Compound, pharmaceutical composition and application thereof

Abstract

The invention relates to a compound as well as a pharmaceutical composition and application thereof, the compound comprises a compound as shown in a formula I or a compound as shown in a formula II: # imgabs0 #. The compound provided by the invention can be combined with Yes1 protein, inhibit the activity of the Yes1 protein, inhibit transcription and cell growth of related genes, and improve the activity of the Yes1 protein. Therefore, the compound can be used for treating diseases related to Yes1 gene amplification or Yes1 protein overexpression.

Description

[0001] The present invention claims priority to the following prior application: Patent application number 202310770047.5 filed with the State Intellectual Property Office of China on June 27, 2023, entitled “Compounds, pharmaceutical compositions and their uses”. The entire text of the application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medical technology, and in particular relates to a compound and a pharmaceutical composition and application thereof. Background Art

[0003] Protein kinase is an important enzyme that catalyzes the phosphorylation process of proteins. It can regulate the activity of proteins through phosphorylation, and can also amplify signals and cause cellular responses through the step-by-step phosphorylation of proteins. Protein kinase plays a key regulatory role in life processes. Abnormalities in protein kinases often lead to the occurrence of malignant diseases such as cancer. Dysregulation of protein kinase function, such as activation through functional acquisition genetic mutations, gene amplification, autonomous activation and chromosomal rearrangement, is closely related to cancer development and progression, and is involved in cancer cell transformation, growth, proliferation and survival.

[0004] At present, protein kinases have been considered as important targets for the development of molecular targeted therapy. Src family kinases (SFKs) are a class of non-receptor protein tyrosine kinases. Src family kinases are a class of membrane-bound proteins, including about nine members, namely: Src, Fyn, Yes1, Lck, Lyn, Hck, Fgr and Blk. Src protein is a non-receptor tyrosine kinase that can be activated by multiple signal transduction pathways. The activated Src kinase activates the corresponding target protein by phosphorylating the tyrosine residues, thereby activating the corresponding signaling pathways, including MAPK, STAT, PI3K / AKT and EGFR, etc. Abnormally activated Src protein is associated with many tumors, and its activity is closely related to the development of tumors. Inhibiting the activity of Src family kinase members in tumor tissues is likely to be an effective means of treating cancer. Currently reported Src kinase family inhibitors include dasatinib, bosutinib, etc., but due to the poor selectivity of these inhibitors, they have not shown sufficient effects when used as Src family kinase inhibitors in clinical practice. Therefore, more selective and effective Src family kinase inhibitors are clinically needed. Summary of the invention

[0005] The present invention provides a compound, a pharmaceutical composition and application thereof. The compound can inhibit the activity of Yes1 protein, the transcription of related genes and cell growth by binding to Yes1 protein, thereby being used for treating diseases related to Yes1 protein.

[0006] The present invention provides a compound represented by formula I or formula II:

[0007]

[0008] In formula (I) and formula (II):

[0009] Ar 1 Selected from C 6-10 aryl, 5-10 membered heteroaryl, 6-membered aryl and 5-20 membered heterocyclic ring, 6-membered aryl and 5-10 membered heteroaryl ring, 5-10 membered heteroaryl and C 3-10 Cycloalkyl groups together form a ring, C 6-10 A cyclic ring composed of an aryl group and a 5-10-membered heteroaryl group;

[0010] Ar 2 Selected from C 6-10 aryl, 5-10 membered heteroaryl, 6-membered aryl and 5-20 membered heterocyclic ring, 6-membered aryl and 5-10 membered heteroaryl ring, 5-10 membered heteroaryl and C 3-10 Cycloalkyl groups together form a ring, C 6-10 A cyclic ring composed of an aryl group and a 5-10-membered heteroaryl group;

[0011] The Ar 1 Unsubstituted or substituted by one, two or more of the following groups: halogen, cyano, hydroxyl, amino, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 1-10 Alkylthio, -NHC 1-10 Alkyl, -N(C 1-10 alkyl) 2 , C 3-10 Cycloalkyl, 3-20 membered heterocyclic group;

[0012] The Ar 2 Unsubstituted or substituted by one, two or more of the following groups: halogen, cyano, hydroxyl, amino, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 1-10 Alkylthio, -NHC 1-10 Alkyl, -N(C 1-10 alkyl) 2 , C 3-10 Cycloalkyl, 3-20 membered heterocyclic group;

[0013] M 1 and M 2are the same or different, each independently selected from CH or N;

[0014] X 1 and X 2 are the same or different, each independently selected from the group consisting of absence, N(R a )、O、S(O) t 、C(O)、C(O)N(R a )、S(O) t N(R a ) or CR b R c ;

[0015] Y is selected from the group consisting of not present, N(R a )、O、S(O) t , CR b R c 、C(O)N(R a ) or S(O) t N(R a );

[0016] R a Selected from hydrogen, deuterium, C(O)C 1-10 Alkyl, -C(O)NR 6 R 7 , -C 1-10 Alkyl C(O)NR 6 R 7 、C(O)3-20 membered heterocyclic group、S(O) 2 C 1-10 Alkyl, S(O) 2 3-20 membered heterocyclic group, C 1-10 Deuterated alkyl, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 3-20 membered heterocyclyl, -3-20 membered heterocyclyl-C 1-10 Alkyl or -C 1-10 Alkyl-3-20 membered heterocyclic group; wherein R a C in the group represented 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-20 membered heterocyclyl, -3-20 membered heterocyclyl-C 1-10 Alkyl or -C 1-10 The alkyl-3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-10 Alkyl, -C 1-10 Alkyl-OH, C 1-10Haloalkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Haloalkoxy, C 3-10 Cycloalkyl, -S(O) 2 C 1-10 Alkyl, C(O)C 1-10 Alkyl, -C(O)NR 6 R 7 , 3-20 membered heterocyclic group and NR 6 R 7 ;

[0017] R b and R c are the same or different and are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C(O)C 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 3-10 Cycloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NHC 1-10 Alkyl, -N(C 1-10 alkyl) 2 or a 3-20 membered heterocyclic group; wherein R b and / or R c C in the group represented 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, -NHC 1-10 Alkyl, -N(C 1-10 alkyl) 2 or the 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Haloalkoxy, C 3-10 Cycloalkyl, 3-20 membered heterocyclic group and NR 6 R 7 ;

[0018] R f is selected from the group consisting of absent, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C(O)C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Alkyl, C 1-10 Alkylthio, -NHC1-10 Alkyl, -N(C 1-10 alkyl) 2 , C 3-10 Cycloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or 3-20 membered heterocyclic group; wherein R f C in the group represented 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 The cycloalkyl or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Haloalkoxy, C 3-10 Cycloalkyl, C 3-4 Heterocyclic group, C 5-10 Heterocyclic group and NR 6 R 7 ;

[0019] R 1 , R 2 , R 3 and R 4 are the same or different and are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, C 1-10 Deuterated alkyl, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 6-10 Aryl, P(O)R 6 R 7 、S(O) 2 R 6 、S(O) 2 NR 6 R 7 NR 6 R 7 、C(O)NR 6 R 7 、C(O)NR 6 、S(O) 2 R 7 NR 6 S(O) 2 R 7 、C(O)R 6 NR 6 C(O)R 7 , 5-10 membered heteroaryl, 5-20 membered heterocyclic group; wherein, C 1-10Deuterated alkyl, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 6-10 At least one of the aryl, 5-10 membered heteroaryl and 5-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Haloalkoxy, NR 6 R 7 、C(=O)NR 6 R 7 、C(=O)NR 6 S(=O) 2 R 7 、P(=O)R 6 R 7 、S(=O) 2 R 6 、S(O) 2 or NR 6 S(=O) 2 R 7 ;

[0020] R 5 Selected from hydrogen, C 1-10 Alkyl (e.g. methyl, ethyl) or cyano;

[0021] R 6 and R 7 are the same or different, each independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 3-10 Cycloalkyl, 3-20 membered heterocyclic group; wherein R 6 and / or R 7 Representative C 1-10 Alkyl, C 3-10 The cycloalkyl and 3-20 membered heterocyclic groups may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, 3-20 membered heterocyclic group; wherein R 6 and R 7A 3-20 membered heterocyclic group may be formed by a nitrogen atom or a phosphorus atom, and the 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Deuterated alkoxy, C 1-10 Haloalkoxy, C 3-10 Cycloalkyl, 3-20 membered heterocyclic group;

[0022] m is 0, 1, 2 or 3, n is 0, 1, 2 or 3, and m+n≤4;

[0023] t is 0, 1, or 2, and S(O) t NR a Where t is 1 or 2.

[0024] According to an embodiment of the present invention, in the compound represented by Formula I or Formula II, X 1 , X 2 , Y are the same or different and are independently selected from the group consisting of absence, N(R a )、O、S、S(O) t 、C(O)、C(O)N(R a )、S(O) t N(R a ) or CR b R c .

[0025] Preferably, X 1 , X 2 , Y are the same or different and are independently selected from the group consisting of absence, N(R a )、O、S、S(O) t , C(O), or CR b R c .

[0026] More preferably, X 1 , X 2 , Y are the same or different and are independently selected from the group consisting of absence, N(R a ), O, S, or CR b R c .

[0027] m is 0, 1, 2 or 3, n is 0, 1, 2 or 3, and m+n≤4; preferably, m is 1 or 2, and n is 1 or 2.

[0028] t is 1 or 2.

[0029] X 1 , X 2 , R in the definition of Ya , each of which is the same or different and is independently selected from hydrogen, or an optionally substituted group: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-20 membered heterocyclic group, -S(O) 2 C 1-10 Alkyl, -C(O)C 1-10 Alkyl, -C(O)-(3-20 membered heterocyclic group), -C(O)NR 21 R 22 , -C 1-10 Alkyl C(O)NR 21 R 22 、-(CH 2 ) p -(3-20 membered heterocyclyl) or -3-20 membered heterocyclyl-C 1-10 Alkyl; the optionally substituted means being monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, C 1-10 Alkyl, hydroxyl C 1-10 Alkyl-, C 1-10 Alkoxy, C 1-10 Alkylthio, -NR 21 R 22 , C 3-10 Cycloalkyl, 3-20 membered heterocyclic group, -C(O)C 1-10 Alkyl, -S(O) 2 C 1-10 Alkyl, -C(O)NR 21 R 22 ; Among them, R 21 , R 22 are the same or different and are independently selected from H, C 1-10 Alkyl; p is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0030] Preferably, R a Each is the same or different and is independently selected from hydrogen, or an optionally substituted group: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) 2 C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)-(3-6 membered heterocyclic group), -C(O)NR 21 R 22 , -C 1-6 Alkyl C(O)NR 21 R22 、-(CH 2 ) p -(3-6 membered heterocyclic group); the optionally substituted group means being monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl-, C 1-6 Alkylthio, -NR 21 R 22 , C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -C(O)NR 21 R 22 ; Among them, R 21 , R 22 are the same or different and are independently selected from H, C 1-6 Alkyl; p is 1, 2, 3, 4, 5, 6, 7 or 8.

[0031] More preferably, R a Each is the same or different and is independently selected from hydrogen, or an optionally substituted group: C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) 2 C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)-(3-6 membered heterocyclic group), -C(O)NR 21 R 22 、-(CH 2 ) p -(3-6 membered heterocyclic group), -(CH 2 ) p -S(O) 2 C 1-6 Alkyl, -(CH 2 ) p -C(O)NR 21 R 22 The optionally substituted means being monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy, C 1-6 Alkylthio, -NR 21 R 22 , C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(O)C 1-6 Alkyl, -S(O) 2C 1-6 Alkyl, -C(O)NR 21 R 22 ; Among them, R 21 , R 22 are the same or different and are independently selected from H, C 1-6 Alkyl; p is 1, 2, 3, 4, 5 or 6.

[0032] Particularly preferably, R a Each is the same or different and is independently selected from hydrogen, or an optionally substituted group: C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) 2 C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)-(3-6 membered heterocyclic group), -C(O)NR 21 R 22 、-(CH 2 ) p -(3-6 membered heterocyclic group), -(CH 2 ) p -S(O) 2 C 1-6 Alkyl, -(CH 2 ) p -C(O)NR 21 R 22 The optionally substituted means being monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy, -NR 21 R 22 、-C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl; wherein R 21 , R 22 are the same or different and are independently selected from H, C 1-6 Alkyl; p is 1, 2 or 3.

[0033] Very particularly preferably, R a Each is the same or different and is independently selected from hydrogen, or an optionally substituted group: C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) 2 C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)-(3-6 membered heterocyclic group), -C(O)NR 21 R22 、-(CH 2 ) p -(3-6 membered heterocyclic group), -(CH 2 ) p -S(O) 2 C 1-6 Alkyl, -(CH 2 ) p -C(O)NR 21 R 22 The optionally substituted means being monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -NR 21 R 22 、-C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl; wherein R 21 , R 22 are the same or different and are independently selected from H, C 1-3 Alkyl; p is 1 or 2.

[0034] Most preferably, R a Each is the same or different and is independently selected from hydrogen, or an optionally substituted group: C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) 2 C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)-(3-6 membered heterocyclic group), -C(O)NR 21 R 22 、-(CH 2 ) p -(3-6 membered heterocyclic group), -(CH 2 ) p -S(O) 2 C 1-6 Alkyl, -(CH 2 ) p -C(O)NR 21 R 22 ; wherein 3-6 membered heterocyclic group, -C(O)-(3-6 membered heterocyclic group) or -(CH 2 ) p-(3-6 membered heterocyclyl) wherein the "heterocyclyl" is selected from oxetane, azetidinyl, N-methylazetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, N-methyltetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, N-methylpiperidinyl, morpholinyl, N-methylmorpholinyl, piperazinyl or N-methylpiperazinyl; the "optionally substituted" means being mono- or poly-substituted by a substituent selected from the following: halogen, cyano, hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy, -NR 21 R 22 、-C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl; wherein R 21 , R 22 are the same or different and are independently selected from H, C 1-3 alkyl.

[0035] R b and R c are the same or different and are independently selected from H, halogen, cyano, hydroxyl, amino, or the following groups which are optionally substituted: C 1-10 Alkyl, C 1-10 Alkoxy, -NHC 1-10 Alkyl, -N(C 1-10 alkyl) 2 The optionally substituted meaning is monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, amino, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkyl, -NHC 1-10 Alkyl, -N(C 1-10 alkyl) 2 .

[0036] Preferably, R b and R c are the same or different and are independently selected from H, halogen, cyano, hydroxyl, amino, or the following groups which are optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 The optionally substituted meaning is monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, -NHC1-6 Alkyl, -N(C 1-6 alkyl) 2 .

[0037] More preferably, R b and R c are the same or different and are independently selected from H, halogen, cyano, hydroxyl, amino, or the following groups which are optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, -NH C 1-6 Alkyl, -N(C 1-6 alkyl) 2 The optionally substituted meaning is monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 .

[0038] Particularly preferably, R b and R c are the same or different and are independently selected from H, halogen, cyano, hydroxyl, amino, or the following groups which are optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy; the optionally substituted means being monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 .

[0039] Most preferably, R b and R c are the same or different and are independently selected from H, halogen, cyano, hydroxyl, amino, or the following groups which are optionally substituted: C 1-3 Alkyl, C 1-3 Alkoxy; the optionally substituted means being monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, -NHC 1-3 Alkyl, -N(C 1-3 alkyl) 2 .

[0040] R 1 , R 2 , R 3 and R 4are the same or different and are independently selected from H, halogen, cyano, hydroxyl, amino, or the following groups which are optionally substituted: C 1-10 Alkyl, C 1-10 Alkoxy, -NHC 1-10 Alkyl, -N(C 1-10 alkyl) 2 The optionally substituted meaning is monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, amino, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkyl, -NH C 1-10 Alkyl, -N(C 1-10 alkyl) 2 .

[0041] Preferably, R 1 , R 2 , R 3 and R 4 are the same or different and are independently selected from H, halogen, cyano, hydroxyl, amino, or the following groups which are optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 The optionally substituted meaning is monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, -NH C 1-6 Alkyl, -N(C 1-6 alkyl) 2 .

[0042] More preferably, R 1 , R 2 , R 3 and R 4 are the same or different and are independently selected from H, halogen, cyano, hydroxyl, amino, or the following groups which are optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 The optionally substituted meaning is monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C1-6 alkyl) 2 .

[0043] Particularly preferably, R 1 , R 2 , R 3 and R 4 are the same or different and are independently selected from H, halogen, cyano, hydroxyl, amino, or the following groups which are optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy; the optionally substituted means being monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 .

[0044] Most preferably, R 1 , R 2 , R 3 and R 4 are the same or different and are independently selected from H, halogen, cyano, hydroxyl, amino, or the following groups which are optionally substituted: C 1-3 Alkyl, C 1-3 Alkoxy; the optionally substituted means being monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, -NHC 1-3 Alkyl, -N(C 1-3 alkyl) 2 .

[0045] M 1 and M 2 are the same or different and are independently selected from CH or N; preferably, M 1 and M 2 CH, or M 1 N and M 2 CH, or M 1 CH and M 2 N; more preferably, M 1 and M 2 For CH.

[0046] R f is selected from the group consisting of absent, halogen, cyano, hydroxyl, amino, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, -NHC 1-10 Alkyl, -N(C 1-10 alkyl) 2 , C3-10 Cycloalkyl, 3-20 membered heterocyclic group; preferably, R f is selected from the group consisting of absent, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 More preferably, R f is selected from the group consisting of absent, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy; particularly preferably, R f is selected from the group consisting of absence, halogen, cyano, hydroxyl, amino; most preferably, R f Select from does not exist.

[0047] R 5 Selected from hydrogen, C 1-10 Alkyl; preferably, selected from hydrogen, C 1-6 Alkyl; more preferably, selected from hydrogen, C 1-3 Alkyl; particularly preferably, selected from hydrogen, methyl, ethyl.

[0048] Ar 1 ,Ar 2 are the same or different and are independently selected from 5-10 membered heteroaryl groups having 1 or 2 heteroatoms selected from N or O, or C 6-10 Aryl, the heteroaryl or aryl is optionally monosubstituted or polysubstituted by a group selected from the following: halogen, cyano, hydroxyl, amino, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, -NHC 1-10 Alkyl, -N(C 1-10 alkyl) 2 , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group.

[0049] Preferably, Ar 1 ,Ar 2 are the same or different and are independently selected from 5-6 membered heteroaryl having 1 or 2 heteroatoms selected from N or O, or phenyl, wherein the heteroaryl or phenyl is optionally mono- or poly-substituted by halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 , C 3-6 Cycloalkyl, 3-6 membered heterocyclic group.

[0050] More preferably, Ar 1 ,Ar 2 are the same or different and are independently selected from 5-6 membered heteroaryl having 1 or 2 heteroatoms selected from N, or phenyl, wherein the heteroaryl or phenyl is optionally mono- or poly-substituted by halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NH C 1-6 Alkyl, -N(C 1-6 alkyl) 2 , C 3-6 Cycloalkyl.

[0051] Particularly preferably, Ar 1 ,Ar 2 are the same or different and are independently selected from 6-membered heteroaryl groups having 1 or 2 heteroatoms selected from N, or phenyl groups, which are optionally mono- or poly-substituted by groups selected from halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 , C 3-6 Cycloalkyl.

[0052] Particularly preferably, Ar 1 ,Ar 2 are the same or different and are independently selected from pyridyl, pyrimidinyl, pyridazinyl, phenyl; which are optionally mono- or poly-substituted by the following groups: halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 , C 3-6 Cycloalkyl.

[0053] Very particularly preferably, Ar 1 is selected from pyridine, which is optionally mono- or polysubstituted by groups selected from the group consisting of halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NHC 1-10 Alkyl, -N(C 1-10 alkyl) 2 , C 3-6 Cycloalkyl.

[0054] Most preferably, Ar1 Selected from halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino mono- or di-substituted with the following groups:

[0055]

[0056] Very particularly preferably, Ar 2 is selected from phenyl, which is optionally mono- or polysubstituted by groups selected from the group consisting of halogen, cyano, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NH C 1-6 Alkyl, -N(C 1-6 alkyl) 2 , C 3-6 Cycloalkyl.

[0057] Most preferably, Ar 2 is selected from phenyl, which is optionally mono- or di-substituted by a group selected from the group consisting of halogen, cyano, hydroxy, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH C 1-3 Alkyl, -N(C 1-3 alkyl) 2 , C 3-6 Cycloalkyl.

[0058] In some embodiments of the present invention, X 1 , X 2 are the same or different and are independently selected from N(R a ), O or S; and Y is selected from not existing; and m=1, n=1.

[0059] In some embodiments of the present invention, X 1 Selected from N(R a ), O or S; and Y is selected from N(R a ), O, S, or CR b R c ; and X 2 is selected from not existing; and m=1, n=1.

[0060] In some embodiments of the present invention, X 2 Selected from N(R a ), O or S; and Y is selected from N(R a ), O, S, or CR b R c ; and X 1is selected from not existing; and m=1, n=1.

[0061] In some embodiments of the present invention, X 1 Selected from CR b R c ; and Y is selected from N(R a ), O, S, or CR b R c ; and X 2 is selected from not existing; and m=1, n=1.

[0062] In some embodiments of the present invention, X 2 Selected from CR b R c ; and Y is selected from N(R a ), O, S, or CR b R c ; and X 1 is selected from not existing; and m=1, n=1.

[0063] According to the present invention, in Formula I or Formula II:

[0064] Ar 1 Selected from C 6-10 Aromatic ring, with 1 to 3 R 8 Heteroatom C 5-10 Aromatic heterocyclic ring, 6-membered aromatic ring and 1 to 3 R 8 Heteroatom C 5-7 The heterocyclic ring, the 6-membered aromatic ring and the 1-3 R 8 Heteroatom C 5-7 Aromatic heterocyclic rings, with 1 to 3 R 8 The 6-membered aromatic heterocyclic ring containing a heteroatom and having 1 to 3 R 8 Heteroatom C 5-7 A heterocyclic ring or a ring having 1 to 3 R 8 The 6-membered aromatic heterocyclic ring containing a heteroatom and having 1 to 3 R 8 Heteroatom C 5-7 Aromatic heterocyclic rings are combined to form a ring, wherein R 8 Selected from N, S or O;

[0065] Ar 2 Selected from C 6-10 Aromatic ring, with 1 to 3 R 8 Heteroatom C 5-10 Aromatic heterocyclic ring, 6-membered aromatic ring and 1 to 3 R 8 Heteroatom C 5-7 The heterocyclic ring, the 6-membered aromatic ring and the 1-3 R 8 Heteroatom C 5-7Aromatic heterocyclic rings, with 1 to 3 R 8 The 6-membered aromatic heterocyclic ring containing a heteroatom and having 1 to 3 R 8 Heteroatom C 5-7 A heterocyclic ring or a ring having 1 to 3 R 8 The 6-membered aromatic heterocyclic ring containing a heteroatom and having 1 to 3 R 8 Heteroatom C 5-7 A fused ring composed of aromatic heterocyclic rings;

[0066] M 1 and M 2 are each independently selected from CH or N;

[0067] X 1 and X 2 Each independently selected from none, NR a , O, S(O) t 、C(O)、C(O)NR a 、S(O) t NR a or CR b R c ;

[0068] Y is selected from NR a , O, S(O) t , CR b R c 、C(O)NR a or S(O) t NR a ;

[0069] R a Selected from hydrogen, deuterium, C(O)C 1-6 Alkyl, C(O)C 3–8 Heterocyclic group, S(O) 2 C 1-6 Alkyl, S(O) 2 C 3–8 Heterocyclic group, C 1-6 Deuterated alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or having 1 to 3 R 8 Heteroatom C 3-12 A heterocyclic group, wherein R a The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclic group in the represented group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Haloalkoxy, C 3-8 Cycloalkyl, C 4-10 Heterocyclic group and NR 6 R 7 ;

[0070] R b and R c Each independently selected from: hydrogen, deuterium, halogen, C(O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or having 1 to 3 R 8 Heteroatom C 3-12 Heterocyclic group, wherein R b and / or R c The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclic group in the represented group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 5-10 Heterocyclic group and NR 6 R 7 ;

[0071] R f Selected from hydrogen, deuterium, C(O)C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or having 1 to 3 R 8 Heteroatom C 3-12 A heterocyclic group, wherein R f The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclic group in the represented group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 5-10 Heterocyclic group and NR 6 R 7 ;

[0072] R 1 , R 2 , R3 and R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, C 1-6 Deuterated alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 6-10 Aryl, P(O)R 6 R 7 、S(O) 2 R 6 、S(O) 2 NR 6 R 7 NR 6 R 7 、C(O)NR 6 R 7 、C(O)NR 6 、S(O) 2 R 7 NR 6 S(O) 2 R 7 、C(O)R 6 NR 6 C(O)R 7 , with 1 to 3 R 8 Heteroatom C 5-12 Heteroaryl or having 1 to 3 R 8 Heteroatom C 3-12 Heterocyclic group, wherein C 1-6 Deuterated alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 6-10 Aryl, with 1 to 3 R 8 Heteroatom C 5-12 Heteroaryl and having 1 to 3 R 8 Heteroatom C 3-12 At least one of the heterocyclic groups may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR 6 R 7 、C(=O)NR 6 R 7 、C(=O)NR 6 S(=O)2 R 7 、P(=O)R 6 R 7 、S(=O) 2 R 6 、S(O) 2 NR 6 R 7 and NR 6 S(=O) 2 R 7 ;

[0073] R 5 is selected from hydrogen, methyl, ethyl or cyano;

[0074] R 6 and R 7 are each independently selected from hydrogen, deuterium or C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, with 1 to 3 R 8 Heteroatom C 3-12 Heterocyclic group, wherein R 6 and / or R 7 The alkyl, cycloalkyl, and heterocyclic groups represented by the present invention may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-12 Heterocyclic group; wherein R 6 and R 7 C can be formed by nitrogen or phosphorus atoms 3-12 Heterocyclic group, the C 3-12 The heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl and C 3-12 Heterocyclic group;

[0075] m is 0, 1, 2 or 3, n is 0, 1, 2 or 3, and m+n≤4;

[0076] t is 0, 1, or 2.

[0077] The present invention also provides a pharmaceutical composition, which comprises a compound represented by Formula I or Formula II.

[0078] The present invention also provides use of the above pharmaceutical composition in preparing drugs for treating diseases associated with Yes1 amplification or Yes1 overexpression.

[0079] According to an embodiment of the present invention, the disease associated with Yes1 amplification or Yes1 overexpression includes cancer, including at least one of esophageal cancer, small cell lung cancer, blood tumor, digestive system tumor, reproductive system tumor, nervous system tumor and head and neck cancer.

[0080] The present invention also provides a method for treating a disease associated with Yes1 amplification or Yes1 overexpression, comprising administering the pharmaceutical composition described above to an individual in need thereof.

[0081] The technical solution of the present invention has at least the following beneficial effects:

[0082] The compound provided by the present invention can competitively target and bind to Yes1 with ATP in the ATP binding pocket of Yes1, and can also bind to the back pocket of Yes1 kinase to increase the affinity of the compound binding to the pocket, so that the N-containing group in the compound binds to the hinge region of Yes1. In addition, the compound of the present invention can also generate electrostatic interactions with the conserved amino acid residues below the ATP binding pocket in Yes1, thereby significantly improving the ability of the compound to competitively bind to Yes1 with ATP, inhibiting the binding of ATP to Yes1 catalytic histone-related sites, and preventing the expression of genes that induce cancer cell growth, and can be used to treat diseases related to Yes1 gene amplification or Yes1 protein overexpression, such as tumors.

[0083] Definitions and explanations of terms

[0084] Unless otherwise defined, all technical terms herein have the same meaning as commonly understood by persons skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. If there are multiple definitions of a term herein, the definition in this patent shall prevail.

[0085] In the present invention, "more" means three or more.

[0086] In the present invention, "polysubstituted" means substituted with two, three, four, five or six substituents.

[0087] In the present invention, the “*” in some groups indicates a connection site.

[0088] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0089] The term "C 1-10"Alkyl" is understood to mean preferably a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. In particular, the C 1-10 Alkyl groups have 1, 2, 3, 4, 5, 6 carbon atoms (“C 1-6 More particularly, the radical has 1, 2 or 3 carbon atoms ("C 1-3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0090] The term "C 2-10 "Alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably "C 2-6 It should be understood that in the C 2-10 When the alkenyl group contains more than one double bond, the double bonds may be separated or conjugated with each other. 2-10 Alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent- 1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl but-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0091] The term "C 2-10"Alkynyl" is understood to mean a linear or branched monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Preferably "C 2-6 "Alkynyl". 2-6 Alkynyl is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 2-methylpent-5-ynyl, 2-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2 ... In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0092] The term "C 3-10 "Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decalin ring.

[0093] The term "having 1 to 3 R 8 Heteroatom C 3-12 "Heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-3 heteroatoms independently selected from N, O and S, and containing 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The heterocyclyl may be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclyl having 1 to 3 R 8 Heteroatom C 3-12The heterocyclic group may include, but is not limited to, a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta [c] pyrrole-2 (1H) -yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl ring. The ring containing the nitrogen atom may be partially unsaturated, i.e. it may contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl. According to the invention, the heterocyclic group is non-aromatic.

[0094] The term "3-20 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O and S, and containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms. Preferred is "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclyl may be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom, if present. In particular, the heterocyclic group may include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl.

[0095] The term "having 1 to 3 R 8 Heteroatom C 5-10The term "aromatic heterocycle" is intended to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 carbon atoms and containing 1 to 3 heteroatoms independently selected from N, O and S. And, in addition, in each case, it may be benzo-fused. In particular, the aromatic heterocycle is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, for example benzo and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, etc.; or azinyl, indolizinyl, purinyl, etc. and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0096] The term "having 1 to 3 R 8 Heteroatom C 5-7 The term "aromatic heterocycle" is intended to include monovalent monocyclic or bicyclic aromatic ring systems having 5, 6 or 7 carbon atoms and containing 1 to 3 heteroatoms independently selected from N, O and S. And, in addition, in each case, it may be benzo-fused. In particular, the aromatic heterocycle is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, for example benzofuranyl, benzothiophenyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, etc.; or acinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0097] The term "5-10 membered heteroaryl" is intended to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which contain 1 to 3 heteroatoms independently selected from N, O and S. And, in addition in each case may be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc. and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolyl, quinazolinyl, isoquinolyl, etc.; or azinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0098] The term "C 6-10 "Aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic or bicyclic hydrocarbon ring having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C 6 aryl), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 "aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. When the C 6-10 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution position, for example, it may be substituted at the ortho position, para position or meta position.

