A kind of fused heterocyclic compound, a pharmaceutical composition containing the same, a preparation method thereof and uses thereof

Abstract

The present invention belongs to the field of medicinal chemistry and relates to a fused heterocyclic compound, a pharmaceutical composition containing the same, a preparation method thereof and uses thereof. Specifically, the present invention provides a compound having the structure of formula I, which exhibits good tumor inhibitory activity and high selectivity, can be used as a highly efficient and highly selective inhibitor, and has anti-tumor activity.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and relates to a fused heterocyclic compound having TGFβR1 inhibitory activity, a preparation method thereof, a pharmaceutical composition containing the same, and its medical use. Background Art

[0002] Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates various cellular responses such as cell proliferation, differentiation, migration, and apoptosis. The TGF-β superfamily includes TGF-β1, TGF-β2, TGF-β3, activin, inhibin, bone morphogenetic protein, etc. TGF-β signal transduction is carried out through two highly conserved single transmembrane serine / threonine kinases, TGFβR1 and TGFβR2 (ACS Med.Chem.Lett., 2018, 9, 1117).

[0003] Smads are important intracellular TGF-β signal transduction and regulatory molecules that can directly transduce TGF-β signals from the cell membrane to the nucleus. The TGF-β / Smads signaling pathway plays an important role in the occurrence and development of tumors. In TGF-β / Smads signal transduction, activated TGF-β first binds to TGFβR2 on the cell membrane surface to form a heterodimeric complex, which is further recognized and bound by TGFβR1. Activated TGFβR1 further phosphorylates Smad2 / Smad3 proteins, which then further bind to Smad4 to form a heterotrimeric complex. This complex enters the nucleus and cooperates with co-activators / inhibitors to regulate the transcription of target genes (Nature, 2003, 425, 577). Any change in any link of the TGF-β / Smads signaling pathway will lead to abnormalities in the signal transduction pathway (PNAS, 2019, 116, 9166).

[0004] The TGF-β signaling pathway is dysregulated in many diseases including cancer. The levels of TGFβR1 protein are significantly increased in gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, liver cancer, lung cancer, cervical cancer, and head and neck cancer cell lines and tumor tissues. Activation of the TGF-β signaling pathway triggers obvious pathological effects in the tumor stroma, including immunosuppression, angiogenesis, and connective tissue hyperplasia. In addition, the TGF-β signaling pathway can enhance the invasiveness of tumor cells, promote epithelial-mesenchymal transition, and increase the tolerance to tumor epithelial cell therapy (Nat.Neurosci., 2014, 17, 943).

[0005] Currently, the development of inhibitors targeting TGFβR1, a key target in the TGF-β signaling pathway, has gradually gained attention in the pharmaceutical industry. The published patent applications include WO 02 / 094833 A1, WO 2009 / 150547 A1, WO 2017 / 035118 A1, WO 2018 / 019106 A1, etc. However, there is still an urgent need for new TGFβR1 inhibitors in this field, especially those with high activity and high selectivity. Summary of the Invention

[0006] Through extensive research, the present invention surprisingly discovers a class of fused heterocyclic compounds and their corresponding preparation methods. These compounds can significantly inhibit the activity of TGFβR1 and have good selectivity between TGFβR1 and TGFβR2. As TGFβR1 inhibitors, they can be used to treat proliferative diseases and apoptosis dysregulation diseases mediated at least in part by the TGF-β signaling pathway, especially diseases mediated at least in part by TGFβR1, such as cancer or fibrosis diseases.

[0007] In a first aspect, the present invention provides a compound having the structure of formula I or a pharmaceutically acceptable form thereof:

[0008]

[0009] Wherein,

[0010] Ar 1 is selected from C 6-10 aryl, 5-10-membered heteroaryl or 5-6-membered heterocyclic group, and the C 6-10 aryl, 5-10-membered heteroaryl or 5-6-membered heterocyclic group is optionally substituted by one or more R 2 ;

[0011] Ar 2 is a 5-10-membered heteroaryl, and the 5-10-membered heteroaryl is optionally substituted by one or more R 3 ;

[0012] A is a 4-10-membered heterocycle, and one or more of the heteroatoms in the heterocycle are independently selected from nitrogen, oxygen, and sulfur;

[0013] X is selected from N or -CR 4 ;

[0014] R 1 is independently selected from hydrogen, deuterium, C 1-6 alkyl, C 3-8 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C1-6 alkoxy-C 1-6 alkylene, C 1-6 haloalkoxy-C 1-6 alkylene, amino, C 1-6 alkylamino, amino-C 1-6 alkylene, C 1-6 alkylamino-C 1-6 alkylene, cyano, oxo, thioxo, C 1-6 alkylacyl, C 1-6 alkoxyacyl, C 1-6 alkylaminoacyl, aminoacyl, carboxyl, 3-8 membered heterocyclic group or 3-8 membered heterocyclic group-C 1-6 alkylene, or multiple Rs 1 form a 3-7 membered ring with the atoms to which they are attached;

[0015] n = 0, 1, 2, 3;

[0016] R 2 each independently selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl;

[0017] R 3 each independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 5-10 membered heteroaryl, -OR a , -NR b R c , -NR b C(=O)R a , -C(=O)R a , -C(=O)OR a or -C(=O)NR b R c ;

[0018] R a each independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group or 3-8 membered heterocyclic group-C 1-6 alkylene;

[0019] R b and R c each independently selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C1-6 Alkylene, C 3-8 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 3- to 8-membered heterocyclic group or 3- to 8-membered heterocyclic group-C 1-6 alkylene, or R b and R c together with the atom to which it is attached form a 3- to 7-membered ring, and the above-mentioned phenyl, 5- or 6-membered heteroaryl or 3- to 8-membered heterocyclic group is optionally substituted by one or more hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, hydroxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy or 3- to 8-membered heterocyclic group;

[0020] R 4 each independently selected from hydrogen, C 1-6 alkyl, halogen, cyano or C 1-6 haloalkyl;

[0021] The pharmaceutically acceptable forms are selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites and prodrugs.

[0022] In a second aspect, the present invention provides specific compounds having the structure of formula I, including:

[0023] (1) 2-(6-methylpyridin-2-yl)-8-(pyridin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

[0024] (2) 4-(5-methyl-2-(6-methylpyridin-2-yl)-6-oxo-6,7-dihydropteridin-8(5H)-yl)nicotinonitrile

[0025] (3) 8-(2-aminopyridin-4-yl)-5-methyl-2-(6-methylpyridin-2-yl)-7,8-dihydropteridin-6(5H)-one

[0026] (4) 4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinonitrile

[0027] (5) 4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyridin-2-amine

[0028] (6) 4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinamide

[0029] (7) N-(2-Hydroxyethyl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinamide

[0030] (8) N-(2-Hydroxypropyl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinamide

[0031] (9) N-(2-Hydroxy-2-methylpropyl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinamide

[0032] (10) N-(1-Hydroxypropan-2-yl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinamide

[0033] (11) N-(1-Hydroxybutan-2-yl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinamide

[0034] (12) N-(1,3-Dihydroxypropan-2-yl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinamide

[0035] (13) 2-(4-((4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol

[0036] (14) N-(3-Methoxy-4-(4-methylpiperazin-1-yl)phenyl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyridin-2-amine

[0037] (15) 2-(6-Methylpyridin-2-yl)-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

[0038] (16) 2-(6-Methylpyridin-2-yl)-8-(1H-pyrazolo[3,4-b]pyridin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

[0039] (17)8-(3H-Imidazo[4,5-b]pyridin-7-yl)-2-(6-methylpyridin-2-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

[0040] (18)4-(2-(6-Methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyrimidine-5-carbonitrile

[0041] (19)6-(2-(6-Methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyrimidin-4-amine

[0042] (20)4-(2-(6-Methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyrimidine-5-carboxamide

[0043] (21)N-(2-Hydroxyethyl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyrimidine-5-carboxamide

[0044] (22)N-(2-Hydroxypropyl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyrimidine-5-carboxamide

[0045] (23)N-(2-Hydroxy-2-methylpropyl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyrimidine-5-carboxamide

[0046] (24)N-(1-Hydroxypropan-2-yl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyrimidine-5-carboxamide

[0047] (25)N-(1-Hydroxybutan-2-yl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyrimidine-5-carboxamide

[0048] (26)N-(1,3-Dihydroxypropan-2-yl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyrimidine-5-carboxamide

[0049] (27) 2-(4-((6-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol

[0050] (28) N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-6-(2-(6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyrimidin-4-amine

[0051] (29) 2-(6-methylpyridin-2-yl)-8-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

[0052] (30) 2-(6-methylpyridin-2-yl)-8-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

[0053] (31) 2-(6-methylpyridin-2-yl)-8-(9H-purin-6-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

[0054] (32) 4-(7-(6-methylpyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)nicotinonitrile

[0055] (33) 4-(7-(6-methylpyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)pyridin-2-amine

[0056] (34) 4-(7-(6-methylpyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)nicotinamide

[0057] (35) N-(2-hydroxyethyl)-4-(7-(6-methylpyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)nicotinamide

[0058] (36) N-(2-hydroxypropyl)-4-(7-(6-methylpyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)nicotinamide

[0059] (37)N-(2-Hydroxy-2-methylpropyl)-4-(7-(6-methylpyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)nicotinamide

[0060] (38)N-(1-Hydroxypropan-2-yl)-4-(7-(6-methylpyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)nicotinamide

[0061] (39)N-(1-Hydroxybutan-2-yl)-4-(7-(6-methylpyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)nicotinamide

[0062] (40)N-(1,3-Dihydroxypropan-2-yl)-4-(7-(6-methylpyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)nicotinamide

[0063] (41)2-(4-((4-(7-(6-methylpyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol

[0064] (42)N-(3-Methoxy-4-(4-methylpiperazin-1-yl)phenyl)-4-(7-(6-methylpyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)pyridin-2-amine

[0065] (43)7-(6-Methylpyridin-2-yl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine

[0066] (44)7-(6-Methylpyridin-2-yl)-1-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine

[0067] (45)1-(3H-Imidazo[4,5-b]pyridin-7-yl)-7-(6-methylpyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine

[0068] (46)4-(2-(5-Chloro-2-fluorophenyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinonitrile

[0069] (47) 4-(2-(5-chloro-2-fluorophenyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyridin-2-amine

[0070] (48) 4-(2-(5-chloro-2-fluorophenyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinamide

[0071] (49) 4-(2-(5-chloro-2-fluorophenyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)-N-(2-hydroxyethyl)nicotinamide

[0072] (50) 4-(2-(5-chloro-2-fluorophenyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)-N-(2-hydroxypropyl)nicotinamide

[0073] (51) 4-(2-(5-chloro-2-fluorophenyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)-N-(2-hydroxy-2-methylpropyl)nicotinamide

[0074] (52) 4-(2-(5-chloro-2-fluorophenyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)-N-(1-hydroxypropan-2-yl)nicotinamide

[0075] (53) 4-(2-(5-chloro-2-fluorophenyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)-N-(1-hydroxybutan-2-yl)nicotinamide

[0076] (54) 4-(2-(5-chloro-2-fluorophenyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)-N-(1,3-dihydroxypropan-2-yl)nicotinamide

[0077] (55) 2-(4-((4-(2-(5-chloro-2-fluorophenyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol

[0078] (56) 4-(2-(5-chloro-2-fluorophenyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)-N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyridin-2-amine

[0079] (57)2-(5-Chloro-2-fluorophenyl)-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

[0080] (58)2-(5-Chloro-2-fluorophenyl)-8-(1H-pyrazolo[3,4-b]pyridin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

[0081] (59)2-(5-Chloro-2-fluorophenyl)-8-(3H-imidazo[4,5-b]pyridin-7-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

[0082] (60)4-(5-Methyl-2-(6-methylpyridin-2-yl)-6,7-dihydropteridin-8(5H)-yl)nicotinonitrile

[0083] (61)4-(5-Methyl-2-(6-methylpyridin-2-yl)-6,7-dihydropteridin-8(5H)-yl)pyridin-2-amine

[0084] (62)4-(5-Methyl-2-(6-methylpyridin-2-yl)-6,7-dihydropteridin-8(5H)-yl)nicotinamide

[0085] (63)N-(2-Hydroxyethyl)-4-(5-methyl-2-(6-methylpyridin-2-yl)-6,7-dihydropteridin-8(5H)-yl)nicotinamide

[0086] (64)N-(2-Hydroxypropyl)-4-(5-methyl-2-(6-methylpyridin-2-yl)-6,7-dihydropteridin-8(5H)-yl)nicotinamide

[0087] (65)N-(2-Hydroxy-2-methylpropyl)-4-(5-methyl-2-(6-methylpyridin-2-yl)-6,7-dihydropteridin-8(5H)-yl)nicotinamide

[0088] (66)N-(1-Hydroxypropan-2-yl)-4-(5-methyl-2-(6-methylpyridin-2-yl)-6,7-dihydropteridin-8(5H)-yl)nicotinamide

[0089] (67)N-(1-Hydroxybutan-2-yl)-4-(5-methyl-2-(6-methylpyridin-2-yl)-6,7-dihydropteridin-8(5H)-yl)nicotinamide

[0090] (68)N-(1,3-Dihydroxypropan-2-yl)-4-(5-methyl-2-(6-methylpyridin-2-yl)-6,7-dihydropteridin-8(5H)-yl)nicotinamide

[0091] (69)2-(4-((4-(5-methyl-2-(6-methylpyridin-2-yl)-6,7-dihydropteridin-8(5H)-yl)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol

[0092] (70)N-(3-Methoxy-4-(4-methylpiperazin-1-yl)phenyl)-4-(5-methyl-2-(6-methylpyridin-2-yl)-6,7-dihydropteridin-8(5H)-yl)pyridin-2-amine

[0093] (71)5-Methyl-2-(6-methylpyridin-2-yl)-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)-5,6,7,8-tetrahydropteridine

[0094] (72)5-Methyl-2-(6-methylpyridin-2-yl)-8-(1H-pyrazolo[3,4-b]pyridin-4-yl)-5,6,7,8-tetrahydropteridine

[0095] (73)8-(3H-Imidazo[4,5-b]pyridin-7-yl)-5-methyl-2-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydropteridine

[0096] (74)N-Methyl-4-(5-methyl-2-(6-methylpyridin-2-yl)-6-oxo-6,7-dihydropteridin-8(5H)-yl)nicotinamide

