INT-21 (45 mg, 107 umol) was added, the reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and rotary evaporated and purified by reverse phase column chromatography to give the target compound 59 (13 mg, yield 24%). ESI-MS (m / z): 487.4 [M+H] +

[0686] 1 H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.60 (s, 1H), 8.59 (s, 1H), 8.26 (s, 1H), 7.79 - 7.76 (m, 2H), 7.34 - 7.31 (m, 2H), 4.81 (s, 1H), 4.19 (s, 2H), 4.14 (s, 2H), 3.97 (dd, J = 5.9, 4.2 Hz, 2H), 3.73 - 3.69 (m, 2H), 1.11 (s, 6H).

[0687] Example 60

[0688] 4-(4-((5-chloro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(hydroxymethyl)phenyl)morpholin-3-one

[0689] Example 60 was prepared by the following steps:

[0690] First Step: Compound INT-15 (30 mg, 89 umol) and compound 46a (42.61 mg, 106 umol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium (8.16 mg, 9 umol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10.32 mg, 18 umol) and potassium phosphate (56.77 mg, 0.26 mmol) were added successively. The reaction mixture was stirred at 120 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, filtered with celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 60a (50 mg, yield 80%). ESI-MS (m / z): 698.3 [M+H] + .

[0691] Second Step: Compound 60a (80 mg, 114 umol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, concentrated, and the residue was purified by preparative chromatography to give compound 60 as a white solid (30 mg, yield 43%). ESI-MS (m / z): 484.1 [M+H] + .

[0692] 1H NMR (500 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 8.27 (s, 1H), 7.53 (dd, J = 8.5, 2.6 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 5.29 (s, 1H), 4.47 (d, J = 13.5 Hz, 1H), 4.41 - 4.31 (m, 2H), 4.25 - 4.14 (m, 2H), 4.01 - 3.92 (m, 1H), 3.69 (s, 1H), 3.49 - 3.40 (m, 1H), 3.06 (d, J = 12.4 Hz, 2H), 2.64 - 2.54 (m, 2H), 1.97 (d, J = 10.8 Hz, 2H), 1.92 - 1.80 (m, 2H).

[0693] Example 61

[0694] 4-(4-((4-(1-((1-((methylamino)methyl)cyclobutyl)methyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0695] Example 61 was prepared by the following steps:

[0696] First step: compound 36b (500 mg, 2.32 mmol), imidazole (474 mg, 6.97 mmol) were dissolved in dichloromethane (8 mL), the temperature of the reaction system was reduced to 0 °C, then tert-butyldiphenylsilyl chloride (957 mg, 3.48 mmol) was slowly added to the reaction system, stirred at room temperature overnight, after the reaction was completed, extracted with ethyl acetate, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain 61a (850 mg, yield 80%). ESI-MS (m / z): 454.5 [M+H] + .

[0697] Second step: sodium hydride was dissolved in a solution of 61a (700 mg, 1.54 mmol) in N,N-dimethylformamide (2 mL) under nitrogen protection, the temperature of the reaction solution was reduced to 0 °C, 61a (700 mg, 1.54 mmol) was added, and the reaction was stirred at 0 °C for one hour. Finally, iodomethane (766 mg, 5.4 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 1) to obtain 61b (550 mg, yield 76%). ESI-MS (m / z): 468.3 [M+H] + .

[0698] Third step: compound 61b (550 mg, 2.32 mmol), tetrabutylammonium fluoride solution in tetrahydrofuran (1 mol / L, 4.7 mL) was dissolved in tetrahydrofuran (8 mL), and stirred at room temperature overnight. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 61c (200 mg, yield 74%). ESI-MS (m / z): 454.5 [M+H] + .

[0699] 1 H NMR (500 MHz, Chloroform-d) δ 3.46 (s, 2H), 3.31 (s, 2H), 2.87 (s, 3H), 2.04-1.88 (m, 3H), 1.83-1.73 (m, 3H), 1.46 (s, 9H).

[0700] Fourth step: compound 61c (40 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL), and methyl sulfonic anhydride (91 mg, 0.52 mmol) and N,N-diisopropylethylamine (112 mg, 0.87 mmol) were added in turn. The reaction mixture was stirred at 0 °C for 4 hours. After the reaction was completed, the reaction solution was washed with saturated aqueous ammonium chloride solution (20 mL x 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 61d (53 mg, yield 99%).

[0701] Step 5: Compound 61d (53 mg, 0.17 mmol) and compound INT-8 (60 mg, 0.17 mmol) were dissolved in acetonitrile (2 mL), and cesium carbonate (112 mg, 0.34 mmol) was added. The reaction mixture was stirred at 80 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (10 mL). The organic phase was washed with water (10 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain compound 61e (50 mg, yield 47%). ESI-MS (m / z): 615.9 [M+H] + .

[0702] Step 6: Compound 61e (50 mg, 81 umol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, concentrated, and the residue was purified by preparative chromatography to obtain white solid compound 61 (20 mg, yield 47%). ESI-MS (m / z): 516.1 [M+H] + .

[0703] 1 H NMR (500 MHz, DMSO-d6) d 10.25 (s, 1H), 8.76 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.82-7.75 (m, 2H), 7.39-7.33 (m, 2H), 4.36 (s, 2H), 4.20 (s, 2H), 3.98 (dd, J = 6.0, 4.2 Hz, 2H), 3.72 (t, J = 5.0 Hz, 2H), 2.52 (s, 2H), 2.40 (s, 3H), 1.97-1.91 (m, 2H), 1.82 (h, J = 6.7 Hz, 4H).

[0704] Example 62

[0705] 4-(4-((5-chloro-4-(1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0706] Example 62 was prepared from the following steps:

[0707] Step 1 : Compound 62a (2 g, 19.2 mmol), triethylamine (8.03 mL, 57.6 mmol) were dissolved in dichloromethane (5 mL), and thionyl chloride (2.1 mL, 28.81 mmol) was added dropwise at 0 °C. The reaction system was slowly warmed to room temperature and reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane (100 mL), washed with saturated aqueous ammonium chloride solution (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. After concentration, the target compound 62b (2.1 g, yield 72%) was obtained.

[0708] Step 2: Compound 62b (2.1 g, 13.98 mmol), ruthenium trichloride monohydrate (315.21 mg, 1.4 mmol) were dissolved in acetonitrile (20 mL) and water (20 mL), and sodium periodate (5.98 g, 27.96 mmol) was added at 0 °C. The reaction system was slowly warmed to room temperature and reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was extracted with dichloromethane (50 mL x 3), washed with saturated aqueous sodium sulfite solution (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. After filtration and concentration, the target compound 62c (2 g, yield 86%) was obtained.

[0709] Step 3: Compound INT-14 (20 mg, 53.94 umol), 62c (17.93 mg, 107.8 umol) were dissolved in acetonitrile (2 mL), and cesium carbonate (52.72 mg, 161.82 umol) was added. The reaction was carried out at 90 °C for 16 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane (10 mL), filtered and concentrated to obtain a residue which was dissolved in acetonitrile (2 mL), and p-toluenesulfonic acid monohydrate (30.78 mg, 161.82 umol) was added. The reaction was carried out at 50 °C for 3 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly concentrated and purified by reverse phase preparative chromatography to obtain compound 62 (2.3 mg, yield 9%). ESI-MS (m / z): 457.4 [M+H] + .

[0710] 1 H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.54 (s, 1H), 8.51 (s, 1H), 8.23 (s, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.32 (d, J = 8.9 Hz, 2H), 4.86 (s, 1H), 4.19 (s, 2H), 4.10 (s, 2H), 4.00 - 3.95 (m, 2H), 3.75 - 3.68 (m, 2H), 3.16 (s, 2H), 0.85 (s, 6H).

[0711] Example 63

[0712] 4-(4-((5-chloro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(hydroxymethyl)phenyl)morpholin-3-one

[0713] Example 63 was prepared from the following steps:

[0714] First Step: Compound 46a (100 mg, 251 umol) and INT-22 (93 mg, 276 umol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium (23 mg, 25 umol), potassium phosphate (107 mg, 502 umol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (29 mg, 50 umol) were added successively. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and filtered with celite. The filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to give compound 63a (90 mg, yield 51%). ESI-MS (m / z): 699.0 [M+H] + .