[0099] The term "C 1-10 "Alkoxy" means "-OC 1-10 Alkyl", where C 1-10 Alkyl has the same meaning as defined above.

[0100] The term "C 1-10 "Alkylthio" means "-SC 1-10 Alkyl", where C 1-10 Alkyl has the same meaning as defined above.

[0101] The term "C 1-10 "Haloalkyl" means C 1-10 The case where one, two or more H in an alkyl group is replaced by a halogen. 1-10 Alkyl and halogen have the same meanings as above.

[0102] The term "C 1-10 "Deuterated alkyl" means C 1-10 One, two or more H in an alkyl group is replaced by deuterium. 1-10 Alkyl has the same meaning as defined above.

[0103] The above term “C 1-10 The definition of "alkyl" also applies to other C-containing 1-10 Alkyl groups, such as -C 1-10 alkyl-3-20 membered heterocyclic group, -3-20 membered heterocyclic group-C 1-10 Alkyl, -C 1-10 Alkyl C(O)NR 6 R 7 、-NHC 1-10 Alkyl, -N(C 1-10 alkyl) 2 In other words, all the terms in this application that contain “C 1-10 The "C" in the "alkyl" group 1-10 Alkyl" has an independent group "C 1-10 The same definition as in "alkyl".

[0104] Similarly, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-20 membered heterocyclyl and the like groups have the same definition throughout. DETAILED DESCRIPTION

[0105] In order to better illustrate the present invention and facilitate understanding of the technical solution of the present invention, the present invention is further described in detail below. It should be clear that the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0106] The present invention provides a compound represented by formula I or formula II:

[0107]

[0108] In Formula I or Formula II:

[0109] Ar 1 Selected from C 6-10 Aromatic ring, with 1 to 3 R 8 Heteroatom C 5-10 Aromatic heterocyclic ring, 6-membered aromatic ring and 1 to 3 R 8 Heteroatom C 5-7 The heterocyclic ring, the 6-membered aromatic ring and the 1-3 R 8 Heteroatom C 5-7Aromatic heterocyclic rings, with 1 to 3 R 8 The 6-membered aromatic heterocyclic ring containing a heteroatom and having 1 to 3 R 8 Heteroatom C 5-7 A heterocyclic ring or a ring having 1 to 3 R 8 The 6-membered aromatic heterocyclic ring containing a heteroatom and having 1 to 3 R 8 Heteroatom C 5-7 Aromatic heterocyclic rings are combined to form a ring, wherein R 8 Selected from N, S or O;

[0110] Ar 2 Selected from C 6-10 Aromatic ring, with 1 to 3 R 8 Heteroatom C 5-10 Aromatic heterocyclic ring, 6-membered aromatic ring and 1 to 3 R 8 Heteroatom C 5-7 The heterocyclic ring, the 6-membered aromatic ring and the 1-3 R 8 Heteroatom C 5-7 Aromatic heterocyclic rings, with 1 to 3 R 8 The 6-membered aromatic heterocyclic ring containing a heteroatom and having 1 to 3 R 8 Heteroatom C 5-7 A heterocyclic ring or a ring having 1 to 3 R 8 The 6-membered aromatic heterocyclic ring containing a heteroatom and having 1 to 3 R 8 Heteroatom C 5-7 A fused ring composed of aromatic heterocyclic rings;

[0111] M 1 and M 2 are each independently selected from CH or N;

[0112] X 1 and X 2 Each independently selected from none, NR a , O, S(O) t 、C(O)、C(O)NR a 、S(O) t NR a or CR b R c ;

[0113] Y is selected from NR a , O, S(O) t , CR b R c 、C(O)NR a or S(O) t NR a ;

[0114] Ra Selected from hydrogen, deuterium, C(O)C 1-6 Alkyl, C(O)C 3–8 Heterocyclic group, C 1-6 Deuterated alkyl, S(O) 2 C 1-6 Alkyl, S(O) 2 C 3–8 Heterocyclic group, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or having 1 to 3 R 8 Heteroatom C 3-12 A heterocyclic group, wherein R a The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclic group in the represented group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 4-10 Heterocyclic group and NR 6 R 7 ;

[0115] R b and R c Each independently selected from: hydrogen, deuterium, halogen, C(O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or having 1 to 3 R 8 Heteroatom C 3-12 Heterocyclic group, wherein R b and / or R c The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclic group in the represented group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 5-10 Heterocyclic group and NR 6 R 7 ;

[0116] R f Selected from hydrogen, deuterium, C(O)C 1-6 Alkyl, C1-6 Deuterated alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or having 1 to 3 R 8 Heteroatom C 3-12 A heterocyclic group, wherein R f The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclic group in the represented group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 5-10 Heterocyclic group and NR 6 R 7 ;

[0117] R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, C 1-6 Deuterated alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 6-10 Aryl, P(O)R 6 R 7 、S(O) 2 R 6 、S(O) 2 NR 6 R 7 NR 6 R 7 、C(O)NR 6 R 7 、C(O)NR 6 、S(O) 2 R 7 NR 6 S(O) 2 R 7 、C(O)R 6 NR 6 C(O)R 7 , with 1 to 3 R 8 Heteroatom C 5-12 Heteroaryl or having 1 to 3 R 8 Heteroatom C 3-12 Heterocyclic group, wherein C 1-6Deuterated alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 6-10 Aryl, with 1 to 3 R 8 Heteroatom C 5-12 Heteroaryl and having 1 to 3 R 8 Heteroatom C 3-12 At least one of the heterocyclic groups may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR 6 R 7 、C(=O)NR 6 R 7 、C(=O)NR 6 S(=O) 2 R 7 、P(=O)R 6 R 7 、S(=O) 2 R 6 、S(O) 2 NR 6 R 7 or NR 6 S(=O) 2 R 7 .

[0118] R 5 is selected from hydrogen, methyl, ethyl or cyano;

[0119] R 6 and R 7 are each independently selected from hydrogen, deuterium or C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, with 1 to 3 R 8 Heteroatom C 3-12 Heterocyclic group, wherein R 6 and / or R 7 The alkyl, cycloalkyl, and heterocyclic groups represented by the present invention may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-12 Heterocyclic group; wherein R 6 and R7 C can be formed by nitrogen or phosphorus atoms 3-12 Heterocyclic group, the C 3-12 The heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-12 Heterocyclic group;

[0120] m is 0, 1, 2 or 3, n is 0, 1, 2 or 3, and m+n≤4;

[0121] t is 0, 1, or 2.

[0122] In the above scheme, the compound represented by formula I and the compound represented by formula II of the present invention contain an indolyl ketone structure, an a group located on the left side of the indolyl ketone structure, and a b group located on the right side of the indolyl ketone structure; wherein the a group can reduce the electron cloud density of the N atom on the adjacent indolyl ketone structure, so that compound I or compound II can generate electrostatic interaction with the conserved amino acid residue below the ATP binding pocket in Yes1 kinase, and can also enhance the hydrogen bonding ability of the NH of indole with the carbonyl group of the hinge region skeleton of Yes1 kinase; in addition, the b group located on the right side of the indolyl ketone structure can bind to the back pocket of Yes1 kinase by introducing a substituent, thereby increasing the affinity of compound I or compound II binding to the pocket of Yes1 kinase. The present invention improves the ability of compound I or compound II to competitively bind to Yes1 with ATP through the synergistic effect of the a group and the b group, can inhibit the binding of ATP to Yes1 with the catalytic histone-related site, and prevents the expression of genes that induce cancer cell growth, and can further be used to treat diseases related to Yes1 gene amplification or Yes1 protein overexpression, such as tumors.

[0123] In some embodiments, Y is selected from NR a 、C(O)NR a or S(O) t NR a The N atom in the above group is connected to the non-electron-withdrawing group, so that the a group can be protonated under physiological conditions. The protonated a group can effectively increase the hydrogen bonding force between the nitrogen atom in the compound and the backbone carbonyl group on the amino acid chain below the ATP binding pocket of the Yes1 protein and the electrostatic interaction force between the aspartic acid residue below the amino acid chain, reduce the electron cloud density of the N atom on the indole ring adjacent to the a group, increase the acidity of NH in the indole fragment, increase the hydrogen bonding force between the backbone carbonyl group, and increase the binding ability of the molecule to the protein pocket, thereby improving the activity of the compound.

[0124] In some embodiments, R f The position of M in the compound represented by Formula I and the compound represented by Formula II 1 and M 2 R can be introduced into the group f Group, specifically, when M 1 =CH,M 2 =CH, M 1 and M 2 The H in can be f Substituted by a substituent, the R f Selected from hydrogen, deuterium, C(O)C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or having 1 to 3 R 8 Heteroatom C 3-12 Heterocyclic group; wherein R f C in the group represented 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 1 to 3 R 8 Heteroatom C 3-12 The heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 5-10 Heterocyclic group and NR 6 R 7 ; When M 2 =N, R f Does not exist.

[0125] In some embodiments, the compounds of the present invention may also be enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, prodrugs, isotopic derivatives and solvates of compounds of formula I or formula II; it can be understood that the compounds of formula I and formula II of the present invention are active reaction substances, and conventional designs can be carried out on the basis thereof, so that the designed compounds can still maintain the pharmacological efficacy of the compounds of formula I and formula II.

[0126] In some embodiments, Ar 1 Select from 1 to 3 R 8 Heteroatom C 5-10Aromatic heterocyclic ring, wherein R 8 Selected from N or O, such as Ar 1 is selected from pyridinyl or pyrimidinyl.

[0127] In some embodiments, Ar 2 Selected from C 6-10 Aromatic rings, such as phenyl.

[0128] In some embodiments of the present invention, Ar 1 is selected from 5-10 membered heteroaryl; the 5-10 membered heteroaryl is further substituted by 1 or 2 C 1-6 Alkyl substitution; for example, Ar 1 selected from those having 1 or 2 N atoms and surrounded by 1 or 2 C 1-3 Alkyl substituted C 5 Heteroaryl; such as Ar 1 Selected from pyridine or pyrimidinyl substituted by 1 methyl group.

[0129] In some embodiments of the present invention, Ar 2 is selected from C substituted by 1, 2 or 3 halogens 6-10 Aryl; for example, phenyl substituted by 1 or 2 halogens; such as phenyl substituted by 1 or 2 Fs.

[0130] In some embodiments, M 1 and M 2 are the same or different and are each independently selected from CH or N.

[0131] In some embodiments of the present invention, in Formula I, M 1 and M 2 Selected from CH; or, M 1 Selected from CH, M 2 Selected from N.

[0132] In some embodiments of the present invention, in Formula II, M 1 and M 2 Selected from CH.

[0133] In some embodiments, X 1 and X 2 The same or different, each independently selected from none, NR a , O or CR b R c .

[0134] In some embodiments, Y is selected from NR a , CR b R c 、C(O)NR a or S(O) t NR a .

[0135] In some embodiments, R a Selected from hydrogen, C(O)C 1-6 Alkyl, C(O)C 3–8 Heterocyclic group, C 1-6 Alkyl, -C 1-6 Alkyl - has 1 to 3 R 8 Heteroatom C 3-12 Heterocyclic group, - having 1 to 3 R 8 Heteroatom C 3-12 Heterocyclyl-C 1-6 Alkyl, -C 1-6 Alkyl C(O)NR 6 R 7 、C(O)NR 6 R 7 、S(O) 2 C 1-6 Alkyl, -C 1-6 Alkyl S(O) 2 C 1-6 Alkyl, S(O) 2 C 3–8 Heterocyclic group, or having 1 to 3 R 8 Heteroatom C 3-12 Heterocyclic group; wherein R a C in the group represented 1-6 Alkyl, C 2-6 Alkynyl or having 1 to 3 R 8 Heteroatom C 3-12 The heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, C 1-6 Alkyl, C(O)C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3 Heterocyclic group, C 4-10 Heterocyclic group and NR 6 R 7 .

[0136] In some embodiments, R b and R c the same or different, each independently selected from hydrogen or C 1-6 Alkyl; wherein R b and / or R c C in the group represented 1-6 The alkyl group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano and NR 6 R 7 .

[0137] In some embodiments, R f Selected from hydrogen or C 1-6 Alkyl; wherein R f C in the group represented 1-6 The alkyl group may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen and cyano;

[0138] In some embodiments, R 1 , R 2 , R 3 and R 4 are the same or different and are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro or C 1-6 Alkyl; among which, C 1-6 The alkyl group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, C 1-6 Alkoxy and NR 6 R 7 .

[0139] In some embodiments, R 5 is selected from hydrogen, methyl or ethyl.

[0140] In some embodiments, R 6 and R 7 The same or different, each independently selected from H, C 1-6 Alkyl or -C 1-6 Alkyl-OH.

[0141] In some embodiments, m is 0 or 1, and n is 0 or 1.

[0142] In some embodiments, t is 2.

[0143] In some embodiments, the compound of formula I or formula II can be selected from any one of the following compounds:

[0144]

[0145]

[0146] Wherein, each group has the above-mentioned definition.

[0147] In some embodiments, in formula (a):

[0148] R a Selected from hydrogen, C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl or 3-20 membered heterocyclic group, wherein R a C in the group represented 1-6 Alkyl, S(O) 2C 1-6 The alkyl or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, C 1-6 Alkyl, 3-20 membered heterocyclic group or NR 6 R 7 , R 6 R 7 Each independently selected from C 1-6 Alkyl; for example, R a Selected from hydrogen, C 1-6 Alkyl (such as methyl, ethyl), S(O) 2 C 1-3 Alkyl [such as S(O) 2 CH 3 ], -C 1-6 Alkyl-OH (such as CH 2 OH, C 2 H 4 OH), -C 1-6 Alkyl-NR 6 R 7 [As CH 2 N(CH 3 ) 2 , C 2 H 4 N(CH 3 ) 2 ], -C 1-6 Alkyl-NH 2 (such as CH 2 NH 2 , C 2 H 4 NH 2 ), 3-20 membered heterocyclic groups (such as oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, hexahydropyridinyl, hexahydropyranyl);

[0149] X 2 Selected from O, NR a or CR b R c , R b and R c is selected from hydrogen or a 3-20 membered heterocyclic group; for example, X 2 Selected from O, N(C 1-6 Alkyl) [such as N(CH 3 )], N(3-20 membered heterocyclyl)[such as N(hexahydropyranyl)], N(3-20 membered heterocyclyl-C 1-6 Alkyl) (such as ) or CH 2 .

[0150] Y is selected from CR b R c , Rb and R c Selected from hydrogen.

[0151] R 3 and R 4 is selected from hydrogen, n is 1;

[0152] M 1 Selected from CH;

[0153] R f Selected from H.

[0154] In some embodiments, in formula (b):

[0155] R a Selected from hydrogen, C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl, C(O)C 1-6 Alkyl, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 alkyl) 2 or a 3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 Alkyl, S(O) 2 C 1-6 Alkyl, C(O)C 1-6 Alkyl, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 alkyl) 2 or the 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, C 1-6 Alkyl, 3-20 membered heterocyclic group; for example, R a Selected from hydrogen, methyl, ethyl, -S(O) 2 CH 3 、-C(O)C 1-6 Alkyl-OH (such as COCH 2 -OH), C 1-6 Alkyl-OH (such as CH 2 OH, C 2 H 4 OH), oxetanyl, azetidinyl, -3-20 membered heterocyclic group C 1-6 Alkyl (e.g., 3-N-methylazetidinyl, 4-N-methylhexahydropyridinyl), tetrahydrofuranyl, tetrahydropyrrolyl, hexahydropyridinyl, hexahydropyranyl, C(O)NHC 1-6 Alkyl-OH (such as )、C(O)N(C 1-6 Alkyl)(C 1-6 Alkyl-OH) (e.g. )、CONHCH3 ;

[0156] X 1 and X 2 Each independently selected from CR b R c , R b and R c Each independently selected from: hydrogen or C 1-6 Alkyl; wherein R b and / or R c C in the group represented 1-6 The alkyl group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano and NR 6 R 7 , R 6 R 7 Each independently selected from H or C 1-6 Alkyl; for example, X 1 Selected from CH 2 , CH(C 1-6 Alkyl) [such as CH(CH 3 )], CH(C 1-6 Alkyl-OH) [such as CH(CH 2 OH)], CH[C 1-6 Alkyl-N(C 1-6 alkyl) 2 ]such as {CH[CH 2 N(CH 3 ) 2 ]}, CH(C 1-6 Alkyl-halogen) [such as CH(CH 2 F)], CH(C 1-6 Alkyl-CN) [such as CH(CH 2 CN)]; X 2 Selected from CH 2 ;

[0157] R 3 and R 4 are each independently selected from hydrogen or C 1-6 Alkyl, where C 1-6 The alkyl group may be substituted by 1 to 3 substituents selected from the group consisting of: hydroxyl; n is 1; for example, R 3 Selected from hydrogen, R 4 Selected from C 1-6 Alkyl-OH; such as R 4 Selected from CH 2 OH, C 2 H 4 OH;

[0158] M 1 Selected from CH;

[0159] R f Selected from H.

[0160] In some embodiments, in formula (c):

[0161] R a Selected from hydrogen, C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl, S(O) 2 3-20 membered heterocyclic group, C(O)C 1-6 Alkyl, C(O)NR 6 R 7 、C(O)NHC 1-6 alkyl, C(O)3-20 membered heterocyclic group, 3-20 membered heterocyclic group, -C 1-6 Alkyl-3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 Alkyl, S(O) 2 C 1-6 Alkyl, S(O) 2 3-20 membered heterocyclic group, C(O)C 1-6 Alkyl, C(O)NR 6 R 7 、C(O)NHC 1-6 alkyl, C(O)3-20 membered heterocyclic group, 3-20 membered heterocyclic group, -C 1-6 The alkyl-3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3-20 membered heterocyclic group, C(O)C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl, NR 6 R 7 , R 6 R 7 Each independently selected from H or C 1-6 Alkyl; for example, R a Selected from hydrogen, methyl, ethyl, C 1-6 Alkyl-OH (such as CH 2 OH, C 2 H 4 OH, 2-hydroxy-2-methylpropyl), C 1-6 Alkyl-C 1-6 Alkoxy (such as methoxyethyl), -S(O) 2 CH 3 、C(O)C 1-6 Alkyl-OH (such as )、C(O)C 1-6Alkyl-NR 6 R 7 (like ), oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, hexahydropyridinyl, hexahydropyranyl, -C 1-6 Alkyl S(O) 2 C 1-6 Alkyl (such as ),-C 1-6 Alkyl-3-20 membered heterocyclic group (such as ),-C 1-6 Alkyl-3-20 membered heterocyclyl-C 1-6 Alkyl (such as ), -3-20 membered heterocyclyl-C 1-6 Alkyl (such as ),-C 1-6 Alkyl-3-20 membered heterocyclic-OH (eg ),-C 1-6 Alkyl-3-20 membered heterocyclyl-halogen (such as ), -3-20 membered heterocyclyl-C(O)C 1-6 Alkyl (such as ), -3-20 membered heterocyclic group S (O) 2 C 1-6 Alkyl (such as )、CONHCH 3 、C(O)NHC 1-6 Alkyl-OH (such as )、C(O)N(C 1-6 Alkyl)(C 1-6 Alkyl-OH) (e.g. );

[0162] R 1 and R 2 the same or different, each independently selected from hydrogen or C 1-6 Alkyl; among which, C 1-6 The alkyl group may be substituted by 1 to 3 substituents selected from the group consisting of: hydroxyl, m is 1; for example, R 1 Selected from hydrogen, R 2 Selected from C 1-6 Alkyl-OH; such as R 2 Selected from CH 2 OH;

[0163] X 1 and X 2 The same or different, each independently selected from CR b R c , R b and R cEach independently selected from: hydrogen or C 1-6 Alkyl; wherein R b and / or R c C in the group represented 1-6 The alkyl group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl; for example, X 1 Selected from CH 2 , X 2 Selected from CH 2 or CH(C 1-6 Alkyl-OH); such as X 2 Selected from CH 2 or CH(CH 2 OH);

[0164] M 1 Selected from CH;

[0165] R f Selected from H.

[0166] In some embodiments, in formula (d):

[0167] M 1 and R f Having the above definition;

[0168] R a Selected from hydrogen, C 1-6 Alkyl, C(O)C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl or 3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 Alkyl, C(O)C 1-6 Alkyl, S(O) 2 C 1-6 The alkyl or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: 1-6 Alkyl, hydroxyl;

[0169] X 1 Selected from NR a , O or CR b R c , where R b and R c Selected from hydrogen;

[0170] R 1 and R 2 is selected from hydrogen, m is 1;

[0171] Y is selected from CR b R c , R b and R cSelected from hydrogen.

[0172] In some embodiments, in formula (e):

[0173] R a Selected from C 1-6 Alkyl or 3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 The alkyl or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, C 1-6 alkyl; the 3-20 membered heterocyclic group is selected from oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, hexahydropyridinyl, hexahydropyranyl; for example, R a Selected from hydrogen, methyl, ethyl, C 1-6 Alkyl-OH (such as CH 2 OH, C 2 H 4 OH, 2-hydroxy-2-methylpropyl), -3-20 membered heterocyclic group-C 1-6 Alkyl (such as ), oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, hexahydropyridinyl, hexahydropyranyl;

[0174] X 1 and X 2 The same or different, each independently selected from CR b R c , R b and R c Each independently selected from: hydrogen or C 1-6 Alkyl; wherein R b and / or R c C in the group represented 1-6 The alkyl group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl; for example, X 1 Selected from CH 2 or CH(C 1-6 Alkyl-OH) [such as CH(CH 2 OH)],X 2 Selected from CH 2 ; or, X 1 Selected from CH 2 , X 2 Selected from CH 2 or CH(C 1-6 Alkyl-OH) [such as CH(CH 2 OH)]; or, X 1 and X 2 All selected from CH 2 ;

[0175] R 3 and R4 Selected from hydrogen, n=1.

[0176] In some embodiments, in formula (f):

[0177] R a Selected from C 1-6 Alkyl or 3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 The alkyl or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, C 1-6 Alkyl; for example, R a Selected from hydrogen, methyl, ethyl, -C 1-6 Alkyl-OH (such as C 2 H 4 OH, 2-hydroxy-2-methylpropyl), S(O) 2 CH 3 、-3-20 membered heterocyclyl-C 1-6 Alkyl (such as ), oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, hexahydropyridinyl, hexahydropyranyl, -C 1-6 Alkyl-3-20 membered heterocyclic group (such as );

[0178] R 1 and R 2 are each independently selected from hydrogen or C 1-6 Alkyl; among which, C 1-6 The alkyl group may be substituted by 1 to 3 substituents selected from the group consisting of: hydroxyl, m = 1; for example, R 1 and R 2 is hydrogen; or, R 1 For H, R 2 C 1-6 Alkyl-OH (such as CH 2 OH, C 2 H 4 OH);

[0179] X 1 and X 2 Each independently selected from CR b R c , R b and R c Each independently selected from: hydrogen or C 1-6 Alkyl; wherein R b and / or R c The alkyl group in the group represented by may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl; for example, X 1 Selected from CH 2 or CH(C 1-6Alkyl-OH) [such as CH(CH 2 OH)],X 2 Selected from CH 2 ; or, X 1 Selected from CH 2 , X 2 Selected from CH 2 or CH(C 1-6 Alkyl-OH) [such as CH(CH 2 OH)]; or, X 1 and X 2 All selected from CH 2 .

[0180] In some embodiments, in formula (g):

[0181] R a Selected from hydrogen, C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl, C(O)C 1-6 Alkyl, -C 1-6 alkyl-3-20 membered heterocyclic group, -3-20 membered heterocyclic group-C 1-6 Alkyl, or 3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 Alkyl, S(O) 2 C 1-6 Alkyl, C(O)C 1-6 Alkyl, -C 1-6 alkyl-3-20 membered heterocyclic group, -3-20 membered heterocyclic group-C 1-6 The alkyl group or the 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: 1-6 Alkyl, hydroxyl, 3-20 membered heterocyclic group, NR 6 R 7 ; R 6 , R 7 Each independently selected from C 1-6 Alkyl; for example, R a Selected from H, methyl, ethyl, C 1-6 Alkyl-OH (such as CH 2 OH, C 2 H 4 OH)、S(O) 2 CH 3 、C(O)C 1-6 Alkyl OH (such as )、C(O)C 1-6 Alkyl NR 6 R 7 (like ), oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, hexahydropyridinyl, hexahydropyranyl, -3-20 membered heterocyclyl-C 1-6 Alkyl (such as ),-C 1-6 Alkyl-3-20 membered heterocyclic group (such as ),-C 1-6 Alkyl-3-20 membered heterocyclic-OH (eg );

[0182] X 2 Selected from NR a , O or CR b R c , R b and R c is selected from hydrogen; for example, X 2 Selected from NH, N(CH 3 ), O or CH 2 ;

[0183] R 3 and R 4 Selected from hydrogen, n=1;

[0184] Y is selected from CR b R c , R b and R c Selected from hydrogen;

[0185] M 1 Selected from CH;

[0186] R f Selected from H.

[0187] In some embodiments, in formula (h):

[0188] R a Selected from hydrogen, C 1-6 Alkyl, C(O)C 1-6 Alkyl, C 1-6 Alkyl C(O)NR 6 R 7 、C(O)C 3–10 Cycloalkyl, C(O)3-20 membered heterocyclic group, S(O) 2 C 1-6 Alkyl, S(O) 2 C 3–10 Cycloalkyl, -3-20 membered heterocyclyl-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 alkyl) 2or a 3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 Alkyl, C(O)C 1-6 Alkyl, C 1-6 Alkyl C(O)NR 6 R 7 、C(O)C 3–10 Cycloalkyl, C(O)3-20 membered heterocyclic group, S(O) 2 C 1-6 Alkyl, S(O) 2 C 3–10 Cycloalkyl, -3-20 membered heterocyclyl-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 alkyl) 2 or the 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, NR 6 R 7 , R 6 R 7 Each independently selected from C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl, C(O)C 1-6 Alkyl, 3-20 membered heterocyclic group; for example, R a Selected from hydrogen, methyl, ethyl, C 1-6 Alkyl-OH (such as CH 2 OH, C 2 H 4 OH, C 3 H 6 OH, 2-hydroxypropyl, ),-C 1-6 Alkyl-C 1-6 Alkoxy (such as methoxyethyl), S(O) 2 CH 3 、C(O)C 1-6 Alkyl OH (such as )、C(O)C 1-6 Alkyl NR 6 R 7 (like ), C 1-6 Alkyl NR 6 R 7 (like ), -C 1-6 Alkyl-CN (such as CH2 CN), C 1-6 Alkyl S(O) 2 C 1-6 Alkyl (such as ), oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, hexahydropyridinyl, hexahydropyranyl, -3-20 membered heterocyclyl-C 1-6 Alkyl (such as ), -3-20 membered heterocyclyl-C 1-6 Alkyl-OH (such as ), -3-20 membered heterocyclyl-C(O)C 1-6 Alkyl (such as ), -3-20 membered heterocyclyl-S(O) 2 C 1-6 Alkyl (such as ),-C 1-6 Alkyl-3-20 membered heterocyclic group (such as ),-C 1-6 Alkyl-3-20 membered heterocyclic-OH (eg ),-C 1-6 Alkyl-3-20 membered heterocyclyl-C 1-6 Alkyl (such as ),-C 1-6 Alkyl-3-20 membered heterocyclic group (OH)-C 1-6 Alkyl (such as ),-C 1-6 Alkyl-3-20 membered heterocyclyl (halogen)-C 1-6 Alkyl (such as ),-C 1-6 Alkyl-3-20 membered heterocyclyl-halogen (such as ), -C(O)oxetanyl, -C(O)azetidinyl, -C(O)tetrahydropyrrolyl, C(O)3-20 membered heterocyclyl-C 1-6 Alkyl (such as )、C(O)3-20 membered heterocyclic group (OH)-C 1-6 Alkyl (such as )、CONHCH 3 、C(O)NHC 1-6 Alkyl-OH (such as )、C(O)N(C 1-6 Alkyl)(C 1-6 Alkyl-OH) (e.g. );

[0189] R 3 and R 4 the same or different, each independently selected from hydrogen or C 1-6 Alkyl; among which, C1-6 The alkyl group may be substituted by 1 to 3 substituents selected from the group consisting of: hydroxyl, n=1; for example, R 3 is hydrogen, R 4 For -C 1-6 Alkyl-OH (such as CH 2 OH); or, R 3 and R 4 All are H;

[0190] X 1 and X 2 Each independently selected from CR b R c , R b and R c The same or different, each independently selected from: hydrogen or C 1-6 Alkyl; wherein R b and / or R c The alkyl group in the group represented by may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl; for example, R b and R c Each independently selected from H or C 1-6 Alkyl-OH (such as CH 2 OH, C 2 H 4 OH);

[0191] M 1 Selected from CH;

[0192] R f Selected from H.