[0097] (75)N-(2-Methoxyethyl)-4-(5-methyl-2-(6-methylpyridin-2-yl)-6-oxo-6,7-dihydropteridin-8(5H)-yl)nicotinamide

[0098] (76)4-(5-Methyl-2-(6-methylpyridin-2-yl)-6-oxo-6,7-dihydropteridin-8(5H)-yl)nicotinamide

[0099] (77)N-(2-Hydroxyethyl)-4-(5-methyl-2-(6-methylpyridin-2-yl)-6-oxo-6,7-dihydropteridin-8(5H)-yl)nicotinamide

[0100] (78)N-(1,3-Dihydroxypropan-2-yl)-4-(5-methyl-2-(6-methylpyridin-2-yl)-6-oxo-6,7-dihydropteridin-8(5H)-yl)nicotinamide

[0101] (79)8-(2-((2-(2-Hydroxypropan-2-yl)pyridin-4-yl)amino)pyridin-4-yl)-5-methyl-2-(6-methylpyridin-2-yl)-7,8-dihydropteridin-6(5H)-one

[0102] (80)8-(2-((3-Methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)-5-methyl-2-(6-methylpyridin-2-yl)-7,8-dihydropteridin-6(5H)-one

[0103] (81)5-Methyl-2-(6-methylpyridin-2-yl)-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)-7,8-dihydropteridin-6(5H)-one

[0104] (82)5-Methyl-2-(6-methylpyridin-2-yl)-8-(1H-pyrazolo[3,4-b]pyridin-4-yl)-7,8-dihydropteridin-6(5H)-one

[0105] (83)8-(3H-Imidazo[4,5-b]pyridin-7-yl)-5-methyl-2-(6-methylpyridin-2-yl)-7,8-dihydropteridin-6(5H)-one

[0106] (84)4-(2-(6-Methylpyridin-2-yl)-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl)nicotinonitrile

[0107] (85)4-(2-(6-Methylpyridin-2-yl)-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl)pyridin-2-amine

[0108] (86)4-(2-(6-Methylpyridin-2-yl)-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl)nicotinamide

[0109] (87)N-(2-Hydroxyethyl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl)nicotinamide

[0110] (88)N-(1,3-Dihydroxypropan-2-yl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl)nicotinamide

[0111] (89)2-(4-((4-(2-(6-Methylpyridin-2-yl)-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol

[0112] (90)N-(3-Methoxy-4-(4-methylpiperazin-1-yl)phenyl)-4-(2-(6-methylpyridin-2-yl)-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl)pyridin-2-amine

[0113] (91)2-(6-Methylpyridin-2-yl)-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine

[0114] (92)2-(6-Methylpyridin-2-yl)-8-(1H-pyrazolo[3,4-b]pyridin-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine

[0115] (93)8-(3H-Imidazo[4,5-b]pyridin-7-yl)-2-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine

[0116] (94)4-(2-(6-Methylpyridin-2-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinonitrile

[0117] (95)4-(2-(6-Methylpyridin-2-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-amine

[0118] (96)4-(2-(6-Methylpyridin-2-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide

[0119] (97)N-(2-Hydroxyethyl)-4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide

[0120] (98)N-(1,3-Dihydroxypropan-2-yl)-4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide

[0121] (99)2-(4-((4-(2-(6-Methylpyridin-2-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol

[0122] (100)N-(3-Methoxy-4-(4-methylpiperazin-1-yl)phenyl)-4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-amine

[0123] (101) 2-(6-Methylpyridin-2-yl)-7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

[0124] (102) 4-(2-(6-Methylpyridin-2-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1H-pyrazolo[3,4-b]pyridine

[0125] (103) 7-(2-(6-Methylpyridin-2-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3H-imidazo[4,5-b]pyridine

[0126] (104) 4-(7-(5-Chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)nicotinonitrile

[0127] (105) 4-(7-(5-Chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)pyridin-2-amine

[0128] (106) 4-(7-(5-Chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)nicotinamide

[0129] (107) 4-(7-(5-Chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)-N-(2-hydroxyethyl)nicotinamide

[0130] (108) 4-(7-(5-Chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)-N-(2-hydroxypropyl)nicotinamide

[0131] (109) 4-(7-(5-Chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)-N-(2-hydroxy-2-methylpropyl)nicotinamide

[0132] (110) 4-(7-(5-Chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)-N-(1-hydroxypropan-2-yl)nicotinamide

[0133] (111) 4-(7-(5-Chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)-N-(1-hydroxybutan-2-yl)nicotinamide

[0134] (112) 4-(7-(5-Chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)-N-(1,3-dihydroxypropan-2-yl)nicotinamide

[0135] (113) 2-(4-((4-(7-(5-Chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol

[0136] (114) 4-(7-(5-Chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)-N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyridin-2-amine

[0137] (115) 7-(5-Chloro-2-fluorophenyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine

[0138] (116) 7-(5-Chloro-2-fluorophenyl)-1-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine

[0139] (117) 7-(5-Chloro-2-fluorophenyl)-1-(3H-imidazo[4,5-b]pyridin-7-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine

[0140] (118) 4-(2-(6-(Trifluoromethyl)pyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinonitrile

[0141] (119) 4-(2-(6-(Difluoromethyl)pyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinonitrile

[0142] (120) 4-(2-(5-Fluoro-6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinonitrile

[0143] (121)4-(2-(3-Fluoro-6-methylpyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinonitrile

[0144] (122)4-(2-(3-Fluoropyridin-2-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinonitrile

[0145] (123)4-(2-(1-Methyl-1H-pyrazol-3-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinonitrile

[0146] (124)4-(2-(1-Isopropyl-1H-pyrazol-3-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinonitrile

[0147] (125)4-(2-(1-Cyclopropyl-1H-pyrazol-3-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)nicotinonitrile

[0148] (126)4-(5,5-Dimethyl-2-(6-methylpyridin-2-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinonitrile

[0149] (127)4-(5,5-Dimethyl-2-(6-methylpyridin-2-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-amine

[0150] (128)4-(5,5-Dimethyl-2-(6-methylpyridin-2-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide

[0151] (129)4-(5,5-Dimethyl-2-(6-methylpyridin-2-yl)-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl)nicotinonitrile

[0152] (130)4-(5,5-Dimethyl-2-(6-methylpyridin-2-yl)-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl)pyridin-2-amine

[0153] (131)4-(5,5-Dimethyl-2-(6-methylpyridin-2-yl)-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl)nicotinamide

[0154] In a third aspect, the present invention provides a method for preparing a compound having the structure of Formula I-2, which comprises the following steps:

[0155] Method 1:

[0156] Step 1-1: Compounds SM1 and SM2 undergo a coupling reaction to obtain compound IM1;

[0157]

[0158] Step 1-2: Compound IM1 and SM3 undergo a substitution reaction to obtain compound IM2;

[0159]

[0160] Step 1-3: Compound IM2 undergoes a demethylation reaction to obtain compound IM3;

[0161]

[0162] Step 1-4: Compound IM3 undergoes a cyclization reaction to obtain the compound of formula I-2;

[0163]

[0164] Wherein, Ar 1 、Ar 2 、R 1 and n are as defined in formula I; LG 1 、LG 2 and LG 3 are leaving groups, each independently selected from methylthio, methanesulfonyl and halogen, preferably bromine or chlorine; W is selected from boronic acid group, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl, tri-n-butyltin group and sodium sulfinate group.

[0165] Method 2:

[0166] Step 2-1: Compounds SM5 and SM2 undergo a coupling reaction to obtain compound IM4;

[0167]

[0168] Step 2-2: Compound IM4 undergoes a demethylation reaction to obtain compound IM5;

[0169]

[0170] Step 2-3: Compound IM5 and SM4 undergo a cyclization reaction to obtain compound IM6;

[0171]

[0172] Step 2-4: Compound IM6 and SM6 undergo a coupling reaction to obtain the compound of formula I-2;

[0173]

[0174] wherein, Ar 1 、Ar 2 、R 1 and n are as defined in Formula I; LG 1 and LG 3 are leaving groups, each independently selected from methylthio, methylsulfonyl and halogen, preferably bromine or chlorine; W is selected from boronic acid group, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, tri-n-butylstannyl and sodium sulfinate group.

[0175] Fourthly, the present invention provides a method for preparing a compound having the structure of Formula I-7, which comprises the following steps:

[0176] Step 3-1: A substitution reaction occurs between compound SM7 and SM8 to obtain compound IM7;

[0177]

[0178] Step 3-2: A reduction and cyclization substitution reaction occurs on compound IM7 to obtain compound IM8;

[0179]

[0180] Step 3-3: A substitution reaction occurs between compound IM8 and compound SM9 to obtain compound IM9;

[0181]

[0182] Step 3-4: A coupling reaction occurs between compound IM9 and SM2 to obtain compound IM10;

[0183]

[0184] Step 3-5: A deprotection reaction occurs on compound IM10 to obtain compound IM11;

[0185]

[0186] Step 3-6: A coupling reaction occurs between compound IM11 and compound SM6 to obtain the compound of Formula I-7;

[0187]

[0188] wherein, Ar 1 、Ar 2 and R 1 are as defined in Formula I; LG 1 、LG 2 、LG3 and LG 4 is a leaving group, independently selected from methylthio group, mesyl group and halogen, preferably bromine or chlorine; PG is a protecting group, selected from 2-(trimethylsilyl)ethoxymethyl, p-methoxybenzyl and benzyl; W is selected from boronic acid group, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl, tri-n-butyltin group and sodium sulfinate group.

[0189] Fifthly, the present invention provides a preparation method of a compound with the structure of formula I-8, which comprises the following steps:

[0190] Step 4-1: The compound IM11 is subjected to a reduction reaction to obtain the compound IM12;

[0191]

[0192] Step 4-2: The compound IM12 and the compound SM6 undergo a coupling reaction to obtain the compound of formula I-8;

[0193]

[0194] wherein, Ar 1 、Ar 2 and R 1 are as defined in formula I; LG 3 is a leaving group, selected from methylthio group, mesyl group and halogen, preferably bromine or chlorine.

[0195] Sixthly, the present invention provides a pharmaceutical composition, which comprises at least one of the above compounds with the structure of formula I or its pharmaceutically acceptable form, and one or more pharmaceutically acceptable carriers.

[0196] Seventhly, the present invention provides a medicine box, which comprises:

[0197] a) At least one of the above compounds with the structure of formula I or its pharmaceutically acceptable form as a first therapeutic agent, or the above pharmaceutical composition as a first pharmaceutical composition;

[0198] b) Optionally, at least one other therapeutic agent as a second therapeutic agent, or a pharmaceutical composition containing other therapeutic agents as a second pharmaceutical composition; and

[0199] c) Optionally, packaging and / or instructions.

[0200] Eighthly, the present invention provides the above compound with the structure of formula I or its pharmaceutically acceptable form or the above pharmaceutical composition, which is used as a TGFβR1 inhibitor for preventing and / or treating at least partially TGFβR1-mediated diseases or disorders (especially cancer or fibrotic diseases).

[0201] In a ninth aspect, the present invention provides the use of the compound having the structure of Formula I or a pharmaceutically acceptable form thereof as defined above, or the above-mentioned pharmaceutical composition as a TGFβR1 inhibitor.

[0202] In a tenth aspect, the present invention provides the use of the compound having the structure of Formula I or a pharmaceutically acceptable form thereof as defined above, or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating a disease or disorder (such as cancer or fibrotic disease) that is at least partially mediated by TGFβR1.

[0203] In an eleventh aspect, the present invention provides a method for preventing and / or treating a disease or disorder (especially cancer or fibrotic disease) that is at least partially mediated by TGFβR1, which comprises the following step: administering a prophylactically and / or therapeutically effective amount of the compound having the structure of Formula I or a pharmaceutically acceptable form thereof as defined above, or the above-mentioned pharmaceutical composition to an individual in need thereof.

[0204] The present invention provides a novel structure fused heterocyclic compound, which can be used as a highly efficient and highly selective TGFβR1 inhibitor, has anti-tumor activity, and has fewer toxic side effects and drug interactions. The synthesis method is mild, the operation is simple and easy, and it is suitable for large-scale industrial production. Detailed Embodiments

[0205] Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described herein; it should also be understood that the terms used herein are only for description and not for limiting specific embodiments.

[0206] [Definition of Terms]

[0207] Unless otherwise specified, the meanings of the following terms in the present invention are as follows.

[0208] The terms "comprising", "including", "having" or "containing" or any other variant thereof are intended to cover non-exclusive or open-ended inclusion. For example, a composition, method or device containing a series of elements is not necessarily limited to the elements that have been explicitly listed, but may also contain other elements not explicitly listed or elements inherent in the above composition, method or device.

[0209] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) atoms (e.g., a hydrogen atom) or groups (e.g., a trifluoromethanesulfonate group) on the specified group are replaced by other atoms or groups, provided that the specified group meets the valence requirements in the current case and forms a stable compound after substitution. Combinations of substituents and / or variables are permitted only if the combination results in a stable compound. If a substituent is described as "optionally substituted with...", the substituent may be unsubstituted or substituted. If a first substituent is described as optionally substituted with one or more of a list of second substituents, one or more hydrogen atoms in the first substituent may be individually or independently replaced by one or more of the list of second substituents, or not replaced.

[0210] The term "one or more" means 1 or more than 1 under reasonable conditions, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0211] When the lower and upper limits of a numerical range are disclosed, any numerical value or any sub-range falling within that range is specifically disclosed. In particular, each numerical range of a parameter disclosed herein (e.g., in the form of "about a to b", or equivalently "approximately a to b", or equivalently "about a - b") should be understood to encompass each numerical value and sub-range therein. For example, "C 1-6 " should be understood to encompass any sub-range and each point value therein, such as C 2-5 、C 3-4 、C 1-2 、C 1-3 、C 1-4 、C 1-5 etc., as well as C1, C2, C3, C4, C5, C6, etc. Again, for example, "3 - 10 yuan" should be understood to encompass any sub-range and each point value therein, such as 3 - 4 yuan, 3 - 5 yuan, 3 - 6 yuan, 3 - 7 yuan, 3 - 8 yuan, 3 - 9 yuan, 4 - 5 yuan, 4 - 6 yuan, 4 - 7 yuan, 4 - 8 yuan, 5 - 7 yuan, 5 - 8 yuan, 6 - 7 yuan, etc., as well as 3, 4, 5, 6, 7, 8, 9, 10 yuan, etc.