[0715] Second Step: Compound 63a (90 mg, 129 umol) was dissolved in 1,4-dioxane (1 mL), and hydrochloric acid 1,4-dioxane solution (4 mol / L, 2 mL) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, it was quenched with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by preparative chromatography to give compound 63 (21 mg, yield 34%) as a white solid. ESI-MS (m / z): 484.3 [M+H] + .

[0716] 1H NMR (500 MHz, DMSO-de) d 9.06 (s, 1H), 8.54 (s, 1H), 8.49 - 8.41 (m, 1H), 8.23 - 8.15 (m, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 7.30 (d, J = 8.5 Hz, 1H), 5.61 (s, 1H), 4.57 (s, 2H), 4.40 - 4.30 (m, 1H), 4.21 (s, 2H), 3.98 (s, 2H), 3.73 (s, 2H), 3.10 - 2.99 (m, 2H), 2.65 - 2.53 (m, 2H), 1.99 - 1.92 (m, 2H), 1.89 - 1.77 (m, 2H).

[0717] Example 64

[0718] 2-((4-(3-oxomorpholino)phenyl)amino)-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile

[0719] Example 64 was prepared by the following steps:

[0720] First Step: Dissolve INT-7 (32.99 mg, 149.81 umol) in anhydrous N,N- dimethylformamide (1 mL), cool to 0 °C, add sodium hydride (6.49 mg, 162.3 umol, 60% purity) to the above reaction solution under nitrogen atmosphere, and react at 0 °C for half an hour. Add INT-23 (50 mg, 124.84 umol) in anhydrous N,N-dimethylformamide (1 mL) to the above reaction solution, keep the reaction solution under nitrogen atmosphere, and stir at room temperature for 12 hours. After the reaction is completed, quench the reaction by adding saturated aqueous ammonium chloride solution (10 mL) to the reaction solution, extract with ethyl acetate (10 mL x 3), wash the combined organic phase with saturated brine (10 mL x 3), dry and concentrate to obtain compound 64a (40 mg, yield 58%). ESI-MS (m / z): 545.6 [M+H] + .

[0721] Second Step: Compound 64a (40 mg, 73.45 umol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added at room temperature. The reaction mixture was continued to stir at room temperature for 3 hours. After the reaction was completed, triethylamine (2 mL) was added, and the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase preparative chromatography to obtain compound 64 (11.37 mg, yield 34%). ESI-MS (m / z): 445.2 [M+H] + .

[0722] 1 H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.85 (s, 1H), 8.54 (s, 1H), 8.27 (s, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.49 - 4.33 (m, 1H), 4.20 (s, 2H), 4.00 - 3.94 (m, 2H), 3.76 - 3.70 (m, 2H), 3.09 - 3.00 (m, 2H), 2.65 - 2.54 (m, 2H), 2.01 - 1.94 (m, 2H), 1.86 - 1.76 (m, 2H).

[0723] Example 65

[0724] 4-(4-((4-(1-(2-amino-2-methylpropyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0725] Example 65 was prepared from the following steps:

[0726] First Step: INT-14 (50 mg, 0.13 mmol), 65a (33.87 mg, 0.13 mmol), cesium carbonate (87.87 mg, 0.27 mmol) were dissolved in acetonitrile (5 mL), stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated to obtain a crude product which was directly used in the next step reaction (60 mg, yield 94.29%). ESI-MS (m / z): 471.8 [M+H] + .

[0727] Second Step: Dissolve 65b (60 mg, 0.13 mmol), reduced iron powder (71.01 mg, 1.27 mmol), ammonium chloride (27.20 mg, 0.51 mmol) in a mixture of ethanol (10 mL) and water (1 mL), the reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was subjected to reverse phase column chromatography to obtain the target compound 65 (15 mg, yield 26.70%). ESI-MS (m / z): 442.2 [M+H] + .

[0728] 1 H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.24 (s, 1H), 7.79 (d, J = 10.0 Hz, 2H), 7.33 (d, J = 10.0 Hz, 2H), 4.19 (s, 2H), 4.09 (s, 2H), 3.98 - 3.96 (m, 2H), 3.72 - 3.70 (m, 2H), 1.58 (s, 2H), 1.01 (s, 6H).

[0729] Example 66

[0730] 4-(4-((5-chloro-4-(2-(piperidin-4-yl)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0731] Example 66 was prepared by the following steps:

[0732] First Step: Dissolve compound INT-28a (2 g, 12.2 mmol) and 66a (4.15 g, 13.4 mmol) in a mixture of 1,4-dioxane (30 mL) and water (3 mL), then sequentially add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (713 mg, 975 μmol) and sodium carbonate (3.9 g, 36.6 mmol), and stir the reaction mixture at 90 °C under nitrogen atmosphere for 16 hours. After the reaction is completed, cool to room temperature, filter the reaction solution through diatomite, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 66b (1.75 g, yield 53%). ESI-MS (m / z): 267.2 [M+H] + .

[0733] Second step: compound 66b (1.75 g, 6.57 mmol) was dissolved in methanol (20 mL), then platinum dioxide (372 mg, 1.64 mmol) was added, and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 48 hours. After the reaction was completed, the reaction solution was filtered through diatomite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 66c (1.32 g, yield 74%). ESI-MS (m / z): 268.8 [M+H] + .

[0734] Third step: compound 66c (1.23 g, 4.58 mmol) was dissolved in N,N-dimethylformamide (15 mL), and N-bromosuccinimide (1.14 g, 6.42 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain solid compound 66d (1.1 g, yield 69%).

[0735] 1 H NMR (500 MHz, DMSO-d6) δ 7.78 (s, 1H), 3.98 (d, J = 13.1 Hz, 2H), 3.19 (tt, J = 11.6, 3.8 Hz, 1H), 2.93-2.81 (m, 2H), 2.02-1.94 (m, 2H), 1.55-1.50 (m, 2H), 1.40 (s, 9H).

[0736] Fourth step: compound 66d (600 mg, 1.73 mmol) and pinacol diboronic acid (1.32 g, 5.2 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL), then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (126 mg, 172 μmol) and potassium acetate (508 mg, 5.18 mmol) were added in sequence, and the reaction mixture was stirred at 90°C under nitrogen atmosphere for 3 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered through diatomite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 2) to obtain compound 66e (438 mg, yield 81%). ESI-MS (m / z): 394.9 [M+H] + .

[0737] Step 5: Compound 66e (150 mg, 0.48 mmol) and 2,4,5-trichloropyrimidine (176 mg, 0.96 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL), then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (35 mg, 48 umol) and sodium carbonate (152 mg, 1.44 mmol) were added successively. The reaction mixture was stirred at 90 °C under nitrogen atmosphere for 16 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound 66f (150 mg, yield 70%). ESI-MS (m / z): 414.8 [M+H] + .

[0738] Step 6: Compound 66f (150 mg, 361 umol) and INT-2b (91 mg, 429 umol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium (33 mg, 36 umol), potassium phosphate (230 mg, 1.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (42 mg, 73 umol) were added successively. The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 16 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was filtered through celite. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain compound 66g (125 mg, yield 60%). ESI-MS (m / z): 571.0 [M+H] + .

[0739] Step 7: Compound 66g (125 mg, 210 umol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.2 mL) was added at room temperature. The reaction mixture was continued to stir at room temperature for 2 hours. After the reaction was completed, triethylamine (0.3 mL) was added, and the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase preparative chromatography to obtain compound 66 (14 mg, yield 14%). ESI-MS (m / z): 470.7 [M+H] + .

[0740] 1H NMR (500 MHz, DMSO-de) d 10.03 (s, 1H), 8.73 (s, 1H), 8.64 (s, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 4.20 (s, 2H), 3.98 (t, J = 5.0 Hz, 2H), 3.72 (t, J = 5.0 Hz, 2H), 3.19 - 3.11 (m, 1H), 3.02 (d, J = 12.7 Hz, 2H), 2.67 - 2.57 (m, 2H), 2.05 - 1.97 (m, 2H), 1.68 - 1.54 (m, 2H).

