CN116023378A - Lactam compounds as HPK1 inhibitors and uses thereof - Google Patents

Lactam compounds as HPK1 inhibitors and uses thereof Download PDF

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CN116023378A
CN116023378A CN202211318129.8A CN202211318129A CN116023378A CN 116023378 A CN116023378 A CN 116023378A CN 202211318129 A CN202211318129 A CN 202211318129A CN 116023378 A CN116023378 A CN 116023378A
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membered
compound
reaction
heterocyclyl
pharmaceutically acceptable
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唐锋
胡治隆
黄炼成
赵盛
刘乐
刘力锋
唐任宏
任晋生
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Nanjing Zaiming Pharmaceutical Co ltd
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Jiangsu Simcere Pharmaceutical Co Ltd
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Abstract

The invention provides a compound shown in a formula (I) or pharmaceutically acceptable salt thereof, a pharmaceutical composition and a preparation method thereof, and the compound is used for inhibiting HPK1Use of the agent.

Description

Lactam compounds as HPK1 inhibitors and uses thereof
The invention claims priority of prior application of lactam compound as HPK1 inhibitor and application thereof, which is submitted to China intellectual property office on 10 months and 26 days of 2021, with patent application number of CN202111244711.X, and of lactam compound as HPK1 inhibitor and application thereof, which is submitted to China intellectual property office on 6 months and 23 days of 2022, with patent application number of CN 202210727676.5. The entire contents of the above-mentioned prior application are incorporated by reference into the present invention.
Technical Field
The present invention relates to a novel lactam compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same and use as an HPK1 inhibitor in the prevention or treatment of related diseases.
Background
One of the main features of cancer is immune evasion capability. Tumor cells inhibit their recognition and attack by the body's immune system through a variety of complex mechanisms. Several strategies for tumor immunotherapy have been devised to counteract this immunosuppression, including mechanisms that interfere with negative regulatory effector T cell function, such as PD1/PDL1 immune checkpoint inhibitors, by blocking the interaction of PD1 and PDL1, to counteract T lymphocyte immunosuppression in PDL 1-highly expressing cancer cells, and antibody development against PD1 or PDL1 inhibitors has also been demonstrated for clinical benefit in a variety of cancer types. In addition, therapeutic antibodies that block the interaction between CD80/CD86 and the T cell co-inhibitory receptor (CTLA-4) can promote T cell expansion in lymphoid tissues at various levels. In addition to these cell surface related proteins, intracellular signaling was found to be involved in immunonegative regulation, where HPK1 (hematopoietic progenitor kinase, also known as MAP4K 1) specifically expressed in hematopoietic cells is a serine/threonine kinase, primarily involved in intracellular immunonegative regulation (Elife 2020,9).
Studies have found that inactivation of HPK1 in human and mouse cells is often accompanied by the development of autoimmune diseases, suggesting that HPK1 regulates immune tolerance in the body. For example, peripheral mononuclear cells (PBMC) from psoriatic arthritis patients and T cells from systemic lupus erythematosus patients all found down-regulation of HPK1 expression (J Autoimmun 2011,37 (3), 180-9); mouse model experiments found that HPK 1-deleted mice were more prone to autoimmune meningitis (Nat Immunol 2007,8 (1), 84-91). In vitro studies demonstrated that antigen stimulation of T and B lymphocytes derived from HPK1 deletions had a stronger activating effect (Cancer immunol. Immunother.2010,59 (3), 419-429), indicating negative regulation of T and B lymphocyte function by HPK 1. In addition, HPK 1-deleted dendritic cells (DC cells) exhibited more potent antigen presentation and T cell activation properties, suggesting that HPK1 is also involved in immune regulation of DC cells.
Upon activation of the T Cell Receptor (TCR) and B Cell Receptor (BCR), cytoplasmic HPK1 is recruited to the vicinity of the cell membrane to be activated, which activates the HPK1 phosphorylates the adaptor protein SLP76 or LAT, thus activating SLP76 as a docking site for the negative regulator protein 14-3-3 pi, mediating the ubiquitination of SLP76, ultimately leading to instability of the TCR signal complex, thus down-regulating TCR signal (J.cell biol.2011,195 (5), 839-853). It has also been found that HPK1 can be activated by prostaglandin E2 (PGE 2) in a PKA-dependent manner, and possibly even by immunosuppressive factors expressed by tumor cells (Blood 2003,101 (9), 3687-3689).
HPK1 compared with wild type -/- The mice show stronger growth inhibition effect on the growth of inoculated isogenic lung cancer tumors. General purpose medicineAnti-tumor immune response study on T cell transplantation mouse model proves that HPK -/- The strong anti-tumor effect of knockout is at least partially T cell dependent. The contribution of dendritic cells to the antitumor activity is also achieved by the fact that dendritic cells are derived from HPK1 -/- DC cell transplantation experiments of deficient mouse bone marrow were confirmed (J.Immunol.2009, 182 (10), 6187-61). Recently, it was found that the HPK1 transgenic mice, which catalyze the inactivation of enzymes, are also effective in inhibiting glioblastoma GL261 growth and enhancing the efficacy of anti-PD 1 treatment of MC38 tumors, as compared to wild-type HPK transgenic mice. Therefore, HPK1 is a potential anti-tumor therapeutic target, and the development of small molecule inhibitors against HPK1 kinase, whether as single drugs or in combination with other immunomodulatory therapeutic strategies, is expected to be effective in anti-tumor therapy.
Disclosure of Invention
The invention provides a compound shown in a formula (I) or pharmaceutically acceptable salt thereof:
Figure BDA0003910244120000011
wherein,,
R 1 selected from C 3 -C 7 Monocyclic cycloalkyl, C 7 -C 12 Bicyclic cycloalkyl, C 4 -C 7 Monocycloalkenyl, C 7 -C 12 Bicyclic cycloalkenyl, 3-7 membered monocyclic heterocyclyl, 7-12 membered bicyclic heterocyclyl, 10-16 membered tricyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 11-14 membered tricyclic heteroaryl or C 6 -C 20 Aryl, said C 3 -C 7 Monocyclic cycloalkyl, C 7 -C 12 Bicyclic cycloalkyl, C 4 -C 7 Monocycloalkenyl, C 7 -C 12 Bicyclic cycloalkenyl, 3-7 membered monocyclic heterocyclyl, 7-12 membered bicyclic heterocyclyl, 10-16 membered tricyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 11-14 membered tricyclic heteroaryl or C 6 -C 20 Aryl is optionally substituted with R 1a Substitution;
R 2 selected from 7-12 membered bicyclic heterocyclyl or 8-10 membered bicyclic heteroaryl,the 7-12 membered bicyclic heterocyclyl or 8-10 membered bicyclic heteroaryl is optionally substituted with R 2a Substitution;
w, Z can be connected by single bond or double bond;
when W, Z are singly linked, W, Z are each independently selected from CR 3 R 4 ；
When W, Z are doubly linked, one of W, Z is selected from CR 5 The other is selected from N, or W, Z is independently selected from CR 5 ；
Y 1 、Y 2 Independently selected from CR 6 Or N;
R 3 、R 4 、R 5 、R 6 independently selected from H, halogen, CN, OH, NH 2 、C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl or 3-10 membered heterocyclyl, said OH, NH 2 、C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl or 3-10 membered heterocyclyl optionally substituted with R 3a Substitution;
x is selected from NH or O;
each R is 1a 、R 2a 、R 3a Independently selected from F, cl, br, I, CN, =o, OH, NH 2 、C 1 -C 6 Alkyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-14 membered heterocyclyl or 5-6 membered heteroaryl, said OH, NH 2 、C 1 -C 6 Alkyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, 4-14 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with R b Substitution;
each R is b Independently selected from D, F, cl, br, I, CN, =o, OH, NH 2 Ethynyl, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-14 membered heterocyclyl, said OH, NH 2 Ethynyl, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-14 membered heterocyclyl optionally substituted with R c Substitution;
each R is c Independently selected from F, cl, br, I, CN, =o, OH, NH 2 、-S(O) 2 CH 3 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-7 membered heterocyclyl, said OH, NH 2 、-S(O) 2 CH 3 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-7 membered heterocyclyl optionally being substituted by R d Substitution;
each R is d Independently selected from F, cl, br, I, CN, =o, OH, NH 2 、N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 4-7 membered heterocyclyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyloxy or 4-7 membered heterocyclyloxy.
In some embodiments, each R b Independently selected from F, cl, br, I, CN, =o, OH, NH 2 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-14 membered heterocyclyl, said OH, NH 2 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-14 membered heterocyclyl optionally substituted with R c And (3) substitution.
In some embodiments, R 1 Selected from 5-6 membered monocyclic heteroaryl, phenyl, 10-16 membered tricyclic heterocyclyl, 11-14 membered tricyclic heteroaryl or 7-12 membered bicyclic heterocyclyl, said 5-6 membered monocyclic heteroaryl, phenyl, 10-16 membered tricyclic heterocyclyl, 11-14 membered tricyclic heteroaryl or 7-12 membered bicyclic heterocyclyl optionally being substituted with R 1a And (3) substitution.
In some embodiments, R 1 Selected from 5-6 membered monocyclic heteroaryl, phenyl, 10-16 membered tricyclic heterocyclyl or 11-14 membered tricyclic heteroaryl, said 5-6 membered monocyclic heteroaryl, phenyl, 10-16 membered tricyclic heterocyclyl or 11-14 membered tricyclic heteroaryl being optionally substituted with R 1a And (3) substitution.
In some embodiments, R 1 Selected from 5-6 membered monocyclic heteroaryl or phenyl, said 5-6 membered monocyclic heteroaryl or phenyl optionally being substituted by R 1a And (3) substitution.
In some embodiments, R 1 Selected from pyridyl, pyrazolyl or phenyl, said pyridyl, pyrazolyl or phenyl being optionally substituted with R 1a And (3) substitution.
In some embodiments, R 1 Selected from pyridyl, said pyridyl optionally being substituted with R 1a And (3) substitution.
In some embodiments, each R 1a 、R 2a 、R 3a Independently selected from F, cl, br, I, CN, =o, OH, NH 2 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-14 membered heterocyclyl, said OH, NH 2 、C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl or 4-14 membered heterocyclyl optionally substituted with R b And (3) substitution.
In some embodiments, R 1a Selected from 5-11 membered heterocyclyl, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or OH, said 5-11 membered heterocyclyl, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or OH is optionally substituted by R b And (3) substitution.
In some embodiments, R 1a Selected from F, CH 3 OH, ethyl, isopropyl,
Figure BDA0003910244120000031
Figure BDA0003910244120000032
The CH is 3 OH, ethyl, isopropyl, >
Figure BDA0003910244120000033
Figure BDA0003910244120000034
Optionally by R b And (3) substitution.
In some embodiments, each R b Independently selected from D, F, cl, br, I, CN, =o, OH, NH 2 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-14 membered heterocyclyl, said OH, NH 2 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-14 membered heterocyclyl optionally substituted with R c Substitution of。
In some embodiments, each R b Independently selected from OH, NH 2 、＝O、CN、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-11 membered heterocyclyl, said OH, NH 2 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-11 membered heterocyclyl optionally being substituted by R c And (3) substitution.
In some embodiments, each R b Independently selected from D, =o, OH, NH 2 Methyl, isopropyl, ethynyl or azetidinyl, said OH, NH 2 Optionally substituted with R c And (3) substitution.
In some embodiments, each R c Independently selected from F, cl, br, I, CN, =o, OH, NH 2 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-7 membered heterocyclyl, said OH, NH 2 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-7 membered heterocyclyl optionally being substituted by R d And (3) substitution.
In some embodiments, each R c Independently selected from F, cl, br, I, CN, OH, NH 2 、C 1 -C 6 Alkyl or 4-7 membered heterocyclyl, said OH, NH 2 、C 1 -C 6 Alkyl or 4-7 membered heterocyclyl optionally being substituted by R d And (3) substitution.
In some embodiments, each R c Independently selected from F, cl, br, I, CN, OH, NH 2 Or C 1 -C 6 Alkyl, said OH, NH 2 Or C 1 -C 6 Alkyl is optionally substituted with R d And (3) substitution.
In some embodiments, each R c Independently selected from NH 2 、CH 3 OH, ethyl, -S (O) 2 CH 3 Pyrrolidinyl, azetidinyl or morpholinyl, said NH 2 、CH 3 OH, ethyl, -S (O) 2 CH 3 Optionally substituted with R d And (3) substitution.
In some embodiments, each R d Independently selected from F, cl, br, I, CN, =o, OH, NH 2 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 4-7 membered heterocyclyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyloxy or 4-7 membered heterocyclyloxy.
In some embodiments, each R d Independently selected from F, cl, br, I, CN, OH or C 1 -C 6 An alkyl group.
In some embodiments, each R d Independently selected from CH 3 F or N (CH) 3 ) 2 。
In some embodiments, R 1a Selected from 4-7 membered heterocyclyl groups, said 4-7 membered heterocyclyl groups optionally being substituted with F, cl, br, I, CN, OH, O (C 1 -C 3 Alkyl group, NH 2 Or C 1 -C 6 Alkyl substitution, the C 1 -C 6 Alkyl is further optionally substituted with N (CH) 3 ) 2 、OH、OCH 3 、
Figure BDA0003910244120000035
And (3) substitution.
In some embodiments, R 1a Selected from 5-6 membered heterocyclyl groups, said 5-6 membered heterocyclyl groups optionally being substituted with F, cl, br, I, CN, OH, NH 2 Or C 1 -C 6 Alkyl substitution.