[0212] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are substantially non-toxic to living organisms. Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by reacting the compounds of the present invention with pharmaceutically acceptable inorganic / organic acids or inorganic / organic bases, and such salts are also referred to as acid addition salts or base addition salts. For a review of suitable salts, see, for example, Jusiak, Soczewinski, et al., Remington’s Pharmaceutical Sciences [M], Mack Publishing Company, 2005 and Stahl, Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use [M], Wiley-VCH, 2002. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0213] The term "pharmaceutically acceptable ester" refers to esters that are substantially non-toxic to living organisms and are hydrolyzed in vivo to the compounds of the present invention or their salts. Pharmaceutically acceptable esters generally include (but are not limited to) esters formed by reacting the compounds of the present invention with pharmaceutically acceptable carboxylic acids or sulfonic acids, and such esters are also referred to as carboxylates or sulfonates.

[0214] The term "isomer" refers to compounds that have the same molecular weight due to having the same number and type of atoms, but differ in the spatial arrangement or configuration of the atoms.

[0215] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a perpendicular plane of asymmetry due to the presence of at least one chiral element (including chiral centers, chiral axes, chiral planes, etc.), and thus can rotate plane-polarized light. Due to the presence of asymmetric centers and other chemical structures in the compounds of the present invention that may lead to stereoisomerism, the present invention also includes these stereoisomers and their mixtures. Since the compounds of the present invention (or their pharmaceutically acceptable salts) contain asymmetric carbon atoms, they can exist in the form of a single stereoisomer, a racemate, a mixture of enantiomers and diastereomers. Generally, these compounds can be prepared in the form of a racemate. However, if desired, such compounds can be prepared or isolated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in a single stereoisomer (purity ≥ 98%, ≥ 95%, ≥ 93%, ≥ 90%, ≥ 88%, ≥ 85% or ≥ 80%). As described hereinafter, the single stereoisomers of the compounds are synthesized from optically active starting materials containing the required chiral centers, or are prepared by separating or resolving a mixture of enantiomeric products, such as converting to a mixture of diastereomers and then separating or recrystallizing, chromatographing, using chiral resolving agents, or directly separating the enantiomers on a chiral chromatographic column. The starting compounds with specific stereochemistry can be either commercially available or prepared according to the methods described hereinafter and then resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "diastereomer" or "diastereoisomer" refers to optically active isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal amounts of single enantiomers (i.e., an equimolar mixture of the two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal amounts of single enantiomers. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

[0216] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (or proton-transfer tautomers) include (but are not limited to) interconversions through proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imidol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0217] The term "polymorph" (or "polymorphic form") refers to the solid crystalline forms of a compound or a complex. Those skilled in the art can obtain polymorphs of a molecule by many known methods. These methods include (but are not limited to) melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Additionally, well-known techniques can be used to detect, classify, and identify polymorphs, including (but not limited to) differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single crystal X-ray diffraction (SCXRD), solid state nuclear magnetic resonance (NMR), infrared spectroscopy (IR), Raman spectroscopy, and scanning electron microscopy (SEM), etc.

[0218] The term "solvate" refers to a substance formed by the binding of a compound of the present invention (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanolates, acetonates, etc.

[0219] The term "nitroxide" refers to a compound formed by the oxidation of a nitrogen atom in the structure of a tertiary amine or a nitrogen-containing (hetero)aromatic ring compound. For example, the nitrogen atom at position 1 in the nucleus of the compound of formula I can form the corresponding nitroxide.

[0220] The term "isotope-labeled compound" refers to a derivative compound formed by replacing a specific atom in the compound of the present invention with its isotope atom. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as 2 H(D), 3 H(T), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 S and 37 Cl.

[0221] The term "metabolite" refers to a derivative compound formed after the metabolism of the compound of the present invention. Further information on metabolism can be found in Goodman and Gilman's: The Pharmacological Basis of Therapeutics (9 th(ed.)[M], McGraw-Hill International Editions, 1996. The present invention encompasses all possible metabolite forms of the compounds of the present invention, i.e., substances formed in an individual administered with the compounds of the present invention. Metabolites of the compounds can be identified by known techniques in the art, and their activities can be characterized by tests.

[0222] The term "prodrug" refers to a derivative compound that can directly or indirectly provide the compounds of the present invention after administration to an individual. Particularly preferred derivative compounds or prodrugs are compounds that can enhance the bioavailability of the compounds of the present invention (e.g., more readily absorbed into the blood) when administered to an individual, or compounds that facilitate the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are known in the art. For example, see T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol. 14, 1975. In addition, the present invention also encompasses compounds of the present invention containing protecting groups. In any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive groups or reactive groups on any relevant molecule, thereby forming chemically protected forms of the compounds of the present invention. This can be achieved by conventional protecting groups, such as those described in T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0223] The term "each independently" means that at least two groups (or ring systems) with the same or similar range of values present in a structure can have the same or different meanings in a particular situation. For example, if substituent X and substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be either hydrogen or halogen, hydroxy, cyano, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X can be either hydrogen or halogen, hydroxy, cyano, alkyl, or aryl.

[0224] As used herein, alone or in combination with other groups, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0225] As used herein, alone or in combination with other groups, the term "alkyl" refers to a straight-chain or branched-chain aliphatic hydrocarbon group. For example, the term "C 1-6 alkyl" as used in the present invention refers to an alkyl group having 1 to 6 carbon atoms. Common alkyl groups include (but are not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl groups in the present invention are optionally substituted by one or more substituents (such as halogen) described in the present invention.

[0226] As used herein, alone or in combination with other groups, the term "alkylene" refers to a straight-chain or branched-chain divalent saturated aliphatic hydrocarbon group, and the two groups (or segments) to which it is attached can be attached to the same carbon atom or different carbon atoms. For example, the term "C 1-6 alkylene" as used herein refers to an alkylene group having 1 to 6 carbon atoms (such as methylene, 1,1-ethylene, 1,2-ethylene, 1,2-propylene, 1,3-butylene, etc.), which is optionally substituted by one or more (such as 1 to 3) substituents described herein (when substituted by halogen, the group is "C 1-6 haloalkylene", such as -CF2-, -C2F4-, -CHF-, etc.).

[0227] As used herein, alone or in combination with other groups, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) identical or different halogen atoms. For example, the term "C 1-6 haloalkyl" as used in the present invention refers to a haloalkyl group having 1 to 6 carbon atoms. Common haloalkyl groups include (but are not limited to) -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, -CH2CH2CF3, -CH2Cl, etc. The haloalkyl groups in the present invention are optionally substituted by one or more substituents described in the present invention.

[0228] As used herein, alone or in combination with other groups, the term "hydroxyalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) hydroxy groups. For example, the term "C 1-6 hydroxyalkyl" as used in the present invention refers to a hydroxyalkyl group having 1 to 6 carbon atoms. Common hydroxyalkyl groups include (but are not limited to) and the like. The hydroxyalkyl groups in the present invention are optionally substituted by one or more substituents described in the present invention.

[0229] As used herein, alone or in combination with other groups, the term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom. Common alkoxy groups include (but are not limited to) methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc. The alkoxy groups in the present invention are optionally substituted with one or more substituents described in the present invention.

[0230] As used herein, alone or in combination with other groups, the term "C 1-6 alkoxy-C 1-6 alkylene" refers to a group in which an alkoxy group is attached to other structures through a C 1-6 alkylene, such as (but not limited to) methoxymethylene, ethoxymethylene, propoxymethylene, isopropoxymethylene, or butoxymethylene, etc. 1-6

[0231] As used herein, alone or in combination with other groups, the term "haloalkoxy" refers to a monovalent straight-chain or branched-chain haloalkyl-O- group that is substituted with at least one atom selected from fluorine, chlorine, bromine, and iodine, may contain unsaturation, and is attached to other groups through a single bond connected to an oxygen atom, such as C 1-6 haloalkoxy, C 1-4 haloalkoxy; common haloalkoxy groups include (but are not limited to) fluoromethoxy (-OCH2F), difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), 1-fluoroethoxy (-OCHFCH3), 2-fluoroethoxy (-OCH2CH2F), 1,2-difluoroethoxy (-OCHFCH2F), 2,2-difluoroethoxy (-OCH2CHF2), 1,2,2-trifluoroethoxy (-OCHFCHF2), 2,2,2-trifluoroethoxy (-OCH2CF3), etc.

[0232] As used herein, alone or in combination with other groups, the term "C 1-6 1-6 haloalkoxy-C 1-6 alkylene" refers to a group in which a haloalkoxy group is attached to other structures through a C 1-6 alkylene, such as (but not limited to) trifluoromethoxymethylene or 1-fluoroethoxymethylene, etc. 1-6

[0233] As used herein, alone or in combination with other groups, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. For example, the term "C 3-8 cycloalkyl" used in the present invention refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. For example, the term "C 3-8"Cycloalkyl" refers to cycloalkyl groups having 3 to 8 carbon atoms. Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings or spiro rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decahydronaphthyl, etc. The cycloalkyl groups in the present invention are optionally substituted by one or more substituents (such as methyl) described in the present invention.

[0234] As used herein, alone or in combination with other groups, the term "heterocyclic group" or "heterocycle" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, for example: fused ring, bridged ring or spiro ring) non-aromatic group, the ring atoms of which consist of carbon atoms and at least one heteroatom selected from nitrogen, oxygen and sulfur. If the valence bond requirements are met, the heterocyclic group can be attached to the rest of the molecule through any ring atom. For example, the term "3-8 membered heterocyclic group" used in the present invention refers to a heterocyclic group having 3 to 8 ring atoms. Common heterocyclic groups include (but are not limited to) oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuryl, dioxolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl or trithianyl. The heterocyclic groups in the present invention are optionally substituted by one or more substituents described in the present invention.

[0235] As used herein, alone or in combination with other groups, the term "aryl" refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated π electron system. For example, the term "C 6-10 aryl" used in the present invention refers to an aryl group having 6 to 10 carbon atoms. Common aryl groups include (but are not limited to) phenyl, naphthyl, anthracenyl, phenanthryl, acenaphthylenyl, azulyl, fluorenyl, indenyl, pyrenyl, etc. The aryl groups in the present invention are optionally substituted by one or more substituents (such as halogen, hydroxyl, cyano, nitro, C 1-6 alkyl, etc.) described in the present invention.

[0236] As used herein, alone or in combination with other groups, the term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic group having a conjugated π-electron system, the ring atoms of which consist of carbon atoms and at least one heteroatom selected from nitrogen, oxygen, and sulfur. If the valence requirements are met, the heteroaryl can be attached to the rest of the molecule through any one of the ring atoms. For example, the term "5-10 membered heteroaryl" as used in the present invention refers to a heteroaryl having 5 to 10 ring atoms. Common heteroaryls include (but are not limited to) thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and their benzo derivatives, pyrrolopyridinyl, pyrazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, purinyl, etc. The heteroaryl in the present invention is optionally substituted by one or more substituents described in the present invention (such as halogen, C 1-6 alkyl, etc.).

[0237] As used herein, alone or in combination with other groups, the term "alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having at least one C═C double bond. For example, the term "C 2-6 alkenyl" as used in the present invention refers to an alkenyl having 2 to 6 carbon atoms. Common alkenyls include (but are not limited to) vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, n-octenyl, n-decenyl, etc. The alkenyl in the present invention is optionally substituted by one or more substituents described in the present invention.

[0238] As used herein, alone or in combination with other groups, the term "alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group having at least one C≡C triple bond. For example, the term "C 2-6 alkynyl" as used in the present invention refers to an alkynyl having 2 to 6 carbon atoms. Common alkynyls include (but are not limited to) ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl in the present invention is optionally substituted by one or more substituents described in the present invention.

[0239] As used herein, alone or in combination with other groups, the term "hydroxy" refers to -OH.

[0240] As used herein, either alone or in combination with other groups, the term "cyano" refers to -CN.

[0241] As used herein, either alone or in combination with other groups, the term "amino" refers to -NH2.

[0242] As used herein, either alone or in combination with other groups, the term "amino-C 1-6 alkylene" refers to a group in which the amino group is linked to other structures through C 1-6 alkylene, such as, but not limited to, aminomethylene, aminoethylene, or aminopropylene, etc.

[0243] As used herein, either alone or in combination with other groups, the term "C 1-6 alkylamino" refers to a group in which the C 1-6 alkyl is linked to other structures through an amino group, including -NH(C 1-6 alkyl) and -N(C 1-6 alkyl)2, such as, but not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, or diethylamino, etc.

[0244] As used herein, either alone or in combination with other groups, the term "C 1-6 alkylamino-C 1-6 alkylene" refers to a group in which the C 1-6 alkylamino is linked to other structures through C 1-6 alkylene, such as, but not limited to, methylaminomethylene or dimethylaminomethylene, etc.

[0245] As used herein, either alone or in combination with other groups, the term "acyl" refers to -C(=O)-.

[0246] As used herein, either alone or in combination with other groups, the term "C 1-6 alkylacyl" refers to a group in which the C 1-6 alkyl is linked to other structures through an acyl group, such as, but not limited to, formyl, acetyl, propionyl, isopropionyl, or butyryl, etc.

[0247] As used herein, either alone or in combination with other groups, the term "C 1-6 alkoxyacyl" refers to a group in which the C 1-6 alkoxy is linked to other structures through an acyl group, such as, but not limited to, methoxyacyl, ethoxyacyl, propoxyacyl, isopropoxyacyl, or butoxyacyl, etc.

[0248] As used herein, either alone or in combination with other groups, the term "aminoacyl" refers to H2N-C(=O)-.

[0249] As used herein alone or in combination with other groups, the term "C 1-6 alkylaminoacyl" refers to a group in which the C 1-6 alkylamino is linked to other structures through an acyl group, such as, but not limited to, methylaminoacyl, ethylaminoacyl, propylaminoacyl, isopropylaminoacyl, or butylaminoacyl, etc.

[0250] As used herein alone or in combination with other groups, the term "oxo group" refers to =O.

[0251] As used herein alone or in combination with other groups, the term "thio group" refers to =S.

[0252] As used herein alone or in combination with other groups, the term "carboxyl group" refers to -COOH.