[0741] Example 67

[0742] 4-(4-((5-chloro-4-(1-(piperidin-3-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0743] Example 67 was prepared from the following steps:

[0744] First Step: Dissolve INT-14 (40.00 mg, 0.11 mmol), 67a (37.98 mg, 0.13 mmol), cesium carbonate (70.30 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL), the reaction solution was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, water (20 mL) was added to quench the reaction, and ethyl acetate (50 mL) was extracted. The organic phase was dried and concentrated, and then directly used in the next step (55 mg, yield 89.75%). ESI-MS (m / z): 568.4 [M+H] +

[0745] Second Step: Dissolve 67b (45 mg, 0.08 mmol) in dichloromethane (3 mL), and add trifluoroacetic acid (1 mL) at 0°C. The reaction solution was stirred at 0°C for 3 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (30 mL) was added to adjust the pH to about 7, dichloromethane (50 mL) was extracted, and the organic phase was dried and concentrated to obtain the crude product. The crude product was subjected to column chromatography to obtain the target compound 67 (15 mg, yield 40.46%). MS (m / z): 469.9 [M+H] +

[0746] 1H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.59 (s, 1H), 8.51 (s, 1H), 8.24 (s, 1H), 7.79 - 7.77 (m, 2H), 7.34 - 7.32 (m, 2H), 4.19 (s, 2H), 4.13-4.10 (m, 2H), 3.98-3.96 (m, 2H), 3.72-3.70 (m, 2H), 2.80-2.71 (m, 2H), 2.44 - 2.40 (m, 1H), 2.26-2.22 (m, 1H), 1.96 (s, 1H), 1.62 - 1.54 (m, 2H), 1.33 - 1.27 (m, 1H), 1.14 - 1.05 (m, 1H).

[0747] Example 68

[0748] 4-acetyl-1-(4-((5-chloro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)piperazin-2-one

[0749] Example 68 was prepared by the following steps:

[0750] First Step: Compound INT-4b (110 mg, 0.38 mmol), 4-dimethylaminopyridine (48.8 mg, 0.38 mmol) were dissolved in acetic anhydride (3 mL), then the mixture was stirred at 60 °C for 3 hours, after the reaction was completed, it was cooled to room temperature, saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, then extracted with dichloromethane (10 mL x 3), the combined organic phase was dried, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 68a (90 mg, yield 71%). ESI-MS (m / z): 329.3 [M+H] + .

[0751] Second Step: Compound 68a (40 mg, 0.17 mmol) and compound INT-24 (65.74 mg, 0.21 mmol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium (16 mg, 17 umol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 34 umol) and potassium phosphate (109.2 mg, 0.51 mmol) were added successively. The reaction mixture was stirred at 120 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the reaction solution was filtered with celite, and the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 8 / 1) to obtain compound 68b (80 mg, yield 88%). ESI-MS (m / z): 526.42 [M+H] + .

[0752] Third Step: Compound 68b (80 mg, 0.15 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL) and water (1 mL), and lithium hydroxide (11 mg, 0.45 mmol) was added. The reaction mixture was stirred at 0 °C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain compound 68 (10 mg, yield 13%) as a white solid. ESI-MS (m / z): 484.4 [M+H] + .

[0753] 1 H NMR (500 MHz, DMSO-d6) d 9.84 (s, 1H), 8.56 (s, 1H), 8.52 (s, 1H), 8.23 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.28 (dd, J = 8.9, 2.8 Hz, 2H), 4.81 (s, 1H), 4.26 (s, 1H), 4.15 (d, J = 2.3 Hz, 3H), 3.82 (q, J = 3.8, 2.5 Hz, 1H), 3.77 (q, J = 5.5 Hz, 2H), 3.67 (t, J = 5.4 Hz, 1H), 2.08 (d, J = 13.5 Hz, 3H), 1.10 (s, 6H).

[0754] Example 69

[0755] 3-amino-1-(4-((5-chloro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)pyrrolidin-2-one

[0756] Example 69 was prepared by the following steps:

[0757] First Step: Compound INT-25 (60 mg, 205 umol) and compound 46a (90.26 mg, 226 umol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium (18.86 mg, 21 umol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (24.53 mg, 42 umol) and potassium phosphate (131 mg, 0.62 mmol) were added successively. The reaction mixture was stirred at 120 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, filtered with celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to obtain compound 69a (114 mg, yield 84%). ESI-MS (m / z): 653.51 [M+H] + .

[0758] Second Step: Compound 69a (114 mg, 171 umol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, it was quenched with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane, and the organic phase was dried and concentrated. The residue was purified by preparative chromatography to obtain compound 69 (10 mg, yield 12%) as a white solid. ESI-MS (m / z): 453.5 [M+H] + .

[0759] 1 H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.58 (s, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 7.78-7.72 (m, 2H), 7.66-7.59 (m, 2H), 4.37 (s, 1H), 3.76-3.68 (m, 2H), 3.55-3.49 (m, 1H), 3.05 (d, J = 12.5 Hz, 2H), 2.59 (t, J = 12.2 Hz, 2H), 2.40-2.31 (m, 1H), 2.01-1.95 (m, 2H), 1.90-1.79 (m, 3H), 1.78-1.71 (m, 1H).

[0760] Example 70

[0761] 4-(4-((4-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0762] Example 70 was prepared from the following steps:

[0763] First Step: Compound 46 (30 mg, 66 umol) and glacial acetic acid (8 mg, 132 umol) were dissolved in N,N-dimethylformamide (3 mL), followed by the addition of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (38 mg, 99 umol) and N,N-diisopropylethylamine (26 mg, 198 umol), the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain compound 70 (5 mg, yield 15%) as a white solid. ESI-MS (m / z): 496.4 [M+H] + .

[0764] 1 H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.63 (s, 1H), 8.51 (s, 1H), 8.25 (s, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 4.64 - 4.56 (m, 1H), 4.53 - 4.46 (m, 1H), 4.19 (s, 2H), 4.00 - 3.96 (m, 2H), 3.94 (s, 1H), 3.73 - 3.68 (m, 2H), 3.25 - 3.17 (m, 1H), 2.76 - 2.68 (m, 1H), 2.05 (s, 5H), 2.02 - 1.92 (m, 1H), 1.86 - 1.76 (m, 1H).

[0765] Example 71

[0766] 4-(4-((5-chloro-4-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0767] Example 71 was prepared from the following steps:

[0768] Step 1: Compound 46 (30 mg, 66 umol) and 2-bromoethyl methyl ether (10 mg, 73 umol) were dissolved in acetonitrile (5 mL), followed by the addition of potassium iodide (11 mg, 66 umol) and potassium carbonate (18 mg, 132 umol), and the reaction mixture was stirred at 60 °C for 16 hours. After the reaction was completed, it was cooled to room temperature, the reaction mixture was quenched with water (10 mL), extracted with dichloromethane (20 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain compound 71 (4 mg, yield 12%) as a white solid. ESI-MS (m / z): 513.1 [M+H] + .

[0769] 1 H NMR (500 MHz, DMSO-d6) d 9.82 (s, 1H), 8.60 (s, 1H), 8.51 (s, 1H), 8.25 (s, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 4.34 - 4.26 (m, 1H), 4.19 (s, 2H), 4.00 - 3.94 (m, 2H), 3.74 - 3.69 (m, 2H), 3.45 (t, J = 5.8 Hz, 2H), 3.25 (s, 3H), 3.02 - 2.96 (m, 2H), 2.53 (d, J = 5.9 Hz, 2H), 2.19 - 2.11 (m, 2H), 2.05 - 1.96 (m, 4H).

[0770] Example 72

[0771] 3-(4-((5-chloro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)-3,9-diazaspiro[5.5]undecan-2-one

[0772] Example 72 was prepared from the following steps:

[0773] Step 1: Compound INT-31 (100 mg, 251.08 umol), INT-26 (108.3 mg, 301.29 umol), tris(dibenzylideneacetone)dipalladium (22.99 mg, 24.11 umol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (29.06 mg, 50.22 umol), cesium carbonate (245.42 mg, 753.23 umol) were dissolved in 1,4-dioxane (5 mL) under nitrogen protection, and stirred at 100 °C overnight. After the reaction was completed, it was cooled to room temperature, filtered through diatomite, concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 72a (70 mg, yield 38%). ESI-MS (m / z): 721.7 [M+H] + .

