CN114853730B - Compounds used as HPK1 kinase inhibitor, preparation method and application thereof - Google Patents

Compounds used as HPK1 kinase inhibitor, preparation method and application thereof Download PDF

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CN114853730B
CN114853730B CN202210590072.0A CN202210590072A CN114853730B CN 114853730 B CN114853730 B CN 114853730B CN 202210590072 A CN202210590072 A CN 202210590072A CN 114853730 B CN114853730 B CN 114853730B
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蒋晟
肖易倍
周立昕
郝海平
姚和权
叶秀全
张阔军
王天雨
王凯振
章翔宇
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China Pharmaceutical University
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Abstract

The invention discloses a compound used as an HPK1 kinase inhibitor, a preparation method and application thereof. Specifically, the invention provides a compound shown as a formula I, wherein the definition of each group is as described in the specification. The compound has excellent HPK1 inhibition activity, so that the compound can be used for a pharmaceutical composition for treating cancers and other diseases related to HPK activity.

Description

Compounds used as HPK1 kinase inhibitor, preparation method and application thereof
Technical Field
The invention relates to a kinase inhibitor and a preparation method and application thereof, in particular to a compound used as an HPK1 kinase inhibitor and a preparation method and application thereof.
Background
Surgical excision, radiation therapy, chemotherapy, small molecule targeted drugs are the primary means for treating cancer, unfortunately, surgical excision is often not a viable option for many forms of cancer or tumor, and radiation therapy and chemotherapy kill tumor cells while also damaging healthy cells. In addition, the instability of the tumor cell genome promotes mutation of the tumor cells, further leading to rapid changes in the cancer genome, which makes it resistant to drugs specifically targeting tumors, which makes cancer treatment difficult. In recent years, cancer patients kill tumor cells through their own immune system, and the improvement of the anti-tumor immunity of the body is a novel strategy for cancer treatment. One such method is to suppress negative regulators of the immune response that maintain peripheral tolerance function, allowing the tumor to be recognized as a nonhexon antigen, thereby overcoming immune escape of tumor cells. Hematopoietic progenitor kinase (HPK 1) is one of the members of the mitogen-activated protein kinase (MAP 4K) family, which also includes GCK/MAP4K2, GLK/MAP4K3, HGK/MAP4K4, KHS/MAP4K5, MINK/MAP4K6.HPK1 is a negative regulator of activation reaction of B cells, T cells and dendritic cells, and inhibiting the expression of HPK1 can pertinently improve the anti-tumor immunity of the organism, and is mainly expressed in hematopoietic cells such as T cells, B cells, dendritic cells, macrophages, mast cells and neutrophils. In T cells, HPK1 modulates the role in T cell activation through TCR signaling pathways. After TCR activation, HPK1 interacts with T cell receptor proteins, phosphorylated by tyrosine kinases Zap70 and Lck, and phosphorylate SLP-76 receptor proteins, down-regulating TCR signaling, thereby inhibiting T cell activation and proliferation. It was found that HPK1 can participate in a number of signaling cascades including the MAKP signaling pathway, the Fas-induced apoptosis pathway, and the NF- κB signaling pathway. Moreover, HPK1 can also inhibit AP-1, and the AP-1 plays roles in promoting proliferation of cells, inhibiting differentiation, promoting invasion and metastasis of tumor cells and the like in tumor formation and development. HPK1 kinase is not expressed in major organs, suggesting that HPK1 kinase inhibitors may not cause any serious complications.
Currently there are no drugs on the market for hematopoietic progenitor kinase (HPK 1) targets.
Disclosure of Invention
The invention aims to: the present invention aims to provide a compound useful as an HPK1 kinase inhibitor having selectivity and high activity; it is another object of the present invention to provide a process for the preparation of compounds useful as inhibitors of HPK1 kinase; it is another object of the present invention to provide the use of a compound useful as an HPK1 kinase inhibitor in the preparation of a pharmaceutical composition for the prevention or treatment of a disease responsive to inhibition of HPK1 activity in a subject.
The technical scheme is as follows: a compound of the invention, or a pharmaceutically acceptable salt, isomer or hydrate thereof, of formula I:
wherein:
X 1 selected from the group consisting of: none, NR, O, S (O) t 、CHR、NRC(O)、C(O)NR、NRC(O)C(O)NR、NRC(O)NR、NRC(S)NR、NRC(O)NRCH 2 、NRC(S)NRCH 2 Wherein, R is selected from the following group: H. c (C) 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or a 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group N, S and O;
X 2 or X 3 Each independently is CH or N; when said X 2 Or X 3 When CH is, can be R a Substitution (i.e. X 2 、X 3 C);
the A ring and the B ring are each independently selected from the group consisting of: H. c (C) 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 An aromatic ring, a 5-10 membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered aromatic ring and a 5-7 membered heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered aromatic ring and a 5-7 membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O and a 5-7 membered heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O and a 5-7 membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O;
R a 、R 1 、R 2 And R is 3 Each independently selected from the group consisting of: H. deuterium, halogen, OH, CN, NO 2 、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 A 5-12 membered heteroaryl group having 1-3 heteroatoms selected from the following group N, S, O, a 3-12 membered heterocyclyl group having 1-3 heteroatoms selected from the following group N, S, O, wherein R is represented by a 、R 1 、R 2 And R is 3 Alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or in the groups representedThe heterocyclic group may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、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 、NR 6 S(＝O) 2 R 7 ；
p and q are each independently 0, 1, 2, 3, 4 or 5.
Further, the compound of formula I has any one of the structures shown in the following formula:
wherein:
X 1 selected from the group consisting of: none, NR, O, S (O) t 、CHR、NRC(O)、C(O)NR、NRC(O)C(O)NR、NRC(O)NR、NRC(S)NR、NRC(O)NRCH 2 、NRC(S)NRCH 2 Wherein, R is selected from the following group: H. c (C) 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or a 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group N, S and O;
X 2 or X 3 Each independently is CH or N; when said X 2 Or X 3 When CH is, can be R a Substitution (i.e. X 2 、X 3 C);
X 5 or X 6 Each independently selected from none, NR b 、O、S(O) t 、C(O)、CR 4 R 5 ；
Y is selected from NR b 、O、S(O) t Or CR (CR) 4 R 5 ；
M 1 、M 2 Or M 3 Each independently is CH or N; and when said M 1 、M 2 Or M 3 In the case of CH, theCan be located at the M 1 、M 2 Or M 3 Upper (i.e. M 1 、M 2 Or M 3 C);
ring a is selected from the group consisting of: H. c (C) 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 An aromatic ring, a 5-10 membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered aromatic ring and a 5-7 membered heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered aromatic ring and a 5-7 membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O and a 5-7 membered heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O and a 5-7 membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O;
R a 、R 1 、R 2 、R 3 and R is 5 Each independently selected from the group consisting of: H. deuterium, halogen, OH, CN, NO 2 、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 A 5-12 membered heteroaryl group having 1-3 heteroatoms selected from the following group N, S, O, a 3-12 membered heterocyclyl group having 1-3 heteroatoms selected from the following group N, S, O, wherein R is represented by a 、R 1 、R 2 、R 3 And R is 5 The alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl groups in the represented groups may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、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 、NR 6 S(＝O) 2 R 7 ；
R b Selected from the group consisting of H, 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 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group N, S, O, wherein R is b The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl groups in the represented groups may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 5-10 membered heterocyclyl and NR 6 R 7 ；
R 4 Selected from the group consisting of: H. deuterium, 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 having 1-3 heteroatoms selected from the group N, S, O 3-12 Heterocyclyl, wherein R is 4 The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl groups in the represented groups may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 5-10 Membered heterocyclyl and NR 6 R 7 ；
R 6 、R 7 Each independently is H or C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, C having 1-3 heteroatoms selected from the group N, S and O 3-12 Heterocyclyl, wherein R is 6 Or R is 7 The alkyl, cycloalkyl, heterocyclyl represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-12 A heterocyclic group.
R 6 R is R 7 Together with the same nitrogen or phosphorus atom to which they are attached, may form C 3-12 Heterocyclyl, which may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 3-12 A heterocyclic group;
n is 1, 2 or 3;
m is 1, 2 or 3; n+m is less than or equal to 4;
p, q are each independently 0, 1, 2, 3, 4 or 5;
t is 0, 1 or 2;
X 1 selected from the group consisting of: none, NR, O, S (O) t 、CHR、NRC(O)、C(O)NR、NRC(O)C(O)NR、NRC(O)NR、NRC(S)NR、NRC(O)NRCH 2 、NRC(S)NRCH 2 Wherein, R is selected from the following group: H. c (C) 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or a 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group N, S and O;
X 2 or X 3 Each independently is CH or N; when said X 2 Or X 3 When CH is, can be R a Substitution (i.e. X 2 、X 3 C);
M 1 、M 2 、M 3 、M 4 or M 5 Each independently is CH or N; and when said M 1 、M 2 、M 3 、M 4 Or M 5 In the case of CH, theCan be located at the M 1 、M 2 、M 3 、M 4 Or M 5 Upper (i.e. M 1 、M 2 、M 3 、M 4 Or M 5 C); when said M 4 And M 5 And when substituted, may form a bicyclic ring together with the atoms to which they are attached; wherein the bicyclic ring may contain one or more heteroatoms selected from N, S and O; and wherein the bicyclic ring is optionally substituted with one, two, three, four or five R 3 ；
Ring a is selected from the group consisting of: H. c (C) 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 An aromatic ring, a 5-10 membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered aromatic ring and a 5-7 membered heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered aromatic ring and a 5-7 membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O and a 5-7 membered heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O and a 5-7 membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O;
R a 、R 1 、R 2 And R is 3 Each independently selected from the group consisting of: H. deuterium, halogen, OH, CN, NO 2 、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 A 5-12 membered heteroaryl group having 1-3 heteroatoms selected from group N, S, O, having 1-3 heteroatoms selected from3-12 membered heterocyclyl of heteroatoms of group N, S, O, wherein R is a 、R 1 、R 2 And R is 3 The alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl groups in the represented groups may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、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 、NR 6 S(＝O) 2 R 7 ；
R 6 、R 7 Each independently is H or C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, C having 1-3 heteroatoms selected from the group N, S and O 3-12 Heterocyclyl, wherein R is 6 Or R is 7 The alkyl, cycloalkyl, heterocyclyl represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-12 A heterocyclic group.
R 6 R is R 7 Together with the same nitrogen or phosphorus atom to which they are attached, may form C 3-12 Heterocyclyl, which may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 3-12 A heterocyclic group;
p, q are each independently 0, 1, 2, 3, 4 or 5;
X 1 selected from the group consisting of: none, NR, O, S (O) t 、CHR、NRC(O)、C(O)NR、NRC(O)C(O)NR、NRC(O)NR、NRC(S)NR、NRC(O)NRCH 2 、NRC(S)NRCH 2 Wherein, R is selected from the following group: H. c (C) 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or a 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group N, S and O;
X 2 or X 3 Each independently is CH or N; when said X 2 Or X 3 When CH is, can be R a Substitution (i.e. X 2 、X 3 C);
M 7 is CR (CR) 8 、NR 8 N, O or S;
M 8 is CR (CR) 8 Or N;
M 9 and M 10 Each independently is C or N, provided that M 9 And M 10 At least one of which is C;
ring a is selected from the group consisting of: H. c (C) 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 An aromatic ring, a 5-10 membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered aromatic ring and a 5-7 membered heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered aromatic ring and a 5-7 membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O and a 5-7 membered heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O and a 5-7 membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O;
The C ring is selected from the group consisting of: c (C) 5-8 Cycloalkyl or a 5-to 8-membered heterocyclic ring having at least 3 ring-forming carbon atoms and 1, 2 or 3 ring-forming heteroatoms independently selected from the group consisting of N, P, O and S; wherein C is 5-8 Cycloalkyl and 5-to 8-membered heterocycle are independently optionally selected from R independently from 1, 2, 3, 4 or 5 8 Is substituted by a substituent of (a); and wherein C 5-8 Two substituents of cycloalkyl or 5-to 8-membered heterocycle are presentOptionally together form a group of groups which is optionally selected from R of 1, 2, 3 or 4 8 Spiro, fused or bridged cycloalkyl substituted with substituents (e.g., C 3-6 Cycloalkyl) or optionally 1, 2, 3 or 4 are independently selected from R 8 Spiro, fused or bridged heterocyclyl (e.g., 3-to 6-membered heterocyclyl);
R 1 、R 2 and R is 3 Each independently selected from the group consisting of: H. deuterium, halogen, OH, CN, NO 2 、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 A 5-12 membered heteroaryl group having 1-3 heteroatoms selected from the following group N, S, O, a 3-12 membered heterocyclyl group having 1-3 heteroatoms selected from the following group N, S, O, wherein R 2 And R is 3 The alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl groups in the represented groups may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、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 、NR 6 S(＝O) 2 R 7 ；
R 8 Selected from the group consisting of: H. halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 6-10 Aryl, having 1-3 heteroatoms selected from group N, S, O5-10 membered heteroaryl of child, 5-12 membered heteroaryl having 1-3 heteroatoms selected from group N, S, O, C (O) R 6 、C(O)OR 6 、C(O)NR 6 R 7 、OC(O)R 6 、OC(O)NR 6 R 7 、SR 6 、S(O) 2 R 6 、P(O)R 6 R 7 、S(O) 2 NR 6 R 7 、NR 6 R 7 、C(O)NR 6 S(O) 2 R 7 、NR 6 S(O) 2 R 7 、NR 6 C(O)R 7 、NR 6 C(O)OR 7 A 3-12 membered heterocyclic group having 1-3 heteroatoms selected from the group N, S, O, wherein R is 1 、R 2 And R is 3 The alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl groups in the represented groups may be substituted with 1 to 4 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、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 、NR 6 S(＝O) 2 R 7 ；
q is 0, 1, 2, 3, 4 or 5;
X 1 selected from the group consisting of: none, NR, O, S (O) t 、CHR、NRC(O)、C(O)NR、NRC(O)C(O)NR、NRC(O)NR、NRC(S)NR、NRC(O)NRCH 2 、NRC(S)NRCH 2 Wherein, R is selected from the following group: H. c (C) 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or a 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group N, S and O;
X 2 or X 3 Each independently is CH or N; when said X 2 Or X 3 When CH is, can be R a Substitution (i.e. X 2 、X 3 C);
M 7 is CR (CR) 8 、NR 8 N, O or S;
M 8 is CR (CR) 8 Or N;
M 9 and M 10 Each independently is C or N, provided that M 9 And M 10 At least one of which is C;
ring a is selected from the group consisting of: H. c (C) 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 An aromatic ring, a 5-10 membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered aromatic ring and a 5-7 membered heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered aromatic ring and a 5-7 membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O and a 5-7 membered heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O and a 5-7 membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O;
R 1 、R 2 and R is 3 Each independently selected from the group consisting of: H. deuterium, halogen, OH, CN, NO 2 、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 A 5-12 membered heteroaryl group having 1-3 heteroatoms selected from the following group N, S, O, a 3-12 membered heterocyclyl group having 1-3 heteroatoms selected from the following group N, S, O, wherein R 2 And R is 3 Alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or hetero in the groups represented The cyclic group may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、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 、NR 6 S(＝O) 2 R 7 ；
R 8 Selected from the group consisting of: H. halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 6-10 Aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from group N, S, O, 5-12 membered heteroaryl having 1-3 heteroatoms selected from group N, S, O, C (O) R 6 、C(O)OR 6 、C(O)NR 6 R 7 、OC(O)R 6 、OC(O)NR 6 R 7 、SR 6 、S(O) 2 R 6 、P(O)R 6 R 7 、S(O) 2 NR 6 R 7 、NR 6 R 7 、C(O)NR 6 S(O) 2 R 7 、NR 6 S(O) 2 R 7 、NR 6 C(O)R 7 、NR 6 C(O)OR 7 A 3-12 membered heterocyclic group having 1-3 heteroatoms selected from the group N, S, O, wherein R is 1 、R 2 And R is 3 The alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl groups in the represented groups may be substituted with 1 to 4 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、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 、NR 6 S(＝O) 2 R 7 ；
q is 0, 1, 2, 3, 4 or 5.