[0253] [General formula compound]

[0254] The present invention provides a compound of formula I or a pharmaceutically acceptable form thereof:

[0255]

[0256] Wherein,

[0257] Ar 1 is selected from C 6-10 aryl, 5-10 membered heteroaryl or 5-6 membered heterocyclic group, and the C 6-10 aryl, 5-10 membered heteroaryl or 5-6 membered heterocyclic group is optionally substituted with one or more R 2 ;

[0258] Ar 2 is a 5-10 membered heteroaryl, and the 5-10 membered heteroaryl is optionally substituted with one or more R 3 ;

[0259] A is a 4-10 membered heterocycle, and one or more heteroatoms in the heterocycle are independently selected from nitrogen, oxygen or sulfur;

[0260] X is selected from N or -CR 4 ;

[0261] R 1 each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 3-8 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkylene, C 1-6 haloalkoxy-C 1-6 alkylene, amino, C1-6 Alkylamino, amino-C 1-6 Alkylene, C 1-6 Alkylamino-C 1-6 Alkylene, cyano, oxo, thio, C 1-6 Alkyl acyl, C 1-6 Alkoxy acyl, C 1-6 Alkylaminoacyl, aminoacyl, carboxyl, 3-8 membered heterocyclic group or 3-8 membered heterocyclic group-C 1-6 Alkylene, or multiple R 1 It forms a 3-7 membered ring with the atom to which it is attached;

[0262] n=0,1,2,3;

[0263] R 2 is independently selected at each occurrence from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-8 Cycloalkyl;

[0264] R 3 is independently selected at each occurrence from hydrogen, deuterium, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, -OR a 、-NR b R c 、-NR b C(=O)R a 、-C(=O)R a 、-C(=O)OR a or -C(=O)NR b R c ;

[0265] R a are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heterocyclyl-C 1-6 Alkylene;

[0266] R b and R c are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy-C 1-6 Alkylene, C 3-8 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 3-8 membered heterocyclyl or 3-8 membered heterocyclyl-C 1-6 Alkylene, or Rb and R c together with the atom to which it is attached forms a 3- to 7-membered ring, and the phenyl, 5- or 6-membered heteroaryl or 3- to 8-membered heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, hydroxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy or a 3- to 8-membered heterocyclic group;

[0267] R 4 is independently selected from hydrogen, C 1-6 alkyl, halogen, cyano or C 1-6 haloalkyl each time it appears;

[0268] The pharmaceutically acceptable forms are selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites and prodrugs.

[0269] In some embodiments of the present invention, A in the above formula I compound or its pharmaceutically acceptable form is a 5- or 6-membered heterocycle, and one or more of the heteroatoms in the heterocycle are independently selected from nitrogen, oxygen and sulfur.

[0270] In some preferred embodiments of the present invention, A in the above formula I compound or its pharmaceutically acceptable form is a 5- or 6-membered heterocycle, and one or more of the heteroatoms in the heterocycle are independently selected from nitrogen and oxygen.

[0271] In some embodiments of the present invention, there is provided a compound of formula I or a pharmaceutically acceptable form thereof:

[0272]

[0273] wherein,

[0274] Ar 1 is selected from phenyl or 5- or 6-membered heteroaryl, and the phenyl or 5- or 6-membered heteroaryl is optionally substituted by one or more R 2 substituents;

[0275] Ar 2 is a 6- to 9-membered heteroaryl, and the 6- to 9-membered heteroaryl is optionally substituted by one or more R 3 substituents;

[0276] A is a 5- or 6-membered heterocycle, and one or more of the heteroatoms in the heterocycle are independently selected from nitrogen, oxygen or sulfur;

[0277] X is selected from N or -CH;

[0278] R 1 is independently selected from hydrogen, C 1-6 alkyl, C3-8 Cycloalkyl, halogen, C 1-6 Haloalkyl, hydroxy, amino, cyano, oxo, C 1-6 Alkyl acyl, C 1-6 Alkoxy acyl, C 1-6 Alkylamino acyl, 4- to 6-membered heterocyclic group or 4- to 6-membered heterocyclic group-C 1-6 Alkylene, or multiple Rs 1 Together with the atoms to which they are attached form a 3- to 7-membered ring;

[0279] n = 0, 1, 2, 3;

[0280] R 2 Each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-8 Cycloalkyl;

[0281] R 3 Each independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -OR a , -NR b R c , -NR b C(=O)R a , -C(=O)R a , -C(=O)OR a or -C(=O)NR b R c ;

[0282] R a Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 6-membered heterocyclic group or 4- to 6-membered heterocyclic group-C 1-6 Alkylene;

[0283] R b and R c Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy-C 1-6 Alkylene, C 3-8 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or 3- to 8-membered heterocyclic group, or R b and R c Together with the atoms to which they are attached form a 4- to 6-membered ring, and the above phenyl, 5- to 6-membered heteroaryl or 3- to 8-membered heterocyclic group is optionally substituted with one or more selected from hydrogen, C1-6 alkyl, C 3-8 cycloalkyl, hydroxy, C 1-6 hydroxyalkyl, C 1-6 substituted by a substituent selected from alkoxy or a 4- to 6-membered heterocyclic group.

[0284] In some preferred embodiments of the present invention, there is provided a compound of formula I or a pharmaceutically acceptable form thereof:

[0285]

[0286] wherein,

[0287] Ar 1 is selected from:

[0288]

[0289] Ar 2 is selected from:

[0290]

[0291]

[0292] A is a 5- to 6-membered heterocycle, and one or more heteroatoms in the heterocycle are optionally selected from nitrogen or oxygen;

[0293] X is selected from N or -CH;

[0294] R 1 is selected from hydrogen, methyl or oxo;

[0295] n = 0, 1, 2, 3.

[0296] In some embodiments of the present invention, the compound of formula I or a pharmaceutically acceptable form thereof as described above is a compound of formula I-1 or a pharmaceutically acceptable form thereof:

[0297]

[0298] wherein, Ar 1 , Ar 2 , X, R 1 and n are as described in formula I; Y is selected from a single bond, carbon, nitrogen, oxygen or sulfur.

[0299] In some embodiments of the present invention, Y in the compound of formula I-1 or a pharmaceutically acceptable form thereof as described above is selected from a single bond, carbon, nitrogen or oxygen.

[0300] In some embodiments of the present invention, X in the compound of formula I, formula I-1 or a pharmaceutically acceptable form thereof as described above is selected from N or -CR 4 ;

[0301] R4 each independently selected from hydrogen, C 1-4 alkyl, halogen, cyano or C 1-4 haloalkyl each time it appears.

[0302] In some preferred embodiments of the present invention, X in the above-mentioned compound of formula I, formula I-1 or its pharmaceutically acceptable form is selected from N or -CR 4 ;

[0303] R 4 each independently selected from hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, cyano or trifluoromethyl each time it appears.

[0304] In some more preferred embodiments of the present invention, X in the above-mentioned compound of formula I, formula I-1 or its pharmaceutically acceptable form is selected from N or -CH.

[0305] In some preferred embodiments of the present invention, the above-mentioned compound of formula I, formula I-1 or its pharmaceutically acceptable form is a compound of formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7, formula I-8 or its pharmaceutically acceptable form:

[0306]

[0307] wherein, Ar 1 、Ar 2 、R 1 and n are as described in formula I.

[0308] In some embodiments of the present invention, Ar 1 in the above-mentioned compounds of formula I, formula I-1 to formula I-8 or their pharmaceutically acceptable forms is selected from phenyl or a 5- or 6-membered heteroaryl group, and the phenyl or 5- or 6-membered heteroaryl group is optionally substituted by one or more R 2 substituents, and R 2 are each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl.

[0309] In some preferred embodiments of the present invention, Ar 1 in the above-mentioned compounds of formula I, formula I-1 to formula I-8 or their pharmaceutically acceptable forms is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl or imidazolyl,

[0310] and the phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl or imidazolyl is optionally substituted by one or more R 2 substituents, and R 2Each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl.

[0311] In some more preferred embodiments of the present invention, Ar in the above compounds of Formula I, Formula I-1 to Formula I-8 or their pharmaceutically acceptable forms 1 is selected from phenyl, pyridyl or pyrazolyl,

[0312] the phenyl, pyridyl or pyrazolyl is optionally substituted with one or more R 2 substituents, and R 2 each independently is selected from hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclopentyl or cyclohexyl.

[0313] In some embodiments of the present invention, Ar in the above compounds of Formula I, Formula I-1 to Formula I-8 or their pharmaceutically acceptable forms 1 is selected from:

[0314] m = 0, 1, 2, 3.

[0315] In some preferred embodiments of the present invention, Ar in the above compounds of Formula I, Formula I-1 to Formula I-8 or their pharmaceutically acceptable forms 1 is selected from:

[0316]

[0317] In some embodiments of the present invention, Ar in the above compounds of Formula I, Formula I-1 to Formula I-8 or their pharmaceutically acceptable forms 2 is a 6- to 9-membered heteroaryl, and the 6- to 9-membered heteroaryl is optionally substituted with one or more R 3 substituents;

[0318] R 3 each independently is selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -OR a -, -NR b R c -, -NR b C(=O)R a -, -C(=O)R a -, -C(=O)OR a or -C(=O)NR b R c ;

[0319] R a Each occurrence is independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 4- to 6-membered heterocyclic group or 4- to 6-membered heterocyclic group-C 1-6 alkylene;

[0320] R b and R c Each occurrence is independently selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkylene, C 3-8 cycloalkyl, phenyl, 5- to 6-membered heteroaryl or 3- to 8-membered heterocyclic group, or R b and R c together with the atom to which it is attached form a 4- to 6-membered ring, and the above phenyl, 5- to 6-membered heteroaryl or 3- to 8-membered heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, hydroxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy or 4- to 6-membered heterocyclic group.

[0321] In some preferred embodiments of the present invention, Ar in the above compounds of Formula I, Formula I-1 to Formula I-8 or their pharmaceutically acceptable forms 2 is selected from pyridyl, pyrrolopyridyl, pyrazolopyridyl, imidazolopyridyl, pyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, purinyl, indolyl or indazolyl,

[0322] and the pyridyl, pyrrolopyridyl, pyrazolopyridyl, imidazolopyridyl, pyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, purinyl, indolyl or indazolyl is optionally substituted by one or more R 3 substituents;

[0323] R 3 are each independently selected from hydrogen, cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -OR a 、-NR b R c 、-NR b C(=O)R a 、-C(=O)R a 、-C(=O)OR a or -C(=O)NR b R c ;

[0324] R a Each independently selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group or 4- to 6-membered heterocyclic group-C 1-4 alkylene;

[0325] R b and R c Each independently selected from hydrogen, C 1-4 alkyl, C 1-6 hydroxyalkyl, C 1-4 alkoxy-C 1-4 alkylene, C 3-6 cycloalkyl, phenyl or 5- to 6-membered heteroaryl, or R b and R c together with the atom to which it is attached form a 4- to 6-membered ring, and the above phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, hydroxy, C 1-4 hydroxyalkyl, C 1-4 alkoxy or 4- to 6-membered heterocyclic group.

[0326] In some more preferred embodiments of the present invention, Ar in the above compounds of Formula I, Formula I-1 to Formula I-8 or their pharmaceutically acceptable forms 2 is selected from pyridyl, pyrrolopyridyl, pyrazolopyridyl, imidazolopyridyl, pyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl or purinyl,

[0327] and the pyridyl, pyrrolopyridyl, pyrazolopyridyl, imidazolopyridyl, pyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl or purinyl is optionally substituted by one or more R 3 substituents;

[0328] R 3 Each independently selected from hydrogen, cyano, C 1-4 alkyl, -NR b R c or -C(=O)NR b R c ;

[0329] R b and R c Each independently selected from hydrogen, C 1-4 alkyl, C 1-6 hydroxyalkyl, phenyl or 5- to 6-membered heteroaryl, and the above phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from hydrogen, C 1-4 alkyl, C1-4 Hydroxyalkyl, C 1-4 substituted by a substituent of an alkoxy group or a 4- to 6-membered heterocyclic group.

[0330] In some more preferred embodiments of the present invention, Ar in the above-mentioned compounds of Formula I, Formula I-1 to Formula I-8 or their pharmaceutically acceptable forms 2 is selected from pyridyl, pyrrolopyridyl, pyrazolopyridyl, imidazolopyridyl, pyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl or purinyl,

[0331] the pyridyl, pyrrolopyridyl, pyrazolopyridyl, imidazolopyridyl, pyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl or purinyl is optionally substituted by one or more R 3 substituents;

[0332] R 3 each independently is selected from hydrogen, cyano, amino,

[0333] In some embodiments of the present invention, Ar in the above-mentioned compounds of Formula I, Formula I-1 to Formula I-8 or their pharmaceutically acceptable forms 2 is selected from:

[0334] wherein, R b and R c are as defined in Formula I, and p = 0, 1, 2, 3.

[0335] In some preferred embodiments of the present invention, Ar in the above-mentioned compounds of Formula I, Formula I-1 to Formula I-8 or their pharmaceutically acceptable forms 2 is selected from:

[0336]

[0337] wherein, R b , R c are as defined in Formula I.

[0338] In some more preferred embodiments of the present invention, Ar in the above-mentioned compounds of Formula I, Formula I-1 to Formula I-8 or their pharmaceutically acceptable forms 2 is selected from:

[0339]

[0340]

[0341] In some embodiments of the present invention, R in the above-mentioned compounds of Formula I, Formula I-1 to Formula I-8 or their pharmaceutically acceptable forms 1Each independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxy, amino, cyano, oxo, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylaminocarbonyl, 4- to 6-membered heterocyclic group or 4- to 6-membered heterocyclic group-C 1-6 alkylene, or multiple R 1 and the atom to which it is attached form a 3- to 7-membered ring.

[0342] In some preferred embodiments of the present invention, R in the above compounds of formula I, formula I-1 to formula I-8 or their pharmaceutically acceptable forms 1 each independently selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, halogen, C 1-4 haloalkyl, hydroxy, amino, cyano, oxo, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-4 alkylaminocarbonyl, 4- to 6-membered heterocyclic group or 4- to 6-membered heterocyclic group-C 1-4 alkylene, or multiple R 1 and the atom to which it is attached form a 3- to 7-membered ring.

[0343] In some more preferred embodiments of the present invention, R in the above compounds of formula I, formula I-1 to formula I-8 or their pharmaceutically acceptable forms 1 each independently selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, hydroxy, oxo, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-4 alkylaminocarbonyl or 4- to 6-membered heterocyclic group.