[0774] Step 2: Compound 72a (70 mg, 97.05 umol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added at room temperature. The reaction mixture was continued to stir at room temperature for 3 hours. After the reaction was completed, triethylamine (2 mL) was added, and the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase preparative chromatography to obtain compound 72 (36.45 mg, yield 61%). ESI-MS (m / z): 521.3 [M+H] + .

[0775] 1 H NMR (500 MHz, DMSO-d6) d 9.81 (s, 1H), 8.60 (s, 1H), 8.51 (s, 1H), 8.33 (s, 2H), 8.27 (s, 1H), 7.75 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 8.9 Hz, 2H), 4.59 - 4.49 (m, 1H), 3.61 (t, J = 6.3 Hz, 2H), 3.30 - 3.22 (m, 2H), 3.06 (t, J = 5.8 Hz, 4H), 2.84 (t, J = 12.1 Hz, 2H), 2.41 - 2.33 (m, 2H), 2.13 - 1.99 (m, 4H), 1.87 (t, J = 6.4 Hz, 2H), 1.72 - 1.60 (m, 4H).

[0776] Example 73

[0777] 4-(4-((5-chloro-4-(2-(piperazin-1-yl)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0778] Example 73 was prepared from the following steps:

[0779] First Step: INT-7 (93.36 mg, 423.94 umol) was dissolved in anhydrous N,N- dimethylformamide (1 mL), cooled to 0 °C, and sodium hydride (16.96 mg, 423.94 umol, 60% purity) was added to the above reaction solution under a nitrogen atmosphere. The reaction solution was reacted at 0 °C for half an hour. INT-27 (150 mg, 326.11 umol) was dissolved in anhydrous N,N-dimethylformamide (1 mL) and added to the above reaction solution. The reaction solution was stirred at room temperature for 12 hours under a nitrogen atmosphere. After the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (10 mL x 3), dried and concentrated to obtain compound 73a (100 mg, yield 53%). ESI-MS (m / z): 572.3 [M+H] + .

[0780] Second Step: Compound 73a (100 mg, 174.8 umol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added at room temperature. The reaction mixture was continuously stirred at room temperature for 3 hours. After the reaction was completed, triethylamine (2 mL) was added, and the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase preparative chromatography to obtain compound 73 (15.58 mg, yield 18%). ESI-MS (m / z): 471.8 [M+H] + .

[0781] 1 H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.45 (s, 1H), 8.38 (s, 1H), 7.82-7.70 (m, 2H), 7.37-7.30 (m, 2H), 4.19 (s, 2H), 4.00-3.93 (m, 2H), 3.74-3.68 (m, 2H), 3.54-3.48 (m, 4H), 2.86-2.74 (m, 4H).

[0782] Example 74

[0783] 4-(4-((4-(1-((1-(aminomethyl)cyclopentyl)methyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0784] Example 74 was prepared from the following steps:

[0785] First Step: Compound 74a (300 mg, 1.23 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), the mixture was stirred at 0 °C for 1 h, then tetrahydroaluminum lithium (60.84 mg, 1.60 mmol) was added, finally the mixture was stirred at room temperature overnight, after the reaction was completed, saturated potassium sodium tartrate solution (10 mL) was added to quench the reaction, then extracted with ethyl acetate (10 mL x 3), the organic phase was combined, dried, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to obtain compound 74b (110 mg, yield 38%).

[0786] 1 H NMR (500 MHz, Chloroform-d) δ 4.91 (s, 1H), 3.90 - 3.66 (m, 1H), 3.28 (s, 2H), 3.07 (d, J = 6.8 Hz, 2H), 1.65 - 1.55 (m, 6H), 1.45 (s, 9H), 1.42 (d, J = 3.2 Hz, 2H), δ 1.26 (d, J = 2.7 Hz, 2H).

[0787] Second Step: Triethylamine (106 mg, 1.05 mmol), dichlorosulfoxide (83 mg, 0.7 mmol), imidazole (142 mg, 2.09 mmol) were dissolved in dichloromethane (5 mL), the mixture was stirred at 0 °C for 1 h, then compound 74b (80 mg, 0.35 mmol) was added, finally the mixture was stirred at room temperature overnight, after the reaction was completed, water (5 mL) and dichloromethane (10 mL) were added to quench the reaction, washed with saturated sodium bicarbonate solution (10 mL), saturated sodium citrate (10 mL), saturated brine (10 mL) in turn, dried, filtered, and rotary evaporated to obtain the crude product 74c (80 mg, yield 83%).

[0788] Third Step: Compound 74c (80 mg, 0.29 mmol) was dissolved in acetonitrile (2 mL) / water (2 mL), then sodium periodate (124 mg, 0.58 mmol), ruthenium trichloride hydrate (6 mg, 29 umol) were added at 0 °C, finally the reaction system was stirred at room temperature overnight, after the reaction was completed, saturated sodium bicarbonate aqueous solution (5 mL) was added to quench the reaction, then extracted with ethyl acetate (10 mL x 3), the organic phase was combined, dried, filtered, and rotary evaporated to obtain 74d (36 mg, yield 43%).

[0789] Fourth step: Compound 74d (36 mg, 0.12 mmol) and compound INT-8 (25 mg, 62 umol) were dissolved in acetonitrile (2 mL), and cesium carbonate (60 mg, 0.18 mmol) was added. The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), washed with water (10 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain compound 74e (28 mg, yield 73%). ESI-MS (m / z): 616.3 [M+H] + .

[0790] Fifth step: Compound 74e (28 mg, 45 umol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (10 mL x 3), dried, concentrated, and the residue was purified by preparative chromatography to obtain white solid compound 74 (10 mg, yield 12%). ESI-MS (m / z): 516.3 [M+H] + .

[0791] 1 H NMR (500 MHz, DMSO-d6) δ 10.25 (d, J = 4.2 Hz, 1H), 8.76 (d, J = 3.9 Hz, 1H), 8.33 (s, 1H), 8.02 (d, J = 3.5 Hz, 1H), 7.82-7.77 (m, 2H), 7.36 (d, J = 8.8 Hz, 2H), 5.42 (d, J = 10.8 Hz, 1H), 4.24 (s, 2H), 4.20 (s, 2H), 3.99-3.96 (m, 2H), 3.72 (t, J = 5.1 Hz, 2H), 3.66-3.61 (m, 2H), 1.61-1.57 (m, 3H), 1.53-1.49 (m, 3H), 1.41-1.37 (m, 2H).

[0792] Example 75

[0793] 4-(4-((5-chloro-4-(1-((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0794] Example 75 was prepared from the following steps:

[0795] First Step: Compound 75a (100 mg, 0.44 mmol) was dissolved in tetrahydrofuran (5 mL), methanesulfonic anhydride (115 mg, 0.66 mmol) and N,N-diisopropylethylamine (171 mg, 1.32 mmol) were added successively, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution (15 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated brine (10 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated to give compound 75b (130 mg, yield 97%).

[0796] Second Step: Compound 75b (130 mg, 0.42 mmol) and compound INT-14 (70 mg, 0.19 mmol) were dissolved in acetonitrile (5 mL), and cesium carbonate (123 mg, 0.38 mmol) was added. The reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the solid was removed by filtration, the filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to give compound 75c (100 mg, yield 91.3%). ESI-MS (m / z): 580.6 [M+H] + .

[0797] Third Step: Compound 75c (100 mg, 0.17 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.6 mL) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by preparative chromatography to give white solid compound 75 (11 mg, yield 12.7%). ESI-MS (m / z): 480.1 [M+H] + .

[0798] 1 H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.59 (s, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 7.81-7.75 (m, 2H), 7.37-7.29 (m, 2H), 5.16-4.93 (m, 1H), 4.19 (s, 2H), 3.97 (dd, J = 6.0, 4.2 Hz, 2H), 3.71 (dd, J = 6.1, 4.0 Hz, 2H), 3.15-3.02 (m, 3H), 2.84-2.64 (m, 3H), 2.53-2.51 (m, 1H), 2.29-2.21 (m, 2H), 2.05-1.89 (m, 2H).