[0193] In some embodiments, in formula (i):

[0194] R a Selected from hydrogen, C(O)C 1-6 Alkyl, C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl, -3-20 membered heterocyclic group-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 alkyl) 2 , -C 1-6 Alkyl C(O)N(C 1-6 alkyl) 2 , -C(O)3-20 membered heterocyclic group or 3-20 membered heterocyclic group; wherein R a C(O)C in the group represented 1-6 Alkyl, C 1-6 Alkyl, S(O) 2C 1-6 Alkyl, -3-20 membered heterocyclic group-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 alkyl) 2 , -C(O)3-20 membered heterocyclic group or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3-20 membered heterocyclic group, S(O) 2 C 1-6 Alkyl, 3-20 membered heterocyclic group and NR 6 R 7 , R 6 R 7 Each independently selected from C 1-6 Alkyl; for example, R a Selected from hydrogen, methyl, ethyl, C 1-6 Alkyl-OH (such as CH 2 OH, C 2 H 4 OH, C 3 H 6 OH, 2-hydroxy-2-methylpropyl, 2-hydroxypropyl, ),-C 1-6 Alkyl-C 1-6 Alkoxy (such as methoxyethyl), oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, hexahydropyridinyl, hexahydropyranyl, C(O)C 1-6 Alkyl OH (such as )、C(O)C 1-6 Alkyl NR 6 R 7 (like ), C 1-6 Alkyl NR 6 R 7 (like ), -3-20 membered heterocyclyl-C 1-6 Alkyl (such as ),-C 1-6 Alkyl-3-20 membered heterocyclic group (such as ),-C 1-6 Alkyl-3-20 membered heterocyclic group (OH)-C 1-6 Alkyl (such as )、-C(O)3-20 membered heterocyclyl-C 1-6 Alkyl (such as ),-C 1-6Alkyl-3-20 membered heterocyclic-OH (eg ),-C 1-6 Alkyl-3-20 membered heterocyclyl-halogen (such as ), -C(O)oxetanyl, -C(O)azetidinyl, -C(O)tetrahydropyrrolyl, CONHCH 3 、S(O) 2 CH 3 、C(O)NHC 1-6 Alkyl-OH (such as )、C(O)N(C 1-6 Alkyl)(C 1-6 Alkyl-OH) (e.g. )-3-20 membered heterocyclyl-halogen (such as ), -3-20 membered heterocyclic group (OH)-C 1-6 Alkyl (such as ), C 1-6 Alkyl-CN (such as CH 2 CN, ),-C 1-6 Alkyl S(O) 2 C 1-6 Alkyl (such as );

[0196] X 2 Selected from CR b R c , R b and R c The same or different, each independently selected from: hydrogen or C 1-6 Alkyl, where R b and / or R c C in the group represented 1-6 The alkyl group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl; for example, R b and R c the same or different, each independently selected from hydrogen or C 1-6 Alkyl-OH (such as CH 2 OH, C 2 H 4 OH);

[0197] M 1 Selected from CH;

[0198] R f Selected from H;

[0199] R 1 and R 2 are each independently selected from hydrogen or C 1-6 Alkyl; among which, C 1-6The alkyl group may be substituted by 1 to 3 substituents selected from the group consisting of: hydroxyl, m = 1; for example, R 1 is hydrogen, R 2 For -C 1-6 Alkyl-OH (such as CH 2 OH); or, R 1 and R 2 Both are H.

[0200] In some embodiments, in formula (j):

[0201] R a Selected from hydrogen, C(O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl C(O)NR 6 R 7 , C(O)3-20 membered heterocyclic group, -C 1-6 alkyl-3-20 membered heterocyclic group, -3-20 membered heterocyclic group-C 1-6 Alkyl or 3-20 membered heterocyclic group; wherein R a C(O)C in the group represented 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl C(O)NR 6 R 7 , C(O)3-20 membered heterocyclic group, -C 1-6 alkyl-3-20 membered heterocyclic group, -3-20 membered heterocyclic group-C 1-6 The alkyl or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, cyano, C 1-6 Alkyl, 3-20 membered heterocyclic group and NR 6 R 7 , R 6 , R 7 The same or different are independently selected from C 1-6 Alkyl; for example, R a Selected from hydrogen, methyl, ethyl, C 1-6 Alkyl-OH (such as CH 2 OH, C 2 H 4 OH), C 1-6 Alkyl NR 6 R 7 [As C 2 H 4 N(CH 3 ) 2 ]、C 1-6 Alkyl-CN (such as CH 2 CN), -C 1-6 Alkyl-C3 Heterocyclic groups (such as ),-C 1-6 Alkyl-3-20 membered heterocyclic group (such as ),-C 1-6 Alkyl-3-20 membered heterocyclic-OH (eg )、C(O)3-20 membered heterocyclyl-C 1-6 Alkyl (such as );

[0202] X 1 Selected from O or CH 2 ;

[0203] R 1 and R 2 is selected from hydrogen, m=1;

[0204] Y is selected from CR b R c , R b and R c Selected from hydrogen.

[0205] In some embodiments of the present invention, Ar 1 Selected from the following groups:

[0206] In some embodiments of the present invention, Ar 2 Selected from 2,6-difluorophenyl, 2-fluorophenyl or phenyl.

[0207] In one embodiment of the present disclosure, in formula (a):

[0208] R a Selected from hydrogen, C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl or having 1 to 3 R 8 Heteroatom C 3-12 A heterocyclic group, wherein R a The alkyl or heterocyclic group in the group represented by may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, C 4-10 Heterocyclic or NR 6 R 7 , R 6 R 7 Each independently selected from C 1-6 Alkyl, R 8 Selected from N or O.

[0209] X 2 Selected from O, NR a or CR b R c , R band R c Each independently selected from: hydrogen.

[0210] Y is selected from CR b R c , R b and R c Each independently selected from: hydrogen.

[0211] R 3 and R 4 are each independently selected from hydrogen, and n is 1.

[0212] In one embodiment of the present disclosure, in formula (b):

[0213] R a Selected from hydrogen, C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl, C(O)C 1-6 Alkyl or having 1 to 3 R 8 Heteroatom C 3-12 Heterocyclic group; wherein R a The alkyl or heterocyclic group in the group represented by may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, C 1-6 Alkyl or C 4-10 Heterocyclic group, R 8 Selected from N or O.

[0214] X 1 and X 2 Each independently selected from CR b R c , R b and R c Each independently selected from: hydrogen or C 1-6 Alkyl, where R b and / or R c The alkyl group in the represented group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano and NR 6 R 7 , R 6 R 7 Each independently selected from H or C 1-6 alkyl.

[0215] R 3 and R 4 are each independently selected from hydrogen or C 1-6 Alkyl, where C 1-6 The alkyl group may be substituted by 1 to 3 substituents selected from the following group: hydroxyl group, and n is 1.

[0216] In one embodiment of the present disclosure, in formula (c):

[0217] R a Selected from hydrogen, C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl, S(O) 2 C 3–8 Heterocyclic group, C(O)C 1-6 Alkyl, C(O)C 3–8 Heterocyclic group or having 1 to 3 R 8 Heteroatom C 3-12 A heterocyclic group, wherein R a The alkyl and cycloalkyl groups represented by the present invention may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 4-10 Heterocyclic group, NR 6 R 7 , R 6 R 7 Each independently selected from H or C 1-6 Alkyl, R 8 Selected from N or O.

[0218] R 1 and R 2 are each independently selected from hydrogen or C 1-6 Alkyl, where C 1-6 The alkyl group may be substituted by 1 to 3 substituents selected from the following group: hydroxyl group, m is 1.

[0219] X 1 and X 2 Each independently selected from CR b R c , R b and R c Each independently selected from: hydrogen or C 1-6 Alkyl, where R b and / or R c The alkyl group in the represented group may be substituted by 1 to 3 substituents independently selected from the following group: hydroxyl group.

[0220] In one embodiment of the present disclosure, in formula (d):

[0221] R a Selected from hydrogen, C 1-6 Alkyl, C(O)C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl or having 1 to 3 R 8 Heteroatom C 3-12 A heterocyclic group, wherein R a The alkyl or heterocyclic group in the group represented by may be substituted by 1 to 3 substituents independently selected from the following groups:1-6 Alkyl, hydroxyl, R 8 Selected from N or O.

[0222] X 1 Selected from NR a , O or CR b R c , where R b and R c Each independently selected from: hydrogen.

[0223] R 1 and R 2 are each independently selected from hydrogen, and m is 1.

[0224] Y is selected from CR b R c , R b and R c Each independently selected from: hydrogen.

[0225] In one embodiment of the present disclosure, in formula (e):

[0226] R a Selected from C 1-6 Alkyl or having 1 to 3 R 8 Heteroatom C 3-12 A heterocyclic group, wherein R a The alkyl or heterocyclic group in the group represented by may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, C 1-6 Alkyl. 8 Selected from N or O.

[0227] X 1 and X 2 Each independently selected from CR b R c , R b and R c Each independently selected from: hydrogen or C 1-6 Alkyl, where R b and / or R c The alkyl group in the represented group may be substituted by 1 to 3 substituents independently selected from the following group: hydroxyl group.

[0228] R 3 and R 4 Each is independently selected from hydrogen, and n=1.

[0229] In one embodiment of the present disclosure, in formula (f):

[0230] R a Selected from C 1-6 Alkyl or having 1 to 3 R 8 Heteroatom C 3-12A heterocyclic group, wherein R a The alkyl or heterocyclic group in the group represented by may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, C 1-6 Alkyl, R 8 Selected from N or O.

[0231] R 1 and R 2 are each independently selected from hydrogen or C 1-6 Alkyl, where C 1-6 The alkyl group may be substituted by 1 to 3 substituents selected from the following group: hydroxyl group, m=1.

[0232] X 1 and X 2 Each independently selected from CR b R c , R b and R c Each independently selected from: hydrogen or C 1-6 Alkyl, where R b and / or R c The alkyl group in the represented group may be substituted by 1 to 3 substituents independently selected from the following group: hydroxyl group.

[0233] In one embodiment of the present disclosure, in formula (g):

[0234] R a Selected from hydrogen, C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl, C(O)C 1-6 Alkyl or having 1 to 3 R 8 Heteroatom C 3-12 A heterocyclic group, wherein R a The alkyl or heterocyclic group in the group represented by may be substituted by 1 to 3 substituents independently selected from the following groups: 1-6 Alkyl, hydroxyl, C 4-10 Heterocyclic group, NR 6 R 7 , R 6 R 7 Each independently selected from C 1-6 Alkyl, R 8 Selected from N or O.

[0235] X 1 and X 2 Each independently selected from NR a , O or CR b R c , R b and R c Each independently selected from: hydrogen.

[0236] R 3 and R 4 Each is independently selected from hydrogen, and n=1.

[0237] Y is selected from CR b R c , R b and R c Each independently selected from: hydrogen.

[0238] In one embodiment of the present disclosure, in formula (h):

[0239] R a Selected from hydrogen, C 1-6 Alkyl, C(O)C 1-6 Alkyl, C(O)C 3–8 Cycloalkyl, S(O) 2 C 1-6 Alkyl, S(O) 2 C 3–8 Cycloalkyl or having 1 to 3 R 8 Heteroatom C 3-12 A heterocyclic group, wherein R a The alkyl or heterocyclic group in the group represented by may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, NR 6 R 7 , R 6 R 7 Each independently selected from C 1-6 Alkyl, R 8 Selected from N or O.

[0240] R 3 and R 4 are each independently selected from hydrogen or C 1-6 Alkyl, where C 1-6 The alkyl group may be substituted by 1 to 3 substituents selected from the following group: hydroxyl group, m=1.

[0241] X 1 and X 2 Each independently selected from CR b R c , R b and R c Each independently selected from: hydrogen or C 1-6 Alkyl, where R b and / or R c The alkyl group in the represented group may be substituted by 1 to 3 substituents independently selected from the following group: hydroxyl group.

[0242] In one embodiment of the present disclosure, in formula (i):

[0243] R a Selected from hydrogen, C(O)C 1-6 Alkyl, C 1-6 Alkyl, S(O) 2 C 1-6 Alkyl or having 1 to 3 R 8 Heteroatom C 3-12 A heterocyclic group, wherein R a The alkyl or heterocyclic group in the group represented by may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 4-10 Heterocyclic group and NR 6 R 7 , R 6 R 7 Each independently selected from C 1-6 Alkyl, R 8 Selected from N or O.

[0244] X 2 Selected from CR b R c , R b and R c Each independently selected from: hydrogen or C 1-6 Alkyl, where R b and / or R c The alkyl group in the represented group may be substituted by 1 to 3 substituents independently selected from the following group: hydroxyl group.

[0245] R 1 and R 2 are each independently selected from hydrogen or C 1-6 Alkyl, where C 1-6 The alkyl group may be substituted by 1 to 3 substituents selected from the following group: hydroxyl group, m=1.

[0246] In one embodiment of the present disclosure, in formula (j):

[0247] R a Selected from hydrogen, C(O)C 1-6 Alkyl, C 1-6 Alkyl or having 1 to 3 R 8 Heteroatom C 3-12 A heterocyclic group, wherein R a The alkyl or heterocyclic group in the group represented by may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, cyano, C 4-10 Heterocyclic group and NR 6 R 7 , R 6 R 7 Each independently selected from C1-6 Alkyl, R 8 Selected from N or O.

[0248] X 1 Selected from O.

[0249] R 1 and R 2 Each is independently selected from hydrogen, m=1.

[0250] Y is selected from CR b R c , R b and R c Each independently selected from: hydrogen.

[0251] The present invention also provides a method for preparing the compounds of formula I and formula II, comprising:

[0252] When R 5 When H, the method comprises:

[0253] Compound Ia reacts with Ib to obtain R 5 A compound of H;

[0254]

[0255] or,

[0256] Compound IIa reacts with Ib to obtain R 5 A compound of H;

[0257]

[0258] When R 5 C 1-10 When the alkyl group is present, the R 5 When the compound is H and R 5 =O reaction to give R 5 C 1-10 Alkyl compounds;

[0259] Wherein, each group has the above-mentioned definition.

[0260] The present invention also provides a method for preparing the compound represented by the above formula I and the compound represented by the above formula II, including any one of the following preparation methods:

[0261] Ar in the intermediates used in the following synthesis methods 1 ,Ar 2 , R 1 , R 2 , R 3、 R4 and R a The compounds represented by formula Ⅰ and formula Ⅱ of the present invention have the same definitions of groups;

[0262] Synthesis method 1:

[0263]

[0264] (1) reacting intermediate 1 with elemental iodine under alkaline conditions to obtain intermediate 2a; or reacting intermediate 1 with NIS (N-iodosuccinimide) under acidic conditions to obtain intermediate 2b;

[0265] In this step, the intermediate 1 mainly refers to the tert-butoxycarbonyl protecting group (tert-butoxycarbonyl, Boc);

[0266] (2) reacting intermediate 2a with p-toluenesulfonyl chloride in the presence of a base to obtain intermediate 3a; or reacting intermediate 2b with p-toluenesulfonyl chloride in the presence of a base to obtain intermediate 3b;

[0267] (3) reacting intermediate 3a with ethyl propiolate in the presence of a base, cuprous iodide and a palladium catalyst to obtain intermediate 4a; or reacting intermediate 3b with ethyl propiolate in the presence of a base, cuprous iodide and a palladium catalyst to obtain intermediate 4b;

[0268] (4) reacting intermediate 4a under acidic conditions to obtain intermediate 5a; or reacting intermediate 4b under acidic conditions to obtain intermediate 5b;

[0269] (5) reacting intermediate 5a with a halide in the presence of a base to obtain intermediate 6a; or reacting intermediate 5b with a halide in the presence of a base to obtain intermediate 6b;

[0270] or,

[0271] Intermediate 5a and aldehyde or ketone are subjected to reductive amination reaction to obtain intermediate 6a; or intermediate 5b and aldehyde or ketone are subjected to reductive amination reaction to obtain intermediate 6b;

[0272] (6) reacting intermediate 6a with acetonitrile under alkaline conditions to obtain intermediate 7a; or reacting intermediate 6b with acetonitrile under alkaline conditions to obtain intermediate 7b;

[0273] (7) reacting intermediate 7a with DMF-DMA (N,N-dimethylformamide dimethyl acetal) to obtain intermediate 8a; or reacting intermediate 7b with DMF-DMA (N,N-dimethylformamide dimethyl acetal) to obtain intermediate 8b;

[0274] (8) reacting intermediate 8a with a salt form of hydrazine under alkaline conditions to obtain intermediate 9a; or reacting intermediate 8b with a salt form of hydrazine under alkaline conditions to obtain intermediate 9b;

[0275] (9) The p-toluenesulfonyl protecting group of intermediate 9a is removed under the action of a base to obtain a compound of formula I; or the p-toluenesulfonyl protecting group of intermediate 9b is removed under the action of a base to obtain a compound of formula II.

[0276] Synthesis method 2:

[0277]

[0278] (1) reacting intermediate 1 with elemental iodine under alkaline conditions to obtain intermediate 2a; or reacting intermediate 1 with NIS (N-iodosuccinimide) under acidic conditions to obtain intermediate 2b;

[0279] (2) reacting intermediate 2a with ethyl pyruvate in the presence of a base and a palladium catalyst to obtain intermediate 3a; or reacting intermediate 2b with ethyl pyruvate in the presence of a base and a palladium catalyst to obtain intermediate 3b;

[0280] (3) Remove Ra from intermediate 3a under the action of acid 1 group to obtain intermediate 4a; or intermediate 3b is stripped of Ra under the action of acid 1 Group to obtain intermediate 4b;

[0281] (4) reacting intermediate 4a with an alkyl halide in the presence of a base to obtain intermediate 5a; or reacting intermediate 4b with an alkyl halide in the presence of a base to obtain intermediate 5b;

[0282] or,

[0283] Intermediate 4a is reacted with aldehyde or ketone through reductive amination to obtain intermediate 5a; or intermediate 4b is reacted with aldehyde or ketone through reductive amination to obtain intermediate 5b;

[0284] (5) reacting intermediate 5a with acetonitrile in the presence of a base to obtain intermediate 6a; or reacting intermediate 5b with acetonitrile in the presence of a base to obtain intermediate 6b;

[0285] (6) reacting intermediate 6a with DMF-DMA (N,N-dimethylformamide dimethyl acetal) to obtain intermediate 7a; or reacting intermediate 6b with DMF-DMA (N,N-dimethylformamide dimethyl acetal) to obtain intermediate 7b;

[0286] (7) Reacting intermediate 7a or intermediate 7b with a salt form of hydrazine in the presence of a base to obtain a compound of formula I; or reacting intermediate 7b with a salt form of hydrazine in the presence of a base to obtain a compound of formula II.

[0287] Synthesis method 3:

[0288]

[0289] The difference from the synthesis method 1 is that the intermediate 1 is replaced by: Synthesis method 4:

[0290]

[0291] Different from the synthesis method 2, the compound of intermediate 1 is replaced by: Synthesis method 5:

[0292]

[0293] (1) Intermediate 1 reacts with elemental iodine under alkaline conditions to obtain intermediate 2a; or intermediate 1 reacts with NIS (N-iodosuccinimide) under acidic conditions to obtain intermediate 2b;

[0294] In this step, X in intermediate 1 is selected from NR a , O, S(O) t 、C(O)、C(O)NR a 、S(O) t NR a or CR b R c .

[0295] (2) intermediate 2a reacts with p-toluenesulfonyl chloride in the presence of a base to obtain intermediate 3a; or intermediate 2b reacts with p-toluenesulfonyl chloride in the presence of a base to obtain intermediate 3b;

[0296] (3) intermediate 3a reacts under the action of a base, a palladium catalyst and ethyl acrylate to obtain intermediate 4a; or intermediate 3b reacts under the action of a base, a palladium catalyst and ethyl acrylate to obtain intermediate 4b;

[0297] (4) intermediate 4a reacts with acetonitrile in the presence of a base to obtain intermediate 5a; or intermediate 4b reacts with acetonitrile in the presence of a base to obtain intermediate 5b;

[0298] (5) intermediate 5a reacts with DMF-DMA (N,N-dimethylformamide dimethyl acetal) to obtain intermediate 6a; or intermediate 5b reacts with DMF-DMA (N,N-dimethylformamide dimethyl acetal) to obtain intermediate 6b;

[0299] (6) intermediate 6a reacts with a salt form of hydrazine in the presence of a base to obtain intermediate 7a; or intermediate 6b reacts with a salt form of hydrazine in the presence of a base to obtain intermediate 7b;

[0300] (7) The intermediate 7a reacts with a base to obtain a compound of formula I; or the intermediate 7b reacts with a base to obtain a compound of formula II.

[0301] Synthesis method 6:

[0302]

[0303] (1) Intermediate 1 reacts with elemental iodine under alkaline conditions to obtain intermediate 2a; or intermediate 1 reacts with NIS (N-iodosuccinimide) under acidic conditions to obtain intermediate 2b;

[0304] (2) intermediate 2a reacts in the presence of a base, a palladium catalyst and ethyl pyruvate to obtain intermediate 3a; or intermediate 2b reacts in the presence of a base, a palladium catalyst and ethyl pyruvate to obtain intermediate 3b;

[0305] (3) intermediate 3a reacts with acetonitrile in the presence of a base to obtain intermediate 4a; or intermediate 3b reacts with acetonitrile in the presence of a base to obtain 4b;

[0306] (4) reacting intermediate 4a with DMF-DMA (N,N-dimethylformamide dimethyl acetal) to obtain intermediate 5a; or reacting intermediate 4b with DMF-DMA (N,N-dimethylformamide dimethyl acetal) to obtain intermediate 5b;

[0307] (5) Intermediate 5a reacts with salt-type hydrazine under alkaline conditions to obtain a compound of formula I; or intermediate 5b reacts with salt-type hydrazine under alkaline conditions to obtain a compound of formula II.

[0308] Synthesis method 7:

[0309]

[0310] Different from the synthesis method 5, the intermediate 1 is replaced by: Synthesis method 8:

[0311]

[0312] Different from the synthesis method 5, the intermediate 1 is replaced by: Synthesis method 9:

[0313]

[0314] (1) Intermediate 1 reacts with NIS (N-iodosuccinimide) or NBS (N-bromosuccinimide) to obtain intermediate 2;

[0315] (2) Intermediate 2 reacts with a base, a palladium catalyst and ethyl pyruvate to obtain intermediate 3;

[0316] (3) Under appropriate conditions, the protecting group on the N atom of intermediate 3 is removed to obtain intermediate 4;

[0317] (4) Intermediate 4 reacts with an alkyl halide in the presence of a base to obtain intermediate 5; or intermediate 4 reacts with an aldehyde or ketone through a reductive amination reaction to obtain intermediate 5;

[0318] (5) Intermediate 5 reacts with acetonitrile under the action of a base to obtain intermediate 6;

[0319] (6) Intermediate 6 reacts with DMF-DMA (N,N-dimethylformamide dimethyl acetal) to obtain intermediate 7;

[0320] (7) Intermediate 7 is reacted with hydrazine in salt form under alkaline conditions to obtain Example.

[0321] Synthesis method 10:

[0322]

[0323] Different from the synthesis method 5, the intermediate 1 is replaced by:

[0324] According to an embodiment of the present invention, when R 5 C 1-10 When alkyl, the method further comprises reacting the product of the above synthesis methods 1 to 10 with R 5 =O to obtain the compound represented by formula I and the compound represented by formula II wherein R 5 C 1-10 Alkyl compounds.

[0325] Preparation of intermediate A:

[0326] Intermediate A1: 5-hydrazino-2-[(2,6-difluorophenyl)oxy]-4-methylpyridine hydrochloride, the chemical formula is as follows:

[0327]

[0328] Synthesis method 1:

[0329]

[0330] Step 1: Add Cs to a DMF solution (100 mL) containing 5-bromo-2-fluoro-4-methylpyridine (5.0 g) and 2,6-difluorophenol (6.84 g) at room temperature. 2 CO 3 (17.14g), the obtained product was fully replaced with nitrogen, heated to 120°C and stirred for 16h until the reaction was complete. After the reaction was completed, the reaction solution was poured into ice water, and solids were washed out. Then, stirring was continued at room temperature for 0.5h and filtered. The filter cake was washed with water, and the solids were collected and dried to obtain the target product intermediate 1 (4.88g). LCMS (ES, m / z): 300.9 [M+H] + .

[0331] Step 2: To a 1,4-dioxane solution (50 mL) containing intermediate 1 (4.7 g) and tert-butyl carbazate (1.7 g) from step 1 was added t-Bu XPhos (1.07 g), Pd 2 (dba) 3 .CHCl 3 (0.8 g) and K 2 CO 3 (5.86g), the nitrogen was fully replaced by the obtained product, and stirred at 100°C for 16h until the reaction was complete. After the reaction was completed, the obtained product was cooled to room temperature and filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target product as intermediate 2 (2.4g). LCMS (ES, m / z): 352.2 [M+H] + .

[0332] Step 3: At room temperature, add HCl gas in 1,4-dioxane solution (50 mL, 4.0 M) to the reaction bottle containing intermediate 2 (2.4 g) of step 2, and stir the resultant at room temperature for 5 h until the reaction is complete. After the reaction is completed, remove the solvent under reduced pressure, add methyl tert-butyl ether to the residue, stir well and filter, wash the filter cake with methyl tert-butyl ether, collect the solid and dry to obtain the target product as intermediate A1 (1.7 g) as a yellow solid. LCMS (ES, m / z): 252.2 [M+H] + .

[0333] Intermediate A1 can also be 5-hydrazino-2-[(2,6-difluorophenyl)oxy]-4-methylpyridine. The synthesis method is as follows:

[0334]

[0335] Step 1: Add Cs to a DMF solution (100 mL) containing 5-nitro-2-fluoro-4-methylpyridine (7.8 g) and 2,6-difluorophenol (7.1 g) at room temperature. 2 CO 3 (24.5g), the obtained product was fully replaced with nitrogen, heated to 80°C, and stirred for 16h until the reaction was complete. After the reaction was completed, the reaction solution was poured into ice water, and solid precipitated. The mixture was stirred at room temperature for 0.5h and then filtered. The filter cake was washed with water, and the solid was collected and dried to obtain the target product intermediate 1 (10.2g). LCMS (ES, m / z): 267.1 [M+H] + .

[0336] Step 2: At room temperature, add the target product intermediate 1 (5.32 g) and acetonitrile (50 mL) of step 1 into a 250 ml three-necked flask, stir the mixture thoroughly to dissolve, add tetrahydroxydiboron (7.20 g) and 4,4'-dimethyl-2,2'-bipyridine (1.56 g). The mixture is fully replaced with nitrogen, heated to 100°C, and stirred at this temperature for 1 hour until the reaction is complete. After the reaction is completed, the mixture is cooled to room temperature and filtered, the filter cake is washed with acetonitrile, and the filtrate is concentrated under reduced pressure to obtain the target product intermediate 2 (4.13 g). LCMS (ES, m / z): 283.1 [M+H] + .

[0337] Step 3: At room temperature, the target product intermediate 2 (2.0 g) of step 2 was dissolved in an aqueous solution of HCl (60 mL, 3.0 M), the mixture was cooled to -5 °C, and an aqueous solution (3 mL) of sodium nitrite (0.88 g) was added dropwise. The mixture was stirred for 45 min at this temperature, and stannous chloride (8.11 g) was added to the resultant in batches. After the addition, the mixture was stirred for 30 min until the reaction was complete. After the reaction was completed, the pH value of the mixture was adjusted to 8 with a 1 M aqueous solution of sodium hydroxide, and the resultant was extracted three times with ethyl acetate, the organic phases were combined, the organic phases were washed with water and saturated brine, the organic phases were dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase medium pressure preparation to obtain the target product intermediate A1 (800 mg). LCMS (ES, m / z): 252.1 [M+H] + .

[0338] Intermediates A2, A3, A4 and A5 were synthesized by a similar synthesis method to intermediate A1, and their chemical names, chemical formulas and LCMS characterizations are shown in Table 1.

[0339] Table 1. Structure of Intermediate A

[0340]

[0341] The following is a further description of the embodiments of the present invention in multiple embodiments. The embodiments of the present invention are not limited to the following specific embodiments. The embodiments can be appropriately modified within the scope of the unchanged main rights.

[0342] The compounds of the present invention are selected from the compounds listed in Table 2 below.

[0343] Table 2

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370] Among them, intermediate A4 is used in Step 7 during the preparation of compound 22, intermediate A2 is used in Step 7 during the preparation of compound 23, intermediate A5 is used in Step 7 during the preparation of compound 24, and intermediate A3 is used in Step 7 during the preparation of compound 25.

[0371] The following examples provide the preparation process of some of the compounds in Table 2. Other compounds for which the detailed preparation process is not provided can be prepared by simply replacing the raw materials with reference to the process in the following examples.

[0372] Example 1

[0373]

[0374] Step 1: At room temperature, add 7-nitro-1,2,3,4-tetrahydroquinoline (5g) and anhydrous tetrahydrofuran (50mL) to a 250mL three-necked flask, mix well, fully replace nitrogen in the above mixture and cool to 0°C, and add NaH (2.02g, 60%) in batches. After the addition, the mixture was stirred at 0°C for 0.5h, and Cbz-Cl (5.74g) was added dropwise to the above mixture. After the addition was complete, the mixture was heated to slowly warm to room temperature and continued to stir for 16h until the reaction was complete. After the reaction was completed, the resultant was cooled to 0°C, quenched with saturated aqueous ammonium chloride solution, and water and ethyl acetate were added to the resultant, stirred thoroughly and separated. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine and washed with anhydrous Na 2 SO 4 After drying, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target product Intermediate 1 (6.7 g) as a yellow oil. LCMS (ES, m / z): 335.1 [M+Na] + .

[0375] Step 2: At room temperature, add the target product intermediate 1 (4.33 g) of step 1 and acetonitrile (43 mL) to a 250 mL three-necked flask, stir thoroughly to dissolve, add tetrahydroxydiboron (5.50 g) and 4,4'-dimethyl-2,2'-bipyridine (1.27 g), fully replace nitrogen with the obtained mixture, heat the obtained product to 100 ° C, and keep it warm for 1 hour under stirring until the reaction is complete. After the reaction is completed, the obtained product is cooled to room temperature, filtered, and the filter cake is washed with acetonitrile. The filtrate is concentrated under reduced pressure to obtain the target product intermediate 2 (3.85 g). LCMS (ES, m / z): 283.1 [M+H] + .