[0344] In some more preferred embodiments of the present invention, R in the above compounds of formula I, formula I-1 to formula I-8 or their pharmaceutically acceptable forms 1 each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, trifluoromethyl, hydroxy or oxo.

[0345] In some more preferred embodiments of the present invention, R in the above compounds of formula I, formula I-1 to formula I-8 or their pharmaceutically acceptable forms 1 each independently selected from hydrogen, methyl or oxo.

[0346] In some preferred embodiments of the present invention, compounds of Formula I-2 to Formula I-8 or pharmaceutically acceptable forms thereof are provided:

[0347]

[0348] Wherein, Ar 1 is selected from:

[0349]

[0350]

[0351] Ar 2 is selected from:

[0352]

[0353] Wherein, R b and R c are as defined in claim 1;

[0354] R 1 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxy, amino, cyano, oxo, carbonyl, C 1-6 alkylacyl, C 1-6 alkoxyacyl, C 1-6 alkylaminoacyl, 4-6 membered heterocyclic group or 4-6 membered heterocyclic group-C 1-6 alkylene, or multiple R 1 form a 3-7 membered ring with the atom to which it is attached;

[0355] m = 0, 1, 2, 3;

[0356] n = 0, 1, 2, 3;

[0357] p = 0, 1, 2, 3.

[0358] Those skilled in the art should understand that the present invention encompasses compounds obtained by any combination of the various embodiments. Embodiments obtained by combining the technical features or preferred technical features in one embodiment with the technical features or preferred technical features in another embodiment are also included within the scope of the present invention.

[0359] In addition, the present invention also provides the following compounds or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs, the structures of which are shown in the following table:

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367] [Preparation Method]

[0368] The present invention provides a preparation method of a compound having the structure of Formula I-2, which comprises:

[0369] Method 1:

[0370] Step 1-1: Compounds SM1 and SM2 undergo a coupling reaction to obtain compound IM1;

[0371]

[0372] Step 1-2: Compound IM1 and SM3 undergo a substitution reaction to obtain compound IM2;

[0373]

[0374] Step 1-3: Compound IM2 undergoes a demethylation reaction to obtain compound IM3;

[0375]

[0376] Step 1-4: Compound IM3 undergoes a cyclization reaction to obtain the compound of Formula I-2;

[0377]

[0378] Wherein, Ar 1 、Ar 2 、R 1 and n are as defined in Formula I; LG 1 、LG 2 and LG 3 are leaving groups, each independently selected from methylthio, methanesulfonyl and halogen, preferably bromine or chlorine; W is selected from boronic acid group, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl, tri-n-butyltin group and sodium sulfinate group.

[0379] In some embodiments of the present invention, step 1-1 in the above preparation method is carried out in a suitable organic solvent or a mixed solution of an organic solvent and water. The organic solvent may be selected from halogenated hydrocarbons (such as DCM, TCM, 1,2-DCE, etc.), MeOH, EtOH, tert-butanol (t-BuOH), DMF, ethers (such as ethylene glycol dimethyl ether (DME), THF, dioxane), aromatic hydrocarbons (such as toluene, xylene) and any combination thereof, preferably toluene or dioxane.

[0380] In some embodiments of the present invention, step 1-1 in the above preparation method is carried out in the presence of a suitable catalyst. The catalyst is preferably a palladium catalyst and may be selected from tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), palladium(II) acetate (Pd(OAc)2), Pd2(dba)3, Pd(PPh3)2Cl2, Pd(PPh3)2Cl2 dichloromethane complex, PdCl2(Amphos)2 and Pd(dppf)Cl2, preferably PdCl2(Amphos)2 or Pd(PPh3)4.

[0381] In some embodiments of the present invention, step 1-1 in the above preparation method is carried out at a suitable temperature, which is 0-200 °C, preferably 50-150 °C.

[0382] In some embodiments of the present invention, step 1-2 in the above preparation method is carried out in a suitable organic solvent or a mixed solution of an organic solvent and water. The organic solvent may be selected from halogenated hydrocarbons (such as DCM, TCM, 1,2-DCE, etc.), MeOH, EtOH, tert-butanol (t-BuOH), DMF, ethers (such as ethylene glycol dimethyl ether (DME), THF, dioxane), aromatic hydrocarbons (such as toluene, xylene) and any combination thereof, preferably toluene or dioxane.

[0383] In some embodiments of the present invention, step 1-2 in the above preparation method is carried out in the presence of a suitable catalyst. The catalyst is preferably a palladium catalyst and may be selected from tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), palladium(II) acetate (Pd(OAc)2), Pd2(dba)3, Pd(PPh3)2Cl2, Pd(PPh3)2Cl2 dichloromethane complex, PdCl2(Amphos)2 and Pd(dppf)Cl2, preferably Pd2(dba)3 or Pd(PPh3)4.

[0384] In some embodiments of the present invention, step 1-2 in the above preparation method is carried out in the presence of a suitable ligand, and the ligand can be selected from triphenylphosphine (PPh3), BINAP, tris(o-tolyl)phosphine (P(o-tol)3), tricyclohexylphosphine tetrafluoroborate (TCHP), and X-PHOS, preferably PPh3 or X-PHOS.

[0385] In some embodiments of the present invention, step 1-2 in the above preparation method is carried out in the presence of a suitable base, the base includes an organic base or an inorganic base, the organic base can be selected from DIPEA, TEA, t-BuOK, and pyridine, and the inorganic base can be selected from K3PO4, NaH, K2CO3, Na2CO3, Cs2CO3, and NaOH, preferably K2CO3 or Cs2CO3.

[0386] In some embodiments of the present invention, step 1-2 in the above preparation method is carried out at a suitable temperature, and the temperature is 0-200 °C, preferably 50-150 °C.

[0387] In some embodiments of the present invention, step 1-3 in the above preparation method is carried out in the presence of a suitable demethylating agent, and the demethylating agent can be selected from aqueous hydrobromic acid and boron tribromide.

[0388] In some embodiments of the present invention, step 1-3 in the above preparation method is carried out at a suitable temperature, and the temperature is 0-200 °C, preferably 50-150 °C.

[0389] In some embodiments of the present invention, step 1-4 in the above preparation method is carried out in a suitable organic solvent, and the organic solvent can be selected from N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, and any combination thereof, preferably N,N-dimethylformamide.

[0390] In some embodiments of the present invention, step 1-4 in the above preparation method is carried out in the presence of a suitable base, and the base can be selected from K3PO4, NaH, K2CO3, Na2CO3, Cs2CO3, and NaOH, preferably K2CO3 or Na2CO3.

[0391] In some embodiments of the present invention, step 1-4 in the above preparation method is carried out at a suitable temperature, and the temperature is 0-200 °C, preferably 0-100 °C.

[0392] Method 2:

[0393] Step 2-1: Compound SM5 and SM2 undergo a coupling reaction to obtain compound IM4;

[0394]

[0395] Step 2-2: The compound IM4 undergoes a demethylation reaction to obtain the compound IM5;

[0396]

[0397] Step 2-3: The compound IM5 and SM4 undergo a cyclization reaction to obtain the compound IM6;

[0398]

[0399] Step 2-4: The compound IM6 and SM6 undergo a coupling reaction to obtain the compound of formula I-2;

[0400]

[0401] wherein, Ar 1 、Ar 2 、R 1 and n are as defined in formula I; LG 1 and LG 3 are leaving groups, each independently selected from methylthio group, methanesulfonyl group and halogen, preferably bromine or chlorine; W is selected from boronic acid group, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl, tri-n-butyltin group and sodium sulfinate group.

[0402] In some embodiments of the present invention, step 2-1 in the above preparation method is carried out in a suitable organic solvent or a mixed solution of an organic solvent and water, and the organic solvent can be selected from halogenated hydrocarbons (such as DCM, TCM, 1,2-DCE, etc.), MeOH, EtOH, tert-butanol (t-BuOH), DMF, ethers (such as ethylene glycol dimethyl ether (DME), THF, dioxane), aromatic hydrocarbons (such as toluene, xylene) and any combination thereof, preferably toluene or dioxane.

[0403] In some embodiments of the present invention, step 2-1 in the above preparation method is carried out in the presence of a suitable catalyst, and the catalyst is preferably a palladium catalyst, and can be selected from tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), palladium(II) acetate (Pd(OAc)2), Pd2(dba)3, Pd(PPh3)2Cl2, Pd(PPh3)2Cl2 dichloromethane complex, PdCl2(Amphos)2 and Pd(dppf)Cl2, preferably PdCl2(Amphos)2 or Pd(PPh3)4.

[0404] In some embodiments of the present invention, step 2-1 in the above preparation method is carried out at a suitable temperature, and the temperature is 0-200 °C, preferably 50-150 °C.

[0405] In some embodiments of the present invention, step 2-2 in the above preparation method is carried out in the presence of a suitable demethylating agent, and the demethylating agent may be selected from aqueous hydrobromic acid and boron tribromide.

[0406] In some embodiments of the present invention, step 2-2 in the above preparation method is carried out at a suitable temperature, and the temperature is 0-200 °C, preferably 50-150 °C.

[0407] In some embodiments of the present invention, step 2-3 in the above preparation method is carried out in a suitable organic solvent, and the organic solvent may be selected from N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, and any combination thereof, preferably N,N-dimethylformamide.

[0408] In some embodiments of the present invention, step 2-3 in the above preparation method is carried out in the presence of a suitable base, and the base may be selected from K3PO4, NaH, K2CO3, Na2CO3, Cs2CO3, and NaOH, preferably K2CO3 or Na2CO3.

[0409] In some embodiments of the present invention, step 2-3 in the above preparation method is carried out at a suitable temperature, and the temperature is 0-200 °C, preferably 0-100 °C.

[0410] In some embodiments of the present invention, step 2-4 in the above preparation method is carried out in a suitable organic solvent or a mixed solution of an organic solvent and water, and the organic solvent may be selected from halogenated hydrocarbons (such as DCM, TCM, 1,2-DCE, etc.), MeOH, EtOH, tert-butanol (t-BuOH), DMF, ethers (such as ethylene glycol dimethyl ether (DME), THF, dioxane), aromatic hydrocarbons (such as toluene, xylene), and any combination thereof, preferably toluene or dioxane.

[0411] In some embodiments of the present invention, step 2-4 in the above preparation method is carried out in the presence of a suitable catalyst, and the catalyst is preferably a palladium catalyst, and may be selected from tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), palladium(II) acetate (Pd(OAc)2), Pd2(dba)3, Pd(PPh3)2Cl2, Pd(PPh3)2Cl2 dichloromethane complex, PdCl2(Amphos)2, and Pd(dppf)Cl2, preferably Pd2(dba)3 or Pd(PPh3)4.

[0412] In some embodiments of the present invention, steps 2-4 in the above preparation method are carried out in the presence of a suitable ligand, and the ligand may be selected from triphenylphosphine (PPh3), BINAP, tris(o-tolyl)phosphine (P(o-tol)3), tricyclohexylphosphine tetrafluoroborate (TCHP), and X-PHOS, preferably PPh3 or X-PHOS.

[0413] In some embodiments of the present invention, steps 2-4 in the above preparation method are carried out in the presence of a suitable base, the base includes an organic base or an inorganic base, the organic base may be selected from DIPEA, TEA, t-BuOK, and pyridine, and the inorganic base may be selected from K3PO4, NaH, K2CO3, Na2CO3, Cs2CO3, and NaOH, preferably K2CO3 or Cs2CO3.

[0414] In some embodiments of the present invention, steps 2-4 in the above preparation method are carried out at a suitable temperature, and the temperature is 0-200 °C, preferably 50-150 °C.

[0415] The present invention provides a preparation method of a compound having the structure of formula I-7, which includes the following steps:

[0416] Step 3-1: Compound SM7 and SM8 undergo a substitution reaction to obtain compound IM7;

[0417]

[0418] Step 3-2: Compound IM7 undergoes a reduction and cyclization substitution reaction to obtain compound IM8;

[0419]

[0420] Step 3-3: Compound IM8 and compound SM9 undergo a substitution reaction to obtain compound IM9;

[0421]

[0422] Step 3-4: Compound IM9 and SM2 undergo a coupling reaction to obtain compound IM10;

[0423]

[0424] Step 3-5: Compound IM10 undergoes a deprotection reaction to obtain compound IM11;

[0425]

[0426] Step 3-6: Compound IM11 and compound SM6 undergo a coupling reaction to obtain the compound of formula I-7;

[0427]

[0428] wherein, Ar 1 、Ar 2 and R 1 are as defined in Formula I; LG 1 、LG 2 、LG 3 and LG 4 are leaving groups selected from methylthio, mesyl and halogen, preferably bromine or chlorine; PG is a protecting group selected from 2-(trimethylsilyl)ethoxymethyl, p-methoxybenzyl and benzyl; W is selected from boronic acid group, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, tri-n-butylstannyl and sodium sulfinate group.

[0429] In some embodiments of the present invention, step 3-1 in the above preparation method is carried out in a suitable organic solvent, and the organic solvent can be selected from halogenated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, etc.), nitriles (such as acetonitrile, etc.), N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide and any combination thereof, preferably dichloromethane.

[0430] In some embodiments of the present invention, step 3-1 in the above preparation method is carried out in the presence of a suitable base, and the base includes an organic base or an inorganic base. The organic base can be selected from N,N-diisopropylethylamine (DIPEA), triethylamine, potassium tert-butoxide and pyridine, and the inorganic base can be selected from K3PO4, NaH, K2CO3, Na2CO3, NaHCO3, Cs2CO3 and NaOH, preferably N,N-diisopropylethylamine (DIPEA) or potassium tert-butoxide.

[0431] In some embodiments of the present invention, step 3-1 in the above preparation method is carried out at a suitable temperature, and the temperature is 0-200 °C, preferably 0-100 °C.

[0432] In some embodiments of the present invention, step 3-2 in the above preparation method is carried out in a suitable organic solvent, and the organic solvent can be selected from alcohols (such as methanol, ethanol), glacial acetic acid and hydrochloric acid and any combination thereof.

[0433] In some embodiments of the present invention, step 3-2 in the above preparation method is carried out in a suitable reducing agent, and the reducing agent can be selected from zinc powder and iron powder.

[0434] In some embodiments of the present invention, step 3-2 in the above preparation method is carried out at a suitable temperature, and the temperature is 0-200 °C, preferably 50-120 °C.