[0799] Example 76

[0800] 4-(4-((5-chloro-4-(5-chloro-1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0801] Example 77

[0802] 4-(4-((5-chloro-4-(3-chloro-1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0803] Examples 76 and 77 were prepared by the following steps:

[0804] First step: INT-17 (160.00 mg, 0.39 mmol), 76a (165.45 mg, 0.59 mmol), cesium carbonate (257.29 mg, 0.79 mmol) were dissolved in N,N-dimethylformamide (10 mL), the reaction was stirred at 100 degrees Celsius for 12 hours under nitrogen protection. After the reaction was completed, the reaction was added to water (30 mL) and extracted with ethyl acetate (60 mL). The organic phase was dried and concentrated to obtain the crude product. The crude product was purified by reverse phase column chromatography to obtain the target compound 76b (40 mg, yield 17.22%). ESI-MS (m / z): 588.1 [M+H] + , 77b (27 mg, yield 11.62%). ESI-MS (m / z): 588.3 [M+H] + .

[0805] Second step: 76b (40 mg, 0.07 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added at 0 degrees Celsius, and the reaction was stirred at 0 degrees Celsius for 3 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (30 mL) was added to adjust the pH to about 7, extracted with dichloromethane (50 mL), and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by reverse phase column chromatography to obtain the target compound (19 mg, yield 57.24%). ESI-MS (m / z): 487.9 [M+H] + .

[0806] 1H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.60 (s, 1H), 8.45 (s, 1H), 7.82-7.80 (m, 2H), 7.30-7.28 (m, 2H), 4.33-4.28 (m, 1H), 4.18 (s, 2H), 3.97-3.95 (m, 2H), 3.71-3.69 (m, 2H), 3.05-3.03 (m, 2H), 2.59-2.54 (m, 2H), 1.97-1.94 (m, 2H), 1.81-1.75 (m, 3H).

[0807] Step 3: Dissolve 77b (27 mg, 0.05 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL) at 0 °C, stir the reaction solution at 0 °C for 3 hours. After the reaction is completed, add saturated aqueous sodium bicarbonate solution (30 mL), adjust the pH to about 7, extract with dichloromethane (50 mL), dry and concentrate the organic phase to obtain a crude product, purify the crude product by reverse phase column chromatography to obtain the target compound 77. ESI-MS (m / z): 488.0 [M+H] + .

[0808] 1 H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.60 (s, 1H), 8.15 (s, 1H), 7.79-7.78 (m, 2H), 7.31-7.29 (m, 2H), 4.49-4.45 (m, 1H), 4.18 (s, 2H), 3.97-3.95 (m, 2H), 3.71-3.69 (m, 2H), 3.08-3.05 (m, 2H), 2.65-2.60 (m, 2H), 1.92-1.85 (m, 5H).

[0809] Example 78

[0810] 5-((5-chloro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(3-oxomorpholino)benzonitrile

[0811] Example 78 is prepared from the following steps:

[0812] First Step: Compound 46a (134 mg, 337 umol) and INT-32 (93 mg, 370 umol) were dissolved in 1,4-dioxane (5 mL), and then 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (31 mg, 34 umol), cesium carbonate (220 mg, 673 umol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I- propyl-11'-biphenyl (36 mg, 67 umol) were added successively. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and then filtered with celite. The filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 78a (120 mg, yield 59%). ESI-MS (m / z): 612.5 [M+H] + .

[0813] Second Step: Compound 78a (63 mg, 103 umol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and water (0.5 mL), and then lithium hydroxide (8 mg, 309 umol) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), washed with ethyl acetate (10 mL x 2), and then the aqueous phase was adjusted to pH 4 with hydrochloric acid aqueous solution (4 mol / L). The aqueous phase was extracted with dichloromethane (10 mL x 2), and then the combined organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain compound 78b (61 mg, yield 99%) as a crude product. ESI-MS (m / z): 598.6 [M+H] + .

[0814] Third Step: Compound 78b (61 mg, 102 umol) and ammonium chloride (14 mg, 261 umol) were dissolved in N,N-dimethylformamide (3 mL), and then 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (75 mg, 196 umol) and N,N-diisopropylethylamine (51 mg, 391 umol) were added successively. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then the residue was purified by preparative chromatography to obtain compound 78c (11 mg, yield 19%) as a white solid. ESI-MS (m / z): 579.1 [M+H] + .

[0815] Fourth step: compound 78c (11 mg, 18 umol) was dissolved in 1,4-dioxane (1 mL), hydrochloric acid 1,4-dioxane solution (4 mol / L, 2 mL) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain white solid compound 78 (3 mg, yield 36%). ESI-MS (m / z): 479.1 [M+H] + .

[0816] 1 H NMR (500 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.99 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 4.65 (s, 2H), 4.43 - 4.33 (m, 1H), 4.21 - 4.17 (m, 2H), 4.15 - 4.10 (m, 2H), 3.13 - 3.01 (m, 2H), 2.66 - 2.57 (m, 2H), 2.04 - 1.96 (m, 2H), 1.94 - 1.82 (m, 2H).

[0817] Example 79

[0818] 4-(4-((4-(2-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0819] Example 79 was prepared from the following steps:

[0820] First step: compound INT-28 (10 mg, 26 umol) and compound INT-2b (8 mg, 38 umol) were dissolved in isopropanol (2 mL), trifluoroacetic acid (1 mg, 8 umol) was added. The reaction mixture was stirred under microwave conditions at 100 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by preparative chromatography to obtain white solid compound 79 (2 mg, yield 16%). ESI-MS (m / z): 505.8 [M+H] + .

[0821] 1H NMR (500 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.87 (s, 1H), 8.24 (s, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.38 (d, J = 8.9 Hz, 2H), 4.20 (s, 2H), 4.02 - 3.91 (m, 4H), 3.77 - 3.70 (m, 2H), 3.53 - 3.45 (m, 2H), 3.40 - 3.35 (m, 1H), 2.06 - 1.99 (m, 2H), 1.83 - 1.73 (m, 2H).

[0822] Example 80

[0823] 4-(4-((5-chloro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(1-hydroxyethyl)phenyl)morpholin-3-one

[0824] Example 80 was prepared by the following steps:

[0825] First Step: Compound INT-29 (68 mg, 194 umol) and compound 46a (116 mg, 291 umol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium (18 mg, 20 umol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 39 umol) and potassium phosphate (123 mg, 0.68 mmol) were added successively. The reaction mixture was stirred at 120 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, filtered with celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain compound 80a (80 mg, yield 67%). ESI-MS (m / z): 612.0 [M+H] + .

[0826] Second Step: Compound 80a (80 mg, 171 umol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, it was quenched with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL x 3), and the organic phase was dried and concentrated. The residue was purified by preparative chromatography to obtain white solid compound 80 (7 mg, yield 10%). ESI-MS (m / z): 497.9 [M+H] + .

[0827] 1 H NMR (500 MHz, DMSO-d6) δ 9.85 (d, J = 4.9 Hz, 1H), 8.69 (d, J = 7.8 Hz, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 4.3 Hz, 1H), 8.35 (d, J = 17.1 Hz, 2H), 7.51 - 7.45 (m, 1H), 7.18 - 7.09 (m, 1H), 4.81 - 4.70 (m, 1H), 4.46 - 4.40 (m, 1H), 4.25 - 4.14 (m, 2H), 4.03 - 3.95 (m, 2H), 3.80 - 3.74 (m, 1H), 3.68 - 3.63 (m, 1H), 3.17 (d, J = 12.7 Hz, 2H), 2.74 (d, J = 12.5 Hz, 2H), 2.05 (d, J = 12.4 Hz, 2H), 1.98 (d, J = 13.5 Hz, 2H), 1.29 (dd, J = 14.4, 6.3 Hz, 3H).