[0376] Step 3: At room temperature, add intermediate 2 (3.85 g), acetonitrile (38 mL) and DMSO (2.5 mL) from step 2 into a 250 mL three-necked flask, stir thoroughly to dissolve, fully replace nitrogen with the mixture, cool to 0 °C, add NIS (3.22 g) to the mixture in batches, slowly warm the mixture to room temperature, and continue stirring for 1.5 h until the reaction is complete. After the reaction is completed, the mixture is quenched with saturated NaHSO 3 The aqueous solution was quenched, and then extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target product intermediate 3 (2.2 g) as a white solid. LCMS (ES, m / z): 409.0 [M+H] + .

[0377] Step 4: At room temperature, add intermediate 3 (1 g) from step 3 and 1,4-dioxane (10 mL) to a 40 mL sample bottle. Stir the mixture thoroughly until it is completely dissolved. Add Pd 2 (dba) 3 (0.31g), N,N-dicyclohexylmethylamine (4.26g), tri-tert-butylphosphine tetrafluoroborate (0.39g) and ethyl pyruvate (1.56g), the resultant was fully replaced with nitrogen, heated to 80°C, and stirred for 4h until the reaction was complete. After the reaction was completed, the resultant was cooled to room temperature, ethyl acetate was added, the resultant was washed with water and saturated brine, anhydrous Na 2 SO 4 After drying, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target product intermediate 4 (640 mg) as a white solid. LCMS (ES, m / z): 379.1 [M+H] + .

[0378] Step 5: At room temperature, add intermediate 4 (615 mg) of step 4, tetrahydrofuran (6 mL) and acetonitrile (334 mg) to a 50 mL three-necked flask. The resulting mixture is fully replaced with nitrogen, cooled to -78 °C, and a tetrahydrofuran solution of NaHMDS (3.6 mL, 1.0 M) is added dropwise. After the addition is completed, the resulting mixture is slowly warmed to room temperature and stirred for 1 hour until the reaction is complete. After the reaction is completed, the resulting mixture is cooled to 0 °C and quenched with a saturated aqueous solution of ammonium chloride. Water and ethyl acetate are added to the resulting mixture, stirred thoroughly and separated, the aqueous phase is extracted twice with ethyl acetate, the organic phases are combined, the organic phases are washed with saturated brine, and anhydrous Na 2 SO 4 After drying, the solvent was removed under reduced pressure, and the residue was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the target product intermediate 5 (175 mg) as a white solid. LCMS (ES, m / z): 374.2 [M+H] + .

[0379] Step 6: At room temperature, add intermediate 5 (165 mg) of step 5 and toluene (10 mL) to a 40 mL sample bottle, stir the mixture until it is completely dissolved, then add N,N-dimethylformamide dimethyl acetal (210 mg), stir the resulting mixture at room temperature for 30 min until the reaction is complete, remove the solvent after the reaction is complete, and purify the residue by beating with n-hexane to obtain the target product intermediate 6 (80 mg). LCMS (ES, m / z): 429.2

[0380] [M+H] + .

[0381] Step 7: At room temperature, add intermediate 6 (70 mg) and EtOH (1 mL) from step 6 to a 10 mL sample bottle, stir thoroughly to dissolve, add intermediate A1 (61.6 mg), mix thoroughly to replace nitrogen, heat to 80 ° C, and stir for 3 h until the reaction is complete. After the reaction is completed, remove the solvent under reduced pressure, slurry the residue with ether, filter and vacuum dry to obtain the target product intermediate 7 (95 mg) as a yellow solid. LCMS (ES, m / z): 635.3 [M+H] + .

[0382] Step 8: At room temperature, add the target product intermediate 7 (95 mg) of step 7 and ethyl acetate (5 mL) to a 50 mL single-necked flask. After the mixture is fully stirred, Pd / C (2.0 mg, 10%) is added. The mixture is fully replaced with hydrogen and stirred at room temperature for 3 h until the reaction is complete. After the reaction is completed, filter, rinse the filter cake with ethyl acetate, and remove the solvent from the filtrate under reduced pressure. The residue is purified by high pressure preparation to obtain the target product compound 1 (15 mg). LCMS (ES, m / z): 501.3 [M+H] + .

[0383] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):10.86(s,1H),8.24(s,1H),8.12(s,1H),7.38(s,2H),7.33-7.29(m,2H),7.19(s,1H),7.12 (s,1H),6.92(s,2H),6.42(s,1H),5.95(s,1H),3.22(s,2H),2.78(s,2H),2.17(s,3H),1.81(s,2H).

[0384] Example 2

[0385]

[0386] Step 1: Dissolve tert-butyl 7-amino-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (2.5 g) in AcOH (25 mL) at room temperature, and add NIS (2.38 g) in batches. The mixture is stirred at room temperature for 1 hour until the reaction is complete. After the reaction is completed, the mixture is quenched with saturated aqueous sodium bisulfite. The resulting mixture is extracted twice with ethyl acetate, and the organic phases are combined. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to obtain the target product intermediate 1 (1 g). LCMS (ES, m / z): 319.1 [M-56+H] + .

[0387] Step 2: Dissolve the intermediate 1 (1.7 g) of the target product of step 1 in 1,4-dioxane (18 mL) at room temperature, add N-methyldicyclohexylamine (5.77 g), tri-tert-butylphosphine tetrafluoroborate (527 mg), Pd 2 (dba) 3(416mg) and ethyl pyruvate (2.11g). After the above mixture is fully replaced with nitrogen, it is heated to 100 degrees Celsius and reacted overnight. LCMS detection shows that the reaction is complete, the mixture is cooled to room temperature and water and ethyl acetate are added. The mixture is fully stirred and separated, the aqueous phase is extracted twice with ethyl acetate, the organic phases are combined, the organic phases are washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate is concentrated under reduced pressure, and the resulting residue is purified by column chromatography to obtain the target product intermediate 2 (1g) as a yellow oil. LCMS (ES, m / z): 289.1 [M-56+H] + .

[0388] Step 3: Under nitrogen atmosphere, add a tetrahydrofuran solution of NaHMDS (6.4 mL, 1.0 M) to a solution of the target product intermediate 2 (1 g) of step 2 and acetonitrile (596 mg) in anhydrous tetrahydrofuran (20 mL) pre-cooled to -78 degrees Celsius. After the addition is completed, the reaction system naturally warms to room temperature and continues to stir for 30 minutes until the reaction is complete. After the reaction is completed, the reaction solution is quenched with a saturated aqueous solution of ammonium chloride, the mixture is extracted with ethyl acetate, the organic phases are combined, the organic phases are dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure to obtain the target product intermediate 3 (800 mg). The crude product is not further purified and is directly used in the next step. LCMS (ES, m / z): 362.2 [M+Na] + .

[0389] Step 4: At room temperature, the target product intermediate 3 (80 mg) of step 3 was dissolved in toluene (1 mL), and N,N-dimethylformamide dimethyl acetal (67 mg) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was slurried with ether to collect the solid. The solid was purified with a preparative plate to obtain the target product intermediate 4 (63 mg). LCMS (ES, m / z): 417.2 [M+Na] + .

[0390] Step 5: At room temperature, the target product intermediate 4 (200 mg) of step 4 was dissolved in ethanol (5 mL), and intermediate A1 (191 mg) was added. The mixture was heated to 80 degrees Celsius under a nitrogen atmosphere and stirred for 3 hours until the reaction was complete. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain the target product intermediate 5 (60 mg). LCMS (ES, m / z): 601.1 [M+H] + .

[0391] Step 6: At room temperature, the target product intermediate 5 (60 mg) of step 5 was dissolved in a 1,4-dioxane solution (5 mL) of HCl gas, and the reaction solution was stirred at room temperature overnight until the reaction was complete. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by preparative chromatography to obtain the target product compound 8 (4.9 mg) as an off-white solid. LCMS (ES, m / z): 501.3 [M+H] + .

[0392] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):11.60(s,1H),8.43(s,1H),8.14(s,1H),7.40-7.25(m,6H),7.08(s,2H) ,6.98-6.96(d,J=8.4Hz,1H),4.20(s,2H),3.08(s,2H),2.77(s,2H),2.18(s,3H).

[0393] Example 3

[0394]

[0395] Step 1: Dissolve tert-butyl 7-amino-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (2.0 g) in AcOH (10 mL) at room temperature. After fully replacing the nitrogen, cool the above solution to 0°C and add NIS (1.89 g) in batches. The mixture is slowly warmed to room temperature and stirred for 1 hour until the reaction is complete. The above mixture is poured into ice water and quenched with saturated aqueous sodium bisulfite solution. The above mixture is extracted twice with ethyl acetate, and the organic phases are combined. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to obtain the target product intermediate 1 (0.26 g). LCMS (ES, m / z): 319.1 [M-56+H] + .

[0396] Step 2: Dissolve the intermediate 1 (1.36 g) of the target product of step 1 in 1,4-dioxane (20 mL) at room temperature, add N-methyldicyclohexylamine (4.57 g), tri-tert-butylphosphine tetrafluoroborate (420 mg), Pd 2 (dba) 3(330mg) and ethyl pyruvate (1.67g), the above mixture is fully replaced with nitrogen, heated to 100 degrees Celsius for 16 hours, until the reaction is complete. After the reaction is completed, the mixture is cooled to room temperature, water and ethyl acetate are added, the mixture is fully stirred and separated, the aqueous phase is extracted twice with ethyl acetate, the organic phases are combined, the organic phases are washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography to obtain the target product intermediate 2 (1.07g). LCMS (ES, m / z): 711.04 [2M+Na] + .

[0397] Step 3: At room temperature, the target product intermediate 2 (1.55 g) of step 2 was dissolved in a 1,4-dioxane solution of HCl (50 mL, 4.0 M), and the mixture was stirred at room temperature for 12 hours until the reaction was complete. After the reaction was completed, the mixture was concentrated, methyl tert-butyl ether was added to the residue, the mixture was fully stirred and filtered, the filter cake was washed with methyl tert-butyl ether, the filter cake was collected, and vacuum dried to obtain the target product intermediate 3 (1.25 g). LCMS (ES, m / z): 245.2 [M+H] + .

[0398] Step 4: At room temperature, the target product intermediate 3 (320 mg) of step 3 was dissolved in MeOH (15 mL), and aqueous formaldehyde solution (83 mg, 37%) and acetic acid (0.1 mL) were added. The mixture was stirred under nitrogen atmosphere for 1 hour, and NaBH 3 CN (164 mg). The mixture was stirred at room temperature for 5 hours until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by chromatography on a silica gel column to obtain the target product intermediate 4 (230 mg). LCMS (ES, m / z): 259.2 [M+H] + .

[0399] Step 5: Dissolve the target product intermediate 4 (160 mg) of step 4 in THF (5 mL) at room temperature and add CH 3CN (297 mg), the mixture was fully replaced with nitrogen and cooled to -40 ° C. To the above mixture was added a tetrahydrofuran solution of NaHMDS (1.5 mL, 2.0 M). After the addition was completed, the reaction solution was slowly raised to 0 ° C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin plate chromatography to obtain the target product intermediate 5 (100 mg). LCMS (ES, m / z): 254.1 [M+H] + .

[0400] Step 6: At room temperature, the target product intermediate 5 (100 mg) of step 5 was dissolved in THF (5 mL), and N,N-dimethylformamide dimethyl acetal (234 mg) was added. The reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain the target product intermediate 6 (130 mg), which was directly used in the next step. LCMS (ES, m / z): 309.2 [M+H] + .

[0401] Step 7: At room temperature, the target product intermediate 6 (130 mg) of step 6 was dissolved in NMP (5 mL), and intermediate A1 (158 mg) and TEA (85 mg) were added. The mixture was heated to 100 ° C under a nitrogen atmosphere and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction mixture was poured into water and stirred thoroughly. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase preparative chromatography to obtain the target product compound 9 (43 mg). LCMS (ES, m / z): 515.1 [M+H] + .

[0402] 1 H NMR (400 MHz, CDCl 3 )δ(ppm):9.36(s,1H),8.21(s,1H),8.10(s,1H),7.51(s,1H),7.25–7.18(m,2H),7.13(s,2H),7.0 4(t,J=8.0Hz,2H),5.83(m,2H),4.05(s,2H),3.19(s,2H),3.09(s,2H),2.68(s,3H),2.26(s,3H).

[0403] Example 4

[0404]

[0405] Step 1: At room temperature, the target product intermediate 3 (321 mg) of step 3 of Example 3 and tert-butyldimethylsilyl acetaldehyde (190 mg) were dissolved in dichloroethane (5 mL), and 1 drop of glacial acetic acid was added. After the mixture was stirred at room temperature for 30 min, NaBH(OAc) was added. 3 (781 mg), the mixture was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, water and ethyl acetate were added to the mixture, and the mixture was separated after sufficient stirring. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the target product intermediate 1 (260 mg). LCMS (ES, m / z): 403.1 [M+H] + .

[0406] Step 2: At -40°C, slowly add a tetrahydrofuran solution of NaHMDS (0.4 mL, 2.0 M) to a tetrahydrofuran solution (5 mL) of the target product intermediate 1 (160 mg) and acetonitrile (81.6 mg). The reaction solution is slowly heated to room temperature under a nitrogen atmosphere and stirred for 0.5 hours until the reaction is complete. After the reaction is complete, the reaction solution is cooled to 0°C again and heated with saturated NH 4 The mixture was quenched with Cl solution, extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target product intermediate 2 (100 mg). LCMS (ES, m / z): 398.3 [M+H] + .

[0407] Step 3: At room temperature, add N,N-dimethylformamide dimethyl acetal (15.0 mg) to a tetrahydrofuran (5 mL) solution of the target product intermediate 2 (50.0 mg) of step 2, and stir the reaction solution at room temperature for 1 hour until the reaction is complete. The reaction solution is concentrated under reduced pressure to obtain the target intermediate 3 (55 mg). LCMS (ES, m / z): 453.1 [M+H] + .

[0408] Step 4: At room temperature, add intermediate A1 (53.7 mg) and triethylamine (22.4 mg) to the NMP (5 mL) solution of the target product intermediate 3 (50.0 mg) of step 3. Heat the reaction solution to 100°C and continue stirring for 1 hour until the reaction is complete. After the reaction is complete, remove the solvent under reduced pressure, dissolve the residue in dichloromethane (5 mL), and add trifluoroacetic acid (2 mL) to the above reaction solution. The reaction solution continues to stir at room temperature for 12 hours until the reaction is complete. After the reaction is complete, remove the solvent under reduced pressure, and add water and ethyl acetate to the residue. Adjust the pH value of the above mixture to 8 with saturated sodium bicarbonate aqueous solution, stir well and separate the liquids, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure, and purify the obtained residue by reverse phase preparative chromatography to obtain the target product compound 13 (9.5 mg). LCMS (ES, m / z): 545.0 [M+H] + .

[0409] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm): δ11.44(s,1H),8.32(s,1H),8.23(s,1H),8.13(s,1H),7.39-7.36(m,3H),7.33-7.29(m,3H),7.13(s,1H),7.06 (s,2H),3.73(s,2H),3.61(t,J=6.2Hz,2H),2.93(t,J=5.4Hz,2H),2.73(t,J=5.8Hz,2H),2.58–2.54(m,2H),2.17(s,3H).

[0410] Example 5

[0411]

[0412] The preparation method of compound 17 is the same as that of compound 13, except that tert-butyldimethylsilyl acetaldehyde is replaced with tetrahydropyrone to obtain the title compound 17. LCMS (ES, m / z): 585.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ(ppm): δ9.49(s,1H),8.20(s,1H),8.09(s,1H),7.56(s,1H),7.25-7.18(m,3H),7.006(s,1H),7.02-6.98(m,2H),5.86(s,2H),4.71- 4.68(m,1H),4.31-4.29(m,1H),4.11-4.10(m,2H),3.76(s,1H),3.58-3.25(m,3H),3.12-3.10(m,1H),2.26(s,3H),2.05-1.96(m,4H).

[0413] Example 6

[0414]

[0415] Step 1: Dissolve 6-amino-2-N-Boc-1,2,3,4-tetrahydro-isoquinoline (1.8 g) in acetic acid (20 mL) at room temperature, and add NIS (1.71 g) to the above solution in batches. The mixture is stirred at room temperature for 1 hour until the reaction is complete. The mixture is poured into ice water and quenched with saturated aqueous sodium bisulfite solution. The mixture is extracted twice with ethyl acetate, the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the target product intermediate 1 (0.5 g). LCMS (ES, m / z): 375.1

[0416] [M+H] + .

[0417] Step 2: Dissolve the intermediate 1 (0.5 g) of the target product of step 1 in 1,4-dioxane (5 mL) at room temperature, add N-methyldicyclohexylamine (1.69 g), tri-tert-butylphosphine tetrafluoroborate (155 mg), Pd 2 (dba) 3 (122mg) and ethyl pyruvate (0.62g). After the above mixture is fully replaced with nitrogen, it is heated to 100 degrees Celsius and stirred for 16 hours until the reaction is complete. After the reaction is completed, the mixture is cooled to room temperature, water and ethyl acetate are added, the mixture is fully stirred and separated, the aqueous phase is extracted twice with ethyl acetate, the organic phases are combined, the organic phases are washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography to obtain the target product intermediate 2 (0.15g). LCMS (ES, m / z): 330.2 [M+H] + .

[0418] Step 3: Under nitrogen atmosphere, add a tetrahydrofuran solution of NaHMDS (1.0 mL, 1.0 M) to a solution of the target product intermediate 2 (150 mg) and acetonitrile (93 mg) in anhydrous tetrahydrofuran (2 mL) pre-cooled to -78 degrees Celsius. After the addition is completed, the reaction system naturally warms to room temperature and continues to stir for 30 minutes until the reaction is complete. After the reaction is completed, the reaction solution is quenched with a saturated aqueous ammonium chloride solution, the mixture is extracted three times with ethyl acetate, the organic phases are combined, the organic phases are dried over sodium sulfate and filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by a preparative chromatography plate to obtain the target product intermediate 3 (140 mg). LCMS (ES, m / z): 284.1 [M+H-56] + .

[0419] Step 4: At room temperature, the target product intermediate 3 (140 mg) of step 3 was dissolved in toluene (2 mL), and N,N-dimethylformamide dimethyl acetal (196 mg) was added. The reaction solution was stirred at room temperature for 1 hour until the reaction was completed. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was slurried with ether to obtain the target product intermediate 4 (140 mg), which was directly used in the next step. LCMS (ES, m / z): 309.2 [M+H] + .

[0420] Step 5: At room temperature, the target product intermediate 4 (140 mg) of step 4 was dissolved in ethanol (3 mL), and intermediate A1 (134 mg) was added. The mixture was heated to 80 degrees Celsius under a nitrogen atmosphere and stirred for 3 hours until the reaction was complete. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain the target product intermediate 5 (150 mg). LCMS (ES, m / z): 601.1 [M+H] + .

[0421] Step 6: At room temperature, the target product intermediate 5 (40 mg) of step 5 was dissolved in a 1,4-dioxane solution (3 mL) of HCl gas, and the reaction solution was stirred at room temperature overnight until the reaction was complete. After the reaction was completed, the solvent was removed under reduced pressure, and the resulting residue was purified by preparative chromatography to obtain the target product compound 56 (3.9 mg) as an off-white solid. LCMS (ES, m / z): 501.4 [M+H] + .

[0422] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):11.43(s,1H),8.32(s,1H),8.13(s,1H),7.49-7.29(m,6H),7.18(s,1H ),7.06(s,2H),4.01(s,2H),3.03-3.00(m,2H),2.89-2.86(m,2H),2.17(s,3H).

[0423] Example 7

[0424]

[0425] Step 1: Add 5-bromo-1,2,3,4-tetrahydroquinoline (10 g) and DMF (60 mL) to a 100 mL three-necked flask at room temperature. After fully replacing the nitrogen in the mixture, cool it to 0 degrees Celsius and add NaH (1.70 g, 60%) in batches. After the addition is complete, stir the mixture at 0 degrees Celsius for 0.5 h. Then, add CH 3 I (20.08g), the reaction system was slowly heated to room temperature and stirred overnight. LCMS detection showed that the raw material reaction was complete. The reaction mixture was cooled to 0 degrees Celsius, and a saturated aqueous solution of ammonium chloride was slowly added to the above mixture to quench the reaction. Water and ethyl acetate were added to the mixture, and the mixture was fully stirred and separated. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a light brown oily target product intermediate 1 (5.5g). LCMS (ES, m / z): 224.0, 226.0 [M+H] + .

[0426] Step 2: At room temperature, add the target product intermediate 1 (5.3 g) of step 1 to a 100 mL three-necked flask and completely dissolve it with THF (50 mL). After the reaction system is fully replaced with nitrogen, cool it to -78 degrees Celsius and drop n-BuLi in n-hexane solution (11.3 mL, 2.5 M). After stirring the mixture at this temperature for five minutes, DMF (6.85 g) is quickly added. The reaction system naturally rises to room temperature and continues to stir for one hour until the reaction is complete as detected by LCMS. The reaction mixture is cooled to 0 degrees Celsius again, quenched by adding saturated aqueous ammonium chloride solution, water and ethyl acetate are added to the mixture, stirred thoroughly and separated, the aqueous phase is extracted twice with ethyl acetate, the organic phases are combined, the organic phases are dried over anhydrous sodium sulfate and filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the target product intermediate 2 (3.5 g) as a light yellow oil. LCMS (ES, m / z): 176.1 [M+H] + .

[0427] Step 3: At room temperature, sodium methoxide (4.69 g) and methanol (20 mL) were added to a 100 mL three-necked flask. After the reaction system was fully replaced with nitrogen, it was cooled to 0 degrees Celsius. Ethyl azidoacetate (14.00 g) and a methanol solution (20 mL) of the target product intermediate 2 (3.8 g) of step 2 were added dropwise to the three-necked flask. The reaction system was naturally cooled to room temperature and stirred at room temperature for 1 hour. After the reaction was completed, the reaction system was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the mixture was separated after sufficient stirring. The aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target product intermediate 3 (2.1 g) as a yellow solid. LCMS (ES, m / z): 273.1 [M+H] + .

[0428] Step 4: At room temperature, add the target product intermediate 3 (2.1 g) of step 3 into a 100 ml three-necked flask, dissolve it completely with xylene (50 mL), fully replace the nitrogen in the reaction system, heat it to 90 degrees Celsius, and continue stirring at this temperature for 2 hours until the reaction is complete. After the reaction is completed, concentrate under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography to obtain the target product intermediate 4 (700 mg) as a light yellow solid. LCMS (ES, m / z): 245.1 [M+H] + .

[0429] Step 5: At room temperature, add the target product intermediate 4 (700 mg) of step 4 and THF (7 mL) into a 50 ml three-necked flask. After the mixture is stirred and completely clarified, the nitrogen is fully replaced. The above solution is cooled to 0 degrees Celsius, and NaH (0.17 g, 60%) is added. After the addition, the mixture continues to stir at 0 degrees Celsius for 0.5 hours. THF solution (5 mL) of TsCl (1.09 g) is added dropwise to the reaction flask. The reaction system is slowly heated to room temperature and stirred for 4 hours until the reaction is complete. After the reaction is completed, the reaction system is cooled to 0 degrees Celsius and saturated NH 4 The mixture was quenched with Cl aqueous solution, and water and ethyl acetate were added to the mixture, and the mixture was separated after sufficient stirring. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was spin-dried to obtain a crude product, which was purified by silica gel column chromatography to obtain the target product intermediate 5 (720 mg) as a light brown solid. LCMS (ES, m / z): 399.1 [M+H] + .

[0430] Step 6: At room temperature, add the target product intermediate 5 (710 mg) of step 5 and THF (20 mL) to a 50 mL three-necked flask, stir the mixture thoroughly until it is completely dissolved, and add acetonitrile (366 mg). After the nitrogen is fully replaced in the above mixture, cool it to -78 degrees Celsius. Add a tetrahydrofuran solution of NaHDMS (2.0 mL, 2.0 M) dropwise to the above reaction system. After the addition is complete, slowly warm the above reaction solution to room temperature and continue stirring for 2 hours until the reaction is complete. The above mixture is cooled to 0 degrees Celsius again and quenched with saturated ammonium chloride aqueous solution. Water and ethyl acetate are added to the mixture, stirred thoroughly and separated, the aqueous phase is extracted twice with ethyl acetate, the organic phases are combined, the organic phases are dried over anhydrous sodium sulfate and filtered, and the filtrate is concentrated to obtain a crude product, which is purified by silica gel column chromatography to obtain the target product intermediate 6 (500 mg) as a light brown solid. LCMS (ES, m / z): 408.1 [M+H] + .

[0431] Step 7: At room temperature, add the target product intermediate 6 (468 mg) of step 6 and toluene (4 mL) to a 20 mL sample bottle. After the above mixture is fully stirred and dissolved, N,N-dimethylformamide dimethyl acetal (547 mg) is added, and the mixture is stirred at room temperature for 20 minutes until the reaction is complete. After the reaction is completed, it is directly concentrated under reduced pressure to obtain a crude product, which is purified by a preparative chromatography plate to obtain the target product intermediate 7 (320 mg) as a light brown solid. LCMS (ES, m / z): 463.2 [M+H] + .

[0432] Step 8: At room temperature, add intermediate A1 (244 mg) and anhydrous ethanol (3 mL) to a 20 ml sample bottle, and stir the mixture until it is completely dissolved. Then add the target product intermediate 7 (300 mg) of step 7 to the sample bottle. After the reaction system is fully replaced with nitrogen, heat it to 80 degrees Celsius and continue stirring for 3 hours until the reaction is complete. After the reaction is completed, remove the solvent under reduced pressure. The resulting residue is purified with a preparation plate to obtain the target product intermediate 8 (370 mg) as a light brown solid. LCMS (ES, m / z): 669.3 [M+H] + .

[0433] Step 9: At room temperature, add the target intermediate 8 (350 mg) and tetrahydrofuran (3.5 mL) from step 8 into a 20 mL sample bottle and stir the mixture thoroughly until it is completely dissolved. 2 CO 3 (1.02 g), Cs was added again after 2 days of reaction 2 CO 3(0.51 g). The mixture was heated to 60°C and stirred for 2 h until the reaction was complete. After the reaction was completed, ethyl acetate was added to the mixture, stirred thoroughly and filtered, the filtrate was concentrated, and the residue was purified by reverse phase preparative chromatography to obtain the target product, compound 88 (68.5 mg), as a dark yellow solid. LCMS (ES, m / z): 515.3 [M+H] + .

[0434] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):11.31(s,1H),8.35(s,1H),8.13(s,1H),7.41-7.37(m,2H),7.35-

[0435] 7.29(m,2H),7.19-7.17(m,2H),7.05(s,2H),6.87-6.85(d,J=8.4Hz,1H) ,3.33(s,2H),3.11(s,2H),2.97-2.94(m,3H),2.178(s,3H),2.01(s,2H).

[0436] Example 8

[0437]

[0438] Step 1: At 0℃, add NaBH 3 CN (2.71 g in batches) was added to an acetic acid solution (30 mL) of 5-bromoquinoline (3.0 g). After the addition, the reaction solution was slowly warmed to room temperature and stirred for 2 hours until the reaction was complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain an oily crude product. Ethyl acetate and water were added to the crude product, and the mixture was separated after sufficient stirring. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target product intermediate 1 (2.0 g). LCMS (ES, m / z): 212.1, 213.1 [M+H] + .

[0439] Step 2: Add Boc anhydride (2.38 g) to an ethanol solution (20 mL) of the target product intermediate 1 (2.0 g) of step 1 at room temperature. 2 Heat to 95°C under protection and continue stirring for 24 hours until the reaction is complete. After the reaction is completed, the reaction solution is concentrated under reduced pressure. The residue is purified by column chromatography to obtain the target product intermediate 2 (1.9 g). LCMS (ES, m / z): 256.0, 258.0 [M-55] + .

[0440] Step 3: Pd(dppf)Cl 2 (0.45g) was added to the methanol (20mL) solution of the intermediate 2 (1.92g) obtained in step 2 and triethylamine (1.85g), and the reaction solution was stirred at 95°C for 16 hours under a carbon monoxide atmosphere. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain the target product intermediate 3 (1.32g). LCMS (ES, m / z): 236.1

[0441] [M+H] + .

[0442] Step 4: At room temperature, LiBH 4 (0.29 g) was added to the THF solution (13 mL) of the target product intermediate 3 (1.32 g) in step 3, and the reaction solution was stirred at room temperature for 10 min and then heated to 50°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, the mixed solution was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product intermediate 4 (1.2 g). LCMS (ES, m / z): 208.1 [M-55] + .

[0443] Step 5: At room temperature, the target product intermediate 4 (1.95 g) of step 4 was dissolved in dichloromethane (60 mL). After the reaction solution was cooled to 0°C, Dess-Martin reagent (4.7 g) was added in batches. The reaction solution was slowly warmed to room temperature and stirred for 0.5 hours until the reaction was complete. 2 S 2 O 3 The aqueous solution was quenched, the mixture was extracted three times with ethyl acetate, the organic phases were combined, and the organic phases were washed with saturated NaHCO 3 The product was washed with aqueous solution and saturated brine, the organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target product intermediate 5 (1.6 g, 74%). LCMS (ES, m / z): 206.1 [M-55] + .

[0444] Step 6: At room temperature, sodium chips (1.38 g) were added in batches to a methanol (60 mL) solution. After the addition, the mixture was heated to 60 ° C and stirred for 0.5 hours until the reaction was complete. After the reaction was completed, the mixture was cooled to 0 ° C and a methanol (4 mL) solution of the target product intermediate 5 (1.6 g) and ethyl azidoacetate (2.81 g) in step 5 was added dropwise. After the addition was completed, the mixture was slowly warmed to room temperature and stirred for 2 hours until the reaction was completed. The reaction solution was heated with saturated NH 4 The product was quenched with Cl aqueous solution and extracted with ethyl acetate. The organic phases were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product intermediate 6 (1.1 g). LCMS (ES, m / z): 275.0 [M-55-28] + .

[0445] Step 7: The target product intermediate 6 (1.1 g) of step 6 was dissolved in xylene (10 mL), and the reaction solution was heated to 140°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target product intermediate 7 (0.83 g). LCMS (ES, m / z): 275.0 [M-55] + .