[0435] In some embodiments of the present invention, step 3-3 in the above preparation method is carried out in a suitable organic solvent or a mixed solution of an organic solvent and water. The organic solvent may be selected from halogenated hydrocarbons (such as DCM, TCM, 1,2-DCE, etc.), DMF, ethers (such as ethylene glycol dimethyl ether (DME), THF, dioxane), and any combination thereof, preferably dioxane.

[0436] In some embodiments of the present invention, step 3-3 in the above preparation method is carried out in the presence of a suitable base. The base includes an organic base or an inorganic base. The organic base may be selected from DIPEA, TEA, t-BuOK, and pyridine. The inorganic base may be selected from K3PO4, NaH, K2CO3, Na2CO3, Cs2CO3, and NaOH, preferably K2CO3 or Cs2CO3.

[0437] In some embodiments of the present invention, step 3-3 in the above preparation method is carried out at a suitable temperature. The temperature is 0-200 °C, preferably 50-150 °C.

[0438] In some embodiments of the present invention, step 3-4 in the above preparation method is carried out in a suitable organic solvent or a mixed solution of an organic solvent and water. The organic solvent may be selected from halogenated hydrocarbons (such as DCM, TCM, 1,2-DCE, etc.), MeOH, EtOH, tert-butanol (t-BuOH), DMF, ethers (such as ethylene glycol dimethyl ether (DME), THF, dioxane), aromatic hydrocarbons (such as toluene, xylene), and any combination thereof, preferably toluene or dioxane.

[0439] In some embodiments of the present invention, step 3-4 in the above preparation method is carried out in the presence of a suitable catalyst. The catalyst is preferably a palladium catalyst and may be selected from tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), palladium(II) acetate (Pd(OAc)2), Pd2(dba)3, Pd(PPh3)2Cl2, Pd(PPh3)2Cl2 dichloromethane complex, PdCl2(Amphos)2, and Pd(dppf)Cl2, preferably PdCl2(Amphos)2 or Pd(PPh3)4.

[0440] In some embodiments of the present invention, step 3-4 in the above preparation method is carried out at a suitable temperature. The temperature is 0-200 °C, preferably 50-150 °C.

[0441] In some embodiments of the present invention, step 3-5 in the above preparation method is carried out at a suitable temperature. The temperature is 0-200 °C, preferably 50-150 °C.

[0442] In some embodiments of the present invention, steps 3-6 in the above preparation method are carried out in a suitable organic solvent or a mixed solution of an organic solvent and water. The organic solvent may be selected from halogenated hydrocarbons (such as DCM, TCM, 1,2-DCE, etc.), MeOH, EtOH, tert-butanol (t-BuOH), DMF, ethers (such as ethylene glycol dimethyl ether (DME), THF, dioxane), aromatic hydrocarbons (such as toluene, xylene) and any combination thereof, preferably toluene or dioxane.

[0443] In some embodiments of the present invention, steps 3-6 in the above preparation method are carried out in the presence of a suitable catalyst. The catalyst is preferably a palladium catalyst and may be selected from tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), palladium(II) acetate (Pd(OAc)2), Pd2(dba)3, Pd(PPh3)2Cl2, Pd(PPh3)2Cl2 dichloromethane complex, PdCl2(Amphos)2 and Pd(dppf)Cl2, preferably Pd2(dba)3 or Pd(PPh3)4.

[0444] In some embodiments of the present invention, steps 3-6 in the above preparation method are carried out in the presence of a suitable ligand. The ligand may be selected from triphenylphosphine (PPh3), BINAP, tris(o-tolyl)phosphine (P(o-tol)3), tricyclohexylphosphine tetrafluoroborate (TCHP) and X-PHOS, preferably PPh3 or X-PHOS.

[0445] In some embodiments of the present invention, steps 3-6 in the above preparation method are carried out in the presence of a suitable base. The base includes an organic base or an inorganic base. The organic base may be selected from DIPEA, TEA, t-BuOK and pyridine, and the inorganic base may be selected from K3PO4, NaH, K2CO3, Na2CO3, Cs2CO3 and NaOH, preferably K2CO3 or Cs2CO3.

[0446] In some embodiments of the present invention, steps 3-6 in the above preparation method are carried out at a suitable temperature. The temperature is 0-200 °C, preferably 50-150 °C.

[0447] The present invention provides a method for preparing a compound having the structure of formula I-8, which comprises the following steps:

[0448] Step 4-1: Compound IM11 is subjected to a reduction reaction to obtain compound IM12;

[0449]

[0450] Step 4-2: Compound IM12 and compound SM6 undergo a coupling reaction to obtain the compound of formula I-8;

[0451]

[0452] wherein, Ar 1 、Ar 2 and R 1 are as defined in Formula I; LG 3 is a leaving group selected from methylthio, mesyl and halogen, preferably bromine or chlorine.

[0453] In some embodiments of the present invention, step 4-1 in the above preparation method is carried out in a suitable organic solvent, and the organic solvent may be selected from halogenated hydrocarbons (such as DCM, TCM, 1,2-DCE, etc.), ethers (such as ethylene glycol dimethyl ether (DME), THF, dioxane), aromatic hydrocarbons (such as toluene, xylene) and any combination thereof, preferably THF.

[0454] In some embodiments of the present invention, step 4-1 in the above preparation method is carried out in the presence of a suitable reducing agent, and the reducing agent may be selected from lithium aluminum hydride, sodium borohydride, borane solution and diisobutylaluminum hydride, preferably lithium aluminum hydride.

[0455] In some embodiments of the present invention, step 4-1 in the above preparation method is carried out at a suitable temperature, and the temperature is 0-200 °C, preferably 0-100 °C.

[0456] In some embodiments of the present invention, step 4-2 in the above preparation method is carried out in a suitable organic solvent or a mixed solution of an organic solvent and water, and the organic solvent may be selected from halogenated hydrocarbons (such as DCM, TCM, 1,2-DCE, etc.), MeOH, EtOH, tert-butanol (t-BuOH), DMF, ethers (such as ethylene glycol dimethyl ether (DME), THF, dioxane), aromatic hydrocarbons (such as toluene, xylene) and any combination thereof, preferably toluene or dioxane.

[0457] In some embodiments of the present invention, step 4-2 in the above preparation method is carried out in the presence of a suitable catalyst, and the catalyst is preferably a palladium catalyst, and may be selected from tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), palladium(II) acetate (Pd(OAc)2), Pd2(dba)3, Pd(PPh3)2Cl2, Pd(PPh3)2Cl2 dichloromethane complex, PdCl2(Amphos)2 and Pd(dppf)Cl2, preferably Pd2(dba)3 or Pd(PPh3)4.

[0458] In some embodiments of the present invention, step 4-2 in the above preparation method is carried out in the presence of a suitable ligand, and the ligand may be selected from triphenylphosphine (PPh3), BINAP, tris(o-tolyl)phosphine (P(o-tol)3), tricyclohexylphosphine tetrafluoroborate (TCHP), and X-PHOS, preferably PPh3 or X-PHOS.

[0459] In some embodiments of the present invention, step 4-2 in the above preparation method is carried out in the presence of a suitable base, and the base includes an organic base or an inorganic base. The organic base may be selected from DIPEA, TEA, t-BuOK, and pyridine, and the inorganic base may be selected from K3PO4, NaH, K2CO3, Na2CO3, Cs2CO3, and NaOH, preferably K2CO3 or Cs2CO3.

[0460] In some embodiments of the present invention, step 4-2 in the above preparation method is carried out at a suitable temperature, and the temperature is 0-200 °C, preferably 50-150 °C.

[0461] [Pharmaceutical composition]

[0462] The term "pharmaceutical composition" refers to a composition that can be used as a drug, which contains a pharmaceutically active ingredient (API) (or therapeutic agent) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to an excipient administered together with the therapeutic agent and is suitable for contacting the tissues of humans and / or other animals within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reaction, or other problems or complications corresponding to a reasonable benefit / risk ratio. Pharmaceutically acceptable carriers that can be used in the present invention include (but are not limited to): a) diluents; b) lubricants; c) binders; d) disintegrants; e) absorbents, colorants, flavorants, and / or sweeteners; f) emulsifiers or dispersants; and / or g) substances that enhance the absorption of the compound, etc.

[0463] The present invention provides a pharmaceutical composition that contains at least one of the above compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7, or formula I-8 or a pharmaceutically acceptable form thereof.

[0464] In some embodiments of the present invention, the above pharmaceutical composition further contains one or more pharmaceutically acceptable carriers.

[0465] The above pharmaceutical composition can act systemically and / or locally. For this purpose, they can be administered by a suitable route, such as by parenteral, topical, intravenous, oral, subcutaneous, intra-arterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular route, or as an inhalant.

[0466] The above-mentioned administration routes can be achieved through suitable dosage forms. The dosage forms that can be used in the present invention include (but are not limited to): tablets, capsules, lozenges, troches, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, etc.

[0467] When administered orally, the above-mentioned pharmaceutical composition can be made into any orally acceptable preparation form, including (but not limited to) tablets, capsules, aqueous solutions, aqueous suspensions, etc.

[0468] The above-mentioned pharmaceutical composition can also be administered in the form of a sterile injectable, including a sterile aqueous or oily suspension, or a sterile aqueous or oily solution. Among them, the carriers that can be used include (but are not limited to): water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterilized non-volatile oils can also be used as solvents or suspension media, such as monoglycerides or diglycerides.

[0469] The above-mentioned pharmaceutical composition can contain 0.01 mg to 1000 mg of at least one of the above-mentioned compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7 or formula I-8, or a pharmaceutically acceptable form thereof.

[0470] The present invention also provides a method for preparing the above-mentioned pharmaceutical composition or its corresponding dosage form, which includes combining at least one of the above-mentioned compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7 or formula I-8, or a pharmaceutically acceptable form thereof, with one or more pharmaceutically acceptable carriers.

[0471] [Kit]

[0472] The term "kit" refers to a combination product that includes a therapeutic agent, optionally other therapeutic agents, and optionally packaging and / or instructions.

[0473] The present invention provides a kit, which includes:

[0474] a) At least one of the above-mentioned compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7 or formula I-8, or a pharmaceutically acceptable form thereof, as a first therapeutic agent, or the above-mentioned pharmaceutical composition as a first pharmaceutical composition;

[0475] b) Optionally, at least one other therapeutic agent as a second therapeutic agent, or a pharmaceutical composition containing other therapeutic agents as a second pharmaceutical composition; and

[0476] c) Optionally, packaging and / or instructions.

[0477] The above-mentioned medicine kit may contain 0.01 mg to 1000 mg of at least one compound of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7 or Formula I-8 or a pharmaceutically acceptable form thereof.

[0478] The present invention also provides a method for preparing the above-mentioned medicine kit, which comprises combining at least one compound of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7 or Formula I-8 or a pharmaceutically acceptable form thereof or the above-mentioned pharmaceutical composition with at least one other therapeutic agent or a pharmaceutical composition containing other therapeutic agents, packaging and / or instructions.

[0479] [Medical Use]

[0480] The compounds of the present invention can show a strong inhibitory effect on TGFβR1, IC 50 Most of the values ​​can reach below 100 nM, and some even reach below 10 nM. At the same time, they show a weak inhibitory effect on TGFβR2, and can be used as TGFβR1 inhibitors (especially TGFβR1 selective inhibitors). Therefore, the present invention provides the use of the above-mentioned Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7 or Formula I-8 compounds or their pharmaceutically acceptable forms or the above-mentioned pharmaceutical compositions as TGFβR1 inhibitors (especially TGFβR1 selective inhibitors).

[0481] In addition, the present application also provides the use of the above-mentioned compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7 or Formula I-8 or their pharmaceutically acceptable forms or the above-mentioned pharmaceutical compositions in the preparation of drugs for preventing and / or treating diseases or conditions mediated at least in part by TGFβR1.

[0482] The term "disease or condition mediated at least in part by TGFβR1" refers to a disease, such as cancer or fibrotic disease, in which at least part of the pathogenesis involves factors related to TGFβR1.

[0483] [Treatment Method]

[0484] The present invention provides a method for preventing and / or treating a disease mediated at least in part by TGFβR1, comprising the following steps: administering a preventive and / or therapeutically effective amount of the above-mentioned compound of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7 or Formula I-8 or a pharmaceutically acceptable form thereof or the above-mentioned pharmaceutical composition to an individual in need thereof.

[0485] The term "effective amount" refers to a dose capable of inducing a biological or medical response in a cell, tissue, organ, or organism (e.g., an individual) and sufficient to achieve the desired prophylactic and / or therapeutic effect.

[0486] The dosing regimen can be adjusted to provide the optimal desired response. For example, it can be administered as a single dose, in divided doses over time, or the dose can be proportionally decreased or increased depending on the circumstances. It is understood that for any particular individual, the specific dosing regimen should be adjusted according to need and the professional judgment of the person administering the dosing composition or supervising the administration.

[0487] The dosage of the compounds of the present invention will depend on the individual case, the severity of the disease or disorder, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective amount is about 0.001 - 10000 mg / kg of subject body weight per day. In suitable cases, an effective amount is about 0.01 - 1000 mg / kg of subject body weight per day. It can be administered at about 0.01 - 1000 mg / kg of subject body weight per day, every two days, or every three days, usually about 0.1 - 500 mg / kg of subject body weight. Exemplary dosing regimens are once or multiple times a day, or once or multiple times a week, or once or multiple times a month. When administered multiple times, the interval between single doses can typically be daily, weekly, monthly, or annually. Alternatively, it can be administered in the form of a sustained-release formulation, in which case a lower dosing frequency is required. The dosing dose and frequency can vary depending on the half-life of the drug in the subject and can also vary depending on whether it is a prophylactic or therapeutic application. In prophylactic applications, relatively low doses are administered over a long period at relatively low-frequency intervals; in therapeutic applications, sometimes relatively high doses need to be administered at shorter intervals until the progression of the disease is retarded or stopped, preferably until the individual shows partial or complete improvement of the disease symptoms, after which prophylactic application can be employed.

[0488] The term "treatment" refers to alleviating or eliminating the targeted disease or disorder. If a subject has received a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, and at least one indicator and symptom of the subject shows observable and / or detectable remission and / or improvement, it indicates that the subject has been successfully "treated". It is understood that treatment includes not only complete treatment, but also incomplete treatment that achieves some biologically or medically relevant results. Specifically, "treatment" means that the compound of the present invention or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, can achieve at least one of the following effects, for example: (1) preventing the occurrence of a disease in an animal that may be predisposed to the disease but has not yet experienced or shown disease pathology or symptomatology; (2) inhibiting the disease (i.e., preventing the further development of pathology and / or symptomatology) in an animal that is experiencing or showing disease pathology or symptomatology; (3) improving the disease (i.e., reversing pathology and / or symptomatology) in an animal that is experiencing or showing disease pathology or symptomatology.