[0828] Example 81

[0829] 4-(4-((4-(1-((1-(aminomethyl)cyclobutyl)methyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0830] Example 81 was prepared by the following steps:

[0831] First Step: Compound 36c (36 mg, 36 umol) and compound INT-14 (30 mg, 81 umol) were dissolved in acetonitrile (2 mL), cesium carbonate (53 mg, 162 umol) was added. The reaction mixture was stirred at 80 °C for 8 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), and the organic phase was washed with water (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 81a (40 mg, yield 87%). ESI-MS (m / z): 568.6 [M+H] + .

[0832] Step 2: Compound 81a (40 mg, 71 umol) was dissolved in 1,4-dioxane (1 mL), hydrochloric acid in dioxane (4 mol / L, 2 mL) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (10 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain white solid compound 81 (3 mg, yield 8%). ESI-MS (m / z): 467.6 [M+H] + .

[0833] 1 H NMR (500 MHz, DMSO-d6) d 9.82 (s, 1H), 8.64 (s, 1H), 8.51 (s, 1H), 8.23 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 4.33 (s, 2H), 4.19 (s, 2H), 3.99 - 3.95 (m, 2H), 3.73 - 3.69 (m, 2H), 2.52 (s, 2H), 1.95 - 1.89 (m, 2H), 1.83 - 1.73 (m, 4H), 1.24 (s, 2H).

[0834] Example 82

[0835] 4-(4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-methoxypyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0836] Example 82 was prepared from the following steps:

[0837] First Step: Compound INT-11 (80 mg, 282.96 umol), INT-2b (70.7 mg, 367.84 umol), methane sulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (12.82 mg, 14.1 umol), cesium carbonate (276.58 mg, 848.88 umol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I- propyl-11'-biphenyl (15.13 mg, 28.2 umol) were dissolved in 1,4-dioxane (5 mL), protected by nitrogen, stirred at 100 °C overnight, after the reaction was completed, cooled to room temperature, the reaction solution was filtered through diatomite, the residue was purified by reverse phase preparative chromatography to obtain white solid compound 82 (56.4 mg, yield 45%). ESI-MS (m / z): 438.8 [M+H] + .

[0838] 1 H NMR (500 MHz, DMSO-d6) d 9.39 (s, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 7.83-7.77 (m, 2H), 7.29-7.24 (m, 2H), 4.19 (s, 2H), 4.12 (s, 2H), 3.98-3.95 (m, 2H), 3.95 (s, 3H), 3.74-3.67 (m, 2H), 1.10 (s, 6H).

[0839] Example 83

[0840] 4-(4-((4-(1-((1-(aminomethyl)cyclobutyl)methyl)-3-chloro-1H-pyrazol-4-yl)-5- chloropyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0841] Example 84

[0842] 4-(4-((4-(1-((1-(aminomethyl)cyclobutyl)methyl)-5-chloro-1H-pyrazol-4-yl)-5- chloropyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0843] Examples 83 and 84 were prepared by the following steps:

[0844] First step: INT-17 (100.00 mg, 0.25 mmol), 36c (108.60 mg, 0.37 mmol), cesium carbonate (160.80 mg, 0.49 mmol) were dissolved in N,N-dimethylformamide (5 mL), the reaction was stirred at 100 degrees Celsius under nitrogen atmosphere for 12 hours, after the reaction was completed, it was cooled to room temperature, water (30 mL) was added to quench the reaction, ethyl acetate (60 mL) was extracted, the organic phase was dried and concentrated to obtain the crude product. The crude product was subjected to reverse phase column chromatography to obtain the target product 83a (100 mg, yield 67.26%). ESI-MS (m / z): 602.1 [M+H] + , 84a (30 mg, yield 20.18%) ESI-MS (m / z): 602.1 [M+H] + .

[0845] Second step: 83a (100.00 mg, 0.17 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added to the above reaction solution at 0 degrees Celsius, the reaction was stirred at 0 degrees Celsius for 3 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (40 mL) was added to adjust the pH of the solution to about 7, dichloromethane (50 mL) was extracted. The organic phase was dried and concentrated to obtain the crude product, which was subjected to reverse phase column chromatography to obtain the target compound 83 (23.38 mg, yield 28.04%). ESI-MS (m / z): 501.9 [M+H] + .

[0846] 1 H NMR (500 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 7.81 (d, J = 10.0 Hz, 2H), 7.29 (d, J = 10.0 Hz, 2H), 4.25 (s, 2H), 4.18 (s, 2H), 3.96 (t, J = 5.0 Hz, 2H), 3.70 (t, J = 5.0 Hz, 2H), 3.32 (s, 2H), 2.47 (s, 2H), 1.91-1.87 (m, 2H), 1.81-1.77 (m, 2H), 1.74-1.71 (m, 2H).

[0847] Step 3: Dissolve 84a (30.00 mg, 0.05 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL) to the above solution at 0 °C, and stir the reaction mixture at 0 °C for 3 h. After the reaction is completed, adjust the pH of the solution to about 7 by adding saturated aqueous sodium bicarbonate solution (40 mL), extract with dichloromethane (50 mL). Dry and concentrate the organic phase to obtain a crude product, which is purified by reverse-phase column chromatography to obtain the target compound 84 (8.00 mg, yield 31.98%). ESI-MS (m / z): 502.0 [M+H] + .

[0852] Example 85

[0853] 4-(4-((5-chloro-4-(3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0854] Example 85 is prepared by the following steps:

[0855]

[0856] Step 1: Dissolve compound 85a (200 mg, 581 μmol) in anhydrous tetrahydrofuran (5 mL), then slowly add n-butyllithium (872 μL, 2.5 mol / L in hexanes) dropwise under a nitrogen atmosphere, stir the reaction mixture at -78 °C for 30 min, then add isopropyl pinacol borate (216 mg, 1.16 mmol), continue to stir the reaction mixture at -78 °C for 2 h. After the reaction is completed, quench the reaction by adding saturated aqueous ammonium chloride solution (20 mL), extract with ethyl acetate (20 mL x 3), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / dichloromethane = 1 / 1) to obtain compound 85b (197 mg, yield 87%). ESI-MS (m / z): 391.1 [M+H] + .

[0857] Second Step: Compound 85b (177 mg, 452 pmol) and INT-4a (108 mg, 588 pmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL), then [1,1’-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (33 mg, 45 pmol) and sodium carbonate (96 mg, 905 pmol) were added successively, and the reaction mixture was stirred at 80 °C under nitrogen atmosphere for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was filtered through diatomite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 85c (180 mg, yield 96%). ESI-MS (m / z): 412.0 [M+H] + .

[0853] Third Step: Compound 85c (100 mg, 243 pmol) and INT-2b (60 mg, 315 pmol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium(0) (22 mg, 25 pmol), potassium phosphate (103 mg, 485 pmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28 mg, 48 pmol) were added successively. The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered through diatomite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 85d (113 mg, yield 82%). ESI-MS (m / z): 568.1 [M+H] + .

[0854] Fourth Step: Compound 85d (113 mg, 199 pmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (113 mg, 995 pmol) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain white solid compound 85 (30 mg, yield 32%). ESI-MS (m / z): 467.8 [M+H] + .

[0855] 1H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.50 (s, 1H), 8.38 (s, 1H), 7.75 - 7.69 (m, 2H), 7.32 - 7.27 (m, 2H), 4.26 - 4.20 (m, 1H), 4.18 (s, 2H), 3.98 - 3.94 (m, 2H), 3.72 - 3.67 (m, 2H), 3.08 - 2.98 (m, 2H), 2.60 - 2.53 (m, 2H), 2.42 (s, 3H), 1.97 - 1.89 (m, 2H), 1.84 - 1.75 (m, 2H).

[0856] Example 86

[0857] 4-(4-((5-chloro-4-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0858] Example 86 was prepared by the following steps:

[0859] First Step: Compound 86a (150 mg, 436 pmol) was dissolved in anhydrous tetrahydrofuran (5 mL), then n-butyllithium (178 pL, 2.5 mol / L in hexanes) was added dropwise slowly under nitrogen atmosphere, the reaction mixture was stirred at -78 °C for 30 minutes, then isopropyl pinacol borate (162 mg, 872 pmol) was added, the reaction mixture was continued to stir at -78 °C for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction, extracted with ethyl acetate (20 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / dichloromethane = 1 / 1) to obtain compound 86b (170 mg, yield 99%). ESI-MS (m / z): 392.0 [M+H] + .