[0446] Step 8: At 0°C, NaH (501 mg) was added in batches to a DMF (8 mL) solution of the target product intermediate 7 (830 mg) of step 7. After the addition, the mixture was stirred at 0°C for 0.5 hours. TsCl (1433 mg) was slowly added dropwise to the above mixture. After the addition, the mixture was slowly warmed to room temperature and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was cooled to 0°C and saturated with NH 4 The mixture was quenched with Cl aqueous solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target product intermediate 8 (930 mg). LCMS (ES, m / z): 429.0 [M-55] + .

[0447] Step 9: At room temperature, the target product intermediate 8 (930 mg) of step 8 was added to a mixed solution of trifluoroacetic acid and dichloromethane (12 mL, v / v = 3 / 1), and the reaction solution was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the target product intermediate 9 (1.05 g). LCMS (ES, m / z): 385.0 [M+H] + .

[0448] Step 10: At room temperature, add a drop of glacial acetic acid and tert-butyldimethylsilyl acetaldehyde (190 mg) to a solution of the target product intermediate 9 (300 mg) obtained in step 9 in dichloroethane (6 mL). Stir the mixture at room temperature for 30 min, then add NaBH(OAc) 3 (495 mg). The reaction solution was stirred at room temperature for 1.5 hours until the reaction was complete. After the reaction was completed, water and ethyl acetate were added to the reaction solution, and the mixture was separated after sufficient stirring. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain the target product intermediate 10 (260 mg). LCMS (ES, m / z): 543.0 [M+H] + .

[0449] Step 11: At -40°C, slowly drop a tetrahydrofuran solution of NaHMDS (0.5 mL) into a tetrahydrofuran solution (5 mL) of intermediate 10 (230 mg) and acetonitrile (86.8 mg) obtained in step 10. The reaction solution was stirred at -40°C for 0.5 hours under a nitrogen atmosphere until the reaction was complete. After the reaction was completed, the reaction solution was quenched with an aqueous ammonium chloride solution, the mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target product intermediate 11 (98 mg). LCMS (ES, m / z): 398.1 [M+H] + .

[0450] Step 12: At room temperature, add N,N-dimethylformamide dimethyl acetal (29.3 mg) to a tetrahydrofuran solution (5 mL) of the target product intermediate 11 (98.0 mg) of step 11, and stir the reaction solution at room temperature for 1 hour until the reaction is complete. After the reaction is complete, the reaction solution is concentrated under reduced pressure to obtain the target product intermediate 12 (107 mg). LCMS (ES, m / z): 453.1 [M+H] + .

[0451] Step 13: At room temperature, triethylamine (35.8 mg) was added to the NMP (5 mL) solution of the target product intermediate 12 (80 mg) and intermediate A1 (85.9 mg) of step 12, and the mixture was heated to 100°C under a nitrogen atmosphere and stirred for 1 hour until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, water and ethyl acetate were added to the reaction mixture, the mixture was fully stirred and separated, the aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin plate chromatography to obtain the target product compound 89 (9.5 mg). LCMS (ES, m / z): 545.0 [M+H] + .

[0452] 1H NMR (400MHz, DMSO-d 6 )δ(ppm):11.27(s,1H),8.36(s,1H),8.12(s,1H),7.39(s,2H),7.31-7.26(m,2H),7.16–7.13(m,2H),7.04(s,2H),6.83(d,J=12.0Hz ,1H),4.62(t,J=5.4Hz,1H),3.56(dd,J=12.0,6.2Hz,2H),3.31–3.26(m,4H),2.91(t,J=6.3Hz,2H),2.17(s,3H),1.93–1.90(m,2H).

[0453] Example 9

[0454]

[0455] Step 1: At room temperature, the target product intermediate 9 (230 mg) obtained in step 9 of Example 8 was dissolved in dichloromethane (5 mL), and TEA (181 mg) and 4-DMAP (7.3 mg) were added. After the mixture was cooled to 0°C, methylsulfonyl chloride (137 mg) was added, and the mixture was slowly heated to room temperature and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain an oily crude product, which was purified by column chromatography to obtain the target product intermediate 1 (218 mg). LCMS (ES, m / z): 462.9 [M+H] + .

[0456] Step 2: Under nitrogen atmosphere, add a tetrahydrofuran solution of NaHMDS (0.4 mL, 2.0 M) to a tetrahydrofuran (5 mL) solution of the target product intermediate 1 (180 mg) of step 1 and acetonitrile (80 mg) which was pre-cooled to -40°C. After the addition was completed, the mixture was slowly warmed to room temperature and continued to stir for 0.5 hours until the reaction was complete. After the reaction was completed, the mixture was cooled to 0°C again, quenched with saturated aqueous ammonium chloride solution, extracted twice with ethyl acetate, and the organic phases were combined. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the target product intermediate 2 (105 mg). LCMS (ES, m / z): 340.0 [M+Na] + .

[0457] Step 3: Add N,N-dimethylformamide dimethyl acetal (33.0 mg) to the tetrahydrofuran solution (5 mL) of the target product intermediate 2 (88.0 mg) of step 2, and stir the reaction solution at room temperature for 1 hour until the reaction is complete. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain the target product intermediate 3 (105 mg). LCMS (ES, m / z): 373.1 [M+H] + .

[0458] Step 4: Add intermediate A1 (52.2 mg) and NaOAc (17.6 mg) to an ethanol (5 mL) solution of intermediate 3 (40.0 mg) of the target product of step 3. The mixture was heated to 90°C and stirred for 3 hours until the reaction was complete. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase preparative chromatography to obtain the target product compound 90 (9.5 mg). LCMS (ES, m / z): 578.9 [M+H] + .

[0459] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):11.74(s,1H),8.43(s,1H),8.13(s,1H),7.47–7.44(m,2H),7.40(s,2H),7.30(dd,J=17.7,8.6Hz ,3H),7.10(s,2H),3.76–3.73(m,2H),3.12(t,J=6.8Hz,2H),2.95(s,3H),2.18(s,3H),2.07–1.97(m,2H).

[0460] Example 10

[0461]

[0462] Step 1: At 0 degrees Celsius, NIS (1.71 g) was added in batches to a solution of 6-amino-2-N-Boc-1,2,3,4-tetrahydro-isoquinoline (1.8 g) in acetic acid (20 mL). After the addition, the mixture was slowly warmed to room temperature and stirred for 1 hour until the reaction was complete. After the reaction was completed, the above mixture was transferred to a saturated aqueous sodium bisulfite solution for quenching, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography to obtain the target product intermediate 1 (1 g). LCMS (ES, m / z): 375.1 [M+H] + .

[0463] Step 2: In N 2 Under protection, N,N-dicyclohexylmethylamine (3.39 g), tri-tert-butylphosphine tetrafluoroborate (310 mg) and Pd were added to a solution of the target product intermediate 1 (1 g) of step 1 and ethyl pyruvate (1.24 g) in 1,4-dioxane. 2 (dba) 3 (245 mg), the mixture was stirred at 100 degrees Celsius overnight, and the reaction was complete after LCMS detection. After the mixture was cooled to room temperature, ethyl acetate was added, and the resulting mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target product intermediate 2 (800 mg). LCMS (ES, m / z): 245.3 [M-100+H] + .

[0464] Step 3: Slowly add a tetrahydrofuran solution (6.4 mL, 1.0 M) of sodium bis(trimethylsilyl)amide in tetrahydrofuran to the intermediate 2 (1 g) obtained in step 2 and acetonitrile (596 mg) in anhydrous tetrahydrofuran solution (10 mL) under a nitrogen atmosphere at -40 degrees Celsius. After the addition is complete, the mixture slowly warms to room temperature and continues to stir for 20 minutes until the reaction is complete. After the reaction is complete, the reaction is quenched with a saturated aqueous solution of ammonium chloride. The mixture is extracted twice with ethyl acetate, the organic phases are combined, the organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, the solvent is removed under reduced pressure, and the residue is slurried with ether to obtain the target product intermediate 3 (700 mg). LCMS (ES, m / z): 340.2 [M+H] + .

[0465] Step 4: At room temperature, N,N-dimethylformamide dimethyl acetal (604 mg) was added to a toluene solution (5 mL) of the target product intermediate 3 (430 mg) of step 3, and the mixture was stirred at room temperature for 30 min until the reaction was complete. After the reaction was completed, the solvent was removed under reduced pressure, the residue was slurried with ether, the solid was collected, and vacuum dried to obtain the target product intermediate 4 (450 mg). LCMS (ES, m / z): 395.2 [M+H] + .

[0466] Step 5: At room temperature, add intermediate A1 (487 mg) to an ethanol solution (8 mL) of the target product intermediate 4 (510 mg) of step 4. After the mixture is fully replaced with nitrogen, it is heated to 80 degrees Celsius and stirred for 3 hours until the reaction is complete. After the reaction is completed, the solvent is removed under reduced pressure. The residue obtained is the target product intermediate 5 (1 g). The residue is not further purified and is directly used in the next reaction. LCMS (ES, m / z): 601.2 [M+H] + .

[0467] Step 6: Dissolve the target product intermediate 5 (100 mg) of step 5 in a 1,4-dioxane solution (3 mL) of HCl gas at room temperature. Stir the mixture at room temperature for 5 hours until the reaction is complete. After the reaction is complete, remove the solvent and purify the residue by high-performance liquid chromatography to obtain the target product compound 115 (10.5 mg) as a yellow solid. LCMS (ES, m / z): 501.4 [M+H] + .

[0468] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):11.70(s,1H),8.44(s,1H),8.34(s,1H),8.14(s,1H),7.43-7.36(m,3H),7.34-7.29( m,3H),7.09(s,2H),7.01(d,J=8.4Hz,1H),4.11(s,2H),3.28(s,2H),3.12(s,2H),2.18(s,3H).

[0469] Embodiment 11

[0470]

[0471] At room temperature, a methanol solution (3 mL) of compound 115 (20 mg) was added to a 50 ml reactor, and then palladium carbon (5 mg, 10%) was added. After the above mixture was fully replaced with hydrogen, it was stirred at room temperature overnight. After the reaction was completed, diatomaceous earth was added, the filtrate was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography to obtain the target product Example 116 (1.2 mg) as a white solid. LCMS (ES, m / z): 515.4 [M+H] + .

[0472] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):11.62(s,1H),8.41(s,1H),8.14(s,1H),7.42-7.24(m,6H),7.06(s,2H),6.95- 6.93(d,J=8.0Hz,1H),3.59(s,2H),3.06(s,2H),2.75(s,2H),2.18(s,3H),1.24(s,3H).

[0473] Example 12

[0474]

[0475] Under nitrogen protection, compound 115 (20 mg) and ethanol (3 mL) were added to a 50 ml reactor. After the mixture was fully stirred and dissolved, palladium carbon (5 mg, 10%) was added. After the mixture was fully replaced with hydrogen, it was stirred at room temperature overnight. After the reaction was completed, diatomaceous earth was added to the mixture, mixed evenly and filtered, the filter cake was washed with a small amount of ethanol, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the target product compound 117 (2.0 mg) as an off-white solid. LCMS (ES, m / z): 529.4 [M+H] + .

[0476] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):11.59(s,1H),8.41(s,1H),8.13(s,1H),7.39-7.24(m,6H),7.06(s,2H),6.96-6. 94(d,J=8.0Hz,1H),3.59(s,2H),3.06(s,2H),2.76(s,2H),2.18(s,3H),1.24-1.13(m,5H).

[0477] Embodiment 13

[0478]

[0479] Step 1: At room temperature, dissolve 1,2,3,4-tetrahydroquinoline (5g) in dichloromethane (50mL) and cool to 0 degrees Celsius, then add boron trichloride (4.40g). The mixture is warmed to room temperature and stirred for 30 minutes, then heated to reflux and continued to stir for 2 hours. The mixture is cooled to 0°C, TEA (7.60g) is added, and the mixture is stirred at 0 degrees Celsius for 10 minutes, and a dichloromethane solution (10mL) of isocyanocyclohexane (4.51g) is added dropwise. After the addition is complete, the mixture is slowly warmed to room temperature and stirred for 3 hours until the reaction is complete. After the reaction is completed, ice water is added to the mixture, stirred thoroughly and then separated, the aqueous phase is extracted 3 times with dichloromethane, the organic phases are combined, 2M hydrochloric acid aqueous solution is added to the organic phase, stirred at room temperature for 1 hour, separated, the pH value of the aqueous phase is adjusted to neutral with saturated sodium bicarbonate, the aqueous phase is extracted 3 times with dichloromethane, the organic phases are combined, the organic phases are dried over anhydrous sodium sulfate and filtered, the filtrate is concentrated, and the residue is purified by silica gel column chromatography to obtain the target product intermediate 3 (4.49 g) as a yellow solid. LCMS (ES, m / z): 162.1 [M+H] + .

[0480] Step 2: At room temperature, the target product intermediate 3 (4 g) of step 1 was dissolved in dichloromethane (40 mL), and trimethyloxonium tetrafluoroborate (7.34 g) was added. After the mixture was fully replaced with nitrogen, it was stirred overnight under reflux and sent for liquid quality detection to complete the reaction. After the mixture was cooled to room temperature, it was quenched with ice water, stirred thoroughly and separated, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain the target product intermediate 4 (2.2 g) as a light yellow solid. LCMS (ES, m / z): 176.1 [M+H] + .

[0481] Step 3: Dissolve sodium methoxide (1.85 g) in anhydrous methanol (13 mL) at room temperature, cool the resulting solution to 0 degrees Celsius, and then slowly drop the target product intermediate 4 (2 g) of step 2 and anhydrous methanol solution (13 mL) of ethyl azidoacetate (5.89 g). After the addition, continue stirring the mixture at 0°C for 1 hour until the reaction is complete. After the reaction is completed, the reaction is quenched with ice water, the mixture is extracted with ethyl acetate 3 times, and the organic phases are combined. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain the target product intermediate 5 (1.5 g) as a yellow oil. LCMS (ES, m / z): 273.1 [M+H] + .

[0482] Step 4: At room temperature, the target product intermediate 5 (1.5 g) of step 3 was dissolved in xylene (15 mL). The solution was fully replaced with nitrogen and heated to 90 degrees Celsius and stirred overnight. LCMS detected that the reaction was complete and the reaction mixture was directly spin-dried. The obtained residue was purified by silica gel column chromatography to obtain the target product intermediate 6 (600 mg) as a yellow solid. LCMS (ES, m / z): 245.1 [M+H] + .

[0483] Step 5: At room temperature, add the target product intermediate 6 (140 mg) of step 4 to a 40 mL sample bottle, then add anhydrous tetrahydrofuran (2 mL), stir well until completely dissolved, fully replace the nitrogen in the above solution and cool to 0 degrees Celsius, then drop LiHMDS tetrahydrofuran solution (2.3 mL, 1.0 M) into the above solution, after the addition is complete, continue to stir the mixture at this temperature for 0.5 h, and then add acetonitrile (47.1 mg). After the addition is complete, slowly warm the mixture to room temperature and continue stirring for 2 hours until the reaction is complete. After the reaction is complete, cool the mixture to 0 degrees Celsius, quench with ice water, extract the mixture three times with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate and filter, concentrate the filtrate, and purify the residue with a preparative chromatography plate to obtain the target product intermediate 7 (48 mg) as a dark red solid. LCMS (ES, m / z): 254.2 [M+H] + .

[0484] Step 6: At room temperature, the target product intermediate 7 (48 mg) of step 5 was dissolved in toluene (0.5 mL), and N,N-dimethylformamide dimethyl acetal (56.2 mg) was added dropwise, and the mixture was stirred at room temperature for 30 min until the reaction was complete. After the reaction was completed, the solvent was removed and the residue was purified by preparative chromatography to obtain the target product intermediate 8 (27 mg) as a dark red solid. LCMS (ES, m / z): 309.1 [M+H] + .

[0485] Step 7: At room temperature, the target product intermediate 8 (27 mg) of step 6 was dissolved in anhydrous ethanol (1 ml), and intermediate A1 (33 mg) was added to the above solution. After the reaction system was fully replaced with nitrogen, it was heated to 80 degrees Celsius and stirred at this temperature for 3 hours until the reaction was complete. After the reaction was completed, the solvent was removed under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography to obtain the target product compound 171 (1.3 mg) as a light yellow solid. LCMS (ES, m / z): 515.3 [M+H] + .

[0486] 1H NMR (400 MHz, DMSO-d 6 )δ(ppm):8.40(s,1H),8.07(s,1H),7.40-7.28(m,4H),7.09-6.95(m,5H),4.26-4.05(s,1H),4.11-4.06(m,1H), 3.89-3.83(m,1H),2.85-2.82(t,J=6Hz,2H),2.57(s,1H),2.14(s,3H),2.10-2.08(m,1H),1.03(d,J=7.2Hz,3H).

[0487] Embodiment 14

[0488]

[0489] Step 1: Dissolve tert-butyl 7-amino-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (2.5 g) in acetic acid (25 mL) at room temperature, slowly add NIS (2.38 g) to the above solution, and stir the mixture at room temperature for 1 hour until the reaction is complete. Pour the above mixture into ice water, quench with saturated sodium bisulfite solution, extract the above mixture twice with ethyl acetate, and combine the organic phases. After washing the organic phase with saturated brine, dry it with anhydrous sodium sulfate and filter it. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the target product intermediate 1 (0.68 g) as a light yellow oil. LCMS (ES, m / z): 319.1 [M-56+H] + .

[0490] Step 2: At room temperature, the target product intermediate 1 (0.68 g) of step 1 was dissolved in 1,4-dioxane (20 mL), and N-methyldicyclohexylamine (2.31 g), tri-tert-butylphosphine tetrafluoroborate (211 mg), Pd 2 (dba) 3 (166 mg) and ethyl pyruvate (498 mg), the above mixture was fully replaced with nitrogen, heated to 100 degrees Celsius and reacted overnight. LCMS detection showed that the reaction was complete, the mixture was cooled to room temperature and quenched with saturated ammonium chloride, the above mixture was extracted twice with ethyl acetate, the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography to obtain the target product intermediate 2 (425 mg). LCMS (ES, m / z): 330.2 [M+H] + .

[0491] Step 3: At room temperature, the target product intermediate 2 (425 mg) of step 2 was dissolved in THF (4 mL), acetonitrile (253 mg) was added, and the mixture was fully replaced with nitrogen and cooled to -40 ° C. A tetrahydrofuran solution of NaHMDS (2.7 mL, 1.0 M) was added dropwise to the above mixture. After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred for 20 min until the reaction was complete. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, and the obtained organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the target product intermediate 3 (490 mg) as a crude product, which was directly used in the next step without further purification. LCMS (ES, m / z): 340.1 [M+H] + .

[0492] Step 4: At room temperature, the target product intermediate 3 (490 mg) of step 3 was dissolved in toluene (5 mL), and N,N-dimethylformamide dimethyl acetal (482 mg) was added. The mixture was stirred at room temperature for 30 min until the reaction was complete. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was slurried with ether, and the solid was collected to obtain the target product intermediate 4 (150 mg). LCMS (ES, m / z): 339.1 [M-56+H] + .

[0493] Step 5: At room temperature, the target product intermediate 4 (20 mg) and intermediate A1 (19 mg) of step 4 were dissolved in EtOH (0.5 mL). The mixture was fully replaced with nitrogen and heated to 80 degrees Celsius, and stirred for 3 hours until the reaction was complete. After the reaction was completed, the solvent was removed under reduced pressure, and the residual solid was the target product intermediate 5 (20 mg). LCMS (ES, m / z): 601.1 [M+H] + .

[0494] Step 6: At room temperature, the target product intermediate 5 (130 mg) of step 5 was dissolved in a 1,4-dioxane solution (5 mL) of HCl gas. The above mixture was stirred at room temperature for 5 hours until the reaction was complete. After the reaction was completed, it was concentrated under reduced pressure and the crude product was purified by high-performance liquid chromatography to obtain the target product compound 189 (3.7 mg) as a yellow solid. LCMS (ES, m / z): 501.3 [M+H] + .

[0495] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):11.58(s,1H),8.42(s,1H),8.14(s,1H),7.43-7.23(m,5H),7.19-7.16(d,J=9.2H z,1H),7.07(s,2H),7.00-6.95(m,1H),4.16(s,2H),3.03(s,2H),2.82(s,2H),2.18(s,3H).

[0496] Embodiment 15

[0497]

[0498] Step 1: Dissolve tert-butyl 7-amino-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (2.0 g) in acetic acid (10 mL) at room temperature. After fully replacing nitrogen, cool the solution to 0°C and slowly add NIS (1.89 g). After the mixture is slowly warmed to room temperature, continue stirring for 1 hour until the reaction is complete. Pour the mixture into ice water and quench with saturated sodium bisulfite solution. The mixture is extracted twice with ethyl acetate, the organic phases are combined, the organic phases are washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the target product intermediate 1 (1.1 g). LCMS (ES, m / z): 319.1 [M-56+H] + .

[0499] Step 2: At room temperature, the target product intermediate 1 (1.1 g) of step 1 was dissolved in 1,4-dioxane (20 mL), and N-methyldicyclohexylamine (3.7 g), tri-tert-butylphosphine tetrafluoroborate (340 mg), Pd 2 (dba) 3 (268mg) and ethyl pyruvate (1.36g). After the above mixture is fully replaced with nitrogen, it is heated to 100 degrees Celsius for 16 hours until the reaction is complete. After the reaction is completed, the mixture is cooled to room temperature and water and ethyl acetate are added. The mixture is fully stirred and separated. The aqueous phase is extracted twice with ethyl acetate, and the organic phases are combined. The organic phases are washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, and the resulting residue is purified by column chromatography to obtain the target product intermediate 2 (930mg). LCMS (ES, m / z): 711.04 [2M+Na] + .

[0500] Step 3: At room temperature, the target product intermediate 2 (0.93 g) of step 2 was dissolved in a 1,4-dioxane solution (50 mL, 4.0 M) of HCl gas, and the mixture was stirred at room temperature for 12 hours until the reaction was complete. After the reaction was completed, the mixture was concentrated, methyl tert-butyl ether was added to the residue, stirred thoroughly, and then filtered. The filter cake was washed with methyl tert-butyl ether, and the filter cake was vacuum dried to obtain the target product intermediate 3 (0.88 g). LCMS (ES, m / z): 245.2 [M+H] + .

[0501] Step 4: At room temperature, the target product intermediate 3 (400 mg) of step 3 was dissolved in MeOH (15 mL), and aqueous formaldehyde solution (45 mg, 37%) and acetic acid (0.05 mL) were added. The mixture was stirred under nitrogen atmosphere for 1 hour, and then NaBH 3 CN (160 mg). The above mixture was stirred at room temperature for 5 hours until the reaction was complete. After the reaction was completed, the above mixture was concentrated under reduced pressure, and the residue was purified by chromatography on a silica gel column to obtain the target product intermediate 4 (310 mg). LCMS (ES, m / z): 259.2 [M+H] + .

[0502] Step 5: Dissolve the target product intermediate 4 (310 mg) of step 4 in THF (5 mL) at room temperature and add CH 3 CN (246.3 mg), the mixture was fully replaced with nitrogen and then cooled to -40 ° C. To the above mixture was added a tetrahydrofuran solution of NaHMDS (1.3 mL, 2.0 M). After the addition was completed, the reaction solution was slowly heated to 0 ° C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, and the obtained organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by thin plate chromatography to obtain the target product intermediate 5 (90 mg). LCMS (ES, m / z): 254.1

[0503] [M+H] + .

[0504] Step 6: At room temperature, the target product intermediate 5 (90 mg) of step 5 was dissolved in THF (5 mL), N,N-dimethylformamide dimethyl acetal (46 mg) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the target product intermediate 6 (120 mg), which was directly used in the next step. LCMS (ES, m / z): 309.0 [M+H] + .

[0505] Step 7: At room temperature, the target product intermediate 6 (72 mg) of step 6 was dissolved in NMP (5 mL), and intermediate A1 (64.5 mg) and TEA (47 mg) were added. The above mixture was heated to 100°C under a nitrogen atmosphere and stirred for 2 hours until the reaction was complete. After the reaction was completed, the reaction mixture was poured into water, extracted three times with ethyl acetate, and the organic phases were combined. The obtained organic phases were washed with saturated brine, dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by reverse phase preparative chromatography to obtain the target product compound 190 (31.4 mg). LCMS (ES, m / z): 515.3 [M+H] + .

[0506] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):11.64(s,1H),8.43(s,1H),8.13(s,1H),7.40–7.37(m,3H),7.33–7.26(m,3H),7.08(s,2H ),7.00(d,J=8.0Hz,1H),3.87(brs,2H),2.88(s,2H),2.74(s,2H),2.49–2.46(m,3H),2.18(s,3H).

[0507] Example 16

[0508]

[0509] Step 1: At room temperature, add acetaldehyde aqueous solution (5 mg, 40%) and acetic acid (3 mg) to a DMA solution (0.5 mL) of compound 189 (20 mg) under nitrogen protection. After the above mixture is stirred at room temperature for 1 hour, sodium cyanoborohydride (5 mg) is added. The above mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure, and the residue is purified by preparative chromatography to obtain 15 mg of crude product. The crude product is purified by high-performance liquid chromatography to obtain the target product compound 191 (2.2 mg) as a yellow solid. LCMS (ES, m / z): 529.3 [M+H] + .

[0510] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):11.60(s,1H),8.47(s,1H),8.14(s,1H),7.42-7.37(m,3H),7.33-7.25(m,3H),7.08(s,2H),7.00- 6.98(d,J=8.4Hz,1H),3.86(s,2H),2.86(s,2H),2.68(m,2H),2.51(m,2H),2.18(s,3H),1.24-1.18(m,3H).

[0511] Embodiment 17

[0512]

[0513] Step 1: At room temperature, the intermediate 3 (300 mg) of step 3 in compound 190 and tert-butyldimethylsilyl acetaldehyde (186 mg) were dissolved in dichloroethane (5 mL), and 1 drop of glacial acetic acid was added. The mixture was stirred at room temperature for 30 min, and NaBH(OAc) was added in batches. 3 (454mg), the above mixture was stirred at room temperature for 5 hours until the reaction was complete. After the reaction was completed, water and ethyl acetate were added to the above mixture, and the mixture was separated after sufficient stirring. The aqueous phase was extracted twice with ethyl acetate and the organic phase was combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on a silica gel column to obtain the target product intermediate 1 (400mg) as a light yellow oil. LCMS (ES, m / z): 403.3 [M+H] + .

[0514] Step 2: At -40°C, slowly add a tetrahydrofuran solution of NaHMDS (1.1 mL, 2.0 M) to a tetrahydrofuran (5 mL) solution of the target product intermediate 1 (400 mg) and acetonitrile (203 mg). The reaction solution was slowly heated to room temperature under a nitrogen atmosphere and stirred for 0.5 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to 0°C again and heated with saturated NH 4 The reaction was quenched with Cl solution, the mixture was extracted twice with ethyl acetate, the organic phases were combined, washed with saturated saline solution, dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target product intermediate 2 (160 mg). LCMS (ES, m / z): 398.3 [M+H] + .

[0515] Step 3: At room temperature, N,N-dimethylformamide dimethyl acetal (48 mg) was added to a tetrahydrofuran solution (5 mL) of the target product intermediate 2 (160 mg) of step 2, and the reaction solution was stirred at room temperature for 1 hour until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the target product intermediate 3 (200 mg) as a crude product, which was directly used in the next step without purification. LCMS (ES, m / z): 453.4 [M+H] + .

[0516] Step 4: At room temperature, add intermediate A1 (122 mg) and triethylamine (89 mg) to the NMP solution (10 mL) of the target product intermediate 3 (200.0 mg) of step 3. Heat the reaction solution to 100°C and continue stirring for 1 hour until the reaction is complete. After the reaction is completed, cool the reaction solution to room temperature, add water and ethyl acetate to the reaction solution, stir well and separate the liquids, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash the organic phases with saturated brine, dry with anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure, and purify the residue by reverse phase preparative chromatography to obtain the target product intermediate 4 (150 mg). LCMS (ES, m / z): 659.0 [M+H] + .

[0517] Step 5: At room temperature, TFA (2 mL) was added to a dichloromethane solution (6 mL) of the target product intermediate 4 (130 mg) of step 4. The mixture was stirred at room temperature for 12 hours until the reaction was complete. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified using a high pressure liquid chromatography preparative separation column to obtain the target compound 192 (30 mg). LCMS (ES, m / z): 545.3 [M+H] + .

[0518] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):11.90(s,1H),8.46(s,1H),8.13(s,1H),7.55(s,1H),7.43-7.41(m,3H),7.33-7.31(m,2H),7 .13-7.10(m,3H),5.42(s,1H),4.85(s,2H),4.61(s,2H),3.97-3.81(m,4H),3.09(s,2H),2.18(s,3H).

[0519] Embodiment 18

[0520]

[0521] Step 1: Add DIEA (317 mg) and 2,2-dimethyloxirane (590 mg) to a solution of ethyl 2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-8-carboxylate (200 mg) in ethanol (10 mL) at room temperature. Heat the mixture to 85°C and stir for 1 hour until the reaction is complete. After the reaction is completed, concentrate under reduced pressure. The residue is purified by column chromatography to obtain the target product intermediate 1 (154 mg). LCMS (ES, m / z): 317.2 [M+H] + .

[0522] Step 2: The target product intermediate 1 (154 mg) of step 1 was dissolved in THF (5 mL) at room temperature and CH 3 CN (99.9 mg) and cooled to -40 ° C, and a tetrahydrofuran solution of NaHMDS (0.6 mL, 1.0 M) was added dropwise. The above mixture was naturally warmed to 0 ° C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution. The organic phase was extracted three times with ethyl acetate and the organic phases were combined. The organic phase was washed with salt, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product intermediate 2 (115 mg). LCMS (ES, m / z): 312.2 [M+H] + .

[0523] Step 3: Add DMF-DMA (44 mg) to a THF (5 mL) solution of the target product intermediate 2 (115 mg) of step 2 at room temperature. The above mixture was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, the above mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target product intermediate 3 (74 mg). LCMS (ES, m / z): 367.2 [M+H] + .