In some embodiments, R 1 Selected from the group consisting of
Figure BDA0003910244120000036
Figure BDA0003910244120000041
Figure BDA0003910244120000051
Figure BDA0003910244120000061
In some embodiments, R 1 Selected from the group consisting of
Figure BDA0003910244120000062
Figure BDA0003910244120000063
Figure BDA0003910244120000071
In some embodiments, R 1 Selected from the group consisting of
Figure BDA0003910244120000072
Figure BDA0003910244120000081
In some embodiments, R 1 Selected from the group consisting of
Figure BDA0003910244120000082
In some embodiments, R 1 Selected from 12-14 membered tricyclic heterocyclyl, said 12-14 membered tricyclic heterocyclyl optionally being substituted with R 1a And (3) substitution.
In some embodiments, R 1a Selected from = O, C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl group, the C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl is optionally substituted with R b And (3) substitution.
In some embodiments, R b Selected from optionally being C 1 -C 6 Alkyl substituted NH 2 。
In some embodiments, R 1 Selected from the group consisting of
Figure BDA0003910244120000083
Figure BDA0003910244120000084
Figure BDA0003910244120000091
In some embodiments, R 2 Selected from 9-10 membered bicyclic heterocyclyl or 9-10 membered bicyclic heteroaryl, said 9-10 membered bicyclic heterocyclyl or 9-10 membered bicyclic heteroaryl optionally being substituted with R 2a And (3) substitution.
In some embodiments, R 2 Selected from 9-membered bicyclic heterocyclyl or 9-membered bicyclic heteroaryl, said 9-membered bicyclic heterocyclyl or 9-membered bicyclic heteroaryl optionally being substituted with R 2a And (3) substitution.
In some embodiments, R 2 Wherein the bicyclic heterocyclic group or bicyclic heteroaryl group contains at least one N atom in the ring atom.
In some embodiments, R 2 Selected from 9-membered bicyclic heteroaryl groups containing at least one N atom in the ring atom of said 9-membered bicyclic heteroaryl groups, said 9-membered bicyclic heteroaryl groups optionally being substituted with R 2a And (3) substitution.
In some embodiments, R 2 Selected from the group consisting of
Figure BDA0003910244120000092
Figure BDA0003910244120000093
Optionally by R 2a And (3) substitution.
In some embodiments, each R 2a Selected from F, cl, br, I, CN, C 1 -C 3 Alkyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl group, the C 1 -C 3 Alkyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl is optionally substituted by D, F, cl, br, I.
In some embodiments, each R 2a Selected from F, cl, br, I, CN or C 1 -C 3 Alkyl, said C 1 -C 3 The alkyl group is optionally substituted with D, F, cl, br, I.
In some embodiments, each R 2a Selected from F, cl, br, I, CN, CH 3 Ethynyl or cyclopropyl group, said CH 3 Optionally substituted with D, F, cl, br, I.
In some embodiments, each R 2a Selected from F, cl, br, I, CN or C 1 -C 3 Alkyl, said C 1 -C 3 The alkyl group is optionally substituted with F, cl, br, I.
In some embodiments, R 2 Selected from the group consisting of
Figure BDA0003910244120000094
Figure BDA0003910244120000095
Figure BDA0003910244120000101
In some embodiments, R 2 Selected from the group consisting of
Figure BDA0003910244120000102
Figure BDA0003910244120000103
In some embodiments, R 2 Selected from the group consisting of
Figure BDA0003910244120000104
In some embodiments, R 2 Selected from the group consisting of
Figure BDA0003910244120000105
In some embodiments, R 3 、R 4 、R 5 、R 6 Independently selected from H, halogen, CN, OH, NH 2 Or C 1 -C 6 An alkyl group.
In some embodiments, R 3 、R 4 、R 5 、R 6 Selected from H.
In some embodiments, Y 1 、Y 2 Independently selected from CH.
In some embodiments W, Z are linked by a single bond, W, Z are each selected from CH 2 。
In some embodiments, W, Z is doubly linked, one of W, Z is selected from CH and the other is selected from N, or W, Z are each selected from CH.
In some embodiments, W, Z is doubly linked, one of W, Z is selected from CH and the other is selected from N.
In some embodiments, W, Z is attached by a double bond, W is selected from CH and Z is selected from N.
In some embodiments, X is selected from NH.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (Ia):
Figure BDA0003910244120000111
wherein one of W, Z is selected from CR 5 The other is selected from N, or W, Z is independently selected from CR 5 ；
R 1 、R 2 、R 5 、Y 1 、Y 2 X is as defined above.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (Ib):
Figure BDA0003910244120000112
wherein one of W, Z is selected from CH and the other is selected from N;
R 1 、R 2 as defined above.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:
Figure BDA0003910244120000113
Figure BDA0003910244120000121
Figure BDA0003910244120000131
Figure BDA0003910244120000141
Figure BDA0003910244120000151
Figure BDA0003910244120000161
the invention also provides a pharmaceutical composition which comprises the compound shown in the formula (I) or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
Further, the invention relates to application of a compound shown in the formula (I) or pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for preventing or treating HPK1 related diseases.
Further, the invention relates to application of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in preparing medicines for preventing or treating tumors.
Further, the present invention relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating HPK 1-related diseases.
Further, the invention relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating tumors.
Further, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating HPK 1-related diseases.
Further, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a tumor.
The invention also relates to a method of treating a disease associated with HPK1 comprising administering to a patient a therapeutically effective dose of a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein.
The invention also relates to a method of treating a tumour, which comprises administering to a patient a therapeutically effective dose of a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein.
In some embodiments, the HPK 1-associated disease is selected from a tumor.
Definition and description of terms
Unless otherwise indicated, the terms used in the present invention have the following meanings, and the groups and term definitions recited in the present invention, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and combined with each other. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
Herein, a method of manufacturing a semiconductor device
Figure BDA0003910244120000162
Representing the ligation site.
The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985, 62:114-120.Unless otherwise indicated, wedge keys and virtual wedge keys are used
Figure BDA0003910244120000163
Representing the absolute configuration of a stereogenic center, using the black real and virtual keys +. >
Figure BDA0003910244120000164
Representing the relative configuration of a stereocenter (e.g., the cis-trans configuration of a alicyclic compound).
The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.
The term "stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers and diastereomers.
The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Particular geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic or other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the definition of compounds of the invention. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms may be present in the substituents such as alkyl groups, and all such isomers and mixtures thereof are included within the definition of compounds of the invention. The asymmetric atom-containing compounds of the present invention may be isolated in optically pure form or in racemic form, which may be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl may be unsubstituted (CH 2 CH 3 ) Monosubstituted (CH) 2 CH 2 F、CH 2 CH 2 Cl, etc.), polysubstituted (CHFCH 2 F、CH 2 CHF 2 、CHFCH 2 Cl、CH 2 CHCl 2 Etc.) or fully substituted (CF) 2 CF 3 、CF 2 CCl 3 、CCl 2 CCl 3 Etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
When any variable (e.g. R a 、R b ) Where the composition or structure of a compound occurs more than once, its definition is independent in each case. For example, if a group is substituted with 2R b Substituted, each R b There are independent options.
When the number of one linking group is 0, such as- (CH) 2 ) 0 -, indicating that the linking group is a bond.
When one of the variables is selected from the group consisting of a chemical bond or is absent, the two groups representing its attachment are directly linked, e.g., when L in A-L-Z represents a bond, it is meant that the structure is actually A-Z.
The linking group referred to herein is arbitrary in its linking direction unless the linking direction is indicated. For example when building blocks
Figure BDA0003910244120000171
L of (3) 1 Selected from "C 1 -C 3 alkylene-O ", in which case L 1 Either the rings Q and R can be connected in a direction from left to right 1 Form a "ring Q-C 1 -C 3 alkylene-O-R 1 ", rings Q and R may be connected in a right-to-left direction 1 Form a "ring Q-O-C 1 -C 3 Alkylene group-R 1 ”。
When the bond of a substituent is cross-linked to two atoms on a ring, the substituent may be bonded to any atom on the ring. For example, structural units
Figure BDA0003910244120000172
R represents 5 Substitution may occur at any position on the phenyl ring.
C herein m -C n Refers to having an integer number of carbon atoms in the m-n range. For example "C 1 -C 10 By "is meant that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
The term "alkyl" refers to a compound of the formula C n H 2n+1 The alkyl group may be linear or branched. The term "C 1 -C 10 Alkyl "is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-di-Methylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, and the like; the term "C 1 -C 6 Alkyl "is understood to mean an alkyl group having 1 to 6 carbon atoms, specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like. The term "C 1 -C 3 Alkyl "is understood to mean a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms. The "C 1 -C 10 Alkyl "may contain" C 1 -C 6 Alkyl "or" C 1 -C 3 Alkyl "and the like, said" C 1 -C 6 The alkyl group may further comprise "C 1 -C 3 An alkyl group.
The term "alkoxy" refers to a group generated by the loss of a hydrogen atom on a hydroxyl group of a straight or branched chain alcohol, and is understood to be "alkyloxy" or "alkyl-O-". The term "C 1 -C 10 Alkoxy "is understood to mean" C 1 -C 10 Alkyloxy "or" C 1 -C 10 alkyl-O- "; the term "C 1 -C 6 Alkoxy "is understood to mean" C 1 -C 6 Alkyloxy "or" C 1 -C 6 alkyl-O- ". The "C 1 -C 10 Alkoxy "may contain" C 1 -C 6 Alkoxy "and" C 1 -C 3 Alkoxy "and the like, said" C 1 -C 6 Alkoxy groups may further comprise "C 1 -C 3 An alkoxy group.
The term "cycloalkyl" refers to a carbocycle that is fully saturated and exists as a single ring, fused ring, bridged ring, or spiro ring, etc. Unless otherwise indicated, the carbocycle is typically a 3 to 12 membered ring. The term "C 3 -C 10 Cycloalkyl "is understood to mean saturated monocyclic, fusedA ring, spiro or bridged ring having 3 to 10 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo [ 2.2.1) ]Heptyl), bicyclo [2.2.2]Octyl, adamantyl, spiro [4.5 ]]Decyl, and the like. The term "C 3 -C 10 Cycloalkyl "may contain" C 3 -C 6 Cycloalkyl ", the term" C 3 -C 6 Cycloalkyl "is understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term "C 3 -C 7 Monocyclic cycloalkyl "means cycloalkyl having 3 to 7 ring carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, in the form of a single ring. The term "C 7 -C 12 Bicyclic cycloalkyl "means cycloalkyl having 7 to 12 ring carbon atoms, in the form of a bicyclic ring, wherein the bicyclic ring is present as a fused, spiro or bridged ring.
The term "C 3 -C 6 Cycloalkyloxy "can be understood as" C 3 -C 6 cycloalkyl-O- ".
The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists as a single ring, fused ring, bridged ring, or spiro ring, and the like. Unless otherwise indicated, the carbocycle is typically a 4 to 12 membered ring. Specific examples of the cycloalkenyl group include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like. The term "C 4 -C 7 Monocyclic cycloalkenyl "refers to cycloalkenyl groups containing 4 to 7 ring carbon atoms and which exist as a single ring. The term "C 7 -C 12 By dicycloalkenyl "is meant a cycloalkenyl group containing 7 to 12 ring carbon atoms and being present in the form of a bicyclic ring, wherein the bicyclic ring is present as a fused, spiro or bridged ring.
The term "heterocyclyl" refers to a fully saturated or partially saturated (not aromatic in nature as a whole) monocyclic, fused, spiro or bridged ring radical having 1 to 5 heteroatoms in the ring atomOr a heteroatom group (i.e., a heteroatom-containing radical) including, but not limited to, a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), a phosphorus atom (P), a boron atom (B), -S (=o) 2 -、-S(＝O)-、-P(＝O) 2 -P (=o) -, -NH-, -S (=o) (=nh) -, -C (=o) NH-, or-NHC (=o) NH-, etc. The term "4-14 membered heterocyclic group" refers to a heterocyclic group having a number of ring atoms of 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and containing 1 to 5 heteroatoms or groups of heteroatoms independently selected from the group consisting of those described above. The term "3-10 membered heterocyclic group" means a heterocyclic group having 3,4, 5, 6, 7, 8, 9, 10 ring atoms and containing 1 to 5 heteroatoms or groups of heteroatoms independently selected from the group consisting of the above. Specific examples of 3-membered heterocyclyl groups include, but are not limited to, glycidylyl; specific examples of 4-membered heterocyclyl groups include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4, 5-dihydro-oxazolyl, or 2, 5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclyl groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H- [1,3,4 ] ]Thiadiazinyl; specific examples of 7-membered heterocyclyl groups include, but are not limited to, diazepinyl. The heterocyclic groups may also be bicyclic and tricyclic heterocyclic groups, wherein specific examples of 5,5 membered bicyclic groups include, but are not limited to, hexahydrocyclopenta [ c ]]Pyrrol-2 (1H) -yl; specific examples of 5,6 membered bicyclo groups include, but are not limited to, hexahydropyrrolo [1,2-a ]]Pyrazin-2 (1H) -yl, 5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a ]]Pyrazinyl or 5,6,7, 8-tetrahydroimidazo [1,5-a ]]And pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above 4-7 membered heterocyclic group, specific examples include, but are not limited to, dihydroisoquinolinyl and the like. The "4-14 membered heterocyclic group" may contain "4-11 membered heterocyclic group", "5-6 membered heterocyclic group", "4-7 membered heterocyclic group" or "3-7 membered heterocyclic group" and the like, and the "3-10 membered heterocyclic group" may contain "5-6 membered heterocyclic group", "4-7 membered heterocyclic group" or "3-7 membered heterocyclic group" and the likeRange. The term "7-12 membered bicyclic heterocyclic group" means a bicyclic heterocyclic group having 7,8, 9, 10, 11, 12 ring atoms and containing 1 to 5 heteroatoms or hetero atom groups independently selected from the above-mentioned ring atoms, wherein the bicyclic ring exists as a condensed ring, a spiro ring or a bridged ring. The "7-12 membered bicyclic heterocyclic group" may comprise a "9-10 membered bicyclic heterocyclic group". The term "10-16 membered tricyclic heterocyclyl" means a tricyclic heterocyclyl having a number of ring atoms of 10, 11, 12, 13, 14, 15, 16 and containing 1 to 5 heteroatoms or heteroatom groups independently selected from the group consisting of the above, wherein the tricyclic rings are present as fused, spiro or bridged rings. The "10-16 membered tricyclic heterocyclic group" may include "12-14 membered tricyclic heterocyclic group". "heterocyclyl" in the present invention may include "heterocycloalkyl", for example "3-10 membered heterocyclyl" may include 3-10 membered heterocycloalkyl ". In the present invention, although some of the bi-or tricyclic heterocyclic groups contain a benzene ring or a heteroaryl ring in part, the heterocyclic groups as a whole remain non-aromatic.
The term "heterocyclyloxy" is understood to mean "heterocyclyl-O-".
The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and exists as a single ring, fused ring, bridged ring, or spiro ring, etc., having 1-5 heteroatoms or groups of heteroatoms (i.e., groups of heteroatoms) in the ring atoms of the ring, including but not limited to nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), and-S (=o) 2 -S (=o) -, -NH-, -S (=o) (=nh) -, -C (=o) NH-, or-NHC (=o) NH-, etc. The term "3-10 membered heterocycloalkyl" refers to a heterocycloalkyl group having a number of ring atoms of 3, 4, 5, 6, 7, 8, 9 or 10 and containing 1 to 5 heteroatoms or groups of heteroatoms independently selected from those described above. The term "3-10 membered heterocycloalkyl" may include "4-10 membered heterocycloalkyl" or "4-7 membered heterocycloalkyl", wherein specific examples of 4 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl or thietanyl; specific examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl Or tetrahydropyrazolyl; specific examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thiaxalkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl or 1, 4-dithianyl; specific examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepinyl, or thiepanyl.
The term "heterocycloalkyloxy" is understood to mean "heterocycloalkyl-O-".
The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic ring radical having a conjugated pi-electron system. The aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms or 6 to 12 carbon atoms. The term "C 6 -C 20 Aryl "is understood to mean aryl having 6 to 20 carbon atoms. In particular having 6 carbon atoms ("C) 6 Aryl "), such as phenyl; or a ring having 9 carbon atoms ("C) 9 Aryl "), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C) 10 Aryl "), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring having 13 carbon atoms ("C) 13 Aryl "), such as fluorenyl; or a ring having 14 carbon atoms ("C 14 Aryl "), such as anthracenyl. The term "C 6 -C 10 Aryl "is understood to mean aryl having 6 to 10 carbon atoms. In particular having 6 carbon atoms ("C) 6 Aryl "), such as phenyl; or a ring having 9 carbon atoms ("C) 9 Aryl "), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C) 10 Aryl "), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
The term "aryloxy" may be understood as "aryl-O-".
The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system containing at least one ring atom selected from N, O, S and the remaining ring atoms being aromatic ring groups of C, which typically have 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms and which contain 1 to 8, preferably 1 to 5 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and their benzo derivatives, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, or isoquinolinyl, or the like; or an axcinyl group, an indolizinyl group, a purinyl group, etc., and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl, and the like. The term "5-6 membered monocyclic heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1 to 3, preferably 1 to 2 heteroatoms independently selected from N, O and S, specific examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl. The term "8-10 membered bicyclic heteroaryl" refers to an aromatic fused bicyclic ring system having 8, 9, 10 ring atoms, containing at least one ring atom selected from N, O, S, the remaining ring atoms being aromatic ring groups of C. The term "8-10 membered bicyclic heteroaryl" may comprise "9-10 membered bicyclic heteroaryl". The term "11-14 membered tricyclic heteroaryl" refers to an aromatic fused tricyclic ring system having 11, 12, 13, 14 ring atoms, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are aromatic ring groups of C.
The term "heteroaryloxy" may be understood as "heteroaryl-O-".
The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to an-OH group.
The term "cyano" refers to a-CN group.
The term "mercapto" refers to a-SH group.
The term "amino" refers to-NH 2 A group.
The term "nitro" refers to-NO 2 A group.
Herein, keys depicted by solid lines and dashed lines
Figure BDA0003910244120000191
Represents a single bond or a double bond. For example, building blocks->
Figure BDA0003910244120000192
Comprises->
Figure BDA0003910244120000193
The term "therapeutically effective amount" means an amount of a compound of the invention that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of the compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and disclosure.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the invention or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the invention to an organism.
The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.
The invention also includes isotopically-labeled compounds of the invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 123 I、 125 I and 36 cl, and the like.
Certain isotopically-labeled compounds of the invention (e.g., with 3 H is H 14 C-tag) can be used in compound and/or substrate tissue distribution analysis. Tritiation (i.e 3 H) And carbon-14 (i.e 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15 O、 13 N、 11 C and C 18 F can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent.
The pharmaceutical compositions of the present invention may be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.
Typical routes of administration of the compounds of the invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, lyophilizing, and the like.
In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, and the like.
The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In all methods of administration of the compounds of formula I described herein, the dosage administered is from 0.01mg/kg to 200mg/kg body weight, preferably from 0.05mg/kg to 50mg/kg body weight, more preferably from 0.1mg/kg to 30mg/kg body weight, either alone or in divided doses.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
The chemical reactions of the embodiments of the present invention are accomplished in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.
The invention adopts the following abbreviations:
Figure BDA0003910244120000211
Detailed Description
The invention is described in detail below by way of examples, which are not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention. All reagents used in the present invention are commercially available and can be used without further purification.
Unless otherwise indicated, the ratio of the mixed solvent is a volume mixing ratio.
Unless otherwise indicated,% refers to weight percent wt%.
The compounds being obtained by hand or by hand
Figure BDA0003910244120000212
Software naming, commercial compounds are referred to by vendor catalog names.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS).The unit of NMR shift is 10 -6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS); IC (integrated circuit) 50 "means half inhibition concentration" means concentration at which half of the maximum inhibition effect is achieved.
The eluent or mobile phase can be a mixed eluent or mobile phase consisting of two or more solvents, the ratio of which is the volume ratio of the solvents, for example, 0-10% methanol/dichloromethane represents that the volume ratio of methanol to dichloromethane in the mixed eluent or mobile phase is 0:100-10:100.
Example 1: synthesis of Compound 001
Figure BDA0003910244120000221
Starting material 1-1 (3.00 g) was dissolved in ACN (30 mL), cooled to 0deg.C, NBS (3.23 g) was added in portions, reacted at 0deg.C for 0.5h, and the reaction was completed by TLC. To the reaction solution were added saturated aqueous sodium sulfite solution (50 mL) and EA (100 mL), the mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (PE: ea=5:1) to obtain 4.20g of intermediate 1-2.
Tert-butyl nitrite (2.53 g) and copper chloride (2.20 g) are dissolved in ACN (20 mL), the temperature is reduced to 0 ℃ under the protection of nitrogen, an ACN (20 mL) solution of intermediate 1-2 (2.00 g) is added dropwise, the reaction is carried out for 16h at 30 ℃ after the dropwise addition, and TLC detection reaction is finished. The reaction mixture was poured into 100mL of water, extracted with EA (50 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated and purified by silica gel column chromatography (PE as eluent) to give 1.80g of intermediate 1-3.
Intermediate 1-3 (1.80 g) was dissolved in CCl 4 (20 mL), NBS (4.86 g) and AIBN (1.12 g) were added and reacted at 80℃for 16 hours under nitrogen protection, after TLC detection, the reaction liquid was directly concentrated and then subjected to silica gel column chromatography (PE: EA=10:1) to obtain 2.30g of intermediate 1-4.
1 H NMR(400MHz,CDCl 3 )δ7.41(d,J＝8.6Hz,1H),7.26(d,J＝8.6Hz,1H),4.48(s,2H),3.94(s,3H).
Intermediate 1-4 (1.61 g) was dissolved in 1, 4-dioxane (10)mL)/water (10 mL), caCO was added 3 (2.82 g), 100 ℃ for 16h, after TLC detection, 50mL of water, 50mL of EA, pad diatomite and filtration are poured into the reaction solution, the solution is separated, the organic phase anhydrous sodium sulfate is dried and filtered, and the filtrate is spin-dried to obtain 1.10g of intermediate 1-5.
Intermediate 1-5 (1.1 g) was dissolved in CCl 4 (20 mL), NBS (870.24 mg) and AIBN (145.98 mg) were added and reacted at 80℃for 4 hours under nitrogen protection, after completion of the TLC detection, the reaction solution was concentrated and then subjected to silica gel column chromatography (PE: EA=10:1) to obtain 1.41g of intermediate 1-6.
Intermediate 1-6 (1.41 g) was dissolved in EtOH (20 mL), hydrazine hydrate (1.63 g,85% purity) was added, reaction was performed at 80℃for 6h, and after completion of the LCMS detection, the reaction solution was concentrated and purified by silica gel column chromatography (DCM: CH) 3 Oh=100:1 to 50:1) to yield 0.85g of intermediate 1-7.LC-MS (ESI) m/z=260.49 [ M+H ]] + 。
Intermediate 1-7 (0.75 g) was dissolved in THF (10 mL) and Boc was added 2 O (1.26 g), DMAP (70.62 mg), at 25℃for 2h, and TLC detection was complete. The reaction mixture was concentrated and chromatographed on silica gel (PE: ea=10:1) to give 0.60g of intermediate 1-8, yield: 58%.
Intermediate 1-9 (251 mg) and intermediate 1-8 (480.0 mg) were dissolved in 1, 4-dioxane (5 mL), and Pd was added 2 dba 3 (122.23 mg), xantphos (154.47 mg) and Cs 2 CO 3 (1.30 g), under the protection of nitrogen, reacting for 6h at 100 ℃, after the completion of LCMS detection, cooling the reaction liquid to room temperature, concentrating the reaction liquid, and performing silica gel column chromatography (PE: EA=5:1-1:1) to obtain 0.31g of intermediate 1-10, wherein the yield: 51%. LC-MS (ESI) m/z=458.91 [ M+H ]] + 。
Intermediate 1-10 (296.18 mg) was dissolved in 1, 4-dioxane (5 mL), and pinacol ester (515.74 mg), XPhos-Pd-G3 (57.30 mg), acOK (199.32 mg) were added to react for 6h at 85℃under nitrogen, after completion of LCMS detection, the reaction mixture was concentrated and subjected to silica gel column chromatography (PE: EA=5:1-2:1) to give 306.0mg of intermediate 1-11.LC-MS (ESI) m/z=550.42 [ M+H ] ] + 。
Intermediate 1-12 (120.0 mg), intermediate 1-11 (343.62 mg) were dissolved in a water (0.5 mL)/1, 4-dioxane (5 mL) mixed solvent, and XPhos-Pd-G2 (44.73 mg), K were added 3 PO 4 (454.24mg)，After the reaction is completed in the detection of LCMS at 100 ℃ under the protection of nitrogen for 6 hours, the reaction liquid is cooled to room temperature and concentrated and subjected to silica gel column chromatography (PE: EA=1:1-0:1) to obtain 155.0mg of crude compound 001. Taking 55.0mg of crude product, and adopting preparative high performance liquid chromatography (chromatographic column: gemini NX-C18; mobile phase: A is 0.1% ammonia water solution; B is acetonitrile, B% is 0% -40%,18 mL/min) to prepare 18.5mg of compound 001.
LC-MS(ESI):m/z＝454.20[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ8.95(d,J＝8.8Hz,1H),8.64-8.61(m,1H),8.15(s,1H),8.06(s,1H),8.02(d,J＝3.0Hz,1H),7.79(d,J＝8.8Hz,1H),7.50-7.44(m,2H),7.17(dd,J＝9.2,1.5Hz,1H),6.98(d,J＝8.9Hz,1H),3.79-3.73(m,4H),3.13-3.07(m,4H),2.34(s,3H).
Example 2: synthesis of Compound 002
Figure BDA0003910244120000231
Intermediate 1-8 (152.0 mg) and intermediate 2-2 (85.33 mg) were dissolved in 1, 4-dioxane (10 mL), and Xantphos (48.92 mg), cs were added sequentially 2 CO 3 (413.16 mg) and Pd 2 dba 3 (38.71 mg) was reacted at 100℃for 4 hours under nitrogen atmosphere. LCMS showed complete reaction of the starting material, filtration of the reaction, spin-drying and column chromatography on silica gel (DCM: meoh=10:1) gave 120.0mg of intermediate 2-3 (77% yield). LC-MS (ESI) m/z=371.84 [ M+H ]] + 。
Intermediate 2-3 (115.0 mg) was dissolved in THF (10 mL) and Boc was added 2 O (81.22 mg) and DMAP (7.58 mg) were reacted at 25℃for 5 hours. LCMS showed the reaction was complete, and the reaction concentrated and chromatographed on silica gel (PE: ea=2:1-2:0) to give intermediate 2-4 (60.0 mg,41% yield). LC-MS (ESI) m/z=471.95 [ M+H ] ] + 。
Intermediate 2-4 (50.0 mg) was dissolved in 1, 4-dioxane (4 mL), and BPD (80.88 mg), acOK (31.26 mg) and XPhos-Pd-G3 (8.99 mg) were added in this order and reacted at 85℃under reflux for 3h. LCMS showed complete reaction of the starting material and silica gel column chromatography (DCM: meoh=10:1) gave 40.0mg of intermediate 2-5 after spin-drying the reaction. LC-MS (ESI) m/z=563.47[M+H] + 。
Intermediate 2-5 (40.0 mg) and intermediate 1-12 (15 mg) were dissolved in 1, 4-dioxane (4 mL) and H 2 To a mixed solvent of O (0.4 mL), XPhos-Pd-G2 (5.59 mg) and K were added in this order 3 PO 4 ·3H 2 O (56.78 mg), reflux reaction at 100℃for 3h under nitrogen. LCMS showed complete reaction of the starting material, spin-drying of the reaction solution, concentration followed by silica gel column chromatography (PE: ea=1:1 to pure EA gradient elution) to give 20.0mg of crude product, followed by high performance liquid chromatography (column: YMC 18; mobile phase: a 0.1% ammonium bicarbonate aqueous solution; B acetonitrile, B%:15% -45%,40 mL/min) to give 2.2mg of compound 002.
LC-MS ESI:m/z＝467.10[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.70(s,1H),11.89(s,1H),8.85(d,J＝8.8Hz,1H),8.55(s,1H),8.07(s,1H),7.99(s,1H),7.94(d,J＝3.0Hz,1H),7.71(d,J＝8.8Hz,1H),7.43-7.36(m,2H),7.11(d,J＝9.1Hz,1H),6.89(d,J＝8.9Hz,1H),3.05(t,J＝5.0Hz,4H),2.42-2.38(m,4H),2.27(s,3H),2.16(s,3H).
Example 3: synthesis of Compound 003
Figure BDA0003910244120000241
Intermediate 2-5 (140.0 mg) and intermediate 3-2 (78.26 mg) (see WO2021/050964A 1) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (0.5 mL), XPhos-Pd-G2 (19.58 mg) and potassium carbonate (103.20 mg) were added in this order under nitrogen protection, and the mixture was heated to 60℃to react for 3 hours. LCMS detection showed complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 3-1 (140 mg).
LC-MS(ESI):m/z＝571.3[M+H] + 。
Intermediate 3-1 (140 mg) was dissolved in methylene chloride (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at 25℃for 30min. LCMS detection showed complete reaction of starting material. The reaction was concentrated, the residue was added to saturated aqueous sodium carbonate, the PH of the system was adjusted to 9 and extracted with dichloromethane (50 ml x 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product was prepared by preparative high performance liquid chromatography (column: YMC 18; mobile phase: A0.05% aqueous ammonia solution; B acetonitrile, B%:30% -60%,25 mL/min) to give compound 003 (12.0 mg).
LC-MS(ESI):m/z＝471.1[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.81(s,1H),12.01(s,1H),8.88(d,J＝8.8Hz,1H),8.13–8.07(m,1H),7.97(d,J＝2.9Hz,1H),7.78(d,J＝8.8Hz,1H),7.70(s,1H)7.67(s,1H),7.52–7.45(m,1H),7.49–7.39(m,1H),6.97–6.89(m,2H),3.12–3.00(m,4H),2.43–2.38(m,4H),2.17(s,3H).
Example 4: synthesis of Compound 004
Figure BDA0003910244120000242
Intermediate 1-7 (2.53 g) was dissolved in N-methylpyrrolidone (25 mL), cooled to 0deg.C, sodium hydride (779.93 mg,60% dispersed in mineral oil) was added under nitrogen protection, and the temperature was raised to 25deg.C for 30min. Cooling to 0 deg.c, adding 2- (trimethylsilyl) ethoxymethyl chloride (3.25 g) dropwise, heating to 25 deg.c and reaction for 3 hr. TLC detects complete reaction of starting material. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed successively with saturated aqueous sodium chloride (50 mL) and water (50 mL). The organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate gradient elution) to give intermediate 4-1 (3.80 g).
Intermediate 4-1 (150.00 mg) and intermediate 4-2 (90.78 mg) (see WO 2015/131080 A1) were dissolved in anhydrous 1, 4-dioxane (5 mL), and tris (dibenzylideneacetone) dipalladium (38.20 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (48.27 mg) and cesium carbonate (407.73 mg) were added in this order under nitrogen protection and reacted at 80℃for 6 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25 ℃, filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 4-3 (160.00 mg).
LC-MS(ESI):m/z＝516.2[M+H] + 。
Intermediate 4-3 (150.00 mg) was dissolved in anhydrous 1, 4-dioxane (5 mL), and under nitrogen, pinacol biboronate (156.77 mg), XPhos-Pd-G3 (26.13 mg) and potassium acetate (90.88 mg) were added and the mixture was heated to 85℃to react for 6 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25 ℃, filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 4-4 (150.00 mg).
LC-MS(ESI):m/z＝608.3[M+H] + 。
Intermediate 4-4 (150.00 mg) and intermediate 3-2 (45.00 mg) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (0.5 mL), and XPhos-Pd-G2 (13.51 mg) and potassium carbonate (71.21 mg) were added under nitrogen protection, and the mixture was heated to 70℃for reaction for 4 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25 ℃, filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 4-5 (80.00 mg).
LC-MS(ESI):m/z＝616.3[M+H] + 。
Intermediate 4-5 (80.00 mg) was dissolved in methylene chloride (5 mL), trifluoroacetic acid (1 mL) was added, the reaction system was concentrated after 3 hours at 25℃and the residue was dissolved in methanol (2 mol/L,5 mL) with ammonia added thereto, and the reaction was continued at 25℃for 3 hours. LCMS detected complete reaction of starting material. The reaction system is concentrated, and the crude product is prepared by adopting a preparative high performance liquid chromatography (chromatographic column: gemini NX-C18; mobile phase: A is 0.1% ammonia water solution; B is acetonitrile, B percent is 0% -40%,18 mL/min) to obtain a compound 004 (11.4 mg).
LC-MS(ESI):m/z＝486.1[M+H] + 。
1 H NMR(400MHz,Chloroform-d)δ8.92(d,J＝8.8Hz,1H),8.17–8.12(m,1H),8.04(d,J＝3.0Hz,1H),7.82(d,J＝8.8Hz,1H),7.75(s,1H),7.73(s,1H),7.58–7.53(m,1H),7.49–7.44(m,1H),7.00–6.90(m,2H),4.31(s,1H),3.32–3.22(m,2H),3.14–3.06(m,2H),1.62–1.56(m,4H),1.16(s,3H).
Example 5: synthesis of Compound 005
Figure BDA0003910244120000251
Intermediate 4-1 (140.00 mg) and intermediate 5-1 (77.04 mg) (see WO 2015/131080 A1) were dissolved in anhydrous 1, 4-dioxane (1 mL), and tris (dibenzylideneacetone) dipalladium (32.89 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (41.57 mg) and cesium carbonate (351.11 mg) were added in this order under nitrogen protection, and the mixture was heated to 100℃and reacted for 6 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25 ℃, filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 5-2 (101.00 mg).
LC-MS(ESI):m/z＝513.2[M+H] + 。
Intermediate 5-2 (101.00 mg) was dissolved in 1, 4-dioxane (5 mL), and under nitrogen protection, pinacol ester (99.97 mg), XPhos-Pd-G3 (16.66 mg) and potassium acetate (57.95 mg) were added and the temperature was raised to 80℃for reaction for 6 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25 ℃, filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 5-3 (84.80 mg).
LC-MS(ESI):m/z＝605.3[M+H] + 。
Intermediate 5-3 (84.80 mg) and intermediate 5-4 (35.00 mg) (see WO 2021/050964 A1) were dissolved in a mixed solvent of 1, 4-dioxane (3 mL) and water (0.3 mL), XPhos-Pd-G2 (10.51 mg) was added under nitrogen, and potassium carbonate (55.38 mg) was added thereto, and the mixture was heated to 70℃to react for 6 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25 ℃, filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 5-5 (45.00 mg).
LC-MS(ESI):m/z＝613.3[M+H] + 。
Intermediate 5-5 (45.00 mg) was dissolved in methylene chloride (5 mL), and trifluoroacetic acid (0.5 mL) was added thereto for reaction at 25℃for 2h. After the reaction system was concentrated, ammonia in methanol (2 mol/L,5 mL) was added, and the reaction was continued at 25℃for 1 hour. LCMS detected complete reaction of starting material. The reaction system is concentrated, and the crude product is prepared by adopting a high performance liquid chromatography (chromatographic column: YMC 18; mobile phase: A is 0.05% ammonia water solution; B is acetonitrile, B percent: 30% -60%,25 mL/min) to obtain a compound 005 (6.3 mg).
LC-MS(ESI):m/z＝483.2[M+H] + 。
1 H NMR(400MHz,Methanol-d 4 )δ8.69(d,J＝8.8Hz,1H),8.11–8.04(m,1H),7.80–7.69(m,3H),7.63(s,1H),7.41–7.31(m,1H),7.06–6.98(m,2H),6.94–6.88(m,1H),4.06(s,8H),2.73(s,3H).
Example 6: synthesis of Compound 006
Figure BDA0003910244120000261
Intermediate 1-8 (196.0 mg) and intermediate 6-1 (135.24 mg) (synthetic reference WO 2021/050964A 1) were dissolved in anhydrous 1, 4-dioxane (10 mL), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (63.07 mg) was added in this order, cesium carbonate (532.76 mg) and tris (dibenzylideneacetone) dipalladium (49.91 mg) under nitrogen protection, and the mixture was heated to 100℃to react for 3 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 6-2 (191.0 mg).
LC-MS(ESI):m/z＝415.2[M+H] + 。
Intermediate 6-2 (191.0 mg) was dissolved in tetrahydrofuran (10 mL), and di-tert-butyl dicarbonate (120.57 mg) and 4-dimethylaminopyridine (11.25 mg) were added to react at 25℃for 16h. LCMS detected complete reaction of starting material. The reaction system was concentrated, and the residue was purified by silica gel column chromatography (gradient elution of petroleum ether/ethyl acetate) to give intermediate 6-3 (133.5 mg).
LC-MS(ESI):m/z＝515.2[M+H] + 。
Intermediate 6-3 (122.0 mg) was dissolved in anhydrous 1, 4-dioxane (10 mL), and under nitrogen protection, pinacol ester (180.47 mg), potassium acetate (69.75 mg) and XPhos-Pd-G3 (20.05 mg) were added in this order and the mixture was allowed to react at 85℃for 3 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25 ℃, filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 6-4 (135.0 mg).
LC-MS(ESI):m/z＝607.3[M+H] + 。
Intermediate 6-4 (135.0 mg) and intermediate 3-2 (69.99 mg) were dissolved in a mixed solvent of 1, 4-dioxane (6 mL) and water (0.6 mL), and XPhos-Pd-G2 (17.51 mg) and potassium carbonate (92.29 mg) were added under nitrogen protection, and the mixture was heated to 60℃to react for 3 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25℃and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 6-5 (89.0 mg).
LC-MS(ESI):m/z＝615.3[M+H] + 。
Intermediate 6-5 (89.0 mg) was dissolved in methylene chloride (5 mL), and trifluoroacetic acid (1 mL) was added thereto for reaction at 25℃for 2h. LCMS detected complete reaction of starting material. The reaction was concentrated and the residue was adjusted to PH 9 by addition of saturated aqueous sodium carbonate and extracted with dichloromethane (20 ml x 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product was prepared by preparative high performance liquid chromatography (column: YMC 18; mobile phase: A0.01% aqueous trifluoroacetic acid solution, B acetonitrile, B%:30% -60%,25 mL/min) to give compound 006 (11.35 mg).
LC-MS(ESI):m/z＝515.1[M+H] + 。
1 H NMR(400MHz,Methanol-d 4 )δ8.98–8.93(m,1H),8.43–8.36(m,1H),8.15(s,1H),8.08(d,J＝3.0Hz,1H),7.93(s,1H),7.86(d,J＝8.8Hz,1H),7.84–7.79(m,1H),7.56–7.49(m,1H),7.40–7.34(m,1H),7.09(d,J＝9.0Hz,1H),4.17–4.08(m,2H),3.93–3.85(m,1H),3.61–3.55(m,1H),3.54–3.47(m,1H),3.41–3.33(m,2H),2.96(s,6H),2.94–2.86(m,1H),2.64–2.56(m,1H).
Example 7: synthesis of Compound 007
Figure BDA0003910244120000271
Referring to the synthesis of intermediate 4-4, except that 2-2 was substituted for 4-2, intermediate 7-1 was obtained.
Intermediate 7-1 (307.0 mg) and starting material 7-2 (94.94 mg) were dissolved in a mixed solvent of 1, 4-dioxane (10 mL) and water (1 mL), XPhos-Pd-G2 (40.76 mg) and potassium carbonate (214.80 mg) were added in this order under nitrogen protection, and the temperature was raised to 80℃for reaction for 3 hours. LCMS detection showed complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 7-3 (138.0 mg).
LC-MS(ESI):m/z＝597.3[M+H] + 。
Intermediate 7-3 (138.0 mg) was dissolved in methylene chloride (5 mL), trifluoroacetic acid (1 mL) was added, the reaction system was concentrated after 2 hours at 25℃and a methanol solution of ammonia (2 mol/L,5 mL) was added thereto, and the reaction was continued at 25℃for 1 hour. LCMS detection showed complete reaction of starting material. The reaction system was concentrated, and the obtained crude product was subjected to preparative high performance liquid chromatography (column: YMC 18; mobile phase: A0.05% aqueous ammonia solution; B acetonitrile, B%:40% -60%,30 mL/min) to give compound 007 (30.0 mg).
LC-MS(ESI):m/z＝467.1[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.81(s,1H),12.06(s,1H),8.95(d,J＝8.8Hz,1H),8.38(d,J＝4.8Hz,1H),8.03(d,J＝3.0Hz,1H),7.91(s,1H),7.81(d,J＝8.8Hz,1H),7.58(d,J＝3.5Hz,1H),7.48–7.45(m,1H),7.14(d,J＝4.8Hz,1H),6.99(d,J＝8.9Hz,1H),6.23(d,J＝3.5Hz,1H),3.88(s,3H),3.16–3.10(m,4H),2.52–2.48(m,4H),2.24(s,3H).
Example 8: synthesis of Compound 008
Figure BDA0003910244120000272
Starting material 8-4 (5 g) was dissolved in anhydrous tetrahydrofuran (80 mL), cooled to 0 ℃, sodium hydride (1.52 g,60% dispersed in mineral oil) was added in portions under nitrogen protection, and after 30min of incubation, deuterated iodomethane (4.05 g) was added dropwise to the reaction system, and the temperature was raised to 25 ℃ for 16h of reaction. LCMS detected complete reaction of starting material. The reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (150 mL). The organic phase was washed successively with saturated aqueous sodium chloride (50 mL) and water (50 mL). The organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate gradient elution) to give intermediate 8-5 (5 g).
LC-MS(ESI):m/z＝214.1[M+H] + 。
Intermediate 8-5 (500 mg) and pinacol biborate (712 mg) were dissolved in 1, 4-dioxane (5 mL), and potassium acetate (458 mg) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (171 mg) were added thereto, followed by 3 times of nitrogen substitution, and then the temperature was raised to 90℃for reaction for 4 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25 ℃, filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate gradient elution) to give intermediate 8-6 (423 mg).
LC-MS(ESI):m/z＝262.3[M+H] + 。
Intermediate 4-1 (460.8 mg) and intermediate 8-1 (296.0 mg) were dissolved in anhydrous 1, 4-dioxane (10 mL), and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (136.8 mg), tris (dibenzylideneacetone) dipalladium (108.3 mg) and cesium carbonate (963.1 mg) were added in this order under nitrogen protection, and the mixture was heated to 100℃to react for 10 hours. TLC detects complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 8-2 (492.5 mg).
LC-MS(ESI):m/z＝559.3[M+H] + 。
Intermediate 8-2 (492.5 mg) and 8-6 (230.0 mg) were dissolved in a mixed solvent of 1, 4-dioxane (15 mL) and water (1.5 mL), and Xphos-Pd-G2 (69.3 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (42.0 mg) and potassium phosphate (560.9 mg) were added under nitrogen, and the mixture was heated to 85℃to react for 10 hours. TLC detects complete reaction of starting material. The reaction solution was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 8-3 (270.0 mg).
LC-MS(ESI):m/z＝658.4[M+H] + 。
Intermediate 8-3 (270.0 mg) was dissolved in methylene chloride (10 mL), trifluoroacetic acid (2 mL) was added, the mixture was reacted at 25℃for 2 hours, the reaction system was concentrated, and then a methanol solution (2 mol/L,20 mL) of ammonia was added, and the reaction was continued at 25℃for 1 hour. TLC detects complete reaction of starting material. The reaction system was concentrated and the crude product was purified by preparative high performance liquid chromatography (column: YMC 18; mobile phase: A0.5% ammonia solution; B acetonitrile, B%:45% -75%,30 mL/min) to give compound 008 (24.0 mg).
LC-MS(ESI):m/z＝528.3[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.82(s,1H),12.05(s,1H),8.95(d,J＝8.8Hz,1H),8.38(d,J＝4.8Hz,1H),8.00(d,J＝3.0Hz,1H),7.92(s,1H),7.82(d,J＝8.8Hz,1H),7.59(d,J＝3.5Hz,1H),7.46–7.40(m,1H),7.14(d,J＝4.9Hz,1H),6.98(d,J＝8.9Hz,1H),6.23(d,J＝3.5Hz,1H),4.38(s,1H),3.16–3.07(m,2H),3.01–2.91(m,1H),2.85–2.76(m,1H),2.46–2.30(m,2H),2.27(s,6H),1.83–1.65(m,1H),1.61–1.48(m,1H),1.47–1.35(m,1H).
Example 9: synthesis of Compound 009
Figure BDA0003910244120000281
The starting material 4-1 (1.2 g) and benzophenone imine (669.6 mg) were dissolved in anhydrous 1, 4-dioxane (20 mL), and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (356.3 mg), tris (dibenzylideneacetone) dipalladium (281.9 mg), and cesium carbonate (3.0 g) were added in this order under nitrogen atmosphere, and the mixture was heated to 100℃to react for 10 hours. TLC detects complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (gradient elution of petroleum ether/ethyl acetate) to give intermediate 9-1 (1.5 g).
Intermediate 9-1 (1.5G) and intermediate 8-6 (946.4 mg) were dissolved in a mixed solvent of 1, 4-dioxane (20 mL) and water (2 mL), and XPhos-Pd-G2 (237.6 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (144.0 mg) and potassium phosphate (1.9G) were added in this order under nitrogen protection, and the mixture was heated to 90℃and reacted for 10 hours. TLC detects complete reaction of starting material. The reaction solution was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (gradient elution of petroleum ether/ethyl acetate) to give intermediate 9-2 (1.6 g).
Intermediate 9-2 (1.6 g) was dissolved in methanol (30 mL), and sodium acetate (538.4 mg) and hydroxylamine hydrochloride (380.0 mg) were added in this order to react for 2 hours at 25 ℃. TLC detects complete reaction of starting material. Aqueous sodium hydroxide (0.1 mol/L,10 mL) was added to the reaction system, and dichloromethane (20 mL. Times.2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate gradient elution) to give intermediate 9-3 (1.2 g).
LC-MS(ESI):m/z＝425.2[M+H] + 。
The starting material 9-3 (180.0 mg) was dissolved in acetonitrile (20 mL), cooled to 0℃and an aqueous solution (5 mL) of p-toluenesulfonic acid monohydrate (241.9 mg) and sodium nitrite (58.5 mg) were added in this order, followed by reaction at a constant temperature for 1h. The reaction was then added with an aqueous solution (5 mL) of potassium iodide (175.9 mg), and the mixture was allowed to react at 25℃for 16h. TLC detects complete reaction of starting material. The reaction was quenched by addition of saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate gradient elution) to give intermediate 9-4 (110.0 mg).
LC-MS(ESI):m/z＝536.1[M+H] + 。
Intermediate 9-4 (110.0 mg) and intermediate 9-5 (70.6 mg) (see WO 2021/050964 A1) were dissolved in 1, 4-dioxane (5 mL), and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (23.8 mg), tris (dibenzylideneacetone) dipalladium (18.8 mg) and cesium carbonate (167.3 mg) were added in this order under nitrogen protection, and the mixture was heated to 50℃to react for 16 hours. TLC detects complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 9-6 (130.0 mg).
LC-MS(ESI):m/z＝672.4[M+H] + 。
Intermediate 9-6 (130.0 mg) was dissolved in methylene chloride (10 mL), trifluoroacetic acid (2 mL) was added, the reaction was carried out at 25℃for 2 hours, and after the concentration of the reaction system, a methanol solution of ammonia (2 mol/L,20 mL) was added, and the reaction was continued at 25℃for 1 hour. TLC detects complete reaction of starting material. The reaction system was concentrated, and the obtained crude product was subjected to preparative high performance liquid chromatography (column: YMC 18; mobile phase: A0.5% ammonia; B%: B is acetonitrile, 56% -86%,25 mL/min) to give compound 009 (21.2 mg).
LC-MS(ESI):m/z＝542.3[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.82(s,1H),12.05(s,1H),8.95(d,J＝8.8Hz,1H),8.38(d,J＝4.8Hz,1H),8.02(d,J＝2.9Hz,1H),7.92(s,1H),7.82(d,J＝8.8Hz,1H),7.59(d,J＝3.5Hz,1H),7.49–7.41(m,1H),7.15(d,J＝4.8Hz,1H),6.98(d,J＝8.9Hz,1H),6.23(d,J＝3.5Hz,1H),3.15(s,3H),3.13–3.02(m,4H),2.48–2.35(m,2H),2.24(s,6H),1.80–1.50(m,4H).
Example 10: synthesis of Compound 010
Figure BDA0003910244120000291
Intermediate 4-1 (233.5 mg) and intermediate 10-1 (150.0 mg) (see WO 2021/050964 A1) were dissolved in anhydrous 1, 4-dioxane (5 mL), and tris (dibenzylideneacetone) dipalladium (54.8 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (69.8 mg), and cesium carbonate (580.0 mg) were added in this order under nitrogen protection, and the mixture was heated to 100℃to react for 6 hours. TLC detects complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 10-2 (300.0 mg).
Intermediate 10-2 (100.0 mg) and intermediate 8-6 (70.0 mg) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (0.5 mL), and Xphos-Pd-G2 (14.0 mg) and potassium phosphate (114.0 mg) were added in this order under nitrogen protection, and the mixture was heated to 85℃to react for 16 hours. TLC detects completion of the starting material reaction. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 10-3 (75.0 mg).
Intermediate 10-3 (75.0 mg) was dissolved in methylene chloride (5 mL), and trifluoroacetic acid (1 mL) was added thereto for reaction at 25℃for 2h. The reaction system was concentrated, and ammonia in methanol (2 mol/L,10 mL) was added thereto, and the reaction was continued at 25℃for 1 hour. LCMS detected complete reaction of starting material. The reaction system was concentrated, and the crude product obtained was subjected to preparative high performance liquid chromatography (column: YMC 18; mobile phase: A0.5% aqueous ammonia solution; B acetonitrile, B%:45% -75%,30 mL/min) to give compound 010 (11.9 mg).
LC-MS(ESI):m/z＝528.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.81(s,1H),12.04(s,1H),8.94(d,J＝8.8Hz,1H),8.38(d,J＝4.8Hz,1H),8.04(d,J＝3.0Hz,1H),7.92(s,1H),7.81(d,J＝8.8Hz,1H),7.58(d,J＝3.5Hz,1H),7.50–7.42(m,1H),7.14(d,J＝4.9Hz,1H),6.97(d,J＝8.9Hz,1H),6.23(d,J＝3.4Hz,1H),4.18(s,1H),3.32–3.25(m,2H),3.13–3.02(m,2H),2.27(s,8H),1.72–1.50(m,4H).
Example 11: synthesis of Compound 011
Figure BDA0003910244120000301
Intermediate 4-1 (220.00 mg) and intermediate 11-1 (147.34 mg) were dissolved in anhydrous 1, 4-dioxane (10 mL), and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (65.32 mg), cesium carbonate (551.75 mg) and tris (dibenzylideneacetone) dipalladium (51.69 mg) were added in this order under nitrogen, and the temperature was raised to 100℃for reaction for 4 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (gradient elution of petroleum ether/ethyl acetate) to give intermediate 11-2 (268.0 mg).
LC-MS(ESI):m/z＝546.2[M+H] + 。
Intermediate 11-2 (257.00 mg) was dissolved in anhydrous 1, 4-dioxane (10 mL), and pinacol biborate (358.00 mg), potassium acetate (138.55 mg) and XPhos-Pd-G3 (39.83 mg) were added in this order under nitrogen protection, and the mixture was heated to 80℃and reacted for 3 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (gradient elution of petroleum ether/ethyl acetate) to give intermediate 11-3 (303.0 mg).
LC-MS(ESI):m/z＝638.4[M+H] + 。
Intermediate 11-3 (276.00 mg) and intermediate 3-2 (136.10 mg) were dissolved in a mixed solvent of 1, 4-dioxane (10 mL) and water (1 mL), XPhos-Pd-G2 (34.01 mg) and potassium phosphate (275.62 mg) were added in this order under nitrogen protection, and the temperature was raised to 60℃for reaction for 4 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 11-4 (330.0 mg).
LC-MS(ESI):m/z＝646.3[M+H] + 。
Intermediate 11-4 (200.0 mg) was dissolved in methylene chloride (10 mL), trifluoroacetic acid (2 mL) was added, the reaction was carried out at 25℃for 2 hours, the reaction system was concentrated, and a methanol solution of ammonia (2 mol/L,5 mL) was added, and the reaction was continued at 25℃for 5 hours. LCMS detected complete reaction of starting material. Concentrating the reaction system, and preparing the obtained crude product by high performance liquid chromatography (chromatographic column: YMC 18; mobile phase: A is 0.05% ammonia water solution; B is acetonitrile, B% is 50% -60%,40 mL/min) to obtain compound 011 (8.5 mg).
LC-MS(ESI):m/z＝516.1[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.90(s,1H),12.12(s,1H),8.98(d,J＝8.8Hz,1H),8.20–8.14(m,1H),8.05(d,J＝3.0Hz,1H),7.85(d,J＝8.8Hz,1H),7.77(s,1H),7.74(s,1H),7.60–7.54(m,1H),7.52–7.46(m,1H),7.02(d,J＝8.9Hz,1H),6.99–6.93(m,1H),4.52(s,1H),4.03–3.97(m,1H),3.69–3.8(m,2H),3.53–3.45(m,1H),3.33–3.28(m,1H),2.71–2.62(m,1H),2.56–2.52(m,1H),1.17(s,3H),1.11(s,3H).
Example 12: synthesis of Compound 012
Figure BDA0003910244120000302
Intermediate 9-1 (1.5G) was dissolved in anhydrous 1, 4-dioxane (15 mL), XPhos-Pd-G3 (259.08 mg), pinacol diboronate (1.55G) and potassium acetate (901.0 mg) were added in sequence under nitrogen, and the temperature was raised to 100℃for reaction for 4h. LCMS detected complete reaction of starting material. The reaction system was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (gradient elution of petroleum ether/ethyl acetate) to give intermediate 12-1 (1.2 g).
Intermediate 12-1 (1.2 g) and intermediate 3-2 (540.0 mg) were dissolved in a mixed solvent of 1,4 dioxane (10 mL) and water (1 mL), and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (158.0 mg) and potassium carbonate (855.0 mg) were added under nitrogen protection, and the mixture was heated to 60℃to react for 6 hours.
LCMS detected complete reaction of starting material. The reaction system was cooled to 25 ℃, filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate gradient elution) to give intermediate 12-2 (750.0 mg).
LC-MS(ESI):m/z＝590.2[M+H] + 。
Intermediate 12-2 (250.0 mg) was dissolved in methanol (10 mL), and sodium acetate (570.0 mg) and hydroxylamine hydrochloride (230.0 mg) were added to react at 25℃for 3 hours. TLC detects complete reaction of starting material. The reaction was quenched by addition of sodium hydroxide solution (0.1 mol/L,10 mL) and extracted with dichloromethane (20 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 12-3 (600.0 mg).
Intermediate 12-3 (400.0 mg) and p-toluenesulfonic acid monohydrate (540.0 mg) were dissolved in acetonitrile (10 mL), cooled to 0℃and slowly added dropwise with a solution of sodium nitrite (130.0 mg) in water (2 mL), followed by reaction at a constant temperature for 1h. A solution of potassium iodide (390.0 mg) in water (2 mL) was slowly added dropwise, the reaction was continued at 0deg.C for 2h, and LCMS detected complete reaction of the starting materials. The reaction was quenched by addition of saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated aqueous sodium thiosulfate (5 mL) and saturated aqueous sodium chloride (10 mL). The organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 12-4 (230 mg).
LC-MS(ESI):m/z＝537.1[M+H] + 。
Intermediate 12-4 (80.0 mg) and intermediate 12-5 (35.0 mg) (see WO 2021/050964 A1) were dissolved in anhydrous 1, 4-dioxane (5 mL), and tris (dibenzylideneacetone) dipalladium (13.7 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (17.6 mg) and cesium carbonate (145.8 mg) were added in this order under nitrogen protection, and the mixture was heated to 50℃to react for 6 hours. LCMS detected complete reaction of starting material. The reaction system was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 12-6 (85.0 mg).
LC-MS(ESI):m/z＝645.3[M+H] + 。
Intermediate 12-6 (85.0 mg) was dissolved in methylene chloride (5 mL), trifluoroacetic acid (1 mL) was added, the reaction was carried out at 25℃for 3 hours, the reaction system was concentrated, and a methanol solution of ammonia (2 mol/L,10 mL) was added, and the reaction was continued at 25℃for 30 minutes. LCMS detected complete reaction of starting material. The reaction system was concentrated, and the obtained crude product was subjected to preparative high performance liquid chromatography (column: YMC 18; A is 0.1% ammonia solution; B is acetonitrile, B% is 25% -55%,25 mL/min) to give compound 012 (18.3 mg).
LC-MS(ESI):m/z＝515.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.89(s,1H),12.08(s,1H),8.94(d,J＝8.8Hz,1H),8.20–8.13(m,1H),8.00(d,J＝2.9Hz,1H),7.85(d,J＝8.8Hz,1H),7.77(s,1H),7.74(s,1H),7.60–7.53(m,1H),7.50–7.43(m,1H),7.02(d,J＝9.0Hz,1H),7.00–6.94(m,1H),4.00–3.94(m,1H),3.94–3.87(m,1H),3.80–3.72(m,1H),3.67–3.55(m,2H),3.49–3.47(m,1H),3.20–3.12(m,1H),3.08–2.96(m,1H),2.82–2.72(m,1H),2.12(s,6H).
Example 13: synthesis of Compound 013
Figure BDA0003910244120000311
Intermediate 12-4 (80.0 mg) and intermediate 13-1 (46.0 mg) (see WO 2021/050964 A1) were dissolved in anhydrous 1, 4-dioxane (1 mL), and tris (dibenzylideneacetone) dipalladium (13.7 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (17.3 mg) and cesium carbonate (97.1 mg) were added in this order under the protection of argon, and the mixture was heated to 50℃to react for 4 hours. TLC detects complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 13-2 (60.0 mg).
Intermediate 13-2 (60.0 mg) was dissolved in methylene chloride (1 mL), trifluoroacetic acid (0.2 mL) was added, the reaction was carried out at 25℃for 2 hours, the reaction system was concentrated, and a methanol solution of ammonia (2 mol/L,2 mL) was added, and the reaction was continued at 25℃for 2 hours. LCMS detected complete reaction of starting material. The reaction system was concentrated, and the crude product obtained was subjected to preparative high performance liquid chromatography (column: YMC 18; mobile phase: A0.05% aqueous ammonia solution; B acetonitrile; B%:50% -60%,40 mL/min) to give compound 013 (29.7 mg).
LC-MS(ESI):m/z＝516.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.06(s,1H),8.97–8.91(m,1H),8.21–8.12(m,1H),8.04(d,J＝3.0Hz,1H),7.84(d,J＝8.8Hz,1H),7.76(s,1H),7.74(s,1H),7.59–7.53(m,1H),7.51–7.43(m,1H),7.02–6.91(m,2H),4.44(s,1H),3.43–3.35(m,2H),3.29(s,3H),3.18(s,2H),3.10–2.98(m,2H),1.77–1.64(m,2H),1.54–1.46(m,2H).
Example 14: synthesis of Compound 014
Figure BDA0003910244120000321
Intermediate 12-4 (75.0 mg) and intermediate 14-1 (30.0 mg) were dissolved in anhydrous 1, 4-dioxane (5 mL), and tris (dibenzylideneacetone) dipalladium (10.3 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (13.0 mg) and cesium carbonate (55.0 mg) were added in this order under nitrogen protection, and the mixture was heated to 50℃to react for 6 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 14-2 (60.0 mg).
LC-MS(ESI):m/z＝675.3[M+H] + 。
Intermediate 14-2 (60.0 mg) was dissolved in methylene chloride (5 mL), trifluoroacetic acid (1 mL) was added, the reaction was carried out at 25℃for 3 hours, the reaction system was concentrated, and a methanol solution of ammonia (2 mol/L,10 mL) was added, and the reaction was continued at 25℃for 30 minutes. LCMS detected complete reaction of starting material. The reaction system was concentrated, and the obtained crude product was subjected to preparative high performance liquid chromatography (column: YMC 18; A is 0.1% aqueous formic acid; B is acetonitrile, B% is 10% -30%,25 mL/min) to give compound 014 (13.8 mg).
LC-MS(ESI):m/z＝545.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.89(s,1H),12.11(s,1H),8.97(d,J＝8.8Hz,1H),8.20–8.14(m,1H),8.03(d,J＝3.0Hz,1H),7.85(d,J＝8.8Hz,1H),7.76(s,1H),7.74(s,1H),7.59–7.53(m,1H),7.50–7.44(m,1H),7.02(d,J＝9.0Hz,1H),6.99–6.92(m,1H),5.25–5.03(m,1H),3.97–3.89(m,1H),3.67–3.54(m,4H),3.53–3.43(m,2H),3.21–3.09(m,2H),2.73–2.65(m,1H),2.64–2.54(m,2H),2.47–2.39(m,1H).
Example 15: synthesis of Compound 015
Figure BDA0003910244120000322
Intermediate 12-4 (55.04 mg) and intermediate 15-1 (40.00 mg) (see WO 2021/050964 A1) were dissolved in anhydrous 1, 4-dioxane (10 mL), and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (11.87 mg), cesium carbonate (100.29 mg) and tris (dibenzylideneacetone) dipalladium (9.40 mg) were added in this order under nitrogen protection, and the mixture was heated to 60℃to react for 4 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 15-2 (64.0 mg).
LC-MS(ESI):m/z＝701.3[M+H] + 。
Intermediate 15-2 (64.0 mg) was dissolved in methylene chloride (10 mL), and trifluoroacetic acid (2 mL) was added thereto for reaction at 25℃for 2h. The reaction system was concentrated, and ammonia in methanol (2 mol/L,5 mL) was added thereto, and the reaction was continued at 25℃for 5 hours. LCMS detected complete reaction of starting material. The reaction system was concentrated, and the crude product obtained was subjected to high performance liquid chromatography (column: YMC 18; mobile phase: A0.05% aqueous ammonia solution; B acetonitrile, B%:50% -60%,40 mL/min) to give compound 015 (15.1 mg).
LC-MS(ESI):m/z＝571.1[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.87(s,1H),12.06(s,1H),8.94(d,J＝8.8Hz,1H),8.19–8.18(m,1H),8.05(d,J＝3.0Hz,1H),7.84(d,J＝8.8Hz,1H),7.76(s,1H),7.73(s,1H),7.59–7.53(m,1H),7.50–7.44(m,1H),7.02–6.91(m,2H),4.19(s,1H),3.59–3.53(m,4H),3.32–3.27(m,2H),3.11–3.01(m,2H),2.54–2.50(m,4H),2.28(s,2H),1.74–1.55(m,4H).
Example 16: synthesis of Compound 016
Figure BDA0003910244120000331
Intermediate 12-4 (80.0 mg) and intermediate 16-1 (40.0 mg) (see WO 2021/050964 A1) were dissolved in anhydrous 1, 4-dioxane (5 mL), and tris (dibenzylideneacetone) dipalladium (13.7 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (17.6 mg) and cesium carbonate (145.8 mg) were added in this order under nitrogen protection, and the mixture was heated to 50℃to react for 6 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 16-2 (60.0 mg).
LC-MS(ESI):m/z＝643.3[M+H] + 。
Intermediate 16-2 (60.0 mg) was dissolved in methylene chloride (5 mL), trifluoroacetic acid (1 mL) was added, the reaction was carried out at 25℃for 3 hours, the reaction system was concentrated, and a methanol solution of ammonia (2 mol/L,10 mL) was added, and the reaction was continued at 25℃for 30 minutes. LCMS detected complete reaction of starting material. The reaction system was concentrated, and the obtained crude product was subjected to preparative high performance liquid chromatography (column: YMC 18; A is 0.1% ammonia solution; B is acetonitrile, B%:27% -55%,25 mL/min) to give compound 016 (12.9 mg).
LC-MS(H-481):m/z＝513.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.87(s,1H),12.07(s,1H),8.95(d,J＝8.8Hz,1H),8.19–8.13(m,1H),8.01(d,J＝3.0Hz,1H),7.84(d,J＝8.8Hz,1H),7.76(s,1H),7.73(s,1H),7.59–7.53(m,1H),7.47–7.40(m,1H),7.03–6.92(m,2H),3.61–3.48(m,2H),2.76–2.65(m,1H),2.45–2.37(m,1H),2.25–2.15(m,1H),2.14(s,6H),2.10–2.02(m,1H),1.88–1.67(m,3H),1.67–1.52(m,1H),1.12–0.99(m,1H).
Example 17: synthesis of Compound 017
Figure BDA0003910244120000332
Intermediate 12-4 (90.0 mg) and intermediate 10-1 (46.0 mg) were dissolved in anhydrous 1, 4-dioxane (5 mL), and tris (dibenzylideneacetone) dipalladium (15.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (19.4 mg), and cesium carbonate (164.0 mg) were added in this order under nitrogen protection, and the mixture was heated to 50℃and reacted for 6 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 17-1 (90.0 mg).
LC-MS(ESI):m/z＝659.3[M+H] + 。
Intermediate 17-1 (90.0 mg) was dissolved in methylene chloride (6 mL), trifluoroacetic acid (1.5 mL) was added, the reaction was carried out at 25℃for 3 hours, the reaction system was concentrated, and a methanol solution of ammonia (2 mol/L,10 mL) was added, and the reaction was continued at 25℃for 30 minutes. LCMS detected complete reaction of starting material. The reaction system was concentrated, and the crude product obtained was subjected to preparative high performance liquid chromatography (column: YMC 18; A is 0.1% ammonia solution; B is acetonitrile, B% is 27% -57%,25 mL/min) to give compound 017 (14.1 mg).
LC-MS(ESI):m/z＝529.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.86(s,1H),12.05(s,1H),8.93(d,J＝8.8Hz,1H),8.18–8.13(m,1H),8.04(d,J＝3.0Hz,1H),7.83(d,J＝8.8Hz,1H),7.76(s,1H),7.73(s,1H),7.59–7.52(m,1H),7.49–7.43(m,1H),7.01–6.91(m,2H),4.14(s,1H),3.31–3.26(m,2H),3.13–3.02(m,2H),2.26(s,6H),2.24(s,2H),1.71–1.52(m,4H).
Example 18: synthesis of Compound 018
Figure BDA0003910244120000341
Intermediate 18-2 (1 g) (see WO 2021/050964 A1), pinacol biborate (1.71 g) was dissolved in anhydrous 1, 4-dioxane (20 mL), and palladium acetate (106.4 mg), tricyclohexylphosphine (265.7 mg) and potassium carbonate (1.31 g) were added under nitrogen protection, and the mixture was heated to 80℃to react for 3 hours. LCMS monitored complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (gradient elution of petroleum ether/ethyl acetate) to give intermediate 18-3 (1.1 g).
LC-MS(ESI):m/z＝259.2[M+H] + 。
Intermediate 10-2 (130 mg) and intermediate 18-3 (90 mg) were dissolved in a mixed solvent of 1, 4-dioxane (2 mL) and water (0.4 mL), XPhos-Pd-G2 (18 mg) and potassium phosphate (186 mg) were added under nitrogen protection, and the mixture was heated to 90℃and reacted for 16 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 18-1 (160 mg).
LC-MS(ESI):m/z＝655.4[M+H] + 。
Intermediate 18-1 (140 mg) was dissolved in methylene chloride (2 mL), trifluoroacetic acid (0.5 mL) was added, and after 1 hour of reaction at 25℃the reaction liquid was concentrated, and then ammonia in methanol (2 mol/L,1 mL) was added, and the reaction was continued at 25℃for 16 hours. LCMS detected complete reaction of starting material. The reaction system was concentrated, and the obtained crude product was subjected to preparative high performance liquid chromatography (column: YMC 18; A is 0.1% aqueous ammonia solution; B is acetonitrile, B%:45% -65%,40 mL/min) to give compound 018 (35 mg).
LC-MS(ESI):m/z＝525.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.77(s,1H),11.95(s,1H),8.92(d,J＝8.8Hz,1H),8.63(d,J＝1.4Hz,1H),8.15(s,1H),8.06(s,1H),8.02(d,J＝3.0Hz,1H),7.78(d,J＝8.8Hz,1H),7.50–7.42(m,2H),7.20–7.15(m,1H),6.94(d,J＝8.9Hz,1H),4.15(s,1H),3.33–3.25(m,2H),3.12–3.02(m,2H),2.34(s,3H),2.26(s,8H),1.71–1.61(m,2H),1.60–1.53(m,2H).
Example 19: synthesis of Compound 019
Figure BDA0003910244120000342
Intermediate 4-1 (133.30 mg) and intermediate 15-1 (100 mg) (see WO 2021/050964 A1) were dissolved in anhydrous 1, 4-dioxane (3 mL), cesium carbonate (133.73 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (19.79 mg), tris (dibenzylideneacetone) dipalladium (15.66 mg) were added under nitrogen protection, and the mixture was heated to 60℃to react for 4 hours. LCMS detection showed complete reaction of starting material. The reaction system was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (gradient elution of petroleum ether/ethyl acetate) to give compound 19-1 (130 mg).
LC-MS(ESI):m/z＝601.2[M+H] + 。
Compound 19-1 (130 mg) and intermediate 8-6 (84.7 mg) were dissolved in a mixed solvent of 1, 4-dioxane (2 mL) and water (0.2 mL), and 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (20.62 mg), XPhos-Pd-G2 (17.01 mg) and potassium phosphate (137.69 mg) were added thereto under nitrogen atmosphere, followed by heating to 80℃and then reaction for 4 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (gradient elution of petroleum ether/ethyl acetate) to give intermediate 19-2 (140 mg).
LC-MS(ESI):m/z＝700.3[M+H] + 。
Intermediate 19-2 (100 mg) was dissolved in methylene chloride (1 mL), trifluoroacetic acid (5 mL) was added thereto, the mixture was reacted at 25℃for 1 hour, the reaction system was concentrated, and then a methanol solution (2 mol/L,1 mL) of ammonia was added thereto, and the reaction was continued at 25℃for 1 hour. LCMS detected complete reaction of starting material. The reaction system was concentrated, and the obtained crude product was prepared by preparative high performance liquid chromatography (column: YMC 18; A is 0.1% ammonia solution; B is acetonitrile, B%:45% -65%,40 mL/min), to give compound 019 (10 mg).
LC-MS(ESI):m/z＝570.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.81(s,1H),12.04(s,1H),8.95(d,J＝8.8Hz,1H),8.38(d,J＝4.8Hz,1H),8.04(d,J＝3.0Hz,1H),7.92(s,1H),7.82(d,J＝8.8Hz,1H),7.59(d,J＝3.4Hz,1H),7.51–7.43(m,1H),7.14(d,J＝4.8Hz,1H),6.97(d,J＝9.0Hz,1H),6.23(d,J＝3.5Hz,1H),4.20(s,1H),3.60–3.52(m,4H),3.33–3.26(m,2H),3.11–3.00(m,2H),2.28(s,2H),1.74–1.55(m,4H).
Example 20: synthesis of Compound 020
Figure BDA0003910244120000351
Intermediate 11-2 (243.40 mg) and intermediate 8-6 (86.07 mg) were dissolved in a mixed solvent of 1, 4-dioxane (2 mL) and water (0.2 mL), and 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (20.95 mg), XPhos-Pd-G2 (17.29 mg) and potassium phosphate (139.92 mg) were added thereto under nitrogen atmosphere, followed by heating to 80℃and then reaction for 4 hours. LCMS detected complete reaction of starting material. The reaction was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (gradient elution of petroleum ether/ethyl acetate) to give intermediate 20-1 (140 mg).
LC-MS(ESI):m/z＝323.2[M/2+H] + 。
Intermediate 20-1 (100 mg) was dissolved in methylene chloride (1 mL), trifluoroacetic acid (5 mL) was added thereto, the mixture was reacted at 25℃for 1 hour, the reaction system was concentrated, and then a methanol solution (2 mol/L,1 mL) of ammonia was added thereto, and the reaction was continued at 25℃for 1 hour. LCMS detected complete reaction of starting material. The reaction system was concentrated, and the crude product obtained was subjected to preparative high performance liquid chromatography (column: YMC 18; A is 0.1% ammonia solution; B is acetonitrile, B% is 45% -65%,40 mL/min) to give compound 020 (12 mg).
LC-MS(ESI):m/z＝515.2[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.84(s,1H),12.10(s,1H),8.98(d,J＝8.8Hz,1H),8.38(d,J＝4.8Hz,1H),8.05(d,J＝3.0Hz,1H),7.92(s,1H),7.83(d,J＝8.8Hz,1H),7.59(d,J＝3.5Hz,1H),7.52–7.45(m,1H),7.15(d,J＝4.8Hz,1H),7.02(d,J＝8.9Hz,1H),6.23(d,J＝3.4Hz,1H),4.51(s,1H),4.03–3.97(m,1H),3.71–3.58(m,2H),3.53–3.45(m,1H),3.34–3.29(m,1H),2.71–2.62(m,1H),2.57–2.52(m,1H),1.17(s,3H),1.11(s,3H).
Example 21: synthesis of Compound 021
Figure BDA0003910244120000361
The starting material 21-1 (15.3 g) was dissolved in anhydrous tetrahydrofuran (50 mL), and di-tert-butyl dicarbonate (34.69 g) and 4-dimethylaminopyridine (1.62 g) were added in this order, and the reaction system was warmed to 75℃and reacted for 2 hours. LCMS showed complete reaction of starting material. The reaction system was cooled to 25℃and concentrated, and the residue was purified by silica gel column chromatography (gradient elution of petroleum ether/ethyl acetate) to give intermediate 21-2 (28.6 g). LC-MS (ESI) m/z=331.0 [ M+H ]] + 。
Intermediate 21-2 (12.0 g) was dissolved in a mixed solvent of 1, 4-dioxane (60 mL) and water (15 mL), and furan-3-ylboronic acid (8.47 g), potassium phosphate (24.10 g) and [1,1' -bis (diphenylphosphine) ferrocene were added sequentially under nitrogen protection]Palladium dichloride (2.77 g), the reaction system was warmed to 95℃and reacted for 2h. LCMS showed complete reaction of starting material. The reaction was cooled to 25 ℃, water (50 mL) was added and extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate gradient elution) to give intermediate 21-3 (10.9 g). LC-MS (ESI) m/z=319.1 [ M+H ] ] + 。
Intermediate 21-3 (10.9 g) was dissolved in ethanol (30 mL) and NaBH was added in portions at 25 ℃ 4 (5.91 g), the reaction system was warmed to 60℃and reacted for 16 hours. LCMS showed complete reaction of starting material. The reaction was cooled to 25 ℃, concentrated, and the residue was extracted with water (100 mL) and dichloromethane (100 ml×4). The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain intermediate 21-4 (5.6 g). LC-MS (ESI) m/z=291.1 [ M+H ]] + 。
Intermediate 21-4 (5.6 g) was dissolved in a mixed solvent of methanol (60 mL) and acetic acid (60 mL), ptO was added 2 (560 mg), hydrogenation at 25℃for 16h. LCMS showed complete reaction of starting material. The reaction system was concentrated, and water (100 mL) was added to the residue to prepare a saturated aqueous sodium carbonate solutionThe pH of the system was adjusted to 9 and extracted with dichloromethane (100 mL. Times.4). The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give intermediate 21-5 (764.0 mg). LC-MS (ESI) m/z=295.2 [ M+H ]] + 。
Intermediate 21-5 (764.0 mg) and N, N-diisopropylethylamine (1.01 g) were dissolved in dichloromethane (20 mL), cooled to 0℃and methylsulfonyl chloride (891.97 mg) was slowly added dropwise thereto, and the temperature was raised to 25℃for 2h. LCMS showed complete reaction of starting material. The reaction was quenched with water (30 mL) and extracted with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give intermediate 21-6 (960.0 mg). LC-MS (ESI) m/z=373.1 [ M+H ] ] + 。
Intermediate 21-6 (764.0 mg) was dissolved in acetonitrile (20 mL), a tetrahydrofuran solution (5.16 mL) of dimethylamine was added dropwise at 25℃and the reaction system was warmed to 80℃and reacted for 3 hours. LCMS showed complete reaction of starting material. The reaction was concentrated to give intermediate 21-7 (507.0 mg). LC-MS (ESI) m/z=322.2 [ M+H ]] + 。
Intermediate 21-7 (507.0 mg) was dissolved in dichloromethane (10 mL), cooled to 0℃and trifluoroacetic acid (4 mL) was added thereto, and the reaction system was warmed to 70℃and reacted for 2 hours. LCMS showed complete reaction of starting material. The reaction was cooled to 25 ℃, concentrated, the residue was added with water (20 mL), the PH of the system was adjusted to 9 with saturated aqueous sodium carbonate, and extracted with dichloromethane (50 mL x 4). The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give intermediate 21-8 (350.0 mg). LC-MS (ESI) m/z=222.2 [ M+H ]] + 。
Intermediate 21-8 (160.0 mg) and intermediate 4-1 (281.97 mg) were dissolved in anhydrous 1, 4-dioxane (10 mL), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (83.67 mg), cesium carbonate (706.71 mg) and tris (dibenzylideneacetone) dipalladium (66.21 mg) were added in this order under nitrogen protection, and the reaction system was warmed to 100℃for 3 hours. LCMS showed complete reaction of starting material. The reaction system was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 21-9 (225.0 mg). LC-MS (ESI) m/z=530.2 [ M+H ] ] + 。
Intermediate 21-9 (225.0 mg) was dissolved in 1, 4-dioxane (10 mL) and the bisboronic acid pinacol ester was added sequentially under nitrogen blanket(323.33 mg), potassium acetate (124.96 mg) and XPhos-Pd-G3 (35.93 mg) were added and the reaction system was warmed to 80℃and reacted for 3 hours. LCMS showed complete reaction of starting material. The reaction was cooled to 25 ℃, filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 21-10 (261.0 mg). LC-MS (ESI) m/z=622.4 [ M+H ]] + 。
Intermediate 21-10 (261.0 mg) and intermediate 3-2 (121.01 mg) (see WO 2021/050964A 1) were dissolved in a mixed solvent of 1, 4-dioxane (10 mL) and water (1 mL), XPhos-Pd-G2 (33.03 mg) and potassium carbonate (174.08 mg) were added in this order under nitrogen protection, and the reaction system was warmed to 60℃and reacted for 10 hours. LCMS showed complete reaction of starting material. The reaction system was cooled to 25℃and filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol gradient elution) to give intermediate 21-11 (181.7 mg). LC-MS (ESI) m/z=630.3 [ M+H ]] + 。
Intermediate 21-11 (181.7 mg) was dissolved in methylene chloride (7.5 mL), trifluoroacetic acid (1.5 mL) was added to 2, the reaction system was concentrated after 3 hours at 25℃and the residue was dissolved in methanol (7 mol/L,5 mL) of ammonia and the reaction was continued at 25℃for 3 hours. LCMS detected complete reaction of starting material. The reaction system was concentrated, and the crude product was prepared by preparative high performance liquid chromatography (column: YMC 18; mobile phase: 0.01% TFA aqueous solution, B%:30% -60%, B was acetonitrile, 25 mL/min) to give compound 021 (2.82 mg).
LC-MS(ESI):m/z＝500.1[M+H] + 。
1 H NMR(400MHz,Methanol-d 4 )δ8.85(d,J＝8.7Hz,1H),8.37(dd,J＝7.6,4.9Hz,1H),8.13(s,1H),7.99–7.94(m,2H),7.88(d,J＝8.7Hz,1H),7.80(dd,J＝8.2,2.5Hz,1H),7.38–7.31(m,1H),7.25(d,J＝8.6Hz,1H),4.66(s,2H),4.15–4.04(m,2H),3.98–3.89(m,1H),3.80–3.73(m,1H),3.68–3.59(m,1H),3.07(s,6H),2.51–2.41(m,1H),2.04–1.93(m,1H).
Referring to the synthetic procedure of the above examples, the following compounds were synthesized:
Figure BDA0003910244120000371
Figure BDA0003910244120000381
Figure BDA0003910244120000391
Figure BDA0003910244120000401
Figure BDA0003910244120000411
Figure BDA0003910244120000421
Figure BDA0003910244120000431
Figure BDA0003910244120000441
Figure BDA0003910244120000451
Figure BDA0003910244120000461
Figure BDA0003910244120000471
test example 1: HPK1 kinase Activity assay
Experimental materials:
HPK1 (MAP 4K 1) 35948 was purchased from Signalchem, #M23-11G
MBP 35951 was purchased from Signalchem, #M42-51N
ADP-Glo was purchased from Promega, # V9102
DMSO was purchased from Sigma
384-well assay plate was purchased from Perkin Elmer #6007290
384-well assay plate was purchased from LABCYTE
MgCl 2 、MnCl 2 DTT, tween-20, HEPES, BSA purchased from Sigma
Experimental instrument:
nano-scale acoustic pipetting system:
Figure BDA0003910244120000481
650 LIQUID HANDLERS(LABCYTE,USA)
multi-label detection analyzer: envision Multilabel Reader (PerkinElmer, USA)
The experimental method comprises the following steps:
the experiment adopts a luminescence method kinase detection mode (ADP-Glo) developed by Promega company TM ) The synthesized compounds were tested for their inhibitory activity against HPK1 kinase. The specific method comprises the following steps: compounds were diluted in ECHO line gradient and transferred into reaction plates at 50 nL/well (384 Kong Baiban, perkin Elmer # 6007290), final compound starting concentration 100nM, 3-fold gradient dilution, 10 concentration points; HPK1 was buffered with kinase reaction buffer (50 mM HEPES (pH 7.5), 0.01% Tween-20,5mM MgCl) 2 The reaction wells were diluted to the appropriate concentration with 0.01% BSA and 0.05mM DTT, 3. Mu.l of enzyme (final concentration 50 nM) or kinase reaction buffer was added to each well, the reaction plate was placed in a centrifuge, centrifuged at 1000 rpm for 30 seconds and incubated on ice for 30 minutes. Mu.l/well of 2.5 XATP (62.5. Mu.M)/MBP substrate mixture (250. Mu.g/mL) was added, centrifuged at 1000 rpm for 30 seconds and incubated at room temperature for 60 minutes. Add 5. Mu.L/well ADP-Glo and mix well and react for 40 minutes at room temperature. ADP-Glo detection substrate was added, 10. Mu.L/well, and incubated for 30 minutes at room temperature. The chemiluminescent signal was read in an enzyme-labeled instrument (Envision, perkin Elmer). Test compound inhibition (n=2) was calculated as: inhibition% = (maximum signal value-signal value for each well)/(maximum) Large signal value-minimum signal value) 100%. The maximum signal value is the reading value of the strongest enzyme reaction activity only containing DMSO; the minimum signal value is the read of the wells without enzyme. Data were imported into MS Excel and curve fitted using XLFit Excel add-in version 5.4.0.8: y=bottom+ (Top-Bottom)/(1+ (IC) 50 X ≡HillSlope), IC is calculated from the fitted curve 50 。
The test results are shown in Table 1.
TABLE 1 HPK1 enzymatic inhibitory Activity of the Compounds of the invention
Compounds of formula (I) HPK1 IC 50 (nM) Compounds of formula (I) HPK1 IC 50 (nM) Compounds of formula (I) HPK1 IC 50 (nM)
001 14.81 023 0.62 051 0.75
002 5.93 024 2.30 052 0.26
003 5.46 025 4.6 053 0.43
004 14.15 026 3.38 054 1.49
005 >100 027 1.32 055 0.86
006 5.65 028 9.07 056 2.1
007 8.79 029 2.83 057 8.8
008 15.4 032 2.97 058 0.21
009 19.45 033 1.1 059 0.61
010 13.05 034 74.87 060 10.5
011 3.14 035 3.88 061 14
012 10.32 036 7.33 062 0.89
013 1.55 039 32.97 063 2.38
014 3.11 043 19.45 064 0.58
015 0.97 044 32.49 065 0.49
016 9.56 045 31.44 066 7.78
017 7.03 046 1.18 067 4.33
018 0.32 047 12.34 068 0.79
019 1.654 048 25.46 069 2.91
020 1.030 049 1.72 070 3.15
022 2.75 050 7.057 071 2.21
Test example 2: t cell activation assay
Experimental materials:
jurkat T cells were purchased from ATCC
RPMI1640 is purchased from Gibco (ThermoFisher, USA)
FBS is purchased from Gibco (ThermoFisher, USA)
anti-CD 3 monoclonal antibody (OKT 3) was purchased from BD Biosciences #566685
anti-CD 28 monoclonal antibody (CD 28.2) was purchased from BD Biosciences #555725
Human IL-2ELISA detection kit was purchased from BD Biosciences #555190
96 well cell culture plates were purchased from Corning
Experimental instrument:
CO 2 cell incubator: thermoFisher (USA)
Multi-label detection analyzer: envision Multilabel Reader (PerkinElmer, USA)
Cell counter: vi-CELL (Beckman, USA)
The experimental method comprises the following steps:
the 96-well cell culture plate is pre-treated with anti-CD 3 antibody, the anti-CD 3 antibody is diluted to 2 mug/mL by PBS, 100 mug/well is added, the cell culture plate is incubated for 4 hours at 37 ℃, and then washed for 1-2 times by PBS, and the cell culture plate is spin-dried for standby; jurkat T cells were collected, counted using a cytometer, and cell density was adjusted to 1X10 per well 5 Cell numbers were seeded into a new cell culture plate. Dissolving the compound with DMSO and performing gradient dilution, adding corresponding holes of the culture plate inoculated with cells, controlling the final concentration of the DMSO below 0.1%, and performing gradient dilution with the initial concentration of the final compound of 10 mu M and 3 times, wherein the concentration points are 8; the cell culture plates were placed in a 37℃incubator and pre-incubated for 1 hour. Transfer of preincubated T cells to CD3 antibody coated cell culture plates, 100. Mu.L/well, cell count 1X10 5 The method comprises the steps of carrying out a first treatment on the surface of the Adding an anti-CD 28 antibody to obtain a final concentration of 1 mug/mL; the cell culture plates were placed in a carbon dioxide cell incubator for 48 hours. Taking cell culture supernatant, diluting with a proper amount, and detecting the content of human IL-2 by adopting an ELISA method. Quantitative conversion was performed based on the amount of standard. Fold count of IL-2 production: fold = IL-2 production/minimum IL-2 production, i.e. DMSO blank wells. Maximum effect refers to the highest fold production of IL-2 under drug treatment.
The test results are shown in Table 2.
TABLE 2T cell activation assay results for the compounds of the invention
Figure BDA0003910244120000491
Figure BDA0003910244120000501

Claims (15)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003910244110000011
wherein,,
R 1 selected from C 3 -C 7 Monocyclic cycloalkyl, C 7 -C 12 Bicyclic cycloalkyl, C 4 -C 7 Monocycloalkenyl, C 7 -C 12 Bicyclic cycloalkenyl, 3-7 membered monocyclic heterocyclyl, 7-12 membered bicyclic heterocyclyl, 10-16 membered tricyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 11-14 membered tricyclic heteroaryl or C 6 -C 20 Aryl, said C 3 -C 7 Monocyclic cycloalkyl, C 7 -C 12 Bicyclic cycloalkyl, C 4 -C 7 Monocycloalkenyl, C 7 -C 12 Bicyclic cycloalkenyl, 3-7 membered monocyclic heterocyclyl, 7-12 membered bicyclic heterocyclyl, 10-16 membered tricyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 11-14 membered tricyclic heteroaryl or C 6 -C 20 Aryl is optionally substituted with R 1a Substitution;
R 2 selected from 7-12 membered bicyclic heterocyclyl or 8-10 membered bicyclic heteroaryl, said 7-12 membered bicyclic heterocyclyl or 8-10 membered bicyclic heteroaryl optionally being substituted with R 2a Substitution;
w, Z can be connected by single bond or double bond;
when W, Z are singly linked, W, Z are each independently selected from CR 3 R 4 ；
When W, Z are doubly linked, one of W, Z is selected from CR 5 The other is selected from N, or W, Z is independently selected from CR 5 ；
Y 1 、Y 2 Independently selected from CR 6 Or N;
R 3 、R 4 、R 5 、R 6 independently selected from H, halogen, CN, OH, NH 2 、C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkyl or 3-10 membered heterocyclyl, said OH, NH 2 、C 1 -C 10 Alkyl group、C 3 -C 10 Cycloalkyl or 3-10 membered heterocyclyl optionally substituted with R 3a Substitution;
x is selected from NH or O;
each R is 1a 、R 2a 、R 3a Independently selected from F, cl, br, I, CN, =o, OH, NH 2 、C 1 -C 6 Alkyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-14 membered heterocyclyl or 5-6 membered heteroaryl, said OH, NH 2 、C 1 -C 6 Alkyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, 4-14 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with R b Substitution;
each R is b Independently selected from D, F, cl, br, I, CN, =o, OH, NH 2 Ethynyl, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-14 membered heterocyclyl, said OH, NH 2 Ethynyl, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-14 membered heterocyclyl optionally substituted with R c Substitution;
each R is c Independently selected from F, cl, br, I, CN, =o, OH, NH 2 、-S(O) 2 CH 3 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-7 membered heterocyclyl, said OH, NH 2 、-S(O) 2 CH 3 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-7 membered heterocyclyl optionally being substituted by R d Substitution;
each R is d Independently selected from F, cl, br, I, CN, =o, OH, NH 2 、N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 4-7 membered heterocyclyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyloxy or 4-7 membered heterocyclyloxy.
2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Selected from 5-6 memberedA monocyclic heteroaryl, phenyl, 10-16 membered tricyclic heterocyclyl, 11-14 membered tricyclic heteroaryl or 7-12 membered bicyclic heterocyclyl, said 5-6 membered monocyclic heteroaryl, phenyl, 10-16 membered tricyclic heterocyclyl, 11-14 membered tricyclic heteroaryl or 7-12 membered bicyclic heterocyclyl being optionally substituted with R 1a And (3) substitution.
3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Selected from the group consisting of
Figure FDA0003910244110000021
Figure FDA0003910244110000022
Figure FDA0003910244110000031
Figure FDA0003910244110000041
4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 Selected from 9-10 membered bicyclic heterocyclyl or 9-10 membered bicyclic heteroaryl, said 9-10 membered bicyclic heterocyclyl or 9-10 membered bicyclic heteroaryl optionally being substituted with R 2a And (3) substitution.
5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 Selected from the group consisting of
Figure FDA0003910244110000042
Said->
Figure FDA0003910244110000043
Optionally by R 2a And (3) substitution.
6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 2a Selected from F, cl, br, I, CN, C 1 -C 3 Alkyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl group, the C 1 -C 3 Alkyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl is optionally substituted by D, F, cl, br, I.
7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 Selected from the group consisting of
Figure FDA0003910244110000051
Figure FDA0003910244110000052
8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 、R 4 、R 5 、R 6 Independently selected from H.
9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y 1 、Y 2 Independently selected from CH.
10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein W, Z is doubly linked, one of W, Z is selected from CH and the other is selected from N, or W, Z is each independently selected from CH.
11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is selected from NH.
12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (Ia):
Figure FDA0003910244110000053
wherein one of W, Z is selected from CR 5 The other is selected from N, or W, Z is independently selected from CR 5 ；
R 1 、R 2 、R 5 、Y 1 、Y 2 X is as defined in claim 1.
13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:
Figure FDA0003910244110000061
Figure FDA0003910244110000071
Figure FDA0003910244110000081
Figure FDA0003910244110000091
Figure FDA0003910244110000101
14. a pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
15. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the manufacture of a medicament for the prevention or treatment of HPK 1-related diseases.
CN202211318129.8A 2021-10-26 2022-10-26 Lactam compounds as HPK1 inhibitors and uses thereof Pending CN116023378A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023193759A1 (en) * 2022-04-07 2023-10-12 Insilico Medicine Ip Limited Hpk1 antagonists and uses thereof
WO2024140679A1 (en) * 2022-12-26 2024-07-04 Insilico Medicine Ip Limited Spirocyclic hpk1 antagonists and uses thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023193759A1 (en) * 2022-04-07 2023-10-12 Insilico Medicine Ip Limited Hpk1 antagonists and uses thereof
WO2024140679A1 (en) * 2022-12-26 2024-07-04 Insilico Medicine Ip Limited Spirocyclic hpk1 antagonists and uses thereof

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