Further, the compound of formula II-a has any one of the structures shown in the following formula:
the compound of the formula II-b has any structure shown in the following formula:
the compound of the formula II-c has any structure shown in the following formula:
the compound of the formula II-d has any structure shown in the following formula:
Further, the compound of formula I has any one of the structures shown in the following formula:
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in another aspect, the present invention provides a method for preparing the above compound, or a pharmaceutically acceptable salt, isomer or hydrate thereof, which is characterized in that: the method is any one of the following methods:
method A:
method B:
and (3) coupling, deprotection and other reactions are carried out by using benzo 1,2, 4-triazine or pyrido 1,2, 4-triazine compounds to obtain the compound shown in the formula I.
In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds described above, or a pharmaceutically acceptable salt, isomer, or hydrate thereof, and a pharmaceutically acceptable excipient.
In another aspect, the invention provides the use of a compound as described above, or a pharmaceutically acceptable salt, isomer or hydrate thereof, in the manufacture of a pharmaceutical composition for the prevention or treatment of a disease responsive to inhibition of HPK1 activity in a subject.
A combination regimen of the above compound, or a pharmaceutically acceptable salt, isomer or hydrate thereof, with other tumor immunotherapeutic agents selected from the group consisting of: small molecule compounds and antibodies (including but not limited to PD-1, PD-L1, CTLA-4, STING agonists, LAG3 antagonists, etc.), tumor targeting agents, tumor vaccines, radiation therapy regimens.
The use of the above compounds and pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates, esters, and deuterated compounds in combination with CAR-T immunotherapy in cancer immunotherapy.
Further, the disease is cancer.
In another aspect, the invention provides the use of a compound as described above, or a pharmaceutically acceptable salt, isomer or hydrate thereof, in an HPK1 kinase inhibitor.
Since the compound of the present invention has excellent inhibitory activity against HPK1 kinase, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable organic or inorganic salts, solvates or hydrates thereof, and the pharmaceutical composition comprising the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of diseases and the like (e.g., cancers) associated with HPK1 kinase activity or expression level.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention within a pharmaceutically acceptable carrier or excipient. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, and more preferably, 10-200mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
By "pharmaceutically acceptable carrier" is meant: one or more compatible liquid or solid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium ethylcellulose, sodium carboxymethylcellulose, cellulose acetate, etc.), gelatin, talc, calcium sulfate, solid lubricants (e.g., stearic acid, magnesium stearate), vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), colorants, polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., tween R, wetting agents (e.g., sodium lauryl sulfate), flavoring agents, preservatives, stabilizers, antioxidants, pyrogen-free water, etc.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
Solid dosage forms for oral administration include capsules, pills, tablets, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as dicalcium phosphate or sodium citrate, or with the following ingredients: (a) fillers or compatibilizers, for example: lactose, sucrose, starch, glucose, mannitol and silicic acid; (b) an adhesive, such as: hydroxymethyl cellulose, gelatin, alginate, polyvinylpyrrolidone, acacia and sucrose; (c) humectants, for example: glycerol; (d) disintegrants, for example: calcium carbonate, agar, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as: kaolin; (i) Lubricants, for example, talc, solid polyethylene glycol, calcium stearate, magnesium stearate, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, capsules, dragees, pills, and granules can be prepared with shell materials and coatings, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, suspensions, solutions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly employed in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example: ethanol, isopropanol, propylene glycol, ethyl acetate, ethyl carbonate, 1, 3-butanediol, dimethylformamide and oils, in particular peanut oil, cottonseed oil, corn germ oil, olive oil, sesame oil and castor oil or mixtures of these substances, etc.
In addition to these inert diluents, the compositions can also include adjuvants such as emulsifying, wetting and suspending agents, flavoring, sweetening, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, for example: polyoxyethylene sorbitol and sorbitan esters, ethoxylated isostearyl alcohols, microcrystalline cellulose, agar and aluminum methoxide or mixtures of these and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or dispersions, anhydrous solutions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and diluents, nonaqueous carriers, solvents or excipients include water, polyols, ethanol and suitable mixtures thereof.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When administered in combination, the pharmaceutical composition further comprises one or more additional pharmaceutically acceptable compounds. One or more of the other pharmaceutically acceptable compounds may be administered simultaneously, separately or sequentially with the compounds of the invention.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and for a human having a body weight of 60kg, the daily dose is usually 1 to 2000mg, preferably 20 to 500mg. Of course, the particular dosage should also take into account factors such as the patient's health, the route of administration, etc., which are within the skill of the skilled practitioner.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages: has excellent HPK1 inhibiting activity, and can be used for preparing pharmaceutical compositions for treating cancers and other diseases related to HPK activity.
Detailed Description
The invention provides a compound shown in the following formula I:
wherein:
X 1 selected from the group consisting of: none, NR, O, S (O) t 、CHR、NRC(O)、C(O)NR、NRC(O)C(O)NR、NRC(O)NR、NRC(S)NR、NRC(O)NRCH 2 、NRC(S)NRCH 2 Wherein, R is selected from the following group: H. c (C) 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or a 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group N, S and O;
X 2 or X 3 Each independently is CH or N; when said X 2 Or X 3 When CH is, can be R a Substitution (i.e. X 2 、X 3 C);
the A ring and the B ring are each independently selected from the group consisting of: H. c (C) 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 An aromatic ring, a 5-10 membered aromatic heterocyclic ring having 1 to 3 hetero atoms selected from the following group N, S, O, a 6-membered aromatic ring and a 5-7 membered heterocyclic ring having 1 to 3 hetero atoms selected from the following group N, S, O, a 6-membered aromatic ring and a 5-7 membered aromatic heterocyclic ring having 1 to 3 hetero atoms selected from the following group N, S, O, a 6-membered heteroaromatic ring having 1 to 3 hetero atoms selected from the following group N, S, O and a 5-7 membered heterocyclic ring having 1 to 3 hetero atoms selected from the following group N, S, O, a 6-membered heteroaromatic ring having 1 to 3 hetero atoms selected from the following group N, S, O and a heteroatom having 1 to 3 hetero atoms selected from the following group N, S, O The 5-7 membered heteroaromatic rings of the children are combined to form a parallel ring;
R a 、R 1 、R 2 and R is 3 Each independently selected from the group consisting of: H. deuterium, halogen, OH, CN, NO 2 、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 A 5-12 membered heteroaryl group having 1-3 heteroatoms selected from the following group N, S, O, a 3-12 membered heterocyclyl group having 1-3 heteroatoms selected from the following group N, S, O, wherein R is represented by a 、R 1 、R 2 And R is 3 The alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl groups in the represented groups may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、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 、NR 6 S(＝O) 2 R 7 ；
p, q are each independently 0, 1, 2, 3, 4 or 5;
in the compound of the formula I, each chiral center is in an R configuration or an S configuration.
Preferably, said X 1 、X 2 、X 3 、Y、M 1 、M 2 、M 3 、M 4 、M 5 、R、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R a 、R b N, m, p, q, t are each independently a corresponding group in a particular compound in each of the examples.
The compounds of the invention may act as HPK1 kinase inhibitors, in preferred embodiments, selective inhibitors of HPK1 kinase.