[0524] Step 4: At room temperature, 2-(2,6-difluorophenoxy)-5-hydrazinopyridine (51.4 mg) and triethylamine (41.4 mg) were added to a solution of the target product intermediate 3 (50 mg) in ethanol (5 mL) in step 3. The mixture was heated to 80°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product Example 194 (9.4 mg). LCMS (ES, m / z): 573.1 [M+H] + .

[0525] 1H NMR (400MHz, MeOD) δ (ppm): 8.37 (s, 1H), 8.09 (s, 1H), 7.48 (d, J = 8.4Hz, 1H), 7.37 (s, 1H), 7.31-7 .26(m,2H),7.19-7.10(m,3H),4.79(s,4H),4.62(s,2H),3.37(s,2H),2.25(s,3H),1.43(s,6H).

[0526] Embodiment 19

[0527]

[0528] Step 1: At room temperature, the intermediate 3 (300 mg) obtained in step 3 of Example 15 was dissolved in MeOH (10 mL), and 3-oxetanone (154 mg) and acetic acid (0.05 mL) were added. The mixture was stirred at N 2 The mixture was heated to 80°C and stirred for 1 hour. After the mixture cooled to room temperature again, NaBH 3 CN (201 mg), after addition, the mixture was heated to 80 degrees Celsius again and stirred for 2 hours until the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on a silica gel column to obtain the target product intermediate 1 (300 mg) as a light yellow oil. LCMS (ES, m / z): 301.3 [M+H] + .

[0529] Step 2: Under nitrogen atmosphere, add a tetrahydrofuran solution of NaHMDS (2.2 mL, 2.0 M) to a THF solution (10 mL) of the target product intermediate 1 (260 mg) obtained in step 1 and acetonitrile (178 mg) which was pre-cooled to -40 degrees Celsius. The reaction solution was naturally warmed to room temperature and stirred for 2 hours until the reaction was complete. After the reaction was completed, the reaction mixture was quenched with a saturated aqueous ammonium chloride solution, and then extracted with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on a silica gel column to obtain the target product intermediate 2 (150 mg). LCMS (ES, m / z): 296.1 [M+H] + .

[0530] Step 3: At room temperature, N,N-dimethylformamide dimethyl acetal (121 mg) was added to a tetrahydrofuran (5 mL) solution of the target product intermediate 2 (150 mg) in step 2, and the reaction solution was stirred at room temperature for 1 hour until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the target product intermediate 3 (200 mg) as a crude product, which was directly used in the next step without purification. LCMS (ES, m / z): 351.0 [M+H] + .

[0531] Step 4: At room temperature, add intermediate A1 (150 mg) and TEA (110 mg) to the NMP solution (10 mL) of the target product intermediate 3 (190 mg) of step 3. After the reaction mixture is fully replaced with nitrogen, it is heated to 100 degrees Celsius and stirred for 2 hours until the reaction is complete. After the reaction is completed, water is added to the reaction solution, and it is filtered after being fully stirred to obtain a yellow solid as a crude product. The crude product is purified by high pressure liquid chromatography to obtain compound 195 (60 mg). LCMS (ES, m / z): 557.3 [M+H] + .

[0532] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):11.92(s,1H),11.06(s,2H),8.44(s,1H),8.13(s,1H),7.52(s,1H),7.41-7.35(m,2H),7.33- 7.29(m,2H),7.15-7.13(m,2H),4.89(s,4H),4.68(s,1H),4.42(s,1H),3.34-3.21(m,4H),2.17(s,3H).

[0533] Embodiment 20

[0534]

[0535] Step 1: At room temperature, add acetaldehyde aqueous solution (5 mg, 40%) and acetic acid (3 mg) to a DMA solution (0.5 mL) of compound 189 (20 mg) under nitrogen protection. After the mixture is stirred at room temperature for 1 hour, sodium cyanoborohydride (5 mg) is added and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure and the residue is purified by preparative chromatography to obtain 15 mg of crude product. The crude product is purified by high performance liquid chromatography to obtain the target product compound 271 (1.1 mg) as a yellow solid. LCMS (ES, m / z): 557.3 [M+H] + .

[0536] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):11.60(s,1H),8.48(s,1H),8.14(s,1H),7.41-7.36(m,2H),7.33 -7.29(m,2H),7.26-7.24(d,J=8.4Hz,1H),7.07(s,2H),6.99-6.97(d,J=8 .4Hz,1H),3.85(s,2H),2.84(s,2H),2.73-2.71(d,J=5.2Hz,2H),2.51(s, 2H),2.18(s,3H),1.64-1.61(m,2H),1.41-1.35(m,2H),0.97-0.95(m,3H).

[0537] Embodiment 21

[0538]

[0539] Step 1: Under nitrogen protection, the target product intermediate 3 (200 mg) of step 3 in Example 14 was dissolved in DCM (8 mL), TEA (144 mg) was added, and the mixture was cooled to 0°C, and methylsulfonyl chloride (81 mg) was added. The reaction solution was slowly heated to room temperature and continued to stir for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by chromatography on a silica gel column to obtain the target product intermediate 1 (200 mg) as a light yellow oil. LCMS (ES, m / z): 323.2 [M+H] + .

[0540] Step 2: At room temperature, the target product intermediate 1 (200 mg) of step 1 was dissolved in THF (8 mL), acetonitrile (127 mg) was added, the reaction system was fully replaced with nitrogen and then cooled to -40 degrees Celsius, and NaHMDS (0.7 mL, 2.0 M) was slowly added dropwise to the above solution. After the addition was completed, the reaction was slowly heated to room temperature and stirred for 2 hours until the reaction was complete. After the reaction was completed, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on a silica gel column to obtain the target product intermediate 2 (150 mg) as a light red oil. LCMS (ES, m / z): 318.2 [M+H] + .

[0541] Step 3: At room temperature, the target product intermediate 2 (130 mg) of step 2 was dissolved in THF (5 mL), and N, N-dimethylformamide dimethyl acetal (54 mg) was added dropwise to the above solution. After the addition was completed, the mixture was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the target product intermediate 3 (179 mg) as a crude product. The crude product was not treated and was directly used in the next step. LCMS (ES, m / z): 373.2 [M+H] + .

[0542] Step 4: At room temperature, add intermediate A1 (133 mg) and TEA (97 mg) to the NMP (8 mL) solution of the target product intermediate 3 (179 mg) of step 3. After the nitrogen is fully replaced, the reaction mixture is heated to 100 degrees Celsius and stirred for 2 hours until the reaction is complete. After the reaction is completed, water and ethyl acetate are added to the reaction solution, and the mixture is separated after sufficient stirring. The aqueous phase is extracted twice with ethyl acetate, and the organic phases are combined. The organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by thin plate chromatography to obtain the target product compound 272 (38.6 mg) as a yellow solid. LCMS (ES, m / z): 579.1 [M+H] + .

[0543] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):11.75(s,1H),8.51(s,1H),8.14(s,1H),7.50(s,1H),7.40(s,2H),7.34-7.31(m,3H) ,7.07-7.05(m,3H),4.67(s,2H),3.50(t,J=5.6Hz,2H),3.01(s,3H),2.95(s,2H),2.18(s,3H).

[0544] Embodiment 22

[0545]

[0546] Step 1: At 0℃, add NaBH 3CN (2.71 g in batches) was added to an acetic acid solution (30 mL) of 5-bromoquinoline (3.0 g). After the addition, the reaction solution was slowly warmed to room temperature and stirred for 2 hours until the reaction was complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain an oily crude product. Ethyl acetate and water were added to the crude product, and the mixture was separated after sufficient stirring. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target product intermediate 1 (2.0 g). LCMS (ES, m / z): 212.1, 213.1 [M+H] + .

[0547] Step 2: Add Boc anhydride (2.38 g) to an ethanol solution (20 mL) of the target product intermediate 1 (2.0 g) of step 1 at room temperature. 2 Heat to 95°C under protection and continue stirring for 24 hours until the reaction is complete. After the reaction is completed, the reaction solution is concentrated under reduced pressure. The residue is purified by column chromatography to obtain the target product intermediate 2 (1.9 g). LCMS (ES, m / z): 256.0, 258.0 [M-55] + .

[0548] Step 3: Pd(dppf)Cl 2 (0.45g) was added to a methanol (20mL) solution of the product (1.92g) obtained in step 2 and triethylamine (1.85g), and the reaction solution was stirred at 95°C for 16 hours under a carbon monoxide atmosphere. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain the target product intermediate 3 (1.32g). LCMS (ES, m / z): 236.1 [M+H] + .

[0549] Step 4: At room temperature, LiBH 4 (0.29 g) was added to the THF solution (13 mL) of the target product intermediate 3 (1.32 g) in step 3, and the reaction solution was stirred at room temperature for 10 min and then heated to 50°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, the mixed solution was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product intermediate 4 (1.2 g). LCMS (ES, m / z): 208.1 [M-55] + .

[0550] Step 5: At room temperature, the target product intermediate 4 (1.95 g) of step 4 was dissolved in dichloromethane (60 mL). After the reaction solution was cooled to 0°C, Dess-Martin reagent (4.7 g) was added in batches. The reaction solution was slowly warmed to room temperature and stirred for 0.5 hours until the reaction was complete. 2 S 2 O 3 The aqueous solution was quenched, the mixture was extracted three times with ethyl acetate, the organic phases were combined, and the organic phases were washed with saturated NaHCO 3 The product was washed with aqueous solution and saturated brine, the organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target product intermediate 5 (1.6 g, 74%). LCMS (ES, m / z): 206.1 [M-55] + .

[0551] Step 6: At room temperature, sodium chips (1.38 g) were added in batches to a methanol (60 mL) solution. After the addition, the mixture was heated to 60 ° C and stirred for 0.5 hours until the reaction was complete. After the reaction was completed, the mixture was cooled to 0 ° C and a methanol (4 mL) solution of the target product intermediate 5 (1.6 g) and ethyl azidoacetate (2.81 g) in step 5 was added dropwise. After the addition was completed, the mixture was slowly warmed to room temperature and stirred for 2 hours until the reaction was completed. The reaction solution was heated with saturated NH 4 The product was quenched with Cl aqueous solution and extracted with ethyl acetate. The organic phases were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product intermediate 6 (1.1 g). LCMS (ES, m / z): 275.0 [M-55-28] + .

[0552] Step 7: The target product intermediate 6 (1.1 g) of step 6 was dissolved in xylene (10 mL), and the reaction solution was heated to 140°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target product intermediate 7 (0.83 g). LCMS (ES, m / z): 275.0 [M-55] + .

[0553] Step 8: At 0°C, NaH (501 mg) was added in batches to a DMF (8 mL) solution of the target product intermediate 7 (830 mg) of step 7. After the addition, the mixture was stirred at 0°C for 0.5 hours. TsCl (1433 mg) was slowly added dropwise to the above mixture. After the addition, the mixture was slowly warmed to room temperature and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was cooled to 0°C and saturated with NH 4The mixture was quenched with Cl aqueous solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target product intermediate 8 (930 mg). LCMS (ES, m / z): 429.0 [M-55] + .

[0554] Step 9: At room temperature, the target product intermediate 8 (930 mg) of step 8 was added to a mixed solution of trifluoroacetic acid and dichloromethane (12 mL, v / v = 3 / 1), and the reaction solution was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the target product intermediate 9 (1.05 g). LCMS (ES, m / z): 385.0 [M+H] + .

[0555] Step 10: At room temperature, add iodoethane (243.0 mg) to a solution of the target product intermediate 9 (300 mg) in acetonitrile (5 mL), add potassium carbonate (322.7 mg), heat the mixture to 70°C, and continue stirring for 16 hours until the reaction is complete. After the reaction is completed, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography to obtain the target product intermediate 10 (135 mg). LCMS (ES, m / z): 413.1 [M+H] + .

[0556] Step 11: Dissolve the target product intermediate 10 (135 mg) of step 10 in tetrahydrofuran (4 mL) and add acetonitrile (67.0 mg). After fully replacing the nitrogen, cool the mixture to -40°C and dropwise add a tetrahydrofuran solution of NaHMDS (0.4 mL, 1.0 M) to the mixture. After the addition is complete, slowly warm the reaction solution to room temperature and continue stirring for 0.5 hours until the reaction is complete. After the reaction is complete, cool the mixture to 0°C and add saturated NH 4 The mixture was quenched with Cl aqueous solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the target product intermediate 11 (104 mg). LCMS (ES, m / z): 422.0 [M+H] + .

[0557] Step 12: At room temperature, N,N-dimethylformamide dimethyl acetal (61.0 mg) was added dropwise to a tetrahydrofuran (5 mL) solution of the intermediate 11 (54.0 mg) obtained in step 11, and the mixture was stirred at room temperature for 0.5 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography to obtain the target product intermediate 12 (55 mg). LCMS (ES, m / z): 323 [M+H] + .

[0558] Step 13: At room temperature, the target product intermediate 12 (55.0 mg) of step 12 was dissolved in ethanol (5 mL), and intermediate A1 (40 mg) was added. The mixture was fully replaced with nitrogen and heated to 80°C, and stirred for 2 hours until the reaction was complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase preparative chromatography to obtain the target product compound 273 (13 mg). LCMS (ES, m / z): 529.2 [M+H] + .

[0559] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):8.23(d,J=7.8Hz,1H),8.09(s,1H),7.25–7.16(m,3H),7.12(s,1H),7.03(t,J=8.0Hz,3H) ,5.77(s,2H),3.42(s,2H),3.03(s,2H),2.25(s,3H),2.14(s,2H),1.75(s,2H),1.24–1.20(m,3H).

[0560] Embodiment 23

[0561]

[0562] Step 1: Add 3-(benzyloxy)cyclobutane-1-one (270 mg) and acetic acid (0.1 mL) to a solution of ethyl 2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-8-carboxylate (250 mg) in DCE (10 mL) at room temperature. Stir the mixture at room temperature for 30 minutes and then add NaBH(OAc) in portions. 3 (187 mg). The above mixture was stirred at room temperature for 3 hours until the reaction was complete. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the target product intermediate 1 (400 mg). LCMS (ES, m / z): 405.2 [M+H] + .

[0563] Step 2: At room temperature, the target product intermediate 1 (400 mg) of step 1 was dissolved in THF (10 mL) and CH 3 CN (51 mg) was cooled to -40 °C, and then a NaHMDS tetrahydrofuran solution (1.5 mL, 1.0 M) was added dropwise. The mixture was naturally heated to 0 °C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with salt, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product intermediate 2 (470 mg). LCMS (ES, m / z): 400.2 [M+H] + .

[0564] Step 3: At room temperature, add DMF-DMA (420 mg) to a THF (15 mL) solution of the target product intermediate 2 (470 mg) of step 2. The mixture was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target product intermediate 3 (150 mg). LCMS (ES, m / z): 455.2 [M+H] + .

[0565] Step 4: At room temperature, add 2-(2,6-difluorophenoxy)-5-hydrazinopyridine (66 mg) and triethylamine (44 mg) to the ethanol (10 mL) solution of the target product intermediate 3 (100 mg) of step 3. Heat the mixture to 80°C and continue stirring for 1 hour until the reaction is complete. After the reaction is completed, concentrate under reduced pressure, and the residue is purified by column chromatography to obtain the target product intermediate 4 (40 mg). LCMS (ES, m / z): 661.2

[0566] [M+H] + .

[0567] Step 5: At room temperature, add 10% Pd / C (20 mg) to a methanol (15 mL) solution of the target product intermediate 4 (40 mg) of step 4. The mixture was heated to 50°C under a hydrogen atmosphere and stirred for 16 hours until the reaction was complete. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain the target product compound 274 (5.3 mg). LCMS (ES, m / z): 571.0 [M+H] + .

[0568] 1HNMR(400MHz,MeOD)δ8.42(s,1H),8.08(s,1H),7.45-7.30(m,2H),7.29-7.26(m,2H),7.18-7.09(m,3H),4.93(d,J=15.6 Hz, 2H), 4.41 (d, J = 15.2Hz, 1H), 4.24-4.10 (m, 1H), 3.79 (s, 1H), 3.53-3.48 (m, 1H), 2.99-2.86 (m, 2H), 2.29-2.18 (m, 5H).

[0569] Embodiment 24

[0570]

[0571] Step 1: Add 3,3-difluorocyclobutane-1-one (195 mg) and acetic acid (0.1 mL) to a solution of ethyl 2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-8-carboxylate (300 mg) in DCE (10 mL) at room temperature. Stir the mixture at room temperature for 30 minutes and then add NaBH(OAc) in portions. 3 (224 mg). The above mixture was stirred at room temperature for 3 hours until the reaction was complete. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the target product intermediate 1 (400 mg). LCMS (ES, m / z): 335.2 [M+H] + .

[0572] Step 2: At room temperature, the target product intermediate 1 (450 mg) of step 1 was dissolved in THF (10 mL) and CH 3 CN (275 mg) was cooled to -40 °C, and then a NaHMDS tetrahydrofuran solution (1.7 mL, 1.0 M) was added dropwise. The mixture was naturally heated to 0 °C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with salt, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product intermediate 2 (550 mg). LCMS (ES, m / z): 330.1 [M+H] + .

[0573] Step 3: At room temperature, DMF-DMA (596 mg) was added to a THF (15 mL) solution of the target product intermediate 2 of step 2 and stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, the above mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target product intermediate 3 (360 mg). LCMS (ES, m / z): 385.2 [M+H]+ .

[0574] Step 4: Add 2-(2,6-difluorophenoxy)-5-hydrazinopyridine (94 mg) to a solution of the target product intermediate 3 (100 mg) in ethanol (10 mL) at room temperature. The mixture was heated to 80°C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product compound 275 (31 mg). LCMS (ES, m / z): 591.3 [M+H] + .

[0575] 1 H NMR (400 MHz, CDCl 3 )δ9.21(s,1H),8.25(s,1H),8.10(s,1H),7.26(s,1H),7.24-7.17(m,2H),7.14(s,1H),7.10(d, J=8.4Hz,1H),7.04(t,J=8.0Hz,2H),5.77(s,2H),3.87(s,2H),3.00-2.62(m,9H),2.27(s,3H).

[0576] Embodiment 25

[0577]

[0578] Step 1: Cool the tetrahydrofuran (20 mL) solution of 3-(benzyloxy)cyclobutane-1-one (1.0 g) to -78°C, drop methylmagnesium bromide (18.9 mL, 1.0 M), and continue stirring the mixture at -78°C for 3 hours until the reaction is complete. After the reaction is completed, pour the reaction solution into a saturated ammonium chloride solution. The mixture is extracted three times with ethyl acetate, and the organic phases are combined. The organic phase is washed with salt, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product is purified by column chromatography to obtain the target product intermediate 1 (880 mg). LCMS (ES, m / z): 193.1 [M+H] + .

[0579] Step 2: At room temperature, add 10% Pd / C (176 mg) to a methanol (10 mL) solution of the target product intermediate 1 (880 mg) of step 1. Stir the mixture at room temperature for 16 hours under a hydrogen atmosphere until the reaction is complete. After the reaction is completed, filter and concentrate the filtrate under reduced pressure to obtain the target product intermediate 2 (540 mg).

[0580] 1 H NMR (400 MHz, CDCl 3)δ3.98(p,J=6.8Hz,1H),2.53-2.42(m,2H),2.14-2.04(m,2H),1.31(s,3H).

[0581] Step 3: Add Dess-Martin (2.46 g) to a solution of the target product intermediate 2 (540 mg) in dichloromethane / tetrahydrofuran (28 mL, v / v=1 / 1) at room temperature. Stir the mixture at room temperature for 16 hours until the reaction is complete. After the reaction is completed, filter and concentrate the filtrate under reduced pressure. The residue is purified by column chromatography to obtain the target product intermediate 3 (310 mg).

[0582] 1 H NMR (400 MHz, CDCl 3 )δ3.29-3.13(m,1H),3.13-2.98(m,1H),1.66(s,1H).

[0583] Step 4: At room temperature, add the target product intermediate 3 (300 mg) and acetic acid (0.1 mL) of step 3 to a solution of ethyl 2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-8-carboxylate (245 mg) in DCE (20 mL). Stir the mixture at room temperature for 30 minutes and then add NaBH(OAc) in batches. 3 (224 mg). Stir at room temperature for 3 hours until the reaction is complete. After the reaction is completed, concentrate under reduced pressure. The resulting residue is purified by column chromatography to obtain the target product intermediate 4 (400 mg). LCMS (ES, m / z): 329.2 [M+H] + .

[0584] Step 5: Dissolve the intermediate 4 (400 mg) of step 4 in THF (10 mL) at room temperature and add CH 3 CN (249 mg) and the reaction solution was cooled to -40 ° C, and NaHMDS tetrahydrofuran solution (1.5 mL) was added dropwise. The above mixture was naturally heated to 0 ° C and continued to stir for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate and the organic phases were combined. The organic phase was washed with salt, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product intermediate 5 (500 mg). LCMS (ES, m / z): 324.2 [M+H] + .

[0585] Step 6: At room temperature, DMF-DMA (551 mg) was added to a THF (15 mL) solution of the target product intermediate 5 of step 5. The mixture was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target product intermediate 6 (230 mg). LCMS (ES, m / z): 379.2 [M+H] + .

[0586] Step 7: At room temperature, add 2-(2,6-difluorophenoxy)-5-hydrazinopyridine (79 mg) and triethylamine (53 mg) to a solution of the target product intermediate 6 (100 mg) in ethanol (5 mL) in step 6. The mixture was heated to 80°C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product compound 276 (49 mg). LCMS (ES, m / z): 585.2 [M+H] + .

[0587] 1 H NMR (400 MHz, DMSO-d 6 )δ11.89(s,1H),10.10(s,1H),8.51(s,1H),8.13(s,1H),7.58(s,1H),7 .46-7.26(m,5H),7.15(s,1H),7.13(s,2H),5.22(s,1H),4.79(d,J=15.2 Hz,1H),4.40(dd,J=15.6,8.0Hz,1H),4.04(dd,J=16.6,8.4Hz,1H),3.63 (s,1H),3.23-3.07(m,3H),2.39-2.26(m,4H),2.18(s,3H),1.32(s,3H).

[0588] Embodiment 26

[0589]

[0590] Step 1: Add DIEA (317 mg) and 2-methyloxirane (475 mg) to a solution of ethyl 2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-8-carboxylate (200 mg) in ethanol (5 mL) at room temperature. Stir the mixture at 85°C for 1 hour until the reaction is complete. After the reaction is completed, concentrate under reduced pressure. The residue is purified by column chromatography to obtain the target product intermediate 1 (188 mg). LCMS (ES, m / z): 303.1 [M+H] + .

[0591] Step 2: The target product intermediate 1 (188 mg) of step 1 was dissolved in THF (5 mL) at room temperature and CH 3 CN (128 mg) was cooled to -40 °C, and then NaHMDS solution (0.8 mL, 1.0 M) was added dropwise. The mixture was naturally heated to 0 °C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with salt, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product intermediate 2 (150 mg). LCMS (ES, m / z): 298.1 [M+H] + .

[0592] Step 3: At room temperature, add DMF-DMA (60 mg) to a THF (5 mL) solution of the target product intermediate 2 (150 mg) of step 2. The mixture was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target product intermediate 3 (120 mg). LCMS (ES, m / z): 353.2 [M+H] + .

[0593] Step 4: At room temperature, add 2-(2,6-difluorophenoxy)-5-hydrazinopyridine (128 mg) to a solution of the target product intermediate 3 (120 mg) in ethanol (5 mL) in step 3. The mixture was heated to 80°C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product compound 277 (16.5 mg). LCMS (ES, m / z): 560.3 [M+H] + .

[0594] 1 H NMR (400MHz, MeOD) δ (ppm): 8.38 (s, 1H), 8.09 (s, 1H), 7.44 (d, J = 8.4Hz, 1H), 7.38 (s, 1H), 7.33-7.26 (m, 2H), 7.16 -7.10(m,3H),4.65-4.59(m,2H),4.35(s,1H),3.56(s,2H),3.21-3.14(m,4H),2.26(s,3H),1.29(d,J=6.4Hz,3H).

[0595] Embodiment 27

[0596]

[0597] Step 1: Add 3-(benzyloxy)cyclobutane-1-one (390 mg) and acetic acid (0.05 mL) to a solution of ethyl 2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-8-carboxylate (150 mg) in DCE (5 mL) at room temperature. Stir the mixture at room temperature for 30 minutes and then add NaBH(OAc) in portions. 3 (390 mg). The above mixture was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the target product intermediate 1 (190 mg). LCMS (ES, m / z): 417.2 [M+H] + .

[0598] Step 2: The target product intermediate 1 (190 mg) of step 1 was dissolved in THF (5 mL) at room temperature and CH 3 CN (94 mg). The mixture was cooled to -40 °C and NaHMDS (0.6 mL) was added dropwise. The mixture was naturally heated to 0 °C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate and the organic phases were combined. The organic phase was washed with salt, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target product intermediate 2 (210 mg). LCMS (ES, m / z): 412.2 [M+H] + .

[0599] Step 3: At room temperature, DMF-DMA (60.8 mg) was added to a THF (5 mL) solution of the target product intermediate 2 (210 mg) of step 2, and the mixture was stirred at room temperature for 0.5 hours until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target product intermediate 3 (171 mg). LCMS (ES, m / z): 467.3 [M+H] + .

[0600] Step 4: Add 2-(2,6-difluorophenoxy)-5-hydrazinopyridine (101 mg) to a solution of the target product intermediate 3 (171 mg) in ethanol (5 mL) at room temperature. Heat the mixture to 80°C and continue stirring for 1 hour until the reaction is complete. After the reaction is completed, concentrate under reduced pressure, and the residue is purified by column chromatography to obtain the target product compound 278 (30.9 mg). LCMS (ES, m / z): 559.2 [M+H] + .

[0601] 1 H NMR (400 MHz, CDCl 3)δ(ppm):9.50(s,1H),8.29(s,1H),8.12(s,1H),7.44(d,J=8.8Hz,1H),7.29(s,1H),7.22-7.15(m, 3H),7.06-7.00(m,2H),3.95(s,2H),3.44(s,4H),3.16(s,4H),2.27(s,3H),2.19(d,J=16.4Hz,2H).

[0602] Embodiment 28

[0603]

[0604] Step 1: Add (methylsulfonyl)ethylene (86.9 mg) and triethylamine (166 mg) to a solution of ethyl 2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-8-carboxylate (200 mg) in DCM (5 mL) at room temperature. The mixture was stirred at room temperature for 6 hours until the reaction was complete. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by column chromatography to obtain the target product intermediate 1 (337 mg). LCMS (ES, m / z): 351.1 [M+H] + .

[0605] Step 2: At room temperature, the target product intermediate 1 (270 mg) of step 1 was dissolved in THF (5 mL) and CH 3 CN (158 mg). The mixture was cooled to -40 °C, and then NaHMDS (1.0 mL, 1.0 M) was added dropwise. The mixture was naturally heated to 0 °C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with salt, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product intermediate 2 (215 mg). LCMS (ES, m / z): 346.1 [M+H] + .

[0606] Step 3: Add DMF-DMA (74 mg) to a THF (5 mL) solution of the target product intermediate 2 (215 mg) of step 2 at room temperature. The above mixture was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target product intermediate 3 (101 mg). LCMS (ES, m / z): 401.1 [M+H] + .

[0607] Step 4: Add 2-(2,6-difluorophenoxy)-5-hydrazinopyridine (109 mg) to a solution of the target product intermediate 3 (101 mg) in ethanol (5 mL) at room temperature. The mixture was heated to 80°C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product compound 279 (28.8 mg). LCMS (ES, m / z): 607.1 [M+H] + .

[0608] 1 H NMR (400MHz, MeOD) δ (ppm): 8.40 (s, 1H), 8.10 (s, 1H), 7.36-7.26 (m, 4H), 7.15-7.05 (m, 3H), 4.06 (s, 2H) ), 3.54 (t, J = 7.2Hz, 2H), 3.17 (t, J = 7.2Hz, 2H), 3.09 (s, 3H), 2.98 (dd, J = 16.4, 4.8Hz, 4H), 2.26 (s, 3H).

[0609] Embodiment 29

[0611]

[0612] Step 1: Add 1-((tert-butyldimethylsilyl)oxy)propan-2-one (213 mg) and acetic acid (0.05 mL) to a solution of ethyl 2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-8-carboxylate (230 mg) in DCE (5 mL) at room temperature. Stir the mixture at room temperature for 30 minutes and then add NaBH(OAc) in portions. 3 (599 mg). The mixture was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the target product intermediate 1 (150 mg). LCMS (ES, m / z): 417.2 [M+H] + .

[0613] Step 2: Dissolve the intermediate 1 (150 mg) of step 1 in THF (5 mL) at room temperature and add CH 3CN (74 mg). The mixture was cooled to -40 °C and a NaHMDS tetrahydrofuran solution (0.5 mL, 1.0 M) was added dropwise. The mixture was naturally heated to 0 °C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate and the organic phases were combined. The organic phase was washed with salt, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product intermediate 2 (125 mg). LCMS (ES, m / z): 412.2 [M+H] + .

[0614] Step 3: Add DMF-DMA (36 mg) to a THF (5 mL) solution of the target product intermediate 2 (125 mg) of step 2 at room temperature. The mixture was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target product intermediate 3 (117 mg). LCMS (ES, m / z): 467.3 [M+H] + .

[0615] Step 4: Add 2-(2,6-difluorophenoxy)-5-hydrazinopyridine (94.5 mg) to a solution of the intermediate 3 (117 mg) of the target product of step 3 in ethanol (5 mL) at room temperature. The mixture was heated to 80°C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product compound 280 (6.4 mg). LCMS (ES, m / z): 559.1 [M+H] + .

[0616] 1 H NMR (400 MHz, CDCl 3 )δ(ppm):9.43(s,1H),8.23(s,1H),8.11(s,2H),7.35(d,J=8.4Hz,1H),7 .23-7.18(m,1H),7.14-7.09(m,3H),7.04(t,J=8.0Hz,2H),5.79(s,2H),4 .50(dd,J=16.0,15.6Hz,2H),4.00(d,J=12.4Hz,1H),3.83-3.77(m,1H),3 .60(s,1H),3.46(s,1H),3.27(s,2H),2.27(s,3H),1.35(d,J=6.8Hz,3H).