[0860] Second step: Compound 86b (170 mg, 434 μmol) and INT-4a (103 mg, 565 μmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL), then [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (32 mg, 43 μmol) and sodium carbonate (92 mg, 869 μmol) were added successively, and the reaction mixture was stirred at 80 °C for 12 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the reaction solution was filtered through diatomite, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 86c (130 mg, yield 73%). ESI-MS (m / z): 413.0 [M+H] + .

[0861] Third step: Compound 86c (130 mg, 315 μmol) and INT-2b (79 mg, 410 μmol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium(0) (29 mg, 32 μmol), potassium phosphate (134 mg, 630 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (37 mg, 63 μmol) were added successively. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered through diatomite, and the filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 86d (177 mg, yield 98%). ESI-MS (m / z): 567.6 [M+H] + .

[0862] Fourth step: Compound 86d (177 mg, 311 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (177 mg, 1.56 mmol) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain white solid compound 8...

Claims

1. A compound represented by Formula I, an isotopic derivative or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ###00001### I wherein: R1represents H, D, halogen, CN, C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy, 3-6 membered heterocycloalkyl; Ar1represents phenyl or 5-6 membered heteroaryl; R2each independently represents H, D, halogen, CN, OR a , NR a R a ', N(R a )COR a ', -CONR a R a ', -C(O)R a , -C(O)OR a , -S(O)2R a , C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein said C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 0, 1, 2, 3 or 4 R 22 ; 2 R2together with the Ar1ring atoms to which they are attached and the atoms therebetween can form a 5-8 membered ring, which can further contain 0, 1, 2 or 3 heteroatoms selected from N, O, S; X, Y each independently represent CH or N; R3represents H, D, halogen, CN, C1-C6alkyl or C1-C6alkoxy, wherein said C1-C6alkyl, C1-C6alkoxy can be optionally substituted with 0, 1, 2, 3 or 4 R 23 substituents; V represents C(O), S(O), S(O)2or S(O)(NR5); W each independently represents CR4R4', C(O), NR5, O, S, S(O), S(O)2or S(O)(NR5); R4, R4independently of one another represent H, D, halogen, CN, OR a , SR a , NR a R a , N(R a )COR a , -CONR a R a , -C(O)R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally can be substituted with 0, 1, 2, 3 or 4 R 24 ; R4, R4' attached to the same C can also form, together with the C atom to which they are attached, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 substituted; two R4attached to the same C atom can together form a 3-8 membered ring which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 substituted; R5each independently represents H, D, -S(O)2R a , -S(O)R a , -C(O)R a , -CONR a R a , -C(O)OR a , C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 0, 1, 2, 3, or 4 R 25 ; R4and R5together with the atom to which they are attached and the atoms therebetween can form a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O, or S, which ring can further comprise 0, 1, 2, or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3, or 4 R 30 substituents; R 22 each independently represents D, oxo, halogen, OR a , NR a R a , N(R a )COR a , -CONR a R a , -C(O)R a , -C(O)OR a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, OR a , NR a R a , C1-C2alkyl or halogenated C1-C2alkyl; two R 22 on the same atom or on different atoms can form a 3-6 membered ring with the atom to which they are attached, said ring can further contain 0, 1, 2 or 3 heteroatoms selected from N, O, S; R 23 , R 24 , R 25 , R 30 each independently denotes D, oxo, halogen, CN, OR a , NR a R a ', N(R a )COR a ', CONR a R a ', -C(O)R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, OR a , NR a R a ', C1-C2alkyl or halogenated C1-C2alkyl; two R 23 , two R 24 , two R 25 , or R 24 and R 25 on the same atom or on different atoms can form a 3-6 membered ring, which can further contain 0, 1, 2 or 3 heteroatoms selected from N, O, S; R a and R a each independently represent H, D, C1-C3alkyl or C3-C6cycloalkyl; m is 1, 2 or 3; n is 2, 3, 4, 5 or 6, and when n is 3, W is not simultaneously CH2.

2. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any preceding claim, wherein, Ar1represents 5 membered heteroaryl; preferably, Ar1represents pyrazolyl, imidazolyl, thiazolyl, isothiazolyl.

3. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any preceding claim, wherein, V represents C(O) or S(O)2.

4. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any preceding claim, wherein, 2 R2do not form a ring.

5. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any preceding claim having a structure according to Formula II: ###00002### Formula II. wherein: R1represents H, D, halogen, CN, C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl or C1-C2 alkoxy; Ar1represents pyrazolyl or thiazolyl; R2each independently represents H, D, halogen, CN, OR a , NR a R a ', N(R a )COR a ', -CONR a R a ', -C(O)R a , -C(O)OR a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 0, 1, 2, 3 or 4 R 22 ; R3represents H, D, halogen, CN, C1-C6alkyl or C1-C6alkoxy, wherein said C1-C6alkyl, C1-C6alkoxy can be optionally substituted with 0, 1, 2, 3 or 4 R 23 substituents; W each independently represents CR4R4', C(O), NR5, O or S(O)2; R4, R4independently of one another represent H, D, halogen, CN, OR a , SR a , NR a R a , N(R a )COR a , CONR a R a , C(O)R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally can be substituted with 0, 1, 2, 3 or 4 R 24 ; R4, R4' attached to the same C can also form, together with the C atom to which they are attached, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 substituents; two R4attached to the same C atom can together form a 3-8 membered ring which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 substituted; R5each independently represents H, D, -S(O)2R a , -S(O)R a , -C(O)R a , -CONR a R a , -C(O)OR a , C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl is optionally substituted with 0, 1, 2, 3, or 4 R 25 ; R4and R5together with the atom to which they are attached and the atoms therebetween can form a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O, or S, which ring can further comprise 0, 1, 2, or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3, or 4 R 30 substituted; R 22 each independently represents D, oxo, halogen, OR a , NR a R a ', N(R a )COR a ', CONR a R a ', -C(O)R a , -C(O)OR a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, OR a , NR a R a ', C1-C2alkyl or halogenated C1-C2alkyl; two R 22 , on the same atom or on different atoms can form a 3-6 membered ring with the atom to which they are attached, said ring can further contain 0, 1, 2 or 3 heteroatoms selected from N, O, S; R 23 , R 24 , R 25 , R 30 each independently denotes D, oxo, halogen, CN, OR a , NR a R a ', N(R a )COR a ', CONR a R a ', -C(O)R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, which C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, OR a , NR a R a ', C1-C2alkyl or halogenated C1-C2alkyl; two R 23 , two R 24 , two R 25 , or R 24 and R 25 on the same atom or on different atoms can form a 3-6 membered ring, which ring can further contain 0, 1, 2 or 3 heteroatoms selected from N, O, S; R a and R a each independently represent H, D, C1-C3alkyl or C3-C6cycloalkyl; m is 1, 2 or 3; n is 2, 3, 4, 5 or 6, and when n is 3, W is not simultaneously CH2.

6. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R1represents H, D, halogen, CN, C1-C2 alkyl, fluorinated C1-C2 alkyl; preferably, R1represents F, Cl, CN, methyl, trifluoromethyl.

7. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any preceding claim wherein, R2each independently represents H, D, halogen, CN, OR a , NR a R a ', N(R a )COR a ', C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein said C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 0, 1, 2, 3 or 4 R 22 ; preferably R2each independently represents H, D, halogen, CN, OR a , NR a R a ', N(R a )COR a ', C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 0, 1, 2, 3 or 4 R 22 ; preferably R2each independently represents halogen, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 0, 1, 2 or 3 R 22 .

8. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any preceding claim, wherein, R2each independently represents halogen, d-C6alkyl, C3-C8cycloalkyl, 4-8 membered 22 substituted.

9. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any of the preceding claims, wherein, R3represents H, D, halogen, CN, methyl or methoxy.

10. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, W each independently represents CR4R4', NR5, O or S(O)2.

11. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R4, R4independently represent H, D, halogen, CN, OR a , SR a , NR a R a , N(R a )COR a , -C(O)R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally can be substituted with 0, 1, 2, 3 or 4 R 24 ; R4, R4on the same C also can form, together with the C atom to which they are attached, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 ; two R4attached to different C atoms can form, together with the atoms to which they are attached and the atoms between them, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 .

12. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R4, R4independently of each other represent H, D, halogen, CN, OR a , SR a , NR a R a , N(R a )COR a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally can be substituted with 0, 1, 2, 3 or 4 R 24 ; R4, R4on the same C can also form, together with the C atom to which they are attached, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 ; two R4attached to different C atoms can form, together with the atoms to which they are attached and the atoms between them, a 3-8 membered ring, which optionally can contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring can further comprise 0, 1, 2 or 3 unsaturated bonds, which ring can further be substituted with 0, 1, 2, 3 or 4 R 30 .

13. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R4, R4independently of one another represent H, halogen, CN, OR a , SR a , NR a R a , N(R a )COR a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally can be substituted with 0, 1, 2 or 3 R 24 ; preferably R4, R4independently of one another represent H, halogen, CN, OR a , SR a , NR a R a , N(R a )COR a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally can be substituted with 0, 1, 2 or 3 halogen or methyl.

14. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R4, R4independently of one another represent H, halogen, CN, OR a , SR a , NR a R a , N(R a )COR a , -C(O)R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl can optionally be substituted with 0, 1, 2 or 3 R 24 ; preferably R4, R4independently of one another represent H, halogen, CN, OR a , SR a , NR a R a , N(R a )COR a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl can optionally be substituted with 0, 1, 2 or 3 halogen or methyl.

15. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R4, R4' attached to the same C can form with the C atom to which they are attached a C3-C6 aliphatic ring or a 4-8 membered heterocyclic ring, which can be substituted with 0, 1, 2 or 3 R 30 R4, R4' attached to the same C can form with the C atom to which they are attached a C3-C6 aliphatic ring or a 4-8 membered heterocyclic ring, which can be substituted with 0, 1, 2 or 3 R 16. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, each R5independently represents H, D, -S(O)2R a , -S(O)R a , -C(O)R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 R 25 ; preferably each R5independently represents H, -S(O)2R a , -C(O)R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted with 0, 1, 2 or 3 R 25 ; preferably each R5independently represents H, -S(O)2R a , -C(O)R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted with 0, 1, 2 or 3 halogen or methyl.

17. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, two R4attached to the same atom, or R4and R5, together with the atom to which they are attached, form a C3-C6aliphatic ring or a 4-8 membered heterocyclic ring, which C3-C6aliphatic ring, 4-8 membered heterocyclic ring can be substituted with 0, 1, 2, or 3 R 30 substituted; 18. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, two R4attached to the same atom, or R4and R5, together with the atom to which they are attached, form a 3-8 membered ring, including unsaturated bonds, preferably a 5-6 membered heteroaromatic ring, which can be substituted with 0, 1, 2 or 3 R 30 substituted.

19. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R 22 each independently represents D, oxo, halogen, OR a , NR a R a , N(R a )COR a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl, or 4-8 membered heterocycloalkyl, which C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, OR a , NR a R a , C1-C2alkyl, or halogenated C1-C2alkyl.

20. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R 22 Each can be independently represented as D, oxo, halogen, or OR. a NR a R a '、N(R a COR a '、-CONR a R a '、-C(O)R a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NR a R a ', C1-C2 alkyl or halo-C1-C2 alkyl substitution, and / or two R on the same atom or different atoms 22 It can form 3-6 membered rings with the atoms it is connected to, and the rings may further contain 0, 1, 2 or 3 heteroatoms selected from N, O, and S; preferably, R 22 Each can be independently represented as D, oxo, halogen, or OR. a NR a R a '、N(R a COR a '、-C(O)R a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NR a R a ', C1-C2 alkyl or halo-C1-C2 alkyl substitution, and / or two R on the same atom or different atoms 22 It can form 3-6 membered rings with the atoms it is connected to, and the rings may further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.

21. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R 22 each independently D, oxo, halogen, OR a , NR a R a , N(R a )COR a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, OR a , NR a R a , C1-C2alkyl or halogenated C1-C2alkyl, and / or two R 22 on the same atom or on different atoms can form a 3-6 membered ring, said ring can further contain 0, 1, 2 or 3 heteroatoms selected from N, O, S; preferably R 22 each independently oxo, halogen, OR a , NR a R a , N(R a )COR a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, OR a , NR a R a , C1-C2alkyl.

22. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R 22 each independently represents oxo, halogen, OR a , NR a R a , N(R a )COR a , CONR a R a , -C(O)R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted by 0, 1, 2 or 3 substituents selected from halogen, OR a , NR a R a ; 23. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R 22 each independently represents oxo, halogen, OR a , NR a R a ', N(R a )COR a ', -C(O)R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted by 0, 1, 2 or 3 substituents selected from halogen, OR a , NR a R a ', C1-C2alkyl.

24. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R 23 , R 24 , R 25 , R 30 each independently denotes D, oxo, halogen, CN, OR a , NR a R a ', N(R a )COR a ', -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally being substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, OR a , NR a R a ', C1-C2alkyl or halogenated C1-C2alkyl.

25. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R 23 , R 24 , R 25 , R 30 each independently denotes D, oxo, halogen, CN, OR a , NR a R a ', N(R a )COR a ', -C(O)R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, which C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, OR a , NR a R a ', C1-C2alkyl or halogenated C1-C2alkyl; two R 23 , two R 24 , two R 25 , or R 24 and R 25 on the same atom or on different atoms can form a 3-6 membered ring with the C and / or N atom to which they are attached, which ring can further contain 0, 1, 2 or 3 heteroatoms selected from N, O, S.

26. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R 23 , R 24 , R 25 , R 30 each independently denotes D, oxo, halogen, CN, OR a , NR a R a ', N(R a )COR a ', -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, which C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 R a , NR a R a ', C1-C2alkyl or halogenated C1-C2alkyl; two R 23 on the same atom or on different atoms can form a 3-6 membered ring, which ring can further contain 0, 1, 2 or 3 heteroatoms selected from N, O, S; preferably, R 24 , R 25 , R 24 and R 25 can form a 3-6 membered ring with the C and / or N atom to which they are attached, which ring can further contain 0, 1, 2 or 3 heteroatoms selected from N, O, S; preferably, R 23 , R 24 , R 25 , R 30 each independently denotes oxo, halogen, CN, OR a , NR a R a ', N(R a )COR a ', -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, which C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted with 0, 1, 2 or 3 R a , NR a R a ', C1-C2alkyl; preferably, R 23 , R 24 , R 25 , R 30 each independently denotes oxo, halogen, CN, OR a , NR a R a , C1-C6alkyl, C3-C6cycloalkyl, or 4-8 membered heterocycloalkyl, which C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl, can be optionally substituted with 0, 1, 2, or 3 halogen, OH, C1-C2alkyl; more preferably, R 23 , R 24 , R 25 , R 30 each independently selected from oxo, F, Cl, CN, OR a , NR a R a ’; 27. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R 23 , R 24 , R 25 , R 30 each independently represents oxo, halogen, CN, OR a , NR a R a ', N(R a )COR a ', -C(O)R a , -S(O)2R a , C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, OH, C1-C2alkyl; preferably R a , R a , R a ' is C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, OH, C1-C2alkyl; more preferably R 23 , R 24 , R 25 , R 30 each independently represents oxo, halogen, CN, OR a , NR a R a ', C1-C6alkyl, C3-C6cycloalkyl or 4-8 membered heterocycloalkyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-8 membered heterocycloalkyl optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, OH, C1-C2alkyl; more preferably R 23 , R 24 , R 25 , R 30 each independently is selected from oxo, F, Cl, CN, OR a , NR a R a '.

28. The compound, isotopic derivative, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of the preceding claims, wherein, R a and R a each independently represent H, D or C1-C3alkyl; 29. A compound having the structure: ###00019### an isotopic derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof.

31. Use of a compound of any one of claims 1-29, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, and a pharmaceutical composition of claim 30, for the manufacture of a medicament for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease or an immune-mediated disease.

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