Preparation of Compounds of formula I
The compounds of formula I of the present invention may be prepared by the following exemplary methods a or B:
Method A:
method B:
and (3) coupling, deprotection and other reactions are carried out by using benzo 1,2, 4-triazine or pyrido 1,2, 4-triazine compounds to obtain the compound shown in the formula I.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Preparation of tert-butyl (3-amino-6-chlorobenzo [ e ] [1,2,4] triazin-8-yl) carbamate, a key intermediate
Step one: boc at room temperature 2 O (53.8 g,247 mmol) was slowly added to a solution of 5-chloro-2-nitroaniline (10 g,57.95 mmol) and DMAP (10.6 g,86.76 mmol) in THF (150 ml) and allowed to react at 70℃for 3h. Cooling to room temperature, concentrating under reduced pressure, and purifying by column chromatography to obtain pale yellowThe compound (5-chloro-2-nitrophenyl) carbamic acid di-tert-butyl ester. MS (ESI) M/Z=373.8 [ M+H ]] + 。
Step two: a solution of potassium tert-butoxide (5.2 g,46.4 mmol) in tetrahydrofuran (20 ml) was slowly added dropwise to a solution of di-tert-butyl (5-chloro-2-nitrophenyl) carbamate (2.17 g,5.8 mmol) and guanidine hydrochloride (1.11 g,11.6 mmol) in tetrahydrofuran (40 ml) at room temperature, the reaction was allowed to warm to 65℃overnight, after the completion of the reaction, cooled to room temperature, saturated ammonium chloride solution was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the bright yellow title compound (3-amino-6-chlorobenzo [ e) was purified by column chromatography ][1,2,4]Triazin-8-yl) carbamic acid tert-butyl ester. MS (ESI) M/Z=296.7 [ M+H ]] + . Preparation of key intermediate 2, 7-iodo-6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinoline
Step one: 7-methoxy-1, 2,3, 4-tetrahydroisoquinoline (6 g,33.85 mmol) and concentrated nitric acid (3.46 g) were added sequentially to pre-chilled trifluoroacetic acid (46 ml) at 0deg.C, and stirred at 0deg.C for 1h, concentrated under reduced pressure, pH 10-11 was adjusted with aqueous 4N NaOH solution, extracted with DCM, the organic phase was dried over anhydrous sodium sulfate, suction filtered, dried, and purified by column chromatography to give 6-methoxy-7-nitro-1, 2,3, 4-tetrahydroisoquinoline (1.85 g, 24.6%). MS (ESI) M/Z=209.2 [ M+H ]] + 。
Step two: to a solution of 7-methoxy-6-nitro-1, 2,3, 4-tetrahydroisoquinoline (7.58 g,46.44mmo 1) in methanol (82 mL) at 0deg.C was added 37% formaldehyde solution (23 mL), and after stirring at 0deg.C for 15 minutes, naBH was added in portions 4 (6.15 g) at room temperature, the resulting mixture was stirred for 3h, quenched with ice water (20 mL), extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate, suction filtered, dried and purified by column chromatography to give 6-methoxy-2-methyl-7-nitro-1, 2,3, 4-tetrahydroisoquinoline. MS (ESI) M/Z=223.2 [ M+H ]] + 。
Step three: in a solution of 7-methoxy-2-methyl-6-nitro-1, 2,3, 4-tetrahydroisoquinoline (8.8 g,39.6mmo 1) in water (10 mL) and EtOH (90 mL) Fe powder (13.2 g,237.60 mmol) and hydrochloric acid (1 ml) were added thereto, stirred at 60℃for 3 hours to a temperature of about room temperature for a time of cooling to a desired value, filtered, the cake was washed with methanol, the filtrate was washed with saturated sodium hydrogencarbonate, and the organic phase was concentrated under reduced pressure and purified by column chromatography to give 6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine. MS (ESI) M/Z=193.3 [ M+H ]] + 。
Step four: paralyenesulfonic acid monohydrate (1.71 g,9 mmol) was added to a solution of 7-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-6-amine (576.8 mg,3 mmol) in acetonitrile (14 ml) at room temperature, cooled to 0deg.C, and KI (1.25 g,7.5 mmol) and NaNO were slowly added dropwise 2 (414 mg,6 mmol) in water (6 ml) was reacted at this temperature for 2 hours and then slowly warmed to room temperature. Saturated sodium bicarbonate aqueous solution is added, ethyl acetate is used for extraction, the organic phase is concentrated under reduced pressure, and the target product 7-iodo-6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinoline is obtained through column chromatography purification. MS (ESI) M/Z=304.1 [ M+H ]] + . Key intermediate 3.n-tert-butoxycarbonyl-N- [ 4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-pyridinyl]Preparation of carbamates
Step one: the N-tert-butoxycarbonyl-N- (4-methyl-5-bromo-3-pyridyl) carbamate is prepared by the same operation procedure as the key intermediate 1 step one. MS (ESI) M/Z=388.3 [ M+H ] ] + 。
Step two: N-tert-Butoxycarbonyl-N- (4-methyl-5-bromo-3-pyridinyl) carbamate (2.383 g,6.16 mmol) was dissolved in N, N-dimethylacetamide (24 mL). To this solution were added bis (pinacolato) diboron (7.823 g,30.8 mmol), KOAc (1.813 g,18.5 mmol) and Pd (dppf) Cl 2 (454 mg,0.62 mmol). The mixture was heated to 90 ℃ under nitrogen and stirred for 2 hours. Cooled to room temperature, quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over sodium sulfate, filtered and evaporated. Purifying the residue by silica gel column to obtain tert-butyl N-tert-butoxycarbonyl-N- [ 4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)) -3-pyridyl]Urethane (2.077 g, 78%). MS (ESI) M/Z=353.2 [ M (boric acid) +H] + 。
Preparation of the key intermediate tert-butyl 4.8-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydropyrido [2,3-b ] [1,4] oxazine-1-carboxylate
Step one: ethyl glycolate (13.17 mL,139.2 mmol) was dissolved in THF (5 mL) and cooled to 0 ℃. Potassium tert-butoxide (13.39 g,119.3 mmol) was added to the solution in portions. After stirring at 0deg.C for 5 min, 5-bromo-2-chloro-4-methyl-3-nitropyridine (5.0 g,19.88 mmol) was added. After stirring at 0 ℃ for 2 min, 15 ml of saturated ammonium chloride was added, followed by extraction with EtOAc, and the organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography to give ethyl 2- ((5-bromo-4-methyl-3-nitropyridin-2-yl) oxy) acetate. MS (ESI) M/Z=320.1 [ M+H ] ] + 。
Step two: ethyl 2- ((5-bromo-4-methyl-3-nitropyridin-2-yl) oxy) acetate (1.3 g,4.07 mmol) and Fe (1.14 g,20.4 mmol) were dissolved in EtOAc (10 mL) and AcOH (5 mL). After heating to 85 ℃ for 16 hours, the reaction mixture was cooled to room temperature and basified with saturated sodium carbonate solution, extracted with EtOAc, the combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 7-bromo-8-methyl-1H-pyrido [2,3-b][1,4]Oxazin-2 (3H) -one, which can be used without further purification in MS (ESI): M/Z=244.1 [ M+H ]] + 。
Step three: under the protection of nitrogen, 7-bromo-8-methyl-1H-pyrido [2,3-b][1,4]Oxazin-2 (3H) -one (331 mg,1.36 mmol) was added to the reaction flask, cooled to 0deg.C, and a solution of borane in THF (4.54 mL,0.9M,3 equiv.) was slowly added, heated to 50deg.C for 30min, cooled to room temperature, and then saturated NaHCO was added dropwise 3 Extracted with EtOAc and the organic layer was dried over sodium sulfate and concentrated in vacuo to give 7-bromo-8-methyl-2, 3-dihydro-1H-pyrido [2,3-b ]][1,4]Oxazines were used without further purification. MS (ESI) M/Z=244.1 [ M+H ]] + 。
Step four: to 7-bromo-8-methyl-2, 3-dihydro-1H-pyrido [2,3-b ] at 0deg.C][1,4]To a solution of oxazine (1 g,4.37 mmol) in tetrahydrofuran (2 mL) was added LiHMDS (8.73 mL,8.73mmol, lmol/L) dropwise. The resulting solution was stirred at 0℃under nitrogen for 0.5 hours. Then, boc anhydride (2.85 g,13.07 mmol) was added and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with methanol (50 mL). The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give 7-bromo-8-methyl-2, 3-dihydropyrido [2,3-b ] ][1,4]Oxazine-1-carboxylic acid tert-butyl ester. MS (ESI) M/Z=230.1 [ M+H ]] + 。
Step five: 7-bromo-8-methyl-2, 3-dihydropyrido [2,3-b][1,4]Oxazine-1-carboxylic acid tert-butyl ester (6.2 g,18.83 mmol), dipinacol diboron (23.93 g,94.22 mmol), pd (dppf) Cl 2 (II) (2.76 g,3.77 mmol) and potassium acetate (5.55 g,56.62 mmol) were added to 1, 4-dioxane (2 mL) and stirred at 90℃for 2.5 hours under nitrogen. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give 8-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydropyrido [2,3-b ]][1,4]Oxazine-1-carboxylic acid tert-butyl ester. MS (ESI) M/Z=376.3 [ M+H ]] + 。
Preparation of the key intermediate 5-tert-butyl (3-fluoro 5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl (methyl) carbamate
Step one: n-bromosuccinimide (15.8 g,89 mmol) was added to a solution of 3-fluoro-5-methylaniline (11 g,88 mmol) in DMF (80 mL) at 0deg.C. The reaction mixture was stirred at 0 ℃ for 30 minutes. After warming to room temperature, the reaction was stirred for an additional 1 hour. Then water and EtOAc were added and the organic phase was washed with saturated aqueous NaHCO 3. The organic phase was then dried over magnesium sulfate and the solvent evaporated under reduced pressure and purified by column chromatography to give 4-bromo-3-fluoro-5-methylaniline. MS (ESI) M/Z=204.0 [ M+H ] ] + 。
Step two: in ice bath, sulfuric acid(4.75 mL,89 mmol) in water (10 mL) was slowly added to a solution of 4-bromo-3-fluoro-5-methylaniline (7.28 g,36 mmol) in acetonitrile (190 mL), after stirring for 5 min, a solution of sodium nitrite (4.92 g,71.4 mmol) in water (10 mL) was added dropwise and the reaction mixture was stirred at 0deg.C for an additional 15 min. Then, a solution of potassium iodide (23.7 g,143 mmol) in water (20 mL) was added, the reaction was stirred for 20 minutes after warming to room temperature, then, the reaction was quenched by adding saturated aqueous sodium thiosulfate solution, the mixture was extracted with ethyl acetate, the combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. Purifying the crude product by column chromatography to obtain 2-bromo-1-fluoro-5-iodo-3-methylbenzene. MS (ESI) M/Z=315.9 [ M+H ]] + 。
Step three: pinacol vinylborate (6.16 mL,34.5 mmol), pd (dppf) Cl 2 (2.40 g,3.3 mmol) and tripotassium phosphate (13.9 g,65.7 mmol) were added to a mixed solution of dioxane (80 ml) and water (13.3 ml). Heating to 70 ℃ under the protection of nitrogen for reaction for 1 hour. After cooling to room temperature, the reaction mixture was filtered through celite, diluted with water, extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography to obtain 2-bromo-1-fluoro-3-methyl-5-vinylbenzene. MS (ESI) M/Z=216.1 [ M+H ] ] + 。
Step four: to a mixed solution of 2-bromo-1-fluoro-3-methyl-5-vinylbenzene (5.46 g,25.4 mmol) in acetone (46 mL) and water (4.6 mL) was added sodium periodate (21.7 g,102 mmol) and 4% aqueous osmium tetroxide (8.07 mL,1.27 mmol) in this order. The reaction was stirred at room temperature for 2 hours. The reaction mixture was then filtered through celite, diluted with water, and extracted with ethyl acetate, the combined organic phases were washed with brine, the organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography. MS (ESI) M/Z=218.0 [ M+H ]] + 。
Step five: 4-bromo-3-fluoro-5-methylbenzaldehyde (1.46 g,6.70 mmol) was added to MeOH (6.70 mL), a 33% solution of methylamine in ethanol (3.15 g,33.5 mmol) and tetraisopropyl titanate (0.982 mL,3.35 mmol) were slowly added under nitrogen, after stirring at room temperature for 3 hours, sodium borohydride (1.01 g,26.8 mmol) was added in portions to the reaction, and stirring was continued at room temperature for 1.5 hours. At this point into the reaction mixtureAmmonia was added and stirring continued for 15 minutes. The reaction was then acidified with 1N HCl and extracted with ethyl acetate. The aqueous phase was taken to be basic and extracted with ethyl acetate and concentrated under reduced pressure to give 1- (4-bromo-3-fluoro-5-methylphenyl) -N-methyl methylamine as a pale yellow oil. MS (ESI) M/Z=231.9 [ M+H ] ] + 。
Step six: to a solution of 1- (4-bromo-3-fluoro-5-methylphenyl) -N-methyl methylamine (1.32 g,5.67 mmol) and triethylamine (1.58 mL,11.34 mmol) in THF (18.9 mL) was added di-tert-butyl dicarbonate (1.58 mL,6.80 mmol) and stirred at room temperature for 1 hour. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. Purifying by column chromatography to obtain (4-bromo-3-fluoro-5-methylbenzyl) (methyl) carbamic acid tert-butyl ester. MS (ESI) M/Z=276.0 [ M+H ]] + 。
Step seven: tert-butyl (4-bromo-3-fluoro-5-methylbenzyl) (methyl) carbamate (573 mg,1.73 mmol) was dissolved in THF (11.5 mL), cooled to-78 ℃, and n-butyllithium (1.6M hexane solution, 1.19mL,1.90 mmol) was slowly added dropwise. The reaction mixture was stirred for 3 minutes, then pinacol 2-isopropylborate (427 ul,2.25 mmol) was added slowly. The reaction was warmed to room temperature and stirred for 5 hours. The reaction was quenched with water, acidified to pH 5-6 using 1N HCl, extracted with ethyl acetate, the organic phase dried over magnesium sulfate and concentrated to give tert-butyl (3-fluoro 5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl (methyl) carbamate the crude product was used in the next step without further purification MS (ESI): M/z=324.2 [ m+h ] ] + 。