[0617] Embodiment 30

[0618]

[0619] Step 1: At room temperature, add 3,6-dioxabicyclo[3.1.0]hexane (141 mg) and triethylamine (166 mg) to a solution of ethyl 2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-8-carboxylate (200 mg) in ethanol (3 mL). The mixture was heated to 90°C and stirred for 7 hours. 3,6-dioxabicyclo[3.1.0]hexane (71 mg) and triethylamine (83 mg) were added to the mixture and stirred for 17 hours until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to obtain the target product intermediate 1 (210 mg). LCMS (ES, m / z): 331.1 [M+H] + .

[0620] Step 2: The target product intermediate 1 (210 mg) of step 1 was dissolved in THF (3 mL) at room temperature and CH 3 CN (130 mg) was cooled to -40 °C and a NaHMDS tetrahydrofuran solution (1.3 mL, 1.0 M) was added dropwise. The mixture was naturally heated to 0 °C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate and the organic phases were combined. The organic phase was washed with salt, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product intermediate 2 (440 mg). LCMS (ES, m / z): 326.1 [M+H] + .

[0621] Step 3: Add DMF-DMA (483 mg) to a THF (5 mL) solution of the target product intermediate 2 (440 mg) of step 2 at room temperature. The mixture was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target product intermediate 3 (70 mg). LCMS (ES, m / z): 381.2 [M+H] + .

[0622] Step 4: Add 2-(2,6-difluorophenoxy)-5-hydrazinopyridine (48 mg) to a solution of the target product intermediate 3 (60 mg) in ethanol (3 mL) at room temperature. The mixture was heated to 80°C and stirred for 16 hours until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product compound 281 (4.9 mg). LCMS (ES, m / z): 587.2 [M+H] + .

[0623] 1H NMR(400MHz,MeOD)δ8.40(s,1H),8.08(s,1H),7.49(d,J=8.4Hz,1H),7.44(s, 1H),7.30(ddd,J=8.4,7.2,4.0Hz,1H),7.26(d,J=4.0Hz,1H),7.18(d,J=8.8Hz ,1H),7.15-7.07(m,2H),4.81-4.73(m,2H),4.36-4.19(m,3H),3.93(dd,J=9. 2, 6.0Hz, 1H), 3.67 (dd, J = 9.6, 5.2Hz, 2H), 3.31 (d, J = 1.6Hz, 4H), 2.25 (s, 3H).

[0624] Embodiment 31

[0625]

[0626] Step 1: At room temperature, add 2-bromo-2-methylpropanol (231 mg) and potassium carbonate (282 mg) to a solution of 1H, 3H, 4H, 7H pyrrolo[2,3-h]isoquinoline-8-carboxylic acid ethyl ester (250 mg) in acetonitrile (15 mL). The mixture was heated to 80°C under a nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain the target product intermediate 1 (200 mg). LCMS (ES, m / z): 333.2 [M+H] + .

[0627] Step 2: Dissolve the target product intermediate 1 (200 mg) of step 1 in methanol (5 mL) at room temperature and add NaBH 4 (48 mg). The above mixture was stirred at room temperature for 3 hours until the reaction was complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target product intermediate 2 (80 mg). LCMS (ES, m / z): 317.0 [M+H] + .

[0628] Step 3: At room temperature, the target product intermediate 2 (80 mg) of step 2 was dissolved in THF (5 mL) and CH 3CN (51 mg) was cooled to -40 °C and a NaHMDS tetrahydrofuran solution (0.3 mL, 1.0 M) was added dropwise. The mixture was naturally heated to 0 °C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate and the organic phases were combined. The organic phase was washed with salt, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product intermediate 3 (90 mg). LCMS (ES, m / z): 312.2 [M+H] + .

[0629] Step 4: At room temperature, DMF-DMA (103 mg) was added to a THF (5 mL) solution of the target product intermediate 3 (90 mg) of step 3 and stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, the above mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target product intermediate 4 (42 mg). LCMS (ES, m / z): 367.2 [M+H] + .

[0630] Step 5: At room temperature, add 2-(2,6-difluorophenoxy)-5-hydrazinopyridine (32 mg) and triethylamine (22 mg) to a solution of the target product intermediate 4 (40 mg) in ethanol (15 mL) in step 4. The mixture was heated to 80°C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product compound 282 (2 mg). LCMS (ES, m / z): 573.2 [M+H] + .

[0631] 1 H NMR(400MHz,MeOD)δ8.43(s,1H),8.07(s,1H),7.47(s,1H),7.44(d,J=8.4Hz,1H),7.35-7.25(m,1H ),7.23(s,1H),7.16-7.05(m,3H),4.78(s,4H),4.54(s,2H),3.84(s,2H),2.23(s,3H),1.52(s,6H).

[0632] Embodiment 32

[0633]

[0634] Step 1: Add 2,6-dimethylpyridine (914 mg) to a solution of 3-hydroxy-2,2-dimethylpropionitrile (470 mg) in DCM (5 mL) at room temperature. The mixture was cooled to -78°C and trifluoromethanesulfonic anhydride (2 g) was slowly added dropwise under a nitrogen atmosphere. The mixture was slowly heated to 0°C and stirred for 1 hour until the reaction was complete. KHSO 4 Solution (w = 5%), and the pH value of the mixture was adjusted to 6-7. The mixture was extracted three times with dichloromethane, and the organic phases were combined. The organic phase was washed with salt, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product intermediate 1 (750 mg).

[0635] Step 2: At room temperature, add DIEA (840 mg) to a solution of ethyl 2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-8-carboxylate (951 mg) in acetonitrile (3 mL). The mixture was heated to 60°C and stirred for 10 minutes, and the target product intermediate 1 (750 mg) of step 1 was added. The mixture was stirred for 1 hour under a nitrogen atmosphere until the reaction was complete. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by column chromatography to obtain the target product intermediate 2 (530 mg). LCMS (ES, m / z): 326.1 [M+H] + .

[0636] Step 3: At room temperature, the target product intermediate 2 (250 mg) of step 2 was dissolved in THF (5 mL) and CH 3 CN (158 mg) was cooled to -40 °C and a NaHMDS tetrahydrofuran solution (0.8 mL, 1.0 M) was added dropwise. The mixture was naturally heated to 0 °C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate and the organic phases were combined. The organic phase was washed with salt, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product intermediate 3 (290 mg). LCMS (ES, m / z): 321.2 [M+H] + .

[0637] Step 4: Add DMF-DMA (324 mg) to a THF (5 mL) solution of the target product intermediate 3 (290 mg) of step 3 at room temperature. The mixture was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target product intermediate 4 (100 mg). LCMS (ES, m / z): 376.2 [M+H] + .

[0638] Step 5: Add 2-(2,6-difluorophenoxy)-5-hydrazinopyridine (100 mg) to a solution of the target product intermediate 4 (100 mg) in ethanol (3 mL) at room temperature. The mixture was heated to 80°C and stirred for 16 hours until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product compound 283 (4.9 mg). LCMS (ES, m / z): 582.3 [M+H] + .

[0639] 1 H NMR (400MHz, MeOD) δ8.30(d,J=0.4Hz,1H),8.06(s,1H),7.41(s,1H),7.28(d,J=2.0Hz,2H),7.23(s,1H),7.11(dt,J=16. 4,8.0Hz,3H),4.68(s,2H),3.73-3.47(m,2H),3.45-3.31(m,1H),3.24(dd,J=13.6,3.2Hz,3H),2.23(s,3H),1.54(s,6H).

[0640] Test Example 1

[0641] Yes1 enzyme inhibitory activity

[0642] 1.1 Compound preparation

[0643] mixture Solvents concentration Test compound Dimethyl sulfoxide (DMSO) 20mmol / L

[0644] 1) Prepare 2× ATP / substrate solution and 2× kinase solution using kinase reaction buffer.

[0645] 2) Use Echo 655 to transfer 50 nL of compound dilution to the 384 assay plate; after centrifugation, add 2.5 μL of 2× kinase solution to the 384 assay plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 10 min;

[0646] 3) Add 2.5 μL of 2× substrate and ATP solution to the 384 assay plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 30 min.

[0647] 4) Prepare 2×XL 665 and antibody detection reagent with detection buffer.

[0648] 5) Add 5 μL of kinase detection reagent to the test plate and incubate at 25°C. Centrifuge at 1000 rpm for 1 min and incubate at 25°C for 1 hour.

[0649] 6) Use BMG high-throughput drug screening multifunctional microplate reader to read the fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665).

[0650] 1.2 Data Analysis

[0651] The reading of the negative control (1% DMSO well) was set as 0% inhibition rate, and the reading of the positive control (the well with the highest concentration of the control compound) was set as 100% inhibition rate. After calculating the inhibition rate, the IC values ​​of the control compound and the test compound were obtained using the nonlinear fitting formula of the software. 50 value (half-maximal inhibitory concentration);

[0652]

[0653] The average of the values ​​of the positive control wells; The values ​​of negative control wells are averaged.

[0654] Graphpad 7.0 software was used for data analysis, and the IC of the compound was obtained using the following nonlinear fitting formula: 50 (half inhibitory concentration)

[0655] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0656] X: log value of compound concentration; Y: compound inhibition rate (% inh); Z' factor calculation equation: Z' = 1-

[0657] 3(SD min +SD max ) / (AVE max -AVE min )

[0658] Where: Min is the positive control Data value, Max is the negative control DMSO Data value, SD is the standard error, and AVE is the average value. The test results are shown in Table 3 (where the positive control is compound SU6656, CAS: 330161-87-0; the negative control is DMSO).

[0659] Table 3. IC values ​​of some compounds for inhibiting Yes1 enzyme activity 50 value

[0660] Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> 1 0.48 127 0.49 8 0.35 129 0.10 9 0.12 189 3.52 11 0.62 190 0.16 13 0.18 191 0.32 14 0.35 192 0.20 17 0.18 193 3.83 56 0.28 194 1.58 57 0.075 195 1.29 80 0.054 198 0.38 88 3.10 201 0.084 89 2.91 217 18.2 90 7.79 271 4.42 115 0.20 272 12.07 116 0.13 273 0.61 117 0.72 276 1.77

[0661] The reagent information used in the experiment is shown in Table 4:

[0662] Table 4. Information on reagents used in the experiment

[0663] Material supplier Product Number Yes1 Carna 08-175 HTRFKinEASE-TKkit PerkinElmer 62TK0PEJ SU6656 MCE HY-B0789 ATP Promega V915B DTT MCE HY-15917 MgCl2 Sigma M1028 DMSO Sigma D4540

[0664] Test Example 2: Pharmacokinetic study in rats

[0665] 1.1 Instruments: High performance liquid chromatograph: SHIMADZU LC-30AD, mass spectrometer: AB SCIEX mass spectrometer TripleQuad 5500, all measured data were calculated and processed using Microsoft Excel, and WinNonlin software was used to calculate relevant pharmacokinetic parameters. The main kinetic parameters T max ,T 1 / 2 ,C max ,AUC 0-24h and AUC inf . Chromatographic column: XSelectHss T32.5μm (2.1x50 mm) Column XP, column temperature 40℃, mobile phase A is water (0.1% formic acid), mobile phase B is acetonitrile, flow rate is 0.60 ml / min, gradient elution is adopted, the elution gradient is 0.30min: 5% B; 1.00min: 98% B; 1.48min: 98% B; 1.51min: 5% B; 2.00min: stop. Injection volume: 1μL.

[0666] 1.2 Animals: Three SD male rats, weighing 180g-300g, were purchased and raised in the experimental animal center for two days before use. They were fasted for 12 hours before administration and 4 hours after administration, and had free access to water during the experiment. Blood samples were taken at the designated time points after oral gavage.

[0667] 1.3 Solvent: 0.5% HPMC + 0.4% Tween 80. Preparation of intragastric administration solution: accurately weigh the compound, add the solvent, and perform ultrasound at room temperature for 5 minutes to completely dissolve the drug, and prepare a 0.5 mg / ml solution.

[0668] Blood was collected at 0.083h, 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 7.0h and 24h after intragastric administration. Blood collection method: 0.2mL of blood was collected from the jugular vein. Anticoagulant: EDTA-K 2 The collected blood samples were transferred to microcentrifuge tubes containing anticoagulants and centrifuged at 4°C, 4000 g for 5 min to separate the plasma. All collected plasma samples were stored at -75 ± 15°C until analysis.

[0669] The compounds were accurately weighed to prepare standard curve working solutions and quality control working solutions of different concentrations, blank plasma was added, plasma standard curves and quality control samples were prepared, and LC-MS / MS analysis was performed after pretreatment by protein precipitation, and then the concentration of the above plasma compounds was tested. All the measurement data were collected and processed by relevant software, and Winnonlin software was used to calculate pharmacokinetic parameters. The kinetic parameters of some representative compounds are shown in Table 5.

[0670] Table 5. Pharmacokinetic parameters of some of the compounds in the examples in rats

[0671]

[0672] According to the data in Table 5, the fused heterocyclic compounds of the present invention are rapidly absorbed in the gastrointestinal tract and have good oral bioavailability.

[0673] The present invention also provides a pharmaceutical composition, which comprises as an active ingredient a compound of formula I or a compound of formula II, or any one of the enantiomers, diastereomers, pharmaceutically acceptable salts, and solvent compounds of the compound of formula I or the compound of formula II. The pharmaceutical composition of the present invention can be used to prepare a drug for treating diseases related to Yes1 amplification or overexpression.

[0674] The pharmaceutical composition disclosed in the present invention may contain one or more auxiliary materials in addition to the above-mentioned compound active substances, and the auxiliary materials include fillers, excipients, disintegrants, binders and wetting agents.

[0675] Depending on the administration method, the composition of the present invention may contain 10% to 90% by weight of the compound of formula I or the compound of formula II as an active ingredient.

[0676] The pharmaceutical composition of the present invention is in the form of an oral preparation or an injection, wherein the oral preparation may be a capsule, a tablet, etc., and the injection may be an intravenous injection, an intramuscular injection, or a subcutaneous injection, etc., and the present invention is not limited thereto.

[0677] Diseases that the pharmaceutical composition of the present invention can be used to treat include cancer, which includes at least one of esophageal cancer, small cell lung cancer, blood tumors, digestive system tumors, reproductive system tumors, nervous system tumors and head and neck cancer.

[0678] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention. Although the present invention is disclosed as above with preferred embodiments, it is not intended to limit the claims. Any person skilled in the art may make several possible changes and modifications without departing from the concept of the present invention. Therefore, the scope of protection of the present invention shall be based on the scope defined by the claims of the present invention.

Claims

1. A compound, characterized in that The compound includes a compound represented by Formula I or Formula II: In formula (I) and formula (II): Ar1 is selected from C 6-10 aryl, 5-10 membered heteroaryl, 6-membered aryl and 5-20 membered heterocyclic ring, 6-membered aryl and 5-10 membered heteroaryl ring, 5-10 membered heteroaryl and C 3-10 Cycloalkyl groups together form a ring, C 6-10 A cyclic ring composed of an aryl group and a 5-10-membered heteroaryl group; Ar2 is selected from C 6-10 aryl, 5-10 membered heteroaryl, 6-membered aryl and 5-20 membered heterocyclic ring, 6-membered aryl and 5-10 membered heteroaryl ring, 5-10 membered heteroaryl and C 3-10 Cycloalkyl groups together form a ring, C 6-10 A cyclic ring composed of an aryl group and a 5-10-membered heteroaryl group; The Ar1 is unsubstituted or substituted by one, two or more of the following groups: halogen, cyano, hydroxyl, amino, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 1-10 Alkylthio, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, C 3-10 Cycloalkyl, 3-20 membered heterocyclic group; The Ar2 is unsubstituted or substituted by one, two or more of the following groups: halogen, cyano, hydroxyl, amino, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 1-10 Alkylthio, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, C 3-10 Cycloalkyl, 3-20 membered heterocyclic group; M1 and M2 are the same or different and are each independently selected from CH or N; X1 and X2 are the same or different and are each independently selected from the group consisting of: a )、O、S(O) t 、C(O)、C(O)N(R a )、S(O) t N(R a ) or CR b R c ; Y is selected from the group consisting of not present, N(R a )、O、S(O) t , CR b R c 、C(O)N(R a ) or S(O) t N(R a ); R a Selected from hydrogen, deuterium, C(O)C 1-10 Alkyl, -C(O)NR6R7, -C 1-10 Alkyl C(O)NR6R7, C(O)3-20 membered heterocyclic group, S(O)2C 1-10 Alkyl, S(O)23-20 membered heterocyclic group, C 1-10 Deuterated alkyl, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 3-20 membered heterocyclyl, -3-20 membered heterocyclyl-C 1-10 Alkyl or -C 1-10 Alkyl-3-20 membered heterocyclic group; wherein R a C in the group represented 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-20 membered heterocyclyl, -3-20 membered heterocyclyl-C 1-10 Alkyl or -C 1-10 The alkyl-3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-10 Alkyl, -C 1-10 Alkyl-OH, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Halogenated alkoxy, C 3-10 Cycloalkyl, -S(O)2C 1-10 Alkyl, C(O)C 1-10 Alkyl, -C(O)NR6R7, 3-20 membered heterocyclyl and NR6R7; R b and R c are the same or different and are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C(O)C 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 3-10 Cycloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NHC 1-10 Alkyl, -N(C 1-10 alkyl) 2 or 3-20 membered heterocyclic group; wherein R b and / or R c C in the group represented 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, -NHC 1-10 Alkyl, -N(C 1-10 The 2- or 3-20-membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxy, cyano, nitro, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-20 membered heterocyclyl and NR6R7; R f is selected from the group consisting of absent, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C(O)C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Alkyl, C 1-10 Alkylthio, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, C 3-10 Cycloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or 3-20 membered heterocyclic group; wherein R f C in the group represented 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 The cycloalkyl or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy, C 3-10 Cycloalkyl, C 3-4 Heterocyclic group, C 5-10 Heterocyclyl and NR6R7; R1, R2, R3 and R4 are the same or different and are independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, C 1-10 Deuterated alkyl, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 6-10 Aryl, P(O)R6R7, S(O)2R6, S(O)2NR6R7, NR6R7, C(O)NR6R7, C(O)NR6, S(O)2R7, NR6S(O)2R7, C(O)R6, NR6C(O)R7, 5-10 membered heteroaryl, 5-20 membered heterocyclic group; wherein C 1-10 Deuterated alkyl, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 6-10 At least one of the aryl, 5-10 membered heteroaryl and 5-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Haloalkoxy, NR6R7, C(=O)NR6R7, C(=O)NR6S(=O)2R7, P(=O)R6R7, S(=O)2R6, S(O)2 or NR6S(=O)2R7; R5 is selected from hydrogen, C 1-10 Alkyl or cyano; R6 and R7 are the same or different and are independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 3-10 Cycloalkyl, 3-20 membered heterocyclic group; wherein R6 and / or R7 represent C 1-10 Alkyl, C 3-10 The cycloalkyl and 3-20 membered heterocyclic groups may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, 3-20 membered heterocyclic group; wherein R6 and R7 can form a 3-20 membered heterocyclic group through a nitrogen atom or a phosphorus atom, and the 3-20 membered heterocyclic group can be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Deuterated alkoxy, C 1-10 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-20 membered heterocyclic group; m is 0, 1, 2 or 3, n is 0, 1, 2 or 3, and m+n≤4; t is 0, 1, or 2, and S(O) t NR a Where t is 1 or 2.

2. The compound according to claim 1, characterized in that X1, X2, and Y are the same or different and are independently selected from the group consisting of: a )、O、S、S(O) t 、C(O)、C(O)N(R a )、S(O) t N(R a ) or CR b R c ; m is 0, 1, 2 or 3, n is 0, 1, 2 or 3; t is 1 or 2; R in the definitions of X1, X2, and Y a , each of which is the same or different and is independently selected from hydrogen, or an optionally substituted group: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-20 membered heterocyclic group, -S(O)2C 1-10 Alkyl, -C(O)C 1-10 Alkyl, -C(O)-(3-20 membered heterocyclic group), -C(O)NR 21 R 22 , -C 1-10 Alkyl C(O)NR 21 R 22 、-(CH2) p -(3-20 membered heterocyclyl) or -3-20 membered heterocyclyl-C 1-10 Alkyl; the optionally substituted means being monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, C 1-10 Alkyl, hydroxyl C 1-10 Alkyl-, C 1-10 Alkoxy, C 1-10 Alkylthio, -NR 21 R 22 , C 3-10 Cycloalkyl, 3-20 membered heterocyclic group, -C(O)C 1-10 Alkyl, -S(O)2C 1-10 Alkyl, -C(O)NR 21 R 22 ; Among them, R 21 , R 22 are the same or different and are independently selected from H, C 1-10 Alkyl; p is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R b and R c are the same or different and are independently selected from H, halogen, cyano, hydroxyl, amino, or the following groups which are optionally substituted: C 1-10 Alkyl, C 1-10 Alkoxy, -NHC 1-10 Alkyl, -N(C 1-10 alkyl)2; the optionally substituted means being monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, amino, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkyl, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2; R1, R2, R3 and R4 are the same or different and are independently selected from H, halogen, cyano, hydroxyl, amino, or the following groups which are optionally substituted: C 1-10 Alkyl, C 1-10 Alkoxy, -NHC 1-10 Alkyl, -N(C 1-10 alkyl)2; the optionally substituted means being monosubstituted or polysubstituted by a substituent selected from the following: halogen, cyano, hydroxyl, amino, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkyl, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2; M1 and M2 are the same or different and are independently selected from CH or N; R f is selected from the group consisting of absent, halogen, cyano, hydroxyl, amino, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, C 3-10 Cycloalkyl, 3-20 membered heterocyclic group; R5 is selected from hydrogen, C 1-10 alkyl; Ar1 and Ar2 are the same or different and are independently selected from a 5-10 membered heteroaryl group having 1 or 2 heteroatoms selected from N or O, or C 6-10 Aryl, the heteroaryl or aryl is optionally monosubstituted or polysubstituted by a group selected from the following: halogen, cyano, hydroxyl, amino, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkylthio, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group.

3. A compound, characterized in that The compound includes a compound represented by Formula I or Formula II: In Formula I or Formula II: Ar1 is selected from C 6-10 Aromatic ring, C with 1 to 3 R8 heteroatoms 5-10 Aromatic heterocyclic ring, 6-membered aromatic ring and C with 1 to 3 R8 heteroatoms 5-7 The heterocyclic ring, the 6-membered aromatic ring and the C having 1 to 3 R8 heteroatoms 5-7 A 6-membered aromatic heterocyclic ring having 1 to 3 R8 heteroatoms and a C 5-7 A 6-membered aromatic heterocyclic ring with 1 to 3 R8 heteroatoms and a C 5-7 A ring composed of aromatic heterocyclic rings, wherein R8 is selected from N, S or O; Ar2 is selected from C 6-10 Aromatic ring, C with 1 to 3 R8 heteroatoms 5-10 Aromatic heterocyclic ring, 6-membered aromatic ring and C with 1 to 3 R8 heteroatoms 5-7 The heterocyclic ring, the 6-membered aromatic ring and the C having 1 to 3 R8 heteroatoms 5-7 A 6-membered aromatic heterocyclic ring having 1 to 3 R8 heteroatoms and a C 5-7 A 6-membered aromatic heterocyclic ring with 1 to 3 R8 heteroatoms and a C 5-7 A fused ring composed of aromatic heterocyclic rings; M1 and M2 are each independently selected from CH or N; X1 and X2 are each independently selected from none, NR a , O, S(O) t 、C(O)、C(O)NR a 、S(O) t NR a or CR b R c ; Y is selected from NR a , O, S(O) t , CR b R c 、C(O)NR a or S(O) t NR a ; R a Selected from hydrogen, deuterium, C(O)C 1-6 Alkyl, C(O)C 3–8 Heterocyclic group, S(O)2C 1-6 Alkyl, S(O)2C 3–8 Heterocyclic group, C 1-6 Deuterated alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C with 1 to 3 R8 heteroatoms 3-12 A heterocyclic group, wherein R a The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclic group in the represented group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 4-10 Heterocyclyl and NR6R7; R b and R c Each independently selected from: hydrogen, deuterium, halogen, C(O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C with 1 to 3 R8 heteroatoms 3-12 Heterocyclic group, wherein R b and / or R c The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclic group in the represented group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 5-10 Heterocyclyl and NR6R7; R f Selected from hydrogen, deuterium, C(O)C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C with 1 to 3 R8 heteroatoms 3-12 A heterocyclic group, wherein R f The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclic group in the represented group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 5-10 Heterocyclyl and NR6R7; R1, R2, R3 and R4 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, C 1-6 Deuterated alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 6-10 Aryl, P(O)R6R7, S(O)2R6, S(=O)2NR6R7, NR6R7, C(=O)NR6R7, C(O)NR6, S(O)2R7, NR6S(O)2R7, C(=O)R6, NR6C(=O)R7, C(=O)R6 with 1 to 3 R8 heteroatoms 5-12 Heteroaryl or C having 1 to 3 R8 heteroatoms 3-12 Heterocyclic group, wherein C 1-6 Deuterated alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 6-10 Aryl, C with 1 to 3 R8 heteroatoms 5-12 Heteroaryl and C having 1 to 3 R8 heteroatoms 3-12 At least one of the heterocyclic groups may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR6R7, C(=O)NR6R7, C(=O)NR6S(=O)2R7, P(=O)R6R7, S(=O)2R6, S(O)2, NR6R7 and NR6S(=O)2R7; R5 is selected from hydrogen, methyl, ethyl or cyano; R6 and R7 are each independently selected from hydrogen, deuterium or C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, C with 1 to 3 R8 heteroatoms 3-12 Heterocyclic group, wherein the alkyl, cycloalkyl, heterocyclic group represented by R6 and / or R7 may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-12 Heterocyclic group; wherein R6 and R7 can form a C 3-12 Heterocyclic group, the C 3-12 The heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl and C 3-12 Heterocyclic group; m is 0, 1, 2 or 3, n is 0, 1, 2 or 3, and m+n≤4; t is 0, 1, or 2.