[0489] The term "administrate / administrating / administration" (or "administering") refers to the process of applying a pharmaceutically active ingredient (such as a compound of the present invention) or a pharmaceutical composition containing a pharmaceutically active ingredient (such as a pharmaceutical composition of the present invention) to an individual or to a site of its cells, tissues, organs, biological fluids, etc., so that the pharmaceutically active ingredient or the pharmaceutical composition comes into contact with the individual or the site of its cells, tissues, organs, biological fluids, etc. Common administration methods include (but are not limited to) oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, etc.

[0490] The term "in need thereof" refers to a doctor's or other caregiver's judgment that an individual needs or will benefit from a prevention and / or treatment process, which judgment is based on various factors within the doctor's or other caregiver's area of expertise.

[0491] The term "individual" (or "subject") refers to a human or non-human animal. The individuals of the present invention include individuals (patients) suffering from a disease and / or disorder and normal individuals. The non-human animals of the present invention include all vertebrates, such as non-mammals, such as birds, amphibians, reptiles, etc., and mammals, such as non-human primates, domestic animals and / or domesticated animals (such as sheep, dogs, cats, cows, pigs, etc.).

[0492] To make the objectives and technical solutions of the present invention clearer, the following describes the implementation schemes of the present invention in detail with reference to examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0493] The reagents or instruments used in the examples are all conventional products that can be obtained commercially. For those without specific conditions noted, they are all carried out under conventional conditions or the conditions recommended by the manufacturer. The term "room temperature" used in the present invention refers to 20°C ± 5°C. When used to modify a certain numerical value or numerical range, the term "about" used in the present invention means including the numerical value or numerical range and the error range acceptable to those skilled in the art for this numerical value or numerical range, for example, the error range is ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.

[0494] In the conventional synthesis methods, as well as in the examples and intermediate synthesis examples, the meanings of the respective abbreviations are shown in the following table.

[0495]

[0496] The structures of the compounds described in the following examples were determined by nuclear magnetic resonance ( 1 1H-NMR) and / or mass spectrometry (MS).

[0497] For nuclear magnetic resonance ( 1 1H-NMR), the measuring instrument used was a Bruker 400 MHz nuclear magnetic resonance spectrometer, and the measuring solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and hexadeuterodimethyl sulfoxide (DMSO-d6), and the internal standard substance was tetramethylsilane (TMS).

[0498] The meanings represented by the abbreviations in the following nuclear magnetic resonance (NMR) data of the examples are as follows:

[0499] s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quartet doublet, ddd: double double doublet, ddt: double double triplet, dddd: double double double doublet, m: multiplet, br: broad peak, J: coupling constant, Hz: Hertz, δ: chemical shift.

[0500] All chemical shift (δ) values are given in units of parts per million (ppm).

[0501] For mass spectrometry (MS), the measuring instrument used was an Agilent 6120B mass spectrometer, and the ion source was an electrospray ionization source (ESI).

[0502] The embodiments of the present invention are prepared by the following method for preparative high performance liquid chromatography (Prep-HPLC) purification.

[0503] Method: A

[0504] Chromatographic column: Sunfire C 18 OBD (5μm * 19mm * 150mm)

[0505] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium bicarbonate)

[0506] Time [min] Mobile Phase A [%] Mobile Phase B [%] Flow Rate [mL / min] 0.00 10 80 28 2.00 10 80 28 18.00 80 10 28

[0507] Method: B

[0508] Chromatographic column: Sunfire C 18 OBD (5μm * 19mm * 150mm)

[0509] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0510] Time [min] Mobile Phase A [%] Mobile Phase B [%] Flow Rate [mL / min] 0.00 10 90 28 3.00 10 90 28 16.00 70 30 28

[0511] Method: C

[0512] Chromatographic column: Sunfire C 18 OBD (5μm * 19mm * 150mm)

[0513] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0514] Time [min] Mobile Phase A [%] Mobile Phase B [%] Flow Rate [mL / min] 0.00 10 90 28 2.00 10 90 28 16.00 90 10 28

[0515] Method: D

[0516] Chromatographic column: Sunfire C 18 OBD (5μm * 19mm * 150mm)

[0517] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium bicarbonate)

[0518] Time [min] Mobile Phase A [%] Mobile Phase B [%] Flow Rate [mL / min] 0.00 10 90 24 2.00 10 90 24 18.00 90 10 24

[0519] Method: E

[0520] Chromatographic column: Sunfire C 18 OBD (5μm * 19mm * 150mm)

[0521] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium bicarbonate)

[0522] Time [min] Mobile Phase A [%] Mobile Phase B [%] Flow Rate [mL / min] 0.00 10 90 24 2.00 10 90 24 18.00 90 10 24

[0523] Method: F

[0524] Chromatographic column: Sunfire C 18 OBD(5μm * 19mm * 150mm)

[0525] Mobile phase A: Acetonitrile; Mobile phase B: Water (containing 0.05% formic acid)

[0526] Time [min] Mobile Phase A [%] Mobile Phase B [%] Flow Rate [mL / min] 0.00 10 90 28 2.00 10 90 28 16.00 90 10 28

[0527] Method: G

[0528] Chromatographic column: Sunfire C 18 OBD(5μm * 19mm * 150mm)

[0529] Mobile phase A: Acetonitrile; Mobile phase B: Water (containing 0.05% trifluoroacetic acid)

[0530] Time [min] Mobile Phase A [%] Mobile Phase B [%] Flow Rate [mL / min] 0.00 10 90 28 2.00 10 90 28 18.00 90 10 28

[0531] Preparation of Compounds

[0532] Example 1: Synthesis of 2-(6-methylpyridin-2-yl)-8-(pyridin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (Compound 1)

[0533]

[0534] Step 1: Synthesis of 4-chloro-5-methoxy-2-(6-methylpyridin-2-yl)pyrimidine (Compound 1-2)

[0535] Dissolve 2,4-dichloro-5-methoxypyrimidine (Compound 1-1, 1 g, 5.59 mmol), 2-methyl-6-(tri-n-butylstannyl)pyridine (2.13 g, 5.59 mmol), and tetrakis(triphenylphosphine)palladium (645.55 mg, 558.65 μmol) in 1,4-dioxane (10 mL). After purging with nitrogen, react at 110 °C under microwave irradiation for 2 hours. Monitor the reaction by LCMS, and the product is obvious. Add an aqueous KF solution and stir, filter, add ethyl acetate and water to the filtrate and stir, separate the layers, dry the organic phase, and concentrate it under reduced pressure to obtain the title compound (865 mg, yield 65.70%).

[0536] ESI-MS (m / z): 236.0 [M + H]+.

[0537] Step 2: Synthesis of 5-methoxy-2-(6-methylpyridin-2-yl)-N-(pyridin-4-yl)pyrimidin-4-amine (Compound 1-3)

[0538] 4-Chloro-5-methoxy-2-(6-methylpyridin-2-yl)pyrimidine (Compound 1-2, 200 mg, 848.65 μmol), 4-aminopyridine (95.84 mg, 1.02 mmol), Pd2(dba)3 (77.71 mg, 84.86 μmol), x-Phos (80.91 mg, 169.73 μmol), and Cs2CO3 (553.01 mg, 1.70 mmol) were dissolved in 1,4-dioxane (5 mL). After purging with nitrogen, the reaction was carried out at 130 °C for 6 hours under microwave irradiation. The reaction was monitored by LCMS, and the product was obvious. The reaction mixture was filtered and concentrated to obtain the crude product, which was purified by preparative high-performance liquid chromatography (Method A). The preparation solution was freeze-dried to obtain 50.00 mg of the title compound.

[0539] ESI-MS (m / z): 290.1 [M+H]+.

[0540] Step 3: Synthesis of 2-(6-methylpyridin-2-yl)-4-(pyridin-4-ylamino)pyrimidin-5-ol (Compound 1-4)

[0541] 5-Methoxy-2-(6-methylpyridin-2-yl)-N-(pyridin-4-yl)pyrimidin-4-amine (Compound 1-3, 50 mg, 170.46 μmol) was dissolved in 48% aqueous HBr (5 mL) and glacial acetic acid (5 mL). The temperature was raised to 100 °C and the reaction was carried out for 12 hours. The reaction was monitored by LCMS, and the product was obvious. The solvent was removed under reduced pressure, and 1N aqueous sodium hydroxide was added dropwise to neutralize. The residue was dissolved in methanol, filtered, and the filtrate was concentrated under reduced pressure and then purified to obtain 27.00 mg of the title compound.

[0542] ESI-MS (m / z): 280.1 [M+H]+.

[0543] Step 4: Synthesis of 2-(6-methylpyridin-2-yl)-8-(pyridin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (Compound 1)

[0544] 2-(6-Methylpyridin-2-yl)-4-(pyridin-4-ylamino)pyrimidin-5-ol (Compound 1-4, 5 mg, 17.90 μmol) was dissolved in DMF (1 mL). After adding Na2CO3 (5.69 mg, 53.71 μmol), 1,2-dibromoethane (10.08 mg, 53.70 μmol, FR) was added dropwise under nitrogen protection. The reaction was carried out at 25 °C for 12 hours, then the temperature was raised to 50 °C and the reaction was continued for 48 hours. The reaction was monitored by LCMS, and the product was obvious with a little remaining raw material. After filtration and concentration, it was purified by preparative high-performance liquid chromatography (Method B), and the prepared solution was freeze-dried to obtain 0.95 mg of the title compound formate.

[0545] 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.44 (s, 2H), 8.37 (s, 3H), 8.10 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.22 (s, 1H), 5.76 (d, J = 15.5 Hz, 2H), 5.26 (s, 2H), 2.65 (s, 3H).

[0546] ESI-MS (m / z): 306.1 [M+H]+.

[0547] Example 2: Synthesis of 4-(5-methyl-2-(6-methylpyridin-2-yl)-6-oxo-6,7-dihydropteridin-8(5H)-yl)nicotinonitrile (Compound 2)

[0548]

[0549] Step 1: Synthesis of ethyl 2-((4-methoxybenzyl)amino)acetate (Compound 2-2)

[0550] 4-Methoxybenzylamine (Compound 2-1, 10 g, 72.90 mmol) was dissolved in dry dichloromethane (100 mL). After adding triethylamine (22.13 g, 218.69 mmol), the mixture was cooled and stirred to 0 °C, and ethyl bromoacetate (14.61 g, 87.48 mmol) was added dropwise. The reaction was allowed to return to 25 °C naturally and continued for 12 hours. Water was added and the mixture was stirred and separated. The organic phase was concentrated and purified by silica gel column chromatography (7% methanol / dichloromethane), and 5.61 g of the title compound was obtained after concentration.

[0551] ESI-MS (m / z): 224.1 [M+H]+

[0552] Step 2: Synthesis of ethyl 2-((2-chloro-5-nitropyrimidin-4-yl)(4-methoxybenzyl)amino)acetate (Compound 2-3)

[0553] 2,4-Dichloro-5-nitropyrimidine (Compound 2-2, 4.87 g, 25.08 mmol) was dissolved in dry dichloromethane (250 mL). Under nitrogen protection, it was cooled and stirred to 0 °C, and a DCM solution of ethyl 2-((4-methoxybenzyl)amino)acetate (5.60 g, 25.08 mmol) and diisopropylethylamine (6.48 g, 50.16 mmol) was added dropwise. The reaction was carried out at a constant temperature for 1 hour. Water was added and stirred, and after standing for liquid separation, the organic phase was dried and concentrated, and purified by silica gel column (16% ethyl acetate / petroleum ether), and 9.30 g of the title compound was obtained by concentration.

[0554] ESI-MS (m / z): 381.0 [M+H]+

[0555] Step 3: Synthesis of 2-chloro-8-(4-methoxybenzyl)-7,8-dihydropteridin-6(5H)-one (Compound 2-4)

[0556] Ethyl 2-((2-chloro-5-nitropyrimidin-4-yl)(4-methoxybenzyl)amino)acetate (Compound 2-3, 8.8 g, 23.11 mmol) was dissolved in glacial acetic acid (60 mL), and reduced iron powder (6.45 g, 115.55 mmol) was added with stirring. The temperature was raised to 100 °C and the reaction was carried out for 1 hour. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column (52% ethyl acetate / petroleum ether), and 3.62 g of the title compound was obtained by concentration.

[0557] ESI-MS (m / z): 305.0 [M+H]+.

[0558] Step 4: Synthesis of 2-chloro-8-(4-methoxybenzyl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 2-5)

[0559] 2-Chloro-8-(4-methoxybenzyl)-7,8-dihydropteridin-6(5H)-one (Compound 2-4, 500 mg, 1.64 mmol) was dissolved in 1,4-dioxane (35 mL). After adding potassium carbonate (679.29 mg, 4.92 mmol), trimethyl phosphate (1.15 g, 8.20 mmol) was added dropwise. The temperature was raised to 90 °C and heated with stirring for 12 hours. The solvent was removed by distillation under reduced pressure, water was added and stirred, and after filtration, the solid was washed with water 3 times and then dried to obtain 396 mg of the title compound.

[0560] ESI-MS (m / z): 319.0 [M+H]+.

[0561] Step 5: Synthesis of 8-(4-methoxybenzyl)-5-methyl-2-(6-methylpyridin-2-yl)-7,8-dihydropteridin-6(5H)-one (Compound 2-6)

[0562] 2-Chloro-8-(4-methoxybenzyl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 2-5, 450 mg, 1.41 mmol), 2-methyl-6-(tributylstannyl)pyridine (593.47 mg, 1.55 mmol), and tetrakis(triphenylphosphine)palladium (163.13 mg, 141.17 μmol) were dissolved in 1,4-dioxane (10 mL). After purging with nitrogen, the mixture was reacted by microwave at 110 °C for 4 hours. After cooling to room temperature, an aqueous potassium fluoride solution was added to the reaction solution, and the mixture was stirred, filtered. Water and ethyl acetate were added to the filtrate and stirred, and then left to stand for liquid separation. The aqueous phase was extracted with ethyl acetate twice, and the organic phases were combined. The combined organic phases were washed with water three times, dried, concentrated, and purified by preparative high performance liquid chromatography (Method C). The preparation solution was freeze-dried to obtain 233 mg of the title compound.