Preparation of the key intermediate 6. Tert-butyl (tert-butoxycarbonyl) (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamate
Step one: and (3) preparing the (3-bromo-2-methylphenyl) (tert-butoxycarbonyl) tert-butyl carbamate by the same operation procedure as the key intermediate 3. MS (ESI) M/z=387.3[M+H] + 。
Step two: and the same key intermediate 3, namely, the operation process of the step two, is used for preparing tert-butyl (tert-butoxycarbonyl) (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamate. MS (ESI) M/Z=434.4 [ M+H ]] + 。
Preparation of the key intermediate 7. Preparation of tert-butyl (tert-butoxycarbonyl) (2, 4-dimethyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate
Step one: the (5-bromo-2, 4-dimethylpyridin-3-yl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester is prepared by the same operation procedure as the key intermediate 3, step one. MS (ESI) M/Z=402.3 [ M+H ]] + 。
Step two: and the preparation of tert-butyl (tert-butoxycarbonyl) (2, 4-dimethyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate is carried out in the same operation as the key intermediate 3, namely the step two. MS (ESI) M/Z=449.4 [ M+H ] ] + 。
Preparation of key intermediate 8 8-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydro-2H-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester
Step one: a solution of 5-bromo-4-methyl-pyridin-3-amine (60.0 g,320.79 mmol) and N-iodosuccinimide (72.2 g,320.92 mmol) in acetic acid (1000 mL) was stirred at 25℃for 12 hours. The reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give 5-bromo-2-iodo-4-methyl-pyridin-3-amine (72 g,177.16mmol,55.2% yield) as a yellow solid. MS (ESI) M/Z=414.1 [ M+H ]] + 。
Step two: 5-bromo-2-iodo-4-methyl-pyridin-3-amine (55 g, 1)A solution of 75.76 mmol) and NaHMDS (360 mL,720 mmol) in tetrahydrofuran (500 mL) was stirred for 30 min. Boc is then added 2 O (43 g,197.25 mmol) and stirred at 25℃for 1.5 h. The resulting solution was diluted with water and then extracted with ethyl acetate. The organic layers were combined and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give tert-butyl N- (5-bromo-2-iodo-4-methyl-3-pyridinyl) carbamate (58 g, 79.9%). MS (ESI) M/Z=374.3 [ M+H ]] + 。
Step three: tert-butyl N- (5-bromo-2-iodo-4-methyl-3-pyridinyl) carbamate (500.0 mg,1.21 mmol), zinc bromo- (3-methoxy-3-oxo-propyl) (15 mL,6.89 mmol) and Pd (PPh) were reacted under nitrogen 3 ) 4 A mixture of (115.0 mg,0.10 mmol) of tetrahydrofuran (10 mL) was warmed to 70℃and stirred for 2 hours. The reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel gives 3- [ 5-bromo-3- (tert-butoxycarbonylamino) -4-methyl-2-pyridinyl]Methyl propionate (313 mg, 65.1%). MS (ESI) M/Z=373.0 [ M+H ]] + 。
Step four: 3- [ 5-bromo-3- (tert-butoxycarbonylamino) -4-methyl-2-pyridinyl]A solution of methyl propionate (313.0 mg,0.79 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (4 mL) was stirred for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give 7-bromo-8-methyl-3, 4-dihydro-1H-1, 5-naphthyridin-2-one (140 mg, 70%). MS (ESI) M/Z=241.0 [ M+H ]] + 。
Step five: 7-bromo-8-methyl-3, 4-dihydro-1H-1, 5-naphthyridin-2-one (120.0 mg,0.47 mmol) in tetrahydrofuran (10 mL) and 1M BH at 60 ℃ 3 Is stirred in THF (1.4 mL,1.42 mmol) for 2 hours. The reaction was quenched with methanol and dilute hydrochloric acid. The mixture was concentrated under vacuum. The resulting 7-bromo-8-methyl-1, 2,3, 4-tetrahydro-1, 5-naphthyridine (70 mg, 61.9%) was purified by column chromatography. MS (ESI) M/Z=227.0 [ M+H ] ] + 。
Step six: naHDMS (0.5 mL,0.26 mmol) was added to 7-bromo-8-methyl-1, 2,3, 4-tetrahydro-1,a solution of 5-naphthyridine (60.0 mg,0.26 mmol) in tetrahydrofuran (10 mL) was added and the mixture was stirred at this temperature for 0.5 h. Then add (Boc) 2 O (100.0 mg,0.46 mmol) and stirred at room temperature for 1 hour. The reaction was quenched with methanol (1 mL). The reaction mixture was concentrated under vacuum. Purification by column chromatography gave 7-bromo-8-methyl-3, 4-dihydro-2H-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester (70 mg, 76.9%). MS (ESI) M/Z=327.0 [ M+H ]] + 。
Step seven: 7-bromo-8-methyl-3, 4-dihydro-2H-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester (30.0 g,91.68 mmol), 4',4',5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (117.0 g,460.63 mmol), pd (dppf) Cl 2 A mixture of (6.7 g,9.17 mmol) and KOAc (27.0 g,275.51 mmol) in 1, 4-dioxane (500 mL) was stirred for 3 hours. The solids were removed by filtration. The mixture was then concentrated under vacuum. Purification by column chromatography gave 8-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydro-2H-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester (30 g, 87.4%). MS (ESI) M/Z=375.0 [ M+H ] ] + 。
Preparation of the key intermediate 9. Tert-butyl (tert-butoxycarbonyl) (4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridazin-3-yl) carbamate
Step one: the (5-bromo-4-methylpyridazin-3-yl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester is prepared by the same operation procedure as the key intermediate 3, step one. MS (ESI) M/Z=389.3 [ M+H ]] + 。
Step two: in the same way as the key intermediate 3, the operation procedure of the step two is to prepare tert-butyl (tert-butoxycarbonyl) (4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridazin-3-yl) carbamate. MS (ESI) M/Z=436.3 [ M+H ]] + 。
Preparation of tert-butyl (tert-butoxycarbonyl) (5-fluoro-2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamate as a key intermediate
Step one: the (3-bromo-5-fluoro-2-methylphenyl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester is prepared in the same operation as the key intermediate 3, step one. MS (ESI) M/Z=405.3 [ M+H ]] + 。
Step two: and the same operation process as the key intermediate 3 in the second step is used for preparing tert-butyl (tert-butoxycarbonyl) (5-fluoro-2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamate. MS (ESI) M/Z=452.3 [ M+H ] ] + 。
Preparation of the key intermediate 11. Tert-butyl (tert-butoxycarbonyl) (5-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridazin-4-yl) carbamate
Step one: the (6-bromo-5-methylpyridazin-4-yl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester is prepared by the same operation procedure as the key intermediate 3, step one. MS (ESI) M/Z=389.3 [ M+H ]] + 。
Step two: and the same key intermediate 3, namely, the operation process of the step two, is used for preparing tert-butyl (tert-butoxycarbonyl) (5-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridazin-4-yl) carbamate. MS (ESI) M/Z=436.3 [ M+H ]] + 。
Preparation of tert-butyl (tert-butoxycarbonyl) (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) phenyl) carbamate as key intermediate 12
Step one: process for the step one of the critical intermediate 3To prepare the (3-bromo-2- (trifluoromethyl) phenyl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester. MS (ESI) M/Z=441.3 [ M+H ]] + 。
Step two: the (tert-butoxycarbonyl) (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) phenyl) carbamic acid tert-butyl ester is prepared by the same operation procedure as the key intermediate 3, namely the step two. MS (ESI) M/Z=488.3 [ M+H ] ] + 。
Preparation of tert-butyl (tert-butoxycarbonyl) (6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazin-2-yl) carbamate as a key intermediate
Step one: the (6-bromopyrazin-2-yl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester is prepared by the same operation procedure as the key intermediate 3 step one. MS (ESI) M/Z=375.2 [ M+H ]] + 。
Step two: in the same way as the key intermediate 3, the operation procedure of the step two is to prepare tert-butyl (tert-butoxycarbonyl) (6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazin-2-yl) carbamate. MS (ESI) M/Z=422.3 [ M+H ]] + 。
Preparation of the key intermediate 14. Tert-butyl (tert-butoxycarbonyl) (4-ethyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate
Step one: and (3) preparing the (5-bromo-4-ethylpyridin-3-yl) (tert-butoxycarbonyl) tert-butyl carbamate by the same operation procedure as the key intermediate 3. MS (ESI) M/Z=402.3 [ M+H ]] + 。
Step two: and the same key intermediate 3, namely the operation process of the step two, preparing tert-butyl (tert-butyloxycarbonyl) (4-ethyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate.MS(ESI):M/Z＝449.4[M+H] + 。
Preparation of tert-butyl methyl (4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate
Step one: the (5-bromo-4-methylpyridin-3-yl) (methyl) carbamic acid tert-butyl ester is prepared by the same operation procedure as the key intermediate 4 in the step four. MS (ESI) M/Z=302.3 [ M+H ]] + 。
Step two: and the same key intermediate 4, namely the operation process of the step five, preparing the methyl (4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamic acid tert-butyl ester. MS (ESI) M/Z=349.3 [ M+H ]] + . Key intermediate 16.4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-pyrrolo [2,3-c]Preparation of pyridine-1-carboxylic acid tert-butyl ester
Step one: the key intermediate 4 is prepared into 4-bromo-2, 3-dihydro-1H-pyrrolo [2,3-c ] in the operation process of the step four]Pyridine-1-carboxylic acid tert-butyl ester. MS (ESI) M/Z=300.2 [ M+H ]] + 。
Step two: the same key intermediate 4 step five operation process, preparing 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-pyrrolo [2,3-c]Pyridine-1-carboxylic acid tert-butyl ester. MS (ESI) M/Z=349.3 [ M+H ]] + . Key intermediate 17.7-bromo-8-methyl-1H-pyrido [2,3-b][1,4]Preparation of oxazin-2 (3H) -ones
Step one: ethyl glycolate (13.17 mL,139.2 mmol) was dissolved in THF (5 mL) and cooled to 0 ℃. Will be Potassium tert-butoxide (13.39 g,119.3 mmol) was added to the solution in portions. After stirring at 0deg.C for 5 min, 5-bromo-2-chloro-4-methyl-3-nitropyridine (5.0 g,19.88 mmol) was added. After stirring at 0 ℃ for 2 min, 15 ml of saturated ammonium chloride was added, followed by extraction with EtOAc, and the organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography to give ethyl 2- ((5-bromo-4-methyl-3-nitropyridin-2-yl) oxy) acetate. MS (ESI) M/Z=320.1 [ M+H ]] + 。
Step two: ethyl 2- ((5-bromo-4-methyl-3-nitropyridin-2-yl) oxy) acetate (1.3 g,4.07 mmol) and Fe (1.14 g,20.4 mmol) were dissolved in EtOAc (10 mL) and AcOH (5 mL). After heating to 85 ℃ for 16 hours, the reaction mixture was cooled to room temperature and basified with saturated sodium carbonate solution, extracted with EtOAc, the combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 7-bromo-8-methyl-1H-pyrido [2,3-b][1,4]Oxazin-2 (3H) -one, which is used without further purification. MS (ESI) M/Z=244.1 [ M+H ]] + 。
Preparation of key intermediate 18- (7-bromo-3, 4-dihydro-1, 5-naphthyridine-1 (2H) -carboxylic acid tert-butyl ester
Step one: 60% sodium hydride (5 g,126 mmol) was added to 100mLN, N-dimethylformamide, and diethyl malonate (20 g,126 mmol) was added dropwise at 0℃and reacted at this temperature for 30min. After the reaction system was clarified, a solution of 5-bromo-2-chloro-3-nitropyridine (10 g,42.1 mmol) as an intermediate in N, N-dimethylformamide (20 mL) was slowly added dropwise to the reaction solution, and the reaction was carried out at room temperature overnight. After the reaction was completed, N-dimethylformamide was dried by spin, the oily substance was dissolved in water, extracted with ethyl acetate, and the organic phase was dried by spin under reduced pressure to obtain a crude intermediate in the form of yellow oil, which was used directly in the next reaction without purification. MS (ESI) M/Z=362.2 [ M+H ] ] + 。
Step two: 60% sodium hydride (2.2 g,53.2 mmol 1) was added to 40mL of N, N-dimethylformamide, diethyl 2- (5-bromo-3-nitropyridin-2-yl) malonate (9.68, 26.2 mmol) was added dropwise at 0deg.C,the reaction was carried out at this temperature for 1h. A solution of ethyl bromoacetate (6.68, 40 mmol) in N, N-dimethylformamide (10 mL) was then slowly added dropwise to the reaction mixture and reacted overnight at room temperature. After completion of the reaction, N-dimethylformamide was dried by spin-drying, and saturated sodium bicarbonate solution (50 mL) was added thereto, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying. Purifying by column chromatography to obtain yellow oily intermediate (5-bromo-3-nitropyridin-2-yl) methane tricarboxylic acid triethyl ester. MS (ESI) M/Z=434.2 [ M+H ]] + 。
Step three: triethyl (5-bromo-3-nitropyridin-2-yl) methane tricarboxylic acid (2.58, 5.6 mmol) was added to 10ml 6N HCl and reacted overnight at 80℃under nitrogen. Cooled to room temperature, the pH was adjusted to 9 with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying. Purifying by column chromatography to obtain yellow oily intermediate 5-bromo-3-nitropyridine-2-ethyl propionate. MS (ESI) M/Z=304.1 [ M+H ] ] + 。
Step four. Ethyl 5-bromo-3-nitropyridine-2-propionate (420 mg,14 mmol) was dissolved in ethanol (10 mL), stannous chloride dihydrate (1.3 g,7 mmol) was added in portions, and the temperature was raised to 80℃and stirred overnight. Cooling to room temperature, filtering to obtain white solid intermediate 7-bromo-3, 4-dihydro-1, 5-naphthyridine-2 (1H) -ketone. MS (ESI) M/Z=208.1 [ M+H ]] + 。
Step five: 7-bromo-3, 4-dihydro-1, 5-naphthyridin-2 (1H) -one (200 mg,0.88 mmol) was dissolved in 5mL of borane in tetrahydrofuran, and the temperature was raised to 80℃for 2H. The reaction mixture was cooled to room temperature and quenched by methanol, 3N HCl (5 mL) was added dropwise, the temperature was raised to 110℃and the reaction was continued for 3h. Cooled to room temperature, saturated aqueous sodium bicarbonate was brought to pH 9 and extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was dried by spin-drying, and purified by column chromatography to give the intermediate 7-bromo-1, 2,3, 4-tetrahydro-1, 5-naphthyridine as a colourless oil. MS (ESI) M/Z=214.1 [ M+H ]] + 。
Step six: the same key intermediate 4 step four operation procedure, prepare (7-bromo-3, 4-dihydro-1, 5-naphthyridine-1 (2H) -carboxylic acid tert-butyl ester MS (ESI) M/Z=314.2 [ M+H ]] + 。
Preparation of the key intermediate 19. Preparation of tert-butyl (tert-butoxycarbonyl) (5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate
Step one: the (5-bromopyridin-3-yl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester is prepared by the same operation procedure as the key intermediate 3, step one. MS (ESI) M/Z=374.3 [ M+H ]] + 。
Step two: in the same way as the key intermediate 3, the operation procedure of the step two is to prepare tert-butyl (tert-butoxycarbonyl) (5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate. MS (ESI) M/Z=421.3 [ M+H ]] + 。
Preparation of key intermediate 20.7-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-imidazo [4,5-b ] pyridine-1-carboxylic acid tert-butyl ester
Step one: the key intermediate 4 is prepared by the operation process of the step four to obtain the 6-bromo-7-methyl-1H-imidazo [4,5-b]Pyridine-1-carboxylic acid tert-butyl ester. MS (ESI) M/Z=313.2 [ M+H ]] + 。
Step two: the same key intermediate 4 step five operation procedure is used for preparing 7-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-imidazo [4,5-b]Pyridine-1-carboxylic acid tert-butyl ester. MS (ESI) M/Z=360.2 [ M+H ]] + . Preparation of tert-butyl (tert-butoxycarbonyl) (4-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate as a key intermediate
Step one: operation of step one with critical intermediate 3 The (5-bromo-4-methoxypyridin-3-yl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester is prepared. MS (ESI) M/Z=404.3 [ M+H ]] + 。
Step two: and the operation process of the key intermediate 3 step two is the same, so that tert-butyl (tert-butoxycarbonyl) (4-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate is prepared. MS (ESI) M/Z=451.3 [ M+H ]] + 。
Preparation of tert-butyl (tert-butoxycarbonyl) (4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) carbamate as a key intermediate
Step one: and (3) preparing the (5-bromo-4-methylpyridin-2-yl) (tert-butoxycarbonyl) tert-butyl carbamate by the same operation procedure as the key intermediate 3. MS (ESI) M/Z=388.3 [ M+H ]] + 。
Step two: in the same way as the key intermediate 3, the operation procedure of the step two is to prepare tert-butyl (tert-butoxycarbonyl) (4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) carbamate. MS (ESI) M/Z=435.3 [ M+H ]] + 。
Preparation of the Critical intermediate 23. Preparation of tert-butyl (tert-Butoxycarbonyl) (5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) carbamate
Step one: the (5-bromopyridin-2-yl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester is prepared by the same operation procedure as the key intermediate 3, step one. MS (ESI) M/Z=374.3 [ M+H ] ] + 。
Step two: the same key intermediate 3 step two operation process, to prepare tert-butyl (tert-butyloxycarbonyl) (5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-yl) carbamic acidAn ester. MS (ESI) M/Z=421.3 [ M+H ]] + . Preparation of key intermediate 24.5-bromo-2- (oxazol-2-yl) pyridine
Step one: to a solution of 5-bromopyridine formyl chloride (0.5 g,2.5 mmol) in EtOH (30 mL) was added 2, 2-dimethoxyethylamine (0.26 g,2.5 mmol) and TEA (1.1 g,10 mml). The reaction mixture was refluxed for 2 hours, concentrated and purified by column chromatography to give 5-bromo-N- (2, 2-dimethoxyethyl) pyridine amide (0.58 g, 80%) as a pale yellow solid. MS (ESI) M/Z=290.1 [ M+H ]] + 。
Step two: to a solution of 5-bromo-N- (2, 2-dimethoxyethyl) pyridine amide (0.58 g,2.0 mmol) in DCM (30 mL) was added concentrated HCl (2 mL). The reaction mixture was stirred at room temperature for 4h, saturated NaHCO was added 3 The solution was brought to pH 7.5 and the organic layer was washed with brine, dried over MgSO4 and concentrated to give 5-bromo-N- (2-oxoethyl) picolinamide as a white solid. MS (ESI) M/Z=244.1 [ M+H ]] + 。
Step three: to a solution of 5-bromo-N- (2-oxoethyl) pyridine amide (0.24 g,1 mmol) in toluene (10 mL) was added Ph 3 PO (0.56 g,2 mmol). The reaction mixture was refluxed overnight, concentrated and purified by column chromatography to give 5-bromo-2- (oxazol-2-yl) pyridine as a white solid. MS (ESI) M/Z=226.1 [ M+H ] ] + 。
Preparation of key intermediate 25.6-bromo-5-methyl 3H-1, 3-benzoxazol-2-one
5-methyl-3H-1, 3-benzoxazol-2-one (500 mg,3.35 mmol) and NBS (650 mg,3.69 mmol) were stirred in acetic acid (10 mL) at 20deg.C for 16H. The reaction mixture was diluted with water (25 mL) and stirring was continued for 15 min. The mixture was then filtered and washed with water to give 6-bromo-5-methyl 3H-1, 3-benzoxazol-2-one as a white solid. MS (ESI) M/Z=229.1 [ M+H ]] + 。
Preparation of key intermediate 26.3-bromo-4-methyl-2-phenylpyridine
2, 3-dibromo-4-methylpyridine (500 mg,2.00 mmol), phenylboronic acid (257 mg, 2.lmmol), tetrakis (triphenylphosphine) palladium (116 mg,0.10 mmol), and anhydrous potassium carbonate (833 mg,6.03 mmol) were added to a mixed solvent of toluene 20mL and water 2 mL. The reaction was carried out at 50℃for 15h under nitrogen. Cooling to room temperature, filtering, distilling under reduced pressure, and purifying by column chromatography to obtain white solid 3-bromo-4-methyl-2-phenylpyridine MS (ESI) with M/Z=249.1 [ M+H ]] + 。
Preparation of key intermediate 27.5-iodo-1, 4-dimethyl-pyrazol-3-amine
Step one: 4-methyl-3-nitro-1H-pyrazole (500 mg,3.93 mmol), iodomethane (837.9 mg,5.9 mmol) and potassium tert-butoxide (484.6 mg,4.33 mmol) were added to a solution of tetrahydrofuran (20 mL) and stirred at 25℃for 1 hour. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give 1, 4-dimethyl-3-nitro-pyrazole as a white solid. MS (ESI) M/Z=142.1 [ M+H ] ] + 。
Step two: 1, 4-dimethyl-3-nitro-pyrazole (530 mg,3.76 mmol) and palladium on carbon (10%) (50 mg,3.76 mmol) were added to methanol (20 mL) at 20deg.C and stirred for 1 hour. After filtration, the filtrate was concentrated under reduced pressure to give 1, 4-dimethylpyrazole-3-amine as a pale yellow oil. MS (ESI) M/Z=112.2 [ M+H ]] + 。
Step three: a solution of 1, 4-dimethylpyrazol-3-amine (1.53 g,13.77 mmol), 2, 5-hexanedione (3.14 g,27.53 mmol) and p-toluenesulfonic acid (0.24 g,1.38 mmol) in toluene (60 mL) was stirred at 110deg.C for 3 hours. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give 3- (2, 5-dimethylpyrrol-1-yl) -1, 4-dimethyl-pyrazole as a grey solid. MS (ESI) M/Z=190.3 [ M+H ]] + 。
Step four: to a solution of 3- (2, 5-dimethylpyrrol-1-yl) -1, 4-dimethyl-pyrazole (500 mg,2.64 mmol) in tetrahydrofuran (20 mL) was slowly added n-butyllithium (1.27 mL,3.17 mmol) at-78deg.C. Stirred at-78℃for 1 hour. Iodine (671.03 mg,2.64 mmol) was then added and stirred at-78℃for 10 minutes. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous sodium thiosulfate. The resulting solution was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give 3- (2, 5-dimethylpyrrol-1-yl) -5-iodo-1, 4-dimethyl-pyrazole as a pale yellow oil. MS (ESI) M/Z=316.2 [ M+H ] ] + 。
Step five: a solution of 3- (2, 5-dimethylpyrrol-1-yl) -5-iodo-1, 4-dimethyl-pyrazole (500 mg,1.59 mmol), potassium hydroxide (444.23 mg,7.93 mmol), hydroxylamine hydrochloride (1.09 g,15.87 mmol) in ethanol (20 mL) and water (20 mL) was stirred at 90℃for 12 h. Concentrated in vacuo and the residue purified by flash chromatography on silica gel to give 5-iodo-1, 4-dimethyl-pyrazol-3-amine as a white solid. MS (ESI) M/Z=238.0 [ M+H ]] + 。
Preparation of tert-butyl (tert-butoxycarbonyl) (4-methoxy-2-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate
Step one: the (5-bromo-4-methoxy-2-methylpyridin-3-yl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester is prepared by the same operation procedure as the key intermediate 3, step one. MS (ESI) M/Z=418.3 [ M+H ]] + 。
Step two: and the preparation of tert-butyl (tert-butoxycarbonyl) (4-methoxy-2-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate is carried out in the same operation as the key intermediate 3, namely the step two. MS (ESI) M/Z=465.4 [ M+H ]] + 。
Preparation of the key intermediate 29. Tert-butyl (tert-butoxycarbonyl) (6-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate
Step one: the (5-bromo-6-methylpyridin-3-yl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester is prepared in the same operation as the key intermediate 3, step one. MS (ESI) M/Z=388.3 [ M+H ]] + 。
Step two: and the same operation process as the key intermediate 3 in the second step is used for preparing tert-butyl (tert-butoxycarbonyl) (6-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate. MS (ESI) M/Z=435.3 [ M+H ]] + 。
Preparation of tert-butyl (tert-butoxycarbonyl) (2-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate as a key intermediate
Step one: the (5-bromo-2-methylpyridin-3-yl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester is prepared in the same operation as the key intermediate 3, step one. MS (ESI) M/Z=388.3 [ M+H ]] + 。
Step two: and the operation process of the key intermediate 3 step two is the same, so that tert-butyl (tert-butoxycarbonyl) (2-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate is prepared. MS (ESI) M/Z=435.3 [ M+H ]] + 。
Preparation of the key intermediate 31.7-bromo-4- [ tert-butyl (dimethyl) silyl ] oxy-8-methyl-3, 4-dihydro-2H-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester
Step one: at 0 DEG CA solution of 5-bromo-2-iodo-4-methyl-pyridin-3-amine (55 g,175.76 mmol) and NaHMDS (360 mL,720 mmol) in tetrahydrofuran (500 mL) was stirred for 30 min. Then add (Boc) 2 O (43 g,197.25 mmol) and stirred at 25℃for 1.5 h. The resulting solution was diluted with water and then extracted with ethyl acetate. The organic layers were combined and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give tert-butyl N- (5-bromo-2-iodo-4-methyl-3-pyridinyl) carbamate as a yellow oil (58 g, 79.9%). MS (ESI) M/Z=414.1 [ M+H ]] + 。
Step two: a solution of tert-butyl N- (5-bromo-2-iodo-4-methyl-3-pyridinyl) carbamate (58 g,140.42 mmol) in tetrahydrofuran (500 mL) was stirred at room temperature for 1 hour. 4-bromo-1-butene (50 g,370.37 mmol) and NaI (55 g,366.67 mmol) were then added and stirred at 95℃for 16 hours. The reaction was then quenched by the addition of water and extracted with ethyl acetate. The organic layers were combined, dried and concentrated in vacuo. Purification by flash chromatography on silica afforded N- (5-bromo-2-iodo-4-methyl-3-pyridinyl) -N-but-3-enyl-carbamic acid tert-butyl ester (30 g, 45.7%) as a yellow oil. MS (ESI) M/Z=467.1 [ M+H ] ] + 。
Step three: n- (5-bromo-2-iodo-4-methyl-3-pyridinyl) -N-but-3-enyl-carbamic acid tert-butyl ester (30 g,64.22 mmol), pd (dppf) Cl 2 A solution of N, N-dimethylformamide (1500 mL) in (2.4 g,3.28 mmol) and TEA (13.1 g,128.43 mmol) was stirred for 1 hour at 110℃under nitrogen. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 7-bromo-8-methyl-4-methylene-2, 3-dihydro-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester (13 g, 59.7%). MS (ESI) M/Z=420.1 [ M+H ]] + 。
Step four: 7-bromo-8-methyl-4-methylene-2, 3-dihydro-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester (13 g,38.32 mmol), ruCl at 25 ℃ 3 (2.4 g,11.59 mmol) and NaIO 4 A solution of (20.5 g,95.79 mmol) in acetonitrile (350 mL), carbon tetrachloride (350 mL) and water (350 mL) was stirred for 1.5 h. The reaction was then quenched by adding 300mL of sodium thiosulfate solution. The resulting solution was adjusted to pH6-7 with sodium bicarbonate and extracted with ethyl acetate. The organic phase is then concentrated under vacuum. Purification by flash chromatography on silica gel afforded 7-bromo-8-methyl-4-oxo-2, 3-dihydro-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester (7 g, 53.5%) as a yellow solid. MS (ESI) M/Z=342.2 [ M+H ] ] + 。
Step five: 7-bromo-8-methyl-4-oxo-2, 3-dihydro-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester (500 mg,1.47 mmol) and NaBH at room temperature 4
A solution of (150 mg,4.05 mmol) in ethanol (30 mL) was stirred for 2 hours. The reaction mixture was diluted with water. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give 7-bromo-4-hydroxy-8-methyl-3, 4-dihydro-2H-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester (400 mg, 71.6%) as a yellow solid. MS (ESI) M/Z=344.2 [ M+H ]] + 。
Step six: to a solution of 7-bromo-4-hydroxy-8-methyl-3, 4-dihydro-2H-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester (330 mg,0.96 mmol) and imidazole (200 mg,2.94 mmol) in dichloromethane (10 mL) at room temperature was added TBDMSCl (293 mg,1.95 mmol) and the resulting solution was stirred under nitrogen at 25℃for 2 hours. Purification by flash chromatography on silica gel gives 7-bromo-4- [ tert-butyl (dimethyl) silyl as a colourless oil]Oxygen-8-methyl-3, 4-dihydro-2H-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester (400 mg, 90.9%). MS (ESI) M/Z=458.5 [ M+H ]] + 。
Preparation of the key intermediate 32.6-bromo-4- ((tert-butyldimethylsilyl) oxy) -5-methyl-3, 4-dihydro-2H-pyranol [2,3-b ] pyridine
Step one: to a suspension of sodium acetate (9.86 g,120 mmol) and 2-methoxy-4-methylpyridine (5 g,39 mmol) in acetic acid (40 mL) was added bromine (6.0 mL,120 mmol). The mixture was then stirred at 80℃for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then taken up in 10% aqueous sodium hydroxide (28 g,698 mmol) and saturated subunit Sodium sulfate solution (15 g,120 mmol) was treated. The resulting mixture was extracted with isopropyl ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated, and purified by column chromatography to give 3, 5-dibromo-2-methoxy-4-methylpyridine as a white solid. MS (ESI) M/Z=281.0 [ M+H ]] + 。
Step two: a solution of 3, 5-dibromo-2-methoxy-4-methylpyridine (7.6 g,27 mmol) in diethyl ether (100 mL) was cooled to-65℃under nitrogen. N-butyllithium (2.5M in hexane, 12mL,29.7 mmol) was added dropwise with constant stirring while maintaining the temperature at-65 ℃. The reaction mixture was cooled to-70 ℃ and stirred under nitrogen for 1 hour. Acrolein (4.43 g,79.12 mmol) was added dropwise at-65 ℃. The reaction was then warmed to room temperature overnight. 30mL of saturated sodium bicarbonate solution was added to quench the reaction. The resulting mixture was extracted with dichloromethane, dried over magnesium sulfate, and then filtered. The filtrate was concentrated to give 1- (5-bromo-2-methoxy-4-methylpyridin-3-yl) prop-2-en-1-ol as a clear oil which was used directly in the next step without further purification. MS (ESI) M/Z=259.1 [ M+H ]] + 。
Step three: to a solution of 1- (3-bromo-6-methoxy-2-methyl-phenyl) prop-2-en-1-ol (16.84 g,65.48 mmol) in dichloromethane (150 mL) was added dess-martin oxidant (41.7 g,98.21 mmol) at room temperature. The reaction was stirred at room temperature overnight and then quenched by the addition of saturated sodium bicarbonate solution. The organic layer was collected. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated, and purified by flash chromatography to give 1- (3-bromo-6-methoxy-2-methyl-phenyl) prop-2-en-1-one (4.81 g, 28.6% in two steps) as a clear oil. MS (ESI) M/Z=257.1 [ M+H ] ] + 。
Step four: to a solution of 1- (5-bromo-2-methoxy-4-methyl-3-pyridinyl) prop-2-en-1-one (4.81 g,18.78 mmol) in acetic acid (80 mL) was added hydrobromic acid (9.5 g,56.35 mmol). The reaction was heated to 100 ℃ for 45 minutes, then cooled to room temperature and extracted with isopropyl ether. The combined organic layers were washed with saturated sodium bicarbonate solution. The organic layer was collected, dried over magnesium sulfate, filtered and purifiedConcentrating under the air. Purification by flash chromatography gave 6-bromo-5-methyl-2, 3-dihydropyrano [2,3-b ] as a white solid]Pyridin-4-ones. MS (ESI) M/Z=443.1 [ M+H ]] + 。
Step five: to 6-bromo-5-methyl-2, 3-dihydropyrano [2,3-b]To a solution of pyridin-4-one (1.81 mg,7.45 mmol) in methanol (50 ml) was added sodium borohydride (657 mg,17.35 mmol). The mixture was stirred at room temperature for 12 hours. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The combined organic layers were then dried over magnesium sulfate, filtered and concentrated to give 6-bromo-5-methyl-3, 4-dihydro-2H-pyrano [2,3-b ] as a white solid]Pyridin-4-ol was used directly in the next step without purification. MS (ESI) M/Z=245.1 [ M+H ]] + 。
Step six: to 6-bromo-5-methyl-3, 4-dihydro-2H-pyranol [2,3-b ]]To a solution of pyridin-4-ol (507.2 mg,2.1 mmol) in dichloromethane (12 mL) was added triethylamine (0.75 mL,5.4 mmol). The mixture was cooled to 0 ℃ under nitrogen and then t-butyldimethylsilyl triflate (0.58 ml,2.47 mmol) was added. The reaction mixture was stirred at room temperature for 45 minutes, then concentrated ammonium chloride solution was added to quench it. The mixture was extracted with dichloromethane and the organic layer was dried over sodium sulfate, filtered and concentrated and purified by column chromatography to give 6-bromo-4- ((tert-butyldimethylsilyl) oxy) -5-methyl-3, 4-dihydro-2H-pyranol [2,3-b ] as a white solid ]Pyridine. MS (ESI) M/Z=359.4 [ M+H ]] + 。
Preparation of the key intermediate 33.6-bromo-5-methyl-3, 4-dihydro-2H-pyrano [2,3-b ] pyridine-4-carbonitrile
Step one: at 0 ℃, 6-bromo-5-methyl-3, 4-dihydro-2H-pyrano [2,3-b ]]A solution of pyridin-4-ol (1.77 g,7.26 mmol) and triethylamine (3.03 ml,21.77 mmol) in dichloromethane (50 ml) was stirred for 5 minutes. Methanesulfonyl chloride (0.84 ml,10.88 mmol) was then added. The mixture was stirred at 0℃for 2 hours. The reaction was quenched with water and extracted with DCM. The organic layers were combined and dried over anhydrous sodium sulfateAnd concentrating under vacuum to give red oil of 6-bromo-4-chloro-5-methyl-3, 4-dihydro-2H-pyrano [2,3-b ]]Pyridine (2.28 g,8.71 mmol) was used directly in the next step without purification. MS (ESI) M/Z=323.2 [ M+H ]] + 。
Step two: 6-bromo-4-chloro-5-methyl-3, 4-dihydro-2H-pyrano [2,3-b ] at 70 ℃]A solution of pyridine (2.29 mg,8.71 mmol) and tetraethylammonium cyanide (4.08 g,26.11 mmol) in toluene (90 ml) was stirred for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 6-bromo-5-methyl-3, 4-dihydro-2H-pyrano [2,3-b ] as a yellow solid ]Pyridine-4-carbonitrile (800.0 mg, 42.42% in two steps). MS (ESI) M/Z=254.1 [ M+H ]] + 。
Key intermediate 34. Tert-butyl (tert-butoxycarbonyl) (4, 6-dimethyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate
Step one: the (5-bromo-4, 6-dimethylpyridin-3-yl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester is prepared by the same operation procedure as the key intermediate 3, step one. MS (ESI) M/Z=402.3 [ M+H ]] + 。
Step two: in the same way as the key intermediate 3, the operation procedure of the step two is to prepare tert-butyl (tert-butoxycarbonyl) (4, 6-dimethyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) carbamate. MS (ESI) M/Z=449.4 [ M+H ]] + 。
Preparation of the key intermediate 35.3-bromo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-5 (4H) -carboxylic acid tert-butyl ester
Step one: 1H-pyrazole-5-carbaldehyde (800 mg,8.33 mmol) and 2- (benzylamino) ethanol (1.182 ml,8.33 mmol) in MeOA solution of H (40 ml) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (5.29 g,24.98 mmol) and AcOH (0.953 ml,16.65 mmol) were then added in portions. The reaction mixture was stirred at room temperature for a further 4 hours. The reaction mixture was quenched with 2mL of water and saturated NaHCO was added 3 The aqueous solution was extracted with ethyl acetate, the organic layer was dried over MgSO4, filtered and concentrated, and the crude product was used directly in the next step without further purification. MS (ESI) M/Z=232.0 [ M+H ]] + 。
Step two: thionyl chloride (4.26 mL,58.3 mmol) was slowly added to a solution of 2- (((1H-pyrazol-5-yl) methyl) (benzyl) amino) ethanol (1.93 g,8.33 mmol) in DCM (40 mL) at 0deg.C, and the mixture was warmed to RT and stirred overnight. The solvent was removed under reduced pressure. The residue was redissolved in DMF (25 mL), 60% NaH (2.0 g,50.0 mmol) was added in portions and stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride, extracted with EtOAc and the organic layer was dried over MgSO 4 Dried, filtered and concentrated. Purifying by column chromatography to obtain 5-benzyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazine (0.876 g,50% yield). MS (ESI) M/Z=214.0 [ M+H ]] + 。
Step three: pd (OH) was taken up at room temperature 2 (348 mg,0.493 mmol) and Boc 2 O (2.77 ml,11.91 mmol) was added to 5-benzyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]In a solution of pyrazine (876 mg,4.11 mmol) in MeOH (20 mL), the reaction mixture was taken up in H 2 Stirring is carried out for 3 hours under an atmosphere. More Pd (OH) is added 2 (348 mg,0.493 mmol) in H 2 The reaction was carried out in the atmosphere for 3 hours. The reaction mixture was filtered through celite, and then the filtrate was concentrated. Purifying by column chromatography to obtain 6, 7-dihydropyrazolo [1,5-a ] ]Pyrazine-5 (4H) -carboxylic acid tert-butyl ester (916 mg,100% yield). MS (ESI) M/Z=224.1 [ M+H ]] + 。
Step four: by reacting 6, 7-dihydropyrazolo [1,5-a ]]Pyrazine-5 (4H) -carboxylic acid tert-butyl ester (480 mg,2.150 mmol) and NBS (383 mg,2.150 mmol) were added to DCM (15 mL) at room temperature and the reaction stirred for 2H. The mixture was diluted with EtOAc and washed with brine, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give 3-bromo-6, 7-dihydropyrazolo [1,5-a]Pyrazine-5 (4H) -carboxylic acid tert-butyl ester. The crude product was not further purified. MS (ESI) M/Z=301.9/303.9[M+H] + . Preparation of key intermediate 36.6-iodo-7-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinoline
Step one, two, three and four: and the operation process of the key intermediate 2 is the same, so that the 6-iodo-7-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinoline is prepared. MS (ESI) M/Z=193.3 [ M+H ]] + 。
Preparation of key intermediate 37.6-iodo-7-methoxy-2, 4-dimethyl-1, 2,3, 4-tetrahydroisoquinoline
Step one: to a solution of 6-methoxy-1-methyl-3, 4-dihydroisoquinoline (840 mg,4.79 mmol) in acetone (20 mL) was added methyl iodide (0.33 mL,5.27 mmol). The reaction was stirred overnight and then concentrated under vacuum to give 6-methoxy-l, 2-dimethyl-3, 4-dihydroisoquinoline-2-ammonium iodide. MS (ESI) M/Z=191.3 [ M+H ] ] + 。
Step two: naBH4 (3.36 mmol) was added in portions to a solution of 6-methoxy-l, 2-dimethyl-3, 4-dihydroisoquinoline-2-iodide (0.65 mmol) in MeOH (8 mL) at 0deg.C, reacted at room temperature for 3 hours using saturated NaHCO 3 Quenching the aqueous solution, extracting with DCM, drying the organic phase with anhydrous sodium sulfate, suction filtering, spin drying, and purifying by column chromatography to obtain 6-methoxy-1, 2-dimethyl-1, 2,3, 4-tetrahydroisoquinoline. MS (ESI) M/Z=192.3 [ M+H ]] + 。
Step three, four, five: and the operation process of the key intermediate 2 is the same, so that the 6-iodo-7-methoxy-2, 4-dimethyl-1, 2,3, 4-tetrahydroisoquinoline is prepared. MS (ESI) M/Z=318.2 [ M+H ]] + 。
Preparation of key intermediate 38.7-iodo-6-methoxy-2, 4-trimethyl-1, 2,3, 4-tetrahydroisoquinoline
Step one: 2- (3-methoxyphenyl) -2-methylpropylene-1-amine (lg, 5.58 mmol) and formic acid (2.8 mL) were added to paraformaldehyde (168 mg,5.59 mmol) at 0deg.C and stirred for 14h at 50deg.C. The resulting mixture was cooled to room temperature, diluted with water, extracted with DCM, the aqueous phase separated, basified with 4N sodium hydroxide solution, extracted with DCM, the combined organic phases dried over anhydrous sodium sulfate, filtered and concentrated to give 2- (3-methoxybenzene) -2-methylpropylamine. MS (ESI) M/Z=192.27 [ M+H ] +.
Step two, three, four and five: and the operation process of the key intermediate 2 is the same, so that 7-iodine-6-methoxy-2, 4-trimethyl-1, 2,3, 4-tetrahydroisoquinoline is prepared. MS (ESI) M/Z=332.2 [ M+H ]] + 。
Preparation of key intermediate 39.8-iodo-9-methoxy-1, 3,4,6,11 a-hexahydro-2H-pyrido [1,2-b ] isoquinoline
Step one: the same procedure as for key intermediate 38 gives 9-methoxy-1, 3,4,6,11 a-hexahydro-2H-pyrido [1,2-b ]]And (3) isoquinoline. MS (ESI) M/Z=218.3 [ M+H ]] + 。
Step two, three and four: the same operation procedure as key intermediate 2 to obtain 8-iodo-9-methoxy-1, 3,4,6,11 a-hexahydro-2H-pyrido [1,2-b ]]And (3) isoquinoline. MS (ESI) M/Z=344.2 [ M+H ]] + 。
Preparation of key intermediate 40.5-bromo-7-iodo-2-methyl-1, 2,3, 4-tetrahydroisoquinoline
Step one: 2-methyl-7-nitro-1, 2,3, 4-tetrahydroisoquinoline (500.0 mg,2.60 mg) was added to trifluoromethanesulfonic acid (6 mL), cooled to 0deg.C, and N-bromosuccinimide (926 mg,5.20 mmol) was added. The reaction was heated to 60 ℃ and then stirred for 19 hours. Then add moreThe reaction was stirred at 60℃for another 5 hours, the resulting mixture was poured into ice water (50 mL), the mixture was diluted with 10% aqueous sodium thiosulfate (20 mL), stirred for 5 minutes, and then aqueous 4N NaOH until the pH was around 10. The mixture is extracted with dichloromethane, washed with 10% sodium thiosulfate aqueous solution, saturated sodium bicarbonate aqueous solution and saturated saline solution, dried with anhydrous sodium sulfate, filtered, dried by suction, and purified by column chromatography to obtain 8-bromo-2-methyl-7-nitro-1, 2,3, 4-tetrahydroisoquinoline. MS (ESI) M/Z=272.1 [ M+H ] ] + 。
Step two, three: and the operation process of the key intermediate 2 is the same, so that the 5-bromo-7-iodo-2-methyl-1, 2,3, 4-tetrahydroisoquinoline is prepared. MS (ESI) M/Z=353.0 [ M+H ]] + 。
Preparation of key intermediate 41.6-fluoro-7-iodo-2-methyl-1, 2,3, 4-tetrahydroisoquinoline
Step one: potassium nitrate (578.47 mg,5.72 mmol) was added portionwise to a solution of 6-fluoro-3, 4-dihydro-2H-isoquinolin-1-one (900 mg,5.45 mmol) in H2SO4 (9 mL) at 0deg.C, reacted at 0deg.C for 2H and poured into ice water, the precipitated solid collected by filtration and dried under vacuum to afford 6-fluoro-7-nitro-3, 4-dihydro-2H-isoquinolin-1-one (1.04 g, 86%). MS (ESI) M/Z=221.3 [ M+H ]] + 。
Step two: to a solution of 6-fluoro-7-nitro-3, 4-dihydro-2H-isoquinolin-1-one (2.02 g,9.09 mmol) in THF (200 mL) was added 1M BH3/THF (45.46 mmol,45.5 mL), stirred under reflux for 20 hours, carefully quenched with methanol (30 mL) under ice-bath, the resulting solution concentrated in vacuo, added to 2N HC1 (50 mL), heated at 80℃for 3 hours, adjusted to pH 7-8 by addition of ammonia, extracted with DCM, the organic phase dried over anhydrous sodium sulfate, filtered with suction, and spun-dried to give 6-fluoro-7-nitro-1, 2,3, 4-tetrahydroisoquinoline (1.89 g, 100.00%). MS (ESI) M/Z=197.2 [ M+H ]] + 。
Step three, four, five: the same operation process as the key intermediate 2 to prepare the 6-fluoro-7-iodo-2-methyl-1, 2,3,4- Tetrahydroisoquinolines. MS (ESI) M/Z=292.1 [ M+H ]] + 。
Preparation of key intermediate 42.2-bromo-5-methyl 4, 7-dihydropyrazolo [1,5-a ] pyrazin-6-one
Step one: a solution of 3-bromo-5-methyl-1H-pyrazole (500.0 mg,3.11 mmol), methyl chloroacetate (505.53 mg,4.66 mmol), tetrabutylammonium iodide (57.3 mg,0.16 mmol) and potassium carbonate (771.43 mg,5.59 mmol) in tetrahydrofuran (10 mL) was stirred at 20℃for 12 hours. The mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give methyl 2- (3-bromo-5-methyl-pyrazol-1-yl) acetate as a white solid. MS (ESI) M/Z=234.1 [ M+H ]] + 。
Step two: a solution of methyl 2- (3-bromo-5-methyl-pyrazol-1-yl) acetate (20 g,85.81 mmol), AIBN (1.41 g,8.58 mmol), NBS (16.80 g,94.4 mmol) in carbon tetrachloride (400 mL) was stirred at 80℃for 2 hours. The resulting mixture was concentrated under vacuum. Flash chromatography of the residue on silica gel gives 2- [ 3-bromo-5- (bromomethyl) pyrazol-1-yl as a yellow solid]Methyl acetate. MS (ESI) M/Z=312.0 [ M+H ]] + 。
Step three: 2- [ 3-bromo-5- (bromomethyl) pyrazol-1-yl]A solution of methyl acetate (900 mg,2.88 mmol) and methylamine (896.08 mg,28.85 mmol) in tetrahydrofuran (10 mL) was stirred at 25℃for 2 hours. The mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give 2-bromo-5-methyl 4, 7-dihydropyrazolo [1,5-a ] as a white solid ]Pyrazin-6-one. MS (ESI) M/Z=231.1 [ M+H ]] + 。
Preparation of the key intermediate tert-butyl 43.4- (4-bromo-1H-pyrazol-1-yl) piperidine-1-carboxylate
Sodium hydride (8.88 mmol, 60% in oil) was added in portions to a solution of 4-bromo-1H-pyrazole (8.07 mmol) in DMF (10 ml) cooled to 0deg.C, stirred for 1H, 1-Boc-4-methanesulfonyloxy piperidine (1.60 g,8.88 mmol) was added to the mixture, and the resulting mixture was heated to 100deg.C.
The reaction was allowed to react for 10h, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate and the organic layer concentrated under vacuum. Purifying with silica gel column chromatography. MS (ESI) M/Z=331.2 [ M+H ]] + 。
Preparation of key intermediate 44.4- (2- (3-bromo-1H-pyrazol-1-yl) ethyl) morpholine
3-Bromopyrazole (6.63 mmol), potassium carbonate (1.83 g,13.3 mmol) was added to acetonitrile (30 mL). The reaction was allowed to react overnight at 60℃and poured onto ice and extracted with DCM. The organic phase was separated, washed with brine and Na 2 SO 4 And (5) drying. The solvent was removed in vacuo and purified by column chromatography to give 4- (2- (3-bromo-1H-pyrazol-1-yl) ethyl) morpholine as a yellow solid. MS (ESI) M/Z=261.1 [ M+H ]] + 。
Preparation of key intermediate 45.2-bromo-4, 5,6, 8-tetrahydropyrazolo [1,5-d ] [1,4] diazepin-7-one
Step one: 2- [ 3-bromo-5- (bromomethyl) pyrazol-1-yl ]A solution of methyl acetate (35.4 g,113.48 mmol) and sodium cyanide (8.87 g,181.02 mmol) in DMSO (550 mL) was stirred at room temperature for 1 hour and the sodium cyanide was carefully quenched. The reaction solution was diluted with EA (2.5L). The solution was washed with water and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and purified by flash chromatography to give methyl 2- (3-bromo-5- (cyanomethyl) -1H-pyrazol-1-yl) acetate. MS (ESI) M/Z=259.1 [ M+H ]] + 。
Step two: to 2- [ 3-bromo-5- (cyanomethyl) pyrazol-1-yl]PtO was added to a solution of methyl acetate (3.0 g,11.62 mmol) in methanol (600 mL) 2 (600 mg,2.64 mmol). At 25 c,the mixture was stirred in 10atm hydrogen for 15 hours. The mixture was filtered. The filtrate was used directly in the next step without purification. MS (ESI) M/Z=263.1 [ M+H ]] + 。
Step three: to 2- [5- (2-aminoethyl) -3-bromo-pyrazol-1-yl]Methyl acetate solution (600 mL) TEA (70 mL) was added. The mixture was stirred at 25℃for 15 hours. The resulting solution was concentrated in vacuo. Flash chromatography of the residue on silica gel gives 2-bromo-4, 5,6, 8-tetrahydropyrazolo [1,5-d ]][1,4]Diaza-7-one. MS (ESI) M/Z=245.1 [ M+H ]] + 。
Preparation of key intermediate 46.2' -bromo-6 ' -methyl-5 ',6' -dihydrospiro [ cyclopropane-1, 4' -pyrazolo [1,5-d ] [1,4] diaza ] -7' (8'H) -one
Step one: to a solution of 3, 5-dibromo-1H-pyrazole (137 g,607 mmol) in MeCN (959 mL) was added tert-butyl 2-chloroacetate (137 g,910mmol,131 mL), K 2 CO 3 (137 g,989 mmol) and TBAI (11.0 g,29.7 mmol). The resulting solution was stirred at 25℃for 12 hours. The combined filtrates were concentrated by filtration to give a residue. The residue was dissolved in EtOAc and washed with water. The organic phase was treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give the crude compound tert-butyl 2- (3, 5-dibromo-1H-pyrazol-1-yl) acetate.
Step two: to a solution of tert-butyl compound 2- (3, 5-dibromo-1H-pyrazol-1-yl) acetate (248 g,729 mmol) in DCM (140 mL) was added TFA (2.08 kg,18.2 mol), and the resulting solution was heated to 80℃and stirred for 2 hours. The combined reaction mixtures were concentrated under reduced pressure to give the crude product. The crude product was diluted with petroleum ether/ethyl acetate (4/1,1.0L) and the resulting suspension was stirred at 25 ℃ for 1 hour and then filtered. The filter cake was collected and dried in vacuo to give the title compound 2- (3, 5-dibromo-1H-pyrazol-1-yl) acetic acid.
Step three: a solution of 2- (3, 5-dibromo-1H-pyrazol-1-yl) acetic acid (15 g,52.84 mmol), N-methacrylamide (5.7 g,80.15 mmol), N-diisopropylethylamine (27 g,208.9 mmol) and HATU (30 g,78.9 mmol) in N, N-dimethylformamide (500 mL) was stirred at room temperature for 16 hours. The resulting mixture was diluted with ethyl acetate and then washed with sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give 2- (3, 5-dibromo-1H-pyrazol-1-yl) -N-methyl-N-propenyl acetamide.
Step four: a mixture of 2- (3, 5-dibromo-1H-pyrazol-1-yl) -N-methyl-N-propenyl acetamide (5 g,14.84 mmol), palladium acetate (166 mg,0.74 mmol), triphenylphosphine (383 mg,1.48 mmol), TBAB (4.8 g, 14.89mmol) and potassium acetate (4.2 g,42.80 mmol) in N, N-dimethylformamide (100 mL) was stirred at 80℃for 10H. After filtration, the filtrate was concentrated in vacuo. The residue was purified on a silica gel column to give 2-bromo-6-methyl-4-methylene-4H, 5H,6H,7H, 8H-pyrazolo [1,5-d ]][1,4]Diaza-7-one. MS (ESI) M/Z=258.1 [ M+H ]] + 。
Step five: a mixture of trimethylsulfoxide iodide (1.29 g,5.86 mmol) and potassium tert-butoxide (650 mg,5.85 mmol) in dimethyl sulfoxide (30 mL) was stirred at room temperature for 30 min. Then 2-bromo-6-methyl-4-methylene-4H, 5H,6H,7H, 8H-pyrazolo [1,5-d is added][1,4]A solution of diaza-7-one (500 mg,1.95 mmol) in dimethyl sulfoxide (3 mL). The mixture was then stirred at 50℃for 12 hours. The reaction mixture was diluted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purifying the residue with silica gel column to obtain 2' -bromo-6 ' -methyl-5 ',6' -dihydrospiro [ cyclopropane-1, 4' -pyrazolo [1,5-d ]][1,4]Diaza-type ]-7 '(8'H) -one. MS (ESI) M/Z=271.10 [ M+H ]] + 。
Preparation of tert-butyl (3-amino-6-chloro-5, 7-difluorobenzo [ e ] [1,2,4] triazin-8-yl) carbamate as key intermediate 47
Step one, two: the same procedure as for key intermediate 1 gives (3-amino-6-chloro-5, 7-difluorobenzo [ e)][1,2,4]Triazines-8-yl) carbamic acid tert-butyl ester. MS (ESI) M/Z=332.7 [ M+H ]] + 。
Preparation of tert-butyl (3-amino-6-chloro-7-difluorobenzo [ e ] [1,2,4] triazin-8-yl) carbamate as key intermediate 48
Step one, two: the same procedure as for key intermediate 1 gives (3-amino-6-chloro-7-difluorobenzo [ e)][1,2,4]Triazin-8-yl) carbamic acid tert-butyl ester. MS (ESI) M/Z=314.7 [ M+H ]] + 。
Preparation of tert-butyl (3-amino-6-chloro-5-fluorobenzo [ e ] [1,2,4] triazin-8-yl) carbamate, a key intermediate 49
Step one, two: the same procedure as for key intermediate 1 gives (3-amino-6-chloro-5-fluorobenzo [ e)][1,2,4]Triazin-8-yl) carbamic acid tert-butyl ester. MS (ESI) M/Z=314.7 [ M+H ]] + 。
Preparation of tert-butyl (3-amino-6-chloro-7-cyanobenzo [ e ] [1,2,4] triazin-8-yl) carbamate, a key intermediate 50 ]
Step one, two: the same procedure as for key intermediate 1 gives (3-amino-6-chloro-7-cyanobenzo [ e) ][1,2,4]Triazin-8-yl) carbamic acid tert-butyl ester. MS (ESI) M/Z=321.7 [ M+H ]] + 。
Preparation of tert-butyl (3-amino-6-chloropyrido [4,3-e ] [1,2,4] triazin-8-yl) carbamate, a key intermediate 51
Step one, two: the same procedure as in key intermediate 1 gives (3-amino-6-chloropyrido [4, 3-e)][1,2,4]Triazin-8-yl) carbamic acid tert-butyl ester. MS (ESI) M/Z=297.7 [ M+H ]] + 。
Preparation of tert-butyl (3-amino-6-chloropyrido [2,3-e ] [1,2,4] triazin-8-yl) carbamate, a key intermediate 52
Step one, two: the same procedure as in key intermediate 1 gives (3-amino-6-chloropyrido [2, 3-e)][1,2,4]Triazin-8-yl) carbamic acid tert-butyl ester. MS (ESI) M/Z=297.7 [ M+H ]] + 。
Synthesis of key intermediate 53: preparation of tert-butyl (6-chloro-3- ((2-morpholinoethyl) amino) benzo [ e ] [1,2,4] triazin-8-yl) carbamate
Key intermediate 1 (2 mmol), 4- (2-chloroethyl) morpholine (2.2 mmol), potassium iodide (2 mmol) were added to acetonitrile (20 ml) and reacted at 110 ℃. After the reaction is completed, cooling to room temperature, adding water, extracting with ethyl acetate, concentrating an organic phase under reduced pressure, and purifying by column chromatography to obtain a target compound (6-chloro-3- ((2-morpholinoethyl) amino) benzo [ e)][1,2,4]Triazin-8-yl) carbamic acid tert-butyl ester. MS (ESI) M/Z=409.9 [ M+H ] ] + 。
Synthesis of key intermediate 54: preparation of 7-bromo-8-methyl-4-oxo-2, 3-dihydro-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester
Step one: a solution of 5-bromo-2-iodo-4-methyl-pyridin-3-amine (55 g,175.76 mmol) and NaHMDS (360 mL,720 mmol) in tetrahydrofuran (500 mL) was stirred at 0deg.C for 30 min. Then add (Boc) 2 O(43g197.25 mmol) and stirred at 25 ℃ for 1.5 hours. The resulting solution was diluted with water and then extracted with ethyl acetate. The organic layers were combined and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give tert-butyl N- (5-bromo-2-iodo-4-methyl-3-pyridinyl) carbamate as a yellow oil (58 g, 79.9%). MS (ESI) M/Z=414.1 [ M+H ]] + 。
Step two: a solution of tert-butyl N- (5-bromo-2-iodo-4-methyl-3-pyridinyl) carbamate (58 g,140.42 mmol) in tetrahydrofuran (500 mL) was stirred at room temperature for 1 hour. 4-bromo-1-butene (50 g,370.37 mmol) and NaI (55 g,366.67 mmol) were then added and stirred at 95℃for 16 hours. The reaction was then quenched by the addition of water and extracted with ethyl acetate. The organic layers were combined, dried and concentrated in vacuo. Purification by flash chromatography on silica afforded N- (5-bromo-2-iodo-4-methyl-3-pyridinyl) -N-but-3-enyl-carbamic acid tert-butyl ester (30 g, 45.7%) as a yellow oil. MS (ESI) M/Z=467.1 [ M+H ] ] + 。
Step three: n- (5-bromo-2-iodo-4-methyl-3-pyridinyl) -N-but-3-enyl-carbamic acid tert-butyl ester (30 g,64.22 mmol), pd (dppf) Cl 2 A solution of N, N-dimethylformamide (1500 mL) in (2.4 g,3.28 mmol) and TEA (13.1 g,128.43 mmol) was stirred for 1 hour at 110℃under nitrogen. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 7-bromo-8-methyl-4-methylene-2, 3-dihydro-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester (13 g, 59.7%). MS (ESI) M/Z=420.1 [ M+H ]] + 。
Step four: 7-bromo-8-methyl-4-methylene-2, 3-dihydro-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester (13 g,38.32 mmol), ruCl at 25 ℃ 3 (2.4 g,11.59 mmol) and NaIO 4 A solution of (20.5 g,95.79 mmol) in acetonitrile (350 mL), carbon tetrachloride (350 mL) and water (350 mL) was stirred for 1.5 h. The reaction was then quenched by addition of 300mL of sodium thiosulfate solution. The resulting solution was adjusted to pH6-7 with sodium bicarbonate and extracted with ethyl acetate. The organic phase is then concentrated under vacuum. Purifying on silica gel by flash chromatography to obtain yellow solid7-bromo-8-methyl-4-oxo-2, 3-dihydro-1, 5-naphthyridine-1-carboxylic acid tert-butyl ester (7 g, 53.5%) in bulk. MS (ESI) M/Z=342.2 [ M+H ] ] + 。
EXAMPLE 1N 3 - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -6-phenylbenzo [ e][1,2,4]Triazine-3, 8-diamine process a:
step one: the key intermediate 1 (400 mg,1.35 mmol) was dissolved in a mixed solution of dioxane (21 ml) and water (3 ml), and pinacol phenylborate (399 mg,2.7 mmol), pd (dppf) Cl was added 2 (197mg, 0.27 mmol), sodium carbonate (429 mg,4.05 mmol), refluxing at 90deg.C under nitrogen for 3h, cooling to room temperature, vacuum filtering with celite, concentrating the filtrate under reduced pressure, and purifying by column chromatography to obtain (3-amino-6-phenylbenzo [ e)][1,2,4]Triazin-8-yl) carbamic acid tert-butyl ester. MS (ESI) M/Z=338.4 [ M+H ]] + 。
Step two: the (3-amino-6-phenylbenzo [ e ] obtained in the previous step][1,2,4]The triazine-8-yl) carbamic acid tert-butyl ester (263.2 mg,0.7 mmol) is dissolved in a mixed solution of toluene (4 ml) and tetrahydrofuran (0.8 ml), key intermediate 2 (212.1 mmol,0.7 mmol), cuprous iodide (136.5 mg,0.7 mmol), N' -dimethylethylenediamine (61.6 mg,0.7 mmol) and potassium phosphate (4476 mg,2.1 mmol) are added, reflux reaction is carried out for 24h under the protection of nitrogen at 110 ℃, the mixture is cooled to room temperature, diatomite is filtered, the filtrate is dried under reduced pressure, and the (3- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -6-phenylbenzo [ e ] is obtained by column chromatography purification ][1,2,4]Triazin-8-yl) carbamic acid tert-butyl ester. MS (ESI) M/Z=513.6 [ M+H ]] + 。
Step three: to (3- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -6-phenylbenzo [ e][1,2,4]To a solution of t-butyl triazin-8-yl) carbamate (51.3 mg,0.1 mmol) in methylene chloride (5 ml) was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 2 hours. Adding saturated sodium bicarbonate to adjust pH to neutrality, extracting with dichloromethane for three times, mixing organic phases, drying under reduced pressure, and purifying by column chromatography to obtain orange-red target compound N 3 - (6-methoxy-2-methyl-1, 2, 3)4-tetrahydroisoquinolin-7-yl) -6-phenylbenzo [ e][1,2,4]Triazine-3, 8-diamine. (37 mg, 89.7%). MS (ESI) M/Z=413.5 [ M+H ]] + 。 1H NMR (400MHz,DMSO-d 6 )δ8.88(s,1H),7.99(s,1H),7.77–7.70(m,2H),7.55–7.52(m,1H),7.51(d,J＝6.1Hz,1H),7.49–7.43(m,1H),6.94–6.86(m,5H),3.90(s,2H),3.86(s,3H),3.01(d,2H),2.95(d,J＝4.9Hz,2H),2.63(s,3H).
Method B:
step one: preparation of tert-butyl (6-chloro-3- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) benzo [ e ] according to the procedure of step two of method A][1,2,4]Triazin-8-yl) carbamate. MS (ESI) M/Z=471.0 [ M+H ]] + 。
Step two: the tert-butyl (6-chloro-3- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) benzo [ e ] obtained in the previous step][1,2,4]Triazin-8-yl) carbamate (1 eq.) is dissolved in dioxane solution and bisboronic acid pinacol ester (1.3 eq.) Pd (dppf) Cl is added 2 (0.2 eq.) sodium carbonate (3 eq.) under nitrogen protection at 90 ℃ for 3h under reflux, cooling to room temperature, filtering with diatomite, concentrating the filtrate under reduced pressure, purifying by column chromatography to obtain tert-butyl (3- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ e) ][1,2,4]Triazin-8-yl) carbamate. MS (ESI) M/Z=563.5 [ M+H ]] + 。
Step three: tert-butyl (3- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ e ]][1,2,4]Triazin-8-yl) carbamate (1 eq.), bromobenzene (1 eq.), pd (dppf) Cl 2 (0.2 eq.) and sodium carbonate (3 eq.) were reacted in a mixed solution of dioxane and water (7:1) under nitrogen protection at 90 ℃ for 3h, cooled to room temperature, celite filtered with suction, the filtrate concentrated under reduced pressure, and purified by column chromatography to give (3- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -6-phenylbenzo [ e ]][1,2,4]Triazin-8-yl) amino groupsAnd (3) tert-butyl formate. MS (ESI) M/Z=513.6 [ M+H ]] + 。
Step four: the orange-red target compound N is prepared by referring to the operation of the step three of the method A 3 - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -6-phenylbenzo [ e][1,2,4]Triazine-3, 8-diamine. MS (ESI) M/Z=413.5 [ M+H ]] + 。
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Biological Activity test example 1HPK1 ADP-Glo enzymatic Activity test
Preparing an enzyme activity test buffer comprising 40mM Tris, pH7.5;20mM MgC12;0.1mg/ml BSA;50uM DTT. The compound was dissolved in pure DMSO and the stock concentration was 10mM. The compound DMSO solution is serially subjected to three-time gradient dilution from 100uM, total 11 concentrations are obtained, diluted compounds are diluted by enzyme activity test buffer solution at a ratio of 1:20, 1ul is taken and added into a working well, and each concentration is two multiple wells. Both negative control wells and positive control wells were added with 1ul of DMSO solution diluted 1:20. Preparation of 2.5 Xsubstrate/ATP working solution was an enzyme activity test buffer containing 45uM ATP and 0.25ug/ul MBP protein, 2ul of 2.5 Xsubstrate/ATP working solution was added to each well. Preparation of 2.5 Xenzyme reaction working solution was an enzyme activity test buffer containing 0.5ng/ul of HPK1 recombinant protein (Signalchem, cat. No. M23-11G-10), 2ul of 2.5 Xenzyme reaction working solution was added to each working well, and only 2ul of enzyme activity test buffer was added to the negative control well. The plate was sealed and centrifuged, and after the reaction was completed, 5ul of ADP-Glo reagent (Promega, cat. V1901) was added to each well and the reaction was continued at room temperature for 40 minutes, 10ul of kinase detection reagent (Promega, cat. V1901) was added and the reaction was continued at room temperature for 20 minutes, and the final luminescence signal was measured.
The mean values of the positive and negative wells were calculated as positive control value (Signalpos) and negative control value (Signalneg), respectively. The Inhibition ratio was calculated from the working well signal value (signalest) according to the formula Inhibition rate= (Signalpos-signalest)/(Signalpos-Signalneg) x 100%. The calculated inhibition rate was plotted as a non-linear fit to a concentration-inhibition rate curve in GraphPad Prism software and IC50 values were calculated.
Biological Activity test example 2GLK ADP-Glo enzymatic Activity test
Preparing an enzyme activity test buffer comprising 40mM Tris, pH7.5;20mM MgC12;0.1mg/ml BSA;50uM DTT. The compound was dissolved in pure DMSO and the stock concentration was 10mM. The compound DMSO solution is serially subjected to three-time gradient dilution from 100uM, total 11 concentrations are obtained, diluted compounds are diluted by enzyme activity test buffer solution at a ratio of 1:20, 1ul is taken and added into a working well, and each concentration is two multiple wells. Both negative control wells and positive control wells were added with 1ul of DMSO solution diluted 1:20. Preparation of 2.5 Xsubstrate/ATP working solution was an enzyme activity assay buffer containing 105. Mu.M ATP and 0.5ug/ul PKA substrate polypeptide, 2ul of 2.5 Xsubstrate/ATP working solution was added to each well. Preparation of 2.5 Xenzyme reaction working solution containing 2.5ng/ul of GLK recombinant protein (Signalchem, cat. No. M25-11G-10) enzyme activity test buffer 2ul of 2.5 Xenzyme reaction working solution was added to each working well, and only 2ul of enzyme activity test buffer was added to the negative control well. The plate was attached and centrifuged, and after the completion of the reaction, ADP-Glo reagent (Promega, cat. V1901) was added to each well for 5ul at room temperature for 40 minutes, followed by kinase detection reagent (Promega, cat. V1901) for 10ul at room temperature for 20 minutes, and the final luminescence signal was measured.
The mean values of the positive and negative wells were calculated as positive control value (Signalpos) and negative control value (Signalneg), respectively. The Inhibition ratio was calculated from the working well signal value (signalest) according to the formula Inhibition rate= (Signalpos-signalest)/(Signalpos-Signalneg) x 100%. The calculated inhibition rate was plotted as a non-linear fit to a concentration-inhibition rate curve in GraphPad Prism software and IC50 values were calculated. The experimental results are shown in the following table:
TABLE 1 results of HPK1, GLK enzyme Activity test experiments
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Claims (7)

1. A compound of formula ii-a, or a pharmaceutically acceptable salt thereof:
wherein:
X 1 is NH; x is X 2 Or X 3 Each independently is CH; x is X 5 Or X 6 Each independently is CH 2 Or none; y is NCH 3 ；M 1 、M 2 Or M 3 Each independently is CH; ring a is selected from the group consisting of: c (C) 6-10 An aromatic ring, a 5-10 membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered aromatic ring and a 5-7 membered heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O, a 6-membered heteroaromatic ring having 1 to 3 heteroatoms selected from the following group N, S, O and a 5-7 membered heterocyclic ring having 1 to 3 heteroatoms selected from the following group N, S, O; r1 is NH2; r2 is H, deuterium, halogen, OH, CN, NO 2 、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 Aryl, NH 2 、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 ；R 3 Is H; r is R 4 Is H, R 5 Is H; r is R 6 、R 7 Each independently is H or C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3 Cycloalkyl groups.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula ii-a has any one of the structures shown in the following formula:
3. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula ii-a has any one of the structures shown in the following formula:
4. a process for the preparation of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: the method is any one of the following methods:
method A:
suzuki coupling, ullman coupling and deprotection reactions are carried out by using benzo 1,2, 4-triazine or pyrido 1,2, 4-triazine compounds to obtain the compound of the formula II-a.
Method B:
and carrying out Ullmann coupling, suzuki coupling and deprotection reaction on the benzo 1,2, 4-triazine or pyrido 1,2, 4-triazine compounds to obtain the compound of the formula II-a.
5. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
6. Use of a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, for the manufacture of an anti-tumour medicament, said tumour being a tumour associated with HPK1 kinase.
7. Use of a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, in an HPK1 kinase inhibitor.
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