4. The compound according to any one of claims 1 to 3, characterized in that The compound of formula I or formula II is selected from any one of the following compounds: In formula (a): R a Selected from hydrogen, C 1-6 Alkyl, S(O)2C 1-6 Alkyl or 3-20 membered heterocyclic group, wherein R a C in the group represented 1-6 Alkyl, S(O)2C 1-6 The alkyl or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, C 1-6 alkyl, 3-20 membered heterocyclic group or NR6R7, R6R7 are each independently selected from C 1-6 alkyl; X2 is selected from O, NR a or CR b R c , R b and R c is selected from hydrogen or a 3-20 membered heterocyclic group; Y is selected from CR b R c , R b and R c Selected from hydrogen; R3 and R4 are selected from hydrogen, n is 1; M1 is selected from CH; R f Selected from H; In formula (b): R a Selected from hydrogen, C 1-6 Alkyl, S(O)2C 1-6 Alkyl, C(O)C 1-6 Alkyl, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 alkyl) 2 or 3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 Alkyl, S(O)2C 1-6 Alkyl, C(O)C 1-6 Alkyl, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 The 2- or 3-20-membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, C 1-6 Alkyl, 3-20 membered heterocyclic group; X1 and X2 are each independently selected from CR b R c , R b and R c Each independently selected from: hydrogen or C 1-6 Alkyl; wherein R b and / or R c C in the group represented 1-6 The alkyl group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, cyano and NR6R7, R6R7 are independently selected from H or C 1-6 alkyl; R3 and R4 are each independently selected from hydrogen or C 1-6 Alkyl, where C 1-6 The alkyl group may be substituted by 1 to 3 substituents selected from the group consisting of: hydroxyl; n is 1; M1 is selected from CH; R f Selected from H; In formula (c): R a Selected from hydrogen, C 1-6 Alkyl, S(O)2C 1-6 Alkyl, S(O)23-20 membered heterocyclic group, C(O)C 1-6 Alkyl, C(O)NR6R7, C(O)NHC 1-6 alkyl, C(O)3-20 membered heterocyclic group, 3-20 membered heterocyclic group, -C 1-6 Alkyl-3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 Alkyl, S(O)2C 1-6 Alkyl, S(O)23-20 membered heterocyclic group, C(O)C 1-6 Alkyl, C(O)NR6R7, C(O)NHC 1-6 alkyl, C(O)3-20 membered heterocyclic group, 3-20 membered heterocyclic group, -C 1-6 The alkyl-3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3-20 membered heterocyclic group, C(O)C 1-6 Alkyl, S(O)2C 1-6 Alkyl, NR6R7, R6R7 are each independently selected from H or C 1-6 alkyl; R1 and R2 are the same or different and are independently selected from hydrogen or C 1-6 Alkyl; among which, C 1-6 The alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of: hydroxyl, where m is 1; X1 and X2 are the same or different and are independently selected from CR b R c , R b and R c Each independently selected from: hydrogen or C 1-6 Alkyl; wherein R b and / or R c C in the group represented 1-6 The alkyl group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl group; M1 is selected from CH; R f Selected from H; In formula (d): M1 is selected from CH; R f Selected from H; R a Selected from hydrogen, C 1-6 Alkyl, C(O)C 1-6 Alkyl, S(O)2C 1-6 Alkyl or 3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 Alkyl, C(O)C 1-6 Alkyl, S(O)2C 1-6 The alkyl or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: 1-6 Alkyl, hydroxyl; X1 selected from NR a , O or CR b R c , where R b and R c Selected from hydrogen; R1 and R2 are selected from hydrogen, m is 1; Y is selected from CR b R c , R b and R c Selected from hydrogen; In formula (e): R a Selected from C 1-6 Alkyl or 3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 The alkyl or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, C 1-6 alkyl; X1 and X2 are the same or different and are independently selected from CR b R c , R b and R c Each independently selected from: hydrogen or C 1-6 Alkyl; wherein R b and / or R c C in the group represented 1-6 The alkyl group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl group; R3 and R4 are selected from hydrogen, n=1; In formula (f): R a Selected from C 1-6 Alkyl or 3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 The alkyl or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, C 1-6 alkyl; R1 and R2 are each independently selected from hydrogen or C 1-6 Alkyl; among which, C 1-6 The alkyl group may be substituted by 1 to 3 substituents selected from the group consisting of: hydroxyl, m = 1; X1 and X2 are each independently selected from CR b R c , R b and R c Each independently selected from: hydrogen or C 1-6 Alkyl; wherein R b and / or R c The alkyl group in the represented group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl group; In formula (g): R a Selected from hydrogen, C 1-6 Alkyl, S(O)2C 1-6 Alkyl, C(O)C 1-6 Alkyl, -C 1-6 alkyl-3-20 membered heterocyclic group, -3-20 membered heterocyclic group-C 1-6 Alkyl, or 3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 Alkyl, S(O)2C 1-6 Alkyl, C(O)C 1-6 Alkyl, -C 1-6 alkyl-3-20 membered heterocyclic group, -3-20 membered heterocyclic group-C 1-6 The alkyl group or the 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: 1-6 Alkyl, hydroxyl, 3-20 membered heterocyclic group, NR6R7; R6, R7 are each independently selected from C 1-6 alkyl; X2 Selected from NR a , O or CR b R c , R b and R c Selected from hydrogen; R3 and R4 are selected from hydrogen, n=1; Y is selected from CR b R c , R b and R c Selected from hydrogen; M1 is selected from CH; R f Selected from H; In formula (h): R a Selected from hydrogen, C 1-6 Alkyl, C(O)C 1-6 Alkyl, C 1-6 Alkyl C(O)NR6R7, C(O)C 3–10 Cycloalkyl, C(O)3-20 membered heterocyclic group, S(O)2C 1-6 Alkyl, S(O)2C 3–10 Cycloalkyl, -3-20 membered heterocyclyl-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 alkyl) 2 or 3-20 membered heterocyclic group; wherein R a C in the group represented 1-6 Alkyl, C(O)C 1-6 Alkyl, C 1-6 Alkyl C(O)NR6R7, C(O)C 3–10 Cycloalkyl, C(O)3-20 membered heterocyclic group, S(O)2C 1-6 Alkyl, S(O)2C 3–10 Cycloalkyl, -3-20 membered heterocyclyl-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 The 2- or 3-20-membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, NR6R7, R6R7 are each independently selected from C 1-6 Alkyl, S(O)2C 1-6 Alkyl, C(O)C 1-6 Alkyl, 3-20 membered heterocyclic group; R3 and R4 are the same or different and are independently selected from hydrogen or C 1-6 Alkyl; among which, C 1-6 The alkyl group may be substituted by 1 to 3 substituents selected from the group consisting of: hydroxyl, n = 1; X1 and X2 are each independently selected from CR b R c , R b and R c The same or different, each independently selected from: hydrogen or C 1-6 Alkyl; wherein R b and / or R c The alkyl group in the represented group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl group; M1 is selected from CH; R f Selected from H; In formula (i): R a Selected from hydrogen, C(O)C 1-6 Alkyl, C 1-6 Alkyl, S(O)2C 1-6 Alkyl, -3-20 membered heterocyclic group-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)2, -C 1-6 Alkyl C(O)N(C 1-6 alkyl)2, -C(O)3-20 membered heterocyclic group or 3-20 membered heterocyclic group; wherein R a C(O)C in the group represented 1-6 Alkyl, C 1-6 Alkyl, S(O)2C 1-6 Alkyl, -3-20 membered heterocyclic group-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 alkyl)2, -C(O)3-20 membered heterocyclic group or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3-20 membered heterocyclic group, S(O)2C 1-6 Alkyl, 3-20 membered heterocyclic group and NR6R7, R6R7 are each independently selected from C 1-6 alkyl; X2 Selected from CR b R c , R b and R c The same or different, each independently selected from: hydrogen or C 1-6 Alkyl, where R b and / or R c C in the group represented 1-6 The alkyl group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl group; M1 is selected from CH; R f Selected from H; R1 and R2 are each independently selected from hydrogen or C 1-6 Alkyl; among which, C 1-6 The alkyl group may be substituted by 1 to 3 substituents selected from the group consisting of: hydroxyl, m = 1; In formula (j): R a Selected from hydrogen, C(O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl C(O)NR6R7, C(O)3-20 membered heterocyclic group, -C 1-6 alkyl-3-20 membered heterocyclic group, -3-20 membered heterocyclic group-C 1-6 Alkyl or 3-20 membered heterocyclic group; wherein R a C(O)C in the group represented 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl C(O)NR6R7, C(O)3-20 membered heterocyclic group, -C 1-6 alkyl-3-20 membered heterocyclic group, -3-20 membered heterocyclic group-C 1-6 The alkyl or 3-20 membered heterocyclic group may be substituted by 1 to 3 substituents independently selected from the following groups: hydroxyl, cyano, C 1-6 Alkyl, 3-20 membered heterocyclic group and NR6R7, R6, R7 are the same or different and are independently selected from C 1-6 alkyl; X1 is selected from O or CH2; R1 and R2 are selected from hydrogen, m=1; Y is selected from CR b R c , R b and R c Selected from hydrogen.

5. The compound according to claim 4, characterized in that In formula (a): R a Selected from hydrogen, C 1-6 Alkyl, S(O)2C 1-3 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-NR6R7 [such as CH2N(CH3)2, C2H4N(CH3)2], -C 1-6 Alkyl-NH2, 3-20 membered heterocyclic group; X2 is selected from O, N(C 1-6 Alkyl) or CH2; Y is selected from CR b R c , R b and R c Selected from hydrogen; R3 and R4 are selected from hydrogen, n is 1; M1 is selected from CH; R f Selected from H; In formula (b): R a Selected from hydrogen, methyl, ethyl, -S(O)2CH3, -C(O)C 1-6 Alkyl-OH, C 1-6 Alkyl-OH, oxetanyl, azetidinyl, -3-20 membered heterocyclic group C 1-6 Alkyl, tetrahydrofuranyl, tetrahydropyrrolyl, hexahydropyridinyl, hexahydropyranyl, C(O)NHC 1-6 Alkyl-OH, C(O)N(C 1-6 Alkyl)(C 1-6 Alkyl-OH), CONHCH3; X1 is selected from CH2, CH(C 1-6 alkyl), CH(C 1-6 Alkyl-OH), CH[C 1-6 Alkyl-N(C 1-6 alkyl)2], CH(C 1-6 Alkyl-halogen), CH(C 1-6 Alkyl-CN); X2 is selected from CH2; R3 is selected from hydrogen, R4 is selected from C 1-6 Alkyl-OH, n is 1; M1 is selected from CH; R f Selected from H; In formula (c): R a Selected from hydrogen, methyl, ethyl, C 1-6 Alkyl-OH, C 1-6 Alkyl-C 1-6 Alkoxy, -S(O)2CH3, C(O)C 1-6 Alkyl-OH, C(O)C 1-6 Alkyl-NR6R7, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, hexahydropyridinyl, hexahydropyranyl, -C 1-6 Alkyl S(O)2C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group, -C 1-6 Alkyl-3-20 membered heterocyclyl-C 1-6 Alkyl, -3-20 membered heterocyclic group-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group-OH, -C 1-6 Alkyl-3-20 membered heterocyclyl-halogen, -3-20 membered heterocyclyl-C(O)C 1-6 Alkyl, -3-20 membered heterocyclic group S(O)2C 1-6 Alkyl, CONHCH3, C(O)NHC 1-6 Alkyl-OH, C(O)N(C 1-6 Alkyl)(C 1-6 Alkyl-OH); R1 is selected from hydrogen, R2 is selected from C 1-6 Alkyl-OH; X1 is selected from CH2, X2 is selected from CH2 or CH(C 1-6 Alkyl-OH); M1 is selected from CH; R f Selected from H; n is 1; In formula (e): R a Selected from hydrogen, methyl, ethyl, C 1-6 Alkyl-OH, -3-20 membered heterocyclic-C 1-6 Alkyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, hexahydropyridinyl, hexahydropyranyl; X1 is selected from CH2 or CH(C 1-6 alkyl-OH), X2 is selected from CH2; or, X1 is selected from CH2, X2 is selected from CH2 or CH(C 1-6 Alkyl-OH); or, X1 and X2 are both selected from CH2; R3 and R4 are selected from hydrogen, n=1; In formula (f): R a Selected from hydrogen, methyl, ethyl, -C 1-6 Alkyl-OH, S(O)2CH3, -3-20 membered heterocyclyl-C 1-6 Alkyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, hexahydropyridinyl, hexahydropyranyl, -C 1-6 Alkyl-3-20 membered heterocyclic group; R1 and R2 are hydrogen; or, R1 is H, R2 is C 1-6 Alkyl-OH; X1 is selected from CH2 or CH(C 1-6 alkyl-OH), X2 is selected from CH2; or, X1 is selected from CH2, X2 is selected from CH2 or CH(C 1-6 Alkyl-OH); or, X1 and X2 are both selected from CH2; m is 1; In formula (g): R a Selected from H, methyl, ethyl, C 1-6 Alkyl-OH, S(O)2CH3, C(O)C 1-6 AlkylOH, C(O)C 1-6 alkyl NR6R7, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, hexahydropyridinyl, hexahydropyranyl, -3-20 membered heterocyclyl-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group, -C 1-6 Alkyl-3-20 membered heterocyclyl-OH; X2 is selected from NH, N(CH3), O or CH2; R3 and R4 are selected from hydrogen, n=1; Y is selected from CR b R c , R b and R c Selected from hydrogen; M1 is selected from CH; R f Selected from H; In formula (h): R a Selected from hydrogen, methyl, ethyl, C 1-6 Alkyl-OH, -C 1-6 Alkyl-C 1-6 Alkoxy, S(O)2CH3, C(O)C 1-6 AlkylOH, C(O)C 1-6 Alkyl NR6R7, C 1-6 Alkyl NR6R7, -C 1-6 Alkyl-CN, C 1-6 Alkyl S(O)2C 1-6 alkyl, oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, hexahydropyridinyl, hexahydropyranyl, -3-20 membered heterocyclyl-C 1-6 Alkyl, -3-20 membered heterocyclic group-C 1-6 Alkyl-OH, -3-20 membered heterocyclyl-C(O)C 1-6 Alkyl, -3-20 membered heterocyclic group -S(O)2C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group, -C 1-6 Alkyl-3-20 membered heterocyclic group-OH, -C 1-6 Alkyl-3-20 membered heterocyclyl-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group (OH)-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclyl (halogen)-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclyl-halogen, -C(O)oxetanyl, -C(O)azetidinyl, -C(O)tetrahydropyrrolyl, C(O)3-20 membered heterocyclyl-C 1-6 Alkyl, C(O)3-20 membered heterocyclic group (OH)-C 1-6 Alkyl, CONHCH3, C(O)NHC 1-6 Alkyl-OH, C(O)N(C 1-6 Alkyl)(C 1-6 Alkyl-OH); n=1;R3 is hydrogen, R4 is -C 1-6 Alkyl-OH; X1 and X2 are each independently selected from CR b R c , R b and R c Same or different, R b and R c Each independently selected from H or C 1-6 Alkyl-OH; M1 is selected from CH; R f Selected from H; In formula (i): R a Selected from hydrogen, methyl, ethyl, C 1-6 Alkyl-OH, -C 1-6 Alkyl-C 1-6 Alkoxy, oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, hexahydropyridinyl, hexahydropyranyl, C(O)C 1-6 AlkylOH, C(O)C 1-6 Alkyl NR6R7, C 1-6 Alkyl NR6R7, -3-20 membered heterocyclyl-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group, -C 1-6 Alkyl-3-20 membered heterocyclic group (OH)-C 1-6 Alkyl, -C(O)3-20 membered heterocyclic group-C 1-6 Alkyl, -C 1-6 Alkyl-3-20 membered heterocyclic group-OH, -C 1-6 Alkyl-3-20 membered heterocyclyl-halogen, -C(O)oxetanyl, -C(O)azetidinyl, -C(O)tetrahydropyrrolyl, CONHCH3, S(O)2CH3, C(O)NHC 1-6 Alkyl-OH, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl-OH), -3-20 membered heterocyclyl-halogen, -3-20 membered heterocyclyl (OH)-C 1-6 Alkyl, C 1-6 Alkyl-CN, -C 1-6 Alkyl S(O)2C 1-6 alkyl; X2 Selected from CR b R c , R b and R c the same or different, each independently selected from hydrogen or C 1-6 Alkyl-OH; M1 is selected from CH; R f Selected from H; R1 is hydrogen, R2 is -C 1-6 Alkyl-OH; or, R1 and R2 are both H; m is 1; In formula (j): R a Selected from hydrogen, methyl, ethyl, C 1-6 Alkyl-OH, C 1-6 Alkyl NR6R7, C 1-6 Alkyl-CN, -C 1-6 Alkyl-C3 heterocyclic group, -C 1-6 Alkyl-3-20 membered heterocyclic group, -C 1-6 Alkyl-3-20 membered heterocyclyl-OH, C(O)3-20 membered heterocyclyl-C 1-6 alkyl; X1 is selected from O or CH2; R1 and R2 are selected from hydrogen, m=1; Y is selected from CR b R c , R b and R c Selected from hydrogen.

6. The compound shown below: (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]quinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(8-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]quinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(8-ethyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]quinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[8-(methylsulfonyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[8-(2-hydroxyethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){8-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]quinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(4-methyl-2,3,4,6-tetrahydro[1,4]oxazinyl[2,3-f]indol-7-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(7-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(7-ethyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(methylsulfonyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl]methanone; 1-{2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-7-yl}-2-hydroxyethyl-1-one; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(2-hydroxyethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(oxetan-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(azetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(1-methylazetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(hexahydropyridin-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(1-methylhexahydropyridin-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl]methanone; (1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}-5-(methylamino)pyrazol-4-yl)(7-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl)methanone; (1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}-5-(ethylamino)pyrazol-4-yl)(7-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl)methanone; (5-amino-1-{6-[(2-fluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(7-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl)methanone; {5-amino-1-[4-methyl-6-(phenyloxy)pyridin-3-yl]pyrazol-4-yl}(7-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]pyridin-3-yl}pyrazol-4-yl)(7-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl)methanone; (5-amino-1-{2-[(2,6-difluorophenyl)oxy]-4-methylpyrimidin-5-yl}pyrazol-4-yl)(7-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(7,8-dimethyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[8-(hydroxymethyl)-7-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){8-[(dimethylamino)methyl]-7-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[8-(fluoromethyl)-7-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl]methanone; {2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-7-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-8-yl}acetonitrile; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[8-methyl-7-(oxetan-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]quinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(5-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]quinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(1,2,3,6-tetrahydro[1,4]oxazinyl[3,2-f]indol-7-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(1-methyl-1,2,3,6-tetrahydro[1,4]oxazinyl[3,2-f]indol-7-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(1-methyl-2,3,4,6-tetrahydro-1H-pyrrolo[2,3-g]quinoxalin-7-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[5-(2-hydroxyethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(2-hydroxyethyl)-1,2,3,6-tetrahydro[1,4]oxazinyl[3,2-f]indol-7-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[5-(oxetan-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[5-(methylsulfonyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]quinolin-2-yl]methanone; 1-{2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]quinolin-5-yl}-2-hydroxyethyl-1-one; 1-{7-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-1,2,3,6-tetrahydro[1,4]oxazinyl[3,2-f]indol-1-yl}-2-hydroxyethyl-1-one; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[5-(azetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[5-(1-methylazetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(1-methylazetidin-3-yl)-1,2,3,6-tetrahydro[1,4]oxazinyl[3,2-f]indol-7-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(oxetan-3-yl)-1,2,3,6-tetrahydro[1,4]oxazinyl[3,2-f]indol-7-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(azetidin-3-yl)-1,2,3,6-tetrahydro[1,4]oxazinyl[3,2-f]indol-7-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydro[1,4]oxazinyl[3,2-f]indol-7-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-2,3,4,6-tetrahydro-1H-pyrrolo[2,3-g]quinoxalin-7-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[5-(hexahydropyridin-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-2,3,4,6-tetrahydro-1H-pyrrolo[2,3-g]quinoxalin-7-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[5-(1-methylhexahydropyridin-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(1-methylpiperidin-4-yl)-1,2,3,6-tetrahydro[1,4]oxazinyl[3,2-f]indol-7-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(1-methylhexahydropyridin-4-yl)-2,3,4,6-tetrahydro-1H-pyrrolo[2,3-g]quinoxalin-7-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(6-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(6-ethyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(2-hydroxyethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(2-methoxyethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(2-hydroxy-2-methylpropyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(methylsulfonyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; 1-{2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-6-yl}-2-hydroxyethyl-1-one; 1-{2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-6-yl}-2-(dimethylamino)ethyl-1-one; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){6-[2-(methylsulfonyl)ethyl]-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl}methanone; 2-{2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-6-yl}-N,N-dimethylacetamide; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(oxetan-2-ylmethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(azetidin-2-ylmethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){6-[(1-methylazetidin-2-yl)methyl]-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(tetrahydrofuran-2-ylmethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(tetrahydrofuran-3-ylmethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(3,4,5,6-tetrahydro-2H-pyran-4-ylmethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){6-[(4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)methyl]-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){6-[(4-fluoro-3,4,5,6-tetrahydro-2H-pyran-4-yl)methyl]-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){6-[(3-hydroxyoxetan-3-yl)methyl]-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(azetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(1-methylazetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(hexahydropyridin-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(1-methylhexahydropyridin-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; 1-(3-{2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-6-yl}azetidin-1-yl)ethyl-1-one; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){6-[1-(methylsulfonyl)azetidin-3-yl]-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl}methanone; (1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}-5-(methylamino)pyrazol-4-yl)[6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(hydroxymethyl)-7-(oxetan-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[5-(hydroxymethyl)-6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[8-(hydroxymethyl)-7-(oxetan-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(hydroxymethyl)-6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(hydroxymethyl)-7-(1-methylazetidin-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[5-(hydroxymethyl)-6-(1-methylazetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[8-(hydroxymethyl)-7-(1-methylazetidin-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(hydroxymethyl)-6-(1-methylazetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(hydroxymethyl)-7-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[5-(hydroxymethyl)-6-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[8-(hydroxymethyl)-7-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(hydroxymethyl)-6-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(hydroxymethyl)-7-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinolin-2-yl]methanone; 2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-N-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinoline-7-carboxamide; 8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-N-methyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-2-carboxamide; 2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-N-(2-hydroxyethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-g]isoquinoline-7-carboxamide 8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-N-(2-hydroxyethyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-2-carboxamide; 8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-N-(2-hydroxyethyl)-N-methyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-2-carboxamide; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(7-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[4,3-b]pyridin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(6-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[3,4-b]pyridin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(2-hydroxyethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[4,3-b]pyridin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(2-hydroxyethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[3,4-b]pyridin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(oxetan-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[4,3-b]pyridin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[3,4-b]pyridin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(2-hydroxy-2-methylpropyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[4,3-b]pyridin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(2-hydroxy-2-methylpropyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[3,4-b]pyridin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(azetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[4,3-b]pyridin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(azetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[3,4-b]pyridin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(1-methylazetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[4,3-b]pyridin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(1-methylazetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[3,4-b]pyridin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[5-(hydroxymethyl)-6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[3,4-b]pyridin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(hydroxymethyl)-6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[3,4-b]pyridin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[8-(hydroxymethyl)-7-(1-methylazetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[4,3-b]pyridin-2-yl]methanone. (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(6-methyl-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(2-hydroxyethyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(methylsulfonyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-2-yl]methanone; 1-{2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-6-yl}-2-hydroxyethyl-1-one; 1-{2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-6-yl}-2-(dimethylamino)ethyl-1-one; 1-{8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-2,3,4,7-tetrahydro[1,4]oxazinyl[2,3-e]indol-4-yl}-2-(dimethylamino)ethyl-1-one; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[4-(2-hydroxyethyl)-2,3,4,7-tetrahydro[1,4]oxazinyl[2,3-e]indol-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(4-methyl-2,3,4,7-tetrahydro[1,4]oxazinyl[2,3-e]indol-8-yl)methanone; 1-{8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-2,3,4,7-tetrahydro[1,4]oxazinyl[2,3-e]indol-4-yl}-2-hydroxyethyl-1-one; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(1,4-dimethyl-2,3,4,7-tetrahydro-1H-pyrrolo[3,2-f]quinoxalin-8-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[4-(2-hydroxyethyl)-1-methyl-2,3,4,7-tetrahydro-1H-pyrrolo[3,2-f]quinoxalin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(oxetan-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[4-(oxetan-3-yl)-2,3,4,7-tetrahydro[1,4]oxazinyl[2,3-e]indol-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(azetidin-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[4-(azetidin-3-yl)-2,3,4,7-tetrahydro[1,4]oxazinyl[2,3-e]indol-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(1-methylazetidin-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[4-(1-methylazetidin-3-yl)-2,3,4,7-tetrahydro[1,4]oxazinyl[2,3-e]indol-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-2,3,4,7-tetrahydro[1,4]oxazinyl[2,3-e]indol-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(hexahydropyridin-4-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[4-(hexahydropyridin-4-yl)-2,3,4,7-tetrahydro[1,4]oxazinyl[2,3-e]indol-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(1-methylhexahydropyridin-4-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[4-(1-methylpiperidin-4-yl)-2,3,4,7-tetrahydro[1,4]oxazinyl[2,3-e]indol-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(oxetan-3-ylmethyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[4-(oxetan-3-ylmethyl)-2,3,4,7-tetrahydro[1,4]oxazinyl[2,3-e]indol-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){6-[(3-hydroxyoxetan-3-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){4-[(3-hydroxyoxetan-3-yl)methyl]-2,3,4,7-tetrahydro[1,4]oxazinyl[2,3-e]indol-8-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(7-methyl-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(7-ethyl-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(2-hydroxyethyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(2-hydroxy-2-methylpropyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(2-methoxyethyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; 1-{2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-7-yl}-2-hydroxyethyl-1-one; 1-{2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-7-yl}-2-(dimethylamino)ethyl-1-one; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[2-(dimethylamino)ethyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; 2-{2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-7-yl}-N,N-dimethylacetamide; {2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-7-yl}acetonitrile; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[2-(methylsulfonyl)ethyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(oxetan-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(azetidin-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(1-methylazetidin-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[1-(2-hydroxyethyl)azetidin-3-yl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; 1-(3-{2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-7-yl}azetidin-1-yl)ethyl-1-one; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[1-(methyldioxyylidene-λ6-thio)azetidin-3-yl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(3-methyloxetan-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(hexahydropyridin-4-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(1-methylhexahydropyridin-4-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(oxetan-3-ylmethyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(3-hydroxyoxetan-3-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(azetidin-3-ylmethyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(1-methylazetidin-3-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(3-hydroxy-1-methylazetidin-3-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(3-fluoro-1-methylazetidin-3-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(3-fluoroazetidin-3-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(oxetan-2-ylmethyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(3-hydroxyoxetan-2-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(tetrahydrofuran-2-ylmethyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(3-hydroxytetrahydrofuran-2-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(4-hydroxytetrahydrofuran-2-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(tetrahydrofuran-3-ylmethyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(3-hydroxytetrahydrofuran-3-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(3-fluorotetrahydrofuran-3-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(4-hydroxytetrahydrofuran-3-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[7-(tetrahydro-1H-pyrrol-2-ylmethyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(1-methyltetrahydro-1H-pyrrol-2-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; {2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-7-yl}(oxetan-2-yl)methanone; {2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-7-yl}(oxetan-3-yl)methanone; {2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-7-yl}(tetrahydro-1H-pyrrol-2-yl)methanone; {2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-7-yl}(1-methyltetrahydro-1H-pyrrol-2-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(3-hydroxy-1-methyltetrahydro-1H-pyrrol-2-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(4-hydroxy-1-methyltetrahydro-1H-pyrrol-2-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(1-methyltetrahydro-1H-pyrrol-3-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(3-hydroxy-1-methyltetrahydro-1H-pyrrol-3-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){7-[(4-hydroxy-1-methyltetrahydro-1H-pyrrol-3-yl)methyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl}methanone; (1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}-5-(methylamino)pyrazol-4-yl)[7-(oxetan-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}-5-(methylamino)pyrazol-4-yl)[7-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; {2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-7-yl}(azetidin-2-yl)methanone; {2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-7-yl}(1-methylazetidin-2-yl)methanone; {2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-7-yl}(azetidin-3-yl)methanone; {2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-7-yl}(1-methylazetidin-3-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-8-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(1-methyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-8-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(2-hydroxyethyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){1-[2-(dimethylamino)ethyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-8-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(1,2,3,7-tetrahydro[1,4]oxazinyl[3,2-e]indol-8-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(1-methyl-1,2,3,7-tetrahydro[1,4]oxazinyl[3,2-e]indol-8-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(2-hydroxyethyl)-1,2,3,7-tetrahydro[1,4]oxazinyl[3,2-e]indol-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){1-[2-(dimethylamino)ethyl]-1,2,3,7-tetrahydro[1,4]oxazinyl[3,2-e]indol-8-yl}methanone; {8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-1-yl}acetonitrile; 2-{8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-1-yl}-N,N-dimethylacetamide; 2-{8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-1,2,3,7-tetrahydro[1,4]oxazinyl[3,2-e]indol-1-yl}-N,N-dimethylacetamide; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(oxetan-3-ylmethyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(oxetan-3-ylmethyl)-1,2,3,7-tetrahydro[1,4]oxazinyl[3,2-e]indol-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(azetidin-3-ylmethyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(azetidin-3-ylmethyl)-1,2,3,7-tetrahydro[1,4]oxazinyl[3,2-e]indol-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){1-[(3-hydroxyoxetan-3-yl)methyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-8-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){1-[(3-hydroxyoxetan-3-yl)methyl]-1,2,3,7-tetrahydro[1,4]oxazinyl[3,2-e]indol-8-yl}methanone; {8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-1-yl}(1-methylazetidin-3-yl)methanone; {8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-1,2,3,7-tetrahydro[1,4]oxazinyl[3,2-e]indol-1-yl}(1-methylazetidin-3-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(2-methyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)(2-ethyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(2-hydroxyethyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(2-methoxyethyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(2-hydroxy-2-methylpropyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(oxetan-3-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(azetidin-3-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(tetrahydrofuran-3-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(hexahydropyridin-4-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(1-methylhexahydropyridin-4-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(1-methylazetidin-3-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; 1-{8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-2-yl}-2-hydroxyethyl-1-one; 1-{8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-2-yl}-2-(dimethylamino)ethan-1-one; 2-{8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-2-yl}-N,N-dimethylacetamide; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(oxetan-2-ylmethyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(oxetan-3-ylmethyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(azetidin-3-ylmethyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){2-[(1-methylazetidin-3-yl)methyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){2-[(3-hydroxy-1-methylazetidin-3-yl)methyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(azetidin-2-ylmethyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){2-[(1-methylazetidin-2-yl)methyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){2-[(3-hydroxy-1-methylazetidin-2-yl)methyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl}methanone; {8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-2-yl}(1-methylazetidin-2-yl)methanone; {8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-2-yl}(1-methylazetidin-3-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){2-[(3-hydroxyoxetan-3-yl)methyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl}methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl){2-[(3-fluorooxetan-3-yl)methyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl}methanone; (1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}-5-(methylamino)pyrazol-4-yl)[2-(oxetan-3-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; {8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-2-yl}(oxetan-3-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(hydroxymethyl)-2-(oxetan-3-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(hydroxymethyl)-7-(oxetan-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[3-(hydroxymethyl)-2-(oxetan-3-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[8-(hydroxymethyl)-7-(oxetan-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methane; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(hydroxymethyl)-2-(1-methylazetidin-3-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(hydroxymethyl)-7-(1-methylazetidin-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[3-(hydroxymethyl)-2-(1-methylazetidin-3-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[8-(hydroxymethyl)-7-(1-methylazetidin-3-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[1-(hydroxymethyl)-2-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[6-(hydroxymethyl)-7-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[3-(hydroxymethyl)-2-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[8-(hydroxymethyl)-7-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinolin-2-yl]methanone; 2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-N-methyl-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinoline-7-carboxamide; 8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-N-methyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-2-carboxamide; 2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-N-(2-hydroxyethyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinoline-7-carboxamide; 8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-N-(2-hydroxyethyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-2-carboxamide; 2-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-N-(2-hydroxyethyl)-N-methyl-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinoline-7-carboxamide; 8-[(5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)carbonyl]-N-(2-hydroxyethyl)-N-methyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline-2-carboxamide; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[5-(hydroxymethyl)-6-(1-methylazetidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-e]pyrido[3,4-b]pyridin-2-yl]methanone; (1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}-5-(ethylamino)pyrazol-4-yl)(2-ethyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl)methanone; (5-amino-1-{6-[(2,6-difluorophenyl)oxy]-4-methylpyridin-3-yl}pyrazol-4-yl)[2-(methylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-8-yl]methanone; (5-amino-1-(6-(2,6-difluorophenoxy)-4-methylpyridin-3-yl)-1H-pyrazol-4-yl)(2-(1-hydroxy-2-methylpropan-2-yl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-H]isoquinolin-8-yl)methanone; 3-(8-(5-amino-1-(6-(2,6-difluorophenoxy)-4-methylpyridin-3-yl)-1H-pyrazole-4-carbonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[2,3-H]isoquinolin-2-yl)-2,2-dimethylpropionitrile.

7. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to any one of claims 1 to 6.

8. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition may be in the form of an oral preparation or an injection.

9. Use of the pharmaceutical composition according to claim 7 or 8 in the preparation of a drug for treating a disease associated with Yes1 amplification or Yes1 overexpression.

10. The use according to claim 9, characterized in that: The diseases associated with Yes1 amplification or Yes1 overexpression include at least one of esophageal cancer, small cell lung cancer, blood tumors, digestive system tumors, reproductive system tumors, nervous system tumors and head and neck cancer.

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