[0563] ESI-MS (m / z): 376.1 [M+H]+.

[0564] Step 6: Synthesis of 5-methyl-2-(6-methylpyridin-2-yl)-7,8-dihydropteridin-6(5H)-one (Compound 2-7)

[0565] 8-(4-Methoxybenzyl)-5-methyl-2-(6-methylpyridin-2-yl)-7,8-dihydropteridin-6(5H)-one (Compound 2-6, 233 mg, 620.63 μmol) was dissolved in trifluoroacetic acid (10 mL), and the temperature was raised to 80 °C and reacted for 12 hours. The reaction was monitored by LCMS, and the product was obvious. Trifluoroacetic acid was removed by distillation under reduced pressure, and methyl tert-butyl ether was added and stirred to precipitate a solid. The solid was filtered, washed twice with methyl tert-butyl ether, and then dried to obtain 217 mg of the trifluoroacetate salt of the title compound.

[0566] ESI-MS (m / z): 256.1 [M+H]+.

[0567] Step 7: Synthesis of 4-(5-methyl-2-(6-methylpyridin-2-yl)-6-oxo-6,7-dihydropteridin-8(5H)-yl)nicotinonitrile (Compound 2)

[0568] 5-Methyl-2-(6-methylpyridin-2-yl)-7,8-dihydropteridin-6(5H)-one (Compound 2-7, 20 mg, 54.16 μmol, trifluoroacetate), 4-chloronicotinonitrile (9.75 mg, 70.40 μmol), Pd2(dba)3 (4.96 mg, 5.42 μmol), X-phos (5.16 mg, 10.83 μmol), Cs2CO3 (52.94 mg, 162.47 μmol) were dissolved in 1,4-dioxane (1 mL). After purging with nitrogen, the mixture was reacted at 130 °C under microwave irradiation for 2 h. The reaction mixture was filtered and purified by preparative HPLC (Method D). The eluent was lyophilized to give the title compound (1.00 mg).

[0569] 1 1H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 1.0 Hz, 1H), 8.87 (dd, J = 5.9, 1.1 Hz, 1H), 8.66 (d, J = 5.8 Hz, 1H), 8.63 (s, 1H), 8.23 (d, J = 7.7 Hz, 1H), 7.90 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 6.62 (s, 2H), 3.46 (s, 3H), 2.64 (s, 3H).

[0570] ESI-MS (m / z): 358.1 [M+H]+.

[0571] Example 3: Synthesis of 8-(2-aminopyridin-4-yl)-5-methyl-2-(6-methylpyridin-2-yl)-7,8-dihydropteridin-6(5H)-one (Compound 3)

[0572]

[0573] 5-Methyl-2-(6-methylpyridin-2-yl)-7,8-dihydropteridin-6(5H)-one (Compound 2-7, 20 mg, 54.16 μmol, TF salt), 4-bromo-2-aminopyridine (12.18 mg, 70.40 μmol), Pd2(dba)3 (4.96 mg, 5.42 μmol), X-phos (5.16 mg, 10.83 μmol), Cs2CO3 (52.94 mg, 162.47 μmol) were dissolved in 1,4-dioxane (1 mL). After purging with nitrogen, the mixture was reacted at 130 °C under microwave irradiation for 1 h. The reaction mixture was filtered and purified by preparative HPLC (Method E). The eluent was lyophilized to give the title compound (1.78 mg).

[0574] 11H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.91 (t, J = 7.1 Hz, 2H), 7.77 (t, J = 7.7 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 6.80 (dd, J = 5.8, 2.1 Hz, 1H), 6.52 (d, J = 2.0 Hz, 1H), 5.96 (s, 2H), 4.56 (s, 2H), 3.38 (s, 3H), 2.53 (s, 3H).

[0575] ESI-MS (m / z): 348.1 [M+H]+.

[0576] Example 4: Synthesis of 4-(5-methyl-2-(6-methylpyridin-2-yl)-6,7-dihydropteridin-8(5H)-yl)pyridin-2-amine (Compound 61)

[0577]

[0578] Step 1: Synthesis of 5-methyl-2-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydropterin (Compound 61-1)

[0579] 5-Methyl-2-(6-methylpyridin-2-yl)-7,8-dihydropteridin-6(5H)-one (Compound 2-7, 200 mg, 0.78 mmol, FR) was dissolved in dry tetrahydrofuran (20 mL). A solution of lithium aluminum hydride (148.68 mg, 3.92 mmol) in tetrahydrofuran was added dropwise under nitrogen protection. After the addition, the temperature was raised to 80 °C and the reaction was carried out for 12 hours. The reaction was quenched by adding 1 mL of water dropwise under ice bath cooling, and then 1 mL of 1 N sodium hydroxide aqueous solution was added dropwise. The mixture was stirred for 10 minutes, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. It was purified by preparative high performance liquid chromatography (Method F), and the preparation was freeze-dried to obtain 50 mg of the title compound.

[0580] ESI-MS (m / z): 242.1 [M+H]+.

[0581] Step 2: Synthesis of 4-(5-methyl-2-(6-methylpyridin-2-yl)-6,7-dihydropteridin-8(5H)-yl)pyridin-2-amine (Compound 61)

[0582] 5-Methyl-2-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydropterin (Compound 61-1, 20 mg, 0.08 mmol), 4-bromo-2-aminopyridine (15.77 mg, 0.09 mmol), Pd2(dba)3 (7.59 mg, 0.008 mmol), X-Phos (7.90 mg, 0.016 mmol), and cesium carbonate (81.02 mg, 0.25 mmol) were dissolved in 1,4-dioxane (1 mL). After purging with nitrogen, the mixture was reacted at 130 °C under microwave irradiation for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and then purified by preparative high performance liquid chromatography (Method G). The resulting solution was lyophilized to obtain 3.65 mg of the trifluoroacetate salt of the title compound.

[0583] 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 5.8 Hz, 2H), 8.00 (s, 2H), 7.94 (d, J = 7.3 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.29 (dd, J = 7.2, 2.1 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 4.06–4.02 (m, 2H), 3.61–3.55 (m, 2H), 3.10 (s, 3H), 2.70 (s, 3H).

[0584] ESI-MS (m / z): 334.1 [M+H]+.

[0585] Pharmacological Activity Test

[0586] Test Example 1: In vitro enzymatic activity inhibition test (TGFβR1).

[0587] Experimental method: According to the instructions of the ADP-Glo TM kinase assay kit (Promega), the inhibitory effect of the compounds of the present invention on the enzymatic activity of TGFβR1 was determined as follows:

[0588] TGFβR1 enzyme was pre-incubated with test compounds at different concentrations (1000 nM, 100 nM, 10 nM) at 30 °C for 30 min, and then TGFβR1 peptide and adenosine triphosphate (ATP) were added to initiate the reaction. After incubation at 30 °C for 3 h, ADP-Glo TM reagent was added, and after incubation at room temperature for 90 min, the kinase detection reagent was added. After incubation at room temperature for 30 min, the chemiluminescence signal value was detected. Using the solvent group (DMSO) as the negative control and the buffer group (without TGFβR1 enzyme) as the blank control, the percentage inhibition rate of compounds at different concentrations was calculated according to the following formula:

[0589] Percentage inhibition rate = (1 - (chemiluminescence signal value of compound at different concentrations - chemiluminescence signal value of blank control) / (chemiluminescence signal value of negative control - chemiluminescence signal value of blank control)) × 100%;

[0590] When the percentage inhibition rate is between 30 - 80%, calculate the half - inhibitory concentration (IC 50 ) or range of the compound according to the following formula:

[0591] IC 50＝ X × (1 - percentage inhibition rate (%)) / percentage inhibition rate (%), where: X is the test concentration of the compound with an inhibition rate between 30 - 80%.

[0592] The experimental results are shown in Table 1 below:

[0593] Table 1. Inhibitory activity of the compounds of the present invention against TGFβR1

[0594] Example Number <![CDATA[IC of TGFβR1 50 (nM)]]> Example 1 20.85±3.14 Example 4 12.62±5.31

[0595] It can be seen from Table 1 that the compounds of the present invention have a significant inhibitory effect on TGFβR1.

[0596] Test Example 2: In vitro enzymatic activity inhibition test (TGFβR2).

[0597] Experimental method: Determine the inhibitory effect of the compounds of the present invention on the enzymatic activity of TGFβR2 according to the instructions of the ADP - Glo TM kinase assay kit (Promega). The steps are as follows:

[0598] Pre - incubate TGFβR2 enzyme with test compounds at different concentrations (1000 nM, 100 nM, 10 nM) at 30 °C for 30 min, then add myelin basic protein (MBP) and adenosine triphosphate (ATP) to initiate the reaction. After incubating at 30 °C for 3 h, add ADP - Glo TM reagent. After incubating at room temperature for 90 min, add the kinase detection reagent. After incubating at room temperature for 30 min, detect its chemiluminescence signal value. Using the solvent group (DMSO) as the negative control and the buffer group (without TGFβR2 enzyme) as the blank control, calculate the percentage inhibition rate of compounds at different concentrations according to the following formula:

[0599] Percentage inhibition rate = (1 - (chemiluminescence signal value of compound at different concentrations - chemiluminescence signal value of blank control) / (chemiluminescence signal value of negative control - chemiluminescence signal value of blank control)) × 100%;

[0600] When the percentage inhibition rate is between 30 - 80%, calculate the half - inhibitory concentration (IC50 ) or range:

[0601] IC 50＝ X × (1 - percentage inhibition rate (%)) / percentage inhibition rate (%), where: X is the test concentration of the compound with an inhibition rate between 30 - 80%.

[0602] The experimental results are shown in Table 2 below:

[0603] Table 2. Inhibition rate of the compounds of the present invention on TGFβR2 enzyme activity

[0604] Example Number <![CDATA[IC of TGFβR2 50 (nM)]]> Example 1 >1000

[0605] It can be seen from Table 2 that the compounds of the present invention have weak inhibitory activity on TGFβR2.

[0606] It can be seen from Table 1 and Table 2 that the compounds of the present invention have a selective inhibitory effect on TGFβR1.

[0607] Test Example III: In vitro cell activity inhibition test.

[0608] Experimental method: According to the instructions of the Bright - Glo TM luciferase assay kit (Promega), the inhibitory effect of the compounds of the present invention on HEK293 - SBE cells was determined as follows:

[0609] Add HEK293 - SBE cells (Bps bioscience) to a 96 - well plate (10% FBS medium), 30,000 cells / well, culture overnight at 37°C and 5% CO2. Replace the medium with 0.5% FBS medium, and add the test compound diluted with 0.5% FBS medium. The highest final concentration of the test compound is 10 μM, and the compound is diluted 4 - fold, with a total of 8 concentration gradients. After culturing for 4 - 5 hours, add 10 μl of TGFβ. The final concentration of TGFβ is 0.5 ng / ml. Add 10 μl of medium to replace TGFβ as the negative control group. In the blank control, no test compound is added, and TGFβ is added. Add Bright Glo reagent to each well and read the chemiluminescence signal value on a microplate reader.

[0610] Calculate the percentage inhibition rate of the compound at different concentrations according to the following formula:

[0611] Percentage inhibition rate = (1 - (chemiluminescence signal value of the test compound - chemiluminescence signal value of the blank control) / (chemiluminescence signal value of the negative control - chemiluminescence signal value of the blank control)) × 100%;

[0612] Plot the percentage inhibition of compounds at different concentrations against the compound concentration, fit the curve according to the four-parameter model, and calculate the IC 50 value by the following formula:

[0613] y = Min+(Max - Min) / (1+(x / IC 50 )^(-Hillslope)), where: y is the percentage inhibition; Max and Min are the maximum and minimum values of the fitted curve respectively; x is the logarithmic concentration of the compound; and Hillslope is the slope of the curve.

[0614] The experimental results are shown in Table 3 below:

[0615] Table 3. Inhibitory effect of the compounds of the present invention on the TGFβ / Smads signaling pathway in HEK293-SBE cells

[0616] Example Number <![CDATA[IC 50 (nM) <!-- 48 -->]]> Example 4 27.53±1.52

[0617] As can be seen from Table 3, the compounds of the present invention have a significant inhibitory effect on the TGFβ / Smads signaling pathway (luciferase reporter gene method) in TGFβ-induced HEK293-SBE cells.

Claims

1. A compound having the structure of Formula I-1 or a pharmaceutically acceptable salt thereof: Wherein, Ar 1 selected from pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl is optionally substituted with one or more R 2 substituents; Ar 2 is a pyridyl or pyrimidinyl group, which pyridyl or pyrimidinyl group is optionally substituted by one or more R 3 substituents; Y is selected from carbon, nitrogen, oxygen or sulfur; X is selected from N or -CR 4 ; R 1 Each independently selected from hydrogen, deuterium, C 1-6 alkyl, halogen, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy or C 1-6 hydroxyalkyl; n＝0,1,2,3； R 2 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl; R 3 Each independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR a or -NR b R c ; R a Each independently selected from hydrogen or C 1-6 alkyl at each occurrence; R b and R c each independently selected from hydrogen, C 1-6 alkyl or C 1-6 hydroxyalkyl; R 4 Each independently selected from hydrogen, C 1-6 alkyl, halogen, cyano or C 1-6 haloalkyl each time it appears.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 2 Each independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl or difluoromethyl.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, Ar 1 Selected from:

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, R 3 Each independently selected from hydrogen, cyano group or amino group.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, Ar 2 Selected from:

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, R 1 selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl or hydroxyl.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, X is selected from N or -CH.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, Wherein, Ar 1 Selected from: Ar 2 Selected from: wherein, R b and R c are as defined in claim 1; R 1 selected from hydrogen, C 1-6 alkyl or halogen; X is selected from N or -CH; Y is selected from carbon, nitrogen or oxygen; m＝0,1,2,3； n＝0,1,2,3； p＝0,1,2,3。 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound having the structure of Formula I-2, I-3, I-4, I-5 or I-8 or a pharmaceutically acceptable salt thereof, wherein, Ar 1 、 Ar 2 、 R 1 and n are as defined in claim 1.

10. The following compound or a pharmaceutically acceptable salt thereof:

11. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

12. Use of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11, in the manufacture of a medicament for preventing and / or treating a disease or disorder mediated at least in part by TGFβR1